Cardiomyopathies

Vertex is pulling back on its genetic medicine research, ending all work related to adeno-associated viruses, or AAVs — the viral vectors commonly used to deliver gene therapies into the body, the company confirmed to Endpoints News . The cuts impact Vertex’s collaborations with at least two biotech startups: the AAV design company Affinia Therapeutics and tRNA therapy company Tevard Biosciences, which uses AAVs. It also calls into question Vertex’s work on CRISPR therapies for genetic muscle diseases. Several bigger pharmaceutical companies, including Biogen , Pfizer , Roche and Takeda , have cut or pared back on AAV gene therapy research in recent years. And several gene therapy biotech companies have trimmed their pipelines and staff as private and public investors sour on the field. This change of fortune was seemingly unimaginable a few years ago. AAV technology ushered in a new era of gene therapy investment and led to several commercial products for diseases, including Roche’s Luxturna for childhood blindness, Sarepta Therapeutics’ Elevidys for Duchenne muscular dystrophy, and Novartis’ Zolgensma for an otherwise fatal neurodegenerative condition in infants. But a panoply of challenges — including costly manufacturing, multimillion-dollar drug prices, slow progress in improving targeted delivery and lingering safety issues — has raised questions about the future of AAV medicines. Vertex did not have any AAV gene therapies in clinical development, despite work on the technology stretching back to at least 2019 when it acquired Exonics Therapeutics for its early-stage CRISPR therapies for two muscle diseases: Duchenne muscular dystrophy (DMD) and myotonic dystrophy type 1 (DM1). Exonics relied on AAV vectors to deliver its therapies to muscles. Vertex has shared few updates on the program since its acquisition. The approach was essentially a permanent version of the commercial exon-skipping therapies for DMD, meaning it wouldn’t fully restore the dystrophin protein that’s broken in people with the disease. A Chinese biotech called HuidaGene has developed a similar CRISPR therapy and has already treated two boys, Endpoints reported last month . The first patient had modest improvement in his walking ability three months after the treatment. It is unknown why Vertex’s own CRISPR therapy has seemingly lagged behind. It is possible that the company is holding out for a more curative approach. It may also have been spooked by multiple deaths in people who received the high doses of AAV needed to reach the body’s many muscles, including two from Pfizer’s experimental therapy , one from Sarepta’s approved drug and one from a custom CRISPR therapy . Heather Nichols, a spokesperson for Vertex, confirmed that the company has discontinued its AAV work, but in an email said that the company’s “commitment to cell and genetic therapies remains strong” and that other investments in DMD and DM1 continue. The company declined to provide further comment on its AAV cuts or make an executive available for an interview. The need for better AAVs, ones that could deliver more of the therapy at lower doses, has been clear for years. Vertex struck a partnership with Affinia in 2020 worth up to $1.6 billion for access to the startup’s viral vectors designed to better target the muscles for treating DMD and DM1 and target the lungs to treat cystic fibrosis, the disease responsible for most of the company’s $11 billion revenue last year. Affinia CEO Rick Modi told Endpoints in an email that his company regained the rights to its muscle-targeting viruses from Vertex in March. He said the earlier work on cystic fibrosis ended in 2022 and rights to those programs were returned then. The startup is currently focused on finishing preclinical studies and designing a clinical trial for its lead candidate, for a heart condition called BAG3 dilated cardiomyopathy. Modi said that Affinia received “the maximum amount of milestone payments” for the research phase of its DMD and DM1 collaboration with Vertex, but he wouldn’t specify the amount. He added that Affinia is looking to license its newly-regained muscle capsids to other companies. Vertex’s step back from AAVs also impacts Tevard Biosciences. The small startup, which is housed in Eli Lilly’s genetics-focused research center that opened in Boston last summer, struck a four-year partnership with Vertex in February 2023 to develop a new class of genetic medicines known as tRNA therapies. In nature, tRNA molecules are part of the machinery that cells use to translate genetic code into proteins. Tevard is one of a few companies developing synthetic versions of these molecules to help skip over genetic mutations that prevent cells from making fully functional proteins. Tevard believes its approach could help restore the vital dystrophin protein missing from the muscles of the 15% of people with DMD whose disease is caused by so-called nonsense mutations. While some companies are trying to package tRNA therapies in lipid nanoparticles, those delivery vessels are not readily taken up by the body’s many muscles, so Tevard planned to use AAVs to deliver its treatment. “We were doing great. The collaboration was going great. But in December, we were informed that they were realigning priorities, and multiple programs were being terminated, including this one,” Tevard CEO Daniel Fischer told Endpoints in an interview. “Two weeks ago, we got the rights back to this program.” Other tRNA companies have also struggled, including HC Bioscience, which shut down in March after “challenges in targeted delivery,” Endpoints previously reported . Fischer said the fate of the DMD program will depend on whether Tevard can find another drugmaker to partner with or raise enough money to move it forward on its own. The company is planning to present data showing that the DMD therapy works in mice at the upcoming American Society of Gene & Cell Therapy meeting later this month.

