Bristol Myers Squibb Co.

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.”

CHICAGO — A new type of targeted cancer drug that blocks a “DNA caretaker” protein called Werner helicase has captured the attention of several big pharma companies in recent years, and the first data appear to reinforce its potential. Cells are typically equipped with critical redundancies for important proteins, but when they mutate in cancer patients, a single protein can become the key to a cell’s life or death. By finding the proteins that aberrant cancer cells need to function and then blocking them, drug developers are building the next generation of targeted cancer treatments. Roche now has the first data for its experimental drug, which takes advantage of what’s known as synthetic lethality, in gynecologic and colon cancers. It was shared this week at the American Association for Cancer Research’s annual meeting in Chicago. In the span of six years, scientists and physicians took a promising drug target identified via CRISPR screening and created a handful of experimental treatments for cancer patients. There are now four different Werner helicase-targeting agents in early-stage clinical trials from Roche, Novartis, GSK and Nimbus Therapeutics — a private drug developer with a track record of doing big deals. “Werner helicase really and truly represents a synthetic lethal vulnerability and therefore a therapeutic opportunity in MSI cancers,” said Timothy Yap, a physician-scientist with the University of Texas MD Anderson Cancer Center, referring to cancers with a specific DNA signature. “That’s really the crux of it and why it was so exciting.” Synthetic lethality is a phenomenon that scientists are exploiting to develop new targeted cancer treatments. Their inspiration is PARP inhibitors (such as AstraZeneca’s Lynparza), a class of drugs used to treat a wide range of cancers including breast and ovarian. PARP inhibitors are a synthetic lethal therapy for cancers with BRCA mutations. In the Phase 1 study, Roche’s experimental drug led to four confirmed responses — two in endometrial cancer, one in colorectal cancer, and one in ovarian cancer — in 35 patients. There was also a fifth unconfirmed response in endometrial cancer. Yap presented the data Sunday at the AACR meeting. The responses mean the drug, which came from Roche’s partnership with Vividion Therapeutics in 2020, shrank the tumors in these patients at least 30%. It’s the first time that researchers have shown the effect of a Werner helicase blocker in people. Many of the patients in the study had gone through several previous treatment regimens. While their cancers were found in a wide range of locations, most of the tumors were considered microsatellite instable, which is a sign of DNA misrepair that physicians frequently look for in cancer diagnoses. The initial science that identified Werner helicase as a potential target showed that knocking it out was lethal to the microsatellite instable cells, and this piqued the interest of drug developers. Microsatellite instability-high cancers make up around 3% of all cancer cases, according to some estimates. The responses to Roche’s drug occurred at a range of doses, from 150 mg a day to 1,000 mg twice a day. In an interview, Ryan Corcoran, director of the gastrointestinal cancer center program at the Massachusetts General Hospital Cancer Center, said there’s not a clear correlation between the responses and dose levels. Researchers typically look for dose dependency (more drug equals better efficacy) in clinical studies as a green flag the treatment is working as intended. Corcoran, who chaired the session where Roche’s clinical trial results were presented, consults for Roche but not on the Werner helicase project. The primary side effects related to the drug were nausea, vomiting and diarrhea. There were no dose-limiting toxicities. Like Novartis had already reported, both GSK and Nimbus disclosed at the meeting that their molecules were non-covalent, meaning they do not permanently bind Werner helicase. This leaves Roche as the lone company developing a covalent, or permanently binding, agent in clinical trials. GSK suggested in its presentation that its drug could work in tumors that acquired resistance to Roche or Novartis’ compounds, but that’s based on animal model data and has not been shown in humans. GSK’s drug comes from a partnership with Ideaya Biosciences, a biotech company that’s focused on developing drugs against synthetic lethalities. In 2019, four papers were published showing Werner helicase could be a promising target for treating microsatellite instable cancers. These cancers tend to respond well to immunotherapy, but patients have few other options beyond those treatments. Of the two studies published in Nature on the same day, one was from Mathew Garnett’s lab at the Wellcome Sanger Institute, while the other was led by Adam Bass, who at the time was at the Dana-Farber Cancer Institute and now leads translational cancer research at Novartis. Using CRISPR screening, researchers from both groups found that Werner helicase was needed in microsatellite instable cancer models but dispensable in models that were microsatellite stable. “When you knock out Werner helicase, in 48 hours, the cells are dead,” Garnett said. “All their DNA is just shattered, and it’s really phenomenal. You had this sense when you saw this genome shattering, that there was something really profound happening to these cells.” There are several other synthetic lethality programs in early-stage trials. Corcoran said he has yet to see results from another class of synthetic lethal drugs that matches the success of PARP inhibitors, though many of these efforts are still early and have yet to report clinical data. One closely-watched effort to leverage synthetic lethality is targeting a protein called PRMT5 in cancers with mutations known as MTAP deletions. This is an area in which Bristol Myers Squibb, Amgen, Ideaya and others are all working on early-stage programs, though readouts so far have been mixed . Eli Lilly and Foghorn Therapeutics last year began a Phase 1 trial for a SMARCA2 inhibitor, which they are studying in patients with SMARCA4-mutated cancers. “Imagine you’re riding a bicycle — it’s a bicycle with two wheels — and one of the wheels is lost, and now you’re riding a unicycle,” Foghorn CEO Adrian Gottschalk said. And so giving a SMARCA2 inhibitor to one of these patients is like taking a stick to the cancer cell’s remaining wheel, he said.

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.