tio2 book Documentation Release 0.0.1

tio2

Sep 11, 2020

Contents

1 Robert Duggan 3

2 Accel 5

3 Tesaro Inc 7

4 Anacor Pharmaceuticals, Inc 11

5 Cerulean Pharma Inc 15

6 Medivation 17

7 Moderna Therapeutics 21 7.1 Introduction...... 21 7.2 History...... 21 7.3 Research...... 22 7.4 2015 DISRUPTOR 50...... 22 7.5 A ‘Moderna’ Cinderella Story: AstraZeneca’s $240M Up Front Share...... 23

8 Genentech 25 8.1 A History of Firsts...... 25

9 juno therapeutics 33 9.1 Company History...... 33

10 Vertex Pharmaceuticals 35 10.1 Vertex story...... 35

11 Alnylam Pharmaceuticals 37 11.1 Therapeutic concept...... 37 11.2 Products...... 37 11.3 Alnylam off as development of key drug discontinued...... 38

12 Celgene Corporation 39 12.1 History...... 39

13 Foundation Medicine 41 13.1 History...... 41

i 13.2 Products...... 41

14 Grail 43 14.1 Grail files for $100M IPO ahead of 2021 launch of multi-cancer liquid biopsy...... 43 14.2 History...... 44

15 Indices and tables 47

Index 49

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This book is meant to be a collention of investing stories and stories for different companies with a focus in biotech pharmaceutical companies. Contents:

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2 Contents CHAPTER 1

Robert Duggan

Robert Duggan, CEO of biotech drugmaker Pharmacyclics PCYC, will pocket over $3.5 billion from the company’s sale to AbbVie ABBV, one of the biggest paydays ever from the buyout of a publicly held company. Under terms of the deal, Duggan will receive $3.55 billion for his 13.6 million shares, about an 18% stake in the biotech company, according to corporate filings. Other senior execs are set for big payouts as well, including Chief Operating Officer Mahkam Zanganeh, whose shares are worth nearly $224.6 million, and director David Smith, who will pocket nearly $46.5 million. All told, directors and senior executives could receive nearly $4 billion in merger-related payments, Pharmacyclics says. Duggan, 70, is a longtime private venture investor and was CEO of surgical systems maker Computer Motion until it was acquired by Intuitive Surgical ISRG in 2003. Duggan began buying Pharmacyclics stock in 2004, eventually amassing nearly a 25% stake. But by 2008, shares had fallen below $1. The company’s fortunes turned on chronic lymphocytic leukemia treatment Imbruvica and a series of drug industry mergers. Pharmacyclics shares currently trade at about $258. Takeover speculation – including interest from Imbruvica partner Johnson & Johnson JNJ – have boosted Pharmacyclics 119% this year alone, based on Tuesday’s $257.75 close. Duggan has declined compensation from the company since becoming CEO in 2008.

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4 Chapter 1. Robert Duggan CHAPTER 2

Accel

A few months after struggling to raise a new fund in 2005, Accel Partners bet $12.2 million on a website run by a college dropout. Seven years later, that wager is poised to be the most profitable ever for a venture firm. Accel, whose partners include Jim Breyer and Kevin Efrusy, is the top outside investor in Facebook Inc., owning about 10 percent. Assuming Facebook is valued at $100 billion, Accel’s stake on paper is worth about $10 billion. When Accel made its Facebook investment, the site had just 2.8 million users – all on college campuses – and was run by a 21-year-old Mark Zuckerberg. Now it has 800 million members worldwide and an estimated $4.27 billion in 2011 sales, according to EMarketer Inc. That explosive growth is poised to deliver an 800-fold return on Accel’s money, catapulting the firm to the forefront of the venture industry. “This is what makes venture capital and Silicon Valley unique in the world,” said Steve Blank, who helped found eight companies and now teaches entrepreneurship at the University of California at Berkeley and Stanford University. “It’s what VCs do incredibly well. Accel, in this one, deserves all of it.” Accel’s prospective payday shows the hits-driven nature of the venture business, where one investment can make an entire fund profitable and establish a firm as the market leader. Kleiner Perkins Caufield & Byers had that distinction from early bets on e-commerce and Web search companies, before missing out on most of the social-media leaders. It later bought shares of Facebook and Twitter Inc. at less favorable prices. IPO Plans Facebook plans to raise $10 billion in the IPO, with a filing coming soon, a person with knowledge of the matter said in November. The offering would value the Menlo Park, California-based company at more than $100 billion, according to the person. Accel, located a 10-minute drive away from Facebook in Palo Alto, isn’t the lone winner among investors. Russia’s Digital Sky Technologies and PayPal Inc. co-founder Peter Thiel are due for a payback too. Greylock Partners and Meritech Capital Partners also are investors, as well as Elevation Partners, co-founded by U2’s Bono. Founded in 1983 by Arthur Patterson and Jim Swartz, Accel was an unlikely investor in Facebook. The firm fo- cused on hardware companies such as UUNet Technologies Inc. and Redback Networks Inc. rather than Internet companies during the dot-com boom of the late 1990s. Google Inc., Amazon.com Inc., Yahoo! Inc. and Netscape Communications Corp. went on to produce billions of dollars for other venture backers. Early Investment Accel began raising money for a more Web-focused fund in the mid-2000s, though that effort faced challenges. Har- vard University and other prospective investors backed out of the fund, forcing Accel to cut the size of it to $440

5 tio2 book Documentation, Release 0.0.1 million – smaller than any investment pool it had raised since 1998. In May 2005, less than six months after completing the fundraising, Accel made one of the first investments: a startup that was then called Thefacebook. Zuckerberg had begun the company during the previous year in his Harvard dorm room. Breyer and Efrusy oversaw Accel’s $12.2 million investment, which assumed a $100 million valuation, and Breyer gained a seat on the Facebook board. “It was a big leap of faith at the time,” Efrusy said in an interview in March. “Any one of these investments you do, in hindsight they may look obvious, but at the time they look scary.” Accel declined to comment for this story, as did Jonathan Thaw, a spokesman for Facebook. Fund’s Payback Investors in Accel’s fund have already seen some of the rewards. By selling 17 percent of its original Facebook stake last year at a $34 billion valuation, Accel paid back investors in the 2005 fund, while holding onto the bulk of its stake for future gains. Accel’s potential payday would generate more than twice the combined gains of Sequoia Capital and Kleiner Perkins in Google’s 2004 IPO, the biggest venture-backed offering until now, according to the National Venture Capital Asso- ciation. Still, Accel’s fortunes will depend on what happens to Facebook’s stock after its IPO. While the venture firm may sell some shares in the offering, it will probably be required to hold the rest for six months, the so-called lock-up period. Google shares more than doubled in the first six months after the Mountain View, California-based company’s IPO, boosting the value of Sequoia’s and Kleiner Perkins’s holdings. In the 1990s, Web companies such as Yahoo and Amazon also gained most of their value after their IPOs. New Model At $100 billion, Facebook would already be the eighth-biggest U.S. technology company by market value. It would be half the size of Google, even with only 15 percent of the revenue. Facebook stayed private longer than its Internet predecessors, meaning the bulk of investors’ gains may have already been realized, said venture capitalist Maha Ibrahim. “Facebook has changed the model a little bit,” said Ibrahim, a partner at Canaan Partners in Menlo Park. “Before, it was very rare for a company of their size to still be private.” As the social-networking market in the U.S. matures, Accel’s partners are scouring the globe for new deals. Breyer is handling investments in China, while Efrusy and Andrew Braccia mine startups in Brazil. Other partners are focusing on Europe, India and Australia. Groupon Deal Accel’s recent success isn’t limited to Facebook. The firm was among the biggest venture winners last year, thanks to its stake in daily-deal site Groupon Inc. In last year’s U.S. IPO market, Accel ranked behind New Enterprise Associates, another Groupon investor, and Sequoia, the biggest venture backer of LinkedIn Corp. Most of Accel’s companies and venture investments in general produce less dramatic results. Coremetrics, a software company backed by Accel, was acquired in 2010 for an undisclosed price, and semiconductor maker Artimi Inc. merged with a competitor in 2008. Even if Facebook generates a record return for the venture industry, it’s unlikely to spur other startups to file for IPOs soon, said Mark Heesen, president of the National Venture Capital Association in Arlington, Virginia. Facebook’s size and brand are unmatched by any other private, venture-backed company, he said this month in an interview on “Bloomberg West.” “I don’t think Facebook will have these huge coattails that people are saying it will have,” Heesen said. “Every other possible IPO that’s out there will have to stand on its own.”

6 Chapter 2. Accel CHAPTER 3

Tesaro Inc

Tesaro was founded in 2010 by a group of pharma industry heavyweights. Rather than spending the time and money to discover drugs, Tesaro acquires compounds from other companies and directs its resources toward the clinical trials needed for FDA approval. Tesaro acquired world-wide rights to niraparib through a 2012 licensing deal with Merck (NYSE: MRK). TESARO is an oncology-focused biopharmaceutical company devoted to providing transformative therapies to people bravely facing cancer. For more information, visit http://www.tesarobio.com/, and follow us on Twitter and LinkedIn. TESARO’s Niraparib Significantly Improved Progression-Free Survival for Patients With Ovarian Cancer in Both Cohorts of the Phase 3 NOVA Trial • The NOVA trial successfully achieved its primary endpoint of PFS in the germline BRCA mutant cohort • The NOVA trial successfully achieved its primary endpoint of PFS in the non-germline BRCA mutant cohort, including both the HRD-positive and overall analysis populations • NOVA is the first successful prospectively designed Phase 3 trial of a PARP inhibitor • NDA and MAA submissions are planned for Q4 2016 WALTHAM, Mass., June 29, 2016 (GLOBE NEWSWIRE) – TESARO, Inc. (NASDAQ:TSRO), an oncology-focused biopharmaceutical company, today announced that the Phase 3 NOVA trial of niraparib successfully achieved its primary endpoint of progression-free survival (PFS). This trial demonstrated that niraparib significantly prolonged PFS compared to control among patients who are germline BRCA mutation (gBRCAmut) carriers, among patients who are not germline BRCA mutation (non-gBRCAmut) carriers but who have homologous recombination deficient (HRD) tumors as determined by the Myriad myChoice® HRD test, and overall in patients who are not germline BRCA mutation carriers. An infographic accompanying this release is available at: http://www.globenewswire.com/NewsRoom/AttachmentNg/ f065a7ab-070d-4dc3-8c87-ae4fa8deabd1 Videos accompanying this release are available at: http://www.globenewswire.com/NewsRoom/AttachmentNg/ 39793bb6-2551-47fa-85a3-b19c97d41e11 http://www.globenewswire.com/NewsRoom/AttachmentNg/6ea284b2-a663-4aeb-96c1-22ac847b460f NOVA is a double-blind, placebo-controlled, international Phase 3 trial of niraparib that enrolled more than 500 patients with recurrent ovarian cancer who were in a response to their most recent platinum-based chemotherapy.

