Success in the Payer Dominated Pharma

invivo.pharmamedtechbi.com july/august 2016 VOL. 34 / NO. 7

INSIDE SMART SEGMENTATION: SUCCESS IN THE PAYERDOMINATED

medtech leadership CVRx’s Investment In HF And PHARMA MARKETPLACE Wider Medtech Industry Set To Pay Off As physicians lose decision-making authority to By Ashley Yeo payers, drug companies need to segment markets Biopharma Strategies more effectively: the patient populations prescribers IO’s Impact On Strategic are most likely to treat and that will spark the Decision-Making In The fewest access battles; and the specific payer lines- Broader Oncology Landscape of-business least inclined to block new drugs’ use. By Seth Berman, Ryan Stover and Anna Pasternak BY ROGER LONGMAN

Diagnostics Dealmaking Rapid Infectious Disease Testing Picks Up Speed By Mark Ratner

clinical Strategies Using Enriched Studies For Post-Approval Evidence Needs By Nancy Dreyer

IN VITRO DIAGNOSTICS Singulex: Next-Gen Immunodiagnostics By Peter Charlish

▼ ONLINE EXCLUSIVE

The ABC Of Innovation And Why The F-Word Should Not Offend By Ashley Yeo

July/August 2016

CVRx’s Investment In HF And Wider 16 Medtech Industry Set To Pay Off Ashley Yeo CVRx president and CEO Nadim Yared believes his company’s second-generation chronic heart failure device could present a serious commercial challenge to the traditional major players in the field. Meantime, with 10 years under his belt as CEO, Yared is focused on building the company, rather 8 than on exits. COVER STORY IO’s Impact On Strategic Decision- Smart Segmentation: 22 Making In The Broader Oncology Success In The Payer-Dominated Landscape Pharma Marketplace Seth Berman, Ryan Stover and Anna Pasternak Roger Longman As physicians lose decision-making authority to Market signals from the pioneering immuno-oncology payers, drug companies need to segment markets therapies suggest a paradigm shift across multiple oncology more effectively: the patient populations prescribers indications in the coming years. To ensure that non-IO are most likely to treat and that will spark the fewest products become successful components of the standard of access battles; and the specific payer lines-of-business care in cancer, drug developers must consider how IO may least inclined to block new drugs’ use. impact clinical development, market access and commercialization strategies. 16 Singulex: 28 Next-Gen Immunodiagnostics Peter Charlish Singulex originally developed its Single Molecule Counting Nadim Yared technology for research applications, but it is poised to launch a clinical diagnostics tool that incorporates the highly sensitive technology.

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4 Around The Industry 4 Rapid Infectious Disease Testing Picks Up Speed Mark Ratner $740m MacroGenics, Janssen Biotech sign second deal for preclinical cancer candidate 5 Brexit Effect On UK Medtech: View From The US Ashley Yeo $796m Chiesi acquires three cardiovascular assets from The Medicines Co. 6 IN VIVO’s Deals Of The Month: June 2016 $911m Pﬁzer, Wave sign potential $911m deal involving metabolic therapies Nancy Dvorin $1163m Celgene and Agios enter new deal focused on metabolic immuno-oncology 34 On The Move $2000m Biogen, UPenn ally in gene therapies for multiple indications Significant recent job changes in pharma, medtech and diagnostics ONLINE ONLY: Top Alliances In May 2016 38 Dealmaking Deals Shaping The Medical Industry, June 2016 38 48 Executive Summaries

EXCLUSIVE ONLINE-ONLY

The ABC Of Innovation And Why The F -Word Should Not Offend Ashley Yeo Organizations need to adopt a “disruption mind-set,” whatever kind of innovation they are pursuing, and the most successful innovators realize that innovation is not just the province of the R&D department but the whole company. So say executives at PA Consulting, whose recent You Asked...We Delivered! report, “Innovation As Unusual,” highlights the importance of Relevant and exclusive online-only the “Innovation Leader” role, and has useful advice for life content at your fingertips 24/7 science and health care innovators. Access your subscription by visiting: invivo.pharmamedtechbi.com ■ Deals In Depth and log in. An overview of biopharma, medtech and diagnostics Don’t have an online user account? Quickly and easily dealmaking in May 2016 create one by clicking on the “Create your account” link at the top of the page. Contact [email protected] or call: (888) 670-8900 or +1 (908) 748-1221 for additonal information.

2 | July/August 2016 | IN VIVO: The Business & Medicine Report | invivo.pharmamedtechbi.com Strategic Transactions Pharma intelligence |

$740m MacroGenics, Janssen Biotech sign second deal for preclinical cancer candidate

$796m Chiesi acquires three cardiovascular assets from The Medicines Co.

$911m Pﬁzer, Wave sign potential $911m deal involving metabolic therapies

$1163m Celgene and Agios enter new deal focused on metabolic immuno-oncology

$2000m Biogen, UPenn ally in gene therapies for multiple indications

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In Vitro Diagnostics

and genetic profiling has made the greatest Rapid Infectious Disease Testing impact: the deep dives into genomics and Picks Up Speed bioinformatics (tumor profiling) and the combination of whole cell separation technolo- Several recent events highlight an increase in the pace of innovation in rapid infectious disease gies and imaging (prenatal screening). But testing. In July, Accelerate Diagnostics Inc. filed a De Novo request to the US Food and Drug an additional component exists in infectious Administration for Evaluation of Automatic Class III Designation of its system for pathogen iden- disease testing – the need for rapid identifica- tification and antibiotic susceptibility testing (AST). A week and a half earlier, Cepheid obtained tion, both to prevent the spread of disease clearance from FDA for expanded claims to its Xpert Carba-R test for detecting carbapenem (hospital-wide surveillance/infection control) resistance genes in multidrug-resistant organisms using rectal swabs in addition to bacterial and to intervene in an individual patient by isolates, significantly cutting testing time. Two months earlier, Luminex Corp. completed a helping choose an effective antibiotic at the tender offer for bloodstream infectious disease test specialist Nanosphere Inc. for $77 million. right dose as quickly as possible. Also in May, the Merck Global Health Innovation Fund (Merck GHI) increased its investment in Developing a system for surveillance, on OpGen Inc. to help fund OpGen’s bioinformatics-heavy platform for infection detection and its own, is commercially problematic, despite control. These moves after Roche drew attention to the space last summer when it paid $190 initiatives from government agencies including million up front and promised another $235 million in product-related milestones for Gene- the Centers for Disease Control & Prevention WEAVE Biosciences Inc. and its platform for rapidly detecting multidrug-resistant organisms and the National Institutes of Health. “There is and analyzing AST or resistance. not a significant amount of reimbursement for doing it,” says Rubin. “It is a missionary sale to “There has been a lot of investment in prod- addition, depending on the specimen type, hospitals.” But taking it the other way around, uct development in microbiology, defined delivering a result much faster than traditional programs offered to hospitals to rapidly identify broadly to include molecular products that microbiology,” Quirk says. patients using fast diagnostics and integrated sit within the microbiology continuum,” says The same is true of OpGen. “Part of the data sets can expand into broader surveillance William Quirk, managing director at Piper Jaf- reason we went for OpGen is we like to be efforts and anti-microbial stewardship at the fray. The interest mirrors automation trends involved in the workflow and dealing with hospital. “If you go into it with just surveillance, ongoing in diagnostics for the better part content and information, as opposed to there is no real path to payment because it is a of the last 15 to 20 years. “When we look trying to cherry pick individual technolo- problem for the future,” Rubin says. Ultimately, at periods in diagnostics when we’ve seen gies where Merck is not focused or does not the government and CDC will start to change significant market shift, it had a lot to do with possess core competency,” says Merck GHI and mandate surveillance, or hospitals will start providing a result that was consistent with executive director David Rubin, PhD. to worry about their quality scores, whether a competitive platform but perhaps there Other developers are in lockstep with Ac- they are protecting people, and using their anti- was an added improvement with respect to celerate and OpGen, creating broad panels biotics optimally, he says, “but first and foremost workflow,” he says. instead of individual tests – a GI panel that they care about rapidly identifying and treating Some of the most notable acquisitions in incorporates an assay looking at Clostridium specific infections.” diagnostics have followed this recipe. Dade difficile infection, for example. Biofire Diag- While Cepheid’s Carba-R assay, for example, Behring Inc., which Siemens AG bought nostics Inc. has improved workflow with is focused on an infection control activity, “we in 2007, gained market share quarter after its multiplex PCR FilmArray line; Genmark know that people will probably be doing that quarter in the 2000s by combining chemistry Diagnostics Inc. is advancing its ePlex system, off label to make decisions about whether to and immunoassay with its Dimension family which gained a CE mark in June 2016; and tra- use a drug like Avycaz [a combination of avibac- of instruments. Gen-Probe Inc., now part of ditional players like Biofire parent bioMerieux tam and ceftazidime],” says Fred Tenover, PhD, Hologic Inc., was last to market with respect SA, Becton Dickinson & Co. and Danaher Cepheid VP, scientific affairs. A hospital needs to an amplified molecular assay for chlamydia/ Corp. are improving blood bottle specimen to know whether it has five people with five gonorrhea, but because it had better automa- prep and analysis. A handful of systems offer totally different resistance genes or if they are tion and better workflow, it took competitive rapid testing directly from whole blood with- the same five, which would mean an outbreak market share over time. Accelerate Diagnostics out an incubation period – T2 Biosystems may be occurring, he says. With that infection “has the makings to continue this long macro Inc.’s T2Candida sepsis test is one. But most control information, the pharmacy can make [trend] in automation,” Quirk says. Its Pheno require performing the test out of a blood decisions on a patient’s therapy as well. system, with a broad panel of 140 assays, is bottle, and T2Candida doesn’t offer specific There’s room for both targeted and more using a combination of fluorescent in situ hy- AST information to determine the appropri- comprehensive measurement approaches – bridization and morphokinetics (a time-lapse ate antibiotic for a patient. analogous to the SNP-based cancer “hot-spot” imaging technique) for phenotypic pathogen Aspects of technology innovation in infec- tests looking at specific regions of genes versus identification and AST. “It is automating what tious disease testing track with those applied next-generation whole genome sequencing. is still a laborious microbiology system and in to other areas where complex molecular “The deep dives are good for empiric therapy,”

4 | July/August 2016 | IN VIVO: The Business & Medicine Report | invivo.pharmamedtechbi.com AROUNDTHEINDUSTRY

Tenover says, when the goal is to build a data- we otherwise might have seen,” he says. ity for Cepheid. “Both of those tests are being base to use when a patient comes in and the The infectious disease testing landscape used in MedImmune clinical trials of their physician is trying to figure out what to treat lags behind the cancer treatment ecosystem, antibody approach to [treating] ventilator- them with initially. “Having the deep data from where many more companies, tests, drugs, associated pneumonia,” Tenover says. thousands of patients can help make the first and as a result, connections between pharma Although the main driver for the Gene- choice of antibiotic,” he says. “But on the other and diagnostics companies exist. “Infectious WEAVE acquisition was as a bolt on to Roche’s hand, you want to get the patient on the right disease testing is figuring out how to make diagnostics business, Roche may well be drug at the right dose as fast as possible. That’s those connections,” Rubin says. Plus, there has using the technology with an eye to devel- where the rapid genotypic test plays out first.” been a lot less investment in antibiotics. As oping companion diagnostics for use with its “It will be interesting to see the practi- technologies that are rapid and integrated portfolio of antibiotic drug candidates . And cal effect of a lot of these technologies on into the workflow come down in cost, “we will an Accelerate spokesperson points out that mortality and on hospital admission time start seeing the type of partnerships and driv- use of the Pheno system could yield valu- for some patients,” says Quirk. “My suspicion ers where pharma and diagnostics [develop- able pharmacokinetic information about the is you are going to see mortality decline and ers] can work more closely together,” he says. drug-bug interaction, such as how fast a drug also intensive care days down, and these in- It’s already happening on a small scale. is working and whether it is totally killing the vestments ultimately will be looked at pretty AstraZeneca PLC’s MedImmune Inc. division organism, in effect moving from establishing favorably by hospital administrations.” It will was able to adapt a Cepheid product for use a minimum inhibitory concentration to a create “a longer tailwind for general microbi- in its clinical trials and also fund development minimum bactericidal concentration. ology investment within the clinical lab than of another product that was not a high prior- By Mark Ratner

Market Access

On Device Regulation Brexit Effect On UK Medtech: In The UK View From The US This last point – device regulation – is highlighted by Chapman as the second major Against the major proviso that it is still early days in the matter of the UK’s “Brexit” from the Euro- potential downside for the medtech sector pean Union, In Vivo asked ZS Associates principal Brian Chapman for some insightful post-Brexit – specifically the prospects of the UK having speculation about the route ahead for the UK’s health care and medtech sectors, seen from the US. to run its own approvals process, separate At present, and while the UK outlook barometer Chapman raises the point about what from the EU system. Would the UK want to needle is pointing clearly to uncertainty and happens to individuals covered by the NHS take national control of the approvals process? negative, Chapman is keen to stress two major who live elsewhere in the EU (treatment paid Chapman’s gut feeling is “probably not,” and health care-related outcomes of the vote. for by the UK but delivered in the country of that the status quo is likely. On the negative residence). He also wonders about the future side, it could be very bad for the UK market On The Future Of The NHS and fate of the NHS labor force, a lot of which and for global companies looking to operate in the UK, he believes. The first relates broadly to the issues sur- is sourced from other EU countries. “There are Were this to arise, where would the UK sit rounding the National Health Service (NHS) a lot of potential risks, and frankly I don’t see in a medtech manufacturer’s list of priorities? and what happens to it – funding- and any upsides for the NHS right now,” he says. “Probably quite low down,” is the response. The staffing-wise. NHS trusts collectively went NHS chief executive Simon Stevens recently UK’s contributions to regional medtech regula- a massive £2.4 billion ($3.1 billion) in debt issued a personal message to all NHS England tion systems (via the Medicines and Healthcare in 2015/16, and trying to claw back that staff (The NHS after the Referendum), on the products Regulatory Agency – MHRA) are well amount, as well as demand financial dis- eve of the NHS’ 68th birthday. It talked about cipline in the current, extended period of documented, and in a worst case scenario establishing an NHS Europe Transition Team to uncertainty brought about by the Brexit vote, might even be seen as a bargaining chip if the deal with the range of EU-related issues that will will be hard to impossible. An NHS financial EU wanted to be hard on the UK for leaving announcement is said to be imminent. [On now have to be considered on the movement the club of 28. However, Chapman cannot see July 21 NHS England allocated an extra £1.8 and regulation of health professionals, procure- the likelihood of this becoming a focal point. billion to trusts, with the aim of cutting the ment rules, cross-border patient entitlements, Would the current climate even dissuade combined provider deficit to around £250 certain public health measures and medicines medtech companies from including the UK million in 2016/17.] and device regulation. in their marketing plans? This actually might

©2016 Informa Business Intelligence, Inc., an Informa company | IN VIVO: The Business & Medicine Report | July/August 2016 | 5 AROUNDTHEINDUSTRY not have changed. The essential consider- driven by worsening cost constraints. Any Upside? ation remains the potential for a product Conversely, “NHS privatization” could It’s hard to find any immediate and significant to substantially reduce costs to the NHS. If lead to increased competition and an upside of the Brexit vote for the innovative it does, then the UK can be a very attractive opening up of opportunities for those medtech sector. However, weaker sterling, market. The downside is that UK decisions are pursuing value-based or outcomes- which dipped below $1.30 two weeks after not made at national level but at local Clinical based agreements. the vote, could present an opportunity for Commissioning Group (CCG) level. • An NHS hampered by worsening finan- UK-based manufacturers to export to Europe Chapman issues a clear warning, “Seen cial constraints would clearly be a less and elsewhere. from the US, the UK can in some cases be attractive place for medtech. Ongoing Additionally, although divergent regulation attractive to US medtech companies in terms exchange rate instability could make might cause medtech companies to depriori- of overlap of cultures and common language, manufacturers less willing to negotiate tize the UK in favor of other European markets, especially if they want to show some results; favorable pricing to access the NHS Sup- were the UK to go it alone and develop its just don’t assume that it’s an easy path to ply Chain or individual trusts. own, more progressive regulation (a quality reimbursement.” • Large capital projects may be put on that the MHRA has brought to bear in past Small companies with novel device hold or become increasingly challeng- EU dealings), the UK could be seen as a more therapies can very often get approval in ing to justify. attractive launch market ahead of the rest of Europe two or more years earlier than in the • Elective procedures, such as joint re- Europe. But the stress is firmly on “could.” US, and Europe – Germany especially, with placements, may be impacted as trusts By Ashley Yeo its pathway for innovation reimbursement attempt to curb spending on non- via its NUB system – can be very attractive essential health care services. for testing the ground, building up studies • Lower-cost alternatives to premium Deals Of and getting experience, even if they are not devices may become more popular, The MONTH directly translatable. But the UK could con- and innovative device adoption may versely make itself less attractive by installing IN VIVO’s editors pick June’s top be stifled. Nevertheless, medtech still alliance, financing and M&A deals. a new approval process, adding to timescales needs to be ready to bring such of- and requiring companies to typically need to ferings to market, and the companies Top Alliances: do even more groundwork in the UK. that do will likely see success through Novartis And As to the Johnson & Johnsons, Medtronics differentiation and innovation. and larger companies in general, there is very • There may be reduced interest in the Xencor’s Big IO Deal little chance they would alter their current acquisition of UK companies to support Novartis AG bolstered its immuno-oncol- UK positioning radically, as they already have tax inversion moves by multinationals. ogy pipeline through a $2.6 billion deal deep involvement in the market. But Brexit (On the other hand, chancellor of the with Xencor Inc. to develop bispecific might eventually mean certain products now former exchequer George Osborne antibodies for cancer. being less likely to get the traction in the UK has pledged to drop the corporation than they once did, says Chapman. tax rate to 15% – closer to the EU low Top Financing: of 12.5% used in EU member state Ginkgo’s Series C ZS’ Early Takeaways On Brexit Ireland. The question of whether his Ginkgo Bioworks, which custom builds successor Philip Hammond retains this Soon after the vote, ZS Associates associate microbes for clients across multiple idea is open.) principal Roz Lawson and manager Will Ran- industries, raised a $100 million Series C • UK academic research would receive dall produced a blog on the main issues and round from Y Combinator’s Continuity areas to monitor for US medtech companies reduced EU funding, and UK compa- Fund, Senator Investment Group, Cascade active in the UK. (What Does Brexit Mean for nies would find it harder to stay at the Investment, Baillie Gifford, Viking Global the NHS and the Medtech Industry?) Its main forefront of innovation. Investors and Allen & Co. LLC. points, in what to some may seem a worst- • The UK may lose its “big five” member case-scenario outcome, include the following: status among the European markets Top M&A: • The money to be saved by the UK leaving for medtech manufacturers, since a the EU is difficult to quantify. The propor- stand-alone UK market would be many Zimmer Biomet tion of the sum that will be allocated to times smaller than the EU27 (the EU Buys LDR the NHS is far from certain. The economic minus the UK). The world’s second-largest orthopedic impact of a post-Brexit recession is likely • There will be considerable uncertainty device firm Zimmer Biomet Holdings to have a significantly greater negative for some time surrounding the UK’s con- Inc. made its biggest move since Zimmer effect on public finances. tinued access to the EU single market and Biomet came together in 2015 with • One likely outcome is an accelera- and any taxation or tariffs that could be a $1 billion acquisition of spine device tion of the existing trend toward the applied to the movement of goods in specialist LDR Holding Corp. privatization of health care services, and out of the UK market.

