Long-term Nexviazyme Therapy Improves Lung Function, Mobility in LOPD

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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Long-term treatment with Nexviazyme (avalglucosidase alfa) safely and effectively improves lung function and walking ability in children and adults with late-onset Pompe disease (LOPD), according to nearly two years of data from the Phase 3 COMET trial.

These findings, along with positive long-term results from the Phase 2 Mini-COMET study in children and adolescents with infantile-onset Pompe disease (IOPD), were presented by Sanofi Genzyme, the therapy’s developer, at the 2022 annual WORLDSymposium, held Feb. 7–11, both in person in San Diego and virtually.

“These new data demonstrate the impact of Nexviazyme to provide sustained effect in key disease measures for both late-onset and infantile-onset Pompe disease,” Alaa Hamed, MD, Sanofi’s global head of medical affairs for rare diseases, said in a press release.

“The research also adds to a growing body of evidence supporting this treatment’s use as a new standard of care for this debilitating, lifelong disease,” Hamed added.

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Nexviazyme is a next-generation enzyme replacement therapy (ERT) meant to succeed Sanofi’s Lumizyme (alglucosidase alfa) — marketed as Myozyme in Europe — which was the first approved ERT for Pompe.

The ERT works by delivering a lab-made version of the missing acid alpha-glucosidase (GAA) enzyme to Pompe patients. As such, it’s expected to prevent toxic glycogen buildup from damaging tissues, particularly muscles. Glycogen is a large sugar molecule used for energy storage.

Compared with Lumizyme, Nexviazyme was designed to improve the therapeutic enzyme’s delivery to muscles and boost glycogen clearance. Preclinical studies showed that the next-generation ERT has a 15 times higher cellular uptake than Lumizyme, and results in comparable glycogen clearance with a dose that’s five times lower.

Nexviazyme was approved in the U.S. last year for LOPD patients ages 1 and older, and in Canada for patients 6 months and older. Similar applications are being reviewed in Europe and Japan.

Regulatory approvals were based on positive data from the ongoing, global COMET trial (NCT02782741), which is testing Nexviazyme against Lumizyme in 100 previously untreated children and adults with LOPD.

Both ERTs were administered directly into the bloodstream every other week at a dose of 20 mg/kg for nearly a year.

Top-line results showed that Nexviazyme-treated patients had greater lung improvements, although it wasn’t statistically significant, and were able to walk farther in six minutes — a common test of aerobic capacity and endurance — than those on Lumizyme.

The trial met its main goal: to show that the next-generation ERT was at least not inferior to, or worked as well as, the standard treatment.

A total of 95 participants completed the one-year treatment period and entered the study’s open-label extension phase, where all will receive Nexviazyme for more than 4.5 years.

The newly presented COMET data involved the 86 patients (91%) who remained on the therapy up to the most recent follow-up at nearly two years. Among them were patients always on Nexviazyme and those who switched from Lumizyme.

Results showed that long-term treatment with Nexviazyme was associated with sustained lung function and mobility improvements, which were greater than those observed in patients who began the next-generation therapy a year later.

Specifically, forced vital capacity, a standard measure of lung function, improved by 2.65 points among those always on Nexviazym relative to the start of the study, and by 0.36 points in those initially on standard ERT.

Patients always on Nexviazyme also were able to walk an average of 18.6 more meters in six minutes after nearly two years, while those switching ERTs walked 4.56 more meters.

These findings highlight a “sustained treatment effect with Nexviazyme along with stabilization of treatment effect in patients switching from [Lumizyme] in respiratory function … and walking distance,” Sanofi stated in the release.

Nexviazyme’s safety profile was comparable between groups, and no new safety concerns were identified among patients who switched to the next-generation therapy in the extension phase. During the extension period, five participants across both groups discontinued treatment because of side effects, and six had serious side effects deemed likely related to the therapy.

At the symposium, Sanofi also presented new data from the ongoing, international Phase 2 Mini-COMET trial (NCT03019406), which is evaluating Nexviazyme’s seven-year safety and preliminary effectiveness against Lumizyme in 22 children and adolescents with IOPD. All had previously failed to respond adequately to the standard ERT.

Participants were given either one of two doses of Nexviazyme (20 or 40 mg/kg) or Lumizyme every two weeks for six months, after which all will receive up to 40 mg/kg of Nexviazyme for up to 6.5 years.

Previous six-month data showed that both Nexviazyme doses were well-tolerated, with no reports of severe side effects. Also, the higher dose was superior to standard ERT at lowering disease-associated biomarkers.

Mini-COMET’s new data, which corresponds to nearly two years of treatment, showed that Nexviazyme was generally well-tolerated, with most side effects being only mildly to moderately severe. There were no serious or severe treatment-related side effects or deaths