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There is currently no therapy approved by the U.S. Food and Drug Administration for maintenance treatment of patients with recurrent ovarian cancer following response to platinum. “We are extremely grateful to the patients, caregivers, and investigators who participated in the NOVA trial. The results of this study, which is the first successful, prospectively designed, randomized, well-controlled Phase 3 study of a PARP inhibitor, demonstrate that a single, daily, oral dose of niraparib is superior to control in prolonging PFS in women with recurrent ovarian cancer,” said Mary Lynne Hedley, Ph.D., President and COO of TESARO. “Importantly, these results show activity of niraparib in a population of ovarian cancer patients beyond those with germline BRCA mutations. In keeping with our mission of responsible drug development, NOVA was designed to define those patients most likely to benefit from niraparib treatment and, in so doing, optimize the benefit/risk profile for patients. We believe we have achieved that goal and look forward to presentation of the full data set from this study at the European Society for Medical Oncology (ESMO) congress in October.” Statistically Significant PFS Results in the gBRCAmut Cohort Among patients who were germline BRCA mutation carriers, the niraparib arm successfully achieved statistical significance over the control arm for the primary endpoint of PFS, with a hazard ratio of 0.27. The median PFS for patients treated with niraparib was 21.0 months, compared to 5.5 months for control (p < 0.0001). Statistically Significant PFS Results in non-gBRCAmut Cohort for Patients with HRD Positive Tumors For patients who were not germline BRCA mutation carriers but whose tumors were determined to be HRD positive using the Myriad myChoice® HRD test, the niraparib arm successfully achieved statistical significance over the control arm for the primary endpoint of PFS, with a hazard ratio of 0.38. The median PFS for patients with HRD-positive tumors who were treated with niraparib was 12.9 months, compared to 3.8 months for control (p < 0.0001). Statistically Significant PFS Results in the Overall non-gBRCAmut Cohort Niraparib also showed statistical signifi- cance in the overall non-germline BRCA mutant cohort, which included patients with both HRD-positive and HRD- negative tumors. The niraparib arm successfully achieved statistical significance over the control arm for the primary endpoint of PFS, with a hazard ratio of 0.45. The median PFS for patients treated with niraparib was 9.3 months, compared to 3.9 months for control (p < 0.0001). The most common (10%) treatment-emergent grade 3/4 adverse events among all patients treated with niraparib were thrombocytopenia (28.3%), anemia (24.8%) and neutropenia (11.2%). Adverse events were generally managed via dose modifications. The discontinuation rate was 14.7% for niraparib treated patients and 2.2% for control. The rates of MDS/AML in the niraparib (1.3%) and control (1.2%) arms were similar. There were no deaths among patients during study treatment. “The majority of women who are diagnosed with advanced ovarian cancer will experience a relapse of their disease, even if they respond to their initial chemotherapy,” said Dr. Tom Herzog, M.D., Clinical Director, University of Cincinnati Cancer Institute and Professor, Department of Obstetrics and Gynecology at the University of Cincinnati. “New treatment options are needed to extend the time in between cycles of platinum-based chemotherapy for these patients, and the results from the NOVA study suggest that niraparib could represent an important new treatment option for many patients with ovarian cancer.” “While the identification of mutations in the BRCA genes was a significant advancement, ovarian cancer remains the deadliest of gynecologic cancers, and new diagnostic and therapeutic options are needed,” said David Barley, Chief Executive Officer of the National Ovarian Cancer Coalition. “The results of the NOVA trial are encouraging for patients and their families, and we look forward to seeing the full results of this study this fall.” About the Phase 3 NOVA Clinical Trial of Niraparib NOVA is a double-blind, placebo-controlled, international Phase 3 trial of niraparib that planned to enroll 490 patients with recurrent ovarian cancer who were in a response to their most recent platinum-based chemotherapy. Patients were enrolled into one of two independent cohorts based on germline BRCA mutation status. One cohort enrolled patients who were germline BRCA mutation carriers (gBRCAmut), and the second cohort enrolled patients who were not germline BRCA mutation carriers (non-gBRCAmut). The non- gBRCAmut cohort included patients with HRD-positive tumors, including those with somatic BRCA mutations and other HR defects, and patients with HRD-negative tumors. Within each cohort, patients were randomized 2:1 to receive niraparib or placebo and were treated continuously with placebo or 300 milligrams of niraparib, dosed as three 100 milligram tablets once per day, until progression. The primary endpoint of this study was progression-free survival (PFS). Secondary endpoints include patient-reported outcomes, chemotherapy-free interval length, PFS2,

9 tio2 book Documentation, Release 0.0.1 overall survival, and other measures of safety and tolerability. More information about this trial is available at http: //clinicaltrials.gov/show/NCT01847274. Niraparib is an investigational agent and, as such, has not been approved by the U.S. FDA or any other regulatory agencies. About Homologous Recombination Deficiency (HRD) Homologous recombination deficiency (HRD) is a defect in high-fidelity, double-strand DNA repair. HRD results from a variety of causes, including mutations in BRCA and other genes involved in DNA repair, as well as other unidentified causes. In cells with HRD, such as BRCA1 and BRCA2 mutant cells, lack of functional DNA repair pathways, including PARP, leads to irreparable double-strand breaks, genomic instability, and ultimately cell death. Because HRD-positive cells are sensitive to DNA-damaging processes, they are reliant upon proper DNA repair by other pathways, including PARP-dependent pathways. Comprehensive assessment of HRD status includes both tBRCA mutational analysis and assessment of genomic in- stability through the combined analysis of HRD biomarker components LOH, TAI, and LST. myChoiceHRD® is a registered trademark of Myriad Genetics, Inc. About Niraparib Niraparib is an oral, once-daily PARP inhibitor that is currently being evaluated in three ongoing pivotal trials. TESARO is building a robust niraparib franchise by assessing activity across multiple tumor types and by evaluating several potential combinations of niraparib with other therapeutics. The ongoing development program for niraparib includes the Phase 3 trial in patients with ovarian cancer (the NOVA trial) as described above; a registrational Phase 2 treatment trial in patients with ovarian cancer (the QUADRA trial); a Phase 3 trial for the treatment of patients with BRCA-positive breast cancer (the BRAVO trial); and a Phase 3 trial in patients with first-line ovarian cancer (the PRIMA trial). Several collaborator-sponsored studies are also underway, including combination trials of niraparib plus pembrolizumab and bevacizumab. Janssen Biotech has licensed rights to develop and commercialize niraparib specifically for patients with prostate cancer worldwide, except in Japan. About Ovarian Cancer Approximately 22,000 women are diagnosed each year with ovarian cancer in the United States, and nearly 80% are diagnosed after the disease has become symptomatic and has progressed to a late stage. Ovarian cancer is the fifth most frequent cause of cancer death among women. Despite high response rates to platinum- based chemotherapy in the second-line advanced treatment setting, 90% of patients will experience recurrence within two years. If approved, niraparib may address the difficult “watchful waiting” periods experienced by patients with recurrent ovarian cancer in between cycles of platinum-based chemotherapy.

10 Chapter 3. Tesaro Inc CHAPTER 4

Anacor Pharmaceuticals, Inc

On May 16, Pfizer announced that it was acquiring Anacor Pharmaceuticals (NASDAQ:ANAC) for the hefty sum of $99.25 in cash per share, or a 55% premium to where Anacor shares closed on Friday. The crown jewel of the $5.2 billion acquisition is crisaborole, a non-steroidal topical anti-inflammatory PDE-4 inhibitor that’s been submitted for regulatory review in the U.S. for mild-to-moderate atopic dermatitis (a type of eczema). Crisaborole is also being studied as a treatment for psoriasis. Pfizer believes that Anacor’s lead compound could generate up to $2 billion in peak annual sales. “Crisaborole is a differentiated asset with compelling clinical data that, if approved, has the potential to be an important first-line treatment option for these patients and the physicians who treat them,” said Albert Bourla, Group President of Pfizer’s Global Innovative Pharma and Global Vaccines, Oncology, and Consumer Health Businesses. That “compelling clinical data” Bourla speaks of comes from the AD-301 and AD-302 phase 3 studies released in mid-July 2015 that showed a statistically significant advantage in clearing the chronic rashes that occur with atopic dermatitis compared to the placebo. In terms of primary endpoint, the percentage of patients experiencing an Investi- gator’s Static Global Assessment (ISGA) score of 0 (clear) or 1 (almost clear) with a minimum two-grade drop at day 29 was 32.8% in AD-301 and 31.4% in AD-302 compared to the placebo’s 25.4% and 18% respective effectiveness. The secondary endpoint, which examined which patients achieved an ISGA of 0 or 1 regardless of whether or not they had a minimum two-grade drop, also demonstrated success for crisaborole. In AD-301 and AD-302, 51.7% and 48.5% of patients experience full or almost-full clearing, which compares to 40.6% and 29.7% full or almost-full clearing, respectively, for the placebo. As icing on the cake, Pfizer also gains access to topical toenail fungal treatment Kerydin, which was approved by the Food and Drug Administration in July 2014. Pfizer believes the deal will not materially affect its outlook in 2016, that it’ll be slightly dilutive to full-year EPS in 2017, and be accretive to its bottom-line in 2018 and each year thereafter. Sounds like a great deal, right? I’m not so sure. Pfizer may have vastly overpaid for Anacor While I’m all for having Pfizer use its cash flow to boost the inorganic growth side of the equation, I’d contend that it vastly overpaid for Anacor when it offered $5.2 billion for the drug developer. Taking this step by step, Pfizer really is getting two assets: kerydin and cirsaborole. Anacor does have other topical anti-inflammatory products in development, but they’re all in the discovery or preclinical stages of development. Aside

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12 Chapter 4. Anacor Pharmaceuticals, Inc tio2 book Documentation, Release 0.0.1 from these two therapies, the only other drug in clinical studies is AN3365 for infections caused by Gram-negative bacteria, and it’s far too early to tell if this clinical therapeutic is effective. Kerydin is, to be blunt, an afterthought in this acquisition. Anacor forged an agreement with Sandoz to help market Kerydin back in 2014, and last year total distribution and commercialization segment revenue was $69.7 million. With peak sales estimates of $400 million, it’s not going to move the needle much for Pfizer. The bigger concern would be for crisaborole. On one hand, there’s probably a better than 50-50 shot at FDA approval come its PDUFA date in January 2017 thanks to the drug’s meeting its primary and secondary endpoints in both studies and its being generally well tolerated by patients. With few options in treating atopic dermatitis, crisaborole could gobble up market share quickly. But, it’s what happens one or two years from now when crisaborole is facing a bounty of potential new competitors that worries me. Celgene’s (NASDAQ:CELG) oral PDE-4 inhibitor Otezla is already approved to treat psoriatic arthritis and plaque psoriasis, but Celgene has hopes of eventually gaining a label expansion for atopic dermatitis as well. In a previously conducted, though small, study involving Otezla that defined treatment benefit as a 50% (or higher) decrease in the Eczema Area and Severity Index (EASI), Otezla delivered a 62% success rate. Keep in mind that EASI and ISGA aren’t comparable measurements, so we can’t simply say one drug is better than the other. But it does suggest that Otezla could be on track to become the first oral eczema treatment for those with moderate-to-severe forms of the disease. In addition, Regeneron Pharmaceuticals (NASDAQ:REGN) and Sanofi (NYSE:SNY) are expected to file for regula- tory approval of injectable dupilumab for the treatment of moderate-to-severe atopic dermatitis in the third quarter. In the LIBERTY AD SOLO1 and SOLO2 trials 37% and 36% of patients who an IGA score of 0 or 1 (clear or nearly clear) compared to just 10% and 8.5% for the placebo. EASI improvement from baseline was also a healthy 72% and 69% for dupilumab compared to just 38% and 31%, respectively, for the placebo. Regeneron and Sanofi’s injection was also well-tolerated. Sny Fb Roche, AstraZeneca, and Chugai in Japan are also working on midstage atopic dermatitis therapies. This is an increas- ingly crowded space, and $2 billion seems like a longshot with other successful therapies making their way down the pipeline. Even with the assumption that crisaborole becomes a blockbuster ($1 billion in annual sales), it could be a very long time before Pfizer realizes a “gain” on its investment. Assuming a healthy margin on crisaborole of say 70%, and taking into account added revenue from Kerydin, the dilutive effect this acquisition could have on 2017 EPS, and the likelihood that crisaborole would take a few years to ramp up sales, it might be 2024 or 2025 before Pfizer finds its $5.2 billion “investment” in Anacor yielding positive results. The good news here is Pfizer is generating more than enough cash flow to facilitate additional deals, and its oncology segment is on fire with an immuno-oncology offering (avelumab) waiting on the wings. The bad news is I don’t believe its acquisition of Anacor was a particularly good move, and I don’t see any immediate benefits to this deal for shareholders.