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Request your free demo today: please visit - www.meddevicetracker.com ©2016 Informa Business Intelligence, Inc., an Informa company | IN VIVO: The Business & Medicine Report | July/August 2016 | 7 Smart Segmentation: Success In The Payer- Dominated PHARMA Marketplace As physicians lose decision-making authority to payers, drug companies need to segment markets more effectively: the patient populations prescribers are most likely to treat and that will spark the fewest access battles; and the specific payer lines-of-business least inclined to block new drugs’ use. BY Roger Longman

et’s be clear: the fundamental assumption on which the pharmaceutical industry’s commercial model was based and still operates – the primacy of the physician as medical decision-maker – is about as valid as center- ing news businesses around press runs and print ads. ■ It’s no secret that physicians are losing deci- There are certainly therapeutic islands in this industry where the sion-making power and payers are gaining assumptionL is temporarily useful (oncology, most obviously, or rare, particularly it. But even for companies that recognize the childhood, diseases). But these are strung out across the vast number of disease shift, understanding what payers want isn’t categories like Pacific archipelagos yard-by-yard losing land to rising seas. simple: they are simply too various. Not that physicians don’t have prescribing influence. If they don’t ask for a drug ■ There is one unifying principle: lacking predict- in the first place, if it doesn’t seem important to test out, it won’t of course get pre- ability around a drug’s budget impact, plans scribed. But do individual physicians wield the power of choice within classes, or are far more likely to exclude a new product, even to experiment with new drugs unavailable on formularies? Not so much – to implicitly or explicitly, from their formularies, not at all. punishments from which it’s very difficult to There seem to be plenty of pharma executives who are ignoring this tectonic ever recover. shift in industry landscape (either out of ignorance, or willfully, because they’ve promised the Street they’d hit particular sales targets). And many have paid the ■ To prevent exclusion, companies must both price in poor launches. demonstrate that the drug provides obviously But it’s been almost equally destructive to acknowledge the change – and yet disproportionate value to a well-defined target misunderstand it. We note, for example, a series of excellent articles by the editors patient population relative to competitors and credibly define the new drug’s budget impact. of The RPM Report starting from the premise that “when it comes to prices, the interests of manufacturers are … diametrically opposed to those of consumers and ■ The bad news: it will be the rare drug whose their agents (insurers, public and private).” (See “Changing The Subject (Part 1): Stop initial targeted population will meet the most Trying To “Win” The Drug Pricing Debate” - Pink Sheet, May 25, 2016 and “Changing the optimistic expectations around total prescrip- Subject (Part 2): Turning Turing Around By Offering A “National Center Of Pharmaceutical tion volumes. The good news: targeted strate- Supply”” - Pink Sheet, May 25, 2016.) gies work – and, appropriately constructed, But it’s hardly that simple. Employers are certainly worried about the rapid increase deliver outsize investment returns. in specialty drug cost. Patients worry about their share of drug cost, which may or may not have much to do with the price. But neither employers nor patients have Executive Summary >> 48 much direct influence on specific coverage policies. They’ve entrusted drug-cost

8 | July/August 2016 | IN VIVO: The Business & Medicine Report | invivo.pharmamedtechbi.com MARKET ACCESS

management to agents – insurers, pharmacy detail, we think there are three basic tasks: was in part a way to make up for that mistake benefit managers (PBMs), specialty pharma- 1. Objectively assess the value of the drug, by virtually shouting the possibility that the cies – who can sometimes make money on from the payer’s point of view, relative to new drugs could cost US payers $50 bil- drugs – and the higher priced the better. existing and coming competition in all lion to $100 billion (which, to put that into The bigger issue for these agents, specifi- relevant subpopulations – and then de- context, is about one-eighth to a quarter of cally insurers, is the predictability of expense. termine the patient population in which the total US drug expense). The unspoken That’s because, by and large, they pass on the drug shows disproportionate value. but scary implication: the new drugs would medical costs to their customers, either 2. Define the economic impact, in that replace ubiquitous, cheap statins. directly or through premiums. The primary population, on each line of a payer’s busi- But it was also true that the manufactur- question for a Medicare plan, for example, ness, recognizing that different lines will ers didn’t much allay payer fears by more is how to accurately bid for new business – see different values to a drug (e.g., the narrowly defining, into readily quantifiable pricing premiums high enough to account commercial fully insured business vs. the subsegments, the specific patients to be for the underlying medical and pharmacy Medicare Prescription Drug Plan line). targeted. Yes, the manufacturers did limit costs but not so high that they’ll lose business the market and communicated that fact to to a plan with sharper forecasting skills. And 3. Build a launch strategy around the results: payers, telling them they’d focus on “high even the most sophisticated health plans do a development program designed to risk” patients (more or less: patients with a pretty poor job of predicting the three key prove the disproportionate value within atherosclerotic cardiovascular disease and components of a pharmaceutical’s economic the target subpopulation; a commercial LDL cholesterol of greater than 100). But for impact: price, usage and rate of uptake. plan constructed to fit the task (perhaps most payers, that definition covers a lot of Given this unpredictability, not to men- more spending on hubs, less on sales people – and, to most payers, it’s not clear tion the underlying cost increases that so reps?); and a payer communication how many. Payers were also worried by the distress payers’ clients, it’s generally easier strategy, put into action 24 months prior hazy definition around another potential to limit the use of expensive drugs or find to launch, that credibly defines the likely use of the drugs – statin intolerance. What cheaper alternatives. That’s why payers economic impact on each line of business exactly was it? How much of it was real? and PBMs have excluded more and more within the plan and to the plan overall. How would one know? How many people brand-name drugs from the prescribable The bad news: it will be the rare drug had the condition? pharmacopeia – either explicitly (“we will whose initial targeted population will Far more limited, and importantly, easier not pay for this drug”) or implicitly, through encompass the entire market that its for payers to define and, to at least some a whole series of increasingly restrictive bar- manufacturer’s more optimistic commercial degree, enumerate through ICD-10 codes, riers. A doctor, or more likely, the office staff, executives foresee. And it will take time and would be patients at very high risk, those might be able to fill out a 40-question prior patience to expand the population beyond patients for whom a new lipid-lowering authorization form, but they’re not likely to the initial segment. therapy would be most logical – patients do so very often. The good news: targeted strategies work with multiple serious risk factors (e.g., pa- For the pharmaceutical company, such – and, appropriately constructed, deliver out- tients with both heart disease and block- exclusions result at best in an extended size investment returns, even if their topline ages in peripheral arteries or super-high commercial coma with severe long-term sales don’t fit the blockbuster expectations of uncontrolled LDL, or both heart disease and sequelae: it dulls or even kills physician executives raised in an era when physicians diabetes, or those who’d had a heart attack curiosity. If physicians can’t experiment made the decisions and didn’t have to take in the previous 12 months). with a new drug, at least on some patients, drug economics into account. Rattled by the PBMs, uncertain about the there’s little hope that they’ll demand its demographics, payers also didn’t have a availability later. Scaring Payers Into good idea of the price. One major national That’s why the single most important Shutdown Mode plan, for example, met with the manufactur- task around drug launches is to make sure In early 2015, as the market prepared for ers four to five months before launch and that the new drugs aren’t excluded. And to the likely introduction later in the year of a asked, having signed a confidential disclo- prevent exclusion, drug companies must pair of drugs for dramatically reducing LDL sure agreement (CDA), for some definition generally do two things. The first is always cholesterol (“bad” cholesterol), so-called around price. One of the manufacturers sug- necessary: demonstrate in a way a payer PCSK9 inhibitors, a flow of stories began to gested, according to the head of this payer’s will credit that the drug provides obviously appear about their likely financial impact. pharmacy program, “the higher end of the disproportionate value to the target patient PBMs led the discussion. Along with $7,000 to $9,000 range. And then just a few population relative to competitors. The sec- most payers and their actuarial consultants, months later, at launch, we saw the price: ond is usually necessary (and always a good they had misjudged the impact of Gilead $14,000. What message did that send us?” idea): make sure that a payer understands Sciences Inc.’s launch of the hepatitis C Clueless about the price, this payer was the new drug’s budget impact. The drug medicine Sovaldi (sofosbuvir), with payers also clueless about uptake. Most payers industry has largely failed to do either. ending up spending billions on unexpected didn’t know how cardiologists, who prescribe To define these principles in a bit more therapy costs. The warning about the PCSK9 mostly oral generics and don’t deal with too

Exhibit 1 Exhibit 1.) But as the payer input into RealEn- Zetia Versus PCSK9i’s Efficacy In Reducing LDL dpoints’ RxScorecard analysis showed, LDL was worth only about 20% of the total efficacy score; 50% went to outcomes (reduction % LDL Reduction of total mortality and cardiovascular events 90 and deaths). But at launch, neither PCSK9i 79.5 could provide outcomes data, whereas Zetia 80 could (it didn’t have great data, but at least it had some). So while in the RxScorecard payer-focused evaluation the two drugs 70 61.9 certainly showed better efficacy than Zetia, they didn’t show as much as the LDL benefit 60 would have implied. (See Exhibit 2.) When the analysis turned to safety and 50 ease of use, Zetia won handily. It was a daily oral, not an injectable; it had a long safety history – Zetia, unlike the PCSK9i’s, was a 40 known and convenient quantity. (See Exhibit 3.) Payers found it easy to require patients to 30 be “stepped through” Zetia before getting a PCSK9i – and there has been no significant backlash from physicians. 20 17.8 It’s always easy in hindsight to say what the companies should have done. But it 10 does seem logical to suggest that much tighter patient targeting – say, on very high- 0 risk patients for whom dramatic LDL lower- Zetia Praluent Repatha ing would have been a prescribing trigger 150 mgs 140 mgs and whose numbers, tightly defined, were less scary to the insurers’ actuaries – might Note: RxScorecard analysis includes results only from IMPROVE-IT, ODYSSEY LONG TERM, and LAPLACE2 have at least got the drugs used more than trials. Percentages are placebo adjusted. Data from moderate-to-high risk patients with sub-optimal they have been, giving prescribers a bit response to statins. more comfort with these new and power- ful agents. (See Exhibit 4.) Presumably, too, SOURCE: RxScorecard companies’ commercial efforts could have been more focused – fewer reps needed, for example – and therefore less expensive. much payer oversight about their choices, “Net net, balancing lower revenues and lower would react to the injectable PCSK9is and costs, we might have come out the same,” he Payer Centricity their inevitable coverage restrictions. “We says – but lost in terms of building the busi- Even those companies that seem to put projected [for the first few months of 2016] ness with new customers. payers at the center of their strategy often 3,000 PCSK9i scripts,” says the pharmacy pro- stumble because they don’t recognize clearly Proving Disproportionate gram head. “In fact, we got 300 – physicians enough that payers aren’t monolithic. Payer Value simply didn’t write for the drugs.” And because preferences, goals and incentives vary plan to this payer was so uncertain about physician Perhaps more importantly, the manufactur- plan and, of equal importance, within plans, reaction and thus impact, its coverage policy, ers didn’t prove, from the payer’s point of based on each individual line of business. written shortly after launch, basically shut view, disproportionate value in the broader (See Exhibit 5.) down approvals: in that period, it approved population segments in which the drugs Let’s start with the latter. For some plans, three prescriptions. look like they could be used. The lead story for example, cost-offsets matter. For others, On the surface, this doesn’t seem so bad for both Sanofi/Regeneron Pharmaceuti- they’re irrelevant – or worse. for the payer: much lower costs. The problem cals Inc.’s Praluent (alirocumab) and Amgen The situation is by no means theoretical. was the revenue side. Blowing its estimates Inc.’s Repatha (evolocumab) was their dra- Novartis AG ran straight into this complica- on the PCSK9s, this plan charged noticeably matic reductions in LDL cholesterol versus tion when it launched its heart failure drug, higher Medicare premiums than other plans the leading non-statin, Merck & Co. Inc.’s Entresto (sacubitril/valsartan). and probably lost several thousand beneficia- Zetia (ezetimibe) – 3.5 times the reduction This remarkable medicine has been ries to its competition, figures this executive. for Praluent and 4.5 times for Repatha. (See proven to reduce cardiovascular events,

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Exhibit 2 The Differences Shrink In A Payer’s‐Eye View Of Overall Efficacy

RxScorecard: Overall Efficacy Score; Statin users at moderate-to-high risk of CV events Overall Efficacy Score I Looking at overall efficacy (including outcomes), 14 Repatha and Praluent superior to Zetia…but not by the same margin shown in LDL reduction. 12 11.5 I Payers weight outcomes (such as preventing heart attacks and strokes) more heavily than 10 anything else. Praluent and Repatha had no 8.7 outcomes data at launch – Zetia’s very modest outcomes data helped shrink efficacy difference. 8 6.7

Note: RxScorecard analysis of these drugs in moderate-to-high 0 risk patients with sub-optimal response to statins. Zetia Praluent 150 Repatha 140 mgs. mgs. SOURCE: RxScorecard and thus at least mitigates the cost of cardiovascuar events, this is one of Entresto’s than it “sells” them (via reimbursement to cardiovascular disease. The Institute for major economic advantages. Indeed, PDPs Medicare and patient co-pays). (See “Cigna’s Clinical and Economic Review (ICER), a don’t want heart failure patients, who tend Bradbury Talks PCSK9 Contracts And Value Ver- US-focused cost-effectiveness watchdog to bring with them lots of co-morbidities sus Volume” - Pink Sheet, May 11, 2016.) that rarely finds a drug that it believes is and thus higher drug expenditures, re- And as with the PCSK9is, payers were scared appropriately priced, reported that Entresto ducing profit for these kinds of payers. So about the number of patients – as many as 5 delivers value for money, more or less at its making it easy for their beneficiaries to get million with heart failure. Defining the target list price. And Novartis has obligingly of- Entresto only encourages enrollment from more carefully around high-risk groups would fered up outcomes-based reimbursement: the kinds of patients they don’t want. at least have done something to reassure pay- if Entresto doesn’t reduce cardiovascular As for its outcomes-based arrangements: ers. And Novartis might have been more likely events, its effective price drops. (See “Aetna: to establish a beachhead from which it could Cigna Corp.’s commercial business signed Entresto’s Label Enabled Outcome-Based Risk later grow the patient base. up – but not its Medicare group. Such a deal Share” - Scrip, June 29, 2016.) Is it therefore any wonder that pharmacy would merely have increased the likelihood departments at many PDPs are making it that sicker patients, with more drug costs, What’s Not To Like? hard to prescribe Entresto and, thus, that No- would have joined the Cigna PDP to get The problem is that many — probably most vartis has struggled to sell a drug otherwise — of the likely Entresto patients are in Medi- access to Entresto. If the drug worked as perfect for this specific patient population? care and most of those in Medicare Prescrip- advertised, the cost to Cigna would stay rela- tion Drug Plans (PDPs). PDPs are responsible tively high. If it didn’t, the PDP would still be Launching Successfully Into for the cost of drugs (Medicare pays roughly paying more in drug costs than it was before The New Pharma Marketplace two-thirds; the plan must take care of the (Entresto replaces generic ACE inhibitors and Companies should be paying close attention rest through its premium). But they get no ARBs) and it would have sacrificed any spread to the case studies of the most challenging benefit for cost-offsets – because it reduces it makes by buying generics more cheaply launches. But they should be paying atten-

Exhibit 3 Adding A Payer Perspective On Safety And Ease-Of-Use Virtually Eliminates The Differences In Value

RxScorecard: Overall Safety/Ease of Use Score; Statin users at moderate-to-high-risk of CV events I Zetia has been around longer so it has a well- established safety profile; Praluent and Repatha Combined Efficacy and Safety & Use Scores had only been studied in patients for a limited amount of time and only in clinical trials. I Safety & Use I Efficacy I Payers think that Zetia, a 1x/day oral drug, is 35 more likely to encourage adherence; patients on Praluent and Repatha have to self-inject. 30

20 18.9 23.5 19 15

5 11.5 6.7 8.7 Note: RxScorecard analysis of these drugs in moderate-to-high 0 risk patients with sub-optimal response to statins. Zetia Praluent 150 Repatha 140 mgs. mgs. SOURCE: RxScorecard tion as well to those recent launches that Nonetheless, payers have been virtually Winning In A Competitive, have succeeded – including those that have unable to limit use. Several of our payer cli- Skeptical Marketplace succeeded without paying much attention ents have established coverage policies that But even in areas where payers can con- at all to payer concerns. stop paying for the drug after six months if trol the field, drug companies can suc- Vertex Pharmaceutical Inc.’s cystic fibro- it doesn’t work. But at least two senior plan ceed in opening access to their products sis follow-on drug Orkambi (lumacaftor/iva- medical executives have told us that almost without much compromise on price caftor), for example, was approved virtually certainly they won’t cut these patients off: – granted they both provide dispropor- at the same time as the PCSK9is. It’s vastly given that the competition to Orkambi is tionate value and segment the market more expensive (roughly $259,000 annually). so skimpy, the potential publicity of a CF effectively. Take Novo Nordisk AS’ obesity And even though CF affects a tiny fraction of patient denied coverage to the Vertex drug, drug Saxenda,(liraglutide) a higher-dose the number of even very-high risk dislipid- even without evidence that it’s working, formulation of its GLP-1 anti-diabetic Victoza. emia patients (perhaps 8,500 patients in the Saxenda is roughly five times the cost of its would be too damaging. US), Orkambi’s label is far broader than that three flailing competitors, Orexigen Thera- Vertex certainly proved that Orkambi of its predecessor drug, Kalydeco (ivacaftor). peutic Inc.’s Contrave (naltrexone plus bu- delivers disproportionate value relative to And with a billion dollars in US sales propion), Vivus Inc.’s Qsymia (phentermine the competition – so much value that most predicted for 2016, the drug makes a differ- plus topiramate) and Arena Pharmaceutical restrictions are mere tokenism. But it’s also a ence to budgets. It works well for some of Inc.’s Belviq (lorcaserin). the patients for whom it’s indicated, but not good example of the relativity of dispropor- And payers certainly haven’t made things nearly as well for many others. tionate value: Orkambi’s efficacy is far less for easy for Novo or for any of the newer Theoretically, Orkambi’s use can be man- its targeted population than Kalydeco’s for obesity drugs, which are burdened with aged: its studied effects are easily measured its much smaller group. But in a disease that significant step edits and prior authoriza- and the relatively small number of patients creates such emotional intensity, its superi- tions when not outright blocked from the concentrated among specialist prescribers ority over the competition is magnified as formulary. And yet of the Big Four national make tracking these metrics fairly simple. is its ability to sidestep payer management. payers, only United Health advantages any

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Exhibit 4 A Potential Scenario: Zetia Versus A PCSK9i In A Very High-Risk Population

RxScorecard: Combined Efﬁcacy and Safety/Ease of Use; I Patients with atherosclerotic cardiovascular Very high risk statin users disease, LDL>100 and another serious cardiovascular risk (e.g., recent heart attack). I Safety & Use I Efﬁcacy 50

I Outcomes data less important in this patient 45 population given population is smaller and deﬁnable – less concerning to payers…even 40 with a PCSK9i priced at a justiﬁed premium 18.9 to Zetia. 35

20 23.5

15 28.5 10

5 8.9 0 Zetia PCSK9i scenario SOURCE: RxScorecard of the three newer, and cheaper, competi- Smart Segmentation For both too close to the subject and hardly tors ahead of Saxenda. A New Customer Base credible to payers. Imagine the FDA’s reac- One major reason: Novo has de-fanged Reviewing the challenges many new drugs tion to a company using its own clinicians arguments about Saxenda’s high price by have faced, we often hear pharmaceutical to test its therapies on patients, all the while focusing, relative to its competitors, on a executives say something to the effect of knowing which patients were getting drug much more narrowly defined, high-risk “payers care only about money – not im- and which placebo. group of obese patients treated mostly by proving health.” And it’s certainly true that There is, in short, no excuse for compa- endocrinologists and diabetologists, not financial performance drives much payer nies not to stress-test their compounds’ primary care docs (indeed, when a drug decision-making. relative value in one of the value frame- company hires a primary care sales force But complaining about payer incentives works on which payers themselves are for a new drug launch, alarm bells go off at does little to advance the strategic conversa- increasingly relying, such as RealEndpoints’ payers). In fact, Saxenda’s label isn’t much tion. What all these case studies show is the RxScorecard or ICER’s Evidence Reports more restrictive than Contrave’s, Qsymia’s or necessity, on the one hand, to objectively (they can use a straw-man version). Indeed, Belviq’s – but Novo made it clear to payers measure value of a new drug from a payer’s CMS itself is intimating that it might use that it was targeting a well-defined group point of view, and, on the other, define its value frameworks for Part B drugs, and of substantially fewer patients. likely economic impact on the payer as a there’s every reason to believe they’ll ex- Another advantage of the strategy: whole and on each line of its business. pand the notion to Part D. because Saxenda’s specialized prescribers If the drug doesn’t deliver clearly defined, But part and parcel of understanding know Victoza and the patients well, they’re disproportional value to the targeted popu- value to payers is understanding economic comfortable using the drug, which isn’t true lation relative to the competition, payers impact: clearly defining and then communi- for its competitors. In short, if most of these will set up a damaging access contest of cating likely costs to payers, for whom accu- drugs have the same payer restrictions (and one kind or another. And disproportional rate forecasting is a fundamental operating despite Saxenda’s higher price), physician value can’t be defined by a company’s own requirement. And that means a much clearer preferences can tip the scales. R&D and marketing executives: they are qualitative and quantitative description of

Exhibit 5 Drugs Impact Different Plans Very Differently

Example uses a hypothetical $14,000 (WAC price) specialty drug 30

20% Rebate 0 45% Rebate

Proﬁts or Liability ($m) -10

-20

-30 Administrative Services Medicare Prescription Only Plan (ASO) Drug Plan (PDP)

Note: Assumes that each line of business has 20K beneficiaries and same coverage policies; also assumes some medical and drug cost-offsets: replaces $750/beneficiary existing drug spend and reduces ER visits by 2% with average ER cost of $2,000. ASO retains 10% of rebate; PDP plan retains 70%; fully insured plan retains 100%.

SOURCE: Real Endpoints analysis

the total population to be treated, an ap- For drug launches today, the key is to proximate price and an estimate of the rate avoid implicit or explicit exclusion; to get RELATED READING of uptake. And as Novartis and others have the drug into the doctors’ hands. Only then “Changing The Subject (Part 1): Stop Trying To discovered, the calculations need to be run will it be possible to build a broader business ‘Win’ The Drug Pricing Debate” - Pink Sheet, May 25, 2016. [PS057669] across a payer’s entire book of business based, as always, on proof of benefit and because each of those lines have different a sharp reckoning of what providing that “Changing the Subject (Part 2): Turning Turing Around By Offering A National Center Of economics. Indeed, a pharma’s strategy may benefit will cost. IV Pharmaceutical Supply” - Pink Sheet, May 25, in fact start with targeting the specific lines IV004900 2016. [PS057670] of business at payers for whom the new “Aetna: Entresto’s Label Enabled Outcome-Based drug’s economic impact is least painful – or Risk Share” - Scrip, June 29, 2016. [SC065552] even profitable. Roger Longman (roger.longman@realend- “Cigna’s Bradbury Talks PCSK9 Contracts And Call it smart segmentation: armed with points.com) is the CEO of Real Endpoints, an Value Versus Volume” - Pink Sheet, May 11, 2016. a clear understanding of relative value and analytics company focused on defining, for [PS079404] targeted population, the drug company its biopharma, payer and provider clients, the relative value and budget impact of new and Access these articles at our online store can then put together a payer-focused de- www.invivo.pharmamedtechbi.com velopment and commercial strategy: the development-stage drugs, as well as their ap- endpoints required to demonstrate value, propriate target populations. He previously the resonant messages and the size and founded and co-led Windhover Information, sales resources the project demands. In Vivo’s original publisher.

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CVRx’s Investment In HF And Wider Medtech Industry Set To Pay Off View your business as a company, not a product line. That is what CVRx president and CEO Nadim Yared uses as a touchstone in moments of strategic decision-making for a company that he says could break into the global top four of its segment.

BY Ashley Yeo

adim Yared is a consummate networker. Indeed, ■ CVRx’s second-generation device the device industry entrepreneur who leads private is about to enter a pivotal trial in Minneapolis-based CVRx Inc. has a lot to network the US ahead of an FDA filing for an about, as he stewards Barostim therapy for the treat- application to treat heart failure, a ment of chronic heart failure and hypertension onto market that extends to 5.1 million Nthe US and EU markets. adults There, and once established, he is confident that the heart failure ■ FDA has shown its collaborative device (the first intended application of which was hypertension) qualities in helping CVRx design will succeed in reaching a part of the market – a large part – that trials for the PMA class device in the existing CRT-D devices cannot. On this basis, CVRx would break novel and innovative ways, and out of SME status and provide serious competition to the industry’s has left the company deeply im- current big three. pressed. CVRx’s second-generation Barostim Neo is designed to electrically ■ Company president and CEO Nad- activate the baroreflex, the body’s natural mechanism that regulates im Yared believes that revenues cardiovascular function. By activating this afferent pathway, the device from the Barostim Neo device reduces sympathetic activity and increases parasympathetic activity could become large enough to to restore autonomic balance. elevate CVRx among the top four Ten years in the role of president and CEO of CVRx as of September global heart failure companies. 2016, Yared presents himself as someone with a broad and deep ■ Not content with merely steering knowledge of his immediate industry, but also as a champion of the CVRx into the commercial phase wider industry as it reaches out to payers and other stakeholders on for the HF application (Barostim issues of broad market access appeal. Neo also has an application in hypertension), Yared holds decision- These qualities have made him a key player over many years within making roles in other organiza- the US industry association AdvaMed, alongside his CEO role and tions, including AdvaMed, which other directorships. This industry involvement culminated recently has tapped him for its key post. in Yared being designated as AdvaMed’s chairman-elect for the next two-year term.

