ASCO's Honest Broker

WEEK OF APRIL 21, 2014 BioCentury THE BERNSTEIN REPORT ON BIOBUSINESS

Volume 22 • Number 16 • Page A1 of 19 Politics, Policy & Law ASCO’s honest broker By Steve Usdin BioCentury This Week Washington Editor A new access program and registry Cover Story Regulation developed by the American Society of Clinical Oncology to facilitate use of off- Honest Brokers — ASCO is developing Pain Politics — FDA Commissioner Mar- label cancer drugs could serve as a model an initiative to facilitate off-label access to garet Hamburg responds to critics of the for independent bodies that could manage targeted cancer therapies. If successful, the agency’s decision to approve Zogenix’s early access to experimental therapies, even system could serve as a model for third- Zohydro and warns about consequences though ASCO itself is not tackling compas- party bodies that could manage early for the integrity of science-based regula- sionate use. access to experimental therapies. tion./A10 ASCO’s initiative is designed to match off-label targeted cancer therapies to indi- Product Discovery & Development Finance vidual patients likely to benefit based on the genomic profile of their tumors, while col- CAR Hits Pothole — Adverse events led Ebb & Flow — Double-dippers defer lecting data about new uses for approved to protocol revisions in Sloan Kettering’s follow-on plans. Snake eyes for Cytos. drugs. trial of CD19-targeted CAR T cells. But Kaleo’s royalty deal. Epirus makes it move. “We should develop programs to make partner Juno Therapeutics and other CAR Steve Harr’s jump to Juno. Also: ALK- it easier to access drugs, but require more players don’t think this indicates a class Abello; Medivir; ThromboGenics; detailed reporting of outcomes, which is just effect./A5 Topotarget; Zogenix, et al./A12 the opposite of the current situation,” CMO Richard Schilsky told BioCentury. “Doing Emerging Company Profile Featured links this week/A11 so would provide treatment options to pa- Stock charts & tables/A19 tients in need and allow us to learn from all Mediating Rare Metabolism — Minoryx these patient experiences.” Company index/A7 both identifies novel chaperones and Like programs that grant early access to repurposes drugs to treat inherited metabolic experimental medicine, or compassionate diseases./A8 access, ASCO plans to limit its off-label Dynamiting Complement — True North’s initiative to patients who are not eligible for TM TNT009 inhibits an upstream target in the BioCentury 100 Indicators See next page classical complement pathway that could lead Week ended 4/18/14 to greater efficacy and an improved safety PRICES VOLUME profile relative to other complement inhibi- 4734.53 772.6M shrs tors./A9 up 1% dn 32% FDA’S PAIN One Month to Amsterdam Hamburg Talks Zohydro The 15th Bio€quity Europe is almost here, featuring the 7th annual BioCentury-Ernst & Young face-off. www.biocenturytv.com See the agenda following A19. See Program Notes on A5

rEVOLUTION Coming New York Calling Only two weeks until the rEVOLUTION Join the 21st meeting of NewsMakers in the Biotech Industry in New York. Symposium kicks off in Boston. Call for Presenting Companies on A13. See announcement following A19. BioCentury, THE BERNSTEIN REPORT ON BIOBUSINESS APRIL 21, 2014 PAGE A2 OF 19 Politics, Policy & Law, sion, that decision has to be made according from previous page “We should develop pro- to prespecified guidelines,” he said. “It has grams to make it easier to to be transparent, and as objective as pos- trials and who have no alternatives. sible — and people have to understand A central feature of the program is the access drugs, but require going in there will be some cases that will be establishment of an honest broker to make more detailed reporting of rejected.” decisions about the allocation of targeted therapies and to collect and analyze out- outcomes, which is just Support needed comes data. the opposite of the If the project is successful for off-label Drug companies will be asked to supply therapies, it could inspire similar schemes current situation.” off-label drugs at no cost, and insurance based on honest brokers affiliated with companies will be asked to pay for all other medical specialty societies that would serve Richard Schilsky, ASCO treatment expenses, Schilsky said. In return, as intermediaries between drug companies drug companies and payers would benefit and patients seeking early access to exper- even for experts,” he added. from the generation of data about off-label imental medicines. Physicians would submit a genomic pro- uses. PhRMA, BIO and their member com- file of a patient’s tumor from a CLIA-certified Schilsky has approached six pharma- panies, as well as patient organizations and lab, along with a proposed treatment plan ceutical companies to discuss the project. congressional staff, are all engaged in sepa- and request for off-label use of a targeted “All have expressed interest in the idea. rate discussions — primarily behind closed therapy, to an honest broker. The dosing None said they are definitely in,” he said. doors — about creating new policies to and regimen would be consistent with label- “No one has said no.” facilitate equitable early access to experi- ing for approved indications. Schilsky said he also has presented the mental therapies. To facilitate such requests, ASCO is concept to “a couple of insurance compa- As BioCentury proposed in a March 31 considering establishing an Internet-based nies. The general response has been: ‘We Commentary, the creation of independent “tumor board” of clinical oncologists and are OK paying for the healthcare costs as third parties is one of several options under molecular pathologists that would review long as we don’t have to pay for the expen- consideration. genomic test results and provide advice to sive drugs.’” To be successful, early access policies physicians, including potential treatment Schilsky also has discussed the concept will have to be aligned with several social options. with senior FDA officials. and scientific trends: social media-fueled The honest broker would review the “FDA feels that if something like this was patient empowerment; the development of application. For approved applications, the set up, it would enhance their understand- highly effective targeted therapies made honest broker would arrange for shipment ing of how these drugs are being used. FDA possible by the integration of molecular of a three-month supply of the drug. The may turn out to be a champion of this kind diagnostics into drug development and clin- patient’s response would be evaluated and, of approach,” he said. ical practice; and a “right to try” movement if appropriate, additional supplies would be Schilsky said ASCO hasn’t determined that is gaining traction among state and dispensed. how much the project will cost or how federal lawmakers. Schilsky said he is “writing a clinical much demand there will be. protocol for what will essentially be an “We plan to start this as a pilot project observational study.” with a limited number of physician practices Access and registry The protocol will be “for patients who scattered around the country, with as many According to Schilsky, ASCO’s program have exhausted all treatment options, but who drugs as we can get into the program was prompted by the realization that many have reasonable performance status, so they initially,” he said. “We want to see if this is oncologists lack the expertise required to have a meaningful chance of benefiting from feasible, if we can we get the drugs to make treatment decisions based on genomic therapy if benefit can be derived.” patients in a reasonable period of time, if test results, as well as the difficulty patients In addition to validating treatment plans, there are any significant patient benefits face in getting reimbursement for off-label the honest broker would maintain a registry from the approach, and if can we get the prescriptions. with information about patient characteris- necessary data from doctors.” “I’m reacting to the rapid penetration of tics and outcomes. ASCO hopes to get the pilot running genetic profiling in the cancer patient pop- ASCO is speaking with several for- and before year end. ulation, with many comprehensive cancer not-for profit entities that could serve as the centers, community hospitals, and commer- honest broker, Schilsky said. cial labs setting up to do multiplex testing,” He noted that clarity about the rules will Pivot point Schilsky said. Interpreting tests results to be key to making an honest broker accept- In a paper describing the program in determine whether a specific genomic vari- able to patients and the public. Nature Reviews Clinical Oncology this month, ant is clinically actionable is “challenging “Any time a third party makes a deci- Schilsky mentioned the possibility of including investigational drugs. But he told Bio- Century ASCO has decided to stick with approved drugs. This Week in SciBX “It was a question of not biting off more than I could chew. Once you get into Contaminating Cancer Genomes — Two European teams have pinpointed a DNA- investigational drugs, you get into a higher protective enzyme as a chemically tractable target whose inhibition kills cancer cells by level of complexity regarding human sub- accelerating DNA damage. SciBX Table of Contents, A3. See next page BioCentury, THE BERNSTEIN REPORT ON BIOBUSINESS APRIL 21, 2014 PAGE A3 OF 19 Politics, Policy & Law, from previous page

ject participation and regulatory oversight,” he said. “There are at least 25 marketed targeted anticancer treatments SciBX This Week that hit 15 or so different genetic targets,” Schilsky added. “We already have a good starting point of the universe of marketed drugs ANALYSIS without having to get into investigational drugs.” ASCO’s project is inspired in part by the growing sophistication COVER STORY of patients who read Contaminating cancer genomes about targeted ther- Two European teams have pinpointed a DNA-protective apies on the Internet “Science is changing, enzyme as a chemically tractable target whose inhibition and request access kills cancer cells by accelerating DNA damage. Both patients are changing, and to off-label therapies, groups have identified small molecule inhibitors of the enzyme and are looking to partner with industry. Schilsky said. it makes great sense that Patient demand approaches and frame- TRANSLATIONAL NOTES that is the result of Translational tidbits social and news me- works for early access will AstraZeneca had a busy March, announcing five new dia reporting about public-private partnerships and launching its Open Innovation new therapies is also evolve and change.” website to list additional partnership opportunities. propelling discus- Amrit Ray, Janssen Pharmaceuticals Expanding into new (bromo)domains sions among life sci- The Neomed Institute has begun development of its first ences companies cancer therapeutic, a BRD4 inhibitor from Epigenetix that about policies for providing early access to experimental drugs. the not-for-profit organization thinks could have a selectiv- “It feels like a pivot point” for early access, said Amrit Ray, ity advantage over competing molecules. CMO at Johnson & Johnson’s Janssen Pharmaceuticals division. “It is positive to have great innovation for patients. It is TARGETS & MECHANISMS positive to have empowerment of patients sharing information, with Unfolding triple-negative breast cancer the ability to ask questions and be in touch.” A team from Weill Cornell Medical College has found a J&J recently revised its policies on early access to investigational unifying feature of triple-negative breast cancers— overactivation of the transcription factor X-box binding drugs, Ray said. The most visible result is a web page with clear protein 1. Blocking expression of the target decreases information about accessing investigational drugs with contact infor- tumor formation and relapse in mice, but more druggable mation for physicians to request access (see Featured Links, A11). targets upstream of it might be better suited for further “We stepped back and made sure the information on how to development. make a request was accessible in one place, with one phone number and one email address,” Ray said. “We made sure those requests THE DISTILLERY go to one common place and are quickly addressed by therapeutic This week in therapeutics area and disease experts.” Inhibiting IL-17A or IL-23 to alleviate periodontitis; antago- He added that policies will need to adapt to the changing nizing KCNA3 to treat asthma; activating CD31 signaling to environment. counter autoimmune and inflammatory conditions; and “When it comes to policies and frameworks for early access, we more… have to get in the mindset of continuously revisiting those ap- This week in techniques proaches,” said Ray. “Science is changing, patients are changing, Isoacyl dipeptides to increase insulin yield from chemical and it makes great sense that approaches and frameworks for early synthesis; binary nylon-3 copolymers containing cationic access will evolve and change.” and hydrophobic subunits for antimicrobial activity; Ray said J&J is participating in discussions on early access markers of distinct SHH-driven medulloblastomas; and policies at BIO and PhRMA, and he will participate in a closed more… meeting on early access at the Brookings Institution. The April 29 workshop is being organized by Darshak Sanghavi, who is Merkin fellow and managing director of economic studies at Brookings’ Engelberg Center for Health Care Reform. Sanghavi told BioCentury the informal meeting is “primarily geared to identify common issues and experiences from major pharma companies, with the goal of identifying some themes that FROM THE MAKERS OF BioCentury AND nature might be addressed in a formal, larger meeting to address compassionate use with a larger group if there is interest.” Request a Free Trial In addition to pharma company executives, the meeting will be attended by a bioethicist and a patient advocate. Speaking on BioCentury This Week television, Sanghavi said there [email protected] is a need to collect some basic information in order to craft new early access policies. “If we don’t even know the magnitude of the issue, then we really See next page BioCentury, THE BERNSTEIN REPORT ON BIOBUSINESS APRIL 21, 2014 PAGE A4 OF 19 Politics, Policy & Law, Just as the federal government has opted from previous page to exercise enforcement discretion in the face of state marijuana laws, it could choose BioCentury can’t even decide how we’re going to fix it,” to allow Arizona, and any other state that THE BERNSTEIN REPORT ON BIOBUSINESS™ he said (see BioCentury This Week, April 13). enacts a similar law, to make experimental Nancy Goodman, founder and execu- drugs available to terminally ill patients Editorial & Research tive director of the advocacy organization without FDA oversight, Corieri said. Newsroom: Kids v Cancer, added that better policies If FDA asserts federal preemption to [email protected] probably would lead to more widespread prevent implementation of the law, the San Carlos, CA: +1 650-595-5333; access to investigational drugs. Goldwater Institute is prepared to litigate Fax: +1 650-595-5589 “I suspect, frankly, that there are fewer the case, she said. Chicago: +1 312-755-0798; compassionate uses issued than we as a “We believe the right to save your own Fax: +1 650-595-5589 society might want,” she said. life is a fundamental right protected by the Washington, DC: +1 202-462-9582; Goodman endorsed the creation of Constitution,” said Corieri. Fax: +1 202-667-2922 organizations that are independent of drug According to Corieri, a 2006 ruling United Kingdom: +44 (0)1865-512184; Fax: +1 650-595-5589 manufacturers to review applications for against the right to access experimental early access. Such decisions could be drugs, issued by the U.S. Court of Appeals www.biocentury.com made by a “third party that would be for the District of Columbia Circuit, “is not responsible for reviewing every case on an binding on any other circuit” and does not expedited basis, understanding both the apply in Arizona. Editor-in-Chief: Karen Bernstein, Ph.D. challenges and limitations the company The case was filed by the Washington Editor: Susan Schaeffer faces, and the probability of a particular Legal Foundation (WLF) and Abigail Managing Editor: Jeff Cranmer investigational drug assisting a patient,” Alliance for Better Access to Develop- Editor, BioCentury Extra: Jennifer Rhodes she said. mental Drugs (see BioCentury, Jan. 21, Executive Editor, SciBX: Steve Edelson Sanghavi suggested third party decision 2008). Senior Editor, Washington: Steve Usdin makers could absorb some of the adminis- Bills similar to HCR 2005 are pending in Senior Editors: C. Simone Fishburn, Ph.D., trative tasks and costs that are barriers for Louisiana and Missouri. Erin McCallister small companies to offer early access. More sweeping legislation has been in- Director of Research: Walter Yang Senior Writers: Chris Cain, Ph.D., “It seems to me that the biggest cost is troduced in the U.S. Congress. The Com- Emily Cukier-Meisner, Michael Flanagan, really the evaluation, the paperwork, maybe passionate Freedom of Choice Act (H.R. Michael J. Haas, Stephen Hansen, tracking [outcomes and] not really the man- 4475), sponsored by Rep. Morgan Griffith Kai-Jye Lou, Lev Osherovich, Ph.D. ufacture of the drug, at least with limited (R-Va.), would allow manufacture, importa- Editorial Staff: Meredith Durkin Wolfe, exceptions,” he said. “All of us can agree tion, distribution and sale of investigational Kevin Lehnbeuter, Lauren Martz, that the last thing we want to do is to impose products outside of a clinical trial for termi- Brian Moy, Derek Smith additional regulatory burden and cost on nally ill patients without restriction by or people who are trying to make life-saving reporting to FDA. BioCentury medications.” H.R. 4475 provides liability protection BioCentury®; the Bernstein Report on Bio- for investigational drug manufacturers; Ar- BusinessTM; Because Real Intelligence is Hard to Find; izona HCR 2005 does not include liability BCIQ; The BioCentury 100; and The Clear Route to Right to try protection. ROI are trademarks of BIOCENTURY PUBLICA- Political support for right to try legisla- TIONS, INC. All contents Copyright © 2014, Publicity about recent efforts by patients BIOCENTURY PUBLICATIONS, INC. ALL to obtain access to unapproved drugs, in- tion could accelerate efforts to craft new RIGHTS RESERVED. SciBX and SciBX: cluding the successful social media cam- early access policies at BIO and PhRMA, Science-Business eXchange are trademarks of Na- paign launched by Josh Hardy’s family, may which oppose efforts to bypass FDA regula- ture America, Inc. that are jointly used by BioCen- have revived the fortunes of the “right to tion of experimental drugs. tury Publications, Inc. and Nature America, Inc. No try” movement. part of BioCentury’s Publications or Website may Last week, the Arizona Senate passed COMPANIES AND INSTITUTIONS MENTIONED be copied, reproduced, retransmitted, disseminat- HCR 2005, a bill that would allow physi- Abigail Alliance for Better Access to De- ed, sold, distributed, published, broadcast, circu- cians to prescribe investigational products velopmental Drugs, Lorton, Va. lated, commercially exploited or used to create derivative works without the written consent of to eligible terminally ill patients who have no American Society of Clinical Oncology BioCentury. “comparable or satisfactory” FDA-approved (ASCO), Washington, D.C. Information provided by BioCentury’s Pub- treatment options. Biotechnology Industry Organization lications and Website is gathered from sources (BIO), Washington, D.C. The bill will be placed on the ballot for that BioCentury believes are reliable; however, voter approval in November unless Gov. Brookings Institution, Washington, D.C. BioCentury does not guarantee the accuracy, Janice Brewer vetoes it. Goldwater Institute, Phoenix, Ariz. completeness, or timeliness of the informa- If the initiative passes, it would be possi- Johnson & Johnson (NYSE:JNJ), New Brun- tion, nor does BioCentury make any warran- ble for patients to receive access to exper- swick, N.J. ties of any kind regarding the information. The imental drugs with the consent of their Kids v Cancer, Washington, D.C. contents of BioCentury’s Publications and Website physician and the drug manufacturer. FDA Pharmaceutical Research and Manufac- are not intended as investment, business, tax or would have no oversight role, according to turers of America (PhRMA), Washington, legal advice, and BioCentury is not respon- Christina Corieri, healthcare policy analyst D.C. sible for any investment, business, tax or legal opinions cited therein. at the Goldwater Institute, a libertarian Washington Legal Foundation (WLF), Wash- think tank that drafted the legislation. ington, D.C. BioCentury, THE BERNSTEIN REPORT ON BIOBUSINESS APRIL 21, 2014 PAGE A5 OF 19 Product Discovery & Development CAR hits pothole

By Emily Cukier-Meisner Cancer Institute (NCI), in an interview cells expressing the CD19 antigen, which Senior Writer broadcast on BioCentury This Week televi- occurs on most B cell malignancies (see Patient deaths prompted Memorial sion on Jan. 26. SciBX: Science-Business eXchange, Oct. 24, Sloan Kettering Cancer Center to On April 6, researchers at Sloan 2013). briefly halt enrollment and update inclu- Kettering (MSKCC) reported progress and Renier Brentjens presented updated sion criteria for its CD19 directed chi- a speed bump for autologous T cells ex- data from MSKCC’s Phase I trial in 22 meric antigen receptor T cell therapy. But pressing the 19-28z chimeric antigen re- adult patients with relapsed B cell acute partner Juno Therapeutics Inc. and ceptor (CAR) specific to the CD19 anti- lymphoblastic leukemia (ALL) who received other CAR players don’t think this will gen. 19-28z CAR T cell therapy after salvage affect development of similar therapies. To create the therapy, T cells are chemotherapy. Brentjens, who is director Adoptive cell therapies are widely seen harvested from a patient and transduced of cellular therapeutics at MSKCC, pre- as the next great advance in the treatment with a vector that expresses a synthetic sented the results at the American As- of cancer. receptor specific for CD19. The receptor sociation for Cancer Research meet- “It’s joined surgery, radiation therapy, consists of heavy and light antibody chains ing. and chemotherapy as a fourth effective fused to one or more T cell costimulatory 19-28z CAR T cell therapy led to way to treat some cancers,” said Steven domains. When reintroduced to the pa- overall complete responses in 18 (86%) Rosenberg, chief of surgery at National tient, the T cells recognize and destroy patients. But during the discussion, MSKCC re- vealed that on March 7 it paused enrollment across its trials of the therapy because of safety concerns. The center then worked with FDA to amend the trial protocols. Late Friday Juno spokesperson Kim James told BioCentury in an email that FDA’s approval of Zohydro ER, a long-acting pain medicine, has created a political and medical controversy that is rippling through state and MSKCC has resumed enrolling patients in federal governments. all trials after FDA approved the amended protocols. James did not say how the Massachusetts Gov. Deval Patrick’s unprecedented step of banning protocols were amended; however, she Zohydro ER sales in the state was halted this week by a preliminary told BioCentury in an earlier email that injunction. the proposed amendments would affect the inclusion criteria and doses, and that And, Sens. Chuck Schumer (D-N.Y.) and Joe Manchin (D-W.Va.) asked Juno’s plans and timelines at MSKCC would HHS Secretary Kathleen Sebelius to overturn FDA’s approval of the drug. not be affected. According to James, 10 deaths oc- On the newest edition of BioCentury This Week television, Host Steve Usdin goes one-on-one with FDA Commissioner Dr. Margaret Hamburg curred in the trial, two of them treatment- to discuss: related. James said, “The 2 patients whose • FDA’s reasons for approving Zohydro ER deaths prompted the MSKCC to amend its protocol died within 2 weeks of adminis- • Assertions that the drug presents a unique or enhanced risk of abuse tration of CAR T cell therapy. One patient had a history of cardiac failure and the • The implications of substituting politics for science in FDA reviews other developed persistent seizures during the second infusion of cells.” Key opinion leaders; sophisticated questions Always on BioCentury This Week television Juno was formed last year to consoli- date immunotherapy programs from MSKCC, Fred Hutchison Cancer Re- Watch Anytime on the Web search Center and Seattle Children’s www.biocenturytv.com Research Institute that span both CAR and T cell receptor (TCR) technology (see BioCentury, Dec. 9, 2013). New weekly shows go online at 9:00 a.m. EDT on Sundays. MSKCC’s 19-28z CAR T cell therapy is Prior shows available 24/7 in the online Program Archive. the most advanced among the biotech’s BioCentury This Week also is broadcast on Sunday in Washington, D.C. three partner institutions, all of which are Watch it on WUSA Channel 9 at 8:30 a.m. EDT developing CAR programs. MSKCC will manage the program until Juno decides BioCentury This Week is brought to you by BIO,Biogen Idec and Johnson & Johnson See next page BioCentury, THE BERNSTEIN REPORT ON BIOBUSINESS APRIL 21, 2014 PAGE A6 OF 19 Product Discovery & Development, of Pennsylvania and partner Novartis AG are studying CTL019 from previous page in Phase II trials to treat ALL and CLL. A costimulatory domain is added to the CD247 (CD3zeta; whether to license it and carry it forward. CD3z) domain in second-generation CARs to enhance T cell MSKCC’s other suspended trials of 19-28z CAR T cells were activation. a Phase I trial to treat relapsed and refractory B cell non- Matthew Riese, assistant professor of medicine in the Division Hodgkin’s lymphoma (NHL), a Phase I trial to treat chronic of Hematology and Oncology at the Medical College of lymphocytic leukemia (CLL) following chemotherapy, a Phase I Wisconsin, said the field hasn’t yet determined the optimal trial to treat relapsed B cell ALL in pediatric and young adult costimulatory domain. patients, and a Phase I/IIa trial to treat relapsed or refractory CLL “It’s clear you need some costimulatory unit — you can’t just or indolent B cell lymphoma. have CD3zeta. It remains to be seen which of those costimulatory Researchers who spoke to BioCentury said the finding receptors is preferred,” he said. shouldn’t interrupt trials of other CD19-targeted therapies Timing is another argument against CRS as the cause of the because each therapy is constructed differently and the toxicities fatal seizures in one patient in the MSKCC study. CRS arises from are still not well understood. T cell expansion and CD19 targeting, and thus should occur The deaths haven’t affected programs at Juno’s other partner after — and not during — a T cell infusion. institutions. James told BioCentury neither Fred Hutchison nor According to Seattle Children’s has stopped trials of their own variants of “Most of these patients earlier results from CD19 targeted CAR T cell therapy, nor do they plan to modify the Phase I ALL trial, the trials. don’t have any other option. the first clinical evidence of CRS — This is a very good chance fevers — starts The cytokine question for them to have a complete about 24 hours af- One unresolved question is whether the toxicities are related ter infusion with 19- to cytokine release syndrome (CRS), a common effect of CAR T remission.” 28z CAR T cells. cells, or are more product-specific. Researchers were unsure Data were pub- whether CRS could underlie the seizure-related death, but Andre Choulika, Cellectis lished in Science generally agreed it could have caused the death of the patient Translational Medi- with history of cardiac failure. cine in February. CRS is a collection of toxicities that arises when infused T Robert Hawkins, professor of medical oncology at the Uni- cells expand and cytokines are rapidly released. Patients who versity of Manchester and Christie Hospital NHS Foun- develop CRS may be treated with high-dose steroid therapy or dation Trust, said it could be possible for CRS to cause toxicity Actemra tocilizumab. The latter is an mAb against the IL-6 during infusion. receptor (CD126) marketed by Roche, its Genentech Inc. “I think it depends on the number of cells infused and the unit and Chugai Pharmaceutical Co. Ltd. to treat RA and location of antigen positive cells,” he said. juvenile idiopathic arthritis. Nevertheless, Hawkins was surprised by the occurrence of a According to Brentjens’ April 6 presentation, CRS is associ- fatal seizure in the MSKCC trial. He acknowledged that a very ill ated with adverse events such as fevers, hypotension and patient could experience hypotension and become febrile in neurologic toxicities that include mental status changes, response to cytokine release, but thought such cases were obtundation (reduced alertness) and seizures. usually controllable. James said mental status changes, obtundation and seizures “Cerebral toxicity wouldn’t be something I would predict for are “most likely related to the cytokine release syndrome — and a CD19 of any description,” he said. the experience across the CAR T field is the risk of CRS is highly He thought enough patients had been treated with CD19- correlated to very high disease burden and CAR T cell expansion targeted CAR T cell therapies across institutions that there (which many of the patients in these early trials have).” would have been more reports of seizures if they were a class However, in the presentation that proceeded Brentjens, effect. discussant Carl June suggested CNS toxicity was not a general Researchers who spoke to BioCentury were more ready to consequence of CRS and instead resulted from off-target effects believe CRS could aggravate cardiac comorbidities. related to the CD28 costimulatory domain used in MSKCC’s “With the high fever that comes up, if the person has heart CAR. problems then maybe the heart couldn’t take it,” said Cellectis June is a professor in the Department of Pathology and S.A. Chairman and CEO Andre Choulika. Laboratory Medicine at the Perelman School of Medicine at the Choulika said enrollment of patients with comorbidities is University of Pennsylvania and director of the translational best left to the discretion of the investigator, but added that the research program at the university’s Abramson Family Cancer risk should be balanced against the severity of the cancer. Research Institute. “Most of these patients don’t have any other option. This is June led the team that first demonstrated CARs could a very good chance for them to have a complete remission,” he potentially cure hematologic cancers. In a 2011 publication in said. Science Translational Medicine, June and colleagues reported that Leslie Popplewell, an associate clinical professor at City of two of three advanced CLL patients went into complete remission Hope, thought patients’ weakened health might have played a after receiving a CART-19 cell therapy. role in the events seen in MSKCC’s trial. That product, now called CTL019, contains a tumor necrosis “These patients have been treated with probably high dose factor (TNF) receptor superfamily member 9 (TNFRSF9; 4-1BB; chemotherapy in the past, and usually don’t come in with perfect CD137) costimulatory domain instead of CD28. The University See next page BioCentury, THE BERNSTEIN REPORT ON BIOBUSINESS APRIL 21, 2014 PAGE A7 OF 19 Product Discovery & Development, thought UCART19 might have a safety from previous page “Cerebral toxicity wouldn’t advantage due to the suicide gene and a CD19 ligand construction less likely to physiology. They are very susceptible to be something I would release cytokines before encountering problems,” she said. predict for a CD19 of antigen.

any description.” COMPANIES AND INSTITUTIONS MENTIONED Limited repercussions American Association for Cancer Re- According to Juno, its other partner Robert Hawkins, search (AACR), Philadelphia, Pa. institutions don’t see MSKCC’s results as University of Manchester Bristol-Myers Squibb Co. (NYSE:BMY), reason to modify their trials. New York, N.Y. According to James, the partner insti- Cellectis S.A. (Euronext:ALCLS), Paris, tutions hold the INDs and manage trials of didn’t expect to change protocols for their France their CD19-targeted CAR T cells. Juno CD19-targeted CAR T therapies as a result Christie Hospital NHS Foundation Trust, has an exclusive option to the products of MSKCC’s disclosure. Manchester, U.K. and will run trials of any it chooses to In an email to BioCentury, Novartis Chugai Pharmaceutical Co. Ltd. (Tokyo: continue developing. It also may instigate said enrollment is ongoing in its clinical 4519), Tokyo, Japan Phase I trials on its own. trials of CTL019. City of Hope, Duarte, Calif. Each of the three research institutions “There is not enough data to suggest Eli Lilly and Co. (NYSE:LLY), Indianapolis, is working with a unique transduction that the specific issues seen in the MSKCC Ind. vector and CAR. trial are reflective of what we can expect Fred Hutchinson Cancer Research Cen- MSKCC’s autologous T cells express a in other CAR trials. Each CAR program is ter, Seattle, Wash. CD19 CAR and include the signaling unique and the therapies being developed Genentech Inc., South San Francisco, Calif. molecules CD28 and CD3zeta. cannot be broadly defined as a single Genzyme Corp., Cambridge, Mass. Fred Hutchinson’s autologous T cells ‘class,’” Novartis wrote. Kite Pharma Inc., Los Angeles, Calif. express a CD19 CAR, 4-1BB and CD3zeta. Kite Pharma Inc. and NCI are test- Juno Therapeutics Inc., Seattle, Wash The product contains defined propor- ing an autologous T cell therapy against Medical College of Wisconsin, Milwaukee, tions of CD4+ and CD8+ T cells. CD19 in Phase I/II to treat diffuse large B Wis. Seattle Children’s Research Institute cell lymphoma (DLBCL). The biotech de- Memorial Sloan Kettering Cancer Cen- autologous T cells contain a defined com- clined to discuss its plans for the trial. ter (MSKCC), New York, N.Y. position of CD4+ and CD8+ T cells that Cellectis is developing UCART19, an Merck KGaA (Xetra:MRK), Darmstadt, express CD19 CAR, 4-1BB, CD3zeta and allogeneic T cell therapy that uses the Germany truncated epidermal growth factor recep- company’s CD19 ligand, a suicide gene, National Cancer Institute (NCI), Bethesda, tor (EGFR) domains. and knockouts of T cell receptor alpha Md. Truncated EGFR acts as both a marker chain (TCRA) and CD52. According to Novartis AG (NYSE:NVS; SIX:NOVN), Basel, to detect the cells and as a “suicide switch” Choulika, knocking out TCR alpha pre- Switzerland that induces cell death in the presence of vents graft-versus-host disease (GvHD) Roche (SIX:ROG; OTCQX:RHHBY), Basel, Erbitux cetuximab from Eli Lilly and and knocking out CD52 protects the cells Switzerland Co., Bristol-Myers Squibb Co. and from immunodepletion by Campath Sanofi (Euronext:SAN; NYSE:SNY), Paris, Merck KGaA. alemtuzumab, a standard of care in CLL. France Of the three programs, MSKCC has Campath is marketed by Sanofi and Seattle Children’s Research Institute, Se- had the most opportunity to collect side its Genzyme Corp. subsidiary. attle, Wash. effect data. The institution has reported Choulika said the company plans to University of Manchester, Manchester, U.K. data for at least 22 patients, compared to begin Phase I testing of UCART19 to treat University of Pennsylvania, Philadelphia, five for Fred Hutchinson and none for CLL in 2Q15. Pa. Seattle Children’s. He said Cellectis would try to learn U.S. Food and Drug Administration (FDA), Other institutions reached by BioCentury from MSKCC’s trial experience, but Silver Spring, Md.