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14 Chapter 4. Anacor Pharmaceuticals, Inc CHAPTER 5

Cerulean Pharma Inc

Cerulean Pharma Inc. (NASDAQ: CERU) announced that the U.S. Food and Drug Administration (FDA) granted Fast Track designation for Cerulean’s lead nanoparticle-drug conjugate, CRLX101, in combination with paclitaxel, for the treatment of platinum-resistant ovarian carcinoma, fallopian tube or primary peritoneal cancer. “We appreciate the FDA’s acknowledgement of CRLX101’s potential in an area of significant unmet medical need,” said Christopher D. T. Guiffre, President and Chief Executive Officer of Cerulean. “We are encouraged by the profound treatment effect observed early in the ongoing clinical trial with the GOG Foundation, Inc. (GOG), and we look forward to working closely with the FDA as we endeavor to bring a new treatment option to women living with platinum-resistant ovarian cancer.” CRLX101 is being evaluated in combination with weekly paclitaxel for the treatment of recurrent platinum-resistant ovarian carcinoma in a Phase 1b/2 clinical trial. Data from the Phase 1b portion of the trial were the subject of an oral presentation at the Gynecologic Oncology 2016 Conference in May. These data showed that five of the first nine patients (56%) enrolled in the trial achieved partial responses. Of note, five of the nine patients enrolled in the Phase 1b trial previously failed Avastin® (bevacizumab) and three of these five patients achieved partial responses. Cerulean is conducting this trial in collaboration with the GOG and expects to provide an update at the European Society for Medical Oncology 2016 Congress. In 2015, CRLX101 was granted Orphan Drug designation for the treatment of ovarian cancer. The FDA’s Fast Track Program is designed to facilitate the development and expedite the review of new drugs that are intended to treat serious conditions and that demonstrate the potential to address unmet medical needs. Drugs that receive this designation benefit from more frequent communications and meetings with FDA to review the drug’s development plan, including the design of the proposed clinical trials and the extent of data needed for approval.

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16 Chapter 5. Cerulean Pharma Inc CHAPTER 6

Medivation

Medivation is an American biopharmaceutical giant which is based in San Francisco. The company is focused on rapidly developing drugs which help in treating serious diseases with limited treatment possibilities. The corporation is enlisted on NASDAQ stock exchange under the symbol MDVN. It has production facilities based in United States along with many Research and Development bases too. David Hung serves the company as its Chairman and CEO and also leads its R and D department. As of 2015, it is one of the most commercially successful new companies to emerge in the United States. The corporation is just a year over a decade old and already has become the most sought after pharmaceutical player in the North American continent. It was founded by David Hung in December 2004 as a result of the acquisition of Medivation Neurology, Inc. Since then, it has collaborated with many other companies from the same industry in order to tighten its grip on the American as well as international markets and also to enhance the workings of its R and D department. Recently it was in the news for collaborating with the European pharmaceutical giant Astellas when the U.S. Food and Drug Administration (FDA) approved the result of its joint venture that produced XTANDI (enzalutamide) capsules. This was a major breakthrough for both the entities as is known to be highly successful in treating patients with metastatic castration-resistant prostate cancer. The procedure of the drug is basically applied in post-chemotherapy of the patients. Product Trialsmedivation1The development, manufacturing and commercialization of XTANDI will be done in col- laboration with Astellas Pharma Inc. in the future, while License and supply agreement has been done in collaboration with CureTech for development, manufacturing and commercialization of its biologic molecules. Medivation’s clin- ical trials as far as prostate cancer is concerned include STRIVE, which currently stands in Phase II clinical trial. AFFIRM and PREVAIL have already completed the enrollment for Phase III clinical trial. PROSPER and EMBARK are in an ongoing enrollment for the Phase III clinical trial. TERRAIN has done so too for the Phase II clinical trial. Apart from these, AR+, ER+ or PgR+, HER2 Normal and TNBC; and HER2 Amplified and AR+ are part of its breast cancer related Phase II clinical trials.Upheavals & AchievementsAbout four years back the company was involved in a lawsuit that was filed against it, when its stocks dropped by a staggering 67% in just one day on its total number of 45 million shares. Izard Nobel LLP was responsible for initiating the case and it carried on for a total four years ending with the decision going in Medivation’s favor and the company getting cleared of all charges. Medivation has managed to win back its reputation since and has managed to establish a firm hold on the market too. Monday, August 22, 2016 - 6:45am EDT Pfizer Inc. (NYSE:PFE) and Medivation, Inc. (NASDAQ:MDVN) today announced that they have entered into a definitive merger agreement under which Pfizer will acquire Medivation, a biopharmaceutical company focused on developing and commercializing small molecules for oncology, for $81.50 a share in cash for a total enterprise value of approximately $14 billion. The Boards of Directors of both companies have unanimously approved the merger, which is expected to be immediately accretive to Pfizer’s Adjusted Diluted

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EPS upon closing, approximately $0.05 accretive in the first full year after close with additional accretion and growth anticipated thereafter. Pfizer does not expect the transaction to impact its current 2016 financial guidance. “The proposed acquisition of Medivation is expected to immediately accelerate revenue growth and drive overall earnings growth potential for Pfizer,” said Ian Read, chairman and chief executive officer, Pfizer. “The addition of Medivation will strengthen Pfizer’s Innovative Health business and accelerate its pathway to a leadership position in oncology, one of our key focus areas, which we believe will drive greater growth and scale of that business over the long-term. This transaction is another example of how we are effectively deploying our capital to generate attractive returns and create shareholder value.” Medivation’s portfolio includes XTANDI® (enzalutamide), an androgen receptor inhibitor that blocks multiple steps in the androgen receptor signaling pathway within the tumor cell. XTANDI is the leading novel hormone therapy in the United States today and generated approximately $2.2 billion in worldwide net sales over the past four quarters, as recorded by Astellas Pharma Inc., with whom Medivation entered an agreement in 2009 to develop XTANDI globally and commercialize jointly in the U.S. Since its approval for advanced metastatic prostate cancer by the U.S. Food and Drug Administration in 2012, XTANDI has treated 64,000 men to date in the U.S. alone. Medivation and Astellas have built a robust development program for XTANDI, including two Phase 3 studies in non-metastatic prostate cancer and another Phase 3 study in hormone-sensitive prostate cancer. It is also being further developed in Phase 2 studies for the potential treatment of advanced breast cancer and hepatocellular carcinoma. In addition, Medivation has a promising, wholly-owned, late-stage oncology pipeline, which includes two development-stage oncology assets, talazoparib and pidilizumab. Talazoparib, currently in a Phase 3 study for the treatment of BRCA-mutated breast cancer, has the potential to be a highly potent PARP inhibitor and could be effi- cacious across several additional tumors. Pidilizumab is an immuno-oncology (IO) asset being developed for diffuse large B-cell lymphoma and other hematologic malignancies and has the potential to be combined with IO therapies in Pfizer’s portfolio. “We believe the combination with Pfizer is the right next step in our growth trajectory and is a testament to the passion and dedication by which the Medivation team has delivered on our mission to profoundly transform patients’ lives through medically innovative therapies,” said David Hung, M.D., founder, president and CEO of Medivation. “This compelling transaction will deliver significant and immediate value to our stockholders and provides new opportunities for our employees as part of a larger company. We believe that Pfizer is the ideal partner to extend the reach of our blockbuster XTANDI franchise and take our promising, late-stage assets – talazoparib and pidiluzimab – to their next stages of development so that they can be made available to patients as quickly as possible.” “The proposed acquisition of Medivation will build upon Pfizer’s success with our IBRANCE® (palbociclib) launch in HR+/HER2- metastatic breast cancer and with our strong immuno-oncology portfolio, and will transform Pfizer into a leading oncology company,” said Albert Bourla, group president, Pfizer Innovative Health. “IBRANCE and XTANDI are anchor brands in breast and prostate cancer respectively, giving Pfizer leadership in two hormone-driven cancers. Similar to IBRANCE in the breast cancer setting, XTANDI is being explored for its potential to move from metastatic prostate cancer to treat earlier stages of non-metastatic prostate cancer. In addition, Medivation’s portfolio within prostate cancer and across diverse tumors will complement Pfizer’s broad IO portfolio. Finally, Medivation adds commercial scale to better compete with other top tier oncology companies in advance of the potential emergence of Pfizer’s IO pipeline expected in the next few years. Together, we believe Pfizer and Medivation can bring the full force of our combined research and resources to combat two of the most common cancers, as well as speed cures and make accessible breakthrough medicines to patients, redefining life with cancer.” Cancer remains the second leading cause of death in the U.S. and a “Top 10” killer worldwide. According to the American Cancer Society, breast cancer and prostate cancer are among the top three cancers by annual incidence in the U.S. There are several parallels between breast and prostate cancer, including the incidence of prostate cancer in the U.S., which is similar to that of breast cancer with approximately 280,000 cases per year. Pfizer expects to finance the transaction with existing cash. Under the terms of the merger agreement, a subsidiary of Pfizer will commence a cash tender offer to purchase all of the outstanding shares of Medivation common stock for $81.50 per share, net to the seller in cash, without interest, subject to any required withholding of taxes. The closing of the tender offer is subject to customary closing conditions, including U.S. antitrust clearance and the tender of a majority of the outstanding shares of Medivation common stock.

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The merger agreement contemplates that Pfizer will acquire any shares of Medivation that are not tendered into the offer through a second-step merger, which will be completed promptly following the closing of the tender offer. Pfizer expects to complete the acquisition in the Third- or Fourth-Quarter 2016. Pfizer’s financial advisors for the transaction were Guggenheim Securities and Centerview Partners, with Ropes & Gray LLP acting as its legal advisor. J.P. Morgan Securities and Evercore served as Medivation’s financial advisors, while Cooley LLP and Wachtell, Lipton, Rosen & Katz served as its legal advisors.

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20 Chapter 6. Medivation CHAPTER 7

Moderna Therapeutics

7.1 Introduction

From wiki Moderna Therapeutics is a biotechnology company that researches and develops protein therapies based on novel messenger RNA (mRNA) technology.[3] The company’s technology uses mRNA made of nucleotide analogs to trigger the body’s natural processes to produce proteins inside the human cell.[4] This approach has the potential to produce therapeutic proteins in vivo to treat a wide range of diseases, including those that cannot be effectively treated with existing methods to develop and manufacture drugs.[5] Moderna’s pipeline of mRNA product candidates covers a broad expanse of drug modalities, including vaccines (both for infectious diseases and personalized cancer vaccines), intracellular/transmembrane proteins, intratumoral expres- sion, and secreted antibodies and proteins.[6] Each modality represents a distinct approach to using the mRNA plat- form to encode proteins that achieve a therapeutic benefit, enabling the company to develop numerous drug candidates across a wide array of therapeutic areas.[7] The company was founded in 2011 in Cambridge, Massachusetts through funding from Flagship Ventures.[8][9][10] Moderna’s founders include Noubar Afeyan of Flagship Ventures, Kenneth R. Chien of Harvard University and the Karolinska Institutet, Robert S. Langer of the Massachusetts Institute of Technology and Derrick Rossi of Boston Children’s Hospital.[11] Moderna is led by Stéphane Bancel, CEO and Director of the Board; Stephen Hoge, M.D., President; Marcello Damiani, Chief Digital Officer; Steve W. Harbin, SVP, Human Resources; Jim R. Kasinger, J.D., General Counsel; Lorence Kim, M.D., CFO and SVP, Business Development, and Tal Zaks, M.D., Ph.D., CMO.[12]

7.2 History

Moderna received venture capital and grant funding of $40 million from Flagship Ventures’ VentureLabs unit and other private investors by December 2012.[3][13] In March 2013, Moderna Therapeutics and AstraZeneca signed a five-year exclusive option agreement to discover, de- velop and commercialize mRNA therapeutics for the treatment of serious cardiovascular, metabolic and renal diseases as well as selected targets in oncology.[14][15] The agreement included a $240 million upfront payment to Moderna,