Views On Compliance Yared’s ability to share experiences and give counsel was on display at the ninth annual Global MedTech Compliance Conference (GMTCC), held in Dublin, Ireland. There, sitting alongside counterparts from Olympus Corp. of the Americas and Teleflex Inc. on a panel address- Executive Summary >> 48 ing global compliance issues, the CVRx CEO, head of a US-focused

16 | July/August 2016 | IN VIVO: The Business & Medicine Report | invivo.pharmamedtechbi.com Medtech Leadership

company of 80 staff, assumed the mantle and agenda. In another developmental step, and outlook of a globally much larger player, we rebranded it to AdvaMed Accel. That was as he shared his views on key industry de- during my time as chair in the last 24 months.” velopments and requirements. This was all happening at a time of struc- “The principle of compliance needs to be tural disconnect between AdvaMed and embraced by the culture of the company fellow US industry body, the Medical Device from the ground up. We find that as we de- Manufacturers Association (MDMA). Now, velop our culture from within, a new set of they work well together, and each has its core values emerges,” he told the meeting’s own areas of specialization and advantages 300 delegates. If this sounds like it might – but eight years ago there was a divergence have come from someone with a longer of opinion. industry pedigree, you’d be right: prior to “We, as an industry, were taken advantage joining CVRx, Yared spent almost 15 years at of because we were divided. Some politicians two industry majors, first at GE Healthcare sought to leverage and play off the associa- and then at Medtronic PLC, holding general tions against each other – MDMA served the manager posts in X-ray imaging and naviga- needs of the smaller companies, and some tion, respectively. were pressing MDMA to accept a device The point is that Yared appears to possess Nadim Yared excise tax waiver for emerging companies. antennae that seek out ways to represent the This would have been just for the smaller broader industry that also suit CVRx’s needs by a multiple of two, given the rising market companies; the larger companies would into the bargain. In 2008, two years after tak- access costs in the regulatory and reimburse- have had to pay more. I didn’t believe this ing over at CVRx, he saw that the US device ment/payer fields. was the best solution – but we all ended up sector needed more support, and decided to Add to that what the CVRx chief calls a getting hit by the device excise tax anyway. throw himself into macro industry develop- certain “frothiness” – a favorite Yared expres- We managed to halve it, but it has still been ments, just as the global economic downturn sion – that was evident among the strategic very deleterious to the industry as a whole.” was starting to bite. consolidators when looking to acquire at-risk Eight years on from that, sitting high up in technologies, and there it was clearly: the per- A Bid For Tax Equality the Convention Center of Dublin, overlook- fect storm. He explained: “Over the years, there Yared said: “My opinion from the get-go ing the River Liffey on an uncommonly warm had been some ‘big misses,’ where companies was that we should have one equal system, May day for the Irish capital, Yared related for had acquired a technology too soon, or the and for several reasons: 1) if we only tax the In Vivo the story of how, back in 2008–09, he technology had not panned out as expected.” larger companies, it would hurt the smaller was inducted into the US medtech lobbying This made the consolidators more risk- companies on multiple fronts: one day we will hall of fame. averse rather than risk-neutral. “It was indeed become a large company ourselves; 2) some the perfect storm for our industry, and I of our funding is coming through these large Perfect Storm figured that it would be very hard for a small companies anyway: if they are taxed higher, “We had had the ‘perfect storm’ – the global firm like CVRx to be able to succeed without they cannot use their funds to invest in small financial crisis that began in fall 2008, the removing some of these obstacles.” companies; and 3) the same principle holds beginnings of the Affordable Care Act [the for the rate and volume of exits: many of the PPACA] and, linked to it, the device excise Working Up The smaller companies get acquired by the larger tax. While our industry was supportive of the AdvaMed Ladder companies, which creates an incentive for need to reform health care, we were not sup- Yared joined AdvaMed in 2008, as a rank and funds to invest in the industry.” portive at all of how the device excise tax was file member, in order to participate in the He reasoned that if these larger companies being brought in, and at the time, we went association’s meetings. But once in the door, were paying more in tax, they would have less through a soul-searching period,” Yared said. he helped create a new interest group – a money to invest or acquire smaller entities There was also pressure to reduce the cost working group called the Emerging Growth – thus there would be fewer exits, and less of care by delaying the introduction of novel Companies Council (EGCC). “Five of us were investment by venture funds. “It’s all linked,” technology. “The belief was that the delayed very vocal about it, and we started to grow he said, adding, “I was against the suggestion launch of new technology would reduce the the number of participants and also stepped of the segregation of the device excise tax cost of care. That is the perception of few up engagement with AdvaMed.” for that reason.” people, and in fact, the opposite is the truth.” “Under the leadership of Michael Minogue Another element in the mix was the fact [CEO of Abiomed Inc.] and Ashley Wittorf The Special Skills Of A Small that the money flow had frozen for a while, [AdvaMed], we converted EGCC into a larger Company CEO and it had become very hard for venture- body with its own separate board of directors. On top of this, Yared explained that he had backed companies to raise money. There was That was four years ago. The group has now moved from a large company to a smaller no liquidity in the market and the cost of get- evolved to a point where it can manage its one, and saw that the internal circle of con- ting a company from “A to Z” was increased own policies and define its own strategic plans tacts was more limited. “In a large company,

©2016 Informa Business Intelligence, Inc., an Informa company | IN VIVO: The Business & Medicine Report | July/August 2016 | 17 Medtech Leadership you’d be, say, general manager of a division, & Co. chairman, CEO and president, Vincent and you’d work with colleagues and share Forlenza. Forlenza is the current chairman thoughts and problems. In a small company, of AdvaMed, but he is to be succeeded by a CEO position can be a very isolated job, and none other than Yared for a two-year term, one where you don’t have peers, but instead the CVRx CEO revealed during our interview. you report to a board of directors, and a team (See “Becton Dickinson Adds A Bigger Jewel To Its of officers reports to you.” The plan I stick String Of Pearls” — IN VIVO, September 2015.). He continued, “So people like me at CVRx As for CVRx itself, there are multiple direc- have to look outside the company for their to religiously is: tions the company could opt to pursue in peers.” His executive coach at the time recom- terms of partnerships. “Like Michael Porter’s mended he join other networking groups – You’re building ‘Five Forces,’ which addresses the different like the Young Presidents Organization (YPO) forces within an industry, you’re always think- for chief executives and business leaders who the business as ing about your customers, your competitors, have achieved success before the age of 45. your distribution and supply sides. Belonging “But I actually found that being a member of a company, not to associations like this trade body [AdvaMed] AdvaMed served a broader purpose. There, or being in a public-private-partnership I networked with small and large compa- as a product.” [MDIC] allows you to identify potential part- nies and observed how they operated and Nadim Yared ners and gauge their expertise in the field, in worked. It gave me a lot of insights as to how – say regulatory, legal, manufacturing, distribu- other CEOs behave, interact and lead.” tion and marketing.” “It allows us to compare ideas and network Events like GMTCC and the annual Ad- with peers.” Yared then went a step further and patient advocacy groups in its aim of vaMed meeting also yield a lot of useful and joined the board of a publicly traded advancing regulatory science. contacts, and access to suppliers on panels company, Hansen Medical Inc., specializing MDIC provides a non-competitive, pre- and on stands. in cardiovascular robotic systems. Adding market arena where companies can collabo- more to the daily workload can be risky rate and share resources to address regulatory Industry Association Value from a time perspective. “The CEO of a small issues from a science – rather than a policy For Small Companies company has many tasks to perform, but only – perspective. “While AdvaMed has been a great place for one objective. If you join another group, the A prime example is the issue of how to us to establish contacts at very high levels, it’s workload mushrooms. Hansen Medical does leverage software modeling to reduce the not a substitute for making connections at all not compete nor overlap with CVRx, but it’s need for clinical trials. “In this case, instead of levels with different organizations. But it’s a still competing for my time during the day.” developing a product and later discovering perfect place to start: through the partnering system at the AdvaMed annual meeting, When the Hansen role came up, it was problems, how can we assess the product’s I built a lot of connections. Now, if I need to around the time that the CVRx board of direc- clinical efficacy through software modeling tors had recommended that Yared actually contact a head of a division or a functional – and then verify it in a smaller clinical trial join the board of a publicly listed company, officer at another company, I know where to setup?” Yared asks. He believes that, if more to gain exposure to the role of CEO of a start, to get the linkage or the introduction,” companies work together with FDA, CMS public entity. “It just happened that Hansen Yared said. and the NIH on this, it could become the Medical was looking for a board member He views the US industry association as the standard. Such issues, and the need to solve with product and commercial expertise in prime forum for connecting and networking. them, is what gave rise to MDIC, where CVRx the cardiovascular capital equipment markets The AdvaMed annual meeting encourages is a founding member and Yared has served – and I’ve been on the board there for over large and medium-sized companies to bring three years now.” on the board since its inception. “I’ve been a their VPs of business development, so that very big advocate of its work,” he said. small companies can network with them Networking, And More and identify business opportunities – right And Another Role For An Networking up to M&A. Industry Champion Yared is also on the board of the Medical Device Innovation Consortium (MDIC), “Advocate” is just the word, as Yared has CVRx’s Priorities the Minneapolis, MN, non-profit organiza- ensured that, primarily via CVRx, he has a As for CVRx, the company is not targeting tion that operates in partnership with the wide input into the industry’s development, any transaction or deal in particular right Food and Drug Administration to improve getting involved in key issues like the threat now. “We are always looking for additional the medical technology environment. The of cyber terrorism. His apparent appetite to expertise, for example, distributors outside group is something of a public/private part- help paint the bigger picture and thereby be the US, as we don’t have distributors in all nership that also combines input from the exposed to key issues calls to mind another the countries we would like. And we always Centers for Medicare and Medicaid Services active ambassador and medtech problem tend to rely on outside expertise in different (CMS), the National Institutes of Health (NIH) solver for the US industry: Becton Dickinson fields, such as in health economics, marketing

18 | July/August 2016 | IN VIVO: The Business & Medicine Report | invivo.pharmamedtechbi.com Medtech Leadership

research or biostatistics. But as to the bigger Strategy For Market The CVRx chief almost marvels at the path strategy, we are not looking to do a business Penetration of events with US authorities. “In 25 years in deal with another entity at this stage.” Yared won’t say when CVRx could be joining the industry, I have never seen such a strong Yared has a firm view on the route that his the big three club in heart failure, as you collaborative, interactive effort.” company is taking. “We’re building this com- might expect. “It’s a step by step thing. Right “With FDA, it’s usually a very different pro- pany right now. The best route to success is now we are commercializing in Europe, cess. Normally, you submit proposals and they always to build a company as an independent where we are focused on getting the prod- comment on them,” he said. But he was pleas- enterprise – if things happen along the way, uct reimbursed country by country, building antly surprised by the experience. “This time, so be it. But the plan I stick to religiously is: awareness of the therapy as we go.” FDA came forward with creative ideas, and ‘You’re building the business as a company, Barostim Neo is already reimbursed in Ger- we would come up with others. We evaluated not as a product.’ Anytime I need to make a many under the ZE code (for certain specific them on a weekly basis. I think this program decision, I run this question past myself: is it procedures and treatments, the supplemen- will be a landmark for FDA in terms of how a product line or a business?” tary payment – Zusatzentgelt – is possible). can we reduce the time to market by a year or And in the US, it was designated an Expe- maybe even two – not by cutting corners, but Targeting A Slice Of The by working very closely and using advanced dited Access Pathway by FDA. “We have just Big Three’s Territory scientific tools, such as Bayesian statistics, to started the US enrollment for our pivotal HF get to answers faster and in a less burdensome And the CVRx team is developing the com- trial,” Yared said. pany precisely because it has the potential for way.” He continued: “I did not expect FDA to success. “There are some start-ups where you Unique Partnership With FDA provide this level of attention, but they have know the technology cannot be developed On Barostim Neo provided us with real, genuine help.” on its own, because it has to be wedded to A PMA product, the Barostim Neo System If I Had My Time Over Again… another product line. A good example of has unique features. The system consists of a Yared will be celebrating 10 years in the CEO this would be an adjunct tool to a specific single extravascular lead that is placed on the role in September 2016. He is proud of his surgery or procedure. In those cases, it’s hard carotid sinus, an implantable pulse generator achievements, but is not above taking advice. for the developing company to own the (IPG) that is placed above the collarbone and “Is there anything I would have done differ- procedure. And it means that down the line, stimulates 40 times more frequently than ently? It would be presumptuous – stupid the tool must be purchased by a company a pacemaker, and a wireless programmer even – for anyone to look back and not learn with a third-party device that can identify the system that allows for non-intrusive, fully from the past; you can always do better,” he procedure,” explained Yared. customizable patient follow-up. The proce- says. Using another favorite expression, he He gave the example of a knee cutting dure to place the lead and IPG is minimally adds, “With hindsight 20/20, there are many guide. It is very difficult to make a sustainable invasive, taking about an hour and a half, skin other things you could have done. But it’s business out of a knee cutting guide. It would to skin. In Europe, where Barostim Neo is CE often hard to know that at the time.” be easier to develop a product line that is sold/ marked, the therapy is used to improve the One regret is the pace of market rollout at distributed by a knee implant manufacturer. quality of life of HF patients, demonstrating CVRx. “I would have wanted the product to Concerns of this nature are not on CVRx’s consistent benefits to those who are not have been already approved in the US and radar. “We have a therapy that has the poten- eligible for CRT. And now in the US, the long- accessible to US patients. We should have tial to make us the fourth-largest cardiovascu- term effects of restoring autonomic balance gone much faster,” says Yared. The reason, lar device company in the world – and maybe in heart failure patients will soon be observed he explained, was that it takes time for some even larger than that – just with this product via the upcoming pivotal trial. innovative technologies to mature. “We had line,” says Yared. “We are targeting two very “It is very exciting, and we are conducting a first-generation device [the Rheos] that large markets: heart failure and hyperten- the study in two stages, where each stage demonstrated the impact of the mechanism sion. In the medical device industry, the CRT leads to a separate FDA approval,” said Yared. of action and showed that the therapeutic product line for heart failure represents one of He stresses that the trial has been designed targets we are going after are very potent, the larger, if not the largest market segment.” very jointly with FDA. “It became a very col- and safe. But the apparatus itself was subop- “Medtronic, Boston Scientific [Boston Scien- laborative, interactive exercise, once FDA timal.” That pushed CVRx back to the drawing tific Corp.] and St. Jude [St. Jude Medical Inc.] determined that our product line has the board in 2010–11, whereafter it developed manufacture CRT, but their devices can only potential to become a useful treatment, has the second-generation device, Barostim Neo. address 25% of HF patients,” said Yared. “We have no known substitutes and meets an unmet a product that can address the remaining 75% need in heart failure – a debilitating and life- More Funding To Come As – and that does not even include the business threatening condition.” Rivals’ Fortunes Mixed to be done with the hypertension device. The Yared continued, “FDA has provided a lot The last time In Vivo sat with Yared coincided market potential is huge, and it requires a lot of of resources to support and guide us in the with CVRx’s Series F funding. That was in muscle and big shoulders to be able to carry design of the trial. So we must give the Center December 2013, and Yared had said back and develop it. It is hard, but doable, and it will for Devices and Radiological Health [CDRH] then that it would be the last round of fund- require a lot of work and sweat.” kudos for that – they did a really good job.” ing. (See “CVRx: Pioneering Hypertension And

Heart Failure Devices – Big Markets Take Big Funding” — IN VIVO, December 2013.) And although that Series F was the last to date, the situation for CVRx has altered, and even What’s while we spoke at the GMTCC, Yared was pondering new funding options for CVRx. He explained that one of the biggest When the Hansen New differences between then and now is the change in market prospects for certain rival role came up, it technologies that were being developed was around the Online? to exploit the market CVRx is entering. “We have seen the successive failures of competing neuromodulation technologies time that the CVRx with dissimilar mechanisms of action – renal denervation [Medtronic’s Simplicity III], board of directors vagal nerve stimulation [Boston Scientific’s NECTAR-HF].” Medtronic’s DEFEAT-HF trial of had recommended spinal cord stimulation for the treatment of heart failure, in fall 2014, was similarly disap- that Yared actually pointing: the implantation of a spinal cord stimulator was not associated with clinical join the board of benefit or improvement in outcomes as a treatment for advanced heart failure. a publicly listed • Quicker access to crucial “While these outcomes have thrown a veil information and insights of uncertainty over the field of neuromodu- company, to gain lation for the treatment of cardiovascular dis- • User-friendly, responsive ease,” said Yared, “it just becomes ever more exposure to the design important for us to remind our stakeholders how Barostim Neo functions differently, as role of CEO of a • Streamined navigation, it’s still the only device designed to work public entity. design and menus at the very top of the autonomic cascade. We also saw the need to raise more money • Robust search capabilites to conduct a pivotal trial before a possible IPO or exit, as from a financial point of view, • Enhanced video, audio the market became a bit more risk averse.” spectacular way can be seen as a burden on and graphics Yared sees all this as a test, of sorts. “When the entire industry – not just for the person we went to raise the Series F, the goal was or player directly affected,” Yared added. For • And much more, to conduct a Phase II trial and get the data the time being, CVRx aims to collect enough clinical and health economic evidence to please visit: – which are ‘phenomenal.’ Execution of the trial was within our control, but the rest of prove the points it wants to make with Barostim Neo – CVRx’s flagship brand. invivo.pharmamedtechbi.com the environment was not, and so, as we see it, our ability to react is being tested,” he said. Right now, and like his “predecessor-in- Clearing the field of opponents is not waiting” at AdvaMed, Yared has his plate always the straightforward ride it may seem. more than full, with the Barostim Neo piv- “When a competitor abandons a market, it otal trial enrolling now, funding to secure is good and bad. Being alone in the market and launch plans to shepherd into place. requires you to do more ‘heavyweight lifting’ If high ambition, a cool head, a realistic to convince regulators, payers, physicians, outlook and an intense work rate with a consumers and users to adopt the technol- potentially ground-breaking technology ogy. When two or more do it together, it’s should be any yardstick, this Minneapolis easier,” said Yared. company must be worthy of close attention Having said that, being a unique player in the coming 24 months. In Vivo in the market has its own advantages. “I will IV004893 IV Pharma intelligence | not say I wish for more competitors, but the disappearance of those competitors in a comments: Email the author: [email protected]

20 | July/August 2016 | IN VIVO: The Business & Medicine Report | invivo.pharmamedtechbi.com Medtech Leadership 9TH ANNUAL MEDICAL TECHNOLOGY EXECUTIVE FORUM SEPTEMBER 29, 2016

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Informa Agenda Ad_RTP.indd 1 7/7/16 5:11 PM Biopharma Strategies

IO’s Impact On Strategic Decision-Making In The Broader Oncology Landscape Market signals from the pioneering immuno-oncology therapies suggest a paradigm shift across multiple oncology indications in the coming years. To ensure that non-IO products become successful components of the standard of care in cancer, drug developers must consider how IO may impact clinical development, market access, and commercialization strategies.

BY Seth Berman, Ryan Stover and Anna Pasternak

ncology is one of the fastest expanding therapeutic ■ The initial success of checkpoint areas in health care, and a strong contributor to this inhibitors and engineered T cell growth is the burgeoning field of immuno-oncology therapies has spawned a surge of (IO). Heralded as the next big revolution in cancer care, investment in the field of immuno- a week rarely passes without an announcement of an oncology. OIO deal or a clinical development update. Recent reports of transfor- ■ More than 750 IO agents are cur- mative efficacy, from dramatic remissions in hematologic cancer to rently under investigation across a overall survival improvements in solid tumors, are fueling interest in IO, broad range of tumor types, which which has the potential to dramatically alter the way we treat cancer. will likely drive rapid and significant Given IO’s likely impact, all cancer drug companies, particularly those changes in oncology treatment. that are developing novel, non-IO agents, should consider their stra- ■ This evolution will consequently tegic decision-making accordingly. Emphasis on and expectations for impact decision-making for all higher response rates and greater durability will raise the efficacy bar novel oncology assets, and in par- across tumor types. As such, the growth of IO will increase the burden ticular for non-IO therapies. on oncology drug manufacturers to demonstrate additional, clinically ■ Moving forward, it will therefore meaningful value. To compete in this future environment, non-IO drug be critical for drug developers to developers need to think strategically regarding the identification of factor in the advancement of IO for attractive white space opportunities and when positioning their agents strategic planning across clinical within the broader oncology landscape. development, market access and commercialization. Depth Of IO Therapeutic Approaches While much of IO in clinical practice is currently centered on anti PD-1/ PD-L1 and anti CTLA-4 agents, these checkpoint inhibitors represent the tip of the iceberg for the field. The next wave of IO therapies exploits a wide range of pathways in tumor immunology. These approaches can be divided into four classes: T Cell Stimulation, Engineered T Cells, An- tigen Presentation and Other Anti-immunosuppression. (See Exhibit 1.) Executive Summary >> 48 Within these classes, T Cell Stimulation is the most prominent in

22 | July/August 2016 | IN VIVO: The Business & Medicine Report | invivo.pharmamedtechbi.com Biopharma Strategies

the market, including the approved PD-1 T cells to induce antigen-specific immune sensitize the immune system to tumor inhibitors Opdivo (nivolumab) from Bristol- reactions. The most prominent are chimeric antigens, and is being harnessed in clinical- Myers Squibb Co. and Keytruda (pembro- antigen receptor T cell (CAR-T) therapies, with stage therapies such as MedImmune LLC/ lizumab) from Merck & Co. Inc., as well as preliminary yet breathtaking hematologic data Inovio Pharmaceuticals Inc.’s DNA vaccine BMS’ CTLA-4 antagonist Yervoy (ipilimumab). from innovators such as Juno, Kite and Novar- for HPV-associated cancers. Meanwhile, Nevertheless, these are not the only mecha- tis. BispecificCD 3 antibodies such as Amgen other anti-immunosuppression approaches nistic options for T cell stimulation. Others Inc.’s Blincyto (blinatumomab) are another aim to capitalize on innate effectors of the in development (e.g., lymphocyte-activation potentially exciting approach, aiming to col- immune system and the tumor microenvi- gene 3 [LAG3] and OX40 [CD134]) seek to locate T cells to tumors for their destruction. ronment to induce heightened responses inhibit regulatory T cell suppression or drive The two other classes of IO therapies to cancer cells, as exemplified by Janssen expansion of effector and memory T cells. are Antigen Presentation and Other Anti- Biotech Inc./Alligator Bioscience AB’s Another widely publicized class of IO agents immunosuppression. Promoting antigen CD40 agonist under investigation for solid is Engineered T Cells. Such programs prime presentation through vaccines could and hematologic tumors.

