Glepaglutide

The FDA’s correspondence includes the decision not to approve Zealand Pharma’s GLP-2 drug glepaglutide for short bowel syndrome.\n The FDA’s ongoing effort to establish a culture of “radical transparency” saw the agency publish another haul of complete response letters (CRLs) yesterday.The latest batch of 89 rejection letters was uploaded Sept. 4 along with a pledge by the agency to begin publicly releasing this type of communication at the same time the documents are issued to sponsoring companies. As with the initial mailbag of more than 200 CRLs that the FDA made available back in July, a dive into yesterday’s letters sheds further light on the agency\'s often-opaque drug review process.Among the letters are some high-profile decisions for the likes of Ultragenyx’s gene therapy for Sanfilippo syndrome type A, Capricor Therapeutics’ Duchenne muscular dystrophy cell therapy and Replimune’s melanoma drug RP1. The contents of the letters often map onto information already in the public domain, but there are still some fresh insights to be gleaned about the FDA’s decision-making process.‘Numerous unreported adverse events’ The FDA’s correspondence certainly sheds more light on the agency’s decision at the end of last year not to approve Zealand Pharma’s GLP-2 drug glepaglutide in short bowel syndrome. That application—which could have set up glepaglutide as a possible challenger to Takeda’s Gattex—was based on results from a single placebo-controlled phase 3 study dubbed EASE-1.The trial hit its primary endpoint, with twice-weekly doses of glepaglutide reducing weekly parenteral support (PS) volume—a measure of tube feeding—by a statistically significant 5.13 liters at 24 weeks compared to baseline. However, once-weekly doses of glepaglutide failed to yield statistically significant reductions in PS.When Zealand announced that it had received the CRL in December 2024, the company didn’t divulge much detail, only confirming that the agency had “concluded that Zealand Pharma’s application did not meet the full requirements for substantial evidence to establish the efficacy and safety of the to-be-marketed dose of glepaglutide.”The full letter from the FDA, which was uploaded yesterday, gives a more detailed insight into the agency\'s rationale. While acknowledging the twice-weekly dosing endpoint win, the FDA pointed to “numerous uncertainties that limit the interpretability and/or persuasiveness of the results.”These included “observed inconsistencies” in PS as a result of adjustments outside of the trial’s protocol, according to the FDA. The inconsistencies “raise concerns that the observed changes in PS volume may have been impacted by factors other than the drug’s efficacy and may not accurately represent PS volume requirements of the subject,” the FDA said in the letter. The agency also noted that “incomplete or missing documentations of urinary output in the 48 hours prior to study visits” were observed in up to 12% of patients in the EASE-1 trial, as well as in 68% of patients in the follow-on EASE-2 study.Meanwhile, an FDA inspection of one of the study’s clinical investigator sites identified “several concerning observations,” including “numerous unreported adverse events” among six of the nine patients enrolled there. Two of these unreported events were considered “serious” and involved patients being hospitalized due to acute kidney injury or hypomagnesemia, respectively.The FDA’s recommendation was for Zealand to conduct a further trial, and the Danish biotech is on track to kick off that study later this year. In the meantime, the company is awaiting an approval decision for glepaglutide from European regulators.Psychedelic uncertainties When it came to the rejection of Lykos Therapeutics’ application for its MDMA candidate midomafetamine to treat post-traumatic stress disorder, the potential objections had been out in the open for a while. Even before the agency sent the CRL in August 2024, the FDA had voiced concerns in briefing documents about whether a clinical trial for an MDMA treatment could ever be properly blinded, given that the drug “produces profound alterations in mood, sensation, suggestibility and cognition.”The agency’s Psychopharmacologic Drugs Advisory Committee had also been unconvinced of approval, in what was the first instance of an FDA committee reviewing a psychedelic treatment.Summarizing the contents of the CRL at the time, Lykos said the letter had “included concerns that Lykos\' clinical data were insufficient to demonstrate durability along with questions about expectancy bias stemming primarily from participants with prior MDMA use.” Reading the full letter reveals that the FDA also echoed specific prior concerns it had raised about the need to record “positive” effects of the treatment as adverse events for the purposes of the study.“As you were specifically advised, regardless of whether a participant, therapist or physician may find a drug experience to be neutral, positive or favorable, events that are relevant to the abuse potential of a drug or potential for impairment should have been captured and reported,” the FDA wrote in its letter.“Because such events were not captured and reported, the studies failed to adequately characterize the safety of midomafetamine, its acute effects, the duration of impairment, or signals of abuse potential within these studies,” the agency added.The last we heard from Lykos, it hadn’t let this setback get it down. As of January, the biotech had met with the FDA to “chart a path forward for an independent third-party review of prior phase 3 clinical data and an additional phase 3 trial.”A matter of timing Regeneron got off lightly when the FDA rejected its application for the T-cell engager odronextamab to treat patients with follicular lymphoma or diffuse large B-cell lymphoma. Announcing the CRL in March 2024, the pharma was keen to stress that the agency had not identified “any approvability issues.”Regeneron’s original plan had been to enroll patients in various confirmatory phase 3 lymphoma trials that formed part of the wide-ranging Olympia program while it sought accelerated approval. Enrollment in the dose-finding portion of these trials had already begun when the company filed its application, but Regeneron explained at the time of the rejection that the FDA decided “the confirmatory portions of these trials should be underway and that the timelines to completion be agreed prior to resubmission” of the application.A close read of the FDA’s letter suggests the agency was certainly skeptical of Regeneron’s proposed time frames.“The current conduct and projected completion date of any of these Olympia trials in follicular lymphoma do not provide sufficient assurance of timely completion of the trial(s),” the letter reads.When it came to resubmitting the application, the FDA said Regeneron would be wise to “demonstrate sufficient progress in the conduct of the confirmatory portion of the confirmatory trial(s) to provide sufficient assurance of timely completion of the trial(s).\"The pharma returned to the FDA with an updated application in February, but this resulted in another rejection a few weeks ago. This time, Regeneron blamed the decision on problems uncovered during an FDA inspection of an Indiana plant now owned by Regeneron’s manufacturing partner Novo Nordisk.Regeneron can at least take some comfort from the fact that despite these U.S. setbacks, odronextamab secured the green light from European regulators back in August 2024.