BioCentury Ampio A16 Dicerna A16 GlaxoSmithKline A11, A16 Company Index AxoGen A13 Durata A13 Goldwater Inst A4 Bellvitge Biomed Res Inst A8 Eli Lilly A7 iPierian A9 April 21, 2014 BIO A2 Epirus Bio A13 J & J A3, A11, A14, A17 Abigail Alliance for Better Access Biolab Sanus A14 Eurofarma Labs A14 Joincare A14 to Dev A4 bluebird bio A8 Express Scripts A11 Juno Therap A5, A14 Alexion A9 Bristol-Myers Squibb A7, A16 FDA A5, A10, A11 Kaleo A13 Alimera A15 Brookings Inst A3 Foundation Med A12 Karyopharm A12 ALK-Abello A15 Cellectis A6 Fred Hutchinson Cancer Research Kids v Cancer A4 Alnylam A16 Christie Hosp NHS Fdn Trust A6 Ctr A5, A14 Kite Pharma A7 Am Assoc for Cancer Res A5 Chugai Pharma A6 Galapagos A16 Lexicon A16 Am Society for Hematology A9 Cytos A12 Genentech A6 Livzon Pharma A14 Am Society of Clinical Oncol A1 Dendreon A14 Genzyme A7 Med College of Wisconsin A6 Amgen A12 DepoMed A13 Gilead A11, A16 See page A18 BioCentury, THE BERNSTEIN REPORT ON BIOBUSINESS APRIL 21, 2014 PAGE A8 OF 19 Emerging Company Profile Minoryx: Mediating rare metabolism

By Michael J. Haas tions with other drug classes such as Senior Writer Minoryx Therapeutics S.L. antioxidants and neuroprotectants to treat Minoryx Therapeutics S.L. has two the disease. Minoryx licensed the IP from complementary strategies for developing Barcelona, Spain IDIBELL in May. therapies to treat inherited metabolic dis- Technology: Small molecule chaper- “We are now doing more preclinical eases involving enzyme deficiencies: iden- ones binding allosteric sites on mutant work to develop a drug with therapeutic tifying small molecule chaperones that can proteins to treat inherited metabolic and commercial potential to treat X-ALD,” restore mutant enzyme function, and diseases Martinell said. repurposing existing drugs to treat the MIN-101 has Orphan Drug designa- Disease focus: Endocrine/metabolic, effects of enzyme deficiency when restor- tion in Europe to treat X-linked ALD. neurology ing function is not an option. Martinell said the first target popula- Minoryx expects its lead compound Clinical status: Preclinical tion for MIN-101 is the subset of patients will treat a different subset of X-linked Founded: 2011 by Marc Martinell, Joan with the adrenomyeloneuropathic form of adrenoleukodystrophy patients than the Aymami and Xavier Barril X-linked ALD that occurs in adulthood, lone product in the clinic for the Orphan University collaborators: Autonomous involves progressive loss of motor func- indication. University of Madrid, Bellvitge Bio- tion, and often does not progress to cere- In inherited metabolic diseases, ge- medical Research Institute, Polytech- bral involvement. netic mutations produce unstable or dys- nical University of Catalonia, St. John The only other therapy in develop- functional enzymes that cells degrade. of God Hospital, Tottori University, ment to treat X-linked ALD is bluebird Pharmacological chaperones can bind and University of Barcelona bio Inc.’s Lenti-D gene therapy, a he- stabilize mutant enzymes, preventing their Corporate partners: None matopoietic stem cell therapy with a degradation and restoring their function. lentiviral vector encoding the wild-type Number of employees: 9 But because chaperones typically mimic ABCD1 gene. It is in Phase II/III testing. the enzymes’ substrates, they can also Funds raised: Not disclosed Martinell said bluebird’s therapy tar- inhibit enzyme activity. Investors: Caixa Capital Risc, In- gets the severe childhood cerebral form of Minoryx circumvents this problem by veready, Business Angels Network of the disease that is frequently fatal in young using its Site-directed Enzyme Enhance- Catalonia children. But he added that MIN-101 could ment Therapy (SEE-Tx) technology to CEO: Marc Martinell potentially treat this form in combination identify allosteric sites on the enzymes Patents: None issued with bluebird’s therapy, because gene that small molecule chaperones can bind therapies do not always address all symp- to stabilize them, said CEO Marc toms of a disease. Martinell. (ABC) transporter D (ALD) member 1 Minoryx’s second program uses SEE- Minoryx has exclusive rights to a patent (ABCD1). ABCD1 deficiency leads to ac- Tx to develop chaperones to treat two application covering the SEE-Tx platform cumulation of fatty acids in the adrenal lysosomal storage disorders caused by from the University of Barcelona, which cortex, CNS and other tissues, resulting in deficiencies in galactosidase beta 1 (GLB1): spun out Minoryx in 2011. adrenal insufficiency, progressive motor GM1 gangliosidosis and mucopolysaccha- However, chaperones may be ineffec- function deficits and — in severe forms of ridosis IVB (MPS-IVB; Morquio’s syndrome tive against highly dysfunctional enzymes, the disease — rapid neurodegeneration to B). The company expects to identify a lead and SEE-Tx requires 3-D enzyme struc- a vegetative state. There are no disease- chaperone next year. tures, which are not available for every modifying therapies approved to treat X- Minoryx has raised €1.5 million ($2.1 enzyme of interest. “So we balance SEE-Tx linked ALD. million) in private funding and grants. with a repurposing approach to look for The 3-D structure of ABCD1 has not Martinell declined to disclose the amount compounds that counteract the cellular been determined, Martinell said. How- raised from any given source. effects of enzyme deficiency,” Martinell ever, the IDIBELL team found that brain He added Minoryx has begun discus- said. tissue from X-linked ALD patients and sions for a series A round that would Minoryx’s most advanced program, mouse models of the disease exhibited advance MIN-101 to the clinic and the MIN-101, is an example of the latter ap- deficits in the peroxisome proliferation chaperone project to the IND stage, as proach. activated receptor (PPAR) gamma path- well as talks with potential corporate part- Martinell declined to disclose the chemi- way. In the mouse models, the generic ners. cal identity and composition of MIN-101. PPAR gamma agonist pioglitazone slowed However, the program is based on work the progression of motor and neurological COMPANIES AND INSTITUTIONS MENTIONED done at Bellvitge Biomedical Research symptoms compared with no treatment. Bellvitge Biomedical Research Institute Institute (IDIBELL) that showed the dia- Last year the IDIBELL team reported (IDIBELL), Barcelona, Spain betes drug pioglitazone could treat X- the findings in Brain and filed a patent bluebird bio Inc. (NASDAQ:BLUE), Cam- linked adrenoleukodystrophy (ALD). application covering the use of pioglitazone bridge, Mass. X-linked ALD is caused by mutations as monotherapy to treat X-linked ALD Minoryx Therapeutics S.L., Barcelona, Spain in the gene encoding ATP binding cassette and its use in formulations or combina- University of Barcelona, Barcelona, Spain BioCentury, THE BERNSTEIN REPORT ON BIOBUSINESS APRIL 21, 2014 PAGE A9 OF 19 Emerging Company Profile True North: Dynamiting complement

By Samantha McGirr But extravascular hemolysis is initiated when Staff Writer True North Therapeutics cleaved C3 fragments deposit onto the sur- True North Therapeutics Inc.’s Inc. face of RBCs, marking them for phagocyto- TNT009 inhibits an upstream target in the sis in the spleen and liver. classical complement pathway that could South San Francisco, Calif. Extravascular hemolysis is “the major lead to greater efficacy and an improved Technology: mAb inhibitor of comple- mechanism through which red blood cells safety profile relative to more advanced ment component 1 s subcomponent are lysed,” Stagliano said. complement inhibitors. The single-asset (C1S) Another potential competitor is Cinryze company is focusing on complement-me- Disease focus: Hematology, renal, neu- from Shire plc. The C1 esterase inhibitor diated Orphan disorders. rology is approved to treat hereditary angioedema The complement system is a cascade of Clinical status: Preclinical (HAE) and is in Phase I testing for autoim- enzymes within the innate immune system Founded: 2013 by Rajeev Dadoo, Jim mune hemolytic anemia. that facilitates the destruction of patho- Scopa, Beth Seidenberg, Nancy Stagliano said TNT009 provides a more gens, but is up-regulated in many inflam- Stagliano and Peter Van Vlasselaer selective mechanism of action than Cinryze. matory diseases. “The term C1 esterase inhibitor is The system has three activation path- University collaborators: Memorial something of a misnomer, as it blocks C1 ways — classical, lectin and alternative — Sloan-Kettering Cancer Center, Weill as well as the lectin and bradykinin sys- which converge at the complement 3 (C3) Cornell Medical College tems. It’s a very nonspecific inhibitor,” protein. Downstream of C3, cleavage of Corporate partners: None Stagliano said. C5 leads to formation of the membrane Number of employees: 10 True North plans to choose a lead attack complex, which causes cell lysis. Funds raised: Not disclosed indication for TNT009 and submit an IND TNT009 is a humanized mAb against Investors: SR One; Kleiner Perkins to FDA late this year. Stagliano said pos- complement component 1 s subcompo- Caulfield & Byers; MPM Capital; Biogen sible indications include hematologic, re- nent (C1S), which sits atop the classical Idec New Ventures nal and dermatologic disorders. The com- pathway. pany hopes to begin Phase I testing in CEO: Nancy Stagliano Cutting off the classical pathway at the early 2015. source should enable greater inhibition of Patents: None issued Stagliano said the company is still complement system activity than com- looking for investors to participate in pounds against targets that are furthest no approved treatments, and off-label an ongoing series A round, which once downstream. At the same time, leaving the therapies produce limited responses or complete should provide enough run- lectin and alternative pathways intact may increase hematological toxicities. way for Phase I testing of TNT009. True should preserve the complement system’s CEO Nancy Stagliano said she is not North does not currently have plans to immunoprotective functions. aware of any other companies targeting partner TNT009. In December, True North presented C1S, and she believes TNT009 will have True North was spun out of iPierian preclinical data at the American Soci- advantages over other complement pro- Inc. last September to develop TNT009. An ety for Hematology meeting for TNT009 tein inhibitors in development for the undisclosed portion of iPierian’s $30 million in cold agglutinin disease (CAD). CAD is same or similar indications. venture round at the time of the spinout a type of autoimmune hemolytic anemia in For example, the C5 inhibitor Soliris served as a series A round for the newco. which autoantibodies bind to red blood eculizumab is in an investigator-initiated, cells (RBCs) at temperatures below 37 German Phase II trial for CAD. Alexion COMPANIES AND INSTITUTIONS MENTIONED degrees Celsius, resulting in activation of Pharmaceuticals Inc. markets the drug Alexion Pharmaceuticals Inc. (NASDAQ: the classical pathway and complement- to treat atypical hemolytic uremic syn- ALXN), Cheshire, Conn. mediated destruction of the cells. drome (aHUS) and paroxysmal nocturnal American Society for Hematology (ASH), In ex vivo assays, TNT009 prevented hemoglobinuria (PNH). Washington, D.C. deposition of complement proteins, ph- Stagliano said, unlike Soliris, TNT009 iPierian Inc., South San Francisco, Calif. agocytosis and lysis of RBCs induced by can block both intravascular and extravas- Shire plc (LSE:SHP; NASDAQ:SHPG), Dublin, autoantibodies from CAD patients. cular hemolysis. Intravascular hemolysis Ireland True North estimates there are about requires downstream C5 cleavage to initiate True North Therapeutics Inc., South San 5,000 CAD patients in the U.S. There are formation of the membrane attack complex. Francisco, Calif.

‘It’s the BioCentury’TM Authoritative. Globally focused. The leading perspective on the strategic issues essential to the formation, development and sustainability of life science ventures into 2014 and beyond. BioCentury, THE BERNSTEIN REPORT ON BIOBUSINESS APRIL 21, 2014 PAGE A10 OF 19 Regulation Pain politics

By Steve Usdin of some of the products really don’t Washington Editor “There is nothing that can, hold water when tested. FDA’s approval of Zohydro ER hy- at the present time, deter a And the one abuse deterrent formu- drocodone bitartrate from Zogenix Inc. lation that has met the FDA criteria for has reignited debates about the best determined abuser.” labeling as abuse deterrent actually only ways to balance the needs of pain pa- provides deterrence against immediate tients and concerns about opioid drug Margaret Hamburg, FDA injection or nasal intake — snorting. addiction, abuse and overdoses. Calls But it does not prevent oral abuse. And from powerful politicians to reverse the majority of opiate overdose and FDA’s decision to approve Zohydro tary Kathleen Sebelius to overrule FDA’s abuse is through the oral route, not have also revived concerns about the approval. injection. politicization of drug oversight. Many of the claims about Zohydro BCTV: Is there any deterrent now or The voices of pain patients have are incorrect, and efforts to trump FDA’s even conceivable that’s going to pre- been drowned out by Zohydro’s critics, approval threaten the integrity of sci- vent somebody who’s determined to in part because critics of FDA’s approv- ence-based regulation, FDA Commis- abuse an opioid from doing that? al have made extraordinary claims about sioner Margaret Hamburg said in an MH: Certainly not in terms of the the drug’s potency and abuse potential. interview with BioCentury This Week televi- formulation of the drug. There is noth- The agency approved Zohydro in sion. Edited excerpts follow. The full inter- ing that can, at the present time, deter October 2013 to manage chronic view is available at www.BioCenturytv.com. a determined abuser. pain severe enough to require a contin- BCTV: Massachusetts and Vermont uous, around-the-clock opioid analge- BioCentury This Week: An advisory have tried to ban Zohydro. Other states sic when alternatives are inadequate. committee voted 11-2 to recommend are talking about it. What are the con- The product is an oral, non-abuse de- against approving Zohydro. Governors, sequences of having states take that terrent extended-release formulation of senators, even the attorney general have unprecedented action of overruling FDA hydrocodone (see BioCentury, Oct. 28, weighed in, questioning the decision. approval? 2013). Why did FDA approve the drug? MH: I do think that it’s quite trou- Sen. Chuck Schumer (D-N.Y.) has Margaret Hamburg: I certainly under- bling. And I understand the motivation been leading the charge against FDA’s stand the broader concerns that are behind some of these actions in terms of decision. In a March 3 press release, motivating some of this in terms of the the pressing need to reduce the burden of Schumer said: “It is baffling that at the terrible public health burden of opiate opiate addiction and preventable disease same time policy makers and law en- addiction, abuse, misuse and overdose. and death. But I think people should step forcement officials are waging a war on But there is a need for adequate pain back and really think very carefully about the growing prescription drug crisis, we treatment of patients. And Zohydro, in what it means for states or the Congress to are essentially rolling out the welcome fact, does represent an important pain start dictating what drugs should be mat to a new, more powerful, and easily medicine for people that respond better approved and which ones should be abused super-drug.” to hydrocodone — or if you need to withdrawn from the marketplace. Efforts by Massachusetts Gov. Deval rotate pain medicines because of chron- You can easily look at scenarios that Patrick to ban Zohydro sales in his state ic use — who don’t want to be exposed are increasingly worrisome where, be- were rebuffed last week by a U.S. Dis- to acetaminophen, which is a leading cause of ideological beliefs or dislike for trict Court judge who ruled that states cause of liver toxicity, often even fatal certain patient categories or other cri- cannot overrule an FDA approval. liver toxicity. teria, drugs that could make a differ- The judge also concluded that al- And all of the other hydrocodone ence in people’s lives get banned. lowing Zohydro to be sold in Massachu- products currently in the marketplace BCTV: Some members of Congress setts is in the public interest. While a are combined with acetaminophen. have written to the HHS secretary and ban would prevent abuse, it would also BCTV: The governor of Massachu- asked her to overrule FDA’s decision. prevent pain patients from “receiving setts and several members of Congress What happens if we have a political the relief Zohydro ER offers,” according have said Zohydro is superpotent and system where political appointees can to the ruling. more addictive than other opioids. overrule FDA on decisions that mem- Nevertheless, Schumer and other MH: One of the common mispercep- bers of Congress don’t like? Obama administration allies, along with tions is that this is the most potent MH: I think it’s very worrisome. FDA prominent Republicans including Rep. opiate out there. And that simply isn’t has a very carefully defined legal regulato- Hal Rogers (R-Ky.), who is chairman of true. The second is that the other opi- ry framework for our decision making. the House Appropriations Committee, ates out there have abuse deterrent Most importantly, we are driven by the are continuing to press for legislation to formulations. And we wish that that science, and there is a set of scientific force the withdrawal of Zohydro. They were so. But in fact, almost without database standards for product review have also asked departing HHS Secre- exception, the abuse deterrent claims and approval. When individuals who have See next page BioCentury, THE BERNSTEIN REPORT ON BIOBUSINESS APRIL 21, 2014 PAGE A11 OF 19 Regulation, is made possible by sponsors that share BioCentury’s interest in from previous page providing a forum for public discussion of critical issues in healthcare. BioCentury This Week’s Sponsors include Biogen Idec very different backgrounds and are in the political environment, Inc., BIO and Johnson & Johnson. not the scientific environment, start making the decisions for the public, you can end up in some very worrisome places. COMPANIES AND INSTITUTIONS MENTIONED U.S. Food and Drug Administration (FDA), Silver Spring, Md. The broadcast of BioCentury This Week in Washington, D.C., Zogenix Inc. (NASDAQ:ZGNX), San Diego, Calif.

Featured links this week Links to the following documents reside online on the BioCentury on Gilead Sciences Inc. (NASDAQ:GILD) and Olysio BioBusiness page of www.biocentury.com. simeprevir from Johnson & Johnson (NYSE:JNJ) and Medivir AB (SSE:MVIR B) for most HCV patients, but says it would be Access to investigational drugs “reasonable” for doctors to defer treatment for some pa- Information about Johnson & Johnson’s Janssen Pharmaceuti- tients until newer therapies are available (see BioCentury cals division’s policies on access to investigational medicines (see Extra, Friday, April 18). Cover Story). Healthcare exchanges Comparative effectiveness trials Figures released by the White House showing that 8 million people The New England Journal of Medicine perspective article from have enrolled in health plans offered on state and federal health researchers at NIH’s NCI on proposals on how to fund compara- insurance exchanges (see BioCentury Extra, Thursday, April 17). tive effectiveness trials for expensive new cancer drugs vs. Orphan drugs cheaper drugs (see BioCentury Extra, Friday, April 18). Summary of actions taken at the April 8-9 meeting of EMA’s Compassionate use Committee for Orphan Medical Products (COMP). — Text of HCR 2005 passed by the Arizona Senate, which would Seasonal influenza vaccines allow physicians to prescribe investigational products to eligible terminally ill patients who have no “comparable or satisfactory” EMA’s interim guidance on safety surveillance for seasonal FDA-approved treatment options (see Cover Story). influenza vaccines. — Text of the Compassion Freedom of Choice Act (H.R. 4475) Specialty drugs introduced in the U.S. House of Representatives, which would allow manufacture, importation, distribution and sale of investi- Analysis from Express Scripts Holding Co. (NASDAQ:ESRX) gational products outside of a clinical trial for terminally ill that said use of specialty drugs was greater in January and patients without restriction by or reporting to FDA (see BioCentury February among enrollees on health exchanges compared with Extra, Wednesday, April 16). patients in commercial health plans (see BioCentury Extra, Mon- day, April 14). Drug assessments Product documentation Joint statement from the American College of Cardiology and American Heart Association on integrating value assessments for — MoxDuo: Briefing documents for the April 22 meeting of treatments into clinical practice guidelines and performance FDA’s Anesthetic and Analgesic Drug Products Advisory measures (see BioCentury Extra, Friday, April 18). Committee to discuss MoxDuo IR morphine/oxycodone to treat moderate to severe acute pain; from QRxPharma Ltd. Endotoxin testing (ASX:QRX; OTCQX:QRXPY) (see BioCentury Extra, Friday, FDA draft guidance for endotoxin testing in single-use intraocu- April 18). lar ophthalmic devices. — NovoEight: Germany’s Institute for Quality and Efficiency in Healthcare (IQWiG) preliminary benefit assessment that con- ESAs cluded NovoEight turoctocog alfa has “no additional benefit” vs. The U.K.’s NICE draft guidance recommending the use of other Factor VIIIs (FVIIIs) to treat and prevent bleeding in erythropoietin-stimulating agents epoetin and darbepoetin to hemophilia A patients; from Novo Nordisk A/S (CSE:NVO; treat cancer treatment-associated anemia (see BioCentury Extra, NYSE:NVO) (see BioCentury Extra, Tuesday, April 15). Tuesday, April 15). —Trobalt: Germany’s Federal Joint Committee (G-BA) preliminary benefit assessment that again concluded that Trobalt HCV retigabine for epilepsy has “no additional benefit” vs. individu- The U.S. Department of Veteran Affairs treatment guidelines alized antiepileptic therapy; from GlaxoSmithKline plc recommending regimens containing Sovaldi sofosbuvir from (LSE:GSK; NYSE:GSK) (see BioCentury, Tuesday, April 15).

Try the searchable BioCentury Archives. BioCentury, THE BERNSTEIN REPORT ON BIOBUSINESS APRIL 21, 2014 PAGE A12 OF 19 Ebb & Flow Wait for it

Pharmacogenetics company Foundation Medicine Inc. CYT003 failed in a Phase IIb trial. (NASDAQ:FMI) and cancer play Karyopharm Therapeutics Cytos was on the verge of bankruptcy in 2012 when a group Inc. (NASDAQ:KPTI) withdrew follow-on plans this month, of investors led by venBio and joined by Abingworth, Aisling and plenty of others are pumping the brakes. Biobankers say Capital and Amgen Inc. (NASDAQ:AMGN) stepped in to save companies are hoping to wait out the market correction — the company. particularly those with plenty of cash. The group provided the Swiss biotech with CHF23.8 million Foundation and Karyopharm were two of the darlings of last ($27.1 million) in equity plus a CHF13.3 million ($15.1 million) year’s IPO class, each raising more money than planned in convertible loan. bumped-up offerings (see BioCentury, Sept. 30, 2013). Chairman and “These first-time follow-ons are completely opportunistic. CEO Christian Itin Karyopharm and Foundation Medicine raised plenty of money said the rationale for “This begs the question of in their IPOs to fund their operations for the foreseeable the mixed financing how anybody is going to future,” noted Susanne Mulligan of Guggenheim Partners. structure was a Foundation raised $121.9 million in September. Karyopharm CHF13.3 million re- succeed developing drugs banked $125.1 million in November. structured convert- for the broader patient Goldman Sachs; JPMorgan; Leerink; and Sanford C. Bern- ible bond that Cytos stein underwrote Foundation’s deal while Karyopharm’s was still had on its population uncontrolled on underwritten by books. BofA Merrill Lynch; The bonds are a steroid and LABA.” “If you don’t need the Leerink; JMP Secu- subordinated to the rities; and Oppen- loan notes. Christian Itin, Cytos money, this is a situation heimer. The injection of where you might want to “They were cash was earmarked for one primary purpose: the Phase IIb trial both just taking of CYT003 to treat allergic asthma. The compound is an wait a month or two.” advantage of what oligonucleotide agonist of toll-like receptor 9 (TLR9). was an extraordi- Investors were impressed by CYT003’s performance in a Christian Hodneland, William Blair narily strong mar- previous Phase II trial, where it significantly improved outcomes ket to opportunis- in 63 patients (see BioCentury, March 26, 2012). tically raise additional capital and/or allow insiders to sell a The new syndicate, along with institutional investors, doubled portion of their holdings,” Mulligan said. down on Cytos last November, providing the company a further However, after filing in mid-March, both companies watched CHF24.3 million ($27.7 million) in a rights offering. the sector-wide correction take a bite out of their valuations. However, last week Cytos said CYT003 missed the primary Since the start of the pullback on Feb. 25, Foundation is off endpoint of reducing Asthma Control Questionnaire (ACQ) $5.90 (18%) to $26.54, while Karyopharm has fallen $8.82 scores at week 12 vs. placebo in 360 patients when added to (22%) to $31.09. Last week, Foundation lost $0.19, while standard controller therapy. Karyopharm finished down $3.92 (11%). Itin said Cytos did everything it could think of to avoid the Ladenburg’s Ed Gordon said both companies, and any large placebo effect seen in prior allergic asthma trials, including others that are holding back for the moment, are making a an extended lead-in period and over-powering the trial, but in calculated bet that this is simply a pause in the bull market. the end it still fell victim to the same issue. “There is nothing in the fundamentals to suggest they would “This begs the question of how anybody is going to succeed be wrong,” he said. developing drugs for the broader patient population uncon- Christian Hodneland of William Blair said he is working on trolled on a steroid and LABA,” he said. confidential deals for clients that are also postponing offerings. Cytos, which plummeted CHF2.72 (95%) to CHF0.15 on the “This is a very different situation than in 2008 through 2010 news last Monday, said it would look to wind down operations. when you didn’t know what was going to happen tomorrow so The company had CHF31 million ($35 million) in cash at you took the money today,” he said. “If you don’t need the March 31. money, this is a situation where you might want to wait a month Both the investors’ notes and the bonds are repayable at or two.” 150% of par, meaning the total amount due at maturity in Hodneland noted that the rate of inbound calls from compa- February 2015 is CHF46 million ($52.5 million). nies thinking about testing the equity market has not slowed. As a result, the new investors can expect to see an undis- — Michael Flanagan closed portion of their investment back, whereas the bondhold- ers may not be so fortunate. Cytos closed last week off CHF2.69 (94%) to CHF0.18. Bad beat — Michael Flanagan Investors rolled the dice on an allergic asthma program from See next page Cytos Pharmaceuticals AG (SIX:CYTN) but the CHF61.3 BioCentury Extra: Online every business day. million ($69.6 million) bet came up snake eyes last week when BioCentury, THE BERNSTEIN REPORT ON BIOBUSINESS APRIL 21, 2014 PAGE A13 OF 19 Ebb & Flow, from previous page

The 21st Annual Undiluted injection Kaleo Inc. is leveraging the royalties from its first marketed NEWSMAKERS product to secure the non-dilutive funding it needs to launch its second product, an auto-injectable form of naloxone to treat IN THE IOTECH NDUSTRY opioid overdose. B I After running a competitive process involving 15 royalty buyers, Kaleo announced on April 7 that it raised $150 million in a note deal with PDL BioPharma Inc. (NASDAQ:PDLI) secured by 100% of Kaleo’s royalties from Auvi-Q epinephrine CALL FOR PRESENTING COMPANIES and 10% of sales of Evzio naloxone on a quarterly basis. Kaleo’s modus operandi is to develop best-in-class products for life-threatening diseases by taking well- established drugs “Royalty monetization is a and delivering them good way to raise non- using newly engi- NewsMakers presents a hand-picked group of neered devices. dilutive money at a prudent public biotech companies whose corporate Kaleo’s first cost of capital.” product, Auvi-Q, is and regulatory milestones will drive stock an auto-injection sys- Spencer Williamson, Kaleo prices. NewsMakers is recognized as the tem delivering epinephrine for emer- industry’s key venue for companies to take gency treatment of severe allergic reaction. their story to Wall Street each Fall. Sanofi (Euronext:SAN; NYSE:SNY) markets Auvi-Q but does not break out sales. Kaleo (formerly Intelliject Inc.) chose to market its second product itself in the U.S., where Evzio was approved this month as the first drug-device naloxone product available outside of a healthcare setting. “There were 16,000 opioid overdoses a year as of 2010, so this is a huge problem,” said President and CEO Spencer Apply to be a Presenting Company Williamson. Email [email protected] Rather than tap the equity markets, Williamson decided to avoid dilution by taking advantage of Kaleo’s future revenues from Auvi-Q. “Royalty monetization is a good way to raise non-dilutive money at a prudent cost of capital, but it is only available if you Save the Date have a high-performing asset like Auvi-Q,” he noted. The notes carry 13% interest and mature in 2029, though WHEN: Williamson said Kaleo plans to pay them off “in the next several Friday, years.” September 26, 2014 PDL has other structured financing arrangements, including deals with infectious disease company Durata Therapeutics Inc. (NASDAQ:DRTX); drug delivery company DepoMed Inc. WHERE: (NASDAQ:DEPO); diagnostic play Wellstat Diagnostics LLC New York City and nerve repair company AxoGen Inc. (NASDAQ:AXGN). Kaleo has begun building a commercial team and will focus on pain specialists. Williamson declined to provide details on reps or sales estimates. Last week, PDL rose $0.41 to $8.41. — Michael Flanagan Sponsorship Opportunities

CONTACT ERIC PIERCE AT European beachhead [email protected] Epirus Biopharmaceuticals Inc. hopes its $36 million series B round and reverse merger with Zalicus Inc. FOR SPONSORSHIP OPPORTUNITIES. (NASDAQ:ZLCS) will enable the biosimilars company to crack the European market. The combined public company will retain Epirus’ name and See next page BioCentury, THE BERNSTEIN REPORT ON BIOBUSINESS APRIL 21, 2014 PAGE A14 OF 19 Ebb & Flow, 5AM Ventures. Livzon CEO Daotian Fu will join Epirus’ board. from previous page Last week, Zalicus was up $0.05 to $1.21. — Samantha McGirr focus on development of BOW-015, a biosimilar of autoimmune drug Remicade infliximab from Johnson & Johnson (NYSE:JNJ) and Merck & Co. Inc. (NYSE:MRK). Early next year, Epirus Morgan Stanley to Juno plans to start a Eu- The potential of Juno Therapeutics Inc. to shift the cancer ropean Phase III treatment paradigm coupled with the cancer immunotherapy trial in rheumatoid “Misses have nothing to do play’s clinical data and management team were enough to lure arthritis (RA). Steve Harr away from Morgan Stanley after 12 years at the bank. Epirus said the with people.” Last month, Juno said Harr will join as CFO and head of merger gives it ac- corporate develop- cess to Zalicus’ Eu- Scott Rocklage, 5AM Ventures ment. ropean clinical trial He is managing “I couldn’t pass up the experience in RA. In 2012, Zalicus discontinued development of director and head Synavive in RA after the selective steroid amplifier containing of global biotech in- opportunity.” dipyridamole and prednisolone did not significantly reduce vestment banking at DAS28-CRP scores vs. prednisolone in a Phase IIb trial. Morgan Stanley, Steve Harr, Morgan Stanley 5AM Ventures’ Scott Rocklage, an Epirus director, said the where he managed miss does not detract from Zalicus’ expertise. more than $20 billion in financing deals and more than $40 “Misses have nothing to do with people,” Rocklage said. billion in M&A transactions. Prior to that, he was a research “Misses have to do with the performance of a specific molecule analyst at the bank. in a specific clinical setting.” “Juno has such a unique combination Epirus submitted a regulatory applica- Money Raised in 2014 of technology, clinical data and most im- tion for BOW-015 in India in November portantly a stellar leadership team that I and in January said it would submit appli- Last week, the biotech industry raised $291 couldn’t pass up the opportunity,” said cations in “targeted emerging markets” million, bringing to $21.1 billion the total Harr, who will join Juno this quarter. over the next 12 months. raised year-to-date. In 2013, a total of $37 Juno’s team includes CEO Hans Bishop, In January, Epirus granted Ranbaxy billion was raised, including $14.4 billion in who was EVP and COO of Dendreon Laboratories Ltd. (NSE:RANBAXY; debt, $10 billion in follow-ons, $2.8 billion in Corp. (NASDAQ:DNDN). Dendreon’s BSE:500359) commercialization rights to PIPEs and other equity, $3.8 billion in IPOs, Provenge sipuleucel-T was the first cancer BOW-015 in India and undisclosed mar- and $5.9 billion in venture capital. Totals immunotherapy approved in the U.S. kets in Southeast Asia and North Africa. include overallotments and warrants, and are “The science and the clinical data will Last October, Epirus partnered with rounded to the nearest millions. be the main driver of the direction of the Orygen Biotecnologia Ltda. to develop company,” said Harr. “The main driver of and commercialize BOW-015 in Brazil. my job will be to ensure that my company Orygen is a JV between Eurofarma has the capital to prosecute on those Laboratorios S.A. and Biolab Sanus opportunities.” Farmaceutica Ltda. Juno is designing and developing im- Rocklage said Epirus does not plan on munotherapies based on chimeric antigen continuing internal development of Zalicus’ receptor (CAR) and T cell receptor (TCR) pipeline. The sole clinical candidate is technology. Z944, which has completed Phase I testing The company’s technology is based on for pain. He said the company may out- research from Fred Hutchinson Can- license the T-type calcium channel blocker. cer Research Center, Memorial Epirus shareholders will hold 81-86% Sloan-Kettering Cancer Center of the combined company, depending on Source: BCIQ: BioCentury Online Intelligence (MSKCC) and Seattle Children’s Re- Zalicus’ net cash when the deal closes. At search Institute. Dec. 31, Zalicus had $18 million in cash. Juno’s $145 million series A round The merger is slated to close this summer. attracted investors Arch Venture Part- Epirus’ B round was led by Livzon ners; Alaska Permanent Fund, through a Mabpharm Inc., a JV between Livzon partnership with Crestline Investors; Bezos Pharmaceutical Group Inc. Expeditions; and Venrock (see BioCentury, (HKSE:1513; SZSE:000513) and Join- Dec. 9, 2013). care Pharmaceutical Group Indus- Harr said he also will be responsible try Co. Ltd. (Shanghai:600380). for “ensuring Juno has the right partner- New investors Adage Capital; Green- ships to maximize value,” and also will woods Investment; Gibralt Capital’s Gibralt continue to look for technologies and U.S. Inc.; Monashee Capital Partners; and molecules to add to Juno’s platform. an affiliate of Mousse Partners also partici- “I think it’s rare that you find compa- pated, along with existing investors TPG nies that have a broad and potentially Biotech; Montreux Equity Partners; and paradigm shifting platform,” he said. Source: BCIQ: BioCentury Online Intelligence See next page BioCentury, THE BERNSTEIN REPORT ON BIOBUSINESS APRIL 21, 2014 PAGE A15 OF 19 Ebb & Flow, from previous page Legal tracks Thomas Duley joined King & Spalding’s Silicon Valley office “When you put together the people and that technology, you as a partner. Duley was of counsel at DLA Piper. have a really high probability that this company will find the right answers going forward.” Juno has options to programs being developed by its aca- Private equity tracks demic partners. MSKCC has resumed five trials of one of them, David Katz departed GTCR as a managing director and co- its 19-28z CAR T cell therapy, after working with FDA to amend head of healthcare investing. the admissions criteria following patient deaths in a study in relapsed B cell acute lymphoblastic leukemia (ALL) (see “CAR Hits Pothole,” A5). Regulatory milestones — Jennifer Rhodes Alimera Sciences Inc. (NASDAQ:ALIM) was off $0.15 to $6.31 last week after saying FDA accepted for review a resubmitted NDA for Iluvien fluocinolone acetonide intravitreal implant Analyst tracks to treat diabetic macular edema (DME). The PDUFA date is Sept. Bert Hazlett departed Roth Capital Partners as a senior 26. FDA issued a complete response letter in October. research analyst covering small- to mid-cap biopharmaceutical Alimera has rights to Iluvien from pSivida Corp. companies. (NASDAQ:PSDV; ASX:PVA), which was up A$0.02 to A$4.02 Pamela Bassett joined Maxim Group LLC in February as an on ASX and up $0.02 to $3.45 on NASDAQ. SVP and senior biotechnology analyst. Bassett founded equity ALK-Abello A/S (CSE:ALK-B) added DKK67 (10%) to research firm Strategy Signal. See next page