21 tio2 book Documentation, Release 0.0.1 a payment that is “one of the largest ever initial payments in a pharmaceutical industry licensing deal that does not involve a drug already being tested in clinical trials.”[14] In October 2013, the Defense Advanced Research Projects Agency (DARPA) awarded Moderna a grant worth up to $24.6 million to research and develop its mRNA drug technology to fight infectious diseases and biological weapons.[16][17] In November 2013, Moderna secured an additional $110M in equity financing to further develop its mRNA Thera- peutics platform as a private company.[18] In January 2014, Moderna and Alexion Pharmaceuticals entered a $125 million deal to aid in the discovery and development of messenger RNA therapeutics used to treat rare diseases. Alex- ion paid Moderna $100 million exchange for 10 product options to develop rare-disease drugs using Moderna’s mRNA Therapeutics platform, and also made another $25 million preferred equity investment in Moderna.[19] In June 2014, CNBC recognized Moderna as one of the top 50 companies whose innovations are having a dramatic impact across their industries, and are poised for hyper-growth.[20] In October 2014, Moderna announced a strategic research and clinical partnership with Karolinska Institutet and Karolinska University Hospital, and established Moderna Therapeutics Sweden in Stockholm as its first expansion outside the U.S.[21] At the beginning of January 2015, Moderna announced that it had raised $450 million in new funding to support further expansion of its mRNA Therapeutics platform across multiple modalities and therapeutic areas. As of this announce- ment, Moderna had secured $950 million in funding through financing activities and commercial partnerships.[22] On January 8, 2015, Moderna launched Valera, a venture focused exclusively on the advancement of vaccines and therapeutics for the prevention and treatment of viral, bacterial and parasitic infectious diseases.[23] Also in January 2015, Moderna announced a license and collaboration agreement with Merck for the discovery and development of vaccines and passive immunity treatments against viral diseases using modified messenger RNA (mRNA). Merck made an upfront cash payment to Moderna of $50 million to commercialize five product candidates, as well as a $50 million equity investment in Moderna.[24] In May 2015, Moderna launched Elpidera, a venture focused exclusively on developing messenger RNA (mRNA) based medicines for the treatment of rare diseases.[25] Also in May 2015, CNBC recognized Moderna the #1 Disruptor on its third-annual CNBC Disruptor 50 list.[26] On October 22, 2015, Moderna launched its fourth venture, Caperna, focused exclusively on the advancement of personalized cancer vaccines.[27]

7.3 Research

In September 2013 Moderna co-founder Kenneth Chien served as senior author to a study published in Nature Biotech- nology, which showed that Moderna’s messenger RNA therapeutics platform induced in vivo production of proteins to stimulate blood vessel growth, repair damaged heart tissue, and improve outcomes in a mouse model of myocardial infarction.[28][29][30][31] Researchers injected mice with a single dose of VEGF-A-coded messenger RNA in the heart shortly following myocardial infarction to trigger production of the VEGF-A protein.[28] Researchers found that “the presence of VEGF-A caused progenitor cells in the heart that would normally become scar tissue follow- ing a myocardial infarction to become vascular tissue.”[29] Mice injected with messenger RNA went on to generate new cardiovascular cells and show improvements on measures of cardiac function and survival when compared with controls.[28][31]

7.4 2015 DISRUPTOR 50

Founders: Noubar Afeyan, Robert Langer, Kenneth Chien, Derrick Rossi Date launched: 2011 Funding: $1 billion Industries disrupted: Pharmaceuticals, biotechnology

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Imagine helping the human body make the medicine it needs to cure a disease. That’s what Moderna Therapeutics is setting out to do. The Cambridge, Massachusetts-based company, founded by a team steeped in the fields of medicine and biology, uses messenger RNA—or mRNA—to give the body’s cells the instructions, or code, they need to create the proteins and antibodies to fight all kinds of diseases, from diabetes and heart disease to certain cancers. One of the chief advantages that Moderna has over other early-stage biotech companies is that its mRNA can focus on fighting multiple diseases at once rather than the typical and time-consuming path of defining and creating a drug therapy for each individual disease. The company already has 45 preclinical programs under way in cardiovascular disease, oncology and other areas and expects to be in clinical trials testing drugs and vaccines for a variety of therapeutic areas within the next two years. Investors—and partners—find this incredibly attractive. The company recently raised an additional $500 million in equity financing and signed pharma giant Merck as a strategic partner to help develop treatment for viral diseases. This adds to Moderna’s existing strategic relationships with AstraZeneca for cardiovascular disease; Alexion for rare diseases, such as life-threatening blood disorders; and the government’s Defense Advanced Research Projects Agency (DARPA) for biodefense. Stéphane Bancel, president and founding CEO, Moderna Therapeutics Source: Moderna Therapeutics Stéphane Bancel, president and founding CEO, Moderna Therapeutics “We are advancing a platform with widespread reach across multiple therapeutic areas and modalities. The broad potential impact of our technology compelled us to rethink how biotech companies develop drugs.” -Stéphane Bancel, CEO of Moderna Therapeutics

7.5 A ‘Moderna’ Cinderella Story: AstraZeneca’s $240M Up Front Share

By Randy Osborne Moderna Therapeutics Inc.’s major win, in the form of a $240 million up-front licensing deal with battered As- traZeneca plc for technology still at the preclinical stage, put the spotlight on messenger RNA therapy (mRNA) and sparked guesswork about whether the wager by the pharma giant can bring enough revenue soon enough. “They wanted a piece of the action, and they wanted a big piece,” Stephane Bancel, president and founding CEO of Moderna, told BioWorld Today. Under the terms, London-based AstraZeneca gets exclusive access to select any target of its choice in cardiometabolic diseases, as well as selected targets in oncology, over a period of up to five years, and Moderna, of Cambridge, Mass., could get as much as $180 million more if three unspecified technical milestones are reached. AstraZeneca has the option to pick as many as 40 drug products for clinical development, and Moderna stands to gain milestone payments related to clinical and commercial progress, along with royalties on drug sales ranging from high single digits to low double digits for each product. Trials and commercialization of therapeutics will be AstraZeneca’s job, and Moderna will be responsible for designing and manufacturing the mRNA against selected targets. Beset by trial failures and facing the patent cliff, AstraZeneca needs the kind of help that Moderna may be able to provide relatively quickly. The firm’s mRNA drugs, intended to trigger cells to make therapeutic proteins without causing an immune response, “enable [developers] to go after new drug targets that are not druggable today, using either small or large molecules,” Bancel said. “This is something very exciting, especially when you think about cardiology, where AstraZeneca is very strong.” The time from target identification to trials is shortened greatly by the approach. “Your body makes proteins like the Amgen plant or the Genzyme plant makes proteins in tanks,” Bancel said, and the method is much less expensive than recombinant proteins. AstraZeneca has other bets. Phase III programs are under way with lesinurad (an inhibitor of the URAT1 transporter in the kidney for gout), olaparib (a PARP inhibitor for BRCA1/BRCA2-mutant ovarian cancer) and selumetinib (a

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MEK inhibitor for lung cancer), all of which look promising to Leerink Swann analyst Seamus Fernandez, he wrote in a research report. The company could file for approval of olaparib in Europe this year, based on subset analyses that regulators there may find acceptable. “When asked about fostamatinib (a SYK inhibitor for rheumatoid arthritis), management conviction was less clear to us,” Fernandez wrote. Deal Shows Pharma’s Willingness to Risk Earlier this week, AstraZeneca said it would cut the payroll by 1 ,600 employees and relocate 2,500 jobs, for a one-time restructuring tab of $1 .4 billion, along with a $500 million capital investment in Cambridge, UK. The company aims to save about $190 million per year, though even that will not be sufficient if R&D does not pan out. Revenues dropped last year and will sink more this year, AstraZeneca has said, due largely because patents have expired and continue to do so in territories around the globe for such stars as Seroquel IR (quetiapine fumarate), Atacand (candesartan cilexetil), Nexium (esomeprazole magnesium delayed-release capsules) and Merrem (meropenem). (See BioWorld Today, March 19, 2013.) In the U.S., patents for proton pump inhibitor Nexium – viewed as particularly important for AstraZeneca – start expiring in 2014. Generics drugmaker Ranbaxy Inc. has gained tentative FDA approval for its version, and others are formulating theirs. For Seroquel, the depression drug that sold more than $4 billion last year, the challenge comes from Teva Pharmaceutical Industries Ltd. “It’s a complete open door now, in mRNA technology,” said Ingmar Hoerr, CEO of Tuebingen, Germany-based Cure- Vac GmbH, reacting to the AstraZeneca deal with Moderna. The speed, efficiency and lower cost of mRNA likely will now come to the attention of other pharma firms, he said. “In regard to speed, it’s the same for us – this is not a problem,” Hoerr told BioWorld Today, adding that “how you get access to targets is just a strategic topic. There are lots of different possibilities. You can just screen what is off patent, just take it, or you can license [your technology] to existing targets, or do your own screening. We already have more than 2,000 different RNA constructs encoding for 2,000 different proteins expressed in cells.” Hoerr likened the mRNA route as a way to “reinvent the gene therapy approach from the 1990s and make it much safer. Messenger RNA was, for a long time, a forgotten biomolecule. Everybody was jumping on proteins or antibodies. I think it’s quite natural that everybody now has begun to explore this new approach.” The AstraZeneca-Moderna deal is likely the largest up-front payment awarded in a preclinical, purely licensing deal on record. Some likened it to the deals in 2010 and 2011 between Abbott and Reata Pharmaceuticals Inc., but that arrangement was structured more like a joint venture. Others compared it to the 2007 agreement between Roche AG and Alnylam Pharmaceuticals Inc., but that one involved an equity stake. (See BioWorld Today, July 10, 2007, Sept. 24, 2010, and Dec. 13, 2011.) Hoerr said AstraZeneca’s move shows “how far they want to take risks right now. It’s quite good news. The vision is very strong.”

24 Chapter 7. Moderna Therapeutics CHAPTER 8

Genentech

8.1 A History of Firsts

Genentech was founded in 1976 by venture capitalist Robert A. Swanson and biochemist Dr. Herbert W. Boyer. In the early 1970s, Boyer and geneticist Stanley Cohen pioneered a new scientific field called recombinant DNA technology. After hearing about Boyer and Cohen’s breakthrough, Swanson placed a call to Boyer and requested a meeting. Boyer agreed to give the young entrepreneur 10 minutes of his time. Swanson’s enthusiasm for the technology and his faith in its commercial viability was contagious, and the meeting extended from 10 minutes to three hours; by its conclusion, Genentech was born. Though Swanson and Boyer faced skepticism from both the academic and business communities, they forged ahead with their idea. Within a few short years, they successfully demonstrated the viability of using recombinant DNA technology to develop products with practical applications and, in so doing, launched a whole new industry. 1976 Robert Swanson and Dr. Herbert Boyer founded Genentech on April 7. 1977 Genentech produced the first human protein (somatostatin) in a microorganism (E. coli bacteria). 1978 Human insulin cloned by Genentech scientists. 1979 Human growth hormone cloned by Genentech scientists. 1980 Genentech went public and raised $35 million with an offering that leapt from $35 a share to a high of $88 after less than an hour on the market. The event was one of the largest stock run-ups ever. 1982 First recombinant DNA drug marketed: human insulin (licensed to Eli Lilly and Company).

