Mavacamten

By helping scientists make generalizations about hypertrophic cardiomyopathy by unearthing the common denominator between mutations, the cells could ultimately lead to more personalized treatment approaches. Hypertrophic cardiomyopathy, or HCM, is a common but potentially lethal heart disease. While researchers have tried for decades to understand the contribution of the many genes linked to the condition, challenges and inefficiencies around growing heart muscle cells with only specific mutations—and no others that could cloud results—has hampered progress. Now, the Allen Institute for Cell Science has taken a step toward solving the problem with six new pluripotent stem cell lines, each of which has a different key gene mutation found in HCM. The cells are the result of a joint effort between the Allen Institute, the University of Washington, the University of California, Santa Barbara and Stanford University. They're the first "disease-specific" cell line collection offered by the institution. “The unique feature of this collaboration is that we generated multiple different mutations, all on the same very well controlled cell background,” Daniel Bernstein, M.D., a pediatric cardiologist at Stanford who both helped develop the cells and has used them in his own lab, told Fierce Biotech Research. The cells don’t have any other genetic mutations that could cause variations in findings, he explained, meaning they will enable researchers to see clearly how they contribute to disease development.  That solves an issue scientists have run up against in the past when trying to study HCM, which is characterized by thickening of the cardiac muscle that can lead to heart failure and other problems including sudden death. There are as many as 1,500 mutations in 25 different genes that can cause the disease, Bernstein said, but they don’t always manifest the same way. Individuals with the same mutation—even within the same family—can have HCM to varying degrees of severity, a phenomenon called incomplete penetrance. One of the most common genes involved is MYH7, which encodes a protein called beta-myosin heavy chain 7, or myosin 7. Researchers know that mutations in MYH7 lead to mutated myosin 7 proteins, but what happens next is much murkier.    “Why does a mutation in myosin 7 lead to [HCM]?” Bernstein said. “Understanding that is a good way to develop new drugs or treatments to either prevent this from happening in the first place, or treat it once it occurs.”  The new cell lines are already making that possible. Bernstein’s lab at Stanford used some with a mutation called G256E—a variant that causes some patients, but not all, to develop HCM at varying degrees of severity—to show that the mutation changes the way myosin 7 functions biomechanically and consequently causes the heart muscle to beat too strongly. The results of these experiments were published May 7 in Proceedings of the National Academy of Sciences.  Had the cell line used in the experiment been generated by taking white blood cells from donor patients, reprogramming them into stem cells, and coaxing them into heart muscle cells—one of the means of creating human heart cells for experiments—variations in patient genetics might have made it difficult to compare how the mechanisms of the G256E mutation differ from others that cause HCM. It also would have been expensive to do so at a large enough volume to generate sufficient data.  Instead, “we know that the cells from the Allen Institute were generated exactly the same way,” Bernstein said. “It’s very highly controlled, which allows us to compare seven or eight mutations across the board for the first time.”  “I can look for commonalities between what [the mutations] do to the protein and heart muscle cells,” he added. “That will tell me what the features of the mutations are that lead to the disease, versus what features have little effect on the disease itself.”  By helping scientists make generalizations about the disease by unearthing the common denominator between mutations, the cells could ultimately lead to more personalized treatment approaches. The first FDA-approved drug for HCM, mavacamten (Bristol Myers Squibb’s Camzyos), is meant to treat all patients with the disease. It may turn out that there are some patients who benefit from the drug more than others based on what genetic mutation they have.  “That’s something that you can either do by trial and error in patient studies, or you can do by studying these mutations in cells,” Bernstein said.

Dive Brief:Shares in Cytokinetics sank by about one-fifth Thursday on news of a funding deal the biotechnology company struck with Royalty Pharma, in which it traded away a stake in future sales of its experimental heart drug for upfront cash.The agreement will give Cytokinetics $250 million at closing and as much as $575 million in total. Royalty Pharma, a specialist in these types of transactions, will earn a higher royalty rate on annual net sales of the drug, aficamten, than it previously had under a prior agreement.To Wall Street analysts and, seemingly, investors, the deal lowers the likelihood of an imminent large pharmaceutical company buyout of Cytokinetics, the prospect of which had buoyed the company this year. Reports in January indicated Novartis, Johnson & Johnson, and AstraZeneca had explored an acquisition.Dive Insight:Cytokinetics deal with Royalty has several parts, tying funding to the biotechs preparations for a commercial launch of aficamten, as well as to new development plans for two other experimental heart drugs. Royalty also agreed to purchase $50 million in Cytokinetics equity as part of a secondary stock offering the company is using to raise approximately $500 million.Taken together, the moves suggest a company preparing to remain independent, rather than readying for a buyout.The substantial financing we think reduces the probability of a takeout, consistent with managements commentary on ability to go it alone, wrote Sean McCutcheon, an analyst at Raymond James, in a client note.Among 29 investors polled by Mizuho Securities, meanwhile, 21 estimated the probability of a Cytokinetics acquisition to now be 1-in-5 or lower, according to a note from Mizuhos Salim Syed. Seventeen had rated the chances of a buyout at 50% or higher prior to news of the Royalty deal.The reported interest in Cytokinetics centers on aficamten, which treats a condition that causes heart muscle to thicken. Known as obstructive hypertrophic cardiomyopathy, it can block the flow of blood and cause symptoms like chest pain, shortness of breath and irregular heartbeats.In December, data from a trial named Sequioa-HCM showed that aficamten treatment helped increase oxygen uptake and improved self-assessed symptom, function and quality of life scores, compared to a placebo.Cytokinetics plans to submit an approval application to the Food and Drug Administration in the third quarter. If cleared by the FDA, aficamten would compete with a marketed drug from Bristol Myers Squibb called Camzyos.Fifty million dollars of the Royalty funding will go towards supporting Cytokinetics preparation for that event. Royalty would get a 4.5% share of annual net sales up to $5 billion, and then 1.0% on any annual net sales above that mark. Previously, Royalty had rights to a 4.5% share of sales up to $1 billion, and 3.5% thereafter.Notably, however, the Royalty deal also gives Cytokinetics what is essentially a loan to fund a Phase 3 study of another heart drug, omecamtiv mecarbil, that the FDA rejected last year and investors had largely written off.The biotech will get $100 million to support that trial in patients with heart failure and reduced ejection fraction. If its successful and omecamtiv mecarbil is approved, Cytokinetics will pay $100 million back to Royalty in installments as well as an incremental 2% royalty. If it fails or the drug isnt approved, Cytokinetics will pay Royalty up to $237.5 million over 4.5 to 5.5 years in fixed quarterly payments.Akash Tewari, an analyst at Jefferies, noted that this provision of the deal has been particularly polarizing for investors, who Tewari said consider omecamtiv mecarbil as a financial burden for Cytokinetics.Additionally, Tewari added, the $500 million stock offering will dilute current shareholders something Cytokinetics CEO Robert Blum previously indicated he was trying to avoid.Shares in the biotech fell by as much as 19.6% Thursday morning to trade at just under $50 apiece. They traded above $100 in December and early January after news of the positive Sequoia-HCM data. '