The Food and Drug Administration has delayed its review of a closely watched gene therapy for Duchenne muscular dystrophy by one month, taking more time to consider whether approval should be initially limited to children who are most likely to benefit.In a statement Wednesday, the treatments developer, Sarepta Therapeutics, said the regulator needs modest additional time to complete its review and will now decide whether to grant an accelerated approval by June 22. The delay will involve final negotiations around the information that would be included in the drugs label, as well as the post-marketing commitments it will require of Sarepta. The FDA had previously set a May 29 deadline for its decision.Sarepta said the regulator is working towards potentially clearing the treatment for use in Duchenne patients between 4 and 5 years of age. An ongoing, placebo-controlled Phase 3 study would serve as a confirmatory trial and, if positive, could support a broader, non-age restricted label, Sarepta added. Results from that trial are expected by the end of the year.A Sarepta spokesperson declined to comment further. Shares of the company fell by 8% at market open Wednesday.Sarepta is seeking FDA clearance based on its treatment's ability to help people with the disease make a diminutive protein, called microdystrophin, thats thought to protect muscle. Additionally, there were signs in testing that some participants did better than medical history suggests they should have.However, in the only placebo-controlled test of Sarepta's gene therapy so far, treatment didn't meaningfully improve patients' function. Further analysis by the company after the fact suggested that participants who were 4 to 5 years old did better than those who were older.The mixed data presents a challenge for the FDA, which has appeared divided over whether to clear the treatment. At a meeting of FDA advisers 12 days ago, agency scientists questioned the significance of microdystrophin and were generally skeptical of Sarepta's results. Their views were shared by some of panelists, who ultimately voted 8-6 to recommend the FDA grant Sarepta an accelerated approval.The results in younger children were the most compelling evidence, Raymond Roos, a professor of neurological science at the University of Chicago Medical Center, said at the meeting. Perhaps the difference in the lack of improvement in the 6- to 7-year olds is because they started at a different level.The ongoing confirmatory study could soon answer some of the doubts held by FDA staff and agency advisers. But the short timeline also raises risks for the FDA, which could approve the therapy only to see that trial produce negative data.Celia Witten, the acting director of the FDA office that reviewed Sareptas therapy, said at the meeting that the FDA would expect to remove the therapy from market if the study fails.Duchenne is a progressive, muscle-wasting condition that almost exclusively affects boys. Because their muscles get weaker with time, its likely that the earlier a gene therapy is administered, the better, Jerry Mendell, the director of Nationwide Childrens Hospitals gene therapy research and a Sarepta study investigator, said in a recent interview.It makes sense, because youre treating robust muscle that is more likely to be receptive to receiving the gene, he said. Scar tissue also builds up as patients age, making it harder for muscles to contract and for the therapy to have an impact. Even if you get transduction and gene expression, those [muscle] fibers are not going to work as well,“ Mendell said.Still, the potential limits for Sareptas treatment, at least initially, are a bit surprising, wrote Brian Abrahams, an RBC Capital Markets analyst who covers Sarepta, in a note to clients. While this had always been viewed as a possible middle-ground to more cleanly justify an expedited approval given the better data in these patients, it had not been formally discussed at length during the [FDA meeting], Abrahams wrote.Editors note: This story has been updated with additional detail, quotes and analyst commentary. '