Earnings on deck

At least 15 biotechs and pharmas are slated to report earnings this week. Three large-cap biotechs — Alexion Pharmaceuticals Inc. (NASDAQ:ALXN), Biogen Idec Inc. (NASDAQ:BIIB) and Gilead Sciences Inc. (NASDAQ:GILD) — are expected to report 1Q14 EPS growth of 30% or more on strong top-line growth. Alexion markets Soliris eculizumab for rare blood disorders and is anticipated to post a 65% increase in 1Q14 revenues to $560 million. Biogen Idec, which launched multiple sclerosis drug Tecfidera dimethyl fumarate in the U.S. last April, is expected to report 41% growth in revenues to $2 billion. Gilead will be posting its first full quarter of sales for HCV drug Sovaldi sofosbuvir, which the company launched in December. The Street expects Gilead to post a 53% jump in revenues to $3.9 billion. Despite an anticipated 24% jump in revenues, Cubist Pharmaceuticals Inc. (NASDAQ:CBST) is expected to report a decline in 1Q14 EPS to breakeven from $0.09 in 1Q13. In January, the company said 2014 SG&A would rise to $310-$320 million to account for a sales force increase and near-term product launches. The infectious disease company reported 2013 SG&A of $258 million. Two big pharmas are expected to report double-digit earnings declines as generic competition continues to erode their top lines. The Street expects revenues for AstraZeneca plc (LSE:AZN; NYSE:AZN) to fall 1% to $6.3 billion and those for Eli Lilly and Co. (NYSE:LLY) to drop 14% to $4.8 billion. AstraZeneca said in February that it expects percentage declines in the teens for 2014 core EPS vs. 2013 as the pharma continues investing in its “pipeline and growth platform.” Pre/ 1Q14 post EPS 1Q13 Expected Company Date mkt est EPS chg Amgen Inc. (NASDAQ:AMGN) 4/22 Post $1.93 $1.96 -2% Cubist Pharmaceuticals Inc. (NASDAQ:CBST) 4/22 Post $0.00 $0.09 -100% Illumina Inc. (NASDAQ:ILMN) 4/22 Post $0.45 $0.46 -2% Gilead Sciences Inc. (NASDAQ:GILD) 4/22 Post $0.88 $0.48 83% Biogen Idec Inc. (NASDAQ:BIIB) 4/23 Pre $2.57 $1.97 30% Thermo Fisher Scientific Inc. (NYSE:TMO) 4/23 Pre $1.40 $1.37 2% AstraZeneca plc (LSE:AZN; NYSE:AZN) 4/24 Pre $1.22 $1.41 -13% Celgene Corp. (NASDAQ:CELG) 4/24 Pre $1.65 $1.37 20% Eli Lilly and Co. (NYSE:LLY) 4/24 Pre $0.70 $1.14 -39% Novartis AG (NYSE:NVS; SIX:NOVN) 4/24 Pre $1.35 $1.32 2% Alexion Pharmaceuticals Inc. (NASDAQ:ALXN) 4/24 Post $1.26 $0.65 94% PerkinElmer Inc. (NYSE:PKI) 4/24 Post $0.44 $0.36 22% Sigma-Aldrich Corp. (NASDAQ:SIAL) 4/24 Post $1.03 $1.01 2% UCB Group (Euronext:UCB) 4/24 NA NA NA NA AbbVie Inc. (NYSE:ABBV) 4/25 Pre $0.68 $0.68 0%

Take advantage of BioCentury Extra. BioCentury, THE BERNSTEIN REPORT ON BIOBUSINESS APRIL 21, 2014 PAGE A16 OF 19 Ebb & Flow, from previous page BioCentury® DKK710 last week after FDA approved a BLA for Grastek, a grass pollen sublingual allergy immunotherapy tablet (AIT) to treat BioCentury’s mission is to provide value-added business information & grass pollen-induced allergic rhinitis, with or without conjunc- analysis for life science companies, investors, academia and government tivitis. on the strategic issues essential to the formation, development and sustainability of life science ventures. After Nordic markets closed for the week, FDA also approved a BLA for Ragwitek, a ragweed sublingual AIT, to treat ragweed BioCentury Publications, Inc. pollen-induced allergic rhinitis, with or without conjunctivitis. BioCentury International Inc. Merck & Co. Inc. (NYSE:MRK) has exclusive North Ameri- can rights to Grastek and Ragwitek. Main Offices Gilead Sciences Inc. (NASDAQ:GILD) gained $3.97 to PO Box 1246 $70 after updates for two of its infectious disease products. On San Carlos CA 94070-1246 Monday, partner Bristol-Myers Squibb Co. (NYSE:BMY) +1 650-595-5333; Fax: +1 650-595-5589 submitted an NDA to FDA for a fixed-dose combination of BMS Chicago: +1 312-755-0798; Fax: +1 650-595-5589 HIV drug Reyataz atazanavir and Gilead’s cobicistat to treat HIV- Washington, D.C.: +1 202-462-9582; Fax: +1 202-667-2922 1 infection in combination with other antiretroviral agents. Later in the week, NHS England approved £18.7 million United Kingdom: +44 (0)1865-512184; Fax: +1 650-595-5589 ($31.3 million) in funding to treat advanced HCV patients with www.biocentury.com Gilead’s Sovaldi sofosbuvir. The U.K.’s NICE is reviewing Sovaldi for chronic HCV, with a first appraisal committee meeting Corporate scheduled for May 15. Karen Bernstein, Ph.D., Chairman & Editor-in-Chief David Flores, President & CEO Clinical milestones Thomas Carey, Vice President/Commercial Operations Bennet Weintraub, Vice President/Administration & CFO Galapagos N.V. (Euronext:GLPG; Pink:GLPYY) was off €0.78 to €15.71 last week after GSK2586184 met the primary Eric Pierce, Publisher endpoint in a Phase IIa trial to treat chronic plaque psoriasis. Tim Tulloch, Associate Publisher GlaxoSmithKline plc (LSE:GSK; NYSE:GSK) has exclusive, Julia Kulikova, Senior Director/Operations worldwide rights to the Janus kinase-1 (JAK-1) inhibitor from Chris Dokomajilar, Director/Business Intelligence Galapagos. Jeffrey Fitzgerald, Director/Multimedia Operations Lexicon Pharmaceuticals Inc. (NASDAQ:LXRX) was up Jamie Gould, Director/Multimedia Business Development $0.04 to $1.63 last week after saying LX4211 met the primary Ravid Lazinsky, Director/Digital Product Manager endpoint in a Phase II trial to treat Type I diabetics. By year end, Greg Monteforte, Director/Marketing & Promotional Services Lexicon plans to start a Phase III trial of the dual sodium-glucose Susan Morgan, Director/Administration & Human Resources cotransporter 1 (SGLT1) and SGLT2 inhibitor in the indication. Jenny Nichols, Production Subscriber Services Subscriber Services: [email protected] Ebb & Flow Account Managers: Orlando Abello, Matt Krebs, Alnylam Pharmaceuticals Inc. (NASDAQ:ALNY) was Michelle Ortega, Ron Rabinowitz down $1.21 to $53.86 last week after Novartis AG (NYSE:NVS; Business Services SIX:NOVN) said it will “significantly reduce” internal discovery Accounting & Billing: [email protected] in RNA therapeutics due to “ongoing challenges with formula- Conferences: [email protected] tion and delivery and the reality that the current range of Data Solutions Support: [email protected] medically relevant targets where siRNA may be used is quite Privacy Policy: [email protected] narrow.” Reprints/Permissions: [email protected] Novartis said it will maintain some employees to work on disease targets the pharma obtained under an RNAi discovery Privacy & Advertising deal with Alnylam. In accordance with its Privacy Policy, BioCentury does NOT sell its customer Fellow RNAi companies also slipped on the week. Tekmira information or usage data to third parties. Pharmaceuticals Corp. (TSX:TKM; NASDAQ:TKMR) was off BioCentury does NOT sell advertising in the BioCentury, the Bernstein Report on C$5.86 (29%) to $14.28 in Toronto and down $5.37 (29%) to BioBusiness or BioCentury Week in Review. BioCentury is pleased to acknowledge $13.05 on NASDAQ. Dicerna Pharmaceuticals Inc. its conference partners and sponsors through unpaid promotional announcements in (NASDAQ:DRNA) fell $1.70 to $16.41. its publications. BioCentury MAY accept paid promotional messages from sponsors, Ampio Pharmaceuticals Inc. (NYSE-M:AMPE) lost $0.17 which are displayed only on BioCentury’s websites. to $5.44 last week after its Vyrix Pharmaceutical Inc. subsidiary USE OF IMAGES: Certain Images used in BioCentury's Publications, Video filed to raise up to $28.8 million in an IPO on NYSE MKT. Ampio Content, Websites, Services, Notices and/or Marketing Materials are licensed from carved off its sexual dysfunction business into Vyrix in Decem- Getty Images (US), Inc. Any such image of a person or object so displayed is being ber. Next half, Vyrix plans to submit an IND for a pair of U.S. used for illustrative purposes only and any such person or object depicted, if any, is Phase III trials for Zertane tramadol in premature ejaculation merely a model. For more information see “Use of Images” found under the “About (PE). Us” tab on the Homepage at www.biocentury.com. See next page BioCentury, THE BERNSTEIN REPORT ON BIOBUSINESS APRIL 21, 2014 PAGE A17 OF 19 Ebb & Flow, Review for relapsed or refractory peripheral T cell lymphoma from previous page (PTCL), with an Aug. 9 PDUFA date. BioAlliance’s pipeline includes Livatag doxorubicin Transdrug (BA-003), which is in a Medivir AB (SSE:MVIR B) was off SEK0.75 to SEK108.25 last Phase III trial for hepatocellular carcinoma (HCC). week after partner Johnson & Johnson (NYSE:JNJ) reported BioAlliance was off €0.32 to €7.18 on the week. $354 million in worldwide sales of Olysio simeprevir in the HCV TxCell S.A. (Euronext:TXCL) was up €0.04 to €5.62 in its drug’s first full quarter of sales. U.S. sales were $291 million. The first week of trading after raising €16.2 million ($22.2 million) pharma launched Olysio in the U.S., Canada and Japan in through the sale of 2.9 million shares at €5.58 in an IPO last December (see “EPS Watch,” A18). week. Next half, TxCell plans to start a Phase IIb trial of Ovasave ThromboGenics N.V. (Euronext:THR) gained €3.49 (18%) to treat refractory Crohn’s disease. Ovasave is an antigen- to €22.37 last week following media reports that companies specific type 1 regulatory T cell-based immunotherapy. including Novartis AG (NYSE:NVS; SIX:NOVN), Shire plc Liver disease company Vital Therapies Inc. (NASDAQ:VTL) (LSE:SHP; NASDAQ:SHPG) and Roche (SIX:ROG; OTCQX: was unchanged in its first day of trading on Thursday after raising RHHBY) are considering making bids for the ophthalmic com- $54 million through the sale of 4.5 million shares at $12 in an pany. ThromboGenics said it does not comment on market IPO. The price values Vital at $253.4 million. The share price is speculation. below the $13-$15 range set this month. In February, ThromboGenics announced it hired Morgan Vital’s human liver cell-based extracorporeal liver assist Stanley and planned to explore strategic options. The move device (ELAD) is in the Phase III VTI-208 trial to treat alcohol- came after disappointing sales for Jetrea ocriplasmin, which induced liver decompensation (AILD), with data expected in ThromboGenics launched in the U.S. last year to treat symptom- 1H15. atic vitreomacular adhesion (VMA). Zogenix Inc. (NASDAQ:ZGNX) was up $0.08 to $2.71 last Topotarget A/S (CSE:TOPO) gained DKK0.31 (10%) to week after the U.S. District Court for the District of Massachu- DKK3.42 after the company and BioAlliance Pharma S.A. setts granted a preliminary injunction stopping Massachusetts’ (Euronext:BIO) said they will merge in a stock deal to create a statewide ban on pain drug Zohydro ER hydrocodone bitartrate company based on Orphan cancers. The deal is slated to close (see “Pain Politics,” A10). in July or August (see B3). — Staff Writer Kevin Lehnbeuter contributed to this week’s Ebb Topotarget’s Beleodaq belinostat is under FDA Priority & Flow

Analyst picks & changes

Company Bank Analyst Coverage Opinion Wk chg 4/17 cls Akebia Therapeutics Inc. (NASDAQ:AKBA) UBS Matthew Roden New Buy 55% $26.09 Roden initiated coverage with a $28 target on the belief that Akebia’s AKB-6548 has blockbuster potential to treat anemia in chronic kidney disease (CKD) patients. Roden said preclinical and clinical data support the safety of AKB-6548 vs. marketed erythropoiesis stimulating agents (ESA), which have black box warnings for increased death and cardiovascular events. The oral hypoxia-inducible factor prolyl hydroxylase (HIF- PH; EGLN) inhibitor is in Phase IIb testing, with data expected in 4Q14. Akebia raised $100M in an IPO in March. Fluidigm Corp. (NASDAQ:FLDM) Leerink Partners Dan Leonard Upgrade Outperform (from 10% $37.10 market perform) Leonard upgraded but maintained his $52 target, noting “demand for single cell gene expression analysis tools remains strong.” He also said Fluidigm’s February acquisition of DVS Sciences Inc., which develops and markets single-cell protein analysis systems, broadens the company’s opportunity set in single-cell research (see BioCentury, Feb. 17). Leonard estimates 2014 revenues of $120.8M. ImmunoGen Inc. (NASDAQ:IMGN) Canaccord John Newman New Buy 8% $13.99 Newman initiated coverage with a $20 target ahead of data next half from the Phase III MARIANNE trial of Kadcyla ado-trastuzumab emtansine (T-DM1; RG3502) in front-line HER2-postive metastatic breast cancer. Newman notes that Kadcyla could eliminate the need for chemotherapy in the setting and estimates a 75% probability of approval. The Genentech Inc. unit of Roche (SIX:ROG; OTCQX:RHHBY) has rights to use ImmunoGen’s TAP antibody-conjugate technology for Kadcyla, which is approved in the U.S. and EU for second-line treatment of HER2- positive metastatic breast cancer. Lpath Inc. (NASDAQ:LPTN) Canaccord John Newman New Buy 3% $4.44 Newman initiated coverage with a $17 target on the belief that Lpath’s iSONEP sphingomab could be a “paradigm-changing” treatment for wet age-related macular degeneration (AMD), with peak worldwide sales potential of $2.4B. Newman said iSONEP targets the underlying cause of AMD as opposed to the current standard of care, which focuses on symptom treatment. Newman expects Lpath to report data in 4Q14 from the Phase IIa Nexus trial evaluating the ocular formulation of a humanized mAb against sphingosine 1-phosphate (S1P). The Medicines Co. (NASDAQ:MDCO) Leerink Partners Joseph Schwartz Downgrade Market perform -2% $24.55 (from outperform) Schwartz also lowered his target to $30 from $27 after speaking with patent specialists on Medicine Co.’s appeal prospects for IP litigation related to its anticoagulant Angiomax bivalirudin. Last month, a judge in the U.S. District Court for the District of Delaware ruled that the company failed to prove a generic version of bivalirudin from Hospira Inc. (NYSE:HSP) infringes Medicines Co.’s patents. The ruling could allow Hospira to launch its generic version as early as June 15, 2015. Schwartz said specialists indicated that the ruling is “legally sound.” BioCentury, THE BERNSTEIN REPORT ON BIOBUSINESS APRIL 21, 2014 PAGE A18 OF 19

EPS watch

At least six biotechs and pharmas reported earnings last week. Actelion Ltd. (SIX:ATLN) added nearly half a billion in market cap last week after posting 1Q14 EPS and revenues that beat the Street’s estimates. The Swiss biotech also reported its first full quarter of sales for Opsumit macitentan. Sales of the hypertension drug launched last November came in at CHF15 million ($17 million).

Johnson & Johnson (NYSE:JNJ) and Roche (SIX:ROG; OTCQX:RHHBY) both ended the week up 2%. J&J reported quarterly EPS and revenues that beat the consensus estimates and announced 1Q14 sales of $354 million for HCV drug Olysio simeprevir, which was launched in December. J&J tacked on $5.9 billion to its valuation last week.

Roche added $4.1 billion to its market cap last week. The pharma announced 5% growth in 1Q14 sales, excluding the impact from exchange rates, helped by sales of cancer drug Avastin bevacizumab. Avastin sales rose 9% to CHF1.6 billion ($1.8 billion). Mcap in $M

1Q14 EPS 1Q14 EPS Growth 4/17 Wk % Mcap 4/17 Company est actual Outcome from 1Q13 cls chg chg chg Mcap Abbott Laboratories (NYSE:ABT) $0.36 $0.41 Beat by $0.05 -2% $38.93 $1.71 5% $2,633.4 $59,952.2 1Q14 net sales fell 3% year-over-over to $5.2B and missed the Street’s estimate of $5.3B; however, the company beat on EPS through cost controls. 1Q14 SG&A fell 1% to $1.8B. 1Q14 sales from established pharmaceuticals fell 7% to $1.2B, while medical device sales were down 1% to $1.3B. Diagnostics sales were up 3% to $1.1B. Sales in emerging markets were $531M, down 9%. Percentage changes include the effect of foreign currency exchange. The company reiterated its 2014 EPS guidance of $2.16-$2.26. Actelion Ltd. (SIX:ATLN) CHF1.04 CHF1.09 Beat by CHF0.05 38% CHF85.85 CHF3.48 4% $477.6 $11,781.9 1Q14 revenues were CHF469M ($529M), up 13% from CHF433M in 1Q13. The Street was expecting CHF445M. 1Q14 sales of pulmonary arterial hypertension (PAH) drug Tracleer bosentan were CHF383M ($432M), up 7% from CHF375M in 1Q13, while sales of new PAH drug Opsumit macitentan were CHF15M ($17M). Percent changes assume constant currency. In February, the company said it expected 2014 core EPS to grow in the low-single digit range over 2013. Baxter International Inc. (NYSE:BAX) $1.09 $1.19 Beat by $0.10 9% $72.81 $0.83 1% $449.9 $39,463.0 1Q14 sales came in at $3.95B, up 15% from $3.45B and above the Street’s estimate of $3.88B. The company attributed the jump in part to its September 2013 acquisition of renal products company Gambro AB. Baxter BioScience revenues, which include plasma-based therapies and vaccines, were up 5% to $1.6B. Revenues for the company’s Medical Products business, which manufactures products used in the delivery of fluids and drugs to patients, were up 22% to $2.3B. Percent changes include the impact of foreign currency exchange. Baxter provided EPS before special items guidance for 2Q14 of $1.18-$1.22 and reiterated 2014 guidance of $5.05-$5.25. In March, Baxter announced that it will split its medical products and biopharmaceuticals businesses into two public companies. Cepheid Inc. (NASDAQ:CPHD) -$0.19 -$0.13 Beat by $0.06 NA $47.93 $1.61 3% $111.5 $3,320.2 The molecular diagnostic company reported a decline in earnings from about breakeven in 1Q13 to a net loss per share of $0.13 in 1Q14, as operating expenses increased by 26% to $58.9M. 1Q14 sales were $106.9M, up 16% from $91.9M in 1Q13 and above the Street’s estimate of $104.9M. Cepheid reiterated its 2014 revenue guidance of $446-$461M and lowered its non-GAAP EPS guidance to $0.19-$0.24 from $0.24-$0.29 following a February convertible notes offering, in which it raised $345M. Johnson & Johnson (NYSE:JNJ) $1.48 $1.54 Beat by $0.06 7% $98.96 $2.09 2% $5,914.7 $280,056.8 1Q14 sales were up 5% to $18.1B from $17.5B and above the Street’s estimate of $18B. Pharmaceutical sales were $7.5B in 1Q14, up 12% from $6.8B. Worldwide sales of new HCV drug Olysio simeprevir were $354M in 1Q14. J&J’s Janssen Research & Development LLC unit has ex- Nordic rights to develop and commercialize Olysio from Medivir AB (SSE:MVIR B). 1Q14 sales of autoimmune drug Remicade infliximab came in at $1.6B, up 2% from 1Q13. Sales of prostate cancer drug Zytiga abiraterone increased by 49% to $512M. Percent changes for sales figures exclude the impact from currency exchange rates. The company increased its 2014 guidance for EPS excluding special items to $5.80-$5.90 from $5.75-$5.85. Roche (SIX:ROG; OTCQX:RHHBY) NA NA NA NA CHF253.50 CHF3.90 2% $4,078.1 $250,569.0 The pharma did not provide 1Q14 earnings figures. 1Q14 sales grew 5% to CHF11.5B ($13B) from CHF11.6B in 1Q13. Among Roche’s top three cancer drugs, MabThera/Rituxan rituximab rose 3% to CHF1.7B ($1.9B) compared with 1Q13; Avastin bevacizumab gained 9% to CHF1.6B ($1.8B); and Herceptin trastuzumab rose 3% to CHF1.5B ($1.7B). 1Q14 sales of breast cancer drug Perjeta pertuzumab increased by 274% to CHF178 million ($201 million), while cancer drug Kadcyla ado-trastuzumab emtansine sales increased by 474% to CHF102 million ($115 million). The pharma reiterated its expectation of low- to mid-single digit sales growth in 2014. All percent changes assume constant currency.

Company Index, NCI A5 Seattle Children’s Res Inst A5, U of Manchester A6 from page A7 Novartis A6, A16, A17 A14 U of Pennsylvania A6 Novo Nordisk A11 Shire A9, A17 Vital Therapies A17 Medivir A11, A17 PDL BioPharma A13 Tekmira A16 Washington Legal Fdn A4 Memorial Sloan Kettering A5, PhRMA A2 ThromboGenics A17 Wellstat Diag A13 A14 pSivida A15 Topotarget A17 Zalicus A13 Merck A14, A16 QRxPharma A11 True North Therap A9 Zogenix A10, A17 Merck KGaA A7 Roche A6, A17 TxCell A17 TM Minoryx A8 Sanofi A7, A13 U of Barcelona A8 ‘It’s the BioCentury’ BioCentury, THE BERNSTEIN REPORT ON BIOBUSINESS APRIL 21, 2014 PAGE A19 OF 19

BioCentury 100 Price & Volume Trend Price Gains Cumulative weekly performance of 100 bioscience stocks. 12-week period. Stocks with greatest % price increase in the week ended April 18. Line shows Price Level change (Left scale. Index base=1000 on May 10, (Priced above $2; 5,000 minimum share volume) 1996). Bars show cumulative volume in millions (right scale). Company Ticker $Close $Chg %Chg Vol(00) Akebia AKBA 26.090 9.230 55% 59400 ThromboGenics THR €22.365 €3.485 18% 14164 Co.don CNWK €3.569 €0.528 17% 1228 Repligen RGEN 15.840 2.190 16% 80008 MedRx 4586 ¥1439 ¥185 15% 4069 Sorrento SRNE 10.550 1.340 15% 3027 Sygnis Pharma LIO1 €5.539 €0.641 13% 1276 Affymetrix AFFX 7.200 0.830 13% 59541 Portola PTLA 23.480 2.700 13% 15336 MediBIC 2369 ¥350 ¥37 12% 25297 Akers Biosciences1 AKER 4.250 0.440 12% 1082 Price Declines Stocks with greatest % price decline (criteria as above). BioCentury tracks 669 issues that report prices and volume daily. The Company Ticker $Close $Chg %Chg Vol(00) BioCentury 100 is a subset used to monitor price and volume trends. uniQure QURE 9.000 -4.040 -31% 4800 Auspex ASPX 20.860 -9.080 -30% 10160 BioCentury London Index Transition Therap2 TTHI 5.590 -2.400 -30% 14423 Tekmira2 TKMR 13.050 -5.370 -29% 81227 Weekly change in the combined market capitalization for 14 bioscience Ultragenyx RARE 42.560 -16.430 -28% 15648 stocks listed on the LSE or AIM, 12-week period. Index base =1000 on Genfit GNFT €19.980 -€7.620 -28% 23654 May 10, 1996. Biocept BIOC 4.950 -1.050 -18% 553 Cellectis ALCLS €4.860 -€0.990 -17% 12759 Oncothyreon ONTY 2.490 -0.480 -16% 38730 Idera IDRA 2.770 -0.510 -16% 154668 Recro REPH 5.500 -0.950 -15% 2463 Fibrocell FCSC 4.130 -0.660 -14% 5441 Cara CARA 13.380 -2.100 -14% 4526 Volume Gains Greatest changes in volume above 5,000 shares. Company Ticker Vol(00) %Chg $Close $Chg Akebia AKBA 59400 830% 26.090 9.230 Transition Therap2 TTHI 14423 346% 5.590 -2.400 Apr 18 Apricus Biosciences APRI 22880 174% 2.380 0.190 Moberg Pharma MOB 546 167% SEK28.7 -SEK0.3 Vectura VEC 113278 159% 125.3p -4.8p ANI Pharmaceuticals ANIP 15885 154% 25.550 -0.370 Evotec EVT 53727 150% €3.470 -€0.320 ThromboGenics THR 14164 139% €22.365 €3.485 Nicox COX 28004 137% €2.445 €0.037 It’s accurate. It’s trusted. Biotest BIO 793 137% €84.82 -€0.88 NeuroVive NVP 5282 131% SEK25.3 -SEK0.4 It delivers. BioGaia BIOG B 5818 120%SEK177.5 SEK8 1 Includes volume from London Stock Exchange Put the power of BioCentury’s team 2 Includes volume from Toronto Stock Exchange and 19 years of industry analysis and reporting behind your data solutions needs BioCentury 100 Advance-Decline Trend BC100 BC100 BC100 Get a Free BCIQ Trial Week Price Stocks Gaining Stocks Declining ended level gaining vol. (00) declining vol. (00) www.biocentury.com/bciq Mar 21 5412.73 35 4491667 65 5476357 Mar 28 4983.60 6 1066487 94 10070179 Intelligence you can trust. Apr 04 4876.60 30 5419770 70 6156391 Because biopharma is our business. Apr 11 4673.74 15 1267833 84 9963999 Apr 18 4734.53 68 5519292 32 2206461 REGISTER NOW

May 21 - 22, 2014 The Hilton Amsterdam Hotel 14 Amsterdam

INITIAL SLATE OF PANELS JUST ANNOUNCED

BioCentury/Ernst & Young Face-Off Bio€quity Europe's Face-Off returns for a 7th year with analysis and commentary from BioCentury's 12th annual survey of European financings needs and Ernst & Young's 28th Annual Beyond Borders Global Biotechnology Report. Panelists include: Dr. Siegfried Bialojan, Head, Life Science Center GmbH, Ernst & Young Arthur Franken, Partner, Gilde Healthcare Susan Schaeffer, Editor, BioCentury Berndt Modig, CFO, Prosensa Holding N.V.

Premier League Challenges Plenary 1 Premier League Challenges Plenary 2

This opening session will debate whether the U.S. is the Premier This parallel opening session asks where do European biotech drugs, League for raising money and what it takes to compete with diagnostics and tools stand on the league tables for differentiation U.S. companies for U.S. capital. Panelists include: and reimbursability on a global playing field? Panelists include: Jörn Aldag, CEO, uniQure N.V. Roel Bulthuis, Managing Director, MS Ventures Dr. Werner Lanthaler, CEO, Evotec AG Dr. Daniel Mahony, Portfolio Manager, Polar Capital Dr. Klaus Wilgenbus, SVP Business Development & Licensing/Strategy, Francesco de Rubertis, Managing Partner, Index Ventures Boehringer Ingelheim GmbH Antoine Papiernik, Managing Partner, Sofinnova Partners Elise Wang, Analyst, Deerfield Management

CEO Bootcamp #5 EMA Fireside Chat How do the Founders Stay in the C-suite?

The European Medicines Agency calls SMEs a "motor of innovation" For a fifth year, Bio€quity Europe provides core lessons for biotech in the EU. Hear from Dr. Jordi Llinares-Garcia — the EMA's Head of CEOs. This year's focus is on how top management skill sets Product Development Scientific Support Department and former change as a company matures. Panelists include: Head of Orphan Drugs at EMA — on how the agency acts as an "enabler" for smaller players, including academia, in the pharma- Matthieu Coutet, Managing Partner, Inserm Transfert Initiative ceutical innovation ecosystem. Dr. Hakan Goker, Partner, MS Ventures Dr. Deborah Harland, Partner, SROne Dr. Allan Marchington, Partner, Apposite Capital Dr. Carole Nuechterlein, Head, Roche Venture Fund

Plenary 1 Seminar International Fundraising: Crossing the Pond for a U.S. IPO — Buyside Q&A Advice from Dealmakers and Investors

This session offers practical advice from experienced dealmakers and Bio€quity Europe brings back the popular Buyside Q&A. These investors on market and regulatory issues in the U.S. Panelists intimate sessions with public investors from the U.S. and EU allow include: insight on what they look for in new issues. Panelists include:

Nathaniel Gardiner, Partner, Co-Chair of Life Sciences Group, Edwards Wildman Jonas Brambeck, Investment Manager, Industrifonden Neil Mackison, Managing Director, Head of European Healthcare, Piper Jaffray Kai Brüning, Senior Portfolio Manager, Apo Asset Management Ian Oliver, Senior Manager, Health Sciences, Biotech, Ernst & Young Saad Gilani, Head, Healthcare Investments, Yorkville Advisors Hans Schikan, CEO, Prosensa Holding N.V. Graziano Seghezzi, Partner, Sofinnova Partners

Click here for the expanded slate of Presenting Companies or go to www.biocentury.com/conferences

Gold Sponsors Ernst & Young MS Ventures Sofinnova Partners Silver Sponsors CLICK HERE Abingworth Gilde Healthcare Oxford Finance TO REGISTER AstraZeneca Index Ventures Piper Jaffray Boehringer Ingelheim Venture Fund Inserm Transfert Initiative Roche Venture Fund Edwards Wildman Johnson & Johnson Innovation Geller Biopharm LSP-Life Sciences Partners or go to Regional Host Committee www.biocentury.com Amsterdam BioMed Cluster/ Axon Euronext Amsterdam Economic Board Deloitte Van Campen Liem T E S  C S O F  D RD I

The rEVOLUTION Symposium has become the place to discuss the most important strategic problems facing pharma and biotech CSOs. We will examine the organization and management of R&D to uncover new disruptive discovery and development models and assess the continued impact of pricing, reimbursement, regulation, and globalization on our industry.

