Venglustat Lowers Gb3 With No Signs of Disease Progression in Trial

Long-term oral treatment led to Gb3 reductions in 5 of 6 men in Phase 2 extension

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Daily treatment with the investigational oral therapy venglustat in men with Fabry disease led to significant reductions in globotriaosylceramide (Gb3 or Gl-3) — the fatty molecule that accumulates to toxic levels in the disease — and no signs of disease progression.

That’s according to up to three years of data from a small Phase 2a clinical trial (NCT02228460) and its extension study (NCT02489344).

“The totality of data from these studies indicates the potential value of venglustat for the long-term treatment of Fabry disease,” the researchers wrote, noting that larger, longer studies are needed to confirm these findings.

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Phase 3 clinical trials PERIDOT and CARAT recruiting adult patients globally

The safety and efficacy of venglustat is being further assessed in adults with Fabry in two currently recruiting placebo-controlled Phase 3 clinical trials: PERIDOT (NCT05206773) and CARAT (NCT05280548).

The PERIDOT trial is investigating venglustat’s effects on abdominal and nerve damage-related pain, while CARAT will evaluate the treatment’s therapeutic effects in left ventricular hypertrophy, a heart condition seen in some Fabry patients. Both are sponsored by Sanofi-Genzyme, which is developing venglustat.

The company-funded Phase 2 study, “Venglustat, an orally administered glucosylceramide synthase inhibitor: assessment over 3 years in adult males with classic Fabry disease in an open-label Phase 2 study and its extension study,” was published in Molecular Genetics and Metabolism. 

In Fabry, a deficiency in the alpha-galactosidase A enzyme prevents the appropriate breakdown of certain fatty molecules. These molecules, especially Gb3, then accumulate in cells, disrupting the function of the body’s tissues.

A standard Fabry treatment is enzyme replacement therapy, which works to provide a working version of the missing enzyme, restoring the body’s ability to break down Gb3.

In contrast, venglustat is a substrate reduction therapy. Instead of working to supply the enzyme needed to digest the fatty molecules, it acts to prevent the generation of the molecules in the first place. It does so by suppressing an enzyme that’s needed for their synthesis.

The Sanofi-sponsored Phase 2a trial enrolled 11 men (median age 24 years; range of 18–37 years) with Fabry disease at eight treatment centers in the U.S., the U.K., France, Poland, and Russia. Participants, who had not previously received any Fabry disease-specific therapy, took oral venglustat (15 mg) once per day for 26 weeks, or about six months.

Of the nine patients who completed the trial, eight chose to enter its open-label extension study, in which they continued to receive venglustat for another 130 weeks, or about 2.5 years.

The totality of data from these studies indicates the potential value of venglustat for the long-term treatment of Fabry disease

Venglustat linked to significant and sustained reduction in Gb3 accumulation

Both trials aimed to assess the therapy’s safety, pharmacodynamics (effects on the body, particularly Gb3 levels), pharmacokinetics (movement into, through, and out of the body), and exploratory efficacy.

Gb3 buildup in skin cells was rated according to severity on a scale of 0–3, with higher scores reflecting more severe accumulation.

Results showed that after six months, Gb3 scores remained unchanged in five men, reduced in three, and increased in one. This meant that venglustat did not have a significant effect on the severity of Gb3 accumulation, failing to meet the trial’s main goal.

However, after three years, five of the six men remaining in the extension trial saw a reduction in Gb3 scores compared with their values at the study’s start, with two men achieving a score of 0, reflecting a complete clearance of the molecule.

When looking more closely at the fraction of cells occupied by Gb3 clumps, a more precise measure, venglustat was associated with a significant reduction in Gb3 accumulation after six months, which was sustained for up to three years.

In addition, the blood levels of molecules in the Gb3 synthesis pathway were rapidly reduced after two weeks and remained significantly reduced throughout the study. Gb3 itself was also significantly reduced in the blood, although these drops were slower and more progressive (by 41.7% at six months and 77.5% at three years).

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Patients showed no signs of disease progression over three-year follow-up

Clinical efficacy measures evaluated in the study demonstrated that patients overall showed no signs of Fabry disease progression in the kidneys, heart, brain, or nervous system over the three-year follow-up.

That finding is notable in light of the fact that “if left untreated, patients with classic Fabry disease are at high risk of developing progressive and/or acute damage to organs, eventually leading to vital organ failure,” the researchers wrote.

They noted, however, that since enrolled patients were relatively young and generally did not have severe organ involvement at the study’s start, it remains to be seen how venglustat would affect patients with more severe disease.

Some participants also reported reductions in bodily and gastrointestinal pain with treatment.

Of the 169 adverse events reported among nine men, most were mild (73%) and unrelated (70%) to venglustat treatment. The most common side effects were headache and cold-like symptoms.

“No deaths or treatment-related life-threatening [adverse events] were reported during the studies,” the team wrote.

A single serious adverse event, related to depressed mood, and leading to study discontinuation was deemed related to venglustat.