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BioWorld's Top 10 Countdown of 2012's Most Impactful Stories

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By the BioWorld Staff

In the six decades since Watson and Crick discovered the structure of DNA, rarely has a year passed in the biopharmaceutical sector which could be defined as boring. The scientific revelations continue to yield intellectual property for businesses to develop. And investors scramble to identify and back potential blockbuster targets.

2012 was no different. BioWorld's editorial team huddled and voted on the 10 most poignant stories which emerged. Drum roll, please . . .

1 . At Pharma's Long-Dreaded Patent Cliff

As blockbuster drugs began going off patent in droves, big pharmas saw sales swoon, creating potential opportunities for nimble biotechs – particularly in technologies such as therapeutic vaccines, stem cells and tissue replacement. Erosion from generics will erase some $148 billion from pharma industry revenues by 2018, according to a report by global consulting firm PwC, and the bloodletting has already begun. U.S. sales of cholesterol drug Lipitor (atorvastatin), marketed by Pfizer Inc., plummeted from $2.7 billion in the first six months of 2011 to $679 million in the first six months of 2012. AstraZeneca plc recorded a 15 percent decline in third-quarter revenues, to $6.68 billion, as loss of exclusivity on four products – Seroquel IR, Atacand, Nexium and Merrem – pounded its bottom line. Revenues from schizophrenia drug Seroquel IR (quetiapine), alone, dropped by more than $850 million, or 82 percent, in the quarter. Merck & Co. Inc. also lost market exclusivity for asthma drug Singulair (montelukast sodium) in the U.S., with global sales declining $734 million, or 55 percent, to $602 million in the third quarter of 2012. Approval of a generic version of the attention deficit hyperactivity drug Adderall XR (mixed amphetamine salts) late in the second quarter of 2012 saw sales of the product by Shire plc fall 32 percent, to $102 million, in the third quarter. And on the eve of reporting its third-quarter earnings, Eli Lilly and Co. confronted a storm warning from Fitch Ratings, which lowered its outlook on the company from "stable" to "negative," calling the pharma's patent cliff the "steepest in the industry" and predicting significant margin compression in 2014, following the potential losses of antidepressant Cymbalta (duloxetine) and Type I diabetes drug Humalog (lispro) next year. Lilly's revenue swoon began in October 2011 with the loss of market exclusivity for antipsychotic Zyprexa (olanzapine), which had exceeded $3 billion in U.S. sales the previous year. Coupled with the patent cliff, pharmas faced falling drug prices in Europe on the back of austerity and uncertainty in the U.S., which continued to grapple with health care reform in the wake of the Affordable Care Act. Challenges facing the pharma industry were accentuated by the rise of biosimilars. (See #4.)

2. The All-Oral HCV Race

In 2011 , treatment for hepatitis C virus (HCV) advanced big time, with the approvals of new protease inhibitors Incivek (telaprevir, Vertex Pharmaceuticals Inc.) and Victrelis (boceprevir, Merck & Co. Inc.), which produced improved cure rates and shorter treatment durations. But those wins proved to be just the warm-up act for the HCV space, which saw the race for an all-oral regimen – i.e., a regimen free of the side-effect-plagued interferon – kick into high gear in 2012. Observers got an early sign in April, when Gilead Sciences Inc. reported a 100 percent sustained virologic response at four weeks with its Ns5B polymerase inhibitor GS-7977 (now known as sofosbuvir) in combination with Bristol-Myers Squibb Co.'s NS5A inhibitor daclatasvir. Gilead opted to forge ahead with its own GS-5585, an in-house drug similar to daclatasvir, and reported stunning interim results at the American Association for the Study of Liver Diseases in November from the Phase II ELECTRON study, showing a 100 percent response rate at 12 weeks with a GS-7977/GS-5885/ribavirin regimen. And Gilead appears to be leading the pack for now, after safety issues derailed former competitor BMS, which discontinued development of nucleoside HCV drug BMS-986094 in August – those toxicity issues also resulted in a clinical hold for a similar program from Idenix Pharmaceuticals Inc. and likely contributed to BioCryst Pharmaceuticals Inc.'s decision to pull an investigational new drug application for BCX5191 later in the year. But a number of other programs are rapidly advancing behind Gilead's from companies such as Vertex Pharmaceuticals, Medivir AB, Achillion Pharmaceuticals Inc., Roche AG, Merck & Co. Inc. and Abbott. Assuming all goes well, analysts have projected the first all-oral regimens to gain approval as early as 2014.

3. Finally, New Obesity Drugs

2012 was a banner year for obesity. June saw the first approval of a new obesity drug in 13 years. The FDA gave its blessing to Arena Pharmaceuticals Inc.'s lorcaserin, marketed as Belviq, for adults with a body mass index (BMI) of 30 or more, or those with a BMI of 27 with a complicating weight-related condition. Right on the heels of that approval, Vivus Inc.'s Qsymia (phentermine/topiramate) also won approval for a very similar patient group, those with a BMI of 30 or more, or those with a BMI of 27 plus one or more obesity-related comorbidity. Not long after, Orexigen Therapeutics Inc. received some long-awaited signals from the FDA that it could explore a faster path to resubmission of its new drug application for Contrave (naltrexone/buproprion). That's encouraging movement in a field that was effectively stalled for many months while the FDA deliberated over how to handle potential cardiovascular risks for obesity drugs. Signs are pointing to plenty of room in the market for the "big three," as well as many other obesity candidates making progress through pipelines.