May 7 - 9, 2014 Mandarin Oriental, Boston 776 Boylston Street Boston, Massachusetts

Limited space remains for R&D Executives To inquire about invitations, please call 650-320-4529 For more information about rEVOLUTION, visit www.wsgr.com/news/revolution

Our speakers & advisors include some of the industry’s leading experts:

Julian Adams, Ph.D. Annalisa Jenkins, MBBS, MRCP Roger Pomerantz, M.D., FACP Infinity Pharmaceuticals Former Head of R&D Pomerantz Life Sciences Lee E. Babiss, Ph.D. Merck Serono Consulting Group Pharmaceutical Product Peter Lebowitz, M.D., Ph.D. John C. Reed, MD., Ph.D. Development Johnson & Johnson Roche Hal Barron, M.D., FACC Calico Roger Longman Norbert Riedel, Ph.D. Real Endpoints Naurex Francis Cuss, MB BChir, FRCP Bristol-Myers Squibb Martin Mackay, Ph.D. Bruce Roth, Ph.D. Alexion Pharmaceuticals Genentech Thomas Daniel, M.D. Celgene Tetsuyuki Maruyama, Ph.D. Elliott Sigal, M.D., Ph.D. Richard DiMarchi, Ph.D. Takeda Pharmaceutical New Enterprise Associates Indiana University Peter Mueller, Ph.D. Marc Tessier-Lavigne, Ph.D. Anthony Ford-Hutchinson, Ph.D. Vertex Pharmaceuticals The Rockefeller University Ford-Hutchinson Consulting Gary J. Nabel, M.D., Ph.D Steven Tregay, Ph.D. Steven Gilman, Ph.D. Sanofi Forma Therapeutics Cubist Pharmaceuticals José-Carlos Gutiérrez-Ramos, Ph.D. Michel Pairet, DVM, Ph.D. Robert Urban, Ph.D. Pfizer Boehringer Ingelheim Johnson & Johnson Innovation Center Michael R. Hayden, MBChB., Dhavalkumar Patel, M.D., Ph.D. Doug Williams, Ph.D. M.D., Ph.D., FRCPC Novartis Biogen Idec Teva Pharmaceuticals

Organized by: WEEK OF APRIL 21, 2014 BioCentury WEEK IN REVIEW

Volume 22 • Number 16 • Page B1 of 26 BioBusiness for the week ended April 18 Management Tracks (Page B8) COMPANY NEWS Using BioCentury Week in Review Astellas Pharma (Tokyo:4503) Dyax (NASDAQ:DYAX) Deals (Page B2) You can read Week in Review online every Monday at GNS Healthcare Acura (NASDAQ:ACUR)/Pfizer (NYSE:PFE) www.biocentury.com Harvard App Regen Tech (NASDAQ:HART) Heart Metabolics Adimmune (Taiwan:4142)/Valneva And you can set your own filters to Iconic Therap (Euronext:VLA; VSE:VLA) customize your personal summary of the Karyopharm Therap (NASDAQ:KPTI) Bio-Rad Labs (NYSE:BIO)/GnuBIO week's corporate, clinical and financial news. Bio-Techne (NASDAQ:TECH)/Shanghai Kite Pharma BioCentury Week in Review is a com- PrimeGene Bio-Tech Nora Therap prehensive compendium of business news BioAlliance (Euronext:BIO)/Topotarget PanOptica for management and investors in bioscience (CSE:TOPO) Tokai Pharma companies. It is organized into three depart- California Peptide Res/Frontier Scientific TransTech Pharma ments: Company News, Clinical News and California Stem Cell/NeoStem (NASDAQ:NBS) 23andMe Financial News. Changchun BCHT Biotech/Mucosis Wilson Therap The index on this page lists all the com- China Natl Pharma Group/Hutchison China WuXi PharmaTech (NYSE:WX) panies covered this week. The news items MediTech (LSE:HCM) in each department are organized alphabeti- Clovis Oncology (NASDAQ:CLVS)/Foundation CLINICAL NEWS cally by company. When more than one Medicine (NASDAQ:FMI) company is listed, the biotech company is Epirus Biopharma/Zalicus (NASDAQ:ZLCS) shown first. Each brief is labeled with one or Regulatory (Page B10) Eternity Healthcare (OTCQB:ETAH)/Kinexus more applicable business categories from Kineta/RLB Holdings Abbott (NYSE:ABT) the following list: Lead Disc Cntr/Daiichi Sankyo (Tokyo:4568) Abiogen Pharma ADMET; Agbio/Environmental; Antibod- MacroGenics (NASDAQ:MGNX)/PolyTherics Alimera (NASDAQ:ALIM)/pSivida (NASDAQ: ies; Autoimmune; Bioinformatics; Bioman- Moberg Pharma (SSE:MOB)/Oracain PSDV; ASX:PVA) ufacturing; Biopharmaceuticals; Biosimilars; Prosonix/Mylan (NASDAQ:MYL) ALK-Abello (CSE:ALK-B)/Merck (NYSE:MRK) Cancer; Cardiovascular; Chemistry; Combi- Qiagen (Xetra:QIA; NASDAQ:QGEN)/CeMM Almirall (Madrid:ALM)/Ironwood Pharma natorial biology; Computational chemistry/ Xencor (NASDAQ:XNCR)/Merck (NYSE: (NASDAQ:IRWD)/Astellas (Tokyo:4503)/ biology; Dental; Dermatology; Diagnostic; MRK) Forest Labs (NYSE:FRX)/AstraZeneca Drug delivery; Endocrine/Metabolic; Finance; (LSE:AZN; NYSE:AZN) Sales & Marketing (Page B5) Functional genomics; Gastrointestinal; Astellas (Tokyo:4503)/Ferring Pharma Gene/Cell therapy; Generics; Genitouri- Anika Therap (NASDAQ:ANIK)/J&J (NYSE:JNJ) AstraZeneca (LSE:AZN; NYSE:AZN) nary; Genomics; Hematology; Hepatic; High Dr. Reddy’s Labs (NYSE:RDY)/Teva Pharma Avita Medical (ASX:AVH) throughput screening; Infectious; Inflamma- (NYSE:TEVA) BioMarin Pharma (NASDAQ:BMRN)/Daiichi tion; Microarrays; Microfluidics; Musculosk- Mylan (NASDAQ:MYL) Sankyo (Tokyo:4568)/Merck KGaA (Xetra: eletal; Neurology; Nutraceuticals; Oph- MRK) Other News (Page B5) thalmic; Other; Pharmaceuticals; Pharmaco- Boehringer Ingelheim genetics; Proteomics; Pulmonary; Renal; Actavis (NYSE:ACT)/Apotex/Dr. Reddy’s Labs Boehringer Ingelheim/Eli Lilly (NYSE:LLY) Supply/Service; Transplant; Veterinary (NYSE:RDY)/Mylan (NASDAQ:MYL)/Or- Genmab (CSE:GEN; OTCBB:GMXAY)/ chid (BSE:524372; NSE:ORCHIDCHEM)/ GlaxoSmithKline (LSE:GSK; NYSE:GSK) Roche (SIX:ROG; OTCQX:RHHBY) Novartis (NYSE:NVS; SIX:NOVN) Gilead (NASDAQ:GILD) Astellas (Tokyo:4503)/U.S. Dept of Justice Pfizer (NYSE:PFE)/Teva Pharma (NYSE:TEVA) Gilead (NASDAQ:GILD)/Bristol-Myers Squibb Delaware State Senate Qiagen (Xetra:QIA; NASDAQ:QGEN) (NYSE:BMY) Federal Joint Committee Roslin Cells/Cell Therapy Catapult/Irish Blood GlaxoSmithKline (LSE:GSK; NYSE:GSK) Genentech/Novartis (NYSE:NVS; SIX:NOVN)/ Transfusion Svc/Loughborough U/NHSBT/ Guerbet (Euronext:GBT) Roche (SIX:ROG; OTCQX:RHHBY) SNBTS/Wellcome Trust/U of Glasgow/U of Myriad Genetics (NASDAQ:MYGN) J&J (NYSE:JNJ)/Scripps Res Inst Edinburgh Novo Nordisk (CSE:NVO; NYSE:NVO) Knight Therap (TSX-V:GUD)/Medicure (TSX- UnitedHealth (NYSE:UNH) Orion (HSE:ORNAV; HSE:ORNBV) V:MPH; Pink:MCUJF) Xenetic Bio (OTCBB:XBIO) Valeant (TSX:VRX; NYSE:VRX)/Meda (SSE: Lytix Bio/Pharmasum Therap Zogenix (NASDAQ:ZGNX) See next page BioCentury Week in Review APRIL 21, 2014 PAGE B2 OF 26

COMPANY NEWS/Deals, Sales & Marketing, Other News, Management Tracks

Acura. The biotech said it may re-launch Oxecta under a new brand DEALS name with a partner (see BioCentury, July 15, 2013). Acura said Pfizer reported about $250,000 in sales of Oxecta in Acura Pharmaceuticals Inc. (NASDAQ:ACUR), Palatine, Ill. 2013. FDA approved the drug in 2011, but Pfizer didn’t launch the drug Pfizer Inc. (NYSE:PFE), New York, N.Y. until early 2013 pending the receipt of FDA’s advice on promotional Business: Neurology materials. Pfizer gained rights to the products through its 2011 acqui- Pfizer returned rights to Oxecta oxycodone to Acura after the sition of King Pharmaceuticals Inc., which had rights from Acura under biotech terminated a 2007 deal granting the pharma North American a 2007 deal (see BioCentury, Nov. 5, 2007 & Oct. 1, 2012). rights to the pain drug and Acura’s Aversion abuse-deterrent technology. On a conference call discussing the termination, Acura said the Adimmune Corp. (Taiwan:4142), Taichung City, Taiwan pharma’s commercial organization “never provided much support to Valneva SE (Euronext:VLA; VSE:VLA), Lyon, France the product after Pfizer de-prioritized its immediate-release opioid Business: Infectious portfolio commencing in 2012.” Acura will make a one-time payment Valneva granted vaccine manufacturer Adimmune rights to develop of $2 million for the termination. Neither company will have royalty and commercialize Valneva’s Japanese Encephalitis (JE) vaccine in Tai- obligations to the other going forward. Acura said it is evaluating its wan. Adimmune will be responsible for obtaining regulatory approval strategic options for the product and other pain products developed using the Aversion technology that the pharma returned last year to See next page

Regulatory, Regulus Therap (NASDAQ:RGLS) Cel-Sci (NYSE-M:CVM) from previous page Seattle Genetics (NASDAQ:SGEN) Cynapsus Therap (TSX:CTH) TherapeuticsMD (NYSE-M:TXMD) Epirus Bio MEDAA)/GlaxoSmithKline (LSE:GSK; Eventus Diagnostics Clinical Status (Page B19) NYSE:GSK) ForSight Vision5 Abbott Labs (NYSE:ABT) Galapagos (Euronext:GLPG; Pink:GLPYY) Clinical Results (Page B12) AbbVie (NYSE:ABBV) Heart Metabolics Auris Med Acorda (NASDAQ:ACOR)/Alkermes Iconic Therap Baxter Intl (NYSE:BAX) (NASDAQ:ALKS)/Biogen Idec (NASDAQ: Knight Therap (TSX-V:GUD) BerGenBio/Rigel Pharma (NASDAQ:RIGL) BIIB) Lorus Therap (TSX:LOR; Pink:LRUSF) BHV Pharma/Kissei Pharma (Tokyo:4547) Agios Pharma (NASDAQ:AGIO) Mucosis Celgene (NASDAQ:CELG)/Clovis Oncology Akebia Therap (NASDAQ:AKBA) Nexvet Biopharma (NASDAQ:CLVS) Aprea Nora Therap Cynapsus Therap (TSX:CTH) Bayer (Xetra:BAYN)/J&J (NYSE:JNJ) Northwest Bio (NASDAQ:NWBO) Cytos Bio (SIX:CYTN) BioAlliance Pharma (Euronext:BIO) OxSyBio DelMar Pharma (OTCBB:DMPI)/Guangxi Capstone Therap (NASDAQ:CAPS)/LipimetiX OxThera Wuzhou Zhongheng (Shanghai:600252) Coronado Bio (NASDAQ:CNDO) PanOptica Galapagos (Euronext:GLPG; Pink:GLPYY)/ Critical Pharma Provista Diagnostics GlaxoSmithKline (LSE:GSK; NYSE:GSK) Dicerna Pharma (NASDAQ:DRNA) Sorrento Therap (NASDAQ:SRNE) Genentech/Chugai (Tokyo:4519)/Roche Dynavax (NASDAQ:DVAX) SQI Diagnostics (TSX-V:SQD) (SIX:ROG; OTCQX:RHHBY) Endo Intl (NASDAQ:ENDP; TSX:ENL)/Aeolus Vital Therap (NASDAQ:VTL) Genocea Bio (NASDAQ:GNCA)/Novavax (OTCQB:AOLS)/Arca (NASDAQ:ABIO)/ Wilson Therap (NASDAQ:NVAX) Medtronic (NYSE:MDT) Zafgen GlaxoSmithKline (LSE:GSK; NYSE:GSK) Karyopharm Therap (NASDAQ:KPTI) Proposed Offerings (Page B26) Lexicon Pharma (NASDAQ:LXRX) PanOptica/Astellas (Tokyo:4503) Oncoethix/Mitsubishi Tanabe (Tokyo:4508) Repros Therap (NASDAQ:RPRX) Angion Biomedica Pharmanest Spectral (TSX:SDI; OTCQX:DIAGF) Synta Pharma (NASDAQ:SNTA) Sorrento Therap (NASDAQ:SRNE) StemCells (NASDAQ:STEM) Vyrix Pharma Ultragenyx Pharma (NASDAQ:RARE) Theravance (NASDAQ:THRX) Zafgen UCB (Euronext:UCB)/Wilex (Xetra:WL6) Preclinical Results (Page B18) Amended Offerings (Page B26) VentiRx Pharma Blueprint Med Mapi-Pharma Celldex Therap (NASDAQ:CLDX) FINANCIAL NEWS Microlin Bio Genkyotex Quotient MacroGenics (NASDAQ:MGNX) Completed Offerings (Page B24) Withdrawn Offerings (Page B26) NanoAntibiotics OncoMed Pharma (NASDAQ:OMED) AAVLife Foundation Med (NASDAQ:FMI) Onconova Therap (NASDAQ:ONTX) Antibe Therap (TSX-V:ATE) Other Financial News (Page B26) OxiGene (NASDAQ:OXGN) Benitec Biopharma (ASX:BLT) Column Group BioCentury Extra: Online every business day. Relypsa (NASDAQ:RLYP) BioCentury Week in Review APRIL 21, 2014 PAGE B3 OF 26

Deals, for oropharyngeal candidiasis. Sitavig is a mucoadhesive formulation of from previous page acyclovir, and Oravig is a mucoadhesive buccal tablet of miconazole. BioAlliance had 2013 sales of €1.5 million ($2 million), while Topotarget in the country and will market the vaccine under a local brand name. had DKK8.3 million ($1.5 million) in revenues for the year. The boards Novartis AG (NYSE:NVS; SIX:NOVN, Basel, Switzerland) has rights to of both companies have approved the deal, which is still subject to market Valneva’s JE vaccine worldwide, excluding Australia, Korea, BioAlliance and Topotarget shareholder approval. The deal is slated to Japan and other Asian markets. Novartis markets the vaccine as Ixiaro. close in July or August. Centerview Partners and Nordea are financial The bioCSL (formerly CSL Biotherapies) subsidiary of CSL Ltd. (ASX:CSL, advisors to BioAlliance, and Bech Bruun is the company’s legal advisor. Melbourne, Australia) markets the vaccine as Jespect in Australia and ABG Sundal Collier is financial advisor to Topotarget, and Kromann New Zealand. The product has Orphan Drug designation in the U.S. Reumert and Dechert are the company’s legal advisors. Valneva said the companies are not disclosing additional details, and Adimmune could not be reached. California Peptide Research Inc., Napa, Calif. Frontier Scientific Inc., Logan, Utah Bio-Rad Laboratories Inc. (NYSE:BIO), Hercules, Calif. Business: Supply/Service GnuBIO Inc., Cambridge, Mass. In January, Frontier’s Echelon Biosciences Inc. subsidiary acquired Business: Genomics California Peptide Research for an undisclosed amount. California Tool supplier Bio-Rad acquired GnuBIO for an undisclosed sum. Peptide Research, which manufactures biochemicals and research GnuBIO’s droplet-based DNA sequencing technology uses microfluidic peptides for pharmaceutical and R&D companies, will relocate opera- and emulsion technology to perform multiplexed reactions in droplets. tions to Salt Lake City, Utah, where Echelon is based. Echelon develops In 2012, GnuBIO received a three-year, $4.5 million grant from the biochemicals, assays and reagents for research in cancer, inflammation, National Human Genome Research Institute to develop technology neurobiology and metabolism. Echelon declined to disclose sales that could reduce the cost of whole-genome sequencing to less than figures for California Peptide Research. $1,000. Bio-Rad said the technology is “well-suited for the clinical diagnostics sequencing market,” but did not provide additional details California Stem Cell Inc., Irvine, Calif. in time for publication (see BioCentury, Sept. 24, 2012). NeoStem Inc. (NASDAQ:NBS), New York, N.Y. Business: Cancer, Gene/Cell therapy Bio-Techne (NASDAQ:TECH), Minneapolis, Minn. NeoStem will acquire stem cell company California Stem Cell for 5.3 Shanghai PrimeGene Bio-Tech Co., Shanghai, China million shares, or about $34.1 million based on NeoStem’s close of Business: Supply/Service $6.40 on April 11, before the deal was announced. California Stem Cell Bio-Techne’s R&D Systems China Co. Ltd. subsidiary will acquire is also eligible for up to $90 million in milestones and royalties, payable PrimeGene in a cash deal slated to close this quarter. PrimeGene in cash or shares. This year, NeoStem plans to start a U.S. Phase III trial develops and commercializes in China recombinant proteins for re- with melapuldencel-T to treat metastatic melanoma, for which the search and diagnostic applications. R&D Systems develops and manu- product has Fast Track and Orphan Drug designation in the U.S. factures purified cytokines, antibodies, immunoassays and biologically California Stem Cell, which had planned to start the trial next month, active small molecules. Bio-Techne said the acquisition expands its has an SPA from FDA for the trial. The product is a tumor cell-specific regional manufacturing capabilities and adds over 400 new protein dendritic cell therapy and will be NeoStem’s most advanced product. products to its product portfolio. PrimeGene had product sales of NeoStem said the purpose of the acquisition is to add a late stage asset about $4 million in 2013, and Bio-Techne reported net sales of $169.7 to their portfolio. million for the six months ended Dec. 31, 2013. Bio-Techne declined California Stem Cell is eligible for a $7.5 million milestone upon to disclose financial terms, and PrimeGene could not be reached. completion of enrollment in the Phase III trial; a $10 million milestone upon FDA approval of a BLA for melapuldencel-T for melanoma; a $5 BioAlliance Pharma S.A. (Euronext:BIO), Paris, France million milestone upon approval of the product in Europe for mela- Topotarget A/S (CSE:TOPO), Copenhagen, Denmark noma; a $2.5 million milestone for the start of a Phase II trial evaluating Business: Cancer, Infectious the product for a second oncology indication; a $2.5 million payment Cancer companies BioAlliance and Topotarget will merge in a stock for completion of enrollment in a Phase II trial evaluating the product deal to create a company focused on Orphan cancers. Topotarget for a second indication; a $2.5 million milestone payment for comple- shareholders will receive two shares of the combined company for tion of enrollment in a Phase III trial evaluating the product for a second every 27 Topotarget shares held. Topotarget shareholders will own indication; a $5 million milestone for FDA approval of a second about a third of the combined company, and BioAlliance shareholders oncology indication; and up to three additional $2.5 million milestones will own the balance. BioAlliance CEO Judith Greciet will be CEO of per approval of a subsequent indication. California Stem Cell is also the combined company, which will retain BioAlliance’s name and will eligible for a 35% royalty on net profit up to a total payment of $50 be dual listed on Euronext and NASDAQ OMX. BioAlliance Chairman million. The deal is slated to close next month. Piper Jaffray served as Patrick Langlois will be chairman of the combined company. financial advisor to California Stem Cell, and K&L Gates was the Topotarget’s Beleodaq belinostat is under Priority Review by FDA company’s legal advisor. Lowenstein Sandler was legal advisor to for relapsed or refractory peripheral T cell lymphoma (PTCL), with an NeoStem. Aug. 9 PDUFA date. Spectrum Pharmaceuticals Inc. (NASDAQ:SPPI, Henderson, Nev.) has North American and Indian rights to the small Changchun BCHT Biotechnology Co., Changchun, China molecule histone deacetylase (HDAC) inhibitor from Topotarget. Mucosis B.V., Groningen, the Netherlands BioAlliance’s pipeline includes Livatag doxorubicin Transdrug (BA- Business: Infectious 003). The nanoparticle formulation of doxorubicin is in a Phase III trial Changchun received exclusive, Chinese rights and non-exclusive for hepatocellular carcinoma (HCC), with data expected in 2016. rights in other undisclosed Asian countries to Mucosis’ SynGEM BioAlliance also has two approved non-cancer products: Sitavig acyclovir respiratory syncytial virus (RSV) vaccine and Mimopath technology for Lauriad for recurrent orofacial herpes; and Oravig/Loramyc miconazole See next page BioCentury Week in Review APRIL 21, 2014 PAGE B4 OF 26

Deals, mune drug Remicade infliximab from Johnson & Johnson (NYSE:JNJ, from previous page New Brunswick, N.J.) and Merck & Co. Inc. (NYSE:MRK, Whitehouse Station, N.J.). Early next year, Epirus plans to start a European Phase III undisclosed disease targets. Changchun will make an equity investment trial of BOW-015. The company submitted a regulatory application for in Mucosis, which is also eligible for milestone payments, plus royalties. BOW-015 in India in November and in January said it would submit Mucosis declined to disclose details, and Changchun could not be applications in “targeted emerging markets” over the next 12 months. reached. The Mimopath technology is based on the Lactococcus lactis Zalicus’ only clinical-stage product is Z944, a T-type calcium channel bacteria, which Mucosis formulates into non-living bacterium-like blocker that has completed Phase I testing for pain. 5AM Ventures’ Scott particles (BLPs) that can be loaded with antigens. SynGEM is comprised Rocklage, an Epirus director, said Epirus does not plan on continuing of BLP-based Mimopath technology carrying trimeric fusion proteins internal development of Z944 but may out-license the product. and is in preclinical testing. The boards of both companies have approved the deal, which is subject to approval by shareholders of both companies. The deal is China National Pharmaceutical Group Corp. (Sinopharm), slated to close this summer. Leerink is financial advisor to Epirus, and Beijing, China Latham & Watkins is the company’s legal advisor. Wedbush PacGrow Hutchison China MediTech Ltd. (LSE:HCM), Hong Kong, China is financial advisor to Zalicus, and Goodwin Proctor is the company’s Business: Supply/Service legal advisor. Hutchison China MediTech (Chi-Med) said it and Sinopharm’s Sinopharm Group Co. Ltd. (HKSE:1099, Shanghai, China) subsidiary Eternity Healthcare Inc. (OTCQB:ETAH), Vancouver, B.C. received regulatory approval in China to establish their JV, Hutchison Kinexus Bioinformatics Corp., Vancouver, B.C. Whampoa Sinopharm Pharmaceuticals Co. Ltd. In December, Chi-Med Business: Diagnostic said it would invest about $9.8 million in cash for a 51% stake in Eternity signed a letter of intent to receive an exclusive, worldwide Sinopharm Group’s Sinopharm Holding Huyong Pharmaceutical Co. license to protein kinases technology from Kinexus’ Kinexus Ltd. subsidiary. The renamed entity will begin operations as a subsidiary Theranostics therapeutic arm to develop and commercialize a test for under Chi-Med’s China Healthcare division on April 25. Hutchison early detection of diabetes. Eternity will own the resulting IP. Kinexus Whampoa Sinopharm will provide sales, distribution and marketing will be eligible for milestones and 1.5% royalties on net sales of the services to major Chinese and multinational third-party pharmaceutical developed product. Eternity said it believes that a test measuring manufacturers. The company will also provide a sales and marketing pancreas function or insulin uptake using kinases may detect diabetes platform for products from the partners (see BioCentury, Jan. 6). years earlier than current tests which measure blood glucose levels. The companies could not be reached in time for additional details. Clovis Oncology Inc. (NASDAQ:CLVS), Boulder, Colo. Foundation Medicine Inc. (NASDAQ:FMI), Cambridge, Mass. Kineta Inc., Seattle, Wash. Business: Pharmacogenetics RLB Holdings, Greenwich, Conn. Foundation Medicine and Clovis expanded a 2012 deal to develop Business: Autoimmune a companion diagnostic for Clovis’ rucaparib. Clovis said the expanded Kineta and investment fund RLB formed JV Kineta RLB LLC to deal incorporates the development of a PMA submission. Foundation develop Kineta compounds, with an initial focus on autoimmune Medicine will build a dedicated laboratory to support development and diseases. The partners provided undisclosed funding to the JV and are FDA approval of the companion diagnostic and is eligible for undis- equal partners, according to Kineta. Kineta’s business model involves closed milestones. Clovis expects Foundation Medicine to submit a partnering its assets at the end of Phase I, and the company doesn’t PMA to FDA in 2017. Clovis also plans to submit an NDA to FDA for currently have the ability to enter a co-development partnership. The rucaparib at the same time to treat platinum-sensitive ovarian cancer. company said that the JV allows for a broader range of partnership The company expects data from the Phase III ARIEL3 trial evaluating options, which may have greater appeal to partners and Kineta’s rucaparib for the indication in 2017. The companies said financial terms investors, which includes RLB. Craig Phillips will be president of Kineta were not disclosed. RLB, while remaining EVP of commercial operations at Kineta. RLB In 2012, the companies partnered to identify biomarkers to develop could not be reached for details. companion diagnostics to select patients likely to respond to rucaparib, Kineta’s lead compound is ShK-186, a synthetic peptide that inhibits an oral inhibitor of poly(ADP-ribose) polymerase-1 (PARP-1) and potassium channel Kv1.3 (KCNA3) that is in Phase Ic testing to treat PARP-2. Clovis has exclusive, worldwide rights to develop and com- psoriatic arthritis, with data expected by year end. Kineta licensed the mercialize rucaparib from Pfizer Inc. (NYSE:PFE, New York, N.Y.), compound from Airmid Inc. (Redwood City, Calif.) in 2009 (see BioCentury, which received rights from Cancer Research UK (London, U.K.) (see July 13, 2009). BioCentury, June 6, 2011 & Aug. 13, 2012). Lead Discovery Center GmbH (LDC), Dortmund, Germany Epirus Biopharmaceuticals Inc., Boston, Mass. Daiichi Sankyo Co. Ltd. (Tokyo:4568), Tokyo, Japan Zalicus Inc. (NASDAQ:ZLCS), Cambridge, Mass. Business: Cancer, Cardiovascular, Endocrine/Metabolic Business: Autoimmune, Biosimilars Daiichi and LDC partnered to discover treatments for cancer, Biosimilar company Epirus will reverse-merge with Zalicus in a cardiovascular and metabolic diseases. Under the initial two-year deal, stock deal. The combined, publicly traded company will retain Epirus’ LDC will identify novel targets from its pan-European network of name and focus on biosimilars. Epirus President and CEO Amit Munshi universities and research organizations. LDC will then screen targets will be president and CEO, and Zalicus President and CEO Mark selected by Daiichi using a library of 200,000 compounds from LDC and Corrigan will be chairman. Epirus shareholders will own 81-86% of the 70,000 compounds from Daiichi. LDC will be responsible for assay combined company, and Zalicus shareholders will own the balance, development and hit validation, and Daiichi will provide research depending on Zalicus’ net cash when the deal closes. At Dec. 31, 2013, funding. For each project, Daiichi will have a “preferred option” to Zalicus (formerly CombinatoRx Inc.) had $18 million in cash. enter in a follow-up discovery deal with LDC to jointly develop Epirus’ lead product is BOW-015, a biosimilar version of autoim- See next page BioCentury Week in Review APRIL 21, 2014 PAGE B5 OF 26

Deals, myeloproliferative neoplasms could help treat the disease. The parties from previous page declined to disclose details. compounds up to the stage of a pharmaceutical lead. The partners could Xencor Inc. (NASDAQ:XNCR), Monrovia, Calif. not be reached for details. LDC spun out from Max Planck Innovation Merck & Co. Inc. (NYSE:MRK), Whitehouse Station, N.J. GmbH (Munich, Germany). Business: Antibodies Xencor received an undisclosed milestone payment from Merck MacroGenics Inc. (NASDAQ:MGNX), Rockville, Md. under a 2013 deal granting the pharma non-exclusive rights to a patent PolyTherics Ltd., London, U.K. covering Fc engineering methods for use in an undisclosed therapeutic Business: Antibodies mAb. The payment was triggered by the start of a Phase I trial of the mAb PolyTherics and MacroGenics extended a 2010 deal to develop that uses Xencor’s XmAb antibody platform IP. Xencor declined to antibody-drug conjugates (ADCs). Under the extension, PolyTherics disclose details, and Merck could not be reached (see BioCentury, July 15, will apply its ThioBridge linker technology to attach different cytotoxic 2013). payloads to a range of bispecific antibodies from MacroGenics’ Dual- Affinity Re-Targeting (DART) platform. Under the original deal, SALES & MARKETING PolyTherics used its TheraPEG technology to extend the half-life of the DART antibodies. PolyTherics said the extended deal now covers a Anika Therapeutics Inc. (NASDAQ:ANIK), Bedford, Mass. wider range of antibodies from MacroGenics’ platform and now in- Johnson & Johnson (NYSE:JNJ), New Brunswick, N.J. cludes application of the ThioBridge linker technology. MacroGenics Business: Autoimmune has an option to license the ThioBridge technology to develop resulting Anika said its U.S. commercialization partner, the DePuy Synthes antibodies. PolyTherics is eligible for undisclosed milestones, plus Mitek Sports Medicine division of Johnson & Johnson’s DePuy Ortho- single-digit percentage royalties. PolyTherics declined to disclose pedics Inc. subsidiary, launched Monovisc for osteoarthritis (OA) in the additional details, and MacroGenics could not be reached. U.S. The launch triggered a $5 million milestone payment to Anika, which is eligible to receive additional performance and sales threshold Moberg Pharma AB (SSE:MOB), Bromma, Sweden milestones, plus royalties. FDA approved the product in February to Oracain ApS, Lyngby, Denmark treat pain and improve joint mobility in patients with OA of the knee. Business: Neurology Monovisc, a single injection product that delivers hyaluronic acid from Moberg received exclusive worldwide rights to develop and com- a non-animal source, is marketed in Canada, the EU and several mercialize Oracain’s lozenge formulation of bupivacaine to treat oral countries in the Middle East and Asia. Anika declined to disclose details, pain. Moberg plans to initially focus development to treat oral mucositis and DePuy could not be reached (see BioCentury, March 3). and plans to start a Phase II trial this year. Oracain will receive SEK1 million ($152,801) up front and is eligible for SEK5 million ($764,001) Dr. Reddy’s Laboratories Ltd. (NYSE:RDY), Hyderabad, India after “successful” Phase II data have been generated. Oracain is also Teva Pharmaceutical Industries Ltd. (NYSE:TEVA), Petah Tikva, eligible to receive a share of future revenues after the revenues have Israel exceeded Moberg’s development costs prior to launch. Business: Neurology Dr. Reddy’s and Teva launched in the U.S. generic versions of Prosonix Ltd., Oxford, U.K. eszopiclone to treat insomnia. The Sunovion Pharmaceuticals Inc. Mylan Inc. (NASDAQ:MYL), Canonsburg, Pa. subsidiary of Dainippon Sumitomo Pharma Co. Ltd. (Tokyo:4506, Business: Inflammation, Generics Osaka, Japan) markets the non-benzodiazepine cyclopyrrolone GABA Mylan received rights to market Prosonix’s generic versions of receptor modulator as Lunesta. Dainippon reported $432 million in asthma product Flixotide/Flovent from GlaxoSmithKline plc (LSE:GSK; North American sales for Lunesta for the nine months ending Dec. 31, NYSE:GSK, London, U.K.) in several regions, including the U.S., EU, 2013. Dr. Reddy’s declined to disclose details, and Teva could not be Canada and Japan. Prosonix’s generics — PSX1001 and PSX1050 — are reached. formulations of fluticasone monotherapy in pressurized metered-dose inhalers. Prosonix plans to submit an MAA to EMA for PSX1001 this year Mylan Inc. (NASDAQ:MYL), Canonsburg, Pa. based on in vitro equivalence data. PSX1050 is the same formulation of Business: Endocrine/Metabolic, Generics fluticasone as PSX1001 but the inhaler includes a dose counter. Prosonix Mylan’s Mylan Pharmaceuticals Inc. subsidiary launched in the U.S. and Mylan are not disclosing further details. GSK reported £796 million a generic version of transdermal contraceptive patch Ortho Evra ($1.3 billion) in 2013 worldwide sales of Flixotide/Flovent. norelgestromin/ethinyl estradiol from Johnson & Johnson (NYSE:JNJ, New Brunswick, N.J.). Mylan will market the generic, which it said is Qiagen N.V. (Xetra:QIA; NASDAQ:QGEN), Venlo, the Netherlands the first for Ortho Evra, as Xulane. Ortho Evra’s wholesale acquisition CeMM Research Center for Molecular Medicine of the Austrian cost per patch is $36.74, with one patch worn each week for the first Academy of Sciences, Vienna, Austria three weeks of 28-day cycles. J&J does not break out Ortho Evra sales. Business: Diagnostic Mylan could not be reached for details. CeMM granted Qiagen an exclusive, worldwide license to the calreticulin (CALR) biomarker. Qiagen plans to use the biomarker to OTHER NEWS develop a CALR diagnostic to aid in prognostic profiling and disease management of myeloproliferative neoplasms. Qiagen said CALR mu- Actavis plc (NYSE:ACT), Dublin, Ireland tations are found in about 15% of cases of myeloproliferative neo- Apotex Inc., Toronto, Ontario plasms. Last December, CeMM reported that myeloproliferative neo- Dr. Reddy’s Laboratories Ltd. (NYSE:RDY), Hyderabad, India plasms patients with CALR mutations have milder forms of the disease Mylan Inc. (NASDAQ:MYL), Canonsburg, Pa. than patients with Janus kinase-2 (JAK-2) V617F mutations and that Orchid Chemicals & Pharmaceuticals Ltd. (BSE:524372; genetic studies suggest neutralizing CALR mutations associated with See next page BioCentury Week in Review APRIL 21, 2014 PAGE B6 OF 26

