Avalglucosidase Alfa Approved for Late-Onset Pompe Disease
Branded as Nexviazyme, Sanofi’s enzyme replacement therapy demonstrated key improvements in measures of disease burden while maintaining its known safety profile.
Karin Knobe, MD, PhD
According to an announcement from Sanofi, the FDA has granted approval to avalglucosidase alfa-ngpt (Nexviazyme) for the treatment of late-onset Pompe disease in patients aged 1 year and older.1 The biologics license application for the long-term enzyme replacement therapy (ERT) was originally accepted for review by the agency in late 2020, after granting the agent breakthrough therapy and fast track designations.2
The therapy is administered as a monotherapy ERT every 2 weeks, with a recommended dose based on body weight—20 mg/kg for patients with late-onset Pompe disease weighing 30 kg or heavier, and 40 mg/kg for those patients under 30 kg—and is administered incrementally via intravenous infusion. It is expected to be available in the US in the coming weeks, according to Sanofi.
"Nexviazyme is a new therapeutic option that offers improvements in both respiratory function and measures of walking for people living with late-onset Pompe disease, 2 hallmark manifestations of this progressive and debilitating disease," Karin Knobe, MD, PhD, head, Rare Disease and Rare Blood Disorder Development, Sanofi, told NeurologyLive. "People may experience disease progression while on therapy, so the availability of another effective option is an important advancement for clinicians and patients alike."
The basis for the application was built on positive data from both the phase 3 COMET trial (NCT02782741) and the phase 2 mini-COMET trial (NCT03019406), which showed improvements over standard of care. In COMET, the ERT agent demonstrated a 2.9-point improvement (standard error [SE], 0.9) in forced vital capacity percent-predicted (FVC%) after 49 weeks of treatment, equaling a 2.4-point greater improvement (95% CI, –0.13 to 4.99) than those treated with Sanofi’s comparator product, alglucosidase alfa (Lumizyme), in a measurement of noninferiority (P = .0074). Statistical superiority over the comparator agent was not achieved, however (P = .06).
“Pompe disease is a debilitating and progressive condition that significantly inhibits mobility and breathing,” Bill Sibold, executive vice president, Sanofi Genzyme, said in a statement.1 “For decades, we’ve made it our responsibility to research how to target the M6P receptor, the key pathway for cellular uptake of enzyme replacement therapy. Nexviazyme is a potential new standard of care for people living with late-onset Pompe disease and delivers on our promise to pursue medicines for patients living with rare diseases.”
Bill Sibold
Additional secondary end point data from COMET showed that those treated with avalglucosidase alfa-ngpt walked 32.2 m (SE, 9.9) further at Week 49 on the 6-minute walk test (6MWT) compared to baseline, and 30 m (95% CI, 1.33-58.69) further than the comparator group. Per the hierarchy of the study protocol, formal statistical testing for all secondary end points was not conducted.
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In February 2021, amid the annual WORLDSymposium meeting, COMET trial investigator Priya S. Kishnani, MD, CL and Su Chen Professor of Pediatrics; medical director, YT and Alice Chen Pediatrics Genetics and Genomics Center; and division chief, Medical Genetics, Duke University Medical Center, told NeurologyLive that these data strengthened the growing body of clinical evidence supporting the use of this agent in late-onset and infantile-onset Pompe disease.3
“The data shows clinically meaningful improvements in respiratory muscle function, mobility, muscle strength and function, and disease-specific biomarkers [urine Hex4], in patients with late-onset Pompe disease, translating into improved health-related quality of life in both adult and pediatric patients,” Kishnani said at the time. “We also see the sustained benefit of treatment with avalglucosidase alfa-ngpt in patients with late-onset Pompe disease who have participated in the NEO-EXT study for up to 6 years.”
With regard to safety in COMET, during the double-blind active-controlled period, serious adverse events (AEs) were reported in 2 (2%) patients treated with avalglucosidase alfa-ngpt and in 3 (6%) patients treated with the active comparator. The most frequently reported AEs (occurring at a rate of >5%) in the study drug patient group were headache, pruritus, nausea, hives, and fatigue. Infusion-associated reactions were reported in 13 (25%) of the avalglucosidase alfa–ngpt-treated patients and in 16 (33%) of patients treated with alglucosidase alfa. Infusion-associated reactions reported in more than 1 patient on avalglucosidase alfa-ngpt were mild to moderate and included headache, diarrhea, itching, hives, and rash. None were deemed severe.
“Nexviazyme is a new and exciting therapeutic option for people with late-onset Pompe disease,” Mazen M. Dimachkie, MD, FAAN, FANA, professor of neurology; chief, Neuromuscular Division; and executive vice chair, Department of Neurology, University of Kansas Medical Center, said in a statement.1 “The phase 3 study results showed meaningful improvements in respiratory function and walking distance, which are impactful in this serious condition.”
Current estimates suggest that Pomspe disease affects 3500 people in the United States, with symptoms presenting at any age. Due to a varying spectrum of clinical presentations and the progressive nature of late-onset Pompe, it can take 7-9 years before patients receive an accurate diagnosis.