临床3期基因疗法

2023-05-19

·FierceBiotech

DMD gene therapy death exposes risks of treating older patients

Cure Rare Disease plans to continue its programs with alternative vectors. Cure Rare Disease has shared a deep dive into the death of the only participant in a gene therapy trial. The nonprofit and its collaborators tied the death of a patient with Duchenne muscular dystrophy (DMD) to an immune reaction to the viral vector, raising concerns about dosing older, more advanced people. Commercial development of DMD gene therapies has focused on younger patients, with Sarepta Therapeutics limiting enrollment in its phase 3 trial to children aged 4 to 8 years old. The restrictive recruitment criteria have stopped many DMD patients from accessing gene therapies in clinical trials run by Sarepta and its rivals. The patient dosed in the Cure Rare Disease clinical trial was 27 years of age, and the therapy had been designed for him. Last year, the nonprofit reported that the patient, who was the brother of its CEO, died after receiving the therapy. The death led to an investigation into what happened after the patient received the therapy, which was designed to use CRISPR transactivation to upregulate an alternate form of a key DMD protein. Writing in preprint journal medRxiv (PDF), Cure Rare Disease described the findings of the investigation. A post-mortem showed injuries to the patient’s lungs, likely caused by a strong immune reaction to the high dose of the adeno-associated virus (AAV) vector that was given to try to ensure sufficient expression to achieve a therapeutic effect. There was minimal expression of the transgene in the liver. At 1×1014 vg/kg, the studied dose was similar to that tested in other clinical trials but resulted in a higher vector genome load, a finding the researchers attributed to the patient’s lower lean muscle mass, 45%. The analysis suggests the patient had “a more severe innate immune reaction than others receiving similar or slightly higher doses of rAAV in microdystrophin gene therapy trials.” Based on the finding, the researchers identified a need for more data on the characteristics that may predispose people to severe innate immune reactions and concluded “dose determination will remain a challenge for custom-designed AAV-mediated therapies, as by definition the precise therapeutic dose will not have been established.” As for the application of CRISPR, the researchers said the toxicity and eventual death of the patient meant that an assessment of the safety and efficacy of the treatment was not possible. Cure Rare Disease plans to continue its programs with alternative vectors.

临床3期基因疗法临床结果

2023-05-12

·Firstwordpharma

FDA panel narrowly backs approval of Sarepta's DMD gene therapy

An FDA advisory panel that convened Friday to discuss the merits of Sarepta Therapeutics' SRP-9001 (delandistrogene moxeparvovec) for ambulatory patients with Duchenne muscular dystrophy (DMD) voted 8 to 6 recommending accelerated approval for the AAV vector-based gene therapy. The filing, granted a priority review late last year, has been assigned a target action date of May 29. "If it were to receive an accelerated approval, it would need to have a confirmatory data from a clinical trial to support continued approval," remarked Peter Marks, director of the FDA's Center for Biologics Evaluation and Research.Earlier in the week, FDA staff scientists had outlined a number of concerns about the application, ultimately concluding that clinical studies of SRP-9001 did "not provide unambiguous evidence" of benefit in ambulatory patients with DMD, and that it also posed a risk of patients not being able to receive other more effective AAV vector-based gene therapies in the future.The agency's presentation on Friday continued in the same vein, casting doubt on the structure of Sarepta's microdystrophin, a shortened form of dystrophin encoded by the therapy, as well as on preclinical testing, clinical trial results and manufacturing.Panel member Nirali Shah, who voted against, said "I don't have any real concerns about the risk of therapy, I think it's well tolerated, but I do remain concerned about the actual benefit, and whether that has been adequately demonstrated without a study that is going to be using the commercialised product." She added that "coming from a field of gene therapy – the product is the process – and I think the confirmatory study needs to be completed." Meanwhile, Rajiv Ratan said he was not convinced that Sarepta's data package "provided plausibility that the expression the microdystrophin would predict clinical outcome."Caleb Alexander, who also voted no, said he agreed that videos shown to the panel of boys who had been treated and appeared to achieve improved muscle function were "compelling and there are good clinicians here that think this product works…but as we heard, accelerated approval is based on more than that, and the threshold of substantial evidence has to be met."The regulatory filing included results from a study, dubbed Study 102, which showed that while SRP-9001 succeeded on the main biological endpoint of micro-dystrophin protein expression, there was no significant difference between SRP-9001 and placebo on the functional endpoint assessing improvement on the North Star Ambulatory Assessment (NSAA) rating scale at 48 weeks. Sarepta is currently evaluating its gene therapy in the Phase III EMBARK trial, also known as Study 301, in about 125 DMD patients between the ages of 4 to 7 years old, and proposes that it could serve as the post-marketing confirmatory study. EMBARK is expected to read out by the end of 2023.Among those who voted yes were Donald Kohn, who said "giving accelerated approval will give patients access to this over the next year, while the results from the definitive study are being analysed….We need to err on the side of patients being given the benefit of access." John Chiorini, who voted yes, said "waiting is not going to be beneficial to the patients."For a more in-depth take, see Spotlight On: Can this week's Duchene gene-therapy AdCom skirt controversy? More to follow.

临床3期基因疗法优先审批加速审批

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