Eleclazine

December 14, 2016 By Karl Thiel for BioSpace.com Many of us will be glad to see the end of 2016, a year that was marked by terrorism both domestic and international, a string of celebrity deaths, a new disease scourge (Zika became the new Ebola), and a whole lot of political turmoil that made for some tense Thanksgiving table conversations. Here in our little corner of the world, there was plenty of volatility too. So without further delay, let’s count down this year’s wholly subjective list of the year’s top 10 biotech trends and events. #10: Brexit. The U.K.'s decision to exit the European Union will likely have some broad-reaching and long-lasting effects, most of which are yet to be felt. In the short term, the move has been on balance positive for U.K.'s pharma sector—for a simple reason. A historically weak pound sterling is helping companies like GlaxoSmithKline and AstraZeneca boost dollar-denominated profits. Rumors initially swirled that both these pharma giants would pull up roots and leave the U.K., but that doesn’t appear to be the case, at least for now. Longer term, it remains to be seen if some of the bigger fears—failure to attract or retain top talent, securing investment, and keeping favorable trade deals—come to fruition. #9: Sharply declining approvals. Both 2014 and 2015 were tough acts to follow. There were 45 novel drugs approved last year; 41 the year before. As I write, there have only been 19 novel drugs approved in 2016—putting this on track to be the worst year since 2007. This isn’t necessarily the FDA’s fault—they can only approve the applications these receive…and some would argue that the agency has, if anything, been overly lenient in granting approvals this year. #8: Lots of big clinical failures. While 2016 has certainly had its bright spots, the year has been more notable for high-pro failures than for its successes. There’s BioMarin’s drisapersen, Celldex Therapeutics’ Rintega, Eli Lilly’s solenuzumab, Alnylam’s Revusiran, Clovis Oncology’s rociletinib, and Bristol Myers-Squibb’s Opdivo in lung cancer. Juno Therapeutics has run into some serious, perhaps program-ending difficulties with JCAR-015. Gilead has had a bad run of luck with almost everything it touched this year, from GS-5745 (in ulcerative colitis) to simtuzumab to eleclazine to Zydelig (in first-line cancer applications). Bluebird Bio went from hot to not after turning out disappointing early results in its sickle cell programs. There have been some great achievements (see below)—but it’s hard to counter-balance this depressing list. #7: The drug price debate continues, then stops, then starts up again. Drug companies always make juicy political targets, so it’s no surprise that the heat stayed high all during this election year. It’s been a debate long on rhetoric and short on substance, with the main result being that companies grew more eager to get in price increases before the music stopped. Some, of course, were a little more ham-fisted about than others (cough, Mylan ). Pharma investors breathed a sigh of relief after the election of Donald Trump (see point #1 below), but that sense of resolution may have come too early. Also, don’t forget about some of the most visible faces of price-gouging— Valeant subsidiary Philidor and its CEO have had criminal charges filed against them, and there may be more to come. Martin Shkreli is guaranteed to be back in the news in 2017, since that’s when his criminal fraud trial is likely to take place. #6: M&A slowed to a comparative crawl. 2015 was a record-breaking year for biopharma M&A, with some $330 billion in deals, even after you factor out the $183 billion Pfizer - Allergan link-up that never happened. Few expected this year to match that sum, but fewer still expected the totals to drop so sharply. The final tallies won’t be in until the New Year, but 2016 was recently running under $100 billion in pharma and biotech M&A. Will a flood of repatriated cash, courtesy of a new Trump tax policy, change the calculus in 2017? I have my doubts (and not only because it will take a while to change the tax code, even with a willing Congress). But it wouldn’t be surprising to see the pace pick up at least a little next year. #5: Market meltdown. The “Trump bump” to the stock market—and the biotech market in particular—was nice for investors while it lasted. Even at its best, it did little to erase what happened in the opening weeks of 2016. As we stand now, the Nasdaq Biotech Index, up less than 2 percent since the