Exhibit 1 Potential Approaches To Harness The Immune System Against Cancer

IO Classes Under Investigation T Cell Stimulation Engineered T Cells

T cell circulation Activating Inhibitory Naïve T cells can be includes blocking Receptors Receptors directed to specific tumor checkpoint inhibitor antigens via engineered pathways or directly T cell receptors or Bispecific l activating T cells T Cell Cel through antibodies Antibody T linking T cells to tumors Examples: PD-1/L1 Examples: CTLA-4 CAR-T Inhibitory Chimeric OX40 TCR Ligands Antigen ell LAG3 Receptor C sTCS Activating Blocking T Agents Agents Bispecific Ab Tumor Antigen A wide variety of T Cell Cell pathways attempt to Presenting tumor-specific remembers overcome antigens can prime the and can Macrophage immunosuppression, adaptive immune system attack tumor Activate predominantly through to recognize tumors Tumor - Macrophage specific T Cell Induce the activation of innate Example Mediators: Antigen Apoptosis immune factors Dendritic cells Examples: Cancer cells T cell is APC Dendritic primed for Prime Interferons Polysaccharides Activate tumor-specific T Cell Immune metabolomics Bacteria Cell APC Cell antigen Innate effector activators Cytokines T Cell Chemokines Antigen Presentation Other Anti-immunosuppression

PD-1/L1 and CAR-T therapies represent only a fraction of the various approaches to harness the immune system against tumors

SOURCE: Citeline | Pharma Intelligence, 2016

Exhibit 2 to consider how IO will impact strategic Potential Approaches To Harness The Immune System Against Cancer decision-making for novel, non-IO agents. Specifically, non-IO drug developers will need to consider the implications of IO Key IO Assets in Clinical Development across three key dimensions: clinical development strategy, pricing and market access, B and commercialization. lid loo So d or Melanoma Leukemia aj Impact On Clinical Development M Lung Lymphoma er Strategy th O Multiple Tumors are highly heterogeneous and in Brain Myeloma most cases unlikely to be cured through a single therapy or target. Accordingly, the

Head and role of non-IO therapies should remain Endometrial Neck a dynamic component of the strategies implemented to treat cancer. Nevertheless, IO drugs will be highly effective in many Pancreatic Cervical instances, resulting in evolving tumor treat-

n i 25 50 75 100 ment paradigms, which consequently may

c assets assets assets assets affect white space opportunities for non-IO

o d

n assets in development. Manufacturers of E Thyroid Fallopian non-IO therapies will thus need to carefully consider how IO approaches may impact clinical development strategy and trial de-

Colorectal sign decisions.

ProstateG

n Efficacy: When evaluating the white

o spaces for a non-IO asset, a key factor to -

Gastric i keep in mind is that the excitement sur-

Ovarian n

r I

y rounding IO does not dictate that these G Esophageal Breast drugs are definitively the best option for a patient. A non-IO therapy may in fact be Bladder Kidney positioned to deliver meaningful efficacy to patients. In non-small cell lung cancer, EGFR inhibitors such as Genentech/OSI Pharmaceuticals LLC’s Tarceva (erlotinib) SOURCE: Citeline | Pharma Intelligence, 2016 remain a first-line option for patients with EGFR mutations, despite the availability of Although the field of IO is still in its But this separation may not last long. Bio- Opdivo and Keytruda. In melanoma, B-Raf nascency, it is already apparent that an pharmaceutical companies are investigating and MEK inhibitors such as Novartis AG’s abundance of pathways may be targeted to combination therapies that span IO classes. Tafinlar + Mekinst (dabrafenib + trametinib) induce the immune system to attack cancer. For example, Roche’s Genentech Inc. is part- may be prescribed ahead of IO agents. Even nering its PD-L1 checkpoint inhibitor with without a companion diagnostic test, a non- Breadth Of Application Kite Pharma Inc.’s CAR-T in non-Hodgkin IO agent may deliver better efficacy than For IO Therapy lymphoma. Many other clinical trials are un- alternative IO drugs. In this scenario, drug The breadth of application for IO agents also derway that also demonstrate the potential developers may seek to position a non-IO appears to be substantial. Since the approval applicability of IO across either solid or liquid asset as an independent, superior option of the checkpoint inhibitors Yervoy, Opdivo tumors. The result is the potential for sub- for treatment. and Keytruda, clinical trials of IO agents have stantial breadth of application for IO across Patient Stratification: Non-IO therapies been expanding at an exponential rate. As of the spectrum of liquid and solid tumors. may also take advantage of patient strati- the beginning of 2016, over 750 unique agents fication stemming from IO approaches. As were being investigated across more than 20 Implications For Non-IO understanding of IO agents increases, and hematologic and solid tumors. (See Exhibit 2.) Asset Strategy as diagnostics improve, select patients may At this time, a general dichotomy cur- Given the depth and breadth of IO, this be identified who would benefit more, rently exists across IO, with T cell stimulatory field is expected to inspire a dramatic shift or less, from a non-IO approach. PD-1/ agents primarily targeting solid tumors and in treatment paradigms. In this future envi- L1 products arguably demonstrate better engineered T cells favoring liquid tumors. ronment, it will become increasingly critical efficacy in patients with higher levels of

24 | July/August 2016 | IN VIVO: The Business & Medicine Report | invivo.pharmamedtechbi.com Biopharma Strategies

PD-L1. This may open the door for a novel Impact On Pricing And Market targeted therapy to prove superior benefit Access Strategy in patients exhibiting low levels of PD-L1. Decision-making regarding clinical devel- Alternatively, individuals with poor health or opment should not be made in a vacuum. compromised immune systems may be bet- Pricing and market access (P&MA) consid- ter candidates for a non-IO drug compared Patient erations, which may factor into clinical trial with antigen presentation or engineered strategy, are equally if not more important T cell approaches, which may be less safe stratification to maximizing the commercial potential of for such patients. These and other patient a novel drug. stratification scenarios may create favorable scenarios may Historically, oncology has been regarded opportunities for non-IO drugs to become as an untouchable therapeutic area. New the preferred treatment choice, rather than create favorable products would typically be fully accessible playing second fiddle to IO. and reimbursed. However, this mentality has IO/Non-IO Combination: Combination opportunities been shifting. regimens may represent another attractive In Europe, cost-effectiveness and overall opportunity for a non-IO agent. Instead for non-IO drugs value proposition are becoming increasingly of going toe-to-toe with an IO agent on relevant. Germany’s Institute of Quality and efficacy benefit, it may be preferable to to become the Efficiency in Healthcare (IQWiG) recently demonstrate additive benefit in tandem issued negative assessments to three on- with an IO drug. In certain indications, preferred treatment cology therapies: Gilead Sciences Inc.’s this may be the best approach to achieve Zydelig (idelalisib), Valeant Pharmaceuticals faster and greater non-IO drug adoption. choice, rather than International Inc.’s Provenge (sipuleucel-T) A combination regimen may be especially and Vifor Pharma Ltd.’s Velphoro (sucroferric compelling if synergistic benefit with an IO playing second oxyhydroxide). The rationale for each was agent is suspected. Research to date sug- that the products did not provide added gests Raf-MEK-ERK inhibitors increase T cell fiddle to IO. benefit over comparator therapies. In the target antigen recognition, and therefore a UK, drastic cost-cutting measures resulted drug developer may determine it is best to in removal of over half of the reimbursed pair a novel inhibitor of this pathway with for squamous cell carcinoma of the head agents in the Cancer Drug Fund in 2015. an IO agent to demonstrate the greatest and neck (SCCHN), and while regulatory Among these were Celgene Corp.’s widely clinical value. approval is anticipated, it is not guaranteed. used Imnovid (pomalidomide) and Rev- Therapeutic Sequencing: Alternatively, Moreover, there is a question of whether limid (lenalidomide) for refractory multiple it may be best to sequence therapies to PD-L1 diagnostics will or will not be used myeloma, and Abraxane (nab-paclitaxel) for achieve optimal efficacy, perhaps position- in clinical practice. For a non-IO agent in metastatic pancreatic cancer. ing a non-IO therapy ahead of or subsequent development for SCCHN, it will be important Movement in the US similarly suggests a to an IO treatment. For instance, a non-IO to identify how to approach Phase III trial growing scrutiny of oncology drug pricing. A drug may up-regulate immune response, design. Should a monotherapy approach number of non-profit organizations and for- suggesting that the non-IO drug should profit enterprises have launched tools that be pursued in later-line patients, and if so, be administered prior to an IO treatment. evaluate drug pricing and value. The Ameri- is the best comparator a chemotherapy or Conversely, delivery of an IO product may can Society for Clinical Oncology (ASCO) has PD-1/L1 drug? Is the best business decision maximize the anti-tumor effect of a non- recommended that alternative payment to target all patients, or only include those IO chemotherapy, positioning the non-IO programs and innovative care models be with low levels of PD-L1? Is it possible to tar- agent subsequent to IO administration. tested to promote high-value cancer care. get earlier-line patients with a combination Clinical Trial Design: Identifying the fu- As part of this effort, ASCO developed an ture white space opportunities comprises regimen? Answering such questions will be initial value framework to assess the relative only the first piece of the clinical strategy critical to determining the appropriate clini- value of new cancer therapies compared equation. An equally important yet difficult cal trial design for a non-IO asset. with established treatments. Memorial Sloan decision relates to late-stage clinical trial The rise of IO is likely to complicate clinical Kettering published DrugAbacus, a tool to design. It is not necessarily straightforward development of a non-IO drug. It is therefore evaluate the price of oncology therapies to identify the most appropriate compara- important to reevaluate and prioritize white relative to their perceived value. Finally, the tor, patient inclusion and exclusion criteria, space opportunities, and to align on the National Comprehensive Cancer Network or treatment sequence. Making this more appropriate clinical trial program to demon- (NCCN) is incorporating cost scores into challenging is that cancer treatment para- strate value for those indications. Doing so is the information it publishes for clinicians digms are not static. For example, PD-1/L1 one of the first steps to ensure downstream and patients. agents are in late-stage development for commercial success. Granted, drastic P&MA changes will not

©2016 Informa Business Intelligence, Inc., an Informa company | IN VIVO: The Business & Medicine Report | July/August 2016 | 25 Biopharma Strategies happen overnight, particularly in the US. This may influence clinical development the impact to a company’s broader oncology Nevertheless, pricing and market access decisions regarding which indications and portfolio. A drug manufacturer should ensure are key considerations when evaluating a patient populations to prosecute against. that the messaging platform for a new, non- new oncology product strategy. Moreover, Ultimately, P&MA has become more than IO agent is coordinated with other products if IO delivers on its promise and raises the a check-the-box exercise for new oncology that are already launched or in development. bar for efficacy, the burden on emerging products. As the market access landscape In so doing, the overall therapeutic area non-IO therapies to demonstrate additional, becomes more restrictive, it will be im- franchise will possess harmonized product meaningful value will be even greater. perative to plan early and pragmatically positioning across the portfolio that enables With this in mind, drug developers should to ensure commercial success following optimal commercialization. carefully evaluate the indications for which a regulatory approval. Conclusions non-IO agent may demonstrate the greatest Impact On Commercialization value. For example, consider a scenario in Although the full impact of IO remains to be Strategy which a non-IO asset is being pursued in two seen, market signals from the pioneering indications. Indication A has a larger patient The growth of IO also creates a need for checkpoint inhibitors and next-generation population, but the anticipated efficacy early consideration of commercialization CAR-T therapies suggest a paradigm shift improvement with the non-IO drug will be strategy for non-IO developers. This is im- across multiple oncology indications in modest. Indication B, on the other hand, is portant across two dimensions. First, drug the coming years. However, IO will not be smaller in terms of addressable patients, but developers should ensure that the market- the silver bullet to cure all cancer. Oncolo- the expected efficacy benefit is more sub- ing and sales teams possess the information gists will be eager to take advantage of all stantial. In the future P&MA landscape, this required for a successful product positioning novel therapies, including non-IO, thereby analysis, while oversimplified, may suggest strategy. Second, non-IO drug developers providing additional arrows in the quiver that Indication B is more attractive given must plan ahead for life cycle management for tumor treatment. To ensure that a novel, non-IO product becomes a successful com- the potential for higher pricing and more and portfolio planning, particularly given ponent of future oncology standard of care, favorable access. the fast-paced market changes stemming drug developers should carefully consider In a similar vein, P&MA considerations may from IO. how IO may impact clinical development, impact the decision to pursue combination Regarding product positioning, drug pricing and market access, and commer- therapy with an IO agent versus a non-IO developers may need to preemptively plan cialization strategies. monotherapy. Envision a situation in which for future competitors, IO and otherwise. IV004894 IV combining a non-IO agent with an IO drug For example, while incorporation of patient- may lead to additive benefit. Although reported outcomes (PROs) and quality of beneficial, the additional clinical value may life (QOL) measures may not be necessary Seth Berman (seth.berman@clearviewhcp. not be perceived as sufficient to justify the for regulatory approval, collecting these com) is a Principal at ClearView Healthcare total cost of the combination regimen. This data may prove important if a competitor Partners specializing in biopharmaceutical may then suggest that executing clinical IO agent is launched with similar overall growth strategy. Ryan Stover (ryan.stover@ development as a monotherapy, potentially survival data. clearviewhcp.com) is a Consultant and Anna in a different indication, may be preferable. Another scenario is if a non-IO drug is com- Pasternak (anna.pasternak@clearviewhcp. Finally, the clinical landscape is likely to plementary to a marketed IO therapy. In this com) is an Analyst at ClearView. evolve. New treatment paradigms can be case, there may be value in generating data adopted into practice relatively quickly. to support messaging that acknowledges the Acknowledgments Given a stricter future P&MA environment, ability to prescribe multiple drugs to attack a The authors would like to acknowledge it will become increasingly important to tumor. Through such an effort, a novel non-IO Anne Cherry for providing assistance with forecast the future standard of care (SOC) agent will be in the best position to achieve this article, in addition to the following in- and determine its impact for a non-IO agent commercial success while providing physi- dividuals who contributed to the research in development. It may be that the non-IO cians with the information needed to make and analysis for Exhibit 2: Garrett Alpha- asset provides compelling value relative informed prescribing decisions. Cobb, Jessica Berard, Jonathan Juliano, Philip to current treatments but is less favorable Notably, all of the decisions regarding a Kenner, Andrew Larsen, Michael Murray and compared with the anticipated future SOC. new, non-IO agent should take into account Sarah Stapleton.

26 | July/August 2016 | IN VIVO: The Business & Medicine Report | invivo.pharmamedtechbi.com Biopharma Strategies

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Singulex originally developed its Single Molecule Counting technology for research applications, but it is poised to launch a clinical diagnostics tool that incorporates the highly sensitive technology. BY Peter charlish

ingulex Inc., the privately held immunodiagnostics com- ■ Singulex says its next-generation pany based in Alameda, CA, is close to market launch of immunodiagnostic assays are 100 its Clarity in vitro diagnostic system. The fully automated times more sensitive than other platform is designed to bring the benefits of the com- current testing platforms, and pany’s Single Molecule Counting (SMC) technology to they eliminate the problem of “not Shospital and reference laboratories. detectable” results. Singulex bills its SMC technology as “the backbone of next generation immunodiagnostics, because it offers “unprecedented sensitivity ■ The company originally developed and dynamic range in the precision measurement of biomarkers,” its Single Molecule Counting technology for research applica- including proteins and nucleic acids. The company is already offering tions, but it is preparing to launch its SMC technology to clinicians through its state-of-the-art CLIA/ a product for clinical use. CAP/NY-accredited clinical laboratory, which was set up at Singulex’s global headquarters in California in 2010. The lab provides physicians ■ Singulex will pursue high-value ap- with data on cardiovascular and inflammatory biomarkers, allowing plications for its Clarity IVD system, them to assess patients for risk of developing cardiovascular disease. starting with an assay for acute As a result of this service, which generated $41 million in revenues in myocardial infarction. 2015, physicians are already appreciating the extra certainty that SMC testing can offer, says Singulex’s president and CEO, Guido Baechler. ■ A point-of-care system that pro- More than 3 million SMC tests have been processed since 2010. vides results in 20 minutes could The SMC technology allows biomarkers to be measured in blood be commercially available in three samples at concentrations as low as 10 femtograms/ml, which is as to four years. much as 100 times more sensitive than other current testing platforms. This opens up a number of possibilities beyond the capabilities of conventional immunoassay-based tests: it has the potential, for example, to identify people who have a particular disease before the appearance of clinical symptoms, leading not only to earlier diagnosis and treatment, but also to the avoidance of unnecessary and expensive diagnostic procedures in those who have symptoms but who do not, in fact, have the disease. The technology can also be used to monitor the progression or recurrence of disease, or its response to treatment, again with greater sensitivity than with other methods. All these characteristics have the potential to lower health care costs as well as improve patient management.

Beginning With Research The use of SMC as a clinical diagnostic tool evolved from Singulex’s development and commercialization of the technology as a life Executive Summary >> 48 science research tool via the Erenna system, which the company

28 | July/August 2016 | IN VIVO: The Business & Medicine Report | invivo.pharmamedtechbi.com IN VITRO DIAGNOSTICS

introduced in 2008. The system includes counted as digital events. fully integrated benchtop analytical in- The instrument records the sum of all strumentation with dedicated software for digital events counted; at high biomarker automated data analysis. Singulex has de- concentrations, when the digital counting veloped research assays for a wide range of mechanism becomes saturated, the sum cardiovascular, infectious disease, oncology, of all photons recorded is computed via a autoimmune, neurology and nephrology One of the benefits proprietary algorithm. In this way a dynamic markers. In addition, users may develop of being able to range of over four orders of magnitude is their own assays. achieved. In July 2015 EMD Millipore, the life sci- quantify biomarkers One of the benefits of being able to quan- ence business of Merck KGAA, headquar- tify biomarkers at such very low concentra- tered in Darmstadt, Germany, acquired at such very low tions highlighted by Singulex is the ability worldwide exclusive rights to Singulex’s SMC to eliminate the problem of “not detectable” technology, including instruments, assays concentrations or “non-quantifiable” results, which can be and services, for research applications. “This difficult to interpret. As well as facilitat- strategic agreement … puts our unique highlighted by ing comparisons between endogenous technology into the best possible hands Singulex is the ability and elevated analyte levels, this capability to optimize its commercial scale-up and facilitates a number of different types of market potential,” Baechler said at the time. to eliminate the investigation, leading to: Commenting on the deal to In Vivo, • more accurate stratification of populations; Baechler says the decision to out-license problem of • pharmacokinetic studies extended over the research applications of the SMC tech- longer periods; nology was made for strategic reasons. “We “not detectable” or more accurate microdosing studies; realized that handling both the research • and clinical applications of the technol- “non-quantifiable” • study of disease progression even when ogy was too much for one company,” he biomarker levels are low; and explains. The situation is similar to that at results, which can be • discovery of new uses for existing bio- Roche in the early 1990s, he says, when the difficult to interpret. markers. polymerase chain reaction (PCR) technology, originally developed by Cetus Corp., The Clarity System was commercialized by Roche for clinical Singulex says that the Clarity system will be diagnostic applications and by Perkin-Elmer No Non-Detectable Results the most sensitive IVD immunoassay system Inc. for research applications. Baechler is in According to Singulex, the SMC technol- for routine diagnostics. Singulex began a position to know: between 1989 and 1994 ogy uses standard immunoassay chemistry development in 2014, in collaboration with and again between 1995 and 2008 he held combined with a digital detection system. the Swiss laboratory automation specialist executive and leadership positions at both The capture step quantifies low-abundance Tecan Group Ltd. The concept combines Roche Diagnostics and Roche Molecular biomarkers in biological fluids using para- Singulex’s SMC technology and custom- Diagnostics. He joined Singulex in Febru- magnetic microparticles coated with spe- ized consumables with Tecan’s Freedom EVO ary 2008 as vice president of diagnostics cific antibodies; the surface chemistry of liquid handling platform to create a fully and then served as senior vice president of the microparticles is designed to improve automated benchtop analyzer targeted at operations. He became president and CEO specific binding efficiency while minimizing clinical diagnostic laboratories. It also incor- in 2013, replacing Philippe Goix, PhD, who non-specific binding. Following capture, the porates a customized one-piece detection had led the company since shortly after its microparticles are magnetically separated vessel designed and manufactured by Sony founding in 2004. and washed to remove unbound protein. DADC BioSciences GMBH (currently being Goix was at the helm in 2010 when three Each biomarker is translated into a signal acquired by STRATEC Biomedical AG). The related whistleblower actions were brought by the addition of fluorescent dye-labeled aim of partnering with Tecan was to ensure against Singulex and Health Diagnostics detection antibodies, with each signal cor- the development of an instrument of the Laboratory Inc. alleging that the companies responding to a single biomarker molecule. highest quality while at the same time re- had violated the False Claims Act by paying The eluate is transferred to a reading plate duce the time to market, Baechler explains. remuneration to physicians in return for where it is aspirated into the instrument’s The Clarity system will feature ready-to-use patient referrals and billing federal health capillary flow system. The interrogation assay reagents that do not require special care programs for medically unnecessary space inside the capillary has a diameter of handling prior to use. Other benefits will testing. In April 2015, Singulex reached roughly 5 μm and is illuminated by a laser: include an advanced workflow with built-in an agreement with the US Department of single fluorescently labeled molecules gen- touch screen with a simple graphical user Justice to resolve the allegations, agreeing erate intense flashes of light as they pass interface, on-board capacity for 12 assays, to pay $1.5 million. through the laser beam. These flashes are throughput of more than 400 tests/shift,