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1984 First laboratory production of Factor VIII, a clotting factor for bleeding in hemophiliacs. Genentech announced agreement to grant license of worldwide production and marketing of Factor VIII to Cutter Biological. 1985 Genentech received approval from the U.S. Food and Drug Administration (FDA) to market its first prod- uct, Protropin (somatrem for injection) growth hormone for children with growth hormone deficiency the first recombinant pharmaceutical product to be manufactured and marketed by a biotechnology company. 1986 Genentech’s interferon alpha-2a licensed to Hoffmann-La Roche, Inc. as Roferon -A received approval from the FDA for the treatment of hairy cell leukemia. Genentech instituted the Uninsured Patients Program, providing free growth hormone for financially needy, uninsured patients in the United States. The program was later expanded to include future products. 1987 Genentech received FDA approval to market Activase (Alteplase, recombinant), a tissue-plasminogen activator (t-PA), to dissolve blood clots in patients with acute myocardial infarction (heart attack). 1989 Genentech opened its day-care center, Genentech’s Second Generation, one of the largest corporate- sponsored day-care centers in the United States at the time. 1990 Roche Holding Ltd. of Basel, Switzerland acquires a majority holding in Genentech. Genentech’s Hep- atitis B vaccine licensed to SmithKline Beecham Biologicals S.A. received FDA approval. Genentech received FDA approval to market Activase for the management of acute massive pulmonary embolism (blood clots in the lungs). 1992 Genentech opened the Founders Research Center, dedicated to founders Robert Swanson and Dr. Herbert Boyer in appreciation of their vision and determination to pursue the promise of biotechnology. 1993 Genentech received FDA approval to market Nutropin [somatropin (rDNA origin) for injection] for treat- ing growth failure in children with chronic renal insufficiency before they undergo kidney transplantation. Genentech received approval to market Pulmozyme (dornase alfa) for treating cystic fibrosis from regula- tory agencies in the United States, Canada, Sweden, Austria and New Zealand. Genentech’s Factor VIII licensed to Miles Inc. (formerly Cutter Biological) in 1984 received FDA approval for the treatment of hemophilia-A. 1994 Genentech announced it would locate its new manufacturing facility in Vacaville, California. Genen- tech received FDA approval to market Nutropin for the treatment of children with growth failure due to inadequate levels of the natural growth hormone in their bodies. 1995 Genentech announced an agreement with Roche Holding, Ltd. to extend for four years Roche’s option to purchase the outstanding redeemable common stock of the company at a predetermined price that esca- lates quarterly up to $82.50 a share. As part of the agreement, Genentech began receiving royalties rather than recording sales on European sales of Pulmozyme and Canadian sales of all Genentech products as

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Roche assumed responsibility for those sales. Genentech received FDA approval to market an accelerated infusion regimen of Activase for the management of acute myocardial infarction. 1996 Genentech celebrated the 20-year anniversary of its founding. Genentech received FDA approval to mar- ket Nutropin AQ [somatropin (rDNA origin) injection] for the treatment of growth failure in children with chronic renal insufficiency before they undergo kidney transplantation and for the treatment of growth hormone deficiency in children. Genentech received FDA approval to market Activase for the treatment of acute ischemic stroke or brain attack. Genentech received FDA approval to market Pulmozyme for treating cystic fibrosis patients with advanced disease. 1997 Genentech and partner IDEC Pharmaceuticals (now Biogen Idec Inc.) received FDA approval to market Rituxan (Rituximab) for the treatment of patients with relapsed or refractory low-grade or follicular, CD20 positive, B-cell non-Hodgkins lymphoma. Genentech received FDA approval to market Nutropin AQ for the treatment of short stature associated with Turner syndrome. Genentech received FDA approval to market Nutropin and Nutropin AQ for the treatment of growth hormone deficiency in adults. Genentech launched a service for patients and their physicians called SPOC Single Point of Contact to provide customer-focused reimbursement assistance. The program became Genentech Access Solutions in 2008. In recognition of the importance of Genentech in establishing the biotechnology industry in South San Francisco, the city renamed the 400 block of Point San Bruno Boulevard to DNA Way, giving Genentech the new street address 1 DNA Way. 1998 Genentech received approval from the FDA to market the humanized antibody Herceptin (Trastuzumab) as a first-line therapy in combination with paclitaxel and as a single agent in second- and third-line therapy for patients with metastatic breast cancer who have tumors that overexpress the HER2 (human epidermal growth factor receptor2) protein. Genentech dedicated its new $250 million manufacturing facility in Vacaville. 1999 Genentech co-founder Robert Swanson was awarded (posthumously) the National Medal of Technology for his foresight and leadership in recognizing the commercial promise of recombinant DNA technology and his seminal role in the establishment and development of the biotechnology industry. Genentech reached a settlement agreement with the U.S. Attorney for the Northern District of California regarding Genentech’s promotion of human growth hormone in the late 1980s and early 1990s. Roche exercised its option to cause Genentech to redeem all of its outstanding special common shares not owned by Roche. Roche announced its intent to publicly sell up to 19 percent of Genentech shares and continue Genentech as a publicly traded company with independent directors. Genentech received FDA approval of additional efficacy results for its growth hormone products — Nutropin and Nutropin AQ — on the effects of growth hormone replacement therapy on spine bone mineral density in young adults with childhood-onset growth hormone deficiency (GHD). On July 20, after about a month-long hiatus due to the Roche redemption, Genentech returned to the New York Stock Exchange (NYSE) with a public reoffering of 22 million shares by Roche, in what is considered the largest public offering in the history of the U.S. healthcare industry. The stock closed the first day of trading at $127, over 31 percent above the public offering price of $97. This was also the first introduction of Genentech’s new NYSE trading symbol, DNA. Roche conducted a secondary offering of 20 million Genentech shares on October 20. The shares were priced at $143.50 per share, making it the largest secondary offering in U.S. history. Genentech and the University of California (UC) agreed to a settlement of the patent infringement lawsuit brought by UC relating to the company’s human growth hormone product, Protropin. Both parties agreed that this settlement was not an admission that Genentech infringed UC’s patent or used the genetic material in question. Genentech and partner Alkermes, Inc. received FDA approval to market Nutropin Depot [somatropin (rDNA origin) for injectable suspension] for the long-term treatment of growth failure due to a lack of adequate endogenous GH secretion.

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2000 Roche conducted a third offering of up to 19 million shares of Genentech stock at $163 per share. Genen- tech announced the purchase of a cell culture manufacturing facility in Porriño, Spain. Genentech sold the facility to Lonza in 2006. Genentech’s state-of-the-art manufacturing facility in Vacaville, Califor- nia, received FDA licensure as a multi-product facility. Genentech received FDA approval of TNKase (Tenecteplase), a modified form of t-PA, for use in mortality reduction associated with acute myocardial infarction (AMI), or heart attack; treatment should be initiated as soon as possible after the onset of AMI symptoms. 2001 Genentech celebrated the 25th anniversary of its founding. Cathflo Activase (Alteplase) was approved by the FDA for the restoration of function to central venous access devices (CVADs). 2002 The FDA approved Nutropin AQ PEN for delivery of Nutropin AQ recombinant growth hormone. A Los Angeles County Superior Court jury voted to award the City of Hope (COH) $300 million in additional royalties and $200 million in punitive damages in the retrial of a contract dispute lawsuit brought by COH against Genentech. Genentech announced it would appeal the judgment in the case to the California Court of Appeal. Genentech received FDA approval to include HER2 gene detection test in Herceptin product labeling. 2003 Genentech received FDA approval for Xolair (Omalizumab) for Subcutaneous Use in adults and ado- lescents (age 12 or older) with moderate-to-severe persistent asthma who have a positive skin test or in vitro reactivity to a perennial aeroallergen and whose symptoms are inadequately controlled with inhaled corticosteroids. Xolair is the first humanized therapeutic antibody for the treatment of asthma and the first approved therapy designed to target the antibody IgE, a key underlying cause of the symptoms of asthma that has an allergic component. Genentech received FDA approval for Raptiva (efalizumab) for the treatment of chronic moderate-to-severe plaque psoriasis in adults age 18 or older who are candidates for systemic therapy or phototherapy. In April 2009, Genentech announced the voluntary withdrawal from the U.S. market of Raptiva. 2004 Genentech received FDA approval for Avastin (bevacizumab) for use in combination with 5-Fluorourcil- based chemotherapy in the treatment of first-line metastatic cancer of the colon or rectum. Avastin is the first FDA-approved therapy designed to inhibit angiogenesis, a process fundamental to cancer growth and metastasis. Genentech broke ground on an expansion of the Vacaville site. When completed, the new facility will be configured with an additional eight 25,000-liter fermentation tanks and, when com- bined with our existing facility, will be the largest biotechnology cell culture manufacturing site of its kind in the world. OSI Pharmaceuticals and Genentech announced that the FDA approved, after priority review, Tarceva (erlotinib) for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least one prior chemotherapy regimen. Tarceva is an oral tablet indicated for daily administration. 2005 Genentech purchased Biogen Idec’s Oceanside, California, biologics manufacturing facility. Genentech received FDA approval for Tarceva (100 mg) in combination with gemcitabine chemotherapy for the treatment of locally advanced, inoperable or metastatic pancreatic cancer in patients who have not received previous chemotherapy. 2006 Genentech celebrated the 30th anniversary of its founding. Genentech received approval from the FDA for Lucentis (ranibizumab injection) for the treatment of neovascular (wet) age-related macular degen-

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eration. Genentech received FDA approval for Rituxan for use in combination with methotrexate for the treatment of adult patients with moderately- to severely-active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies. Genentech received FDA approval for Herceptin as part of a treatment regimen containing doxorubicin, cyclophosphamide and paclitaxel, for the adjuvant treatment of patients with HER 2-positive, node-positive breast cancer. Genentech received FDA approval for Avastin in combination with carboplatin and paclitaxel for the first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic non-squamous NSCLC. Genentech and Lonza finalized an agreement for Lonza to purchase Genentech’s manufacturing facility in Porriño and to continue to supply Avastin for Genentech under a supply agreement. Concurrently, Genentech entered into a supply agreement for the manufacture of certain Genentech products at Lonza’s facility currently under construction in Singapore, with the right to exercise an exclusive option to purchase the facility between 2007 and 2012. 2007 Genentech finalized its acquisition of Tanox, enabling Genentech to improve the Xolair business and acquire Tanox’s product pipeline. 2008 In January 2008, Genentech received FDA approval for Herceptin (Trastuzumab) as a single agent, for the adjuvant treatment of HER2-overexpressing node-negative (ER/PR-negative or with one high risk fea- ture) or node-positive breast cancer, following multi-modality anthracycline-based therapy. In February 2008, Genentech received accelerated approval from the FDA for Avastin (bevacizumab), in combination with paclitaxel chemotherapy, for the treatment of patients who have not received chemotherapy for their metastatic HER2-negative breast cancer. In April 2008, The California Supreme Court overturned the award of $200 million in punitive damages resulting from the contract dispute lawsuit brought by City of Hope against Genentech. In May 2008, Genentech received FDA approval for Herceptin (trastuzumab) as part of a treatment regimen containing doxorubicin, cyclophosphamide, and docetaxel, and also as part of another regimen containing docetaxel and carboplatin, for the adjuvant treatment of HER2 overexpress- ing, node-positive, or high-risk node-negative breast cancer. In July 2008, Genentech received a proposal from Roche to acquire all of the outstanding shares of Genentech stock not owned by Roche. 2009 In March 2009, Roche and Genentech announced that they have signed a merger agreement under which Roche will acquire the outstanding publicly held interest in Genentech for US$95.00 per share in cash, or a total payment of approximately US$46.8 billion to equity holders of Genentech other than Roche. In May 2009, Genentech received accelerated approval by the FDA for Avastin (bevacizumab) for people with glioblastoma with progressive disease following prior therapy. In August 2009, Genentech received FDA approval for Avastin (bevacizumab) plus interferon-alfa for people with metastatic renal cell carcinoma, the most common type of kidney cancer. 2010 In January 2010, Genentech received FDA approval for Actemra (tocilizumab) to treat adults with moder- ately to severely active rheumatoid arthritis (RA) after at least one other medicine called a tumor necrosis factor (TNF) antagonist has been used and did not work well. In February 2012. Genentech received FDA approval for Rituxan (Rituximab) in combination with fludarabine and cyclophosphamide (FC) for peo- ple with previously untreated and previously treated CD20-positive chronic lymphocytic leukemia (CLL). In April 2010, Genentech received FDA approval for Tarceva (erlotinib) as a maintenance treatment for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. In June 2010, Genentech received FDA approval for Lucentis (ranibizumab injection) for the treatment of macular edema following reti- nal vein occlusion (RVO). In June 2010, Richard Scheller, Ph.D., Executive Vice President, Research and Early Development (gRED), won the 2010 Kavli Prize in Neuroscience, awarded for outstanding achievement in advancing our knowledge and understanding of the brain and nervous system. In August 2010, Genentech received FDA approval for longer use of Valcyte (valganciclovir hydrochloride) in adult