election. It is down over 20 percent year-to-date. A number of other points in this list help explain why. #4: The (controversial) rise of antisense. Antisense has been kicking around since the 1980s without much commercial success. While that technically continued to be true this year, it’s about to change. Spinraza, the antisense drug for spinal muscular atrophy developed by Ionis Pharma and Biogen , produced strong enough results in a study of infantile onset spinal muscular atrophy that the trial was stopped early. Since then, robust signals have been seen in patients with later-onset disease. And the drug reportedly has a reasonably clean safety pro since side effects and safety concerns have dogged some other antisense drugs. Then there’s Sarepta’s eteplirsen, trade-named Exondys 51, approved to treat Duchenne muscular dystrophy is a specific subset of patients. The decision to approve was controversial and, according to some, undermined the credibility of the FDA. Certainly it remains unclear whether the drug’s miniscule effect on dystrophin production will create a meaningful change in the course of the disease. But that probably won’t stop it from racking up hundreds of millions of dollars in sales. #3: CAR-T meltdown? Cancer immunotherapy has been so hot over the past few years that some pundits have bemoaned a lack of research dollars going elsewhere. CAR-T seems like an obvious next step—a way to program T-cells to attack specific cancers. And early clinical results have shown astounding success, producing apparent cures in leukemia. But the therapy has turned out to be quite dangerous in some situations, dousing another fire that burned so bright for biotech in 2015. That’s been particularly true for Juno Therapeutics , which has put its pivotal trial of JCAR-015 on clinical hold twice. Novartis , once arguably the leader in the area, seemingly stepped back from CAR-T this past summer, dissolving its dedicated unit, bringing programs back into the larger organization and perhaps putting less emphasis on the technology (though they continue to push forward). Kite Pharma is the beneficiary of these developments, yet investors are regarding the company warily. The stock is down sharply for the year and well off its 52-week high even as it files for its first approval. Call it another case of hype waking up to reality: CAR-T remains a very promising technology, but it’s still unclear how effective it will be outside of blood cancers, and how it will be used even in leukemias, where oncologists will have to weigh up robust results against serious potential risks. #2: CRISPR goes public. At the start of the year, there were zero pure-play companies in the CRISPR space. Now there are three— Editas Medicine , Intellia Therapeutics , and CRISPR Therapeutics —not to mention a bunch more companies dabbling in the space. But these companies—which have had a mixed-at-best reception with investors—are only the tip of the iceberg, held back in part by complex and acrimonious intellectual property disputes. CRISPR has exploded around the world, with the University of Pennsylvania planning a seeming Hail Mary pass into clinical trials thanks to funding from the Parker Institute, only to be beaten to the punch by Sichuan University in China. Even without clinical trials, the technology is making all sorts of experiments possible—even if some raise safety or ethical issues. By this time next year, perhaps we’ll all have access to giant CRISPR beagles . #1: Trump elected president. This election upset takes the number one spot. But what it means for the biotech sector (or anything else) remains unclear. Trump has certainly been known to spout anti-science rhetoric and anti-vaxxer drivel. He’s said he wants to cut drug prices, using mechanisms like reimportation and direct Medicare negotiation. But then he went mum on those topics. And then he started up again, so who knows? He has said he wants to streamline FDA and get medicines to people more quickly, pushing a popular political hot button. But does that mean a bigger FDA budget, laxer standards, or something else? It seems likely, based on both his rhetoric and his choice of Rep. Tom Price (R-Ga.) as Secretary of Health and Human Services , that he plans to make good on his promise to repeal and replace Obamacare. Yet how will that play out? The Affordable Care Act has generally been popular with drug companies, because it has given them millions of new customers. But it has also come with new regulatory burdens, like