Other News, The move comes after legislation that includes eliminating the assess- from previous page ments came into effect April 1. G-BA had suspended in December 2013 planned and ongoing assessments of drugs that were launched before NSE:ORCHIDCHEM), Chennai, India January 2011 after the legislation was introduced. G-BA said it will Roche (SIX:ROG; OTCQX:RHHBY), Basel, Switzerland destroy dossiers that have already been submitted. The legislation, Business: Musculoskeletal which does not affect assessments that have already been completed, The U.S. Court of Appeals for the Federal Circuit reaffirmed a lower also extends Germany’s drug pricing freeze — which sets drug prices court’s decision and found invalid claims related to once-monthly oral at 2009 levels — through Dec. 31, 2017, and sets the country’s administration of Roche’s Boniva ibandronate to treat osteoporosis. mandatory drug rebates at 7%. In Hoffmann-La Roche Inc. et al. vs. Apotex et al., the court upheld a 2012 ruling of the U.S. District Court for the District of New Jersey Genentech Inc., South San Francisco, Calif. invalidating eight claims of U.S. Patent No. 7,718,634 and 10 claims of Novartis AG (NYSE:NVS; SIX:NOVN), Basel, Switzerland U.S. Patent No. 7,410,957. Roche argued that previous studies showing Roche (SIX:ROG; OTCQX:RHHBY), Basel, Switzerland intermittent and daily ibandronate treatment were equally effective had Business: Ophthalmic focused on bone mass density (BMD) instead of reducing fracture risk. Roche and Novartis confirmed French authorities began an inves- However, the court said BMD is a “powerful surrogate” for measuring tigation relating to Lucentis ranibizumab and Avastin bevacizumab. The fracture risk and thus the studies “established at least a reasonable French Competition Authority said in a statement that it raided expectation” of success of the once-monthly regimen. The court also companies suspected of anticompetitive practices in marketing wet found that the 150 mg dose of Boniva was obvious because previous age-related macular degeneration (AMD) drugs. Roche and Novartis studies showed that the efficacy of ibandronate depends on the total said they are cooperating with the authorities but did not disclose dose administered over a given period and not the amount administered specific next steps. Last month, the Italian Competition Authority fined at any single point in time. Thus, the court said it was reasonable to Novartis €92 million ($127.8 million) and Roche €90.5 million ($125.8 expect a once-monthly 150 mg dose would have similar efficacy to a daily million) after investigating alleged anticompetitive practices between 5 mg dose shown to be effective in previous studies. the pharmas regarding the sale of Lucentis and Avastin (see BioCentury, Roche filed suit against Actavis, Apotex, Dr. Reddy’s, Mylan and March 17). Orchid in the U.S. District Court for the District of New Jersey alleging Novartis has rights to Lucentis, a humanized mAb fragment against patent infringement after the companies submitted ANDAs to FDA for VEGF-A, outside North America from the Genentech unit of Roche. generic versions of Boniva. Roche markets oral and IV formulations of Lucentis is approved in the EU to treat wet AMD and visual impairment Boniva to treat osteoporosis in postmenopausal women and an oral due to diabetic macular edema (DME) and due to central retinal vein formulation to prevent osteoporosis in postmenopausal women. occlusion (RVO). The drug is also approved in the EU to treat visual Roche reported CHF208 million ($233.7 million) in 2013 worldwide impairment due to choroidal neovascularization (CNV) secondary to sales of the bisphosphonate that inhibits osteoclast-mediated bone pathologic myopia. Roche’s Avastin, a humanized mAb against VEGF, is resorption. The company could not be reached for next steps. approved for certain cancers and is used off label as a cheaper alternative to Lucentis for wet AMD and DME. Astellas Pharma Inc. (Tokyo:4503), Tokyo, Japan U.S. Department of Justice, Washington, D.C. Johnson & Johnson (NYSE:JNJ), New Brunswick, N.J. Business: Infectious The Scripps Research Institute, La Jolla, Calif. Astellas will pay $7.3 million to the U.S. Department of Justice to Business: Other resolve civil claims alleging off-label promotion of antifungal drug The institute launched Scripps Advance to identify and invest in early Mycamine micafungin. The DoJ investigated the pharma for off-label stage biomedical research projects. Under the initiative, Scripps Ad- promotion of the product for pediatric use prior to approval for the vance will partner with pharmas to select and fund projects from the population. Last June, FDA approved an sNDA for Mycamine to treat institute and other academic sources, with the goal of spinning out the pediatric patients ages four months or older. Roche (SIX:ROG; programs into single-asset companies. Todd Huffman, president of OTCQX:RHHBY, Basel, Switzerland) co-promotes Mycamine in the Scripps Advance, said selected projects will receive amounts “compa- U.S. The product is an echinocandin that inhibits beta 1,3-D-glucan rable to seed funding.” Huffman is also head of new ventures and synthase and thus interferes fungal cell wall synthesis. The pharmas do director of drug discovery partnerships at the institute. He said Scripps not break out sales for Mycamine (see BioCentury, July 1, 2013). Advance does not have a target number of companies with which it is aiming to partner. Delaware State Senate, Dover, Del. Scripps Advance’s first pharma partner is the Johnson & Johnson Business: Biosimilars California Innovation Center. J&J said selected projects may be co- The Delaware State Senate passed a bill that authorizes pharmacists funded by Scripps or by other pharmas, and that the collaboration will to substitute an FDA-approved interchangeable biosimilar for a pre- focus on J&J’s areas of strategic interest, including oncology, immunol- scribed biological product. The bill would allow substitution if the ogy, neuroscience, cardiovascular/metabolic and infectious disease pharmacist provides notice, records information on the label and indications. dispensation record and maintains a three-year record of such substi- The first company to come out of Scripps Advance is Padlock tutions. The bill has been referred to the Delaware House of Repre- Therapeutics, which is developing autoimmune therapies against peptidyl sentatives Health & Human Development Committee. arginine deiminase (PADI; PAD). Atlas Venture funded Padlock, but Huffman declined to disclose details. Huffman is a co-founder of Federal Joint Committee (G-BA), Berlin, Germany Padlock. J&J established Johnson & Johnson Innovation LLC to identify Business: Pharmaceuticals and accelerate development of early stage life science innovations. G-BA formally ended assessments of drugs that were launched California Innovation Center is part of the division. before January 2011, when drug pricing law AMNOG came into effect. See next page BioCentury Week in Review APRIL 21, 2014 PAGE B7 OF 26

Other News, proposed closure of the site, which affects up to 371 roles. The board from previous page approved the closure in February (see BioCentury, Nov. 11, 2013).

Knight Therapeutics Inc. (TSX-V:GUD), Westmount, Quebec Pfizer Inc. (NYSE:PFE), New York, N.Y. Medicure Inc. (TSX-V:MPH; Pink:MCUJF), Winnipeg, Manitoba Teva Pharmaceutical Industries Ltd. (NYSE:TEVA), Petah Tikva, Business: Cardiovascular Israel Medicure hired Knight as an advisor to advance the company’s U.S. Business: Autoimmune, Neurology, Generics specialty pharmaceutical business and “corporate development initia- Teva received rights to launch a generic version of Pfizer’s Celebrex tives.” Medicure has rights from Merck & Co. Inc. (NYSE:MRK, celecoxib for pain and autoimmune indications after the parties settled a Whitehouse Station, N.J.) to Aggrastat tirofiban in the U.S., where it 2013 suit under which Pfizer alleged that an ANDA from Teva seeking to markets the non-peptide integrin alpha(2b)beta(3) (GPIIb/IIIa; CD41/ market the generic infringed reissued U.S. Patent No. RE44048. Pfizer said CD61) antagonist in combination with heparin to treat acute coronary that the settlement includes a license allowing Teva to launch its generic syndrome (ACS), including patients who are to be managed medically in the U.S. in December 2014 and that under certain conditions Pfizer and those undergoing percutaneous transluminal angioplasty (PTCA) would be eligible to receive royalties through Dec. 2, 2015, which is when or atherectomy. At Feb. 28, Medicure had C$44,774 ($40,225) in cash the ‘048 patent expires. Pfizer said that additional terms of the settlement and a nine-month net loss of C$902,404 ($810,720). Knight declined to are confidential, and Teva could not be reached for comment. provide further details, and Medicure could not be reached. Pfizer also said it plans to continue its defense of the ‘048 patent, Knight is owned by the former Paladin Labs Inc. shareholders and which it maintains is valid and properly granted. Earlier this year, the was created to house Paladin’s Impavido miltefosine after Endo Inter- U.S. District Court for the Eastern District of Virginia granted summary national plc (NASDAQ:ENDP; TSX:ENL, Dublin, Ireland) acquired judgment invalidating the reissue of the patent for obviousness-type Paladin. FDA approved Impavido to treat cutaneous, mucosal and double patenting. The U.S. Patent and Trademark Office (PTO) reissued visceral leishmaniasis last month. The alkylphosphocholine analog that the patent in March 2013, extending the original May 30, 2014, expira- inhibits cholinephosphate cytidyltransferase is also approved for leish- tion date to Dec. 2, 2015. Celebrex, a cyclooxygenase-2 (COX-2) maniasis in Europe, India and Central and South America (see BioCentury, inhibitor, had 2013 worldwide revenues of $2.9 billion (see BioCentury, Nov. 11, 2013 & March 24, 2014). March 18, 2013 & March 17, 2014).

Lytix Biopharma A/S, Tromso, Norway Qiagen N.V. (Xetra:QIA; NASDAQ:QGEN), Venlo, the Netherlands Pharmasum Therapeutics A/S, Tromso, Norway Business: Diagnostic Business: Neurology Qiagen said it will close its site in Gaithersburg, Md., by early 2015 Infectious disease and cancer company Lytix spun out Pharmasum and move activities to its facilities in Germantown, Md. The company to develop PST-900, a dual-specificity tyrosine-(Y)-phosphorylation also said it will invest an additional $10 million to upgrade its facilities regulated kinase 1A (DYRK1A) inhibitor to treat dementia. Pharmasum in Frederick, Md., and Germantown, which will become the manufac- hopes to move the discovery-stage compound into the clinic in 2016. turing site for some of its highest-volume diagnostic assays, including Pharmasum will be led by CEO Anders Fugelli and CSO John Svendsen. the Digene HC2 HPV DNA test, an HPV-based cervical cancer screening Fugelli was Lytix’s head of business development and commercializa- test. The company also plans to move manufacturing to Germantown tion, and Svendsen was head of exploratory research. The company is for its QuantiFERON-TB Gold test for latent tuberculosis. looking to raise £2 million ($3.3 million). Qiagen said the investment brings to $50 million the amount it has Lytix said dementia is not within the company’s commercial strat- committed to its Maryland facilities over the past two years. Together egy. Lytix’s LTX-109 is a topical synthetic antimicrobial peptidomimetic with its Frederick campus, Qiagen employs about 550 employees at the that is in Phase II testing to treat impetigo. three sites in Maryland.

Novartis AG (NYSE:NVS; SIX:NOVN), Basel, Switzerland Roslin Cells Ltd., Edinburgh, U.K. Business: Chemistry, Pharmaceuticals Cell Therapy Catapult, London, U.K. Novartis said it will “significantly reduce” its internal discovery Irish Blood Transfusion Service, Dublin, Ireland efforts in RNA therapeutics due to “ongoing challenges with formula- Loughborough University, Leicestershire, U.K. tion and delivery and the reality that the current range of medically NHS Blood and Transplant (NHSBT), Hertfordshire, U.K. relevant targets where siRNA may be used is quite narrow.” The Scottish National Blood Transfusion Service (SNBTS), Edinburgh, pharma said it will maintain a small group in the field and will look for U.K. partnering opportunities, but said the decision will result in “some” job University of Glasgow, Glasgow, U.K. eliminations. Novartis has 26 full-time employees in its RNA therapeu- University of Edinburgh, Edinburgh, U.K. tics program. The Wellcome Trust, London, U.K. Novartis said it will maintain some employees to work on disease Business: Gene/Cell therapy, Hematology targets the pharma obtained under a RNAi discovery deal with Alnylam The Wellcome Trust granted a £5 million ($8.4 million) strategic Pharmaceuticals Inc. (NASDAQ:ALNY, Cambridge, Mass.). In 2010, award to the BloodPharma consortium led by SNBTS to generate red Novartis finalized a selection of 31 targets for which it has exclusive blood cells from pluripotent stem cells for transfusions. Roslin will rights to discover, develop and commercialize RNAi therapeutics (see manufacture the red blood cells at its GMP facility in Edinburgh. The BioCentury, Sept. 27, 2010). consortium plans to begin clinical testing with the therapy in 2016. Separately, Novartis appointed advisory firm PharmaVentures to explore options for the future of Novartis’ R&D site in Horsham, U.K., UnitedHealth Group Inc. (NYSE:UNH), Minneapolis, Minn. which could include reusing part of the site for a science or business Business: Infectious park. The Horsham site conducts research in respiratory and gas- On a conference call to discuss the company’s 1Q14 earnings, trointestinal diseases, as well as discovery chemistry, biomarker, UnitedHealth CFO Dan Schumacher said the insurer recorded a little metabolism and pharmacokinetics research. In November, Novartis See next page BioCentury Week in Review APRIL 21, 2014 PAGE B8 OF 26

Other News, tacking on an amendment to a bill that would place an 18-month from previous page moratorium on Zohydro. The bill is in the Senate’s Commerce Com- mittee. Ohio legislatures are considering a bill that would add Zohydro more than $100 million in costs in the quarter for HCV treatments, to the list of scheduled I controlled substances. Ohio prohibits healthcare which President and CEO Stephen Hemsley said was a result of “the professionals from prescribing schedule I drugs. Earlier this month, rapid launch of an effective and very expensive” new HCV therapy. Vermont Gov. Peter Shumlin issued an emergency rule placing restric- Hemsley declined to provide specifics, but said the “aggressive U.S. tions on hydrocodone prescriptions, including Zohydro, that requires pricing practices on this have been well-publicized, and continues to be prescribers to conduct and document a risk assessment, document that quite controversial.” Hemsley added that UnitedHealth is “working the prescription of a hydrocodone without an abuse-deterrent formu- diligently to ensure this medication is applied under clinically appropri- lation is required for the management of pain and receive a signed ate standards.” Schumacher attributed the costs to pent-up demand and consent form from the patient (see BioCentury, April 14). said UnitedHealth’s costs are “not inconsistent with what folks are Last year, Zogenix partnered with Altus Formulation Inc. (Montreal, seeing across the industry.” Quebec) to develop abuse-deterrent formulations of Zohydro. The Gilead Sciences Inc. (NASDAQ:GILD, Foster City, Calif.) has been company said it expects to launch abuse-deterrent formulations in 2016 under pressure from insurers and pharmacy benefit managers as well (see BioCentury, Nov. 11, 2013). as patient groups and legislators to reduce the price of its newly Zohydro uses Spheroidal Oral Drug Absorption System (SODAS) launched HCV drug, Sovaldi sofosbuvir, which has a wholesale acqui- drug delivery technology from Alkermes plc (NASDAQ:ALKS, Dublin, sition cost of $84,000 for a 12-week course. Earlier this month, Ireland), which is eligible for double-digit royalties. Alkermes acquired pharmacy benefit manager Express Scripts Holding Co. (NASDAQ:ESRX, the technology through its acquisition of the Elan Drug Technologies St. Louis, Mo.) said it will ask plan sponsors to “stand side-by-side” with business of Elan Corp. plc. In December, Perrigo Co. acquired Elan and the pharmacy benefit manager to encourage Gilead to provide Sovaldi the combined company incorporated in Ireland under the name Perrigo at a “more reasonable price.” Sovaldi is a single isomer of a nucleotide Co. plc (NYSE:PRGO; Tel Aviv:PRGO, Dublin, Ireland) (see BioCentury, analog HCV NS5B polymerase inhibitor (see BioCentury, April 14). Sept. 26, 2011 & Dec. 23, 2013).

Xenetic Biosciences Inc. (OTCBB:XBIO), Lexington, Mass. MANAGEMENT TRACKS Business: Hematology In 1Q14, U.K.-based Xenetic Biosciences plc became U.S.-based Boards of Directors Xenetic Biosciences Inc. In January, Xenetic Biosciences plc delisted from LSE and completed a reverse merger with Xenetic Biosciences Inc. Heart Metabolics Ltd., London, U.K. (formerly General Sales and Leasing Inc.). In February, Xenetic Bio- Business: Cardiovascular sciences Inc. began trading on OTCBB under the ticker “XBIO.” In Appointed: Robert Adelman, managing partner at venBio; Alan March, the company relocated its headquarters to Lexington, Mass., O’Connell, partner at Seroba Kernel Life Sciences; and Stephen Thomp- from London, U.K. The company said it believes it will be “better able son, managing director of Brandon Capital Partners to attract and retain qualified scientific researchers and other staff in its new Lexington location due to the Boston area having a wealth of Iconic Therapeutics Inc., Atlanta, Ga. talent in orphan drug development and market launch expertise.” Business: Ophthalmic, Cancer Xenetic’s ErepoXen is a long-acting erythropoietin (EPO) in Phase III Appointed: Todd Foley, managing director at MPM Capital; Johan testing for anemia in chronic kidney disease (CKD). Kordel, senior partner at Lundbeckfond Ventures; and Bruce Robertson, Last November, General Sales and Leasing Inc. and Xenetic Bio- managing director at H.I.G. BioVentures sciences plc agreed on a proposed reverse merger (see BioCentury, Nov. 18, 2013). Nora Therapeutics Inc., Palo Alto, Calif. Business: Genitourinary Zogenix Inc. (NASDAQ:ZGNX), San Diego, Calif. Appointed: Heath Lukatch, partner at Novo Ventures Business: Neurology A judge in the U.S. District Court for the District of Massachusetts PanOptica Inc., Mount Arlington, N.J. granted Zogenix’s motion for a preliminary injunction thus stopping Business: Ophthalmic Massachusetts’ statewide ban on Zogenix’s pain drug Zohydro ER Appointed: Thomas Dyrberg, senior partner at Novo Ventures hydrocodone bitartrate. Zogenix said the preliminary injunction be- See next page comes effective on April 22, after which Zohydro ER will be available in Massachusetts while the suit is ongoing. There are no scheduled upcoming hearings listed on the docket for the suit. BioCentury Week in Review Earlier this month, Zogenix filed the suit — Zogenix, Inc. v. Patrick BioCentury Week in Review is published by — challenging Massachusetts Gov. Deval Patrick’s executive order BIOCENTURY PUBLICATIONS INC., banning the prescription or distribution of Zohydro ER hydrocodone PO Box 1246 San Carlos CA 94070-1246. Phone 650-595-5333. bitartrate to treat pain. On March 28, Patrick declared opiate addiction Fax 650-595-5589. David Flores, President & CEO; Karen Bernstein, Ph.D., Chairman & Editor-in-Chief a public health emergency and directed state authorities to immediately prohibit the prescription or sale of Zohydro ER until FDA approves an BioCentury®; The Bernstein Report on BioBusiness™ ; The abuse-deterrent formulation. Zogenix launched Zohydro ER — an oral, BioCentury 100™ ; and The Clear Route to ROI™ are trademarks non-abuse deterrent, extended-release (ER) formulation of of BIOCENTURY PUBLICATIONS INC. All contents © Copyright 2014, BIOCENTURY PUBLICATIONS INC. hydrocodone — in select pharmacies in March (see BioCentury, March ALL RIGHTS RESERVED. No part of this publication may be 31 & April 14). photocopied or reproduced in any form, retransmitted, or stored in a Several other states are also taking steps to limit the use or retrieval system without prior written consent of the publisher. distribution of Zohydro. The New Hampshire Senate is considering BioCentury Week in Review APRIL 21, 2014 PAGE B9 OF 26

Management Tracks, Karyopharm Therapeutics Inc. (NASDAQ:KPTI), Natick, Mass. from previous page Business: Cancer, Inflammation Hired: Christopher Primiano as VP, general counsel and secre- Wilson Therapeutics AB, Stockholm, Sweden tary, formerly counsel at Wilmer Cutler Pickering Hale and Dorr Business: Endocrine/Metabolic LLP Appointed: Genghis Lloyd-Harris, partner at Abingworth; and Bali Muralidhar, partner at MVM Life Science Partners Kite Pharma Inc., Los Angeles, Calif. Business: Cancer Promoted: Margo Roberts to CSO from VP of research Management Transitioned: Cynthia Butitta to COO, while remaining CFO Astellas Pharma Inc. (Tokyo:4503), Tokyo, Japan Business: Pharmaceuticals Tokai Pharmaceuticals Inc., Cambridge, Mass. Promoted: Jeffrey Bloss to SVP of medical affairs Americas in Astellas’ Business: Cancer Astellas Scientific and Medical Affairs (ASMA) Inc. division from VP of ASMA Hired: Karen Ferrante as head of R&D and CMO, formerly oncology therapeutic area head and Cambridge, Mass. site head at Takeda Dyax Corp. (NASDAQ:DYAX), Burlington, Mass. Pharmaceutical Co. Ltd. Business: Inflammation, Ophthalmic Hired: Todd Bazemore as EVP and chief commercial officer, formerly TransTech Pharma LLC, High Point, N.C. VP of managed markets at the Sunovion Pharmaceuticals Inc. subsidiary Business: High throughput screening, Chemistry of Dainippon Sumitomo Pharma Co. Ltd. Transitioned: Stephen Holcombe to president of TransTech and affiliate company High Point Pharmaceuticals LLC from SVP of GNS Healthcare Inc., Cambridge, Mass. TransTech, while remaining CFO of TransTech; he succeeds Adnan Business: Pharmacogenetics Mjalli, who resigned as president and CEO of TransTech, while Hired: Mark Pottle as CFO, formerly CFO of N-of-One Inc. remaining a director of both companies and CEO of affiliate company High Point Clinical Trials Center LLC Harvard Apparatus Regenerative Technology Inc. (NASDAQ:HART), Holliston, Mass. 23andMe Inc., Mountain View, Calif. Business: Gene/Cell therapy Business: Diagnostic Hired: Saverio La Francesca, a cardiothoracic surgeon, as CMO; for- Hired: Jill Hagenkord as CMO, a newly created position, formerly SVP merly director of the Exvivo lung perfusion laboratory at the Depart- of medical strategy at Invitae Corp. ment of Cardiovascular Surgery and Transplantation at the DeBakey Heart and Vascular Center at the Houston Methodist Hospital WuXi PharmaTech Inc. (NYSE:WX), Shanghai, China Business: Supply/Service Iconic Therapeutics Inc., Atlanta, Ga. Hired: Steve Yang as EVP and COO, formerly VP and head of Asia and Business: Ophthalmic, Cancer emerging markets for the innovative medicines unit (iMED) at Hired: William Greene, a venture partner at MPM Capital, as CEO; he AstraZeneca plc; he succeeds Edward Hu, who remains CFO and also succeeds Kirk Dornbush, who becomes president and COO, while becomes chief investment officer remaining a director

The search for intelligent life We know you have many choices for headlines. But finding real intelligence is a lot harder. That’s why top managers and investors in the life sciences community depend on BioCentury, the Bernstein Report on BioBusinessTM for its leading perspective on the strategic issues essential to the formation, development and sustainability of life science ventures in 2014 and beyond. ‘It’s the BioCentury’TM BioCentury Week in Review APRIL 21, 2014 PAGE B10 OF 26

CLINICAL NEWS

Clinical activities and selected announcements for the week ended April 18. Product: Ragwitek ragweed Allergy Immunotherapy Tablet (AIT) (MK- 3641) (formerly SCH 039641) REGULATORY Business: Inflammation FDA approved a BLA from Merck for Ragwitek, a ragweed sublingual Abbott Laboratories (NYSE:ABT), Abbott Park, Ill. AIT, to treat ragweed pollen-induced allergic rhinitis, with or without Product: Architect Clinical Chemistry Hemoglobin A1c (HbA1c) test conjunctivitis, in patients 18-65 years of age. The pharma plans to launch Business: Diagnostic Ragwitek in the U.S. this month. The U.S. approval triggered an FDA granted 510(k) clearance for Abbott’s Architect Clinical undisclosed milestone payment to ALK-Abello from Merck. Under a Chemistry HbA1c test to aid physicians in diagnosing and monitoring 2007 deal, ALK-Abello is eligible for up to DKK1.6 billion ($296.8 diabetes and identifying people at risk for the disease. Abbott said the million) in milestones from Merck for a portfolio of AITs — tablet- test will be available in the U.S. “in the coming weeks.” The chemilu- based sublingual allergen immunotherapies — against grass pollen, minescent microparticle immunoassay, which runs on Abbott’s Archi- ragweed and house dust mite allergy. ALK-Abello is also eligible for tect c8000 System, quantitatively determines the percent of HbA1c or royalties and payments for supplying the products to Merck. the HbA1c concentration in human whole blood and hemolysate. The company markets the test in several countries in Europe, Asia, Latin Almirall S.A. (Madrid:ALM), Barcelona, Spain America, Africa and Canada. Ironwood Pharmaceuticals Inc. (NASDAQ:IRWD), Cambridge, Mass. Astellas Pharma Inc. (Tokyo:4503), Tokyo, Japan Abiogen Pharma S.p.A., Pisa, Italy Forest Laboratories Inc. (NYSE:FRX), New York, N.Y. Product: Nerixia neridronic acid AstraZeneca plc (LSE:AZN; NYSE:AZN), London, U.K. Business: Musculoskeletal Product: Constella linaclotide (Linzess) (ASP0456) Abiogen and Clinigen Group Ltd. (Burton-on-Trent, U.K.) an- Business: Gastrointestinal nounced the start of a named-patient program in the EU to provide Almirall said it will no longer market Constella linaclotide in access to Nerixia neridronic acid to treat osteogenesis imperfecta. Germany after failing to agree on a price with Germany’s Statutory Clinigen’s Clinigen Global Access Programs (GAP) will manage the Health Insurance Funds Association (GKV-Spitzenverband). In Octo- program, which excludes Italy, where the aminobisphosphonate was ber, Germany’s Federal Joint Committee (G-BA) said the guanylate approved in 2002 and is already available. The disease is characterized cyclase C (GCC; GUCY2C) agonist has “no additional benefit” for by fragile bones that break easily and low bone mass that may lead to irritable bowel syndrome with constipation (IBS-C) vs. a change in diet deformities and pain. and symptom-specific treatment (see BioCentury, Oct. 21, 2013). Almirall has exclusive rights to Constella in Europe and the Com- Alimera Sciences Inc. (NASDAQ:ALIM), Alpharetta, Ga. monwealth of Independent States (CIS) from Ironwood. Almirall de- pSivida Corp. (NASDAQ:PSDV; ASX:PVA), Watertown, Mass. clined to disclose details of its negotiations with GKV-Spitzenverband, Product: Iluvien fluocinolone acetonide intravitreal implant (formerly and Ironwood said it respects Almirall’s “expertise in managing these Medidur FA) local markets.” Business: Ophthalmic Astellas has exclusive rights from Ironwood to develop and com- Alimera and pSivida said FDA accepted for review a resubmitted mercialize linaclotide in Japan, Indonesia, Korea, the Philippines, Tai- NDA from Alimera for Iluvien fluocinolone acetonide intravitreal wan and Thailand. In October 2012, Ironwood partnered with implant to treat diabetic macular edema (DME). The PDUFA date is Sept. AstraZeneca to co-develop and co-commercialize linaclotide in China 26. In October, FDA issued a complete response letter for the (see BioCentury, Oct. 29, 2012). Ironwood and Forest co-commercialize injectable insert that delivers fluocinolone acetonide to the retina. linaclotide as Linzess in the U.S. Alimera markets Iluvien in Europe to treat chronic DME (see BioCentury, Dec. 23, 2013). Alimera has rights to the product from pSivida under a Astellas Pharma Inc. (Tokyo:4503), Tokyo, Japan 2008 deal (see BioCentury, March 24, 2008; Nov. 14, 2011 & Aug. 20, 2012). Ferring Pharmaceuticals A/S, Saint-Prex, Switzerland Product: Firmagon degarelix (Gonax) (ASP3550) ALK-Abello A/S (CSE:ALK-B), Horsholm, Denmark Business: Cancer Merck & Co. Inc. (NYSE:MRK), Whitehouse Station, N.J. The U.K.’s NICE issued a final appraisal determination (FAD) Product: Grastek grass pollen Allergy Immunotherapy Tablet (AIT) recommending Ferring’s Firmagon degarelix to treat advanced hor- (Grazax) (MK-7243) mone-dependent prostate cancer only in a subgroup of patients with Business: Inflammation spinal metastases who present signs or symptoms of spinal cord FDA approved a BLA from Merck for Grastek, a grass pollen compression. The gonadotropin-releasing hormone (GnRH) antago- sublingual AIT, to treat grass pollen-induced allergic rhinitis, with or nist is approved in the EU to treat advanced hormone-dependent without conjunctivitis, in patients 5-65 years of age. The pharma plans prostate cancer. The FAD is in line with draft guidance issued in to launch Grastek in the U.S. late this month. The U.S. approval triggered December (see BioCentury, Jan. 6). an undisclosed milestone payment to ALK-Abello from Merck. Under In 2006, Ferring granted Astellas rights to degarelix in Japan, where a 2007 deal, ALK-Abello is eligible for up to DKK1.6 billion ($296.8 it is approved as Gonax to treat prostate cancer. Ferring also markets million) in milestones from Merck for a portfolio of AITs — tablet- Firmagon in the U.S. based sublingual allergen immunotherapies — against grass pollen, ragweed and house dust mite allergy. ALK-Abello is also eligible for AstraZeneca plc (LSE:AZN; NYSE:AZN), London, U.K. royalties and payments for supplying the products to Merck. The Product: Olaparib (AZD2281, KU-0059436) pharma launched Grastek in Canada in February, and ALK-Abello Business: Cancer markets it as Grazax in Europe (see BioCentury, Feb. 10). See next page BioCentury Week in Review APRIL 21, 2014 PAGE B11 OF 26

Regulatory, therapy designation in the U.S. for the indication (see BioCentury, Sept. from previous page 23, 2013).

FDA’s Oncologic Drugs Advisory Committee will meet on June 25 Boehringer Ingelheim GmbH, Ingelheim, Germany to discuss an NDA from AstraZeneca for olaparib as maintenance Eli Lilly and Co. (NYSE:LLY), Indianapolis, Ind. treatment of platinum-sensitive relapsed ovarian cancer in patients Product: Empagliflozin/linagliptin who are in response to platinum-based chemotherapy. The pharma said Business: Endocrine/Metabolic it submitted the NDA earlier this year, but declined to disclose when Boehringer and Eli Lilly said FDA accepted for review an NDA for or the PDUFA date. The poly(ADP-ribose) polymerase (PARP) inhibi- a combination tablet of empagliflozin, a sodium-glucose cotransporter tor is also under review in Europe (see BioCentury, Sept. 30, 2013). 2 (SGLT2) inhibitor, and linagliptin, a xanthine-based dipeptidyl pepti- The NDA covers use of olaparib in patients with germline breast dase-4 (DPP-4) inhibitor, to treat adults with Type II diabetes. Boehringer cancer early onset (BRCA) mutation as detected by an FDA-approved declined to disclose the PDUFA date or when the application was test. Earlier this month, Myriad Genetics Inc. (NASDAQ:MYGN, Salt submitted. Lilly could not be reached. Lake City, Utah) submitted the first of 4 modules of a PMA to FDA for Last month, FDA issued a complete response letter for Jardiance BRACAnalysis test as a companion diagnostic for olaparib. empagliflozin while EMA’s CHMP backed approval of the product to Myriad markets BRACAnalysis to assess a woman’s risk of devel- treat Type II diabetes (see BioCentury, March 10 & March 24). Empagliflozin oping breast or ovarian cancer based on detecting genetic mutations in is also under review in Japan. Linagliptin is approved for Type II diabetes the BRCA1 and BRCA2 genes. as Tradjenta in the U.S., as Trajenta in the EU and as Trazenta in Japan. In 2011, Boehringer and Lilly partnered to co-develop and co- Avita Medical Ltd. (ASX:AVH), Perth, Australia commercialize a portfolio of diabetes candidates, including empagliflozin Product: ReCell Spray-on-Skin and linagliptin (see BioCentury, Jan. 17, 2011). Business: Dermatology Avita said FDA granted an investigational device exemption (IDE) Genmab A/S (CSE:GEN; OTCBB:GMXAY), Copenhagen, Denmark for ReCell Spray-on-Skin for use in up to 12 patients with life-threat- GlaxoSmithKline plc (LSE:GSK; NYSE:GSK), London, U.K. ening wounds and insufficient healthy skin to harvest for skin grafts. The Product: Arzerra ofatumumab (HuMax-CD20) product is in Phase III testing in the U.S. Business: Cancer Separately, the U.K.’s NICE issued draft guidance noting that ReCell FDA approved an sBLA from GlaxoSmithKline expanding the label Spray-on-Skin “shows promise” for treating acute burns, but that there for Arzerra ofatumumab to include first-line treatment of chronic is not yet enough evidence to allow the agency to recommend its lymphocytic leukemia (CLL). The new indication covers the use of routine use. NICE recommended additional research to address clinical Arzerra in combination with chlorambucil when fludarabine-based and cost-benefit uncertainties. The cultured epithelial autograft sus- therapy is inappropriate. The product has breakthrough therapy des- pension in spray formulation has CE Mark approval and is marketed to ignation from FDA for the indication. GSK markets the human mAb treat skin wounds that require replacement of epithelial tissue, burns, against CD20 in the U.S. and EU to treat CLL refractory to fludarabine and for plastic, reconstructive and cosmetic procedures in China and and alemtuzumab. An application to add the first-line indication to Australia and in countries in the Middle East and EU. Arzerra’s European label is under review (see BioCentury, Oct. 7, 2013). The pharma has worldwide co-development and commercialization BioMarin Pharmaceutical Inc. (NASDAQ:BMRN), Novato, Calif. rights to Arzerra from Genmab. Daiichi Sankyo Co. Ltd. (Tokyo:4568), Tokyo, Japan In 2012, Sanofi (Euronext:SAN; NYSE:SNY, Paris, France) and its Merck KGaA (Xetra:MRK), Darmstadt, Germany Genzyme Corp. unit withdrew MabCampath/Campath alemtuzumab Product: Kuvan sapropterin dihydrochloride (6R-BH4) from the European and U.S. market. Sanofi now markets alemtuzumab Business: Endocrine/Metabolic as Lemtrada in Europe for relapsing forms of multiple sclerosis (MS). BioMarin said FDA extended market exclusivity for Kuvan sapropterin dihydrochloride by 6 months to June 2015. The company Gilead Sciences Inc. (NASDAQ:GILD), Foster City, Calif. markets Kuvan to treat hyperphenylalaninemia (HPA) due to phenylke- Product: Sovaldi sofosbuvir (GS-7977) (formerly PSI-7977) tonuria (PKU) in patients from birth to 6 years of age. The pediatric Business: Infectious extension is for Kuvan tablets and powder for oral solution, which the NHS England approved £18.7 million ($31.3 million) in funding to agency approved in December. treat patients with advanced HCV infection with Gilead’s Sovaldi The small molecule formulation of tetrahydrobiopterin (6R-BH4) sofosbuvir. Treatment will be limited to patients at significant risk of is approved in the U.S. to treat HPA due to PKU and in Europe to treat death or who require liver transplantation, a population NHS estimates HPA due to PKU or tetrahydrobiopterin deficiency. The drug has at about 500 patients. The U.K.’s NICE is reviewing Sovaldi for chronic Orphan Drug status in the U.S. and EU. HCV, with a first appraisal committee meeting scheduled for May 15. BioMarin has ex-Japanese rights to Kuvan from Daiichi Sankyo. Gilead markets the nucleotide analog HCV NS5B polymerase inhibitor Merck has rights outside North America and Japan from BioMarin. in the U.S., EU and Canada to treat HCV infection.

