New trial data show oral venglustat beats ERT for neurological symptoms
Study found similar control of key non-neurological Gaucher type 3 symptoms
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Sanofi‘s experimental oral therapy venglustat was better than its enzyme replacement therapy (ERT) Cerezyme (imiglucerase) at easing neurological symptoms in people with Gaucher disease type 3.
That’s according to new data from the LEAP2MONO Phase 3 clinical trial (NCT05222906), presented as late-breaking research last week at the 22nd annual WORLDSymposium. Data also showed that a daily tablet of venglustat was as effective as Cerezyme at controlling key non-neurological disease symptoms.
Current treatment options for Gaucher type 3
Cerezyme is currently the only therapy approved in the U.S. to treat the non-neurological symptoms of Gaucher disease type 3, but no therapies are approved to treat neurological symptoms in these patients.
Based on these findings, Sanofi plans to file applications with regulatory agencies worldwide seeking approval of the therapy for Gaucher type 3.
“These findings underscore Sanofi’s commitment to rare disease research and the promise we aim to deliver for people living with these conditions,” Houman Ashrafian, executive vice president and head of research and development at Sanofi, said in a company press release.
“What excites us most is the potential to address critical unmet medical needs. A daily pill could make a serious difference for Gaucher patients facing neurological challenges,” Ashrafian added. “Most importantly, none of this would be possible without the courage of the patients and families who participate in our studies, and for that we owe them a debt of gratitude.”
Gaucher disease is a genetic disorder caused by defects in the glucocerebrosidase (GCase) enzyme, which normally helps break down certain fatty molecules. Without enough working GCase, these fatty molecules build up to toxic levels in cells, damaging organs and tissues.
The most common type of Gaucher disease, type 1, causes symptoms such as liver and spleen enlargement and blood cell abnormalities, but does not cause neurological problems. By contrast, Gaucher type 2 causes severe neurological symptoms that usually lead to death in early childhood.
Gaucher type 3 lies between these two extremes. People with this form of the disease experience neurological symptoms, but they are usually less severe than in type 2 and often appear later in childhood or adulthood.
How enzyme replacement therapy works
ERT works by delivering a working version of the GCase enzyme to the body and can help manage the non-neurological symptoms of Gaucher type 3. However, ERT therapies generally cannot cross from the blood into the brain, so they have limited ability to treat neurological symptoms of the disease.
Currently, the only approved treatment for Gaucher type 3 in the U.S. is Sanofi’s Cerezyme, but the therapy can only help manage non-neurological complications of the disease.
Venglustat belongs to a different class of therapies called substrate reduction therapies (SRT), which are designed to limit production of the fatty molecules whose toxic buildup drives Gaucher disease.
By reducing production of these molecules, SRTs aim to slow their buildup and help limit disease progression. While two SRTs are approved for Gaucher disease, these molecules also cannot reach the brain, so they also cannot ease the neurological symptoms of the disease.
Venglustat, however, can cross from the bloodstream into the brain and is designed to address both neurological and non-neurological symptoms of Gaucher type 3.
Inside the Phase 3 venglustat clinical trial
To test this idea, Sanofi launched the LEAP2MONO trial, which enrolled 43 adults and adolescents ages 12 and older with Gaucher type 3. All participants had been on Cerezyme or other ERT for at least three years before entering the study and had been clinically stable for at least one year.
In the LEAP2MONO study, participants were randomly assigned to receive either Cerezyme or oral venglustat for 52 weeks, or about one year. The study’s main goals were to determine whether venglustat improved outcomes on two standardized measures of neurological function: the Scale for Assessment and Rating of Ataxia (SARA) modified total score and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).
What excites us most is the potential to address critical unmet medical needs. A daily pill could make a serious difference for Gaucher patients facing neurological challenges.
Sanofi reported that the study met its main goal, with patients on venglustat performing significantly better on these two neurological measures than those on Cerezyme.
Key secondary goals of LEAP2MONO were to assess whether venglustat was at least as good as Cerezyme at controlling nonneurological symptoms of Gaucher type 3.
The four key goals included changes in spleen and liver volume, as well as in levels of hemoglobin (the protein that carries oxygen in the blood) and platelets (cell fragments that help blood clot). Gaucher commonly causes low hemoglobin and platelet levels.
According to Sanofi, LEAP2MONO met three of its four key secondary endpoints, with venglustat performing as well as Cerezyme on measures of spleen volume, liver volume, and hemoglobin levels.
Sanofi also said that venglustat was generally well tolerated in the study. The most common safety issue was headache, which was reported in a similar proportion of patients on venglustat and Cerezyme (14.3% and 18.2%, respectively). Nausea, spleen enlargement, and diarrhea were also common side effects, and were reported more often among patients given venglustat than among those on Cerezyme.
