Clinical benefit of Applied's govorestat questioned after detailed SORD study reveal

2024-03-11

临床3期优先审批临床2期申请上市

Shares in Applied Therapeutics were down as much as 10% on Monday after the company disclosed more details of a Phase III study in sorbitol dehydrogenase (SORD) deficiency revealing the extent to which its proposed treatment, govorestat (AT-007), fell short of functional endpoints.

The aldose reductase inhibitor is already under priority review at the FDA as a treatment for classic galactosemia despite failing a Phase III paediatric study last year. At the time, CEO Shoshana Shendelman said the study had nevertheless demonstrated "compelling evidence" of clinical benefit. An FDA decision on that application is due on August 28, and the agency plans to convene an advisory panel to discuss the filing. Regulators in Europe have also accepted the drug for review for galactosemia.

The latest study, called INSPIRE, randomised 56 patients with SORD deficiency to receive either govorestat or placebo. The condition, an autosomal recessive form of hereditary neuropathy, results when loss of SORD prevents the body from converting sorbitol to fructose, leading to high sorbitol levels accumulating in the tissues and causing nerve damage over time.

At the moment, there are no FDA-approved therapies to reduce sorbitol levels in the nervous system. Govorestat works by inhibiting the conversion of glucose to sorbitol.

Last month, Applied said an interim analysis of the INSPIRE study showed a significant correlation between sorbitol levels and the prespecified CMT-FOM endpoint which measures functional ability of patients with neuropathies. The composite endpoint consists of 10m walk-run test (10MWR), 4-stair climb, sit-to-stand test, 6-minute walk test (6MWT) and dorsiflexion.

However, the company said at the time that there was no effect on the final primary endpoint of 10MWR at the 12-month interim readout, so the study would continue blinded through to 24 months. The company did not give any details, but Baird analysts noted that an initial read of the data looked "reviewable."

"We think the initial results from the Phase III INPSIRE study look good enough to get an FDA review for a Subpart H approval," the analysts said, adding that "govorestat has repeatedly shown the ability to substantially reduce sorbitol, the only factor with bioplausability for causality."

In the interim data analysis released Monday, Applied highlighted "trends" on CMT-FOM measures linked to walking ability, such as 10MWR (p=0.258), dorsiflexion (p=0.314) and 6MWT (p=0.606), although these were not significant. There was no substantial effect on stair climb or sit-to-stand test.

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