requirements to compile and submit data to Patient Centered Outcomes Research Institutes. What is simply repealed and what is replaced will have a big impact on companies. Here’s another irony: One interesting impact of Obamacare is that it gives the president fairly broad authority to enact price controls when Medicare grows at a certain level beyond inflation—as it is expected to do in 2017 for the first time since the law was passed. So biopharma companies who’ve thus far seen the most favorable side of the law may be saved from its restrictions just before the hammer comes down—if Trump and Congress do indeed repeal. But maybe Trump will decide he likes the authority in the current law. However it goes down, it’s going to be an interesting 2017. - Karl Thiel Read the BioPharm Executive online newsletter December 14, 2016. Sign-up for the free monthly subscription to the BioPharm Executive Related Jobs VP, Clinical Development Director, Genomics VP, Clinical Development Director of Operations VP, Sales Director, Biostatistics View More Jobs

November 3, 2016 By Mark Terry , BioSpace.com Breaking News Staff A Catch-22 in biopharma is the fallout if you develop a drug that cures the disease. No more customers! Although that hasn’t exactly happened to Gilead Sciences and hepatitis C (HCV), it’s definitely a factor in the company’s decision to shift its research-and-development efforts away from HCV. Todd Campbell , writing for The Motley Fool, takes a look . At yesterday’s third-quarter report, Gilead indicated that its HCV products, Harvoni, Sovaldi and Epclusa, brought in $3.3 billion in this year’s third quarter, down from $4.8 billion in the same period last year. Prior to about 2013, patients with HCV were treated with several multidrug cocktails that had significant side effects and required about 48 weeks or more of treatment. Sovaldi was approved in 2013 and was largely replaced by Harvoni, although Sovaldi is used in non-genotype 1 patients. HCV has six genotypes, with genotype 1 being the most common, accounting for about 70 percent of chronic HCV cases in the U.S. Harvoni is a combination of Sovaldi and ledipasivir, and mostly used in genotypes 1 and 4. The company’s latest, Epclusa, is mostly used in genotype 2 and 3 patients. The length of treatment is about 12 weeks, sometimes only 8. The cure rate is pretty close to 100 percent. So Gilead’s HCV franchise is being hit by its own success—fewer existing patients. In addition, AbbVie and Merck & Co. have newer HCV drugs out that are cheaper than Gilead’s products, although not necessarily better. But they’re forcing Gilead to cut prices and offer discounts, which also digs into its revenue. The company has a fourth-generation HCV product, a three-drug cocktail, Sof/Vel/Vox that is being evaluated in late-stage trials. At the company’s third-quarter conference call, John Milligan , Gilead’s chief executive officer, said, “From a pipeline perspective, with SOF/VEL/VOX being our fourth generation of HCV product now being approved, there really isn’t much left in terms of unmet medical need. And so from a pipeline perspective, this is really the end of what we’ll be developing in terms of HCV molecules and that will allow us then to turn our attention to the important aspects in our fibrosis and NASH franchises and our oncology franchises. So, we’ve really largely turned our attention away from HCV to those areas already.” That may not cheer up investors much. In addition to its dropping HCV sales, the company provided a list of recently failed clinical trials and abandoned programs. Those included terminating GS-5745 for ulcerative colitis and Crohn’s disease. Its eleclazine (GS-6615) failed to meet its primary endpoint in ventricular tachycardia, ventricular fibrillation, or VT/VG, and implanted cardioverter-defibrillators. And Gilead essentially giving up on pushing forward with its HCV research will give AbbVie and Merck a chance to eat up some of their share if they can come up with drugs that are more effective—which generally speaking means that the treatments don’t take as long—and less expensive. And Johnson & Johnson is currently studying a multidrug cocktail that includes a drug by Achillion Pharmaceuticals , that might have a treatment regimen as short as six weeks. As Campbell writes, “For now, Gilead Sciences’ dominance in the indication doesn’t appear to be in question, but if the company rests too heavily on its laurels, it may see its market share fall if competitors ramp up their efforts.”