Revusiran

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 4, 2016 By Mark Terry , BioSpace.com Breaking News Staff On October 5, Cambridge, Mass.-based Alnylam Pharmaceuticals announced that it was discontinuing development of revusiran for hereditary ATTR amyloidosis with cardiomyopathy (hATTR-CM). The decision was made on the basis of unexpected patient deaths. At its third-quarter conference call the company provided more details. Alnylam works in the field of RNA interference (RNAi). This is based on how genes are turned on and off. ATTR amyloidosis is a progressively debilitating and often fatal disease caused by an accumulation of transthyretin (TTR) in peripheral tissues. The TTR protein is mostly produced in the liver and normally carries vitamin A. On October 5, the company disclosed that there had been 18 patient deaths in the trial. During the conference call, the company’s chief medical officer, Akshay Vaishnaw , said that there had been another death. Of the original 18 deaths, 16 were receiving revusiran. The trial has 206 patients, all with ATTR cardiomyopathy. They were randomized two-to-one to receive revusiran versus placebo. Vaishnaw said there was a “perfectly balanced distribution” of the deaths between the active drug arm and the placebo arm. Although the data monitoring committee recommended the trial be halted, the company has said “there was no conclusive evidence of drug-related peripheral neuropathy” that would have caused the deaths. “We have established a team to evaluate all the revusiran data,” Vaishnaw said during the call. “To the extent possible, we intend to provide you with an update on our progress at our upcoming R&D day in December, but you should expect that our evaluation may take months to reach conclusive results.” Investors are concerned that the safety issues for revusiran cast a shadow over all of Alnylam’s RNAi technology. The company has more than half-a-dozen other compounds in clinical trials. That’s a realistic concern. On September 30, the company presented 10 posters and oral presentations at the 12th Annual Meeting of the Oligonucleotide Therapeutics Society (OTS) in Montreal, Quebec. In that group, it presented data from its Phase I/II study of ALN-AAT to treat AAT deficiency-associated liver disease (alpha-1 liver disease), where three patients showed asymptomatic, transient increased liver enzymes. As a result, that trial was halted. In a statement, the company said, “Since the target patient population for ALN-AAT has established liver disease, Alnylam plans to advance a follow-on molecule targeting a different sequence for further development. Specifically, the Company is finalizing selection of a new Development Candidate—ALN-AAT02—and plans to rapidly advance this compound towards the clinic, with a planned CTA filing in 2017.” In 2014, Alnylam developed an alliance with Sanofi Genzyme to accelerate and broaden RNAi therapeutic development. Alnylam holds product rights in North America and Western Europe. Sanofi Genzyme picked up the right to access specific programs in Alnylam’s current and future Genetic Medicines pipeline, including ALN-AAT in the rest of the world through the end of 2019. Alnylam has taken a huge hit recently. Shares traded on September 27, 2016 for $78.09. They plunged to $36.21 on October 6 and are currently trading for $33.63. Shares had a yearly high of $108.96 on December 4, 2015.