4. Two Firsts: Biologic Blockbuster and Biosimilar MAb

Pulling in nearly $8 billion in global sales in 2011 , Abbott's Humira (adalimumab) became the first biologic to become the best-selling drug in the world. The biologic continued to rack up new indications in 2012, strengthening its position as a mega-blockbuster and adding to the allure of monoclonal antibodies (MAbs) as biosimilar targets. Speaking of which, Celltrion Inc.'s Remsima (infliximab) became the world's first officially approved biosimilar MAb when it got the nod from the Korean Food and Drug Administration in June. Celltrion had hoped to have the Remicade (Janssen Biotech Inc.) biosimilar also approved in Europe before year-end. While the U.S. FDA has yet to approve a biosimilar, it made some strides when it released three biosimilar guidances in February.

5. The Rocky Fundraising Road Continued

On the capital markets, biotechnology has done remarkably well despite the continuing turbulent economic landscape, particularly in Europe. According to the BioWorld Stock Report, the sector is poised to close out 2012 up a healthy 25 percent from where it started at the beginning of the year. However, biotech companies have not been able to emulate that success in raising capital. The $17.1 billion raised to date is 26 percent shy of the total generated at the same time last year. It has been particularly tough sledding for private companies trying to raise venture capital and globally they have raised $3.5 billion year-to-date, down 20 percent compared to the same period last year. It looks like the average deal size has also dropped significantly as the number of deals for both periods are about the same.

6. JOBS Act + FDASIA Pass Despite U.S. Political Squabbles

While the U.S. Congress was split by partisan quibbling for much of the year, the two sides came together to pass the Jumpstart Our Business Startups (JOBS) Act and the FDA Safety and Innovation Act (FDASIA). The JOBS Act is expected to have a significant impact on small biotechs by providing new fundraising options and easing the burden of complying with securities laws. FDASIA, or PDUFA V, also will have a big impact on biopharma. Besides setting prescription drug and medical device fees for the next five years, the legislation created new user fees for generic and biosimilar drugs. It also set new performance goals for the FDA, made two pediatric bills permanent, included provisions to advance "breakthrough therapies" and new antibiotics, and stiffened penalties on adulterating, stealing or counterfeiting drugs.

7. Genomics Finally Arrives (with a Real Purpose)

The completion of the human genome sequence in 2002 raised expectations for a new era of genomics and personalized medicine that turned out to be difficult to live up to. Instead of immediately unlocking cures to countless diseases, the genome seemed to raise 1 ,000 new questions for every one it answered, and in 10 years, little progress has been made in terms of putting that knowledge to use in real-life patients. All of that is beginning to change, though. Not only has 2012 seen the usual parade of scientific advances in genomics, but those advances are making regular appearances in clinical stage research, and becoming deal targets in themselves. More companion diagnostics are being approved, such as Quest Diagnostics Inc.'s anti-JCV antibody test for use with multiple sclerosis drug Tysabri, to screen out patients at risk for a brain infection. The year closed out with two large acquisition deals for genomics companies. Amgen plunked down $415 million to acquire DeCode Genetics, a genomics company that was threatened with bankruptcy liquidation just three years ago. And in September, Chinese company BGI-Shenzhen launched a tender offer for all outstanding shares of Complete Genomics Inc., a major player in the U.S. genomics space, for $117.6 million. It's clear that genomics assets are becoming necessary for growing biotech companies in the here and now, rather than as a minor sideline to be investigated for the future.

8. The First Gene Therapy Is Approved

In theory, gene therapy could abolish the biopharmaceutical industry one day. In reality the insertion of genes to prevent or treat diseases is rife with complex hurdles. But in a major first step for the modality, Glybera (alipogene tiparvovec), a gene therapy from uniQure BV for the super-rare inherited disorder lipoprotein lipase (LPL) deficiency, won marketing approval from the European Commission in November. The first patient was slated to get a commercial form of the product in Germany around the middle of 2013. While awaiting the official nod from regulators, uniQure screened 319 patients and found 32 with the relevant mutation in the LPL gene. The company has four more gene therapy products given clearance to enter clinical trials in Europe.

9. Through the Thicket of Alzheimer's Failures

Alzheimer's drug discovery found itself in a puzzling spot in 2012. Late-stage clinical trials in the indication continued to do what they have been doing for years – fail. This year added Eli Lilly and Co.'s candidate solanezumab, and Pfizer Inc. and Johnson & Johnson's bapineuzumab, which originated with Elan Corp. plc, to the rubble heap. But several research studies provided the strongest evidence yet that misprocessing of amyloid precursor protein or APP is indeed a cause of Alzheimer's disease, not just its consequence. In other words, targeting plaques should work – but it doesn't. Ideas for how to translate what is understood about the basic science of Alzheimer's disease into a working drug include starting treatment earlier, and interfering with the very earliest steps of APP processing in order to prevent the formation of oligomer intermediates as well as the plaques that have been the most common target of experimental therapeutics. But in 2012, that translation once again remained elusive.

10. A Nobel Prize for Regenerative Medicine Breakthrough

Another new treatment modality with as much promise as gene therapy but equally as challenging, gene therapy's troth is to harness the body's own regenerative and healing capabilities. A pair of UK scientists brought regenerative medicine a giant step forward in 2012 with their finding that cells can be reprogrammed to regain pluripotency, and the Nobel Prize in Physiology or Medicine went to stem cell researchers John Gurdon and Shinya Yamanaka. Gurdon's first work in the field came to light a half century ago, when his experiments with frog egg cells were published, though skeptics were many. The much-younger Yamanaka's investigations focused on genes that control the immaturity of embryonic cells, using them to reprogram other cells.