capacity to hold 48 primary sample tubes cardiac patients, which uses a relatively high filed and/or published patents relating to and a continuous inventory of on-board dose of radiation and is expensive. Over 90% individual biomarker applications: the focus resources. of nuclear stress tests currently carried out of this portfolio is primarily cardiovascular, The first placements of the instrument for are negative, which adds significant un- but it also includes rheumatoid arthritis and premarket evaluation are currently under- necessary cost to the health care system. kidney disease markers. way in Spain and the UK, with the aim of Studies carried out at the University Hospital generating sufficient data to support Eu- of Basel, Switzerland, have shown that the New Money, New Market ropean approval by the beginning of 2017. average saving achieved by incorporating Privately held since its founding in 2004, Three evaluation sites in the US are also cardiac troponin I testing into the diagnostic Singulex attempted to go public in 2012, being rolled out, again with the intention of workup of suspected cardiac patients (and but withdrew the IPO three months after generating data for an FDA approval submis- thereby eliminating unnecessary scintig- filing, citing poor market conditions. It has sion in early 2017. The company will be pur- raphy studies) is about $364 per patient. received multiple rounds of financing over suing the 510(k) route for the Clarity system. Applying this model to the whole of the the years from backers including OrbiMed Baechler reports Singulex has already had a US would save around $2.5 billion per year, Advisors, Prolog Ventures, Fisk Ventures number of positive conversations with the Singulex says. and JAFCO. FDA to help guide this process. Looking further ahead, Baechler says Sin- A new investor signed on in May 2016, when Grifols SA, a leading producer of High-Value Diagnostics gulex is developing a point-of-care system therapeutic plasma products with a pres- Applications that will permit SMC testing to be carried out at the patient’s bedside and provide results ence in more than 100 countries, announced Part of Singulex’s strategy for the launch of within 20 minutes: commercial introduc- a $50 million equity investment in Singulex, the Clarity system will be to focus on high- tion in Europe is provisionally planned for thereby increasing its stake in the US com- value applications. The first of these will be the end of 2019, subject to the necessary pany to 20%. The deal gives Grifols, based an assay for cardiac troponin I. Low con- approvals, and for 2020 for the US. The in Barcelona, Spain, an exclusive worldwide centrations of cardiac troponin I measured license for the use and sales of Singulex’s on presentation to the emergency room instrument will be based on a dry blotting SMC technology for the screening of blood have been shown to have a high negative system, and basic feasibility has already been and plasma, and represents a major ad- predictive value for the identification of established using cardiac troponin I as the vancement in further ensuring the safety of acute myocardial infarction (AMI). Last year, biomarker. The company is now concentrat- the European Society of Cardiology estab- ing on miniaturizing the optics involved blood and plasma products, the two firms lished a new guideline to rule out AMI in with the aim of developing a microfluidic said in an announcement. patients presenting with chest pains (2015 cartridge “about the size of a coffee cup.” Along with revenues from its lab business ESC Guidelines for the management of acute Its strategy is to create the market for SMC and future Clarity system sales (subject to coronary syndromes in patients presenting testing with the Clarity system, and then to approval of the device), Baechler anticipates without persistent ST-segment elevation, further exploit the market with the point- that partnerships, like the one with Grifols, European Heart Journal 2016;37:267–315): of-care system. will play a major role in financing the com- patients with cardiac troponin I levels of In support of these developments, pany’s ambitious plans for the future, such less than 5 pg/ml can be safely ruled out as Singulex owns a broad IP portfolio. The as the point-of-care system. “We continually not having AMI. Unlike other platforms, the company holds six issued and four filed explore additional external funding oppor- Clarity system is capable of measuring down patents relating to the Erenna system (in tunities, although we don’t have specific to this level of sensitivity. the US and in the rest of the world), and the plans for additional rounds of funding at Baechler says that applying the Singulex Clarity system is supported by 11 issued and this time,” he adds. IV cardiac troponin I assay also helps avoid the nine pending patents. In addition, the firm IV004899 unnecessary use of nuclear stress testing in has a portfolio of 10 issued patents and 26 comments: Email the author: [email protected]

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Using Enriched Studies For Post-Approval Evidence Needs These days, clinical trial sponsors are being asked to provide empirical evidence to many stakeholders with diverse needs and to do so efficiently. By taking a holistic view of post-approval evidence needs, it is possible to address many stakeholders, thereby minimizing expense while increasing the likelihood of getting data that are fit for a variety of purposes.

BY Nancy Dreyer

The European Medicines Agency (EMA) banking of genetic material. To be successful, a sponsor recently made a move that could force drug developers needs to understand what type of study and data are to rethink how they manage their evidence needs after needed to meet stakeholder expectations. market approval. In June 2015, EMA released a draft If sponsors respond to each stakeholder’s questions scientific guideline regarding post-authorization ef- in isolation, they will start many projects, with skilled ficacy studies (PAES) and what evidence should be manpower for each, cross-training, and a series of studies, gathered in the European Union (EU). In addition, a each designed to address one main objective. The more guidance that describes the regulatory aspects for the post-approval study requirements, the more study setup fulfillment of imposed PAES has also been published. (See and execution costs, and the risk that any given study “EU Postmarket Efficacy Studies To Get More ‘Predictability,” still may not answer questions from all stakeholders in Pink Sheet, August 2015 [PS078802].) an acceptable manner. The guidance on PAES established circumstances in By taking a holistic view of post-approval evidence which EU regulators could require efficacy studies for all needs, it is possible to address many stakeholders’ needs, medicines, rather than only when there are questions thereby minimizing expense while increasing the likeli- about the efficacy of the medicine that need further hood of getting data that are fit for a variety of purposes. evaluation in certain situations. The new guidance Toutlines situations where a PAES could be imposed, Post-Approval Evidence Needs including to address uncertainties related to specific Enriched studies use existing health care data coupled patient groups not studied in clinical trials, to evaluate with selective prospective data collection for robust, surrogate endpoints used for marketing authorization, patient-centered insights in real-world experience, and are or in response to changes in scientific knowledge that a good approach to meeting PAES and other post-approval bring into question any criteria used to demonstrate the evidence needs. This approach can be particularly valu- efficacy of a medicinal product. able in PAES because it offers clinically rich data on diverse These days, clinical trial sponsors are being asked to subgroups at low cost, since researchers only prospectively provide empirical evidence for many stakeholders with collect those critical data not readily available otherwise. diverse needs and to do so efficiently. The requirement As sponsors may be obligated to conduct PAES for to evaluate how well treatments work in real-world set- market approval in the EU, this requirement should be tings, in ways that are meaningful to clinicians, patients used as stimulus to design and gather data for several and health systems, means sponsors will have to gather purposes, ideally within the same study framework. In- more and different evidence to demonstrate both short- formation can be gathered about effectiveness and and longer-term benefits and risks. The type of evidence treatment safety in general, or as relates to specific pa- needed may require some data collection and even bio- tient subgroups and geography. The incremental costs Executive Summary >>48 of adding data elements can be minimal, particularly if

32 | July/August 2016 | IN VIVO: The Business & Medicine Report | invivo.pharmamedtechbi.com CLINICAL STRATEGIES

much of the necessary data already exist and treatment compared with usual care con- tudinal data about the patient populations of are accessible electronically. The result can ducted in a small region in a country covered interest that are not appropriate for a Phase II be pragmatic evidence that will command by national health insurance. The Salford or III trial, but may help support a value story the attention of clinicians, patients and pay- Lung study is a pragmatic randomized con- or provide information about possible label ers, all who make important decisions about trolled trial (pRCT) that is being conducted expansion, should the product be successful. whether these drugs will be prescribed or to study a once-daily combination of a How will you know if your data and used, and how much if any reimbursement long-acting β agonist and inhaled cortico- a study design are good enough for the will be provided. steroid in a novel delivery system intended purpose at hand? This topic has received Consider how the enriched study ap- to treat asthma and chronic obstructive considerable attention recently. The Good proach was used to evaluate the efficiency pulmonary disease (COPD). The study is Clinical Practice and CONSORT guidelines of treatment for myocardial infarction. The being conducted in the Manchester region for clinical trials had long been considered goal of the TASTE trial in Sweden was to in- of the UK, where patients are covered by sufficient. These days, however, there are vestigate the real-world clinical effectiveness the UK National Health Service (NHS). The additional guidance documents to help of routine intracoronary thrombus aspiration study is comparing the effectiveness of stakeholders understand the basic require- before primary percutaneous coronary inter- vilanterol/fluticasone furoate in a dry-pow- ments for a good study of drug safety or vention (PCI) in patients with ST-segment der inhaler with existing therapies for COPD comparative effectiveness. In fact, develop- elevation myocardial infarction. It was a fairly and asthma over a 12-month period. After ing guidance documents based on consen- large study, with more than 7,000 patients randomization, patients receive “usual” care sus has become a popular sport. who were recruited from existing registries for one year through the NHS. Effectiveness Some guidance activities, like the and then randomized to groups assigned and safety data are monitored and collected GRACE (Good ReseArch for Comparative to manual thrombus aspiration followed by using an electronic health record. The care Effectiveness) Checklist, stand out from PCI or PCI only. Investigators were able to experience for patients has only minimal dis- others because of the extensive validation tribution since their medical care providers use the best features of a large-scale clinical efforts. (See online-only sidebar.) The GRACE continue to prescribe as usual and patients registry, which allowed for broad inclusion Checklist is a simple 11-item checklist that obtain their medications from their usual criteria, combined with the benefits of ran- outlines basic elements of what makes an community pharmacist. The study sponsor domized treatment assignment to achieve observational study of comparative effec- only bears the cost of active study activities, a simplified enrollment process, low enroll- tiveness good enough to be relied on. The (e.g., randomization, special study clinical ment costs and high rates of follow-up. As checklist has been tested empirically against visits and tests), whereas the bulk of data an added benefit of conducting this study systematic reviews and expert opinions and collection activities are untaken through using patients recruited from a registry, the has been fine-tuned through use by testers usual care, not as a study-funded activity. investigators were able to follow patients from five continents and a wide variety of The TASTE and Salford examples illustrate who declined to participate, allowing them backgrounds. how enriched studies can be used to study to evaluate selection bias, since most of the It would be ideal if we could conduct efficacy in the most rigorous fashion – using same data were already being collected studies of treatment effectiveness using randomization to offset selection biases that for these patients in the registries. The trial are always present in non-interventional treat- existing data exclusively but experience showed that routine thrombus aspiration ment decisions – and then taking advantage shows us that the important clinical, ex- before PCI as compared with PCI alone did of the fact that routinely collected data are posure and outcome data are not always not reduce 30-day mortality among patients largely sufficient for characterizing the real- recorded, and when they do exist, they may with STEMI – a practical answer to an im- world experience after treatment assignment. not be accessible to researchers. Instead of portant question – enabled in large part by total reliance on prospective data collec- clever study design and execution. Think Ahead tion, either through clinical trials or non- When you use enriched data to col- Enriched studies will return the most benefits interventional studies, investigators can use lect the information you need, you get an if stakeholders are identified early and in- enriched studies to generate reliable data for infusion of knowledge enabling multiple cluded in the planning. This process requires many purposes and answer more questions evaluations using a common data set. In careful direction and a firm hold on the reins at little additional cost, laying a foundation some cases this approach may answer all since sometimes projects can escalate to for addressing many questions of interest to efficacy questions, eliminating the need five or more times their original budget if payers, patients, physicians and regulatory for new research; for others, it can provide additional objectives are simply piled on, one agencies through a single research program. a head start, allowing sponsors to better after another, without substantial attention IV004904 IV scope the prospective data collection they to where data come from and the quality of will need to perform to fill in the remaining data (and study design) that are appropriate Nancy Dreyer, PhD (Nancy.Dreyer@Quintiles. knowledge gaps. to answer the questions at hand. Sometimes com) is Global Chief of Scientific Affairs and Now, consider the example of a clinical sponsors build patient registries early in Senior Vice President, Quintiles Real-World and trial of a novel once-daily investigational development, for example, to capture longi- Late Phase Research.

BENSON, Trey HEALY, John MCCOLLOUGH, Dawn To: XBiotech Inc., VP, Commercial To: exosome Diagnostics Inc., To: XBiotech Inc., VP, Dev. & Mktg. (June) VP, Informatics (May) Clinical Ops. (May) From: edgemont Pharmaceuticals, From: GnuBIO/Bio-Rad Laboratories, From: Biogen Inc., Head, VP, Mktg. VP, Informatics Medical Research phone: 512-386-2900 phone: 646-843-4945 phone: 512-386-2900

BISHOP, John E. HELLMANN, Carsten MEHTA, Khush F. To: Genocea Biosciences Inc., SVP, To: ALK-Abello AS, Pres. & CEO (May) To: cardioDx Inc., Pres. & CEO (June) Pharmaceutical Sciences (May) From: Merial, CEO From: siemens AG, Global Head, From: Momenta Pharmaceuticals Inc., phone: +45 4574 7576 Healthcare Enterprise Solutions SVP, Pharmaceutical Sciences phone: 650-745-2788 phone: 617-876-8191 HERRON, Jennifer L. NEUMAN, Linda, MD To: Ariad Pharmaceuticals Inc., EVP, BLUM, Leonard M. To: sunesis Pharmaceuticals Inc., Chief Commercial Officer (May) To: omeros Corp., Chief Bus. & VP, Clinical Dev. (June) From: Bristol-Myers Squibb Co., Commercial Officer (May) From: puma Biotechnology Inc., Lead, Commercial From: Theravance Inc., SVP, Senior Medical Dir. Transformation & Chief Commercial Officer phone: 650-266-3500 Operating Model phone: 206-676-5000 phone: 617-494-0400 RABINOWICZ, Adrian L., MD BOSLEY, Robert To: sancilio Pharmaceuticals Co. Inc., To: dnA Diagnostics Center, JOSLYN, Alan, PhD CMO (June) EVP, CFO (June) To: oragenics Inc., Pres. & CEO (June) From: Acorda Therapeutics Inc., SVP, From: serta Simmons Bedding, From: Lazarus Pharmaceuticals, Partner Clinical Dev. & Medical Affairs SVP, Finance phone: 813-286-7900 phone: 561-847-2302 phone: 513-881-7800 KEHOE, James RICHARDSON, Chris CADY, Roger K., MD To: Takeda Pharmaceutical Co. Ltd., To: Keystone Heart Ltd., To: Alder BioPharmaceuticals Inc., CFO (June) Pres. & CEO (May) VP, Neurology (June) From: Kraft Foods Group US, CFO From: direct Flow Medical Inc., From: headache Care Center, phone: +81 6 6204 2111 International Pres. & CCO Medical Dir. phone: +972 4 615 8000 phone: 425-205-2900 KINGSLEY, Tony To: The Medicines Co., RIGGS, Robert CELEBI, John Pres. & COO (May) To: prisyna, Dir., Mktg. (May) To: X4 Pharmaceuticals Inc., From: Biogen, EVP, From: Blu Theory Solutions, Dir., COO (June) Global Commercial Ops. Sales & Mktg. Program Dev. From: igenica Biotherapeutics Inc., CBO phone: 973-290-6000 phone: 855-774-7962 phone: 857-529-8300 LAGARDE, Michel SABLE, Carole, MD FARDIS, Maria, PhD To: patheon Inc., Pres. (May) To: Vitae Pharmaceuticals Inc., To: Lion Biotechnologies Inc., From: JLL Partners, Managing Dir. CMO (June) Pres. & CEO (June) phone: 919-226-3200 From: Revolution Medicines Inc., CMO From: Acerta Pharma BV, COO phone: 215-461-2000 phone: 212-946-4856 LEVY, Adam SAHMOUD, Tarek, MD, PhD FOREST, Pierre To: miRagen Therapeutics Inc., To: h3 Biomedicine Inc., CMO (June) To: Mauna Kea Technologies SA, CBO (June) From: Boehringer Ingelheim, COO (June) From: Wedbush Securities, SVP VP, Oncology Clinical From: corten SAS, Founder phone: 303-531-5952 Dev. & Medical Affairs, US phone: +33 1 48 24 03 45 phone: 617-252-5000 MARTENS, Juergen A., PhD GERMANO, Geno To: neos Therapeutics Inc., Chief SCHADE, Christian S. To: intrexon Corp., Pres. (June) Technology & Ops. Officer (May) To: Aprea AB, Pres. & CEO (June) From: pfizer Inc., Group Pres., From: MannKind Corp., COO From: omthera Pharmaceuticals Inc., Global Innovative Pharma phone: 972-408-1300 EVP, CFO phone: 301-556-9900 phone: +46 8 50884504

34 | July/August 2016 | IN VIVO: The Business & Medicine Report | invivo.pharmamedtechbi.com New At The Helm ONTHEMOVE

Directors

SCHILKE, Tobin AHRENS-TOWNSEND, Mark To: Achaogen Inc., CFO (July) To: Kane Biotech Inc., Director (June) From: Roche Products Ltd., CFO phone: 204-453-1301 phone: 650-800-3636 Michael Becker, CFO Relmada Therapeutics EDWARDS, Marc SILVERSTEIN, Martin, MD To: Kane Biotech Inc., Director (June) To: Gilead Sciences Inc., phone: 204-453-1301 EVP, Strategy (May) From: Anthem, EVP, FIORINO, Tony, MD, PhD Chief Strategy Officer To: navidea Biopharmaceuticals Inc., phone: 650-574-3000 Director (May) phone: 614-793-7500 STEVENS, Anthony Christopher (Chris), MD FOURTEAU, Patrick To: Arsanis Inc., CMO (June) To: Repros Therapeutics Inc., From: Consultant Michael Bush, President Chairman (May) phone: 781-819-5704 Ganeden Biotech phone: 281-719-3400

TADIGOTLA, Vasisht FRIEND, Cynthia, PhD To: exosome Diagnostics Inc., To: Bruker BioSciences Corp., Head, Informatics (June) Director (May) From: courtagen Life Sciences Inc., phone: 978-663-3660 Senior Scientist phone: 646-843-4945 GREENE, Mark I., MD, PhD To: navidea Biopharmaceuticals Inc., THEOHARIS, Stefanos, PhD Director (May) To: cell Medica Ltd., SVP, phone: 614-793-7500 Head, Pipeline Strategy & John Celebi, COO Corp. Partnering (May) X4 Pharmaceuticals From: apceth GMBH & Co. KG, CBO GRÉGOIRE, Sylvie phone: +44 20 7554 4070 To: corvidia Therapeutics, Chair (June) phone: 917-322-2216 TYLE, Praveen, PhD To: Lexicon Pharmaceuticals Inc., VP, R&D (May) JOHNSON, David From: osmotica Pharmaceutical Corp., To: presage Biosciences Inc., Pres. & CEO Director (June) phone: 281-863-3000 phone: 800-530-5404

VERDOORN, Todd Sylvie Grégoire, Chair JORN, Deborah A. To: diaMedica Inc., CSO (May) Corvidia Therapeutics To: orexigen Therapeutics Inc., From: intuitive Quantitation LLC, Director (May) Chief Scientist phone: 858-875-8600 phone: 763-710-4455 JOSHI, Arvind WARREN, James, PhD To: Kane Biotech Inc., Director (June) To: homology Medicines Inc., phone: 204-453-1301 VP, Manufacturing (June) From: bluebird bio Inc., Senior Dir., KAYE, Edward M., MD Vector Dev. & Manufacturing To: cytokinetics Inc., Director (May) phone: 781-301-7277 phone: 650-624-3000 Khush Mehta, President & CEO CardioDx

Directors

KOHRS, Doug PRICHARD, Sarah SOUTHWELL, David To: MedShape Inc., Director (June) To: Kane Biotech Inc., Director (June) To: inVentiv Health Inc., Director (May) phone: 404-249-9155 phone: 204-453-1301 phone: 800-416-0555

RENAUD, Philip KRENITSKY, Kevin, MD STRIPE, Dennis To: Kane Biotech Inc., Chairman (June) To: stemina Biomarker Discovery Inc., To: MedShape Inc., Director (June) phone: 204-453-1301 Director (May) phone: 404-249-9155 phone: 608-204-0104 RICE, Michael To: navidea Biopharmaceuticals Inc., WALKER, John P. MULDER, David Director (May) To: Zosano Pharma Corp., To: cyanotech Corp., Director (May) phone: 614-793-7500 Chairman (May) phone: 808-326-1353 phone: 510-745-1200 SMITHBURG, William NAWICKI, Mark To: chromaDex Corp., To: Kane Biotech Inc., Director (June) Independent Director (June) phone: 204-453-1301 phone: 949-419-0288

Promotions

BARRY, James, PhD DESOUZA, Francis SHERMAN, Mike To: inspireMD Inc. To: illumina Inc. To: endocyte Inc. new Title: pres. & CEO (June) new Title: pres. & CEO (July) new Title: pres. & CEO (June) previous Title: coo previous Title: pres. previous Title: cFO & COO phone: +972 3691 7691 phone: 858-202-4500 phone: 765-463-7175

BECKER, Michael D. LABRUCHERIE, Gil M. SIKORSKI, Robert, MD, PhD To: nektar Therapeutics To: Five Prime Therapeutics To: Relmada Therapeutics Inc. new Title: sVP, CFO (June) Inc. new Title: cFO (May) previous Title: sVP, General Counsel & new Title: cMO (June) previous Title: sVP, Finance & Corp. Dev. Secretary previous Title: sVP, Global Clinical Dev. phone: 610-272-2071 phone: 415-482-5300 phone: 415-365-5600

BUSH, Michael NICHOLSON, John YOUNG, Kevin To: Ganeden Biotech Inc. To: nektar Therapeutics To: Gilead Sciences Inc. new Title: pres. (May) new Title: sVP, COO (June) new Title: coo (May) previous Title: sVP previous Title: cFO previous Title: senior Advisor phone: 440-229-5200 phone: 415-482-5300 phone: 650-574-3000

Advisors Resignations

EBISAWA, Motohiro, PhD NELSON, Thomas DRYSDALE, Doug To: dBV Technologies SA, Scientific To: Biotricity Inc., Advisor (June) From: pernix Therapeutics Holdings Inc., Advisor (June) phone: 800-590-4155 Chmn., Pres. & CEO (May) phone: +33 1 55 42 78 78 phone: 800-793-2145 RICE, J. Bernard HOLTZMAN, Steven To: Biotricity Inc., Advisor (June) FRENCH, J. Michael To: compugen Ltd., Strategic Bus. phone: 800-590-4155 From: Marina Biotech Inc., Chmn., Pres. Advisor (May) & CEO (June) phone: +972 3 765 8585 phone: 425-908-3600

36 | July/August 2016 | IN VIVO: The Business & Medicine Report | invivo.pharmamedtechbi.com ONTHEMOVE In Vivo Pharma intelligence |

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invivo.pharmamedtechbi.com ©2016 Informa Business Intelligence, Inc., an Informa company | IN VIVO: The Business & Medicine Report | July/August 2016 | 37 dealmaking This issue’s Dealmaking covers deals made: June 2016 Derived from Strategic Transactions, Informa’s premium source for tracking life sciences deal activity, the Dealmaking column is a survey of recent health care transactions listed by relevant industry segment – In Vitro Diagnostics, Medical Devices, Pharmaceuticals, and Research, Analytical Equipment and Supplies – and then categorized by type – Acquisition, Alliance, or Financing.