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kidney transplant patients at high risk for cytomegalovirus (CMV) disease. In October 2010, Genentech received FDA approval for Herceptin (Trastuzumab) was approved, in combination with cisplatin and capecitabine or 5-fluorouracil, for the treatment of patients with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic dis- ease. In October 2010, Genentech launched Faces of MBC, to raise awareness about metastatic breast cancer and help support those living with the disease 2010 marks the 25th anniversary of Genentech’s first product approval. 25 years ago, on October 18, 1985, Genentech received FDA approval to market its first product, a growth hormone for children with growth hormone deficiency. It was the first recombi- nant biotech drug to be manufactured and marketed by a biotechnology company. 2011 Genentech celebrated the 35th anniversary of its founding. In January 2011, Genentech received FDA approval Actemra (tocilizumab) for inhibition and slowing of structural joint damage, improvement of physical function, and achievement of major clinical response in adult patients with moderately to severely active rheumatoid arthritis (RA), when given in combination with methotrexate (MTX). In January 2011, Genentech received FDA approval Rituxan (rituximab) as a maintenance treatment for patients with ad- vanced follicular lymphoma who responded to initial treatment with Rituxan plus chemotherapy (in- duction treatment). In April 2011, Genentech received FDA approval ACTEMRA (tocilizumab) for the treatment of active Systemic Juvenile Idiopathic Arthritis (SJIA) in patients two years of age and older. In April 2011, Genentech received FDA approval Rituxan (rituximab), in combination with corticosteroids, as a new medicine for adults with Wegener’s Granulomatosis (WG) and Microscopic Polyangiitis (MPA). In August 2011, Genentech received FDA approval for Zelboraf (vemurafenib) for the treatment of BRAF V600E mutation-positive, inoperable or metastatic melanoma, as determined by an FDA-approved test. In November 2011, the FDA revoked approval of Avastin (bevacizumab) for treatment of metastatic breast cancer (mBC) in the United States. 2012 In January 2012, Genentech received FDA approval for Erivedge (vismodegib) for the treatment of adults with a type of skin cancer, called basal cell carcinoma (BCC), that has spread to other parts of the body or that has come back after surgery or that their healthcare provider decides cannot be treated with surgery or radiation. In May 2012, Genentech launched Faces of Skin Cancer, to learn more about and better support the advanced skin cancer community. In June 2012, Genentech received FDA approval for Perjeta (pertuzumab) in combination with Herceptin (trastuzumab) and docetaxel chemotherapy for the treatment of people with HER2-positive metastatic breast cancer (mBC) who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. In August 2012, Genentech received FDA approval for Lucentis (ranibizumab injection) for treatment of diabetic macular edema (DME), an eye condition in people with diabetes that causes blurred vision, severe vision loss and sometimes blindness. In September 2012, Genentech launched the Lung Cancer Project. The Lung Cancer Project aims to determine if subconscious biases exist for lung cancer, and if so, to understand why people are biased, how those biases impact lung cancer care and to address misperceptions of lung cancer. In October 2012, Genentech received FDA approval for Actemra (tocilizumab) for the treatment of adults with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response to one or more disease-modifying antirheumatic drugs (DMARDs). Ian Clark was selected as the San Francisco Business Times 2012 Most Admired CEO in the Public Companies category. 2012 marked the 20th Anniversary of the Genentech Goes to Town program in South San Francisco. The program supports neighboring communities by encouraging employees to take a break from work and get to know local businesses. Genentech, the Banner Alzheimer’s Institute, and the National Institutes of Health are collaborating on the first-ever prevention trial in cognitively healthy individuals who are likely to develop Alzheimer’s disease due to their genetic history. In December 2012, Genentech received FDA approval for Tamiflu (oseltamivir phosphate) for the treatment of acute, uncomplicated influenza to include infants two weeks of age and older. The approval makes Tamiflu the only prescription oral antiviral medicine approved to treat people of all ages, from infants two weeks of age to elderly people. 2013

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Working Mother magazine named Genentech one of the “100 Best Companies for Working Mothers.” This is the 19th year Genentech has appeared on the list. Genentech was named one of the “top em- ployers in the biopharmaceutical industry” by Science magazine. This is the twelfth year Genentech has appeared on the list. We have been ranked the #1 company eight times. In January 2013, Genentech received FDA approval for Avastin (bevacizumab) in combination with fluoropyrimidine-based irinote- can or oxaliplatin chemotherapy for people with metastatic colorectal cancer (mCRC). In February 2013, Genentech received FDA approval for Kadcyla™ (ado-trastuzumab emtansine or T-DM1) for the treat- ment of people with HER2-positive metastatic breast cancer (mBC) who have received prior treatment with Herceptin (trastuzumab) and a taxane chemotherapy. Kadcyla is the fourth medicine from Genen- tech to receive FDA approval for people with advanced cancers within the past two years. In April 2013, Genentech received FDA approval for Actemra (tocilizumab) for the treatment of polyarticular juvenile idiopathic arthritis. The medicine can be used in children two years of age and older with active disease. In May 2013, Genentech received FDA approval of Tarceva (erlotinib) for the initial (first-line) treatment of people with metastatic non-small cell lung cancer whose tumors have certain epidermal growth factor receptor (EGFR) activating mutations as detected by an FDA-approved test. The FDA also approved the cobas EGFR Mutation Test, which was developed by Roche and validated in the pivotal EURTAC study. In September 2013, Richard Scheller, Ph.D., Executive Vice President, Research and Early Development (gRED), was named a winner of the 2013 Albert Lasker Basic Medical Research Award, which is given annually to a scientist whose fundamental investigations have provided techniques, information, and con- cepts contributing to the elimination of major causes of disability and death. In September 2013, the FDA granted accelerated approval for Genentech’s Perjeta (pertuzumab) regimen for neoadjuvant treatment (use before surgery) in people with high-risk, HER-2 positive early stage breast cancer. The Perjeta regi- men is the first neoadjuvant breast cancer treatment approved by the FDA and also the first to be approved based on pCR data. In October 2013, Genentech announced plans to invest more than $285 million for the expansion of its biologics manufacturing facilities in Vacaville and Oceanside. The Vacaville facility will become the largest producer of biologic medicines for the Roche Group, but also the largest biotech manufacturing facility in the world. In October 2013, Genentech received FDA approval for the subcuta- neous formulation of Actemra (tocilizumab) for the treatment of adults with moderately to severely active rheumatoid arthritis (RA) who have used one or more disease-modifying antirheumatic drugs (DMARDs), such as methotrexate (MTX) that did not provide enough relief. In October 24, 2013, the Smithsonian’s National Museum of American History unveiled the “Birth of Biotech” showcase display, which com- memorates breakthrough scientific discoveries and the use of genetic engineering to make medicines that improve patients’ lives. The display features more than 130 artifacts related to Genentech’s history and role in the creation of the biotechnology industry. In December 2013, Ian Clark, CEO, accepted The Economist Innovation Award on behalf of Genentech, which recognized Genentech for its impressive track record in research and scientific innovation. In November 2013, Genentech received FDA approval for Gazyva™ (obinutuzumab) in combination with chlorambucil chemotherapy for the treatment of peo- ple with previously untreated chronic lymphocytic leukemia. Gazyva is the first medicine approved with the FDA’s Breakthrough Therapy Designation and the fifth cancer medicine from Genentech approved by the FDA in the past three years. 2014 FORTUNE named Genentech one of the “100 Best Companies to Work For” for the 16th consecutive year. In March 2014, Genentech received FDA approval for Xolair (omalizumab) for the treatment of chronic idiopathic urticaria (CIU), a form of chronic hives. The new use is for people 12 years of age and older who remain symptomatic despite treatment with H1-antihistamine therapy.

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32 Chapter 8. Genentech CHAPTER 9

juno therapeutics

Juno Therapeutics is a biopharmaceutical company founded in 2013 through a collaboration of the Fred Hutchinson Cancer Research Center, Memorial Sloan-Kettering Cancer Center and pediatrics partner Seattle Children’s Research Institute. The company was launched with an initial investment of $120 million, with a remit to develop a pipeline of cancer immunotherapy drugs.[2] The company raised $300 million through private funding and a further $265 million through their IPO.

9.1 Company History

In December 2014 the company signed an agreement with Opus Bio, Inc for a chimeric antigen receptor (CAR-T) cell product candidate targeting CD22.[3] In April 2015 the company entered into a collaboration with MedImmune (a subsidiary of Astra Zeneca) investigating combination treatments for cancer. The trials will assess combinations of MEDI4736 and one of Juno’s CD19 directed chimeric antigen receptor T cell candidates.[4] In May 2015, the company announced its intention to acquire Stage Cell Therapeutics for up to $223 million.[5] Later in the same month the company launched a collaboration, with Editas Medicine, to create CAR-T and high-affinity T cell receptor therapies to treat cancer, with the potential to generate up to $737 million-plus for Editas.[6] In June, the company announced it would acquire X-Body for more than $44 million.[7] In June, the company announced a 10-year partnership with Celgene valued at $1 billion.[8] As part of the deal Celgene will pay Juno $150 million and acquire 9.1 million new Juno shares (valued at $93, existing Juno shares rose 26% to $58.38). Celgene will gain the right to sell Juno’s therapies around the world. This partnership surpasses the previous highest record when Pfizer agreed to a deal with Merck KGaA in 2014.[9] In January 2016 Juno announced it had acquired AbVitro, allowing it to use next-generation single cell sequencing platforms to complement its ability to create T cells engineered to target a broad array of cancer targets.[10] Later in July of the same year, the company announced it would acquire RedoxTherapies for $10 million.[11] In August the company announced it would license rights from Memorial Sloan Kettering Cancer Center and Eureka Therapeutics for a novel, fully human binding domain targeting B-cell maturation antigen.

