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Applied Pressure: After Regulatory Redirect, Mixed Trial Results Pose Challenges for Drugmaker and Patient Group

News – April 24

April 24, 2023

By Daniel S. Levine

Brittany Cudzilo’s daughter Ansell, 5, was born with the rare metabolic condition galactosemia. The condition affected her ability to speak, remember, and control her behavior. She had difficulty forming friendships because she couldn’t remember other children’s names.

Ansell has been participating in a late-stage clinical trial of govorestat, an experimental therapy being developed by Applied Therapeutics to treat galactosemia. Cudzilo said because the study is blinded, she can’t say for sure that her daughter has been on placebo or treatment but said there has been dramatic improvement in her daughter’s condition that others have seen.

“When people see her and they haven’t seen her for a month or two, they almost always say something about, ‘I cannot believe how she’s speaking. I can’t believe how I can understand her. I can’t believe that she’s using multiple words, complex words. Her vocabulary is great,’” said Cudzilo, who said Ansell’s constant meltdowns have stopped and she can have relationships because her memory has improved. “We’ve seen so much change.”

But the future for govorestat is uncertain. Applied Therapeutics has been frustrated by the way the U.S. Food and Drug administration has approached the drug. While the company was readying to apply for accelerated approval for govorestat, the agency derailed those plans at the end of 2021 when it told the company to hold off because, despite earlier discussions with the agency about the use of a biomarker measure as a surrogate endpoint, it said that clinical outcomes data would likely be necessary for approval.

Now, topline data from a phase 3 clinical study showed what the company characterized as “compelling evidence of clinical benefit” as well as a “favorable safety profile,” but failed to show statistical significance in the study’s primary endpoint, a composite sum of four endpoints to measure improvements in behavior, activities of daily living, oral expression, and listening comprehension. The company notes than when oral expression and listening comprehension are removed, the study showed “highly statistically significant benefits of treatment compared to placebo.”

The company said it is requesting a meeting with the FDA prior to a potential filing of an application in the second half of 2023 to seek approval to market govorestat. But the company says its experience with the agency reflects a bigger problem with the way it works with rare disease drug developers, which have received sometimes changing and even contradictory instructions from the agency about how best to proceed toward an approval. The situation is made more complex in that govorestat is also in development as a treatment for the hereditary neuropathy SORD deficiency, but different divisions within the agency are the point of contact for the company on regulatory matters, each with their own approach.

Shoshana Shendelman, president and CEO of Applied Therapeutics, said a change in leadership in the Division of Rare Diseases and Medical Genetics at the FDA occurred after the company started its development program. She said the previous director, Drago Roman, used various tools that the agency has to approve drugs sooner for rare diseases. She said the division under Kathleen Donohue has a different way of thinking about things like accelerated approval and biomarker-based programs, something she said has contributed to a lack of approvals by the division at a time when other offices within the agency have approved a stream of rare disease therapies.

“We have gone through a few different cycles of change under the new leadership, our pediatric study in 2020 that had been previously designed and agreed to as a biomarker-based study with a clinical outcomes trial as confirmatory post-approval was put on clinical hold, not for safety reasons but for design reasons, which I think on its own is something that’s a bit of a shock,” Shendelman said.

Applied is not alone. Earlier this year on the Global Gene’s podcast RARECast, Reenie McCarthy, CEO of Stealth Biotherapeutics, discussed similar frustrations in navigating the FDA as her company sought to advance its experimental therapy for Barth syndrome, an ultra-rare and life-threatening condition.

Galactosemia is a rare genetic metabolic disease resulting in an inability to metabolize the simple sugar galactose. Galactose is found in foods but is also produced by the body. When not metabolized properly, galactose is converted to the toxic metabolite, galactitol, which causes neurological complications, including deficiencies in speech, cognition, behavior, and motor skills, and also results in juvenile cataracts and ovarian insufficiency in women. There are approximately 3,000 patients with galactosemia in the United States and 80 new births per year.

Govorestat crosses the blood brain barrier and inhibits aldose reductase, an enzyme that converts galactose into galactitol, a toxic metabolite that builds up in tissues and organs and can cause long-term disease complications. In an animal model of galactosemia, govorestat reduced toxic galactitol levels and prevented disease complications. Clinical trials have shown it significantly reduced plasma galactitol levels vs. placebo in adults and children with galactosemia.

People with galactosemia must adhere to a restricted diet that avoids any foods containing lactose, such as dairy products. Even so, the body will produce galactose on its own, which causes damage to people with galactosemia. Govorestat does not end the need for dietary restrictions, but it is intended to prevent endogenous galactose, in people with galactosemia, from forming into the sugar alcohol galactitol, which is neurotoxic.

“We’ve now been collecting that clinical outcomes data, which we believe is very strong clinical outcomes data, that should support an approval, but it’s been very difficult to stay within the restrictions of some of the trial design that’s been set upon us,” said Shendelman. “That primary outcome did not hit statistical significance because we had speech imposed on us as one of the outcomes and these children are all on speech therapy, and good news, speech therapy works, but it’s very difficult to measure an impact of a drug on speech with kids on varying degrees and levels of speech therapy. When we remove speech therapy from the clinical outcome, then we have a highly statistically significant effect.”

A spokeswoman for the FDA, through email, told Rare Daily she could not respond to questions provided to the agency for this story because of the need to protect the integrity of the review process and information relating to an unapproved application.

Patient advocates share the frustration with Applied. Cudzilo, whose daughter is a participant in the Applied study, is also vice president of the Galactosemia Foundation. She said her organization has made multiple efforts to help the agency understand the needs of the galactosemia patient community. After the FDA advised Applied Therapeutics that it would likely need outcomes data for an approval, the organization in March 2022 conducted a focus group of galactosemia patients and caregivers and shared those results with the agency. It followed that up with a formal patient-focused drug development meeting in September 2022 with several FDA staff in attendance. A Voice of the Patient report is still being completed, but she said the organization has been unable to elicit feedback, comments, or questions from the agency in response to those efforts or other communications it has sent other than a generic “thank you for reaching out.”

“It has been frustrating that a division that is solely based on seeing and meeting the needs of a rare disease community have not made an effort to communicate why they’ve been doing what they’re doing, especially when we have made such an effort to communicate with it,” she said. “It is hard to not be disheartened by that and to not be very frustrated.”

Cudzilo said the galactosemia community deserves treatment if there’s a safe treatment available. She believes the endpoints have been proven that there is change in these children and that delays by the agency will have dire consequences for children with the condition. While her daughter Ansell has been able to get treatment through the Applied Therapeutics study, her youngest daughter Louise, who is 18 months old, also has galactosemia but is too young to meet the study’s enrollment criteria. She also fears Ansell may lose access to the drug if it does not win approval.

“I think about my kids. I want them to have the opportunities I’ve had—to have a career that I love, a family that I love, to be able to balance my checkbook, and have a schedule,” she said. “I want those things for them, and I think this treatment can do that. It would be heartbreaking if my child did not have this medicine. Since she’s had it now, I don’t know how I would go forward as a parent. I have to do everything I can.”

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