In Vitro Diagnostics Pharmaceuticals Daiichi Europe gets rights to Nektar’s breast cancer therapy Onzeald

Alliances Mergers & Acquisitions Dr. Reddy’s acquires eight US ANDAs from Teva

Aytu licenses MiOXSYS to various European Merck buys Afferent for $500mm cash and Eisai, Novartis co-promote Eisai’s Lenvima/ partners $750mm in potential earn-outs Afinitor combo in the US Oncology firms Oncternal and Tokalas merge Eleven partners IL-6 antagonist assets with Roche Medical Devices Savara buys fellow respiratory disease- focused firm Serendex Innovent licenses EpimAb’s FIT-Ig platform for bispecific antibody development Mergers & Acquisitions Alliances MedImmune and Genisphere in oncology Terumo acquires US aneurysm tie-up embolization device maker Sequent Sorrento’s TNK and 3SBio form immunotherapies joint venture Impax acquires generic drug portfolio from Teva; Teva returns rights to ANDA for Vitrolife AB acquires IVF technology EA Pharma to co-promote Humira in Japan generic Concerta companies Octax and MTG with AbbVie GK Medgenics gets option to Kyowa Hakko’s Zimmer Biomet pays $1bn for spine device CRISPR gets license to stem cell IP from mAb for pediatric IBD maker LDR Holding Anagenesis Takeda and Roivant launch Myovant; Nephron gets rights to budesonide Takeda grants rights Financings inhalation suspension from Apotex Shire gets global rights to Pfizer’s Phase II AirXpanders brings in $A6.7mm through Ariad grants Biologix FZCo. Iclusig rights in IBD therapy private placement the MENA region Takeda gets rights to Theravance’s GI NeuroMetrix grosses $21.3mm in private Pint Pharma gets Latin American rights to motility project TD8954 placement of preferred stock Ariad’s Iclusig Ultragenyx and Takeda pen rare disease Nevro nets $146mm in public convertible Array, Pierre Fabre, and Merck KGAA deal notes financing conduct combo trial for BRAF-mutant Zydus Cadila acquires two ANDAs from colorectal cancer Teva Second Sight Medical nets $19.4mm via oversubscribed rights offering Aspen pays $520mm up front plus milestones for rights to seven of AZ’s Financings Sensus Healthcare’s IPO nets $11.8mm anesthetic products Private placement brings €30mm to Grunenthal gets lesinurad rights in Europe Titan Medical secures $16mm investment arGEN-X from Shanghai Jugu and Latin American from AZ Aurinia grosses $7.1mm through private Viveve Medical nets $14.4mm in FOPO Revance acquires assets of BTRA’s placement botulinum toxin patent estate Regenerative medicine company Biotime Cadila, Lipidor collaborate on psoriasis nets $16.5mm in FOPO candidate Clearside Biomedical goes public netting Kite Pharma develops CAR candidates $46.9mm using Cell Design’s molecular “on/off switches” RDO nets $14.8mm for Corbus

38 | July/August 2016 | IN VIVO: The Business & Medicine Report | invivo.pharmamedtechbi.com DEALMAKING

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In Vitro Diagnostics WEB aneurysm embolization system. WEB earned the CE mark in 2010 and the company is now seeking Rights offering brings $17.1mm to Cytori Alliances FDA approval, a process with which Terumo will now assist. In March 2016, Sequent completed patient Dermira nets $118.4mm in FOPO /In Vitro Diagnostics enrollment in an IDE trial to assess the WEB system’s safety and effectiveness in treating both ruptured Flexion nets $72.4mm through follow-on Aytu BioScience Inc. and unruptured intracranial aneurysms (IAs). Based offering Durviz SL on Sequent’s MicroBraid technology--a dense mesh Parallabs assembled from a large quantity of very fine wires--the Global Blood nets $112.8mm through Tani Medikal WEB is a self-expanding device implanted (via a femoral artery access catheter) into the aneurysm to disrupt public offering Teco Medical Instruments GMBH intrasaccular flow by closing the neck of the aneurysm THP Medical Products Vertirebs from inside. With its intrasaccular approach that uses Public offering nets $18.9mm for GMBH established biomaterials, the system can also treat GlycoMimetics Aytu BioScience Inc. granted various partners licenses to different types of IAs as well as other neurovascular commercialize its MiOXSYS semen analysis system in Eu- abnormalities such as arteriovenous fistulae. Sequent ImmunoGen nets $96.7mm through rope, where it obtained the CE mark in January 2016. (Jun.) Medical’s VIA microcatheter, available in three sizes, is private notes offering approved in the US and Europe for placing and retriev- The MiOXSYS is Aytu’s in vitro diagnostic platform for ing the WEB device. Since its 2007 inception, Sequent Biopharma Kadmon files for IPO assessing the level of oxidative stress in semen to Medical brought in $62mm in venture financing diagnose infertility. It uses electrochemical biosen- through backers Delphi, Domain, USVP, and Versant. Lion Biotechnologies privately sells sor technology to quantitatively measure ejaculate Terumo first entered the neurovascular device market volume, total sperm, sperm concentration, total $100mm of its common and preferred through its 2006 buy of MicroVention, which gave motility, progressive motility, and morphology for it a broad portfolio of neuroendovascular therapies, shares determining semen quality. MiOXSYS was also ap- including the HydroCoil embolic system line of polymer proved in Canada in March 2016 and the company hydrogel coated platinum coils. It expects the current Medgenics nets $18.8mm via FOPO has initiated clinical trials in the US to obtain FDA acquisition of Sequent Medical to further enhance its approval there. Recent study results demonstrated catheter-based offerings to treat IAs. Moleculin Biotech’s IPO nets $8.6mm the system’s accuracy in analyzing frozen and thawed semen samples, thus broadening its potential uses. Vitrolife AB Paratek nets $51.9mm via FOPO Under this agreement, the following partners will have rights in the specified territories: Tani Medikal Medical Technology Vertriebs GMBH Pieris Pharmaceuticals raises $16.5mm in (ELISA-based diagnostics and hospital equipment) Octax Microscience GMBH private placement in Turkey; Teco Medical Instruments GMBH (hemo- Swedish device firm Vitrolife AB acquired private stasis and coagulation instruments and reagents) German company Octax Microscience GMBH (laser Biopharma company Regulus Therapeutics in Germany and Switzerland; Parallabs (supplies, systems and imaging software for in vitro fertilization receives $30mm loan from Oxford Finance workstations, and equipment for IVF, andrology, and (IVF)) and its affiliated distributor companyMedical transgenic labs) in France and the UK; THP Medical Technology Vertriebs GMBH (MTG; devices and dis- Products Vertirebs GMBH (radiopharmaceuticals, in Sarepta nets $37.3mm via common stock posables for use in assisted reproduction technologies vitro diagnostics, and research reagents) in Austria; (ART)). (Jun.) offering and Durviz SL (microbiology and molecular biology diagnostics and instrumentation and lab equipment Octax’s ART laser systems, used to remove embryotic Vascular Biogenics nets $22.3mm through and systems for IVF and ART) in Spain. cells for use in IVF procedures such as pre-implanta- RDO tion genetic screening (PGS) and pre-implantation genetic diagnosis (PGD), are based on its EyeWare VBI Vaccines closes $13.6mm PIPE multi-purpose imaging and archival software. These Medical Devices platforms include the Laser Shot (a microsurgical infrared laser), which can be adapted and installed Mergers & Acquisitions on microscopes that are used in laser-related tech- /Medical Devices niques such as assisted hatching, biopsies, and sperm viability testing, and NaviLase, an upgraded version Terumo Corp. with increased speed and automation, used as a Sequent Medical Inc. standalone system or as an add-on to the Laser Shot. Octax also makes digital video cameras for detailed To help establish and grow its presence in the global sperm, oocyte, or embryo imaging as well as related neurovascular market, Terumo Corp. acquired private equipment for ART microscopy, analysis, and image US device company Sequent Medical Inc. (makes and processing. Affiliated company MTG distributes these sells aneurysm treatment systems). (Jun.) Octax IVF laser and imaging products in Germany, Terumo will pay $280mm in cash at closing, with Austria, and Switzerland and also has its own lines of another potential $100mm in development- and laboratory systems and equipment. MTG’s offerings commercialization-based earn-outs. Sequent de- include ART microscope, imaging, media handling, veloped, manufactures, and now sells in Europe the and incubator workstations for the IVF lab; andrology

and cryopreservation equipment for semen analysis $A6.7mm ($4.9mm) through the oversubscribed private when it first set a range in March, but then modified and biological sample/specimen handling, processing, placement of 26,315,790 CHESS Depositary Interests the S-1 filing to reflect a new range of 1.75mm shares labeling, management, freezing, storage, and trans- (CDIs)--representing 8.77 Class A common shares--at at $6.25 a month before closing the offering. (Jun.) port; and consumables such as dishes, storage vials $A0.76 per CDI (an 11% discount) to new and returning Investment Banks/Advisors: Neidiger Tucker Bruner and straws, catheters, and embryo culture media. MTG shareholders. Most of the funds will support commer- Inc.; Northland Securities also makes monitoring systems for quality control and cialization of AeroForm in Australia and a launch in the assurance in the lab setting and offers consulting, train- US. Canaccord Genuity was the placement agent. (Jun.) ing, service and maintenance, and after-sales support Titan Medical Inc. Investment Banks/Advisors: Canaccord Genuity Inc. programs for its customers. Together these companies Titan Medical Inc. (robotic surgical system for mini- had 2015 sales of €8.5mm ($9.5mm) on net income mally invasive surgery (MIS)) received a $16mm invest- of €2mm ($2.2mm). The acquisition not only broadens NeuroMetrix Inc. ment from Shanghai Jugu Equity Investment Fund. The Vitrolife’s existing ART product portfolio of software, Through a securities purchase agreement, wearable placement will be executed with two closings, the first culture media, and embryo imaging and monitoring technology maker NeuroMetrix Inc. (neurostimulation on June 30, 2016, with the purchase of 16.4mm shares systems within IVF, but also strengthens its technology devices, biosensors, and point-of-care tests for chronic at $Cdn0.746 (an 8% discount), and the second clos- involvement through platforms that support and make pain) issued 21.3k Series D convertible preferred shares ing for the purchase of an additional 11.5mm shares more efficient Vitrolife’s existing procedures--including at $1k to a single institutional investor. The preferred at $Cdn0.746. The company will use the proceeds for sperm preparation, oocyte retrieval, intra-cytoplasmic stock converts into 11.8mm common shares at $1.805, its development and commercialization of the SPORT sperm injection (ICSI), and embryo culture, transfer, a 10% premium. NeuroMetrix also issued five-year war- surgical system. (Jun.) vitrification, and slow-freezing--enabling it to now offer rants redeemable for 11.8mm common shares at a $1.69 patients improved results. Octax and MTG will combine exercise price. A portion of the proceeds will be used to Viveve Medical Inc. to form a new business unit within Vitrolife, which will redeem $13.8mm of the company’s Series C convertible be based in Bruckberg, Germany (the current location preferred stock. Rodman & Renshaw was the placement Viveve Medical Inc. (radiofrequency device for vaginal of both companies) and directed by Paul Gassner, PhD, agent and received five-year purchase warrants redeem- laxity) netted $14.4mm in a follow-on public offering MTG’s current CEO, who will report to Vitrolife´s CEO able for 590k common shares at $2.26. (Jun.) of 3.1mm shares, including the overallotment, at $5. Thomas Axelsson. It will use the proceeds to fund R&D and regulatory Investment Banks/Advisors: Rodman & Renshaw expenses for additional products and to support com- Zimmer Biomet Holdings Inc. Capital Group Inc. mercialization, marketing, and sales efforts for its Viveve LDR Holding Corp. radiofrequency system. Approved in Canada, Europe, Nevro Corp. Hong Kong, and certain Asian countries, Viveve is sold Zimmer Biomet Holdings Inc. is paying $1bn ($37 in those regions through various partners. The com- per share, a 70% premium) to acquire LDR Holding Nevro Corp. (devices to treat chronic pain) netted pany, seeking US approval for the device, submitted Corp., which is developing devices for treating spine $145.5mm through the public offering of $150mm ag- a 510(k) application in March 2015 and plans to begin disorders. (Jun.) gregate principal amount of 1.75% convertible senior an IDE study sometime this year. (Jun.) notes due 2021. (The company had initially proposed Zimmer will finance the transaction using cash-on- an offering of $125mm aggregate principal amount.) Investment Banks/Advisors: Craig-Hallum Inc.; Laden- hand (at the end of March 2016 it had $997mm) and The notes convert to 10.3770 shares of common stock burg Thalmann & Co. Inc.; Maxim Group LLC existing availability under its revolving credit facility. per $1k principal (equivalent to $96.37/share; the stock Once the transaction closes, the company will issue was averaging $69.16). Nevro will use about $21mm of $750mm in senior unsecured notes to repay the credit the proceeds to fully repay its term loan with Capital Pharmaceuticals facility. LDR’s leading product is the Mobi-C cervical Royalty Partners. Additional proceeds will go toward disc replacement (CDR), the only artificial cervical disc ongoing US commercialization efforts for its Senza with FDA approval for replacement of both single- and implantable spinal cord stimulator, which received Mergers & Acquisitions two-level discs. It also offers MIVo minimal implant vol- PMA a year ago for indications in chronic intractable /Pharmaceuticals ume surgery products for lumbar and cervical fusion pain of the trunk and limbs. (Jun.) procedures. With the LDR buy, Zimmer positions itself Afferent Pharmaceuticals Inc. Investment Banks/Advisors: JMP Securities LLC; JP Mor- as a leader in CDR within the $10bn spine market. LDR Merck & Co. Inc. joins Zimmer’s Spine & Craniomaxillofacial division led gan & Co.; Leerink Partners LLC; Morgan Stanley & Co. by Adam Johnson, and will provide 68 sales reps to be Merck & Co. Inc. agreed to pay $500mm up front to integrated into Zimmer’s force which will cross-sell the Second Sight Medical Products Inc. acquire Afferent Pharmaceuticals Inc., a seven-year two firms’ products to customers. LDR’s president and old private biotech developing treatments for neuro- Second Sight Medical Products Inc. (implantable CEO Christophe Lavigne and general manager Patrick genic diseases. (Jun.) visual prosthetics) netted $19.4mm through an over- Richard will stay on board taking on key leadership subscribed rights offering, issuing 6mm common Afferent could also get up to $750mm in earn-outs roles. Several law firms have commenced investiga- shares (it originally said it was offering up to 10mm based on clinical and commercial achievements. tions looking into whether LDR board members shares) at $3.315 (a 12% discount). The company will The company, a Roche spin-out, is developing lead breached their fiduciary duties by accepting a share retain $19.8mm of the subscriptions received and compound AF219 in Phase IIb trials for refractory price that undervalues the company. This is Zimmer’s the rest will be returned to investors. Proceeds will chronic cough and Phase II for idiopathic pulmonary third acquisition this year. In March is scooped up support the ongoing post-market trial of its Argus II fibrosis with cough. The candidate is non-narcotic skeletal implant developer Ortho Transmission and retinal prosthesis systems for dry age-related macular P2X3 antagonist originally discovered at Roche, but a month later it bought musculoskeletal device firm degeneration and further expand global markets. later discontinued. (One of the lead scientists that Cayenne Medical, both for an undisclosed sum. Invest- Additional money will pay for continued develop- discovered AF219 took the compound off of Roche’s ment Banks/Advisors: Goldman Sachs & Co. (Zimmer ment of the Orion I visual cortical prosthesis for blind hands and co-founded Afferent in 2009 along with in- Biomet Holdings Inc.); Bank of America Merrill Lynch patients. Broadridge Corporate Issuer Solutions was the vestors Pappas Ventures, Third Rock Ventures, Domain (LDR Holding Corp.) subscription and information agent. (Jun.) Associates, New Leaf Partners, and Roche Ventures.) Afferent’s other clinical-stage project AF130 is in Financings Phase I for resistant hypertension and preclinical Sensus Healthcare Inc. /Medical Devices studies for migraine. The addition of Afferent’s AF219 Sensus Healthcare Inc. (noninvasive skin cancer could be key for Merck, which is seeing a steady and treatment) netted $11.8mm through its initial public continuing decline in its respiratory business due to AirXpanders Inc. offering of 2.3mm common shares (including the over- generic competition and lack of promising pipeline Public firm AirXpanders Inc. (developed the Aero- allotment) at $5.50. Investors also received three-year candidates. Afferent raised at least $78mm through Form tissue expander used in patients undergoing warrants to buy 2.3mm shares at $6.75. The company venture rounds, including a $55mm crossover round breast reconstruction following mastectomy) grossed originally intended to sell 1.8mm shares at $10-12 in July 2015 that was oversubscribed and included