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34 Chapter 9. juno therapeutics CHAPTER 10

Vertex Pharmaceuticals

Vertex Pharmaceuticals is an American Pharmaceutical company based in Boston, Massachusetts. Vertex was founded in 1989 by Joshua Boger[2] and Kevin J. Kinsella.[3] Vertex was one of the first biotech firms to use an explicit strategy of rational drug design rather than combinatorial chemistry. By 2004, its product pipeline focused on viral infections, inflammatory and autoimmune disorders, and cancer. It maintains headquarters in South Boston, Massachusetts, and two research facilities, in San Diego, California, and Oxford, England. The company’s beginnings were profiled by Barry Werth in the 1994 book The Billion-Dollar Molecule[3] and its further development in his 2014 book, The Antidote: Inside the World of New Pharma.[4] In 2009, the company had about 1,800 employees, including 1,200 in the Boston area.[2] In January 2014, Vertex completed its move from Cambridge, Massachusetts to Boston, Massachusetts, and took residence in a new, $800 million complex. Located on the South Boston waterfront, it will mark the first time in the company’s history that all of the roughly 1,200 Vertex employees in the Greater Boston area will be working together. Since late 2011, when Jeffrey M. Leiden joined Vertex as CEO, Vertex has ranked among the top 15 best performing companies on the Standard & Poor’s 500. Vertex shares increased 250 percent in the same period.[5] Vertex posted only one annual profit since it was founded in 1989.[5]

10.1 Vertex story

Vertex Pharmaceuticals (NASDAQ:VRTX) is a rare biotech success story. Started in 1989 by chemist Joshua Boger, the company was fueled for many years by three key ingredients: a unique approach to drug discovery, the tenacious dedication of a small group of scientists, and an ambitious long-term vision. It took decades for Vertex to translate its research and development efforts into FDA approved products. Investors who were early believers in the biotech’s mission and willing to take on risk, however, have been rewarded for their patience; shares are up more than 1,760% since the stock’s IPO in 1991. But don’t for a minute think that Vertex’s trek to commercialization was easy, or that the company is no longer facing challenges. Over more than two decades, Vertex has faced management shake-ups, suffered growing pains as it shifted its focus from drug discovery to sales and marketing, and has had to reinvent itself numerous times to stay relevant in this

35 tio2 book Documentation, Release 0.0.1 ever-changing industry. In 2011, for example, Vertex boasted the fastest drug launch in history after its hepatitis C therapeutic, Incivek, surpassed $1 billion in sales after its first year on the market. Those sales quickly eroded, however, after competitors emerged with more effective antiviral medications. Vertex was able to avoid disaster by quickly shifting its focus to its cystic fibrosis program, and shares have climbed almost 87% over the last twelve months as investors expect the company to expand its portfolio and develop more breakthrough therapies in the years to come. To gain more insight into the history of Vertex Pharmaceuticals and learn what it truly takes to create a winning business in the fiercely competitive biotech industry, Fool.com’s health-care bureau chief Max Macaluso spoke with Barry Werth, an award-winning journalist who has followed Vertex almost from the day it opened its doors. Werth’s book The Billion-Dollar Molecule, widely regarded as a must-read for passionate biotech investors, offered an inside look at Vertex soon after it was established. Earlier this month, Werth released a sequel, The Antidote: Inside the World of New Pharma, which continues the Vertex story and chronicles the company’s path from a fledgling start-up to a company with a multibillion-dollar market cap.

36 Chapter 10. Vertex Pharmaceuticals CHAPTER 11

Alnylam Pharmaceuticals

Alnylam Pharmaceuticals is a biopharmaceutical company focused on the discovery, development and commercializa- tion of RNA interference (RNAi) therapeutics for genetically defined diseases. The company was founded in 2002 and is headquartered in Cambridge, Massachusetts. In 2016, Forbes included the company on its “100 Most Innovative Growth Companies” list.

11.1 Therapeutic concept

Main article: RNA interference Most drug discovery seeks molecules which associate with a “target” associated with a disease and interfere with its function, thus remediating the disease at a molecular level. Examples include small molecule HIV protease inhibitors, which are taken orally, and via the bloodstream, make their way to cells infected with the HIV virus, and block a key enzyme, virally encoded enzyme, HIV protease, by occupying its active site, thereby refusing access of a key viral component, and preventing a key step in the HIV virus life cycle (scission of the HIV polyprotein). A different approach targets the production of a protein required for the development of the disease. RNAi was discovered to be a natural mechanism for silencing genes through cleavage and degradation of mRNA, first discovered in C. elegans in 1998 by Andrew Fire and Craig Mello.[28] Genes encode the information necessary for cells to synthesize proteins, and proteins made abnormally cause many human diseases. When a mutant gene is silenced, the cell stops making the abnormal protein specified by that gene, potentially improving the course of the disease. In 2001, Alnylam founders began using small interfering RNAs, known as siRNAs, to silence genes by targeting mRNA in mammalian cells.[29]

11.2 Products

In 2016, Alnylam Pharmaceuticals had 18 potential treatments[30] in various development stages across three Strategic Therapeutic Areas (STArs), Genetic Medicine, Cardio-Metabolic Disease and Hepatic Infectious Disease. In 2016, the company had two candidates in phase III studies, patisiran, a treatment targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR), in patients with familial amyloidotic polyneuropathy (FAP) and revusiran, for the treatment of familial amyloidotic cardiomyopathy (FAC).[31]

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11.3 Alnylam off as development of key drug discontinued

Wednesday, 5 Oct 2016 | 5:11 PM ET | 02:46 Alnylam Pharmaceuticals said on Wednesday it would halt development of an experimental therapy for a rare genetic condition that can cause heart failure, after a late-stage study showed that patients given the drug were more likely to die than patients treated with a placebo. Alnylam shares fell more than 48 percent following the announcement and ended the day at $36.21 a share. The drug, revusiran, was being developed for treating hereditary amyloidosis with cardiomyopathy, a condition in which amyloid plaque — similar to the substance found in the brains of Alzheimers’ patients — collects in organs including the heart, where it can cause heart failure. Alnylam specializes in a technology known as RNA interference (RNAi), which prevents genes from making their designated proteins. Revusiran was designed to target the gene involved in producing the abnormal protein which causes amyloidosis. Amyloidosis is diagnosed in 6 to 10 Americans per million each year, according to the American Heart Association, though it is likely underdiagnosed. Alnylam said study safety monitors recommended that the Phase III trial be suspended after patients on a previous study developed neuropathy, or nerve pain. Unblinded data subsequently “revealed an imbalance of mortality in the revusiran arm as compared to placebo.” The company said the decision does not affect its lead product patisiran, which is currently in Phase III development for treatment of amyloidosis with polyneuropathy, or any other Alnylam investigational RNAi therapeutic program. Alnylam also said current data across its other programs, including a cholesterol-lowering drug partnered with The Medicines, do not show evidence of drug-related neuropathy. Shares of The Medicines declined 8 percent to close at $35.33. Alnylam last month halted development of an earlier-stage RNAi compound after observing elevated liver enzymes in healthy volunteers.

38 Chapter 11. Alnylam Pharmaceuticals CHAPTER 12

Celgene Corporation

Celgene Corporation is an American biotechnology company that manufactures drug therapies for cancer and inflam- matory disorders. It is incorporated in Delaware and headquartered in Summit, New Jersey. The company’s major products are Thalomid (thalidomide), which is approved for the acute treatment of the cutaneous manifestations of moderate to severe erythema nodosum leprosum (“ENL”), as well as in combination with dexamethasone for patients with newly diagnosed multiple myeloma, and Revlimid (lenalidomide), for which the company has received FDA and EMA approval in combination with dexamethasone for the treatment of multiple myeloma patients who have received at least one prior therapy. Revlimid is also approved in the United States for the treatment of patients with transfusion- dependent anemia due to Low- or Intermediate-1-risk Myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities. Both Thalomid and Revlimid are sold through proprietary risk-management distribution programs to ensure safe and appropriate use of these pharma- ceuticals. Vidaza is approved for the treatment of patients with MDS. Celgene also receives royalties from Novartis Pharma AG on sales of the entire Ritalin family of drugs, which are widely used to treat Attention Deficit Hyperactivity Disorder (ADHD). Celgene Cellular Therapeutics, a subsidiary, is a public cord blood bank.

12.1 History

In 1986, Celgene, originally a unit of the Celanese Corporation, was spun off as an independent company following the merger of Celanese Corporation with American Hoechst Corporation. In July 1998, Celgene received approval from the FDA to market Thalamid for the acute treatment of the cutaneous manifestations of moderate to severe ENL. In April 2000, Celgene reached an agreement with Novartis Pharma AG to license d-MPH, Celgene’s chirally pure version of RITALIN. The FDA subsequently granted approval to market d-MPH, or Focalin, in November 2001. In August 2000, Celgene acquired Signal Pharmaceuticals, Inc., a privately held company that searches for and de- velops pharmaceuticals that regulate disease-related genes. Signal Pharmaceuticals, Inc. now operates as Celgene Research San Diego, a wholly owned subsidiary of Celgene Corporation. In December 2002, Celgene acquired Anthrogenesis, a privately held New Jersey-based biotherapeutics company and cord blood banking business, which is developing technology for the recovery of stem cells from placental tissues

39 tio2 book Documentation, Release 0.0.1 following the completion of full-term successful pregnancies. Anthrogenesis now operates as Celgene Cellular Ther- apeutics, a wholly owned subsidiary of Celgene. In December 2005, Celgene received approval from the FDA to market Revlimid for the treatment of patients with transfusion-dependent anemia due to Low- or Intermediate-1-risk MDS associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities. In May 2006, Celgene received approval for Thalamid in combination with dexamethasone for the treatment of patients with newly diagnosed multiple myeloma. In June 2007, Celgene received full marketing authorization for Revlimid in combination with dexamethasone as a treatment for patients with multiple myeloma who have received at least one prior therapy by the European Commis- sion. In March 2008, Celgene closed its $2.9 billion acquisition of Pharmion Corporation. In December 2009, Celgene announced the acquisition of Gloucester Pharmaceuticals.[4] In June 2010 Celgene Corporation and Abraxis BioScience Inc. jointly announced the signing of a definitive merger agreement in which Celgene has agreed to acquire Abraxis BioScience.[5] In 2010 Celgene looked to relocate its UK headquarters from Riverside House in Windsor to a new development Stockley Park, Uxbridge.[6] In January 2012, Celgene and Avila Therapeutics, Inc., a privately held biotechnology company developing targeted covalent drugs that treat diseases through protein silencing, announced a definitive merger agreement under which Celgene Corporation will acquire Avila Therapeutics, Inc. Under the terms of the merger agreement, Celgene will acquire Avila Therapeutics, Inc. for $350 million in cash, plus up to $195 million for milestones contingent upon the development and regulatory approval of AVL-292, as well as up to $380 million in potential milestone payments contingent upon the development and approval of candidates generated from the Avilomics platform.[7] Citing a market capitalization of US$67 billion, and stock appreciation of 107%, Celgene was Forbes Magazine’s number 2 ranked drug company of 2013.[8] In 2014, Celgene and OncoMed Pharmaceuticals entered into a cancer stem cell therapeutic development agreement encompasing demcizumab and five other biologics from OnoMed’s pipeline.[9] Also in 2014, Sutro Biopharma entered into a strategic collaboration and option agreement with Celgene Corporation to discover and develop multispecific antibodies and antibody drug conjugates (ADCs). This new agreement follows the December 2012 collaboration between the two companies and focuses on the field of immuno-oncology, while fur- ther broadening the Sutro platform for discovery, development, and manufacture of best-in-class biotherapeutics.[10] In April 2015, Celgene announced it would commence a collaboration with Astrazeneca, worth $450 million, studying their Phase III immuno-oncology drug candidate MEDI4736.[11] Later in the same month Celgene announced it would acquire Quanticel for up to $485 million aimed at enhancing their cancer drug pipeline through Quanticels epigenetic modifier targeting applications.[12] In June 2015 Celgene announced it had licensed Lyceras RORgamma agonist portfolio for up to $105 million and continue to develop its Phase I lead compound LYC-30937 for the treatment of inflammatory bowel disease. The licensing opportunity gives Celgene the option to acquire Lycera.[13] In July 2015, the company announced it would acquire Receptos for $7.2 billion in a move to strengthen the company’s inflammation and immunology areas.[14] News of the deal sent Celgene shares up 5.7% in after hours trading. In May 2016, the company announced it would launch partnership with Agios Pharmaceuticals, developing metabolic immuno-oncology therapies. The deal could net more than $1 billion for Agios.