Boehringer Ingelheim GmbH, Ingelheim, Germany Gilead Sciences Inc. (NASDAQ:GILD), Foster City, Calif. Product: Volasertib (BI 6727) Bristol-Myers Squibb Co. (NYSE:BMY), New York, N.Y. Business: Cancer Product: Atazanavir/cobicistat The European Commission and FDA granted Orphan Drug desig- Business: Infectious nation to Boehringer’s volasertib to treat acute myelogenous leukemia Bristol-Myers Squibb submitted an NDA to FDA for a fixed-dose (AML). The polo-like kinase 1 (PLK1; STPK13) inhibitor is in the Phase combination of its HIV drug Reyataz atazanavir and cobicistat from III POLO-AML-2 trial in combination with low-dose cytarabine to treat Gilead to treat HIV-1 infection in combination with other antiretroviral previously untreated AML in patients ages ≥65 years who are ineligible agents. Gilead and BMS partnered for the fixed-dose combination in for intensive remission induction therapy. Volasertib has breakthrough See next page BioCentury Week in Review APRIL 21, 2014 PAGE B12 OF 26

Regulatory, Novo Nordisk A/S (CSE:NVO; NYSE:NVO), Bagsvaerd, Denmark from previous page Product: NovoEight turoctocog alfa (Novoeight, recombinant FVIII) (NN7008) 2011 (see BioCentury, Oct. 31, 2011). Business: Hematology BMS markets Reyataz, an HIV protease inhibitor. Gilead’s cobicistat Germany’s Institute for Quality and Efficiency in Healthcare (IQWiG) is approved in the EU as Tybost as a pharmacokinetic enhancer of said in a preliminary benefit assessment that NovoEight turoctocog alfa protease inhibitors atazanavir and Prezista darunavir from Johnson & from Novo Nordisk has “no additional benefit” vs. other Factor VIIIs Johnson (NYSE:JNJ, New Brunswick, N.J.) as part of antiretroviral (FVIIIs) to treat and prevent bleeding in hemophilia A patients. IQWiG combination therapy to treat HIV-1 infection in adults. said the company did not submit relevant studies or “valid data” from Last year, FDA issued a complete response letter for single-agent other sources. Comments are due May 6, with a final assessment from cobicistat in the indication related to deficiencies at Gilead’s manufac- Germany’s Federal Joint Committee (G-BA) expected in early July. turing facility in Foster City. In a February 10-K, the company said it Novo also markets the third-generation recombinant FVIII (rFVIII) in recently submitted responses to FDA regarding the deficiencies. The the U.S. and Japan, where it is known as Novoeight. inhibitor of cytochrome P450 family 3 subfamily A (CYP3A; CYP3) is approved in the EU and U.S. as part of Gilead’s Stribild, a once-daily Orion Corp. (HSE:ORNAV; HSE:ORNBV), Espoo, Finland tablet comprising elvitegravir, cobicistat and Gilead’s Truvada Product: Bufomix Easyhaler budesonide/formoterol emtricitabine/tenofovir (see BioCentury, May 6, 2013). Business: Inflammation Orion said Ireland and Hungary approved its Bufomix Easyhaler GlaxoSmithKline plc (LSE:GSK; NYSE:GSK), London, U.K. budesonide/formoterol to treat asthma and chronic obstructive pul- Product: Tanzeum albiglutide (Eperzan) monary disease (COPD) in patients ages >12 years. The approvals are Business: Endocrine/Metabolic the first under the EU’s decentralized procedure; Sweden acted as the FDA approved Tanzeum albiglutide from GlaxoSmithKline to treat reference member state. Bufomix is also under review in Iceland, Type II diabetes as monotherapy or as add-on therapy. GSK plans to Norway and Switzerland. launch Tanzeum in the U.S. next quarter, but declined to comment on Easyhaler is a device-metered dry powder inhaler. Budesonide, a pricing. The drug is a once-weekly, glucagon-like peptide-1 (GLP-1) corticosteroid, was already approved for use on the Easyhaler to receptor agonist comprised of 2 copies of modified human GLP-1 fused control asthma. Formoterol, a long-acting adrenergic receptor beta 2 in series to human albumin. Tanzeum has a black box warning on the risk agonist (LABA), was approved for use on the Easyhaler to treat asthma of thyroid C cell tumors and was approved with a REMS comprising a and COPD. Orion is partnered with Takeda Pharmaceutical Co. Ltd. communication plan. GSK is required to conduct a postapproval cardio- (Tokyo:4502, Osaka, Japan) to co-market the product in European vascular outcomes trial; the pharma declined to comment on a timeline countries, including Austria, Benelux countries, France, Germany, for starting the trial. The European Commission approved albiglutide Greece, Italy, Poland, Portugal, Spain and Switzerland (see BioCentury, as Eperzan last month (see BioCentury, March 31). Aug. 15, 2011).

Guerbet S.A. (Euronext:GBT), Villepinte, France Valeant Pharmaceuticals International Inc. (TSX:VRX; NYSE:VRX), Product: Lipiodol ethiodized oil Montreal, Quebec Business: Diagnostic Meda AB (SSE:MEDAA), Solna, Sweden FDA approved an sNDA from Guerbet for Lipiodol ethiodized oil GlaxoSmithKline plc (LSE:GSK; NYSE:GSK), London, U.K. for selective hepatic intra-arterial use for imaging tumors in adults with Product: Trobalt retigabine (Potiga, ezogabine) known hepatocellular carcinoma (HCC). The iodinated contrast agent Business: Neurology obtained from poppy seed oil is already marketed in the U.S. for Germany’s Federal Joint Committee (G-BA) issued a preliminary hysterosalpingography in adults and lymphography in adults and chil- benefit assessment saying that epilepsy drug Trobalt retigabine from dren. The product has Orphan Drug status to manage patients with GlaxoSmithKline has “no additional benefit” vs. individualized antiepileptic known HCC. The sNDA was approved under section 505(b)(2) of the therapy. According to G-BA, GSK did not submit complete, necessary data. Food, Drug and Cosmetic Act, which allows sponsors to reference data The pharma, which does not market Trobalt in Germany, said proving on safety and efficacy from scientific literature or from previously Trobalt’s additional benefit vs. the comparator would be “methodologi- approved products. cally impossible.” Comments on the assessment are due May 6, with a final assessment from G-BA expected in early July. Myriad Genetics Inc. (NASDAQ:MYGN), Salt Lake City, Utah This is the second assessment for Trobalt in Germany. In 2012, G- Product: BRACAnalysis BA said the potassium channel opener and potentiator of GABA had no Business: Diagnostic additional benefit, and GSK requested a new benefit assessment (see Myriad submitted to FDA the first of 4 modules of a PMA for its BioCentury, May 14, 2012 & Jan. 21, 2013). Last year, EMA updated BRACAnalysis test as a companion diagnostic for olaparib from Trobalt’s label to restrict its use to last-line therapy in patients with AstraZeneca plc (LSE:AZN; NYSE:AZN, London, U.K.). An MAA for partial epilepsy (see BioCentury, June 3, 2013). olaparib is under review in Europe as maintenance treatment of GSK has rights to develop and commercialize Trobalt from Valeant, platinum-sensitive relapsed serous ovarian cancer in patients with which has a license from Meda. breast cancer early onset (BRCA) mutations. AstraZeneca said it submitted an NDA to FDA for the poly(ADP-ribose) polymerase CLINICAL RESULTS (PARP) inhibitor earlier this year, but declined to disclose when it submitted the application or the PDUFA date. FDA’s Oncologic Drugs Auris Medical AG, Basel, Switzerland Advisory Committee will meet on June 25 to discuss the NDA. Product: Esketamine (AM-101) Myriad markets BRACAnalysis to assess a woman’s risk of devel- Business: Other oping breast or ovarian cancer based on detecting genetic mutations in Molecular target: NMDA receptor the BRCA1 and BRCA2 genes. See next page BioCentury Week in Review APRIL 21, 2014 PAGE B13 OF 26

Clinical Results, vomiting/nausea and anemia, which were not considered to be related to from previous page treatment. There was 1 treatment-related serious adverse event characterized by chest discomfort and increased heart rate during infusion. Description: Intratympanicly injected non-competitive antagonist of By year end, Baxter plans to submit a regulatory application to FDA NMDA receptors for BAX 111 as an on-demand treatment for vWD. The company also Indication: Treat acute peripheral (inner ear) tinnitus plans to start a trial to evaluate BAX 111 as a prophylactic treatment Endpoint: Change from baseline in minimum masking level at day 90; for vWD by year end. BAX 111 has Orphan Drug designation in the U.S. loudness match, tinnitus loudness, tinnitus annoyance, sleep difficul- and EU for vWD. Baxter markets Advate for the treatment and ties, Tinnitus Handicap Inventory 12 (THI-12) questionnaire, Patient prophylaxis of bleeding in hemophilia A patients. Global Impression of Change (PGIC) and safety Status: Phase IIb data BerGenBio A/S, Bergen, Norway Milestone: Phase III data (year end 2015) Rigel Pharmaceuticals Inc. (NASDAQ:RIGL), South San Francisco, A double-blind, European Phase IIb trial in 248 patients aged 18-65 Calif. with persistent acute inner ear tinnitus showed that 3 intratympanic Product: BGB324 (formerly R428) injections of 0.27 or 0.81 mg/mL AM-101 over 3 consecutive days each Business: Cancer missed the primary endpoint of improving minimum masking level from Molecular target: AXL receptor tyrosine kinase (AXL) (UFO) baseline to day 90 vs. placebo (7.9 dB for both doses vs. 8.2 dB for Description: Small molecule inhibitor of AXL receptor tyrosine kinase placebo, p=0.9919). Auris said that AM-101 did demonstrate a dose- (AXL; UFO) dependent and persistent improvement in several patient-reported Indication: Treat cancer outcomes vs. placebo. In patients with unilateral tinnitus following Endpoint: Safety and pharmacokinetics; maximum tolerated dose (MTD) acute acoustic trauma or otitis media, 0.81 mg/mL AM-101 significantly Status: Phase Ia data improved tinnitus loudness, annoyance, tinnitus-related sleep difficul- Milestone: Start Phase Ib (2014) ties and overall tinnitus impact as measured by the THI-12 question- An open-label Phase Ia trial in 32 healthy volunteers showed that naire from baseline to day 90 vs. placebo (p<0.02 for all). Specifically, single doses of up to 1.5 g oral BGB324 were well tolerated. Data were the mean improvement in tinnitus loudness at day 90 was 28% in the low- presented at the American Association for Cancer Research meeting dose AM-101 arm and 48% in the high-dose AM-101 arm vs. 9% for in San Diego. BerGenBio plans to start Phase Ib trials with BGB324 in placebo. Additionally, 44% of patients in the low-dose AM-101 arm and non-small cell lung cancer (NSCLC) and acute myelogenous leukemia 64% of patients in the high-dose AM-101 arm rated their tinnitus (AML) patients this year. BerGenBio has exclusive, worldwide rights severity as “much improved” or “very much improved” at day 90 vs. 35% to BCB324 from Rigel under a 2011 deal. of patients receiving placebo. Auris said the treatment effects of AM-101 were “somewhat less BHV Pharma Inc., Research Triangle Park, N.C. pronounced” in patients with bilateral tinnitus since only 1 ear was Kissei Pharmaceutical Co. Ltd. (Tokyo:4547), Nagano, Japan treated as a precautionary safety measure. AM-101 was well tolerated. Product: Remogliflozin etabonate (BHV091009, KGT-1681) (formerly The trial enrolled patients with tinnitus triggered by acute acoustic trauma, GSK189075) sudden deafness or otitis media. Data were published in Otology & Business: Endocrine/Metabolic Neurotology. AM-101 is in the North American Phase III TACTT2 trial and Molecular target: Sodium-glucose cotransporter 2 (SGLT2) the European Phase III TACTT3 trial for acute inner ear tinnitus. Patients Description: Sodium-glucose cotransporter 2 (SGLT2) inhibitor who complete either trial will be eligible to enroll in the open-label Indication: Treat Type II diabetes AMPACT1 and AMPACT2 safety trials and receive up to 3 treatment Endpoint: Change from baseline in HbA1c at week 12; fasting plasma cycles with AM-101 over up to 9 months. Patients from TACTT2 will glucose (FPG), serum lipids, body weight and safety enroll in AMPACT1, while those from TACTT3 will enroll in AMPACT2. Status: Phase IIb data Data from TACTT2 and TACTT3 are expected in late 2015. Milestone: Additional Phase IIb data (06/2014); start Phase IIb (2014) BHV and Islet Sciences Inc. (OTCBB:ISLT, New York, N.Y.) re- Baxter International Inc. (NYSE:BAX), Deerfield, Ill. ported data from a pair of double-blind, dose-ranging, placebo- and Product: BAX 111 (RVWF) pioglitazone-controlled Phase IIb trials in 563 treatment-naïve patients Business: Hematology with Type II diabetes showing that all doses of once- and twice-daily Molecular target: von Willebrand factor (vWF) remogliflozin met the primary endpoint of reducing HbA1c from Description: Recombinant human von Willebrand factor (vWF) baseline to week 12 vs. placebo. Additionally, in the first trial (n=322), Indication: Treat von Willebrand disease (vWD) all doses of twice-daily remogliflozin produced a significant trend in Endpoint: Number of patients with treatment success for treated bleeding reducing HbA1c from baseline to week 12 (reductions of 1-1.4%, episodes; health-related quality of life, safety and pharmacokinetics p<0.001 for the dose response). In the second trial (n=241), once-daily Status: Phase III data remogliflozin at doses above the lowest dose tested produced a Milestone: Additional Phase III data (2014); start clinical trial (year end significant trend in reducing HbA1c from baseline to week 12 (reduc- 2014); submit regulatory application (year end 2014) tions of 0.5-0.8%, p<0.047 for the dose response). Top-line data from an open-label, international Phase III trial in 37 All doses of once- and twice-daily remogliflozin met the secondary patients with severe hereditary vWD showed that on-demand treatment endpoint of reducing FPG from baseline to week 12 vs. placebo. with IV BAX 111 given with or without Advate octocog alfa met the primary Additionally, twice-daily remogliflozin led to significant reductions in endpoint of the number of patients with treatment success for treated body weight of 1.36-3.51 kg from baseline to week 12 vs. placebo, while bleeding episodes, defined as a mean efficacy rating score of <2.5 points once-daily remogliflozin at doses above the lowest dose tested led to on a 4-point scale. Specifically, on-demand treatment with BAX 111 led to significant reductions of 1.44-1.51 kg on the endpoint vs. placebo. treatment success in 100% of the 22 patients who experienced bleeds Remogliflozin was well tolerated. Data from both trials will be presented during the trial. There were no reports of inhibitor development or at the American Diabetes Association meeting in San Francisco in June. thrombotic events. The most common adverse events were headache, See next page BioCentury Week in Review APRIL 21, 2014 PAGE B14 OF 26

Clinical Results, reduces exposure variability compared to the free base capsule formu- from previous page lation (see BioCentury, May 13, 2013 & Sept. 2, 2013). Clovis is enrolling T790M-positive patients in 2 expansion cohorts Additionally, BHV and Islet Sciences said twice-daily dosing of in the Phase II portion of the trial. The first cohort is enrolling 150-200 remogliflozin led to increases in LDL-C and rates of genital fungal patients directly after progression on their first and only TKI therapy infections that were not observed with once-daily dosing of to receive twice-daily 500, 750 or 1,000 mg CO-1686. The second remogliflozin. The companies said the data are consistent with the cohort is enrolling about 150 patients directly after progression on longer plasma exposure from twice-daily dosing having a greater effect their second or later TKI therapy or subsequent chemotherapy to on evening postprandial glucose excursions and shorter plasma expo- receive twice-daily 750 or 1,000 mg CO-1686. sure from once-daily dosing limiting the undesirable effects of nighttime This year, the company plans to start 3 registration trials with CO- inhibition of SGLT2. As a result, BHV and Islet Sciences have developed 1686 — the Phase II/III TIGER1 trial in newly diagnosed patients who a once-daily biphasic formulation of remogliflozin designed to maintain have not received TKI therapy; the Phase II TIGER2 trial in patients who the efficacy of twice-daily dosing and the safety of once-daily dosing. progressed after their first and only TKI therapy; and the Phase III Islet Sciences said the biphasic formulation has completed a Phase I trial, TIGER3 trial in patients who progressed after later-line TKI therapy. with a Phase IIb trial in Type II diabetes slated to start this year. TIGER1 and TIGER2 will begin this quarter, while TIGER3 is slated to Remogliflozin is also in Phase II testing to treat non-alcoholic start next half. Clovis has exclusive, worldwide rights to develop and steatohepatitis (NASH), with a Phase IIb trial slated to start this year. commercialize CO-1686 from Avila Therapeutics Inc., which Celgene BHV has exclusive rights outside of Japan, Korea and Taiwan to develop acquired (see BioCentury, May 31, 2010 & March 12, 2012). and commercialize remogliflozin from Kissei (see BioCentury, Jan. 10, 2011). Last month, Islet Sciences signed a letter of intent to acquire BHV Cynapsus Therapeutics Inc. (TSX:CTH), Toronto, Ontario in a stock deal. The acquisition is slated to close this summer (see Product: APL-130277 BioCentury, March 17). GlaxoSmithKline plc (LSE:GSK; NYSE:GSK, Business: Neurology London, U.K.) previously had rights to remogliflozin from Kissei under Molecular target: Dopamine receptor a deal that was terminated in 2009. Takeda Pharmaceutical Co. Ltd. Description: Sublingual thin film strip formulation of apomorphine, a (Tokyo:4502, Osaka, Japan) markets Actos pioglitazone. small molecule dopamine receptor agonist Indication: Treat Parkinson’s disease (PD) Celgene Corp. (NASDAQ:CELG), Summit, N.J. Endpoint: Safety and pharmacokinetics Clovis Oncology Inc. (NASDAQ:CLVS), Boulder, Colo. Status: Interim pilot trial data Product: AVL-301, CO-1686 Milestone: Submit NDA (2016) Business: Cancer Interim data from 9 healthy volunteers in the single-arm, placebo- Molecular target: Epidermal growth factor receptor (EGFR) controlled pilot CTH-104 trial showed that a single dose of 25 mg Description: Small molecule that inhibits the T790M EGFR mutant and sublingual APL-130277 was well tolerated. Cynapsus said the 25 mg dose the initial activating EGFR mutations of APL-130277 did result in more adverse events with a greater severity Indication: Treat non-small cell lung cancer (NSCLC) than that seen with the 15 mg dose of APL-130277 in a previous trial, but Endpoint: Safety, pharmacokinetics, maximum tolerated dose (MTD), the side effects were mild to moderate and were not dose limiting. The recommended Phase II dose, objective response rate (ORR) and company also said the 25 mg dose of APL-130277 produced a concentra- duration of response; progression-free survival (PFS) tion of apomorphine in the blood associated with an expected minimum Status: Additional Phase I data efficacious concentration — about 3 ng/mL — for over 2 hours. Milestone: Start Phase II (2Q14); start Phase III (2H14); submit NDA Cynapsus previously reported data from the placebo-controlled, (2015) crossover pilot CTH-103 trial in 29 healthy volunteers showing that 10 Clovis reported additional data from the first 62 patients treated and 15 mg doses of sublingual APL-130277 were better tolerated than with CO-1686 at efficacious doses — defined as twice-daily 900 mg subcutaneous apomorphine. Additionally, the company said there were doses of the free base capsule formulation or any dose of the dose-limiting adverse events at the 3 mg subcutaneous apomorphine hydrobromide salt tablet formulation — in the dose-escalation Phase dose that prevented dosing of a third cohort to compare a 25 mg dose I portion of an open-label, international Phase I/II trial. In 22 evaluable of APL-130277 to a 4 mg dose of subcutaneous apomorphine (see patients confirmed to have the dominant EGFR resistance mutation BioCentury, Jan. 20). T790M, there were 14 partial responses (ORR=64%) and 6 cases of Next quarter, the company plans to complete the pilot CTH-105 stable disease. In T790M-positive patients, PFS of greater than 6 months trial of APL-130277 in apomorphine-naïve PD patients and the CTH-200 has been observed and median PFS has not yet been reached. Median PFS bridging study. A safety trial in apomorphine-naïve PD patients is slated in T790M-negative patients was 3 months (n=12). to be completed by year end 2015. Cynapsus plans to submit an NDA CO-1686 was well tolerated with only 1 patient discontinuing to FDA for APL-130277 to treat PD in 2016. The company hopes to treatment due to adverse events. The most common adverse events submit the NDA under section 505(b)(2) of the Food, Drug and were hyperglycemia, nausea, diarrhea, reduced appetite and vomiting, Cosmetic Act, which allows sponsors to reference data on safety and and the most common grade 3 adverse event was hyperglycemia. The efficacy from the scientific literature or from previously approved trial enrolled patients with metastatic or unresectable recurrent products. The Britannia Pharmaceutical Ltd. subsidiary of Stada NSCLC and a documented EGFR mutation who have progressed on Arzneimittel AG (Xetra:SAZ, Bad Vilbel, Germany) markets subcuta- prior EGFR-directed tyrosine kinase inhibitor (TKI) therapy. Data neous apomorphine as Apo-Go for PD. were presented at the European Lung Cancer meeting in Geneva. The trial originally was evaluating a free base capsule formulation Cytos Biotechnology AG (SIX:CYTN), Schlieren, Switzerland of CO-1686, which was deemed to not be effective at twice-daily doses Product: CYT003, CYT003-QbG10 of <900 mg. Last August, Clovis began dosing patients with twice-daily Business: Inflammation 500-1,000 mg doses of a hydrobromide salt tablet formulation of CO- Molecular target: Toll-like receptor 9 (TLR9) 1686. Clovis said the tablet formulation improves absorption and See next page BioCentury Week in Review APRIL 21, 2014 PAGE B15 OF 26

Clinical Results, Pharmaceutical Co. subsidiary has rights to VAL-083 in China, where from previous page it is known as DAG for Injection, to treat chronic myelogenous leukemia (CML) and lung cancer — its approved indications in China (see Description: Virus-like particle (VLP) containing an oligonucleotide BioCentury, Nov. 5, 2012). The Genentech Inc. unit of Roche (SIX:ROG; agonist of toll-like receptor 9 (TLR9) OTCQX:RHHBY, Basel, Switzerland) markets Avastin in the U.S., while Indication: Treat allergic asthma Roche markets it elsewhere. Merck & Co. Inc. (NYSE:MRK, Whitehouse Endpoint: Asthma control questionnaire (ACQ) Station, N.J.) markets Temodar. Status: Phase IIb discontinued Milestone: Additional Phase IIb data (05/2014) Galapagos N.V. (Euronext:GLPG; Pink:GLPYY), Mechelen, Belgium Cytos discontinued a double-blind, international Phase IIb trial in GlaxoSmithKline plc (LSE:GSK; NYSE:GSK), London, U.K. about 360 patients with moderate to severe allergic asthma not suffi- Product: GSK2586184 (formerly GLPG0778) ciently controlled on standard controller therapy after top-line data Business: Autoimmune showed that all 3 dose levels of subcutaneous CYT003 missed the primary Molecular target: Janus kinase-1 (JAK-1) endpoint of improving ACQ score from baseline to week 12 vs. placebo. Description: Janus kinase-1 (JAK-1) inhibitor Cytos said patients in the placebo arm and in all CYT003 arms achieved a Indication: Treat chronic plaque psoriasis “clinically relevant” improvement in ACQ score. CYT003 also did not Endpoint: Proportion of patients achieving a Psoriasis Area and Severity show a significant improvement over placebo in all additional endpoints, Index (PASI) 75 response at week 12; PASI 50 and PASI 90, Physician including lung function. Patients received subcutaneous CYT003 or pla- Global Assessment (PGA) scores and safety cebo 7 times over 10 weeks. Based on the data, Cytos decided to Status: Phase IIa data discontinue and unblind the trial instead of continuing with a planned 9- Milestone: NA month, blinded observation period. Additional data will be presented Top-line data from the double-blind, German and U.K. Phase IIa at the American Thoracic Society meeting in San Diego in May. JAK116679 trial in 66 patients with chronic plaque psoriasis showed that In March, Cytos amended its notes with Abingworth, venBio, twice-daily 400 mg oral GSK2586184 met the primary endpoint of a greater Aisling and Amgen Inc. (NASDAQ:AMGN, Thousand Oaks, Calif.) to proportion of patients achieving a PASI 75 response at week 12 vs. placebo. convert CHF13.3 million ($15.2 million) in outstanding notes plus Galapagos and partner GlaxoSmithKline declined to disclose whether the accrued interest to shares of Cytos common stock upon achievement twice-daily 100 and 200 mg doses of GSK2586184 met the endpoint. The of the primary endpoint in the Phase IIb trial (see BioCentury, April 7). most common adverse events reported were headache and nasopharyn- Since Cytos did not achieve the condition for conversion, the company gitis. GSK, which conducted the trial, said it will review the complete data now considers the prospects of raising sufficient new funding to be from all trials with GSK2586184 before determining next steps. “remote.” As a result, Cytos said it is evaluating options for an “ordinary In February, GSK discontinued due to “lack of effect” a Phase II trial winding down of operations and liquidation of the company or a evaluating GSK2586184 to treat systemic lupus erythematosus (SLE) possible bankruptcy.” The company said it also has started the process after the first planned interim analysis met undisclosed pre-defined for a mass dismissal of its 36 employees. As of March 31, Cytos had stopping criteria. At the same time, the pharma also placed an open- CHF31 million ($35 million) in cash. label Phase I/II trial with GSK2586184 for ulcerative colitis (UC) on hold. Galapagos said the UC trial remains on hold (see BioCentury, March DelMar Pharmaceuticals Inc. (OTCBB:DMPI), Vancouver, B.C. 3). In 2012, GSK exercised an option to license exclusive, worldwide Guangxi Wuzhou Zhongheng Group Co. Ltd. (Shanghai:600252), rights to develop and commercialize GSK2586184 from Galapagos. Wuzhou, China Galapagos is eligible for up to €34 million ($46.6 million) in milestones, Product: VAL-083 (DAG for Injection) plus double-digit royalties (see BioCentury, Feb. 27, 2012). Business: Cancer Molecular target: DNA Genentech Inc., South San Francisco, Calif. Description: Small molecule bifunctional alkylating agent Chugai Pharmaceutical Co. Ltd. (Tokyo:4519), Tokyo, Japan Indication: Treat glioblastoma multiforme (GBM) Roche (SIX:ROG; OTCQX:RHHBY), Basel, Switzerland Endpoint: Maximum tolerated dose (MTD); objective response rate Product: Bitopertin (RO4917838) (R1678, RG1678) (ORR) Business: Neurology Status: Additional Phase I/II data Molecular target: Glycine transporter type 1 (GlyT1) (SLC6A9) Milestone: Start Phase II (2H14) Description: Glycine transporter type 1 (GlyT1; SLC6A9) inhibitor Data from 26 patients with refractory GBM in the first 5 cohorts of Indication: Treat persistent, predominant negative symptoms of schizo- an open-label, U.S. Phase I/II trial showed that 1.5, 3, 5, 10 and 20 mg/ phrenia m2 doses of IV VAL-083 were well tolerated with no treatment-related Endpoint: Mean change from baseline in Positive and Negative Symptom adverse events or dose-limiting toxicities (DLTs) reported. The MTD Scale (PANSS) negative symptoms factor scores at week 24; safety has not yet been reached. A 6th cohort is evaluating a 30 mg/m2 dose Status: Phase III discontinued of VAL-083. The trial is enrolling GBM patients previously treated with Milestone: NA surgery and/or radiation if appropriate and who failed both Avastin Roche disclosed in its 1Q14 earnings that it discontinued the bevacizumab and Temodar temozolomide unless contraindicated. Data double-blind, placebo-controlled, international Phase III MoonLyte and were presented at the American Association for Cancer Research SunLyte trials evaluating once-daily oral bitopertin as an add-on to meeting in San Diego. antipsychotic therapy based on futility analyses. MoonLyte was enroll- Last September, DelMar said FDA approved revising the dosing ing 600 patients with sub-optimally controlled symptoms of schizo- scheme to accelerate dose escalation in the trial. Under the revised phrenia, while SunLyte was enrolling 630 patients with persistent, schedule, DelMar skipped the 15 and 25 mg/m2 doses of VAL-083 (see predominant negative symptoms of schizophrenia. Roche also con- BioCentury, Sept. 13, 2013). DelMar reported data from the 1.5, 3 and 5 ducted a futility analysis of the double-blind, placebo-controlled, inter- mg/m2 cohorts of the trial in June 2013. VAL-083 has Orphan Drug national Phase III NightLyte trial evaluating bitopertin as an add-on to designation in the U.S. for glioma. Guangxi Wuzhou’s Guangxi Wuzhou See next page BioCentury Week in Review APRIL 21, 2014 PAGE B16 OF 26