40 | July/August | IN VIVO: The Business & Medicine Report | invivo.pharmamedtechbi.com DEALMAKING investments by Fidelity Management & Research Co. will be tasked with developing and commercializing Ariad Pharmaceuticals Inc. (lead), Jennison Associates LLC, New Leaf Ventures, cancer immunotherapies. (Jun.) Biologix FZCo. Partner Fund Management, Redmile Group, Tekla The JV is 51% owned by 3SBio, which contributes Biologix FZCo. licensed exclusive rights to sell Ariad Healthcare Investors, and Tekla Life Science Investors. $10mm to the firm’s operations, and 49% owned Pharmaceuticals Inc.’s Iclusig (ponatinib) in the Middle by TNK. TNK grants exclusive rights to its chimeric East and North Africa (MENA) regions for chronic my- Oncternal Therapeutics Inc. antigen receptor T-cell technology targeting carci- eloid leukemia and Philadelphia-positive (Ph+) acute Tokalas Inc. noembryonic antigen-positive cancers. (CEA-positive lymphoblastic leukemia. (Jun.) cancers include colorectal, lung, liver, and breast tu- Cancer drug development firms Oncternal Thera- The deal includes Bahrain, Saudi Arabia, Kuwait, mors.) The new firm also gets rights to two additional peutics Inc. and Tokalas Inc. have merged into one Oman, Qatar, the United Arab Emirates, Lebanon, CARs for cell therapy use in the greater China market entity which will carry the Oncternal name, and be led and other selected countries. Biologix will initially sell including the mainland, Hong Kong, and Macau. by Tokalas CEO Dr. James Breitmeyer. Financial details the drug as an investigational product on a named- were not disclosed. (Jun.) patient in certain countries prior to regulatory ap- The combined entity will have two clinical stage AbbVie Inc. proval, and later commercialize it to all patients in projects in its coffers. Oncternal brings to the table its AbbVie GK the licensed regions. Ariad gets more than 50% of cirmtuzumab, an anti-ROR1 monoclonal antibody in Eisai Co. Ltd. net product sales through a supply transfer price. The Phase I for relapsed or refractory chronic lymphocytic EA Pharma Co. Ltd. deal also includes the option for a future acquirer of leukemia. Oncternal licensed the compound from UC Eisai Co. Ltd.’s subsidiary EA Pharma Co. Ltd. received Ariad to buy back the Iclusig rights within three years San Diego earlier this year and has plans to initiate ad- rights to co-promote in Japan AbbVie Inc.’s (through its from the current deal date for an agreed upon price. ditional trials in CLL, mantle cell lymphoma, and breast Japanese subsidiary AbbVie GK) fully human anti-TNF-a cancer. The merged company will also work on Tokalas’ monoclonal antibody Humira (adalimumab) for gastro- Ariad Pharmaceuticals Inc. TK216, an ets-family transcription factor inhibitor enter- intestinal disease indications including ulcerative colitis, Pint Pharma Gesellschaft MBH ing Phase I trials for Ewing sarcoma. TK216 originated at Crohn’s disease, and intestinal Behçet’s disease. (Jun.) Georgetown University; additional trials are planned Ariad Pharmaceuticals Inc. granted Pint Pharma Ge- between Georgetown and the new Oncternal with AbbVie is the marketing and manufacturing autho- sellschaft MBH exclusive rights to sell Iclusig (ponatinib) TK216 for glioblastoma and prostate cancer. rization holder for the drug and Eisai is responsible for chronic myeloid leukemia and Philadelphia-positive for distribution. The companies will also continue (Ph+) acute lymphoblastic leukemia in Argentina, Brazil, Chile, Colombia, and Mexico following regulatory ap- Savara Pharmaceuticals co-promoting Humira for ex-GI indications including proval in those territories. (Jun.) Serendex Pharmaceuticals AS rheumatoid arthritis and for conditions--such psoriasis vulgaris, arthropathic psoriasis, ankylosing spondylitis, Pint will sell the drug as an investigational product on a Expanding its pipeline of orphan respiratory thera- and polyarticular juvenile idiopathic arthritis--that fail named-patient basis prior to approval; Ariad and Pint will pies, Savara Pharmaceuticals is acquiring Danish to sufficiently respond to existing therapies. together submit the drug for approval in the licensed firm Serendex Pharmaceuticals AS for an undis- regions. (It is already approved in the US, EU, Australia, closed sum in an all-stock deal, which also includes Anagenesis Biotechnologies Switzerland, Israel, and Canada.) Ariad gets up to $15mm milestone-based earn-outs. (Jun.) Anagenesis Biotherapies Inc. in up-front and regulatory milestone payments, plus The transaction gives Savara two programs. Serendex’s CRISPR Therapeutics over 50% of net product sales through a product supply lead compound is Phase II/III Molgradex, an inhaled ver- transfer price. The deal includes a provision providing Anagenesis Biotechnologies licensed CRISPR Thera- sion of granulocyte-macrophage colony-stimulating an acquirer of Ariad the option to buy back rights to the peutics exclusive global rights to technology surround- factor (GM-CSF) for treating autoimmune pulmonary drug within three years of the alliance date by making ing paraxial mesoderm multipotent cells (P2MCs) for use alveolar proteinosis (PAP). Molgradex may also be undisclosed but specified payments. Concurrent with in treating all human muscle diseases. (Jun.) applicable for other indications by stimulating the the Pint licensing, Ariad also announced that it granted innate immune system to enhance microbial killing The P2MC IP enables the efficient and reproducible Biologix FZCo. exclusive rights to sell Iclusig in the or repair of impaired lung tissue. The second product production of differentiated skeletal muscle cells Middle East and North Africa (MENA) region. candidate acquired by Savara is a preclinical inhaled from stem cells. Anagenesis’ P2MC technology was form of Factor VIIa for diffuse alveolar hemorrhage, a developed with the support from the French Muscular Array Biopharma Inc. condition in which there is bleeding into the alveoli Dystrophy Association, Inserm Transfert, Centre Na- Pierre Fabre Group of the lungs where oxygen exchange occurs. These tional de la Recherche Scientifique, and University of Merck KGAA projects are complementary to Savara’s AeroVanc Strasbourg. CRISPR will use the IP in combination with (vancomycin), in Phase II for the methicillin-resistant its own CRISPR/Cas9 gene editing platform to create Array BioPharma Inc., Pierre Fabre Group, and Merck Staphylococcus aureus lung infection in cystic fibro- ex vivo therapies, initially for Duchenne muscular dys- KGAA are together conducting a Phase III trial of a sis patients. If approved, the drug would be the first trophy, using muscle satellite stem cells. As part of the combination of three cancer drugs for the treatment inhaled antibiotic for the condition. AeroVanc also agreement, Olivier Pourquié, PhD, Anagenesis’ scientific of BRAF-mutant colorectal tumors. (Jun.) has potential as a PAP treatment based on clinical founder and professor at Harvard Medical School and The BEACON CRC trial’s primary endpoint is over- evidence from academically sponsored pilot studies Brigham and Women’s Hospital, will serve as a consul- all survival, while secondary endpoints include and case reports on inhaled GM-CSF. As a part of the tant to CRISPR. The partnership will be the foundation progression-free survival and objective response rate. acquisition, Serendex delisted from the Oslo Stock for Anagenesis’ newly created US cell therapy-focused The study combines binimetinib (an MEK inhibitor Exchange--it went public in 2014. When the merger division Anagenesis Biotherapies Inc. in Phase III trials for melanoma and Phase II for other closes, Serendex will cease to exist and its employees solid tumors), encorafenib (BRAF inhibitor in Phase will transfer to a newly formed Savara entity that will Apotex Inc. III for melanoma and Phase II for colorectal, thyroid, remain in Denmark. Nephron Pharmaceuticals Corp. and blood cancers), and Erbitux (cetuximab; marketed for colorectal and head and neck cancers and in trials Apotex Inc. licensed to Nephron Pharmaceuticals Alliances for other solid tumors). Array owns enocorafenib and Corp. the ANDA for generic budesonide inhalation binimetinib, and granted Pierre Fabre exclusive global /Pharmaceuticals suspension. (Jun.) development and commercialization rights (exclud- Nephron will handle manufacturing, marketing, and dis- 3SBio Inc. ing the US, Canada, Japan, Korea, and Israel) in 2015. tribution of 0.5mg/2mL and 0.25mg/2mL dosage forms 3SBio-TNK Joint Venture (As part of that agreement, Pierre Fabre now agrees of the product in unit-dose vials. Budesonide inhalation to co-fund 40% of the costs of the BEACON trial; the Sorrento Therapeutics Inc. suspension is the generic version of AstraZeneca’s Pul- 2015 partnership is on similar terms, with PF funding TNK Therapeutics Inc. micort Respules. The inhaled corticosteroid is used for the 40% of costs and Array shouldering 60%.) Merck KGAA TNK Therapeutics Inc., a division of Sorrento Thera- maintenance treatment of asthma and as prophylactic owns Erbitux outside of the US and Canada, and will peutics Inc., and 3SBio Inc. created a joint venture that therapy in children ages 12 months to 8 years. supply it to all of the trial sites in its territories.

Aspen Pharmacare Holdings Ltd. disorders, and depression. In 2003 BTRA licensed Cell Design’s “on/off switch” custom cell engineering Aspen Global Inc. the technology to the Wisconsin Alumni Research technology programs an immune cell’s specificity AstraZeneca PLC Foundation (WARF) and went on to sublicense it that and guides it to selectively recognize, disable, and same year to Mentor Corp. (acquired by J&J’s Ethicon destroy cancer cells. Kite gets exclusive rights to AstraZeneca PLC granted Aspen Global Inc. ex-US rights in 2008), which used the technology to develop a develop and sell CAR T-cell therapies containing to seven of its marketed anesthetic products. (Jun.) botulinum toxin type A candidate it named PurTox as the switches directed at targets for acute myeloid Aspen paid $520mm in cash up front and could a therapeutic for the neurological movement disorder leukemia, and also has an exclusive option to develop hand over up to $250mm in a sales-related milestone cervical dystonia and in aesthetic use for glabellar and commercialize similar compounds for B-cell payment plus double-digit royalties. AZ agreed to rhytides (wrinkles). PurTox had reached Phase III when malignancies. For the rights, Kite paid $2mm up-front manufacture and supply all of the products to Aspen J&J suspended its development in 2012 for unknown and made a $6mm equity investment in Cell Design. over the next ten years on a cost-plus basis, and then reasons (but possibly related to the disappearance of (It also made a separate investment through Cell Aspen will take over all responsibilities. Included in clinical trial batches that impeded FDA approval) and Design’s concurrently announced Series A round.) the deal are Diprivan (propofol), a general sedative/ the BTRA/WARF/Mentor licensing agreement was Additionally, Kite could provide up to $9mm in R&D anesthetic; topical anesthesia cream EMLA (lidocaine/ terminated in 2014. The current deal gives Revance funding, up to $56.5mm in development, regulatory, prilocaine), and the local anesthetics Xylocaine/ BTRA’s botulinum toxin-related patents and patent and sales milestones, and tiered single-digit royal- Xylocard/Xyloproct (lidocaine/lignocaine), Marcaine applications as well as the rights of first negotiation ties. Kite’s president and CEO Arie Belldegrun, PhD, (bupivacaine), Naropin (ropivacaine), Carbocaine and first refusal to BTRA’s other patents surround- joined Cell Design’s board of directors, while David (mepivacaine), and Citanest (prilocaine). Global sales ing botulinum toxin. In exchange, Revance will pay Chang, MD, PhD, EVP, R&D and CMO, joins the board for all seven products in 2015 totaled $592mm. AZ li- $2mm up front and up to an additional $16mm in as an observer. censed out the products to expand their global reach, development, regulatory, and sales milestones. The and to benefit from the cash influx and downstream additional IP expands Revance’s neuromodulation- Daiichi Sankyo Co. Ltd. royalties while the Big Pharma focuses on other core focused patent holdings to over 330. The company Daiichi Sankyo Europe GMBH products in its pipeline and portfolio. plans to use BTRA’s assets to develop new indications Nektar Therapeutics for its own aesthetic and therapeutic neurotoxins Nektar Therapeutics granted Daiichi Sankyo Europe AstraZeneca PLC pipeline. Lead candidate daxibotulinumtoxinA (botu- GMBH exclusive rights to sell its breast cancer therapy Grunenthal GMBH linum toxin type A) is formulated as both a topical (RT001 in Phase III for lateral canthal lines (crow’s feet) Onzeald (etirinotecan pegol) in Europe, Switzerland, AstraZeneca PLC granted Grunenthal GMBH ex- and in Phase II for hyperhidrosis (excessive sweating)) and Turkey. (Jun.) clusive rights throughout Europe and Latin America and an injectable (RT002 in Phase II for glabellar lines Onzeald completed Phase III trials for advanced to develop and commercialize Zurampic (lesinurad), and cervical dystonia) using Revance’s carrier-peptide breast cancer, and Nektar plans to pursue condi- a urate transporter 1 (URAT1) inhibitor approved to delivery system TransMTS, designed for delivery of tional approval for the compound (using data from treat hyperuricemia in adults with uncontrolled gout. large-molecule therapeutics to a targeted site. the Phase III trial) in advanced breast cancer patients Grunenthal also gets rights to an allopurinol/lesinurad with a history of brain metastases. Daiichi will pay fixed-dose combination in Phase III trials for the same Cadila Pharmaceuticals Ltd. $20mm up front, $35mm in regulatory milestones indication. (Jun.) Lipidor AB ($10mm upon first commercial sale following con- Grunenthal could pay up to $230mm in sales and Lipidor AB and Cadila Pharmaceuticals Ltd. are col- ditional approval in Europe and $25mm upon first other milestones, plus royalties up to the low- laborating on the development and commercialization sale following final marketing approval), $25mm double-digits (Strategic Transactions assumes a of Lipidor’s topical spray formulation of calcipotriol (a in sales milestones, and 15-20% royalties (15% of range of 1-30%). Zurampic was approved by the Vitamin D agonist) for mild to severe psoriasis. (Jun.) net sales in Turkey and 20% for the rest of Europe). FDA in December 2015 and the EMA in February Nektar is responsible for funding and conducting 2016, but has not yet been launched. AZ will initially The compound is formulated using Lipidor’s Akvano the confirmatory trial to support MAA approval by manufacture and supply the product to Grunenthal, topical drug delivery technology, which consists of the EMA, with a filing for the conditional approval and after September 302, 2021, Grunenthal will have vegetable-derived lipids and an active pharmaceuti- expected sometime this month. the option to take over manufacturing. AZ originally cal ingredient (API) dissolved in a water-free solvent. When this mixture is applied to skin, the solvent gained Zurampic through its April 2012 billion-dollar Dr. Reddy’s Laboratories Ltd. evaporates, placing a lipid layer in immediate and acquisition of Ardea Biosciences, but has now started Teva Pharmaceutical Industries Ltd. off-loading it to partners in order to focus on other direct contact with the skin surface for even distri- key therapeutic areas. In April of this year, Ironwood bution of the API, allowing its fast diffusion into the Dr. Reddy’s Laboratories Ltd. acquired a portfolio Pharmaceuticals paid $100mm up front for US rights stratum corneum (unlike creams or ointments, which of eight Abbreviated New Drug Applications in the to the therapy (and committed to up to $165mm in require rubbing into the skin before the lipids are US from Teva Pharmaceutical Industries Ltd. for milestones). Grunenthal’s pipeline contains projects released). Lipidor develops Akvano formulations for $350mm in cash. (Jun.) for pain, inflammation, and rare diseases. Last month, APIs for which patents have expired, resulting in a less Teva is divesting these assets as a closing condi- it added to its hospital products business through the challenging regulatory approval process than an NCE. tion for its pending Allergan acquisition. The total in-licensing of a surgical glue from Adhesys. Lipidor’s Akvano version of calcipotriol, which already combined revenue for the branded versions of the completed Phase I/IIa, demonstrated positive results products was $3.5bn in the 2015FY. Dr. Reddy’s in efficacy and tolerability versus the API alone and Botulinum Toxin Research already has 79 filed ANDAs pending approval in showed a significant antipsoriatic effect compared to the US and the acquisition will further strengthen Associates Inc. Leo Pharma’s Daivonex, a marketed calcitriol solution its presence in that region. ReVance Therapeutics Inc. and cream. Cadila will perform Phase III trials in India, Revance Therapeutics Inc. acquired Botulinum Toxin which are slated to begin this year. Cadila, with an Eisai Co. Ltd. Research Associates Inc.’s botulinum toxin patent expertise in manufacturing many dosage forms, has portfolio covering various indications, compositions, multiple manufacturing and R&D facilities in India and Novartis AG and formulations. (Jun.) API synthesis is one of its core businesses. This deal Novartis Pharmaceuticals Corp. will help get Lipidor’s product into the Indian market. The patent estate--assigned to BTRA by principal in- Novartis AG and Eisai Co. Ltd. will co-promote in ventor Gary Borodic, MD (of Harvard Medical School the US the latter’s Lenvima (lenvatinib mesylate), Cell Design Labs Inc. and the Massachusetts Eye and Ear Infirmary), who along with Novartis’ Afinitor (everolimus), within developed the mechanism involving the toxin’s safe Kite Pharma Inc. the advanced renal cell carcinoma (RCC) indication. (Jun.) administration and dosing as a therapeutic--covers Cell Design Labs Inc. agreed to develop its molecular over 70 patents/applications comprising different “on/off switches” for Kite Pharma Inc. to use in the In addition to RCC, Lenvima--an oral tyrosine kinase compositions and formulations and diverse indica- development of chimeric antigen receptor (CAR) inhibitor against multiple targets, including vascular tions, including aesthetics, inflammation, pain, mood candidates for cancer. (Jun.) endothelial growth factors (VEGF) 1, 2, and 3--is also

42 | July/August | IN VIVO: The Business & Medicine Report | invivo.pharmamedtechbi.com DEALMAKING approved for thyroid cancer in over 40 countries, Eleven Biotherapeutics Inc. when EBI031 reaches the Phase II and III stages, in including the US since February 2015. It’s now also Roche exchange for terminating remaining diligence and in Phase III for liver cancer and Phase II for lung and milestone/royalty obligations. Concurrent with the Eleven Biotherapeutics Inc. licensed Roche exclusive uterine cancers and melanoma. Through a 2015 Roche transaction, Eleven filed an IND for EBI031, an global rights to its preclinical ophthalmic antibody trial collaboration, Eisai is combining Lenvima and IL-6 antagonist for diabetic macular edema and uve- EBI031, plus all of its IL-6 antagonist antibody technol- its own Halaven (eribulin) in combination with itis. The Big Pharma will be responsible for conduct- ogy. Roche has a license to patents and know-how, Merck & Co. Inc.’s Keytruda (pembrolizumab) in ing any new FDA-required good laboratory practice plus the right to sublicense. (Jun.) a Phase Ib/II study for solid tumors. Lenvima was toxicology studies plus any other activities related FDA cleared for the RCC indication just last month; Roche pays $7.5mm up front and up to $262.5mm in to the IND. Eleven will handle some IND clearance the approval is tied to a combination regimen that regulatory, development, and commercial milestones responsibilities, too. Roche will pay for and conduct involves administering the drug to RCC patients, covering up to two indications. For the first indica- future development of EBI031 except for any pre-IND along with Novartis’s already-marketed anticancer tion, the payments are $72.5mm for development approved tissue cross-reactivity studies started by agent Afinitor, following one prior anti-angiogenic milestones, $50mm for regulatory milestones, and Eleven, which will cover those costs. Eleven devel- therapy. Afinitor was launched in the US for RCC in $75mm in commercial milestones; the milestones for oped EBI031, which is delivered via the intravitreal 2009 and is also in development for various other the second indication total $65mm and cover devel- route, using its AMP-Rx platform. The biotech also solid tumor and blood cancers. Under the current opment and regulatory achievements. Eleven is also used this technology to produce isunakinra (EBI005) agreement, sales representatives from both com- entitled to 7.5-15% royalties on EBI031 products and for dry eye and allergic conjunctivitis. Isunakinra, an panies will promote the Lenvima/Afinitor combo to 50% on products containing other IL-6 compounds. IL-1 antagonist, had been Eleven’s lead candidate and US oncologists. The partners will also collaborate If EBI031’s IND becomes effective on or before Sep- reached Phase III. However, in Q4 2015, the company on associated commercial and medical activities, tember 15, 2016, Eleven gets a $22.5mm milestone, stated that top-line results showed the antibody did providing physicians with any further science- otherwise the first payment will be reduced to not display statistical significance on any endpoints based findings.S ales of their respective products $20mm. Regarding the lower $20mm payment, it in the severe allergic conjunctivitis indication (and it will continue to be booked by each company. Eisai may be broken up: if, to achieve IND effectiveness, the had previously failed in dry eye). Eleven terminated believes Novartis, through the expertise of its US FDA requires Roche, or the company chooses on its development and had been reviewing several strate- subsidiary Novartis Pharmaceuticals Corp., will own, to initiate a good laboratory practice toxicology gic alternatives, including the sale of the company. It aid Eisai in stimulating product sales within this study, designed such that the last dose administered had also divested to Albumedix its Supermin albumin territory. Eisai already sells in the US chemotherapy- to animals is more than 15 weeks after the first dose, variants used in extending systemic drug concentra- induced nausea and vomiting (CINV) drugs Aloxi Roche would pay $5mm upon the start of the study tion. The up-front and potential additional cash from (palonosetron hydrochloride) and Akynzeo (netu- and $15mm when the IND becomes effective. The Roche may allow Eleven to re-invest in its pipeline. pitant/palonosetron), both co-promoted there with deal includes two opportunities for Roche to make Currently the only other active program it has is a Helsinn under a recently revised 2010 agreement. one-time payments ($135mm or $220-265mm), VEGF pathway inhibitor at the discovery stage for

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©2016 Informa Business Intelligence, Inc., an Informa company | IN VIVO: The Business & Medicine Report | July/August 2016 | 43 DEALMAKING wet AMD and diabetic macular edema. Roche’s oph- Impax Laboratories Inc. facture, and commercialize the product in US and thalmic portfolio is driven by Lucentis, a treatment for Teva Pharmaceutical Industries Ltd. Canada. It is also responsible for development and regulatory approval in the EU, and would transfer the wet AMD that yields over $1bn in revenue annually. Impax Laboratories Inc. acquired a portfolio of 18 approval to Kyowa. The parties will equally split profits The product already faces biosimilar competition in marketed, approved and pipeline generics from Teva from sales in the US and Canada, and Kyowa will pay some markets, and as a result, sales are forecasted Pharmaceutical Industries Ltd. and Allergan affiliates Medgenics low double-digit royalties (ST assumes 10- to decrease gradually, down to $819mm by 2021 for $586mm (funded from $400mm in new term loans 30%) on sales outside the US and Canada. Under the according to Datamonitor Healthcare. Roche’s oph- with the balance from cash on hand). The product di- thalmic pipeline is fairly small, with only six other second option, Medgenics gets exclusive develop- vestitures were mandated by the FTC as a condition of ment, manufacturing, and commercialization rights candidates besides EBI031. Teva’s pending acquisition of Allergan’s global generics in the US, Canada, and EU. Medgenics and Kyowa will business (just last week Teva sold off the rights to eight split profits 75% and 25%, respectively, and Kyowa will EpimAb Biotherapeutics ANDAs to Dr. Reddy’s.) (Jun.) pay low double-digit royalties on sales outside the Innovent Biologics Inc. Concurrently, Teva also returned full commercial US, Canada, and EU. In both structures, Kyowa gets In its first licensing deal, start-up EpimAb Biothera- rights to the ANDA (developed by CorePharma) for global commercial rights in territories not licensed peutics granted Innovent Biologics Inc. rights within the generic equivalent Concerta to Impax (previ- by Medgenics. Medgenics would pay up to $18mm the Chinese market to develop bispecific antibodies ously partnered with Teva in 2011). Up to $40mm in and $28mm in regulatory milestones under option 1 for multiple targets using its Fabs-In-Tandem Immuno- contingent payments will be made to Teva upon the and option 2, respectively. Studies have shown that pediatric IBD and other autoimmune diseases have globulin (FIT-Ig) platform. (Jun.) achievement of certain commercialization events. The drugs being acquired include 15 currently loss of function mutations in the decoy receptor 3 Bispecific antibodies are created by engineering two marketed generics, one approved generic product (DcR3) protein, which can reduce inflammation by different monoclonal antibodies (mAbs) and merging and two approved strengths (not yet launched), one binding pro-inflammatory proteins such as LIGHT. their key structures into one molecule. Through the pipeline generic drug and one pipeline strength of a Therefore, an anti-LIGHT monoclonal antibody may rearrangement of the DNA sequences of two mAbs currently marketed product pending approval, and substitute for DcR3 in affected pediatric IBD patients into three constructs, EpimAb’s FIT-Ig platform enables one generic under development. The products are and help control inflammation. molecular biologists to generate bispecific FIT-Igs a mix of solid oral, inhalable, injectable, and topical that don’t require significant structural modifications dosage forms. The marketed generics generated Myovant Sciences Ltd. and maintain the biological function of their parent approximately $150mm in net sales in 2015 and Roivant Sciences Ltd. mAbs. Because the technology enables the Fab the pending and development pipeline programs Takeda Pharmaceutical Co. Ltd. are projected to bring in $3.1bn in sales in the year (fragment antigen-binding) domains in each arm of Takeda Pharmaceutical Co. Ltd. and Roivant Sciences ended March 2016. The newly acquired generics the antibody to work in tandem to form a tetravalent Ltd. together launched Myovant Sciences Ltd., a new increase Impax’s portfolio by nearly 31% to a total bispecific antibody with four independent binding biotech that will be focused on therapies for women’s of 64 products differentiated across multiple dos- sites, the process does not require linker or peptide health conditions and prostate cancer. (Jun.) connectors or any mutations to the Fc fusion protein. age forms. Concurrently, Impax entered into supply agreements with Teva and its subsidiaries for a period Takeda granted Myovant exclusive rights to two of EpimAb’s FIT-Ig-generated molecules demonstrate of two years in which Teva agreed to supply certain its pipeline projects. The company gets worldwide similar properties to therapeutic antibodies. Under marketed generic and pipeline products to Impax rights (excluding Japan and other Asian countries) to the agreement, Innovent will use the FIT-Ig platform (may be extended by one year for pipeline products relugolix, in Phase III for uterine fibroids, endometriosis, in the development of multiple bispecific antibodies and by three one year terms for all other). The transac- and prostate cancer. It also gains a global license to within China. In exchange, EpimAb will get an up- tion is expected to be immediately accretive to 2016 TAK448 (RVT602), which is in Phase II trials for infertility front payment and milestones up to $120mm, plus earnings, will enhance Impax’s earnings growth, and in women. Myovant is headed by Lynn Seely, MD, who royalties. Innovent also has the right to sub-license will increase utilization of manufacturing resources. was formerly the chief medical officer at Medivation resulting programs outside of China, for which Epi- Investment Banks/Advisors: Greenhill & Co. Inc. (Teva and led development of that firm’s $2bn prostate can- mAb will receive an undisclosed share of the profits. Pharmaceutical Industries Ltd.); RBC Capital Markets cer drug Xtandi. (Medivation is in the process of being Although no specific indications were specified, (Impax Laboratories Inc.) acquired by Sanofi under a $9bn hostile takeover bid; Innovent has a pipeline of ten preclinical antibodies Seely served as CMO from 2005 through 2015.) in over 12 indications, including cancer and cardio- Kirin Holdings Co. Ltd. vascular, autoimmune, and metabolic diseases. It has Kyowa Hakko Kirin Co. Ltd. Pfizer Inc. mAb development partnerships with Eli Lilly (2015) Medgenics Inc. Shire PLC and Adimab (2013). Kyowa Hakko Kirin Co. Ltd. is partnering its Phase Pfizer Inc. licensed Shire PLC worldwide rights to II-ready anti-LIGHT monoclonal antibody with Med- its Phase II inflammatory bowel disease candidate Genisphere LLC genics Inc. (Jun.) PF00547659. (Jun.) AstraZeneca PLC Terms of the agreement have not been disclosed. MedImmune LLC Medgenics will conduct a signal finding study to assess the drug in treating severe pediatric onset PF00547659 is a fully-human monoclonal antibody MedImmune LLC and Genisphere LLC will develop inflammatory bowel disease. The work will be done targeting mucosal addressin cell adhesion molecule 1. The compound is being studied as a treatment for nanoparticles using Genisphere’s 3DNA scaffold with up in collaboration with the Children’s Hospital of Phila- both Crohn’s disease and ulcerative colitis. Phase III to six Medimmune oncology molecules. MedImmune delphia’s Dr. Robert Baldassano. (The company and trials are expected to commence following consul- has an option to license resulting compounds. (Jun.) CHOP have been collaborating in pediatric rare and tation with global health authorities. Shire has been orphan genetic diseases since November 2014.) Once Genisphere gets an up-front payment and additional looking to move into specialty areas, including those the study is completed, Medgenics has the option development milestones and royalties if MedImmune of unmet need for gastrointestinal conditions. There to license the compound for severe pediatric onset exercises its option for development and commer- are already several IBD drugs on the market includ- IBDs such as Crohn’s disease and ulcerative colitis, and ing market-leader Humira (sold by AbbVie) however cialization rights. 3DNA is a nanoscale multivalent other specified pediatric onset rare and orphan auto- many of the therapies will be losing their patents in scaffold made from strands of DNA linked together immune diseases. Upon exercise, Medgenics would the coming years, paving the way for biosimilars. with complementary sequences. The platform allows make a payment in the low single-digit millions (Stra- for the targeted delivery of small molecules, biolog- tegic Transactions assumes $1-2mm) to Kyowa, which ics, and nucleic acids via antibodies attached to the will then choose within 60 days one of two potential Takeda Pharmaceutical Co. Ltd. surface of the scaffold. The companies had been pre- collaboration structures--either a co-development/ Theravance Biopharma Inc. viously working together for two years to investigate co-commercialization partnership (option 1) or a Theravance Biopharma Inc. granted Takeda Pharma- the implications of combining Genisphere’s platform licensing agreement (option 2). Under the first option, ceutical Co. Ltd. exclusive global development and and MedImmune’s work. Medgenics gets exclusive rights to develop, manu- commercialization rights to TD8954, a selective 5HT4

