Sanofi’s Next-generation ERT Halts Progression of Pompe Disease in Patients, Interim Trial Data Show

Sanofi Genzyme’s next-generation enzyme replacement therapy (ERT), avalglucosidase alfa, safely halts disease progression in people with Pompe disease, according to interim data from two Phase 2 clinical trials.

The trial’s results were the focus of oral and poster presentations at the 16th Annual WORLDSymposium, held Feb. 10–13, in Orlando, Florida.

Pompe disease is caused by acid alpha-glucosidase (GAA) enzyme deficiency, leading to the toxic build-up of glycogen (a large sugar molecule used for energy storage) in several tissues. The result is widespread weakness in both skeletal muscles, including those involved in breathing, and those of the heart.

The disease can develop as a rapidly progressive, severe form in the first months or first year of life (called infantile-onset Pompe disease) or as a slowly progressive, milder form later in life during childhood or adulthood (late-onset Pompe disease).

Currently, the only approved treatment for Pompe disease is an ERT — alglucosidase alfa — in which the GAA enzyme is delivered to patients once or twice a week. Alglucosidase alfa is marketed by Sanofi as Lumizyme in the U.S. and Myozyme in Europe.

Sanofi’s next-generation ERT, avalglucosidase alfa, was designed to improve GAA uptake by the body and boost glycogen clearance in target tissues.

Three international clinical trials are currently evaluating avalglucosidase alfa in people with infantile- or late-onset Pompe disease. They include the Phase 2 NEO-EXT study (NCT02032524), the Phase 2 Mini-COMET study (NCT03019406), and the Phase 3 COMET study (NCT02782741).

NEO-EXT is an open-label extension study of the completed Phase 1 NEO1 clinical trial (NCT01898364). NEO1 was a six-month, dose-escalating study which evaluated avalglucosidase alfa’s safety, tolerability, pharmacokinetics (uptake, distribution, and elimination in the body), pharmacodynamics (the therapy’s effects on the body), and preliminary effectiveness in 24 people with late-onset Pompe disease.

Among NEO1 participants, 14 had received previous alglucosidase alfa treatment (treatment-switch patients), while 10 had not received any previous treatment (treatment-naïve patients).

Two presentations, oral and poster, titled “NEO1 and NEO-EXT studies: Long-term safety and exploratory efficacy of repeat avalglucosidase alfa dosing for 5.5 years in late-onset Pompe disease patients,” provided NEO-EXT data of 17 patients who receive 20mg/kg of avalglucosidase alfa, once every other week, for 5.5 years.

Results showed that avalglucosidase alfa’s safety profile was consistent with that previously reported in the NEO1 study, with no life-threatening adverse events or deaths. The most common treatment-related adverse events were fatigue, headache, nausea, and rash (each experienced by three patients or 17.6%).

Moreover, both treatment-naïve and treatment-switch patients showed stabilization in lung and motor function, compared with the natural history of the disease. Notably, treatment-naïve patients showed greater therapeutic improvements than those who had previously received treatment.

Lung function was assessed using the forced vital capacity (FVC) — the total volume of air that can be forcefully exhaled — while motor function was measured by the 6-minute walking test, which measures the distance an individual is able to walk in six minutes.

“Results from the NEO-EXT study are consistent with the safety and preliminary efficacy data reported in the NEO1 study with avalglucosidase alfa in late-onset Pompe disease,” Mazen M. Dimachkie, MD, NEO-EXT’s lead investigator, said in a press release. Dimachkie is also a professor of neurology, vice-chairman of research programs, and the director of the neuromuscular division at Kansas University Medical Center.

Mini-COMET is a three-year study comparing the safety profile and preliminary effectiveness of avalglucosidase alfa with alglucosidase alfa in 22 patients (under 18 years) with infantile-onset Pompe disease.

Participants, who had to have a history of incomplete responses to alglucosidase alfa treatment, were randomly assigned to one of three patient groups.

Group 1 patients are receiving 20mg/kg of avalglucosidase alfa, while those in group 2 are being given 40mg/kg of avalglucosidase alfa, every other week. Participants in group 3 were randomized again to receive either 40mg/kg of avalglucosidase alfa every other week or alglucosidase alfa at their current stable dose (within a range of 20mg/kg every other week to 40mg/kg weekly).

Six-month results from Mini-COMET were also shared in poster and oral presentations, titled, “Mini-COMET study: Safety, immunogenicity, and preliminary efficacy for repeat avalglucosidase alfa dosing in patients with infantile-onset Pompe disease (IOPD) who were previously treated with alglucosidase alfa and demonstrated clinical decline.”

Data showed that both doses of avalglucosidase alfa were well-tolerated, with no severe treatment-related adverse events, no treatment discontinuations due to adverse events, and no deaths.

The most commonly reported adverse events were mild to moderate in severity, and included vomiting and fever (each experienced by six patients or 27.3%), upper respiratory tract infections (five patients or 22.7%), and cough and rash (four patients or 18.2% each).

“These safety and tolerability results are promising for the future development of avalglucosidase alfa treatment in infantile-onset Pompe patients,” said David Kronn, MD, mini-COMET’s lead investigator and an associate professor of pediatrics at New York Medical College.

In addition, the levels of disease burden biomarkers — creatine kinase and hexose (or glucose) tetrasaccharide — were reduced or stable in all three groups after six months of treatment, which Kronn stated was “very encouraging.”

The greatest reductions in biomarkers levels were observed in patients treated with the higher dose of avalglucosidase alfa (40mg/kg), while those continuing alglucosidase alfa treatment showed the lowest reductions.

The Phase 3 COMET study is evaluating whether avalglucosidase alfa leads to greater therapeutic effects than alglucosidase alfa (each given at a 20mg/kg dose every other week) in treatment-naïve children and adults with late-onset Pompe disease.

COMET has completed enrollment and its primary goal is assessing avalglucosidase alfa’s effects on patients’ lung function — measured by FVC in the upright position, Sanofi stated in email correspondence. The company expects to have COMET topline results later this year.