Cytokinetics\' addition of a REMS plan constituted a \"major\" application amendment, triggering a three-month delay.\n To REMS, or not to REMS.That, apparently, was the question for Cytokinetics, which has seen any potential approval for its experimental heart drug delayed by an extra three months over an unusual safety program omission and addition. Aficamten, a cardiac myosin inhibitor, had been on the books with the FDA for a potential approval by (or before) Sept. 26 for obstructive hypertrophic cardiomyopathy.This disease, characterized by the blood flow from the heart being reduced by the thickening of the heart\'s muscular wall, already has an approved treatment on the market in the form of Bristol Myers Squibb’s cardiac myosin inhibitor Camzyos.Cytokinetics was hoping to get into this market that has seen Camyzos bring in just over $600 million last year, but, now, those hopes will be on hold a while longer.The whole issue revolves around REMS, the shorthand for the FDA\'s Risk Evaluation and Mitigation Strategy programs. REMS are typically demanded by the FDA for potentially risky drugs and are a common requirement for heart disease meds.In a twist of fate, BMS also had a similar FDA REMS delay back in 2021, but its medicine was ultimately approved in 2022.In the U.S., Camzyos can only be used via a REMS program because it can cause the heart to become too relaxed, increasing the risk of heart failure. In its statement released after-hours Thursday, May 1, Cytokinetics said it had submitted its new drug application with the FDA without a plan for REMS, seemingly with the agency’s blessing. But not so fast: The FDA has now looked over the application and in fact does want a REMS plan “based on the inherent characteristics of aficamten,\" the company explained. While Cytokinetics has now provided the plan, the addition has been regarded as a “Major Amendment to the NDA,” according to the biotech, thus adding a mandatory three months to the review. The drug\'s decision is now expected by Dec. 26.Analysts at Evercore ISI were perplexed, saying in a note to clients: “We didn’t see this one coming. The most surprising part to us is that [aficamten\'s] NDA was originally submitted without an accompanying REMS. Was that actually the FDA’s guidance to the company or some sort of miscommunication? We assume the former given that the application was accepted.”The analysts added, however, that “the REMS was not expected to be the main differentiator for [aficamten].\" Shares in the biotech were down around 10% premarket. “We remain confident in the distinct benefit-risk and pharmaceutic profile of aficamten and continue to expect a differentiated label and risk mitigation profile upon its potential approval by FDA,” said Robert Blum, Cytokinetics’ president and CEO, in the release.“We look forward to continuing our constructive engagement with the FDA regarding the NDA for aficamten.”

Cytokinetics said late Thursday that the PDUFA date for its heart disease therapy aficamten would be delayed by three months to Dec. 26. The lag would allow the FDA to review a major change to its marketing application, namely the submission of a drug safety program or REMS. The major surprise here is that the company did not include a REMS in its original NDA filing. Stifel analysts described the omission as “not at all the Street’s expectation.” Previously, Cytokinetics’ management had said it would propose a REMS package when it submitted the NDA, they wrote on a Thursday note. Cytokinetics’ stock $CYTK was down by as much as 12% premarket Friday as investors digested the arguably unnecessary delay. The company appeared to suggest that the FDA was OK with the initial lack of a REMS, saying that it previously had pre-NDA discussions with the agency that led to the REMS-free filing, which the FDA accepted. The agency subsequently demanded a safety program “based on the inherent characteristics of aficamten,” though no extra clinical trials are needed. The PDUFA delay comes as the biopharma sector is keeping a close eye on the FDA, concerned that cuts could impact approval timelines . Aficamten is intended to treat the rare heart muscle condition obstructive hypertrophic cardiomyopathy, and in its pivotal trial, the cardiac myosin inhibitor beat placebo at improving oxygen uptake as patients exercised. Importantly, on a cross-trial basis, aficamten looked better than the existing medication for the disease, Bristol Myers Squibb’s Camzyos. Bristol Myers included a REMS program in its original NDA filing for Camzyos. That drug too had its approval date pushed back, from January to April 2022, to allow the FDA to assess updates to the proposed safety measures. In mid-April, the label of BMS’ drug was updated to lessen the REMS requirements, cutting the frequency of heart echo monitoring from every three to every six months, and lifting a ban on patients taking certain other drugs. Cytokinetics believes that aficamten will end up with differentiated REMS requirements to Camzyos, with even fewer restrictions.