iStock, undefined undefined Perhaps the most interesting of the pile of FDA rejection letters was for Lykos Therapeutics’ MDMA therapy. Letters sent to Stealth BioTherapeutics, Regeneron and more were also released as the agency also promised future CRLs “promptly after they are issued to sponsors.” Going forward, the FDA will make complete response letters publicly available “promptly after they are issued to sponsors,” the agency said in a release late morning on Thursday. A the same time, the FDA released a cache of rejection letters from 2024 and 2025, following the 200 older rejections made public this summer. Like last time, many of the complete response letters (CRLs) were heavily redacted, or rehashed drug rejections that have already been publicized. Perhaps the most interesting of the pile was the rejection letter for Lykos Therapeutics’ midomafetamine (MDMA) therapy, which had been submitted to treat post-traumatic stress disorder. The drug went through a tumultuous advisory committee meeting in 2024, only to be rejected by the FDA in August that year. Much of the drama surrounding the drug’s rejection has already been revealed, particularly as the company has tried to recover from the crushing blow. In the letter, the FDA seemed to zero in on unreported safety events at two sites and the potential for abuse during the treatment process, which is conducted in an in-patient setting. The letter explains that Lykos did not submit information on events that the participant or therapist considered “positive or favorable,” which would be necessary to assess signals of abuse or patient impairment. “There are substantial concerns about the reliability of the safety data which limit our ability to adequately assess the safety of midomafetamine for the treatment of PTSD,” the FDA wrote. Other issues included the durability of the therapy, design issues in the study and the high proportion of patients who had reported previously using MDMA. The FDA recommended a new study to demonstrate the durability of the effect, minimize the potential for bias and characterize safety. The agency also recommended that Lykos conduct an audit of the serious safety concerns raised during the adcomm, which included allegations of a therapist abusing a patient. Another letter provides details of Stealth BioTherapeutics’ rejection for elamipretide . The biotech had been seeking approval of the therapy for Barth syndrome, an ultra-rare genetic disorder that causes muscle weakness, fatigue and heart failure. About 85% of patients with Barth die by the age of five. In announcing the rejection in May, Stealth did not detail the FDA’s specific concerns. In the letter, the FDA acknowledges the challenging nature of Barth syndrome and the need for an approved treatment. The agency said it evaluated the submitted packet carefully, employing “regulatory flexibility” for the rare and serious disease. Stealth had proposed using several surrogate endpoints, including left ventricle stroke volume, a measure of the amount of blood being pumped from the left ventricle during a single heartbeat. The company suggested that these could reasonably predict clinical benefit. Nevertheless, the FDA was “unable to conclude that these approaches establish the effectiveness of elamipretide for traditional or accelerated approval.” Instead, the agency suggested that Stealth resubmit the application under the accelerated pathway using the surrogate endpoint of muscle strength of the knee extensors. The FDA flagged that Stealth’s SPIBA-201 study did not meet its primary endpoints, noting that in Part 2 of the study the endpoints were based on patient effort and could be subject to bias if patients knew they were on the study drug. The FDA also noted deficiencies at the drug manufacturing facility. Stealth resubmitted the application for elamipretide in August. Elsewhere in the cache was the FDA’s short and sweet rejection of Regeneron’s odronextamab. The company had already revealed that the FDA had concerns with the manufacturing site that were not specific to Regeneron’s drug. The site in question is operated by Catalent, which was acquired by Novo Holdings and transferred to Novo Nordisk last year. Another letter provided details of Zealand Pharma’s rejection for glepaglutide, although much of the details had been released by the biotech itself in December 2024 . The same goes for a letter explaining the controversial rejection of Replimune’s RP1 . After the CRL was received in July, 22 experts involved in the clinical trial that underpinned the application responded to the FDA’s specific concerns, defending the trial design and its outcomes. At the time, analysts even alleged the possibility of political interference by Center for Biologics Evaluation and Research (CBER) Vinay Prasad. One notable difference in the release of this cache of letters is that the letter writer’s name was redacted, whereas the previous 200 letters released in July included that information. The FDA also released a letter rejecting Rocket Pharmaceuticals’ gene therapy Kresladi. The company at the time of the June 2024 rejection said the agency had requested additional chemistry, manufacturing and controls information to complete its review. The newly released letter is mostly redacted, with no new information revealed.