Clinical Results, Indication: Treat sub-optimally controlled symptoms of schizophrenia from previous page Endpoint: Mean change from baseline in Positive and Negative Symptom Scale (PANSS) positive symptoms factor scores at week 12; safety antipsychotic therapy, but decided to continue the trial. NightLyte is Status: Phase III discontinued enrolling 600 patients with sub-optimally controlled symptoms of Milestone: NA schizophrenia. Roche disclosed in its 1Q14 earnings that it discontinued the Roche conducted the futility analyses on MoonLyte, SunLyte and double-blind, placebo-controlled, international Phase III MoonLyte and NightLyte after bitopertin missed the primary endpoint in 3 other Phase SunLyte trials evaluating once-daily oral bitopertin as an add-on to III trials in the SearchLyte program — TwiLyte, FlashLyte and DayLyte. antipsychotic therapy based on futility analyses. MoonLyte was enroll- The pharma disclosed in its earnings that the double-blind, interna- ing 600 patients with sub-optimally controlled symptoms of schizo- tional Phase III TwiLyte trial in 600 patients with sub-optimally con- phrenia, while SunLyte was enrolling 630 patients with persistent, trolled symptoms of schizophrenia missed the primary endpoint of predominant negative symptoms of schizophrenia. Roche also con- improving PANSS positive symptoms factor scores from baseline to ducted a futility analysis of the double-blind, placebo-controlled, inter- week 12 vs. placebo. In January, Roche said bitopertin missed the national Phase III NightLyte trial evaluating bitopertin as an add-on to primary endpoint of improving PANSS negative symptoms factor scores antipsychotic therapy, but decided to continue the trial. NightLyte is in both the FlashLyte and DayLyte trials, which each enrolled over 600 enrolling 600 patients with sub-optimally controlled symptoms of patients with persistent, predominant negative symptoms of schizo- schizophrenia. phrenia (see BioCentury, Jan. 27). Roche conducted the futility analyses on MoonLyte, SunLyte and SearchLyte comprises 6 Phase III trials evaluating bitopertin as an NightLyte after bitopertin missed the primary endpoint in 3 other Phase add-on to antipsychotic therapy in over 3,600 patients with schizophre- III trials in the SearchLyte program — TwiLyte, FlashLyte and DayLyte. nia. Negative symptoms of schizophrenia include social withdrawal and The pharma disclosed in its earnings that the double-blind, international lack of motivation and sub-optimally controlled symptoms of schizo- Phase III TwiLyte trial in 600 patients with sub-optimally controlled phrenia include hallucinations and delusions. Bitopertin is also in the symptoms of schizophrenia missed the primary endpoint of improving Phase II SkyLyte trial to treat obsessive compulsive disorder (OCD). PANSS positive symptoms factor scores from baseline to week 12 vs. Chugai, which is majority owned by Roche, has rights in Japan. placebo. In January, Roche said bitopertin missed the primary endpoint of improving PANSS negative symptoms factor scores in both the Indication: Treat sub-optimally controlled symptoms of schizophrenia FlashLyte and DayLyte trials, which each enrolled over 600 patients Endpoint: Mean change from baseline in Positive and Negative Symptom with persistent, predominant negative symptoms of schizophrenia (see Scale (PANSS) positive symptoms factor scores at week 12; safety BioCentury, Jan. 27). Status: Phase III discontinued SearchLyte comprises 6 Phase III trials evaluating bitopertin as an Milestone: NA add-on to antipsychotic therapy in over 3,600 patients with schizophre- Roche disclosed in its 1Q14 earnings that it discontinued the nia. Negative symptoms of schizophrenia include social withdrawal and double-blind, placebo-controlled, international Phase III MoonLyte and lack of motivation and sub-optimally controlled symptoms of schizo- SunLyte trials evaluating once-daily oral bitopertin as an add-on to phrenia include hallucinations and delusions. Bitopertin is also in the antipsychotic therapy based on futility analyses. MoonLyte was enroll- Phase II SkyLyte trial to treat obsessive compulsive disorder (OCD). ing 600 patients with sub-optimally controlled symptoms of schizo- Chugai, which is majority owned by Roche, has rights in Japan. phrenia, while SunLyte was enrolling 630 patients with persistent, predominant negative symptoms of schizophrenia. Roche also con- Genocea Biosciences Inc. (NASDAQ:GNCA), Cambridge, Mass. ducted a futility analysis of the double-blind, placebo-controlled, inter- Novavax Inc. (NASDAQ:NVAX), Rockville, Md. national Phase III NightLyte trial evaluating bitopertin as an add-on to Product: GEN-003 antipsychotic therapy, but decided to continue the trial. NightLyte is Business: Infectious enrolling 600 patients with sub-optimally controlled symptoms of Molecular target: Infected cell polypeptide 4 (ICP4) schizophrenia. Description: T cell vaccine consisting of the infected cell polypeptide Roche conducted the futility analyses on MoonLyte, SunLyte and 4 (ICP4) and gD2 antigens from herpes simplex virus-2 (HSV-2) com- NightLyte after bitopertin missed the primary endpoint in 3 other Phase bined with the saponin-derivative adjuvant Matrix M III trials in the SearchLyte program — TwiLyte, FlashLyte and DayLyte. Indication: Treat herpes simplex virus type 2 (HSV-2) infection The pharma disclosed in its earnings that the double-blind, international Endpoint: Safety; immunogenicity as measured by humoral (antibody) Phase III TwiLyte trial in 600 patients with sub-optimally controlled and T cell responses to vaccine antigens and the proportion of days with symptoms of schizophrenia missed the primary endpoint of improving viral shedding PANSS positive symptoms factor scores from baseline to week 12 vs. Status: Additional Phase I/IIa data placebo. In January, Roche said bitopertin missed the primary endpoint Milestone: Additional Phase I/IIa data (mid-2014); start Phase II (2014) of improving PANSS negative symptoms factor scores in both the Additional data from a double-blind, placebo-controlled, dose-esca- FlashLyte and DayLyte trials, which each enrolled over 600 patients lation, U.S. Phase I/IIa trial in 143 patients with moderate to severe HSV- with persistent, predominant negative symptoms of schizophrenia (see 2 infection who were otherwise healthy showed that GEN-003 containing BioCentury, Jan. 27). 30 µg each of ICP4 and gD2 reduced the number of clinical lesion days at SearchLyte comprises 6 Phase III trials evaluating bitopertin as an 6 months by 72% compared to baseline (p<0.001).Additionally, Genocea add-on to antipsychotic therapy in over 3,600 patients with schizophre- said the 50% reduction from baseline in mean viral shedding that was nia. Negative symptoms of schizophrenia include social withdrawal and observed at day 71 was maintained at 6 months following the 3 doses of lack of motivation and sub-optimally controlled symptoms of schizo- GEN-003 (p<0.001). Data were presented at the World Vaccine Congress phrenia include hallucinations and delusions. Bitopertin is also in the in Washington D.C. Phase II SkyLyte trial to treat obsessive compulsive disorder (OCD). Last year, Genocea reported that doses of GEN-003 containing 10, Chugai, which is majority owned by Roche, has rights in Japan. 30 or 100 µg each of ICP4 and gD2 given on days 0, 21 and 42 reduced See next page BioCentury Week in Review APRIL 21, 2014 PAGE B17 OF 26

Clinical Results, Indication: Treat Type I diabetes from previous page Endpoint: Total daily bolus amount of exogenous insulin required to maintain or improve glycemic control; total exogenous daily bolus and mean 28-day viral shedding from baseline to day 71 by 2%, 51% and 30%, basal insulin use, amount of exogenous use at each meal, change in respectively, vs. a 12% increase for placebo (p<0.001 for the 30 and 100 fasting plasma glucose (FPG) and postprandial glucose µg doses) (see BioCentury, Sept. 23, 2013). This year, Genocea plans to Status: Phase II data start a Phase II trial with GEN-003. Genocea has rights to use the Matrix Milestone: Start Phase III (year end 2014) M adjuvant in vaccines for 6 infectious diseases from Isconova AB, which Top-line data from a double-blind, U.S. Phase II trial in 33 Type I Novavax acquired (see BioCentury, Aug. 29, 2011). diabetics inadequately controlled on either an insulin pump or multiple insulin injection therapy showed that once-daily 400 mg oral LX4211 GlaxoSmithKline plc (LSE:GSK; NYSE:GSK), London, U.K. given before breakfast for 28 days met the primary endpoint of reducing Product: Darapladib (SB-480848) total daily mealtime bolus insulin dose vs. placebo. Specifically, LX4211 Business: Cardiovascular reduced total daily mealtime bolus insulin dose from baseline to day 28 Molecular target: Lipoprotein-associated phospholipase A2 (PLA2G7) by 32% compared to a 6% reduction for placebo (p=0.007). LX4211 also (PAFAH) (Lp-PLA2) met the secondary endpoints of reducing mean HbA1c from baseline to Description: Small molecule inhibitor of vascular inflammation mediator day 28 (0.55% vs. 0.06%, p=0.002), increasing time spent in a glucose lipoprotein-associated phospholipase A2 (PLA2G7; PAFAH; Lp-PLA2) range of 70-180 mg/dL (11.8% vs. a reduction of 1.9%, p=0.003), reducing Indication: Treat chronic coronary heart disease (CHD) time spent in hyperglycemic range (10.7% vs. an increase of 4.6%, Endpoint: Composite of major adverse cardiovascular events (MACE) p=0.002) and reducing body weight (1.72 kg vs. an increase of 0.5 kg, consisting of cardiovascular death, non-fatal myocardial infarction (MI) p=0.005) vs. placebo. LX4211 was well tolerated with no discontinuations and non-fatal stroke; major and total coronary events including CHD due to adverse events and no increase in hypoglycemia reported. death, non-fatal MI, urgent and non-urgent coronary revascularization By year end, Lexicon plans to start a Phase III trial with LX4211 to and hospitalization for unstable angina, individual components of MACE treat Type I diabetes with a primary endpoint of reduction in HbA1c. and all-cause mortality The company said it plans to partner LX4211 prior to starting Phase III Status: Additional Phase III data testing to treat Type II diabetes, for which the product has completed Milestone: NA a Phase IIb trial (see BioCentury, July 2, 2012 & July 22, 2013). Additional data from the double-blind, international Phase III STA- BILITY trial in 15,828 patients with chronic CHD showed that once- Oncoethix S.A., Lausanne, Switzerland daily 160 mg oral darapladib plus standard of care (SOC) met the Mitsubishi Tanabe Pharma Corp. (Tokyo:4508), Osaka, Japan secondary endpoints of reducing the rates of major coronary events Product: OTX015, Y-803 (9.3% vs. 10.3%, p=0.045) and total coronary events (14.9% vs. 16.1%, Business: Cancer p=0.019) vs. placebo plus SOC. Major coronary events comprised CHD Molecular target: Bromodomain containing 2 (BRD2); Bromodomain death, MI or urgent coronary revascularization for myocardial ischemia, containing 3 (BRD3) while total coronary events comprised CHD death, MI, hospitalization Description: Synthetic small molecule inhibitor of BET bromodomain for unstable angina or any coronary revascularization procedure. containing 2 (BRD2), BRD3 and BRD4 Additionally, darapladib plus SOC did not significantly improve any of Indication: Treat hematologic malignancies the individual components of MACE — cardiovascular death (4.5% vs. Endpoint: Dose-limiting toxicities (DLTs) and maximum tolerated dose 4.7%, p=0.59), MI (4.6% vs. 5.1%, p=0.11) or stroke (1.9% for both, (MTD); safety and pharmacokinetics p=0.92) — vs. placebo plus SOC. There was no difference in the rate Status: Interim Phase Ib data of all-cause mortality between treatment groups (7.3% for both, Milestone: NA p=0.87). Median follow-up was 3.7 years. SOC could include a statin, Interim data from an open-label, European Phase Ib trial in patients aspirin and blood pressure medications. Data were published in the with acute leukemia and other hematologic malignancies showed that New England Journal of Medicine and presented at the American College once-daily 10, 20, 40 and 80 mg and twice-daily 40 mg doses of oral of Cardiology meeting in Washington, D.C. OTX015 led to no DLTs. In patients with acute leukemia, the MTD was Last November, GlaxoSmithKline reported that darapladib plus not reached at the once-daily 80 mg dose or the twice-daily 40 mg dose. SOC missed the primary endpoint of reducing the occurrence of any The MTD was also not reached at the once-daily 80 mg dose for patients component of the composite of MACE vs. placebo plus SOC (9.7% vs. with other hematologic malignancies, but Oncoethix said the MTD was 10.4%, p=0.199) (see BioCentury, Nov. 18, 2013). GSK said it is waiting for exceeded at the twice-daily 40 mg dose in patients with other hemato- data from the Phase III SOLID-TIMI 52 trial of darapladib to treat acute logic malignancies. Grade 3/4 adverse events were reversible throm- coronary syndrome (ACS) to “better understand” the STABILITY bocytopenia, neutropenia, diarrhea and elevated transaminases. findings. Data from SOLID-TIMI 52 are expected this quarter. The In 28 patients evaluable for response, 4 patients with refractory or pharma gained darapladib through its 2012 acquisition of Human relapsed secondary or post-treatment acute myelogenous leukemia Genome Sciences Inc. (see BioCentury, Aug. 6, 2012). (AML) achieved significant peripheral and bone marrow blast decrease or clearance, including 1 complete remission and 1 complete remission Lexicon Pharmaceuticals Inc. (NASDAQ:LXRX), The Woodlands, with incomplete platelet recovery (CRp). Additionally, 1 patient with Texas diffuse large B cell lymphoma (DLBCL) had a partial response and 1 Product: LX4211 tablet patient with lymphoplasmacytic lymphoma had a metabolic partial Business: Endocrine/Metabolic response. Data were presented at the American Association for Molecular target: Sodium-glucose cotransporter 1 (SGLT1); Sodium- Cancer Research meeting in San Diego. Last year, Mitsubishi Tanabe glucose cotransporter 2 (SGLT2) granted Oncoethix exclusive, worldwide rights to OTX015. The pharma Description: Dual sodium-glucose cotransporter 1 (SGLT1) and SGLT2 retains rights to the compound in certain Asian countries (see BioCentury, inhibitor June 18, 2012). See next page BioCentury Week in Review APRIL 21, 2014 PAGE B18 OF 26

Clinical Results, Indication: Treat mucopolysaccharidosis VII (MPS VII; Sly syndrome) from previous page Endpoint: Safety and reduction of total urinary glycosaminoglycan (GAG) excretion; 6-minute walk test (6MWT), 3-minute stair climb Pharmanest AB, Solna, Sweden test (3MSCT), pulmonary function as measured by forced vital capacity Product: SHACT (FVC), forced expiratory volume in 1 second (FEV1) and maximal Business: Neurology voluntary ventilation (MVV1), and growth velocity for height and weight Molecular target: NA Status: Preliminary Phase I/II data Description: Topical 4% formulation of lidocaine Milestone: Additional Phase I/II data (2H14); start Phase III (2H14) Indication: Treat pain associated with hysteroscopies Preliminary data from 3 patients ages 5-30 years with MPS VII in an Endpoint: Feasibility of administering SHACT in conjunction with open-label, U.K. Phase I/II trial showed that 2 mg/kg IV UX003 given hysteroscopy; safety every other week for 2, 6 and 12 weeks, respectively, led to no serious Status: Feasibility study data adverse events and no infusion-associated reactions. Additionally, Milestone: NA urinary GAG excretion decreased by about 30-50% beginning at week An open-label, Swedish feasibility trial in 10 women undergoing 2. At the 12-week assessment of the first patient, absolute liver size was hysteroscopies in an outpatient setting showed that SHACT did not reduced by about 11%. A dose-exploration and long-term extension negatively interfere with the examination and that the product can be will follow the 12-week primary analysis phase. The trial is enrolling used in the outpatient setting to ease pain and discomfort. No safety up to 5 patients. Data were presented at the American College of or tolerability issues were reported. Pharmanest said pain relief was Medical Genetics and Genomics meeting in Nashville. not evaluated in the trial. The company plans to conduct an efficacy trial Next half, Ultragenyx plans to start a Phase III trial with UX003, to evaluate pain relief with SHACT in the indication, but could not be which has Orphan Drug designation in the U.S. and EU. Ultragenyx reached for when the trial will start. licensed rights to the product from St. Louis University (St. Louis, Mo.) Last year, Pharmanest reported data from a Phase II trial in 218 in 2012 (see BioCentury, Jan. 16, 2012). women ages 18-45 years showing that topical SHACT given during intrauterine device (IUD) insertion significantly reduced pain by 30% as PRECLINICAL RESULTS measured by a visual analog scale (VAS) vs. placebo (p<0.0001) (see BioCentury, Sept. 2, 2013). Karolinska Development AB (SSE:KDEV, Blueprint Medicines, Cambridge, Mass. Solna, Sweden) owns 63% of Pharmanest. Product: BLU9931 Business: Cancer Sorrento Therapeutics Inc. (NASDAQ:SRNE), San Diego, Calif. Indication: Treat hepatocellular carcinoma (HCC) Product: Resiniferatoxin (RTX) In mouse xenograft models of fibroblast growth factor 19 (FGF19) Business: Neurology amplified and FGF19 overexpressing HCC, oral BLU9931 led to sus- Molecular target: Transient receptor potential vanilloid 1 (TRPV1) tained, dose-dependent tumor regression. Data were presented at the (VR1) American Association for Cancer Research Meeting in San Diego. Description: Non-opiate agonist of the transient receptor potential Blueprint plans to start clinical testing with the selective small molecule vanilloid 1 (TRPV1; VR1) receptor inhibitor of fibroblast growth factor receptor 4 (FGFR4; CD334) in Indication: Treat severe refractory pain in patients with cancer 2015. FGF19 is the ligand of FGFR4. Endpoint: Safety and maximum tolerated dose (MTD); Brief Pain Index (BPI), Functional Assessment of Cancer Therapy-General scale (FACT- Celldex Therapeutics Inc. (NASDAQ:CLDX), Needham, Mass. G) and pain intensity numeric rating scale (NRS) scores Product: CDX-014 (formerly CR014-vcMMAE) Status: Phase I/II data Business: Cancer Milestone: NA Indication: Treat ovarian cancer and renal cell carcinoma (RCC) Researchers at NIH reported data from 6 patients with advanced In mouse xenograft models of ovarian cancer and RCC, 75, 150 and cancer and severe refractory pain in the first 2 cohorts of an open-label, 300 µg intraperitoneal injections of CDX-014 on days 0, 4, 8 and 12 each dose-escalation, U.S. Phase I/II trial showing that single intrathecal injec- significantly improved percent survival vs. saline-treated controls tions of 13 and 26 µg resiniferatoxin led to an overall mean improvement (p<0.05 for all). Data were presented at the American Association for from baseline to week 2 in BPI pain interference score of 1.6 points and Cancer Research Meeting in San Diego. CDX-014 is an antibody-drug in FACT-G score of 6.5 points. Patients also achieved an average 20% conjugate (ADC) composed of a humanized anti-hepatitis A virus reduction in pain intensity NRS score from baseline to week 2. cellular receptor 1 (HAVCR1; TIM1) mAb and monomethyl auristatin Resiniferatoxin was well tolerated with no opioid-like toxicities re- E (MMAE). In 2015, Celldex plans to start Phase I testing with CDX-014 ported. The trial plans to enroll 1 additional cohort to receive a higher to treat RCC and potentially other TIM1-expressing tumors. dose of resiniferatoxin. The trial was sponsored by NIH’s National Institute of Dental and Craniofacial Research (NIDCR). Data were pre- Genkyotex S.A., Plan-les-Ouates, Switzerland sented at the American Society of Regional Anesthesia and Pain Medicine Product: GKT137831 meeting in Chicago. Sorrento said it plans to “rapidly” begin a randomized, Business: Pulmonary controlled trial with resiniferatoxin, but could not be reached for details. Indication: Treat idiopathic pulmonary fibrosis (IPF) Sorrento gained resiniferatoxin through its 2013 acquisition of Sherrington In aged mice with established pulmonary fibrosis, GKT137831 led to Pharmaceuticals Inc. (see BioCentury, Oct. 21, 2013). a reversal of persistent fibrosis and improved survival. Data were published in Science Translational Medicine. The dual NADPH oxidase 1 (NOX1) Ultragenyx Pharmaceutical Inc. (NASDAQ:RARE), Novato, Calif. and NOX4 inhibitor is in Phase II testing to treat diabetic nephropathy. Product: UX003 (RhGUS) Business: Endocrine/Metabolic MacroGenics Inc. (NASDAQ:MGNX), Rockville, Md. Molecular target: NA Product: MGD007 Description: Recombinant human glucuronidase beta (rhGUS) See next page BioCentury Week in Review APRIL 21, 2014 PAGE B19 OF 26

Preclinical Results, Business: Cancer from previous page Indication: Treat squamous cell carcinoma of the head and neck (SCCHN) In a mouse model of SCCHN, KGP94 significantly delayed tumor Business: Cancer growth at doses of ≥10 mg/kg vs. control mice. Data were presented Indication: Treat colorectal cancer at the American Association for Cancer Research meeting in San Diego. In a mouse xenograft model of colorectal cancer, doses as low as 4 µg/ OxiGene could not be reached for next steps for the small molecule kg IV MGD007 inhibited tumor growth. In cynomolgus monkeys, once- cathepsin L inhibitor. weekly doses of up to 200 µg/kg MGD007 for 4 weeks were well tolerated. Data were presented at the American Association for Cancer Research Regulus Therapeutics Inc. (NASDAQ:RGLS), San Diego, Calif. meeting in San Diego. Next half, MacroGenics plans to start a Phase I trial Product: Anti-miR-221 with MGD007 to treat colorectal cancer. MGD007 is a bi-specific antibody Business: Cancer developed using MacroGenics’ Dual-Affinity Re-Targeting (DART) tech- Indication: Treat hepatocellular cancer (HCC) nology that is designed to redirect T cells to target glycoprotein A33 In a mouse xenograft model of HCC, thrice-weekly subcutaneous transmembrane (GPA33; A33)-expressing colorectal cancer cells. Servier 25 mg/kg anti-microRNA-221 (miR-221) oligonucleotides for 3 weeks (Neuilly-sur-Seine, France) has an exclusive option from MacroGenics to significantly inhibited tumor growth vs. vehicle-treated controls license rights to develop and commercialize MGD007 under a 2012 deal (p<0.005). Data were presented at the American Association for (see BioCentury, Sept. 24, 2012). Cancer Research meeting in San Diego. Regulus said further preclinical testing of the product is in progress. Earlier this year, Sanofi NanoAntibiotics Inc., Surfside, Fla. (Euronext:SAN; NYSE:SNY, Paris, France) extended a 2010 deal to Product: Efflux pump inhibitor discover, develop and commercialize microRNA therapeutics to treat Business: Infectious Orphan indications and cancer. Under the extension, Regulus granted Indication: Treat bacterial infections Sanofi an exclusive option to develop and commercialize Regulus’ In Staphylococcus epidermis bacteria incubated in vitro with tracer dye preclinical program targeting miR-221 (see BioCentury, June 28, 2010; July to monitor the bacteria’s membrane transport systems, NanoAntibiotics’ 1, 2013 & Feb. 10, 2014). efflux pump inhibitor inhibited expulsion of dye, while no dye retention was observed in untreated bacteria. According to NanoAntibiotics, Seattle Genetics Inc. (NASDAQ:SGEN), Bothell, Wash. bacteria efflux pumps are defense mechanisms that expel antibiotics Product: SGN-CD70A before they are able to reach their target and subsequently kill the Business: Cancer bacteria. The company said additional studies are ongoing, but could not Indication: Treat cancer be reached for details. In renal cell carcinoma (RCC) and non-Hodgkin’s lymphoma (NHL) cell lines, SGN-CD70A induced targeted cell killing via DNA damage. OncoMed Pharmaceuticals Inc. (NASDAQ:OMED), Redwood City, Data were presented at the American Association for Cancer Research Calif. meeting in San Diego. SGN-CD70A is an antibody-drug conjugate Product: OMP-305B83 (ADC) composed of an anti-CD70 mAb attached to a pyrrolobenzodi- Business: Cancer azepine (PBD) dimer. Next half, Seattle Genetics plans to start Phase Indication: Treat solid tumors I testing with SGN-CD70A. OncoMed said OMP-305B83 showed significant in vivo antitumor efficacy in various solid tumors, delayed tumor recurrence following TherapeuticsMD Inc. (NYSE-M:TXMD), Boca Raton, Fla. termination of chemotherapy and reduced the frequency of tumor- Product: Estradiol VagiCap (TX 004-HR) (formerly TX 12-004-HR) initiating cells. Data were presented at the American Association for Business: Endocrine/Metabolic Cancer Research meeting in San Diego. Next half, OncoMed plans to Indication: Treat moderate to severe symptoms of vulvar and vaginal submit an IND to FDA for the bi-specific antibody against delta-like 4 atrophy associated with menopause (DLL4) and VEGF. Last year, OncoMed granted Celgene Corp. A rabbit irritation study showed that TX 004-HR was “non-irritant” (NASDAQ:CELG, Summit, N.J.) exclusive options to jointly develop following a 28-day repeated application to the vaginal mucosa. and commercialize up to 6 of OncoMed’s cancer stem cell products, TherapeuticsMD said the study was conducted to meet an FDA require- including OMP-305B83. Celgene can exercise the options during or ment for any new component of a novel delivery system. The company after completion of Phase I trials (see BioCentury, Dec. 9, 2013). reported data from a Phase I trial with TX 004-HR last year (see BioCentury, Nov. 11, 2013). Next quarter, TherapeuticsMD plans to start Onconova Therapeutics Inc. (NASDAQ:ONTX), Newton, Pa. Phase III testing with the 17-beta estradiol using a VagiCap softgel Product: ON 1233000 capsule technology. TX 004-HR is being developed under section Business: Cancer 505(b)(2) of the Food, Drug and Cosmetic Act, which allows sponsors Indication: Treat mantle cell lymphoma (MCL) and multiple myeloma to reference data on safety and efficacy from the scientific literature or (MM) from previously approved products. In a mouse xenograft model of MCL, once-daily 100 mg/kg ON 123300 inhibited tumor growth with “little evidence of toxicity.” In a mouse CLINICAL STATUS xenograft model of MM, 100 mg/kg ON 123300 given every other day significantly inhibited tumor growth vs. vehicle-treated controls. Data Abbott Laboratories (NYSE:ABT), Abbott Park, Ill. were presented at the American Association for Cancer Research meeting Product: Absorb (bioresorbable vascular scaffold) in San Diego. ON 123300 is an inhibitor of cyclin dependent kinase 4 Business: Cardiovascular (CDK4), CDK6 and NUAK family SNF-like kinase 1 (NUAK1; ARK5). Molecular target: Mammalian target of rapamycin (mTOR) (FRAP) (RAFT1) OxiGene Inc. (NASDAQ:OXGN), South San Francisco, Calif. Description: Everolimus-eluting bioabsorbable scaffold made of Product: KGP94 See next page BioCentury Week in Review APRIL 21, 2014 PAGE B20 OF 26

Clinical Status, Endpoint: Overall survival (OS); progression-free survival (PFS), objec- from previous page tive response rate (ORR) and safety Status: Phase III started polylactic acid Milestone: NA Indication: Treat coronary artery disease (CAD) AbbVie began a double-blind, placebo-controlled, U.S. Phase III trial Endpoint: Non-inferiority at 1 year in target lesion failure (TLF), defined to compare oral veliparib in combination with carboplatin plus paclitaxel as composite of cardiac death, myocardial infarction (MI) or ischemic- vs. carboplatin plus paclitaxel in about 900 patients. driven target lesion revascularization; change in mean lumen diameter (MLD) and change in mean lumen area (MLA) within the scaffold Acorda Therapeutics Inc. (NASDAQ:ACOR), Ardsley, N.Y. Status: Completed pivotal trial enrollment Alkermes plc (NASDAQ:ALKS), Dublin, Ireland Milestone: Pivotal trial data (2014) Biogen Idec Inc. (NASDAQ:BIIB), Weston, Mass. Abbott completed enrollment of about 2,000 patients with ischemic Product: Ampyra dalfampridine (Fampyra fampridine - EU) (BIIB041) heart disease caused by de novo native coronary artery lesions in the Business: Neurology single-blind, U.S. pivotal ABSORB III trial comparing Absorb vs. the Molecular target: Potassium channel company’s marketed Xience V or Xience Prime everolimus-eluting coro- Description: Sustained-release formulation of 4-aminopyridine (4-AP) nary stent systems. Abbott plans to report data from the European Indication: Treat post-stroke walking deficits ABSORB II trial in about 500 patients this year. Absorb has CE Mark Endpoint: NA approval and is marketed in Europe, the Middle East and parts of Latin Status: Phase III delayed America and Asia-Pacific, including India, Hong Kong, Malaysia and New Milestone: Start Phase III (2H14) Zealand. Abbott has a license to use everolimus, an mTOR inhibitor, in Acorda said it will delay the start of a Phase III trial to evaluate once- stents from Novartis AG (NYSE:NVS; SIX:NOVN, Basel, Switzerland). daily Ampyra in patients with post-stroke walking deficits to 2H14 from 2Q14. Acorda said the manufacturer of the once-daily formulation had Indication: Treat coronary artery disease (CAD) informed it of an alcohol dose dumping finding in vitro. Acorda will Endpoint: In-segment late loss at 1 year; device and procedural success, perform a clinical study in healthy volunteers to determine whether the myocardial infarction (MI) or ischemic-driven target lesion finding exists in vivo. The study is expected to complete next quarter. revascularization Ampyra is marketed in the U.S. to improve walking ability in multiple Status: Completed pivotal trial enrollment sclerosis (MS) patients and has conditional approval in the EU as Fampyra Milestone: Pivotal trial data (2014) fampridine. Acorda, which granted Biogen Idec rights to the compound for Abbott completed enrollment of about 400 patients with ischemic all indications outside the U.S., has worldwide rights from Alkermes. heart disease caused by de novo native coronary artery lesions in the Alkermes gained the product through its 2011 acquisition of the Elan Drug Chinese pivotal ABSORB China trial evaluating comparing Absorb vs. Technologies drug delivery business of Elan Corp. plc, which Perrigo Co. the company’s marketed Xience V everolimus-eluting coronary stent plc (NYSE:PRGO, Tel Aviv:PRGO, Dublin, Ireland) acquired. system. Abbott plans to report data from the European ABSORB II trial in about 500 patients this year. Absorb has CE Mark approval and is Agios Pharmaceuticals Inc. (NASDAQ:AGIO), Cambridge, Mass. marketed in Europe, the Middle East and parts of Latin America and Asia- Product: AG-348 Pacific, including India, Hong Kong, Malaysia and New Zealand. Abbott Business: Endocrine/Metabolic has a license to use everolimus, an mTOR inhibitor, in stents from Molecular target: NA Novartis AG (NYSE:NVS; SIX:NOVN, Basel, Switzerland). Description: Oral small molecule activator of pyruvate kinase R Indication: Treat pyruvate kinase deficiency Indication: Treat coronary artery disease (CAD) Endpoint: Safety and pharmacokinetics Endpoint: Non-inferiority at 1 year in target lesion failure (TLF); late Status: Phase I started loss at 13 months, change in average lumen diameter, change in average Milestone: NA lumen area Agios began a double-blind, placebo-controlled, U.S. Phase I trial to Status: Completed pivotal trial enrollment evaluate single ascending-doses of oral AG-348 in about 48 healthy Milestone: Pivotal trial data (2014) volunteers. Abbott completed enrollment of about 400 patients with ischemic heart disease caused by de novo native coronary artery lesions in the Akebia Therapeutics Inc. (NASDAQ:AKBA), Cambridge, Mass. Japanese pivotal ABSORB Japan trial evaluating comparing Absorb vs. Product: AKB-6548 the company’s marketed Xience Prime everolimus-eluting coronary Business: Hematology stent system. Abbott plans to report data from the European ABSORB Molecular target: Hypoxia-inducible factor prolyl hydroxylase (HIF- II trial in about 500 patients this year. Absorb has CE Mark approval and PH) (EGLN) is marketed in Europe, the Middle East and parts of Latin America and Description: Oral hypoxia-inducible factor prolyl hydroxylase (HIF- Asia-Pacific, including India, Hong Kong, Malaysia and New Zealand. PH; EGLN) inhibitor Abbott has a license to use everolimus, an mTOR inhibitor, in stents Indication: Treat anemia in patients with chronic kidney disease (CKD) from Novartis AG (NYSE:NVS; SIX:NOVN, Basel, Switzerland). Endpoint: Proportion of patients achieving or maintaining a hemoglobin response; need for transfusion and/or erythropoietin-stimulating agent AbbVie Inc. (NYSE:ABBV), Chicago, Ill. (ESA) rescue and safety Product: Veliparib (ABT-888) Status: Completed Phase IIb enrollment Business: Cancer Milestone: Phase IIb data (4Q14) Molecular target: Poly(ADP-ribose) polymerase (PARP) Akebia completed enrollment of 209 CKD patients who are not Description: Oral inhibitor of poly(ADP-ribose) polymerase (PARP) dependent on dialysis in a double-blind, placebo-controlled, U.S. Phase Indication: Treat previously untreated patients with locally advanced or IIb trial evaluating oral AKB-6548 once daily for 20 weeks. metastatic squamous non-small cell lung cancer (NSCLC) See next page BioCentury Week in Review APRIL 21, 2014 PAGE B21 OF 26

Clinical Status, Description: Nanoparticle formulation of doxorubicin from previous page Indication: Treat hepatocellular carcinoma (HCC) Endpoint: Overall survival (OS); time to progression, best response, Aprea AB, Solna, Sweden safety, quality of life (QOL) and pharmacoeconomics Product: APR-246 (PRIMA-1MET) Status: Phase III ongoing Business: Cancer Milestone: Complete Phase III enrollment (year end 2015); Phase III data Molecular target: p53 (year end 2016) Description: Small molecule quinuclidinone that promotes correct BioAlliance said an independent DSMB for a fourth time recom- folding of p53 mended continuation of the open-label, international Phase III ReLive Indication: Treat relapsed, platinum-sensitive, high-grade serous ova- trial evaluating 20 and 30 mg/m2 IV Livatag in about 400 patients with rian cancer HCC resistant or intolerant to sorafenib based on safety data. The Endpoint: Safety and pharmacokinetics (Phase Ib) and progression-free DSMB meets every 6 months and/or after the recruitment of 75 patients survival (PFS) (Phase II); overall survival (OS), overall response rate in ReLive (see BioCentury, Oct. 28, 2013). (ORR) and safety (Phase II) Livatag has Orphan Drug designation in the U.S. and EU to treat Status: Phase Ib/II started HCC. Bayer AG (Xetra:BAYN, Leverkusen, Germany) and Onyx Phar- Milestone: NA maceuticals Inc., which Amgen Inc. (NASDAQ:AMGN, Thousand Oaks, Aprea began the 2-part, European Phase Ib/II PiSARRO trial to Calif.) acquired, market Nexavar sorafenib. evaluate IV APR-246 in combination with carboplatin and pegylated doxorubicin in about 180 patients. The open-label first part will Capstone Therapeutics Corp. (NASDAQ:CAPS), Tempe, Ariz. evaluate multiple ascending-doses of APR-246, while the randomized, LipimetiX LLC, Boston, Mass. controlled second part will compare APR-246 plus carboplatin and Product: AEM-28 pegylated doxorubicin vs. carboplatin plus pegylated doxorubicin. APR- Business: Endocrine/Metabolic 246 has completed a Phase I/II trial for refractory hematologic malignan- Molecular target: Low-density lipoprotein receptor-related proteins cies and prostate cancer. The product has Orphan Drug designation in (LRP); Heparan sulfate proteoglycan receptor Europe to treat acute myelogenous leukemia (AML). Description: Apolipoprotein E (APOE) mimetic Indication: Treat hypercholesterolemia Bayer AG (Xetra:BAYN), Leverkusen, Germany Endpoint: Safety and pharmacokinetics Johnson & Johnson (NYSE:JNJ), New Brunswick, N.J. Status: Phase Ia started Product: Xarelto rivaroxaban (BAY 59-7939) Milestone: NA Business: Cardiovascular LipimetiX Development LLC began a double-blind, placebo-con- Molecular target: Factor Xa trolled, Australian Phase Ia trial to evaluate single and multiple ascend- Description: Direct Factor Xa inhibitor ing-doses of IV AEM-28 in about 36 healthy volunteers with elevated Indication: Reduce the risk of symptomatic deep vein thrombosis (DVT) cholesterol. LipimetiX Development is a JV between Capstone and and/or pulmonary embolism (PE) due to a concurrent medical illness LipimetiX LLC formed in 2012 to develop LipimetiX’s mimetics of after hospital discharge APOE, including AEM-28 (see BioCentury, Aug. 13, 2012). AEM-28 has Endpoint: Time to first occurrence of symptomatic venous throm- Orphan Drug designation in the U.S. to treat homozygous familial boembolism (VTE) event and VTE-related death and time to first hypercholesterolemia (hoFH). occurrence of major bleeding; time to an occurrence of VTE-related death, time to first occurrence of a symptomatic VTE, time to first Coronado Biosciences Inc. (NASDAQ:CNDO), Burlington, Mass. occurrence of a composite of symptomatic VTE and all-cause mortality Product: Trichuris suis ova (TSO) (CNDO-201) and time to an occurrence of all-cause mortality Business: Neurology Status: Phase III started Molecular target: NA Milestone: NA Description: Ova from the porcine helminth Trichuris suis that acts as a Bayer began the double-blind, placebo-controlled, international natural immunomodulator to regulate T cells and inflammatory cytokines Phase III MARINER trial to evaluate 7.5 and 10 mg oral Xarelto once daily following colonization of the host intestinal tract for 45 days in about 8,000 patients hospitalized for acute medical illness Indication: Treat autism spectrum disorder (ASD) who were discharged. Bayer markets Xarelto in the EU to prevent Endpoint: Aberrant Behavior Checklist (ABC) subscale scores; change atherothrombotic events in combination with standard antiplatelet from baseline in Children’s Yale-Brown Obsessive Compulsive Scale therapy after acute coronary syndrome (ACS) in adults with elevated (CY-BOCS), Clinical Global Impression Improvement Scale (CGI-I), cardiac biomarkers, to treat PE and DVT, to prevent VTE in patients social responsiveness scale (SRS) and social communication question- undergoing hip or knee replacement surgery, and to prevent stroke and naire (SCQ) systemic embolism in patients with non-valvular atrial fibrillation (AF) Status: Phase II started and recurrent DVT and PE following an acute DVT. Milestone: NA Xarelto is approved in the U.S. to prevent DVT and PE in patients Coronado said investigators at the Hadassah-Hebrew University undergoing hip or knee replacement surgery, to reduce the risk of Medical Center began a double-blind, placebo-controlled, Israeli Phase stroke and systemic embolism in patients with non-valvular AF, to treat II trial to evaluate 2,500 or 7,500 Trichuris suis ova every other week for DVT or PE and to reduce the risk of recurrent DVT. Johnson & Johnson 16 weeks in 60 ASD patients ages 6-17 years. Last November, Coronado has U.S. rights to the product from Bayer. said partner Dr. Falk Pharma GmbH (Freiburg, Germany) discontinued the Phase II TRUST-II trial to treat Crohn’s disease (CD) due to a “lack BioAlliance Pharma S.A. (Euronext:BIO), Paris, France of efficacy” of TSO in a second interim analysis (see BioCentury, Nov. 11, Product: Livatag doxorubicin Transdrug (BA-003) 2013). Coronado said it will continue to work to advance the develop- Business: Cancer ment of TSO for the treatment of autoimmune diseases. TSO is also in Molecular target: DNA See next page BioCentury Week in Review APRIL 21, 2014 PAGE B22 OF 26