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Pink Sheet SScricrip Pharma intelligence | Pharma intelligence | DEALMAKING receptor agonist in Phase II trials for gastrointestinal purchase of 2.7mm shares at €11.10 (a 2% discount). Dermira Inc. Buyers included MPM Oncology Impact Fund (lead), motility disorders. (Jun.) Spec pharma Dermira Inc. (dermatology therapeu- Aquilo Capital, Burrage Capital, Dafna Capital, Per- Takeda paid $15mm up front and is responsible for tics) netted $118.4mm through the follow-on offer- ceptive Advisors, and additional new and returning milestones and double-digit royalties, including up ing of 4.5mm shares at $28. The company will use backers. (Jun.) to $110mm in development, regulatory, and sales the proceeds to fund R&D, regulatory submission, milestones for the indication EFI, or enteral feeding commercialization, and sales and marketing costs intolerance (and other intravenously dosed indica- Aurinia Pharmaceuticals Inc. associated with its pipeline candidates DRM04 (which tions). There are currently no approved treatments Aurinia Pharmaceuticals Inc. raised $7.1mm through just completed Phase III with an NDA submission for EFI, a condition that puts critically ill hospitalized the private sale of 3mm units at $2.36 (a 17% discount). expected the second half of 2017) for hyperhidrosis, patients at increased risk for malnutrition. TD8954 Each unit consisted of one common share and 0.35 or excessive sweating; Cimzia (certolizumab pegol)- could improve gastric emptying time in such patients, of a two year common share purchase warrant ex- -a marketed rheumatoid arthritis drug it in-licensed and has received fast-track designation by the FDA. ercisable at $2.77. The units were purchased by the from UCB in 2014--which Dermira’s developing for Gastroenterology is a key therapy area for Takeda. company’s chairman, CEO, and other officers, among plaque psoriasis (in Phase III, with topline data an- Earlier this year, the company penned a deal with other investors. Canaccord Genuity was the place- ticipated by the end of the first quarter of 2017); and enGene for the development of a ‘Gene Pill’ for the ment agent. Proceeds will support initiation of Phase DRM01 for acne vulgaris (in Phase IIb, with Phase III oral delivery of therapeutic genes or antibodies to III trials for voclosporin, a calcineurin inhibitor for lupus targeted for the first half of 2017). (Jun.) the gut lining to treat GI diseases. nephritis. (Jun.) Investment Banks/Advisors: Cowen & Co. LLC; Gug- genheim Partners LLC; Leerink Partners LLC; Needham Takeda Pharmaceutical Co. Ltd. Investment Banks/Advisors: Canaccord Genuity Inc. & Co. Inc. Ultragenyx Pharmaceutical Inc. BioTime Inc. Ultragenyx Pharmaceutical Inc. and Takeda Pharma- Flexion Therapeutics Inc. ceutical Co. Ltd. are joining forces to develop and com- BioTime Inc. (regenerative medicine) netted $16.5mm mercialize therapies for rare genetic diseases. (Jun.) through a follow-on public offering of 7.3mm shares at Flexion Therapeutics Inc. (developing therapies for $2.39. The company will use the offering proceeds to musculoskeletal conditions) netted $72.4mm through Takeda agreed to invest up to a total of $65mm in Ul- fund R&D. BioTime is focused on advancing OpRegen the public sale of 5.5mm common shares at $14. Pro- tragenyx in two tranches. It will initially make a $25mm for age-related macular degeneration (Phase I/IIa), ceeds will support activities surrounding the planned equity purchase and hand over $15mm in cash, and later ASTOPC1 for spinal cord injury rehabilitation (Phase I/ NDA submission for Zilretta (triamcinolone; FX006), (at Ultragenyx’s option within the next 12 months) will IIa), and ASTVAC2 (preclinical) for non-small cell lung a sustained-release intra-articular non-opioid pain make another $25mm equity investment. Ultragenyx cancer (ASTOPC1 and ASTVAC2 are being developed reliever for patients with osteoarthritis. (Jun.) first gets exclusive rights to a pre-determined (but by subsidiary Asterias). (Jun.) undisclosed) preclinical Takeda compound, along with Investment Banks/Advisors: BMO Financial Group; Jan- an exclusive option to co-develop and co-promote that Investment Banks/Advisors: Chardan Capital Markets; ney Montgomery Scott Inc.; Laidlaw & Co.; RBC Capital candidate in additional therapy areas. The partners also Ladenburg Thalmann & Co. Inc.; Oppenheimer & Markets; Wells Fargo Securities LLC entered into a five-year research collaboration where Ul- Co. Inc. tragenyx has an option to license up to five more Takeda Global Blood Therapeutics Inc. rare disease projects (following joint selection and Clearside Biomedical Inc. Global Blood Therapeutics Inc. (developing treat- validation activities). Lastly, Takeda to has an option to ments for blood-based diseases) netted $112.8mm sell any of the licensed candidates in Asia, and also holds Ophthalmic-focused Clearside Biomedical Inc. netted through a public sale of 6.4mm common shares at the option to exclusively license one of Ultragenyx’s $46.9mm in its initial public offering of 7.2mm com- $18.75. Proceeds will fund development activities, pipeline projects in Japan. For all compounds involved mon shares priced at $7 each. The company planned including completion of Phase I/II trials with GBT440 in the deal, each company is eligible for development to sell 4mm shares priced between $14-16. (Jun.) for sickle cell disease; planned trials for GBT440 for and sales milestones from the other, plus royalties on Investment Banks/Advisors: Needham & Co. Inc.; RBC idiopathic pulmonary fibrosis and other hypoxemic any drugs that make it to the market. Capital Markets; Stifel Nicolaus & Co. Inc.; Wedbush pulmonary disorders; and initiation of development PacGrow Life Sciences of GBT018713 for the treatment of hereditary angio- Teva Pharmaceutical Industries Ltd. edema. (Jun.) Zydus Cadila Corbus Pharmaceuticals Investment Banks/Advisors: Cowen & Co. LLC; JP Zydus Cadila acquired two ANDAs from Teva Holdings Inc. Morgan Chase & Co.; Morgan Stanley & Co.; Wedbush Pharmaceutical Industries Ltd. as a precondition Corbus Pharmaceuticals Holdings Inc. (therapies for PacGrow Life Sciences for Teva’s pending acquisition of Allergan’s generics inflammatory and fibrotic diseases) netted $14.8mm business. In the past few weeks, several other firms through the registered direct offering of 5.96mm GlycoMimetics Inc. including Dr. Reddy’s and Impax have acquired common shares at $2.50 each (a 24% discount) to various ANDAs that Teva has divested as part of the institutional and accredited investors including Percep- GlycoMimetics Inc. (uses its glycobiology technology Allergan acquisition. (Jun.) tive Advisors, Ghost Tree Capital, and DAFNA Capital to develop therapies for sickle cell disease, cancer, and The ANDAs were acquired by subsidiary Zydus World- Management, The company will use the money for other serious conditions) netted $18.9mm through a wide DMCC and include an already commercialized ongoing development of Phase II Resunab for cystic public offering of 3.3mm common shares at $6.10. ANDA and a pipeline ANDA for a transdermal patch. fibrosis, systemic sclerosis, dermatomyositis, and sys- Some proceeds will fund ongoing studies of GMI1271, The market size for the two generics is estimated at temic lupus erythematosus. (Jun.) a novel E-selectin antagonist that is in Phase I/II trials $200mm. Zydus has made significant investments in and was recently granted Fast Track designation by the transdermal manufacturing technology and acquired Cytori Therapeutics Inc. FDA for acute myeloid leukemia. (Jun.) a transdermal manufacturing facility in the US a few Cytori Therapeutics Inc. grossed $17.1mm through a Investment Banks/Advisors: Cowen & Co. LLC; Jefferies years ago. The company continues to seek out ad- & Co. Inc.; Stifel Nicolaus & Co. Inc.; SunTrust Banks Inc. ditional inorganic growth opportunities in the US. rights offering of 6.7mm units at $2.55 apiece. (Inves- tors subscribed to a total of 6.7mm common shares and 3.35mm warrants to buy shares at $3.06.) Cytori is ImmunoGen Inc. Financings developing cell therapies based on stem and regen- ImmunoGen Inc. (antibody-drug conjugates for can- /Pharmaceuticals erative cells from adipose tissue to address conditions cer) netted $96.7mm through the private placement including rare and orphan diseases, orthopedics, of $100mm principal amount of its 4.50% senior notes, cardiovascular disease, genitourinary disorders, and arGEN-X NV which convert to common at a rate of 238.7775 per acute and chronic wounds. (Jun.) Institutional investors put €30mm ($33.5mm) into $1k or approximately $4.19 per share. (The company’s antibody engineering firm arGEN-X NV through the Investment Banks/Advisors: Maxim Group LLC shares averaged $5.55 at the time of the sale.) Proceeds

46 | July/August | IN VIVO: The Business & Medicine Report | invivo.pharmamedtechbi.com DEALMAKING

editorial office 52 Vanderbilt Avenue • 11th floor, will fund clinical trials (including experimental therapy 10% premium). Each unit consists of one common New York, NY 10017 manufacturing) and additional corporate purposes. or non-voting Series A convertible share (strike price invivo.pharmamedtechbi.com Interest is payable semi-annually in arrears beginning of $2.00; preferred shares are priced at $2,015 and are on January 1, 2017. Investors included JP Morgan convertible into 1,000 common shares), 0.40 five-year customer service [email protected] (purchased $79mm of the notes) and Canaccord warrants to purchase one share at $2.00, and 0.20 Genuity, Oppenheimer, and William Blair, which each five-year warrants to purchase one share at $3.00. The purchased $7mm. (Jun.) company will use the proceeds to further develop its managing editor Nancy Dvorin products including PRS080, PRS060, and PRS343. (Jun.) Kadmon Corp. LLC health care editor Investment Banks/Advisors: Cowen & Co. LLC; Op- Ashley Yeo Kadmon Holdings LLC (biopharmaceuticals for unmet penheimer & Co. Inc. needs), which operates through its wholly owned senior editor Peter Charlish Kadmon Corp. subsidiary, filed for its IPO. (Jun.) Regulus Therapeutics Inc.

senior editor, data Investment Banks/Advisors: Citigroup Inc.; HC Wain- Regulus Therapeutics Inc. (oligonucleotide drug John Hodgson wright & Co.; JMP Securities LLC; Jefferies & Co. Inc. discovery; targets microRNAs) entered into a $30mm loan and security agreement with Oxford Finance LLC. editorial staff The company will use the proceeds from the loan Jessica Merrill Lion Biotechnologies Inc. Sten Stovall for working capital and to advance its pipeline. The Lion Biotechnologies Inc. (developing cancer immu- facility matures on June 1, 2020 and has interest-only Amanda Micklus, Principal Analyst notherapies based on tumor infiltrating lymphocytes) payments for the first two years, bearing an interest contributing editors grossed $100mm through the private sale of 9.7mm rate of 8.51% plus the greater of 0.44% or three month Deborah Erickson, Regina Paleski common shares at $4.75 (a 17% discount) and 11.4mm LIBOR. $20mm will paid out immediately upon execu- Mark Ratner, Marc Wortman Series B preferred shares at $4.75. Each preferred share tion of the agreement and will be used to further converts to common at $4.75. Buyers included Quogue develop Phase II RG101, with the remaining $10mm research manager Capital, OrbiMed Advisors, Frazier Healthcare Partners, tranche available upon the achievement of certain Steven Muntner Broadfin Capital, and less than ten other institutional milestones. (Jun.) and accredited investors. Jefferies and Piper Jaffray deals analysts were the placement agents. (Jun.) Beth Detuzzi, Deanna Kamienski Sarepta Therapeutics Inc. Maureen Riordan Investment Banks/Advisors: Jefferies & Co. Inc.; Piper Sarepta Therapeutics Inc. (RNA-targeted therapeutics Jaffray & Co. for rare infectious and other diseases) netted $37.3mm publication design supervisor through the sale of 2.1mm common shares at $17.84 Gayle Rembold Furbert Medgenics Inc. each. (Jun.) senior publication designer Medgenics Inc. (developing orphan drugs, with a Janet Haniak Investment Banks/Advisors: Credit Suisse Group; Rob- focus on pediatrics) netted $18.8mm through the ert W. Baird & Co. Inc. publication designers follow-on public offering of 3.64mm common shares Jean Marie Smith, Paul Wilkinson at $5.50 each. (Jun.) Vascular Biogenics Ltd. Investment Banks/Advisors: JMP Securities LLC; Jeffer- advertising Vascular Biogenics Ltd. (also known as VBL Thera- ies & Co. Inc.; Needham & Co. Inc. Christopher Keeling peutics) netted $22.3mm through a registered direct offering of 4.4mm common shares at $5.50 (a 39% corporate sales Moleculin Biotech Inc. John Lucas, Elissa Langer premium to the 10-day market average). Rodman & Alicia McNiven Cancer therapeutics developer Moleculin Biotech Renshaw was the placement agent. The company is Inc. netted $8.6mm through its initial public offer- developing treatments for cancer and inflammation/ technology operations manager immune-mediated diseases. (Jun.) Chris Trudeau ing of 1.5mm shares at $6. The company originally hoped to sell between 1.4-2mm common shares at Investment Banks/Advisors: Rodman & Renshaw vp, e-strategy & development $5-6 apiece. (Jun.) Adam Gordon Capital Group Inc. Investment Banks/Advisors: Network 1 Financial managing director Securities Inc. Phil Jarvis VBI Vaccines Inc. VBI Vaccines Inc. (vaccines for infectious diseases and Paratek Pharmaceuticals Inc. immune-oncology applications) grossed $13.6mm Paratek Pharmaceuticals Inc. (developing antibiotics through a private placement of 3.27mm common In Vivo: The Business & Medicine Report [ISSN 2160-9861] based on tetracycline chemistry) netted $51.9mm shares priced at $4.16 (a slight discount). Lead investors is published monthly, except for the combined July/August through the follow-on sale of 4.25mm common Opko Health and Perceptive Advisors were joined by issue, by Informa Business Intelligence, Inc., 52 Vanderbilt shares at $13 each. The company will use some of the Arch Venture Partners. (Jun.) Avenue, 11th floor, New York, NY 10017. Tel: 888-670-8900(US); proceeds for an oral-only Phase III trial of omadacycline +1-908-547-2200 (outside US); Fax: 646-666-9878. for acute bacterial skin and skin structure infections Subscriptions cost $2,630 (online and print) per year. Office (ABSSSI) and to fund activities needed to submit the of publication, The Sheridan Group, 66 Peter Parley Row, NDA for omadacycline in ABSSSI and community- Berlin, CT 06037. Postmaster: Send address changes to acquired bacterial pneumonia (CABP). (Jun.) Informa Business Information, 52 Vanderbilt Avenue, 11th floor, Investment Banks/Advisors: BTIG LLC; Guggenheim New York, NY 10017. Partners LLC; Ladenburg Thalmann & Co. Inc.; Leerink © 2016 by Informa Business Intelligence, Inc., an Informa company. Partners LLC All rights reserved. Pieris Pharmaceuticals Inc. No part of this publication may be reproduced in any form or incorporated into any information retrieval system without the Pieris Pharmaceuticals Inc. (anticalin products for cancer, asthma, and anemia) raised $16.5mm in a written permission of the copyright owner. private placement of 8.2mm units at $2.015 each (a

Summary of article from page 8 Smart Segmentation: Success In The Payer-Dominated Pharma Marketplace By Roger Longman Putting payers at the center of drug launch competition in all relevant subpopulations – new drugs on each line of a payer’s business, strategies isn’t enough because payers are and then determine the patient population recognizing that different lines will see differ- not monolithic entities. To avoid exclusion in which the drug shows disproportionate ent values to a drug. Such targeted strategies from formularies, pharmas must assess the value. Within that target population, devel- can work and, if appropriately constructed, value of their new drugs from the payer’s opers must define the economic impact of deliver outsized investment returns. point of view, relative to existing and coming

Summary of article from page 16 CVRx’s Investment In HF And Wider Medtech Industry Set To Pay By Ashley Yeo CVRx president and CEO Nadim Yared believes FDA has shown its collaborative qualities in global heart failure companies. Not content his company’s second-generation chronic helping CVRx design trials for the PMA class with merely steering CVRx into the commercial heart failure device could present a serious device in novel and innovative ways, and phase for the HF application (Barostim Neo commercial challenge to the traditional has left the company deeply impressed. also has an application in hypertension), major players in the field. It is about to enter Nadim Yared believes that revenues from the Yared holds decision-making roles in other a pivotal trial in the US ahead of an FDA Barostim Neo device could become large organizations, including AdvaMed, which has filing for an application to treat heart failure, enough to elevate CVRx among the top four tapped him for its key post. a market that extends to 5.1 million adults.

Summary of article from page 22 IO’s Impact On Strategic Decision-Making In The Broader Oncology Landscape By Seth Berman, Ryan Stover and Anna Pasternak The initial success of checkpoint inhibitors rapid and significant changes in oncology that non-IO products become successful and engineered T cell therapies has spawned treatment. Market signals from the pioneer- components of the standard of care in cancer, a surge of investment in the field of immuno- ing immuno-oncology therapies suggest drug developers must consider how IO may oncology. More than 750 IO agents are a paradigm shift across multiple oncology impact clinical development, market access currently under investigation across a broad indications in the coming years. To ensure and commercialization strategies. range of tumor types, which will likely drive

Summary of article from page 28 Singulex: Next-Gen Immunodiagnostics By Peter Charlish Singulex originally developed its Single assays are 100 times more sensitive than with an assay for acute myocardial infarction. Molecule Counting technology for research other current testing platforms, and they A point-of-care system that provides results in applications, but it is poised to launch a eliminate the problem of “not detectable” 20 minutes could be commercially available clinical diagnostics tool. The company says results. Singulex will pursue high-value in three to four years. its next-generation immunodiagnostic applications for its Clarity IVD system, starting

Summary of article from page 32 Using Enriched Studies For Post-Approval Evidence Needs By Nancy Dreyer These days, clinical trial sponsors are being start many projects, with skilled manpower evidence needs, it is possible to address many asked to provide empirical evidence to many for each, cross-training, and a series of studies, stakeholders’ needs, thereby minimizing ex- stakeholders with diverse needs and to do each designed to address one main objective. pense while increasing the likelihood of get- so efficiently. If sponsors respond to each But by taking a holistic view of post-approval ting data that are fit for a variety of purposes. stakeholder’s questions in isolation, they will

48 | July/August 2016 | IN VIVO: The Business & Medicine Report | invivo.pharmamedtechbi.com