Venglustat named breakthrough therapy by FDA for Gaucher type 3
Oral medication shows potential to help manage neurological symptoms
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The U.S. Food and Drug Administration (FDA) has granted breakthrough therapy status to Sanofi‘s experimental oral medication for Gaucher disease type 3, venglustat, which has shown potential in a clinical trial for improving measures of neurological function in people with this form of the genetic disorder.
While there is an approved therapy in the U.S. for Gaucher type 3, it does not help manage neurological symptoms in these patients.
This FDA designation is granted to therapies designed to treat serious or life-threatening conditions that have shown promise in clinical testing. The goal of such status is to speed the development and review of important new therapies.
“This regulatory milestone recognizes the significant unmet medical need for people living with type 3 Gaucher disease, particularly those experiencing progressive neurological deterioration,” Karin Knobe, MD, PhD, global head of clinical development for rare diseases at Sanofi, said in a company press release announcing the FDA’s award.
Gaucher disease is caused by mutations in the gene encoding glucocerebrosidase (GCase), an enzyme that breaks down certain fatty molecules inside cells. In Gaucher, the lack of functional GCase causes these fatty molecules to accumulate to toxic levels in cells, leading to symptoms such as blood abnormalities, enlarged organs, and bone problems.
Gaucher type 3 is a relatively rare form of the disease marked by neurological symptoms that typically manifest in late childhood or adulthood and progress relatively slowly.
This contrasts with Gaucher type 1, which is marked by the absence of neurological symptoms, and Gaucher type 2, characterized by severe neurological problems that arise in early infancy and worsen rapidly.
In trial, venglustat bested approved therapy Cerezyme
In the U.S., Sanofi’s enzyme replacement therapy (ERT) Cerezyme (imiglucerase) — given by an intravenous, or into-the-vein infusion — is the only approved treatment for type 3 Gaucher disease. The therapy works by delivering a functional version of GCase, helping cells clear the excess fatty molecules.
Generally, however, ERTs have a limited ability to reach the brain and cannot ease the neurological symptoms of Gaucher. For this reason, Cerezyme is specifically indicated to help manage the nonneurological complications of Gaucher type 3; no treatments are approved to manage neurological symptoms in these patients.
Venglustat is an oral substrate reduction therapy (SRT) designed to block the activity of glucosylceramide synthase, a protein that helps produce the fatty molecules that build up to toxic levels in Gaucher. The therapy basically aims to shut down production of these fatty molecules, thereby lessening the toxic buildup that drives Gaucher symptoms.
Importantly, venglustat is able to easily cross into the brain, so it has the potential to help address both neurological and nonneurological symptoms of the disease, according to Sanofi.
The new FDA designation was based on data from the LEAP2MONO Phase 3 clinical trial (NCT05222906), which enrolled 43 children and adults with Gaucher type 3. These patients, ages 12 and older, were clinically stable on long-term ERT before starting the trial. The participants were randomly assigned to take Cerezyme or venglustat for a year.
Data presented last month showed that LEAP2MONO hit its main goal: Venglustat was significantly better than Cerezyme at improving standardized measure of neurological function. A daily tablet of venglustat also was as effective as Cerezyme at controlling key nonneurological disease symptoms.
The therapy was also generally well tolerated, with no new safety signals, the company said. Common side effects that were more frequently reported with the SRT than Cerezyme included nausea and diarrhea, as well as spleen enlargement.
Sanofi is now planning to use these data to support an application requesting the approval of venglustat for Gaucher type 3. The company said it plans to pursue global filing this year.
“The positive LEAP2MONO findings are an encouraging step forward in the research and development process, and we will continue collaborating with the FDA to advance this potential treatment option,” Knobe said.