40 Chapter 12. Celgene Corporation CHAPTER 13

Foundation Medicine

Foundation Medicine, Inc. is an American company based in Cambridge, Massachusetts which develops, manufac- tures, and sells genomic profiling assays based on next-generation sequencing technology for solid tumors, hemato- logic malignancies, and sarcomas.[1]

13.1 History

Foundation Medicine was founded in Cambridge, Massachusetts. The company was conceived after Broad Institute researchers Levi Garraway and Matthew Meyerson published a 2007 paper detailing a method for large-panel testing of 238 DNA mutations. Foundation Medicine launched in 2010 with a $25 million Series A financing led by Third Rock Ventures. The com- pany released its first commercial assay, or test, called FoundationOne in 2012. The company also began partnering with pharmaceutical companies to analyze patient samples. The first such program was piloted with Novartis in 2011, and by 2018, the company had more than 30 partnerships. Foundation Medicine launched its second test, a hematological biomarker assay called FoundationOneHeme, in 2013. The company held its initial public offering in August 2013. The following year, Priority Health in Michigan became the first healthcare plan in the United States to cover the company’s tests. In 2016, using FoundationCore data, Foundation Medicine released anonymized records detailing genomic data on cancers from 18,000 adult patients to the National Cancer Institute’s (NCI) Genomic Data Commons (GDC) portal. In June, 2018, Roche announced it would acquire Foundation Medicine.

13.2 Products

Foundation Medicine’s products include genomic tests used to test solid tumors and blood-based cancers and sarcomas, as well as data services. FoundationOne CDx is a CGP test providing information for five tumor types: ovarian, lung, breast, colorectal, and melanoma.

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FoundationOne Liquid FoundationOne Heme The company’s FoundationCore database contains more than 300,000 genomic profiles sourced from the results of the company’s assays as well as information on over 150 subtypes of cancer.

42 Chapter 13. Foundation Medicine CHAPTER 14

Grail

14.1 Grail files for $100M IPO ahead of 2021 launch of multi-cancer liquid biopsy

[The artical link](https://www.medtechdive.com/news/grail-files-for-100m-ipo-ahead-of-2021-launch-of-multi-cancer-liquid-biops/ 584906/) 1. Grail on Wednesday filed with the U.S. Securities and Exchange Commission to raise up to $100 million in an initial public offering ahead of the anticipated launch of its multi-cancer liquid biopsy screening test for use in asymptomatic individuals. 2. The Illumina spinout expects to launch the product, Galleri, as a lab developed test (LDT) in 2021. Based on data generated to date, Grail estimates screening people aged 50 years and older using Galleri could avert 39% of deaths from cancers that would otherwise kill within five years. 3. Grail’s SEC filing acknowledges that getting insurers’ support for asymptomatic screening could be challenging. Yet, with $686 million in the bank as of June 30 and more to come from the IPO, the company believes it has the resources to ride out near-term challenges and establish itself as a force in the nascent liquid biopsy market. Dive Insight: Grail spun out of genome sequencing giant Illumina at the start of 2016 with the support of backers including ARCH Venture Partners, Bezos Expeditions and Bill Gates. Over the next few years, Grail raised a series of big financing rounds to fund a huge R&D program that saw it enroll 115,000 people across its foundational studies, with IPO rumors swirling along the way. While other liquid biopsy startups focused on detecting a single cancer, Grail set out to create a single test that screens for tens of tumors. The work has now advanced to the point that Grail is gearing up for commercialization. If all goes to plan, the company will introduce Galleri and a test to “accelerate diagnostic resolution for patients for whom there is a clinical suspicion of cancer” first as LDTs next year before seeking FDA approval in 2023. After bringing Galleri to market, Grail will push for the test’s integration into the management of the 40 million patients who already visit their physicians for standard-of-care cancer screening. Grail is pitching the test as a way to detect cancers earlier and, in doing so, reduce morbidity, mortality and costs associated with late-stage diagnoses. Yet, the risk of false positives could mean Grail faces pushback from insurers hesitant to back the cost of additional diagnostic workup, the company outlined in its preliminary prospectus. Grail will try to counter those concerns

43 tio2 book Documentation, Release 0.0.1 with evidence of the value of its test, pointing to modeling that suggests Galleri may “detect nearly 70% of cancers resulting in death within five years at an earlier stage.” That would translate into the aversion of 39% of otherwise expected deaths. Grail’s calculations are based on a study in which Galleri detected more than 50 cancers, including more than 45 types that are not explictly recommended for screening today. The study linked Galleri to a positive predictive value of 43% and found it would yield 7,000 false positives per million tests. That compares favorably to existing single-cancer screening tests such as mammograms. Researchers at Grail achieved that level of performance by zeroing in on methylation patterns that indicate the presence and location of a cancer. Further work led to a targeted approach, eliminating the need to perform costly whole-genome methylation. Other liquid biopsy companies have factored elements other than methylation into their tests. For example, Freenome, which raised $270 million last month, also looks at immune DNA signatures. The Form S-1 states Grail is assessing “multi-omic approaches including evaluation of additional analytes and biofluids” but is confident its existing approach can detect low level signs of cancer in the blood. Some of the money from the IPO, which has a placeholder fundraising target of $100 million, will support such ongoing development work but the focal point is commercial preparations. Grail put another piece of the preparations in place in June when it leased space in North Carolina to add to its capacity. COVID-19 could disrupt the build, the paperwork warns, leaving Grail reliant on its existing site in California that may be unable to meet demand. How much demand Galleri generates will partly depend on the success of Grail’s rivals. The IPO filing named Guardant Health, Exact Sciences, Freenome, Thrive Earlier Detection and ArcherDX among its competitors, several of which have tested liquid biopsies in studies of more than 10,000 people. However, Grail sees itself as partly insulated from competition, stating that not “many companies would have the financial resources to invest in population-scale clinical trials and rigorous analytics to compete with our products.” Behind Grail, Illumina’s billion-dollar diagnostics startup (https://medcitynews.com/2017/03/ behind-grail-illumina-startup/)

14.2 History

With a billion dollars in private financing and a test projected to generate a terabyte of data per person, Grail has seeded a new category of diagnostics and Big Data. So who is Grail, the cancer diagnostics company that last week raised what could be the largest-ever equity financing round in biopharma history? How has it shaped a field of diagnostics into a billion-dollar venture in just over a year? While the company hasn’t been particularly forthcoming with information, a lot can be gleaned from CEO Jeff Huber’s presentation at the Future of Genomic Medicine conference held in San Diego last week. After over a decade at Google, Huber’s Big Data background led him to Illumina and then Grail, as fate cast him a personal role in the pursuit of early cancer detection. Rochester Regional Health chooses Datos platform to minimize coronavirus pandemic mitigation risks Concerned with an influx of COVID 19 patients, Rochester Regional Health deployed Datos Health’s telehealth platform in only 4 days to protect hospital staff and better manage home hospitalized patients. DATOS HEALTH Science is full of coincidental success stories, most famously the discovery of penicillin. It’s not clear yet whether Grail will have the same impact, but a similar unintended observation by the Illumina research and discovery team led to its creation. In 2013, Illumina acquired Verinata Health, a company focused on noninvasive prenatal testing (NIPT). That science came from the discovery that small fragments of fetal DNA cross the placenta during pregnancy. With sensitive tools,

44 Chapter 14. Grail tio2 book Documentation, Release 0.0.1 scientists learned how to isolate the fetal DNA to safely screen for any chromosomal abnormalities that might impact the infant’s development. By the time Illumina acquired Verinata, the prenatal test had been run over 100,000 times, Huber said. It worked extremely well, except for a handful of cases — around 20 — where a foreign signal was detected. The researchers struggled to identify the source of the signal, theorizing that it could be some rare fetal abnormality. Several months later, the 20-odd babies were all born healthy and the team went back to the drawing board. Around the same time, Illumina hired the former director of the National Cancer Institute, Rick Klausner. He took a look at the data in question and promptly declared that it was cancer, Huber recounted. Unfortunately for the 20 women involved, Klausner was right. The prenatal test had detected tumor fragments known as cell-free DNA (cfDNA) circulating in the bloodstream. “They were finding cancers with perfect specificity, literally 100 percent accuracy,” Huber said. Other NIPT companies and academic groups have reported similar findings. The catch was that the cancers were late-stage. The test couldn’t change patient outcomes. “And that led to the light bulb within Illumina of saying, OK, if this test that was developed for this other purpose, that doesn’t have the kind of sensitivity that it would need to have but is still detecting the signal, what would it take to be able to go from the late-stage diagnoses that are happening here, to be able to detect cancer in its earliest stages,” Huber said. Illumina’s R&D team began working on the science, embarking on a partnership with Memorial Sloan-Kettering that continues to this day. As the potential of the technology came to light, Huber said the discussions turned from, “wow this is a really good business idea,” to the realization that they had a moral and ethical imperative to make this test a reality. The vision Grail has a concise way of explaining its overarching aim. For cancers discovered in the earliest stages, stage one and stage two, the prognosis is typically positive; a 70-90 percent survival rate depending on the cancer type. Cancer that is discovered late-stage, stage three and stage four, is roughly the inverse, Huber said. Some 80-90 percent of patients die. Grail wants to drastically shift the odds in the patient’s favor by detecting cancer early. It would take the form of an omnipotent blood test that is routine, preventive and actionable. Is that a moonshot or a logical extension of the technology? It’s too early to know. Grail spun out of Illumina just over one year ago. During that time, the company built a dedicated facility in Menlo Park, California, which Huber believes to be the highest capacity sequencing lab in the world. From an initial team of 40 ex-Illumina employees, the staff now number 160. For a population-wide cancer screening test, Grail knows it needs to work on a large scale. To that end, it has already launched its first multicenter clinical trial, dubbed the Circulating Cell-free Genome Atlas (CCGA) study. The aim is to analyze blood samples from 10,000 participants; 7,000 with cancer and 3,000 controls to build a detailed reference library for what a normal blood profile looks like. Huber said the studies will ultimately scale to hundreds of thousands of patients to generate enough data on different cancer types and stages. To detect cancer in its very earliest stages requires sensitivity down to a handful of molecules in a tube of blood. That’s where the ultra-deep, ultra-wide sequencing comes in. Huber described the high-intensity approach as an order of magnitude deeper than traditional liquid biopsy sequencing. “The net effect of that is that we’re generating on the order of a terabyte of data for every test that we do,” he said. (This scale is one of the reasons why the company doesn’t refer to its tests as liquid biopsies, a Grail spokeswoman said via email.)

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If the company can realize its aim to embed itself in the medical system as a routine test, the data calculations become enormous. Starting with just the adult population in the United States — approximately 100 million people per year — would make Grail the first “zettabyte-scale application,” Huber said. That’s 1,000,000,000,000,000,000,000 bytes; roughly the size of the likes of Amazon, Google and Facebook. Collecting, organizing and gleaning insights at that scale will be an immense challenge. However, it does readily explain the unprecedented scale of its Series B financing round. It’s also partly why Huber is at the helm as well. As a 12-year veteran of Google, he was first recruited to join the Illumina board to inject some Big Data knowledge into the team. That path led to Grail. It’s not all abstract Behind the technology and the Silicon Valley idealism is a painful authenticity that stems from Huber himself. Long before the huge financing round was closed, he was burdened with the responsibility to do something meaningful in this space. In 2014, Huber’s wife Laura was unexpectedly diagnosed with stage four colon cancer. He told the Future of Genomic Medicine audience that there were few warning signs and no risk factors. She was 46, healthy, and did not have a family history of the disease. After 18 months of intense treatment, Laura passed away. It was November 2015. A month later, Huber was ap- proached by the Illumina team about taking the helm at Grail, given his very personal connection. It’s a tough topic to discuss with strangers, but undeniably relevant. “I’m very confident that if Grail had existed three or four years earlier that Laura could have had a very different outcome,” Huber told the audience.

46 Chapter 14. Grail CHAPTER 15

Indices and tables

• genindex • modindex • search

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48 Chapter 15. Indices and tables Index

A Accel,3 B biotech, 19, 24, 31, 33, 36, 38, 40, 42 C celgene, 38 F Facebook,3 G Genentech, 24 I investment,1,3 J Juno, 31 M Moderna, 19 mRNA, 19 O oncology,1 P Pharmacyclics,1 T Tesaro,6 V VC,1 W Waltham,6

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