Clinical Status, receive 2 doses of Heplisav at 0 and 1 month or 3 Engerix-B doses at 0, from previous page 1 and 6 months. Dynavax said the trial was designed to address a February 2013 complete response letter for Heplisav and is intended to provide a investigator-initiated Phase II trials to treat ulcerative colitis (UC), sufficiently-sized safety database for FDA to complete its review of a BLA multiple sclerosis (MS), autism and psoriasis. In 2012, Coronado and for Heplisav (see BioCentury, March 4, 2013; June 17, 2013 & Oct. 28, 2013). Dr. Falk finalized a deal to co-develop and commercialize TSO to treat HBV-23 will evaluate all subjects for safety for 1 year. CD (see BioCentury, March 26, 2012). In February, Dynavax withdrew an MAA from EMA for Heplisav after the agency said Heplisav’s safety database was too small to rule out a Critical Pharmaceuticals Ltd., Nottingham, U.K. risk of less common serious adverse events (see BioCentury, Feb. 24). Product: Teriparatide nasal spray (CP046) GlaxoSmithKline plc (LSE:GSK; NYSE:GSK, London, U.K.) markets Business: Musculoskeletal Engerix-B to treat HBV infection. Molecular target: Parathyroid hormone (PTH) receptor Description: Nasal spray formulation of teriparatide, a human parathy- Endo International plc (NASDAQ:ENDP; TSX:ENL), Dublin, Ireland roid hormone (PTH) fragment, formulated using CriticalSorb nasal Aeolus Pharmaceuticals Inc. (OTCQB:AOLS), Mission Viejo, Calif. delivery technology Arca biopharma Inc. (NASDAQ:ABIO), Broomfield, Colo. Indication: Treat osteoporosis Medtronic Inc. (NYSE:MDT), Minneapolis, Minn. Endpoint: Pharmacokinetics; percentage of radiolabelled formulation Product: Gencaro bucindolol deposited and cleared from the nose as measured by gamma scintigraphy Business: Cardiovascular Status: Phase I started Molecular target: Adrenergic receptor beta (ADRB) Milestone: NA Description: Non-selective beta blocker and mild vasodilator Critical Pharmaceuticals and the University of Nottingham Indication: Prevent atrial fibrillation (AF) (Nottingham, U.K.) began an open-label, U.K. Phase I trial to compare Endpoint: Time to first event of symptomatic AF/atrial flutter or all- single doses of 22.5, 45 and 90 µg CP046 vs. 20 µg subcutaneous cause mortality during the 24 week follow-up after conversion to stable teriparatide in about 7 healthy volunteers. The trial will evaluate 2 nasal sinus rhythm; time to first event of AF/atrial flutter or all-cause delivery devices. Critical Pharmaceuticals is developing the product mortality at week 24, proportion of patients with ventricular tachycar- with the university under a 2012 deal (see BioCentury, Feb. 27, 2012). Eli dia, ventricular fibrillation or symptomatic supraventricular tachycar- Lilly and Co. (NYSE:LLY, Indianapolis, Ind.) markets teriparatide as dia at week 24 and total number of hospitalization days Forteo in the U.S. and as Forsteo in the EU to treat osteoporosis in Status: Phase IIb/III started postmenopausal women. Milestone: NA Arca began the double-blind, placebo-controlled, U.S. Phase IIb/III Dicerna Pharmaceuticals Inc. (NASDAQ:DRNA), Watertown, Mass. GENETIC-AF trial to compare 6.25, 12.5, 25, 50 and 100 mg oral Product: DCR-MYC Gencaro twice daily vs. 25, 50, 100 and 200 mg oral Toprol-XL Business: Cancer metoprolol succinate twice daily in about 620 patients with a genetic Molecular target: v-myc myelocytomatosis viral oncogene homolog variant of ADRB1 who have heart failure and reduced left ventricular (MYC) (c-Myc) ejection fraction (LVEF). Laboratory Corp. of America Holdings Description: Dicer substrate short interfering RNA targeting v-myc (NYSE:LH, Burlington, N.C.) is genotyping the patients. The company myelocytomatosis viral oncogene homolog (MYC; c-Myc) mRNA and Arca are collaborating to develop a companion diagnostic. Indication: Treat cancer The Phase IIb portion will enroll about 200 patients, and the Phase Endpoint: Maximum tolerated dose (MTD) and safety; pharmacokinet- III portion will enroll an additional 420 patients. Arca will also conduct ics and objective response or disease stabilization a substudy with Medtronic to continuously monitor cardiac rhythms of Status: Phase I started all patients in the Phase IIb portion. The substudy will measure AF Milestone: Phase I data (2H15) burden, defined as a patient’s actual time in AF regardless of symptoms. Dicerna began an open-label, dose-escalation, U.S. Phase I trial to Arca has rights to Gencaro from CPEC LLC, a company jointly owned evaluate IV DCR-MYC, with a starting dose of 0.1 mg/kg, given on days by Aeolus and Endo. AstraZeneca plc (LSE:AZN; NYSE:AZN, London, 1, 8 and 15 in 28-day cycles in about 66 patients with solid tumors, U.K.) markets Toprol-XL to treat hypertension, angina and heart failure. multiple myeloma (MM) or lymphoma who are refractory or unrespon- sive to standard therapies. Karyopharm Therapeutics Inc. (NASDAQ:KPTI), Natick, Mass. Product: Selinexor (KPT-330) Dynavax Technologies Corp. (NASDAQ:DVAX), Berkeley, Calif. Business: Cancer Product: Heplisav (V270) Molecular target: Exportin 1 (XPO1) (CRM1) Business: Infectious Description: Oral selective inhibitor of nuclear export (SINE) protein Molecular target: Toll-like receptor 9 (TLR9) exportin 1 (XPO1; CRM1) Description: Hepatitis B surface antigen (HBsAg) given with Indication: Treat acute myelogenous leukemia (AML) immunostimulatory DNA sequences that target toll-like receptor 9 Endpoint: Maximum tolerated dose (MTD); safety, overall response (TLR9) rate (ORR), complete response rate and biomarkers Indication: Prevent HBV infection Status: Phase I started Endpoint: Non-inferiority of peak seroprotection rate (SPR) in Type II Milestone: NA diabetics at week 28 and safety Karyopharm began an open-label, U.S. Phase I trial to evaluate oral Status: Phase III started selinexor in combination with IV decitabine in up to 42 patients with Milestone: Complete Phase III enrollment (year end 2014); complete relapsed or refractory AML and patients ages ≥60 years with newly Phase III (4Q15) diagnosed AML who are ineligible for intensive chemotherapy. Patients Dynavax began the double-blind, U.S. Phase III HBV-23 trial to compare will receive decitabine on days 1-10 and selinexor twice weekly for 3 Heplisav vs. Engerix-B in 8,250 patients ages 18-70 years. Subjects will See next page BioCentury Week in Review APRIL 21, 2014 PAGE B23 OF 26

Clinical Status, III EUPHRATES trial of Toraymyxin. The company said the increase from previous page “enhances the likelihood of demonstrating, with sufficient power, a statistically and clinically significant effect.” In March, Spectral Diagnos- weeks beginning on day 11 of a 31-day cycle for up to 4 cycles. Otsuka tics said EUPHRATES did not meet the stopping rules for safety, efficacy Pharmaceutical Co. Ltd. (Tokyo, Japan) markets Dacogen decitabine. and futility and that the DSMB requested additional analysis of the patients prior to completing the recalculation (see BioCentury, March PanOptica Inc., Mount Arlington, N.J. 17). EUPHRATES, which has enrolled 271 patients, is comparing Astellas Pharma Inc. (Tokyo:4503), Tokyo, Japan Toraymyxin plus standard of care (SOC) vs. SOC alone. The company Product: PAN-90806 also said it plans to submit a protocol amendment to FDA to include Business: Ophthalmic an additional exclusion criterion at the DSMB’s recommendation. Molecular target: Vascular endothelial growth factor (VEGF) Description: Small molecule selective inhibitor of VEGF StemCells Inc. (NASDAQ:STEM), Newark, Calif. Indication: Treat wet age-related macular degeneration (AMD) Product: HuCNS-SC (human neural stem cells) Endpoint: Safety Business: Neurology Status: Phase I started Molecular target: Not applicable Milestone: Phase I data (year end 2014) Description: Purified human neural stem cells PanOptica began a 2-month, open-label, U.S. Phase I trial to evaluate Indication: Treat chronic spinal cord injury (SCI) 3 dose levels of topical ocular PAN-90806 daily in about 30 patients with Endpoint: Safety; changes in sensation, motor and bowel/bladder function active, subfoveal choroidal neovascularization associated with wet Status: Completed Phase I/II enrollment AMD. PanOptica has exclusive, worldwide rights to PAN-90806 for Milestone: Interim Phase I/II data (05/2014); final Phase I/II data (mid- ophthalmic indications from OSI Pharmaceuticals Inc., now part of 2015) Astellas (see BioCentury, Jan. 10, 2011). StemCells completed enrollment of 12 patients with chest-level injury to the spinal cord in an open-label, international Phase I/II trial Repros Therapeutics Inc. (NASDAQ:RPRX), The Woodlands, Texas evaluating HuCNS-SC cells transplanted into the spinal cord. The trial Product: Androxal enclomiphene enrolled 7 patients with complete paralysis classified as A on the Business: Endocrine/Metabolic American Spinal Injury Association Impairment Scale (AIS) and 5 pa- Molecular target: Androgen receptor; Estrogen receptor tients with incomplete paralysis classified as AIS B. Patients who Description: Trans-isomer of clomiphene citrate complete the trial are eligible to enroll in a separate 4-year observa- Indication: Treat secondary hypogonadism tional study. Last year, the company reported data from the first 3 Endpoint: Composite endpoint of normal 24-hour average testoster- patients in the trial (see BioCentury, Feb. 18, 2013). This year, the company one levels (300-1,040 ng/dL) and sperm concentration (≥15 million/ plans to start a Phase II trial with HuCNS-SC cells to treat cervical SCI. mL); proportion of patients with a mean sperm concentration of <15 million/mL after 16 weeks Theravance Inc. (NASDAQ:THRX), South San Francisco, Calif. Status: Completed Phase III enrollment Product: TD-4208 (formerly GSK1160724) Milestone: Submit NDA (4Q14) Business: Pulmonary Repros completed enrollment of 120 patients in the double-blind, Molecular target: Muscarinic receptor placebo-controlled, U.S. Phase III ZA-305 trial comparing 12.5 or 25 mg Description: Inhaled long-acting muscarinic antagonist (LAMA) oral Androxal vs. AndroGel 1.62% testosterone gel for 16 weeks. The Indication: Treat chronic obstructive pulmonary disease (COPD) company said it expects to complete enrollment of 120 patients in the Endpoint: Trough forced expiratory volume in 1 second (FEV1) at day identical Phase III ZA-304 trial “in the next few weeks.” In 4Q14, Repros 28; serial FEV1 on day 1 and 28 and safety plans to submit an NDA to FDA for Androxal to treat secondary Status: Phase IIb started hypogonadism. The company previously said FDA agreed to head-to- Milestone: NA head studies to compare Androxal against approved testosterone Theravance began the double-blind, placebo-controlled, U.S. Phase replacement products for possible inclusion in Androxal’s label. Re- IIb Study 0117 to evaluate 44, 88, 175 and 350 µg TD-4208 once daily pros said the studies are intended to expand Androxal’s label and that delivered via a jet nebulizer for 28 days in about 350 patients with the studies’ completions will not affect the timeline of the NDA moderate to severe COPD. This quarter, Theravance expects to com- submission. AbbVie Inc. (NYSE:ABBV, Chicago, Ill.) markets AndroGel. plete its split into 2 publicly traded companies to separate its partnered late-stage respiratory assets from its R&D. One company — Theravance Spectral Diagnostics Inc. (TSX:SDI; OTCQX:DIAGF), Toronto, Inc. — will manage all development and commercial responsibilities plus Ontario potential royalty revenues for long-acting adrenergic receptor beta 2 Product: Toraymyxin polymyxin B immobilized fiber column agonist (LABA) products partnered with GlaxoSmithKline plc (LSE:GSK; Business: Infectious NYSE:GSK, London, U.K.). TD-4208 will be part of the other company Molecular target: NA — Theravance Biopharma — after the split. Description: Hemoperfusion absorption column made of polystyrene fiber immobilized with the antibiotic polymyxin B UCB Group (Euronext:UCB), Brussels, Belgium Indication: Treat septic shock Wilex AG (Xetra:WL6), Munich, Germany Endpoint: Mortality at 28 days; mortality at 90 days and at 6 and 12 Product: WX-554, MK-554 months Business: Cancer Status: Phase III ongoing Molecular target: MEK Milestone: Complete Phase III enrollment (1H16) Description: Orally available, small molecule MEK inhibitor Spectral Diagnostics plans to increase enrollment to 650 patients Indication: Treat solid tumors from 360 following a planned sample size recalculation recommended Endpoint: Safety, pharmacokinetics and clinical activity by a DSMB in the double-blind, sham-controlled, North American Phase See next page BioCentury Week in Review APRIL 21, 2014 PAGE B24 OF 26

OFFERINGS & SECURITIES TRANSACTIONS

Week ended 4/17/14. Shares after Price: C$0.60 Cel-Sci Corp. (NYSE-M:CVM), Investors: Institutional investors; offering refers to shares outstand- Shares after offering: 36.4 million Vienna, Va. Dexcel Pharma ing. Proceeds are gross, not net. Note: The company raised Business: Cancer, Infectious Note: Each unit comprises a share Shares offered don’t include C$909,960 ($829,429) in the Date completed: 4/17/14 and a five-year warrant to pur- overallotments. Currency rates second close of a private place- Type: Follow-on chase a share at C$0.81. Existing used in the week: A$=$0.9398; ment, bringing the total raised Raised: $10 million investor Dexcel Pharma pur- C$=$0.9115; €=$1.3851; £= to C$3.9 million ($3.6 million). Units: 7.1 million chased 6.2 million units for C$4 $1.673; SEK=$0.1528 Antibe raised C$3 million ($2.7 Price: $1.40 (unit) million ($3.6 million) in the offer- million) in the first close of the Shares after offering: 65.4 million ing and now holds a 17.5% stake. offering in March. Underwriters: Dawson James Se- Completed Offerings curities; Laidlaw Epirus Biopharmaceuticals Benitec Biopharma Ltd. (ASX: Note: Each unit comprises a share Inc., Boston, Mass. AAVLife, Paris, France BLT), Sydney, Australia and a six-month warrant to pur- Business: Biosimilars, Autoim- Business: Neurology, Gene/Cell Business: Functional genomics, chase 0.25 shares, with each whole mune, Antibodies therapy Proteomics warrant exercisable at $1.58. Date completed: 4/16/14 Date completed: 4/15/14 Date completed: 4/15/14 Type: Venture financing Type: Venture financing Type: Private placement Cynapsus Therapeutics Inc. Raised: $36 million Raised: $12 million Raised: A$15.7 million ($14.8 (TSX:CTH), Toronto, Ontario Investors: Livzon Mabpharm; Ad- Investors: Versant Ventures; million) Business: Drug delivery, Neurol- age Capital Management; Green- Inserm Transfert Initiative Shares: 14.7 million ogy woods Investment; Gibralt U.S.; Price: A$1.07 Date completed: 4/15/14 Monashee Capital; Mousse Part- Antibe Therapeutics Inc. (TSX- Shares after offering: 114.9 mil- Type: Private placement of units ners; TPG Biotech; Montreux Eq- V:ATE), Hamilton, Ontario lion Raised: C$25 million ($22.8 mil- uity Partners; 5AM Ventures Business: Inflammation, Neurol- Placement agents: Maxim Group; lion) ogy, Autoimmune Lodge Corporate Units: 38.5 million Eventus Diagnostics Inc., Mi- Date completed: 4/7/14 Investors: RA Capital Management; Price: $0.65 (unit) ami, Fla. Type: Private placement Perceptive Advisors; Special Situ- Shares after offering: 78.6 million Business: Diagnostic, Cancer Raised: C$909,960 ($829,429) ations Funds; Sabby Management; Placement agents: M Partners; Date completed: 4/15/14 Shares: 1.5 million institutional investors Noble Financial Capital Markets See next page

Clinical Status, VentiRx Pharmaceuticals Inc., Seattle, Wash. from previous page Product: VTX-2337 Business: Cancer Status: Development discontinued Molecular target: Toll-like receptor 8 (TLR8) Milestone: NA Description: Small molecule toll-like receptor 8 (TLR8) agonist Wilex disclosed in its 1Q14 earnings that it discontinued develop- Indication: Treat recurrent or persistent epithelial ovarian, fallopian ment of WX-554. The compound was in an open-label, dose-escalation, tube or primary peritoneal cancer in patients who have failed prior U.K. Phase Ib/II trial to treat solid tumors. The company said the therapy discontinuation is part of its restructuring announced in January (see Endpoint: Overall survival (OS); progression-free survival (PFS) and BioCentury, Feb. 3). Wilex has rights to WX-554 from UCB under a 2009 safety deal (see BioCentury, Jan. 12, 2009). Wilex said it is discussing further Status: Completed Phase II enrollment terms for WX-554 with UCB. Milestone: Phase II data (year end 2015) VentiRx completed enrollment of >290 patients with recurrent or Product: WX-037 persistent epithelial ovarian, fallopian tube or primary peritoneal Business: Cancer cancer who have failed prior platinum-based chemotherapy in a double- Molecular target: Phosphoinositide 3-kinase (PI3K) blind, placebo-controlled, North American Phase II trial comparing Description: Phosphoinositide 3-kinase (PI3K) inhibitor VTX-2337 plus Doxil doxorubicin vs. Doxil alone. Patients will Indication: Treat solid tumors receive VTX-2337 on days 3, 10 and 17 of a 28-day cycle for the first Endpoint: Dose-limiting toxicities (DLTs); safety and pharmacokinetics 4 cycles. Patients will receive VTX-2337 on day 3 only starting with Status: Development discontinued the fifth cycle. VentiRx, which is conducting the trial with the Milestone: NA Gynecologic Oncology Group, expects event-driven analysis of the Wilex disclosed in its 1Q14 earnings that it discontinued development trial in late 2015. of WX-037. The compound was in an open-label, dose-escalation, U.K. In July, VentiRx began the Phase II ACTIVE8 trial to evaluate 3 mg/ Phase I trial evaluating WX-037 alone and in combination with WX-554 m2 IV VTX-2337 plus standard of care to treat squamous cell carcinoma to treat solid tumors. The company said the discontinuation is part of its of the head and neck (SCCHN). Celgene Corp. (NASDAQ:CELG, restructuring announced in January (see BioCentury, Feb. 3). Wilex has rights Summit, N.J.) has an exclusive option to acquire VentiRx following to WX-037 and WX-554 — an orally available, small molecule MEK Phase II data of VTX-2337 in ovarian or head and neck cancer (see inhibitor — from UCB under a 2009 deal (see BioCentury, Jan. 12, 2009). BioCentury, Oct. 8, 2012). Johnson & Johnson (NYSE:JNJ, New Brunswick, Wilex said it is discussing further terms for both compounds with UCB. N.J.) markets doxorubicin as Doxil in the U.S. and elsewhere as Caelyx. BioCentury Week in Review APRIL 21, 2014 PAGE B25 OF 26

Completed Offerings, Investors: MPM Capital; Lundbeck- kets; Roth Capital Partners; up to 2.3 million additional shares from previous page fond Ventures; H.I.G. BioVentures Cormark Securities at $7.50 under the deal. Note: The financing is a series B- Overallotment: 7.5 million Type: Venture financing 1 round. OxSyBio Ltd., London, U.K. Raised: $2.7 million Mucosis B.V., Groningen, the Business: Biomanufacturing Investors: Private investor; exist- Knight Therapeutics Inc. (TSX- Netherlands Date completed: 4/16/14 ing investors V:GUD), Westmount, Quebec Business: Infectious Type: Venture financing Business: Infectious Date completed: 4/15/14 Raised: £500,000 ($836,500) ForSight Vision5 Inc., Menlo Date completed: 4/10/14 Type: Venture financing Investor: IP Group Park, Calif. Type: Private placement of war- Raised: €5 million ($6.9 million) Note: The company raised Business: Ophthalmic rants Investors: Changchun BCHT Bio- £500,000 ($836,500) in the first Date completed: 4/16/14 Raised: C$180.1 million ($164.1 technology; BioGeneration Ven- tranche of a £1 million ($1.7 mil- Type: Venture financing million) tures; MedSciences Capital; NV lion) seed financing. Raised: $15 million Shares after offering: 22 million NOM; Utrecht University Hold- Investors: H.I.G. BioVentures; Investors: Company management ing OxThera AB, Uppsala, Sweden Morgenthaler Ventures; Versant Note: Knight raised C$180.1 mil- Business: Endocrine/Metabolic Ventures; Technology Partners; lion ($164.1 million) through the Nexvet Biopharma, Melbourne, Date completed: 4/16/14 Delphi Ventures sale of 34.3 million warrants at Australia Type: Venture financing C$5.25 per warrant. The war- Business: Veterinary Raised: SEK70 million ($10.7 mil- Galapagos N.V. (Euronext:GLPG; rants will be exercisable at no Date completed: 4/16/14 lion) Pink:GLPYY), Mechelen, Belgium cost at the earlier of the fifth Type: Venture financing Investors: Kurma Partners; Idin- Business: Autoimmune, Muscu- business day following the issu- Raised: $31.5 million vest Partners; Mayo Clinic; exist- loskeletal, Functional genomics ance of a final prospectus cover- Investors: Farallon Capital Man- ing investors Date completed: 4/10/14 ing the common shares underly- agement; Adage Capital Partners; Type: Warrant exercise ing the warrants; or Aug. 11. Foresite Capital; Tavistock Life PanOptica Inc., Mount Arling- Raised: €2.4 million ($3.3 mil- Knight President and CEO Sciences; existing investors ton, N.J. lion) Jonathan Goodman purchased Placement agent: Cowen Business: Ophthalmic Shares: 304,791 about 7.6 million warrants, or Date completed: 4/15/14 Price: Not disclosed about C$40 million ($36.5 mil- Nora Therapeutics Inc., Palo Type: Venture financing Shares after offering: 30.1 million lion) in the offering. Knight is Alto, Calif. Raised: Not disclosed Investors: Company management; owned by the former Paladin Labs Business: Genitourinary Investors: Novo Ventures; Third company directors Inc. shareholders and was created Date completed: 4/17/14 Rock Ventures; SV Life Sciences to house Paladin’s Impavido Type: Venture financing Note: PanOptica raised an un- Heart Metabolics Ltd., London, miltefosine after the company’s Raised: $18 million disclosed amount in a tranched U.K. acquisition by Endo International Investors: Novo A/S; Burrill; Pros- series B round for up to $45 Business: Cardiovascular plc (NASDAQ:ENDP; TSX:ENL, pect Venture Partners; Rho Ven- million. Date completed: 4/17/14 Dublin, Ireland) (see BioCentury, tures; Vivo Ventures Type: Venture financing Nov. 11, 2013). Provista Diagnostics Inc., Phoe- Raised: Not disclosed Northwest Biotherapeutics nix, Ariz. Investors: venBio; Seroba Kernel Lorus Therapeutics Inc. (TSX: Inc. (NASDAQ:NWBO), Bethes- Business: Diagnostic Life Sciences; Brandon Capital LOR; Pink:LRUSF), Toronto, On- da, Md. Date completed: 4/16/14 Partners; AshHill Investments tario Business: Cancer Type: Venture financing Note: Heart Metabolics raised an Business: Cancer, Gene/Cell Date completed: 4/15/14 Raised: $6 million undisclosed amount in the first therapy Type: Direct public offering Investors: Existing investors tranche of a planned $20 million Date completed: 4/10/14 Raised: $15 million series A round. Type: Follow-on Shares: 2.3 million Sorrento Therapeutics Inc. Raised: C$25 million ($22.8 mil- Price: $6.60 (NASDAQ:SRNE), San Diego, Ca- Iconic Therapeutics Inc., At- lion) Shares after offering: 56 million lif. lanta, Ga. Shares: 50 million Placement agent: H.C. Wain- Business: Cancer, Antibodies Business: Ophthalmic, Cancer Price: C$0.50 wright Date completed: 4/16/14 Date completed: 4/16/14 Shares after offering: 112.3 mil- Investor: Institutional investor Type: Debt financing Type: Venture financing lion Note: The investor has a one-year Raised: $7.5 million Raised: $20 million Underwriters: RBC Capital Mar- “overallotment right” to purchase See next page

BioCentury makes people think We know you have many choices for headlines. But if you need to know what the news means, there is only one journal — BioCentury, the Bernstein Report on BioBusinessTM — that is recognized by key decision makers as the best source of perspective, interpretation and analysis for top managers and investors in the biotech community. BioCentury Week in Review APRIL 21, 2014 PAGE B26 OF 26

Completed Offerings, Raised: $7.5 million Date announced: 4/18/14 Underwriters: UBS; Baird; Cowen from previous page Investors: Oxford Finance; MidCap Type: IPO Overallotment: 750,000 Financial To be raised: Up to $86.3 million Note: Quotient amended its IPO Investors: Oxford Finance; Sili- Note: Zafgen drew down $7.5 Shares: TBD on NASDAQ and now plans to sell con Valley Bank million from its new, $20 million Price: TBD 5 million shares at $9-$11. The Note: Sorrento received an addi- senior credit facility. Underwriters: Leerink Partners; company amended its IPO earlier tional $7.5 million under its Sep- Cowen; Canaccord; JMP Securities this month to sell 5 million shares tember senior credit facility, bring- Note: The company is seeking to at $14-$16. Last month, the com- Proposed Offerings ing the total raised to $12.5 million. list its shares on NASDAQ. pany filed to raise up to $75 million.

SQI Diagnostics Inc. (TSX- Angion Biomedica Corp., Amended Offerings Withdrawn Offerings V:SQD), Toronto, Ontario Uniondale, N.Y. Business: Diagnostic Business: Renal, Pulmonary Date completed: 4/10/14 Date announced: 4/14/14 Mapi-Pharma Ltd., Ness Ziona, Foundation Medicine Inc. Type: Private placement of units Type: IPO Israel (NASDAQ:FMI), Cambridge, Mass. Raised: C$4.2 million ($3.8 mil- To be raised: Up to $34.5 million Business: Drug delivery, Generics Business: Pharmacogenetics lion) Shares: TBD Date announced: 4/17/14 Date announced: 4/15/14 Units: 8.4 million Price: TBD Type: IPO Type: Follow-on Price: C$0.50 (unit) Underwriter: Aegis Capital To be raised: Up to $42.9 million Underwriters: JPMorgan; Gold- Shares after offering: 56.3 million Note: The company is seeking to Shares: 2.9 million man Sachs Placement agents: Euro Pacific lists its shares on NASDAQ. Price: $13-$15 Note: Foundation Medicine with- Canada; H.C. Wainwright; Kings- Underwriter: Aegis Capital drew its follow-on, citing market dale Capital Markets Synta Pharmaceuticals Corp. Overallotment: 428,571 conditions. Note: Each unit comprises a share (NASDAQ:SNTA), Lexington, Note: The company amended its and a two-year warrant to pur- Mass. IPO on NASDAQ and now plans Other Financial News chase a share at C$0.65. Business: Cancer, Autoimmune to sell 2.9 million shares at $13- Date announced: 4/14/14 $15. In March, Mapi-Pharma filed Vital Therapies Inc. (NASDAQ: Type: Private placement to raise up to $46 million. The Column Group, San Fran- VTL), San Diego, Calif. To be raised: Up to $5 million cisco, Calif. Business: Hepatic Shares: 1.3 million Microlin Bio Inc., New York, Business: Finance Date completed: 4/16/14 Price: $4.01 N.Y. Date announced: 4/11/14 Type: IPO Shares outstanding prior: 90.4 Business: Cancer Biotech VC firm The Column Raised: $54 million million Date announced: 4/16/14 Group has raised $175.9 million Shares: 4.5 million Investor: Company director Type: IPO of a planned $250 million for its Price: $12 Note: Synta Director Bruce To be raised: Up to $32.7 million second fund, according to an SEC Shares after offering: 21.1 million Kovner — the company’s largest Shares: 2.7 million filing. The firm could not be Underwriters: BofA Merrill Lynch; stockholder — owns about a 31.7% Price: $10-$12 reached for details in time for Credit Suisse; William Blair; stake. After the offering, Kovner Underwriters: Brean Capital; Sum- publication. According to its Canaccord will own about a 32.7% stake. mer Street website, The Column Group in- Overallotment: 675,000 Overallotment: 409,091 vests $15-$30 million in 10-12 Vyrix Pharmaceutical Inc., Note: The company amended its companies per fund; the firm Wilson Therapeutics AB, Greenwood Village, Colo. IPO on NASDAQ and now plans closed its first fund with about Stockholm, Sweden Business: Endocrine/Metabolic to sell 2.7 million shares at $10- $250 million in 2008, according to Business: Endocrine/Metabolic Date announced: 4/16/14 $12. The company also added an SEC filing. Date completed: 4/16/14 Type: IPO Brean Capital and Summer Street Type: Venture financing To be raised: Up to $28.8 million as underwriters and dropped Sun- Relypsa Inc. (NASDAQ:RLYP), Raised: Not disclosed Shares: TBD rise Securities. In January, Microlin Redwood City, Calif. Investors: Abingworth Manage- Price: TBD Bio filed to raise $25 million Business: Endocrine/Metabolic ment; MVM Life Science Partners; Underwriters: Aegis Capital; through the sale of a to-be-deter- Date announced: 4/16/14 HealthCap Fordham Financial Management mined number of shares at $6-$8. Relypsa raised $13.2 million Note: The company raised an un- Note: Vyrix, a subsidiary of Am- through the sale of 538,775 shares disclosed amount in a $40 million pio Pharmaceuticals Inc. (NYSE- Quotient Ltd., Penicuik, U.K. at $24.50 to cover the overallot- tranched series B round. M:AMPE, Greenwood Village, Business: Diagnostic ment from its April 10 follow-on, Colo.), is seeking to list its shares Date announced: 4/14/14 bringing the total raised in the Zafgen Inc., Cambridge, Mass. on NYSE MKT. Type: IPO offering to $101.2 million. The Business: Endocrine/Metabolic To be raised: Up to $55 million company, which closed Thursday Date completed: 4/17/14 Zafgen Inc., Cambridge, Mass. Shares: 5 million at $22.83, has 33.8 million shares Type: Debt financing Business: Endocrine/Metabolic Price: $9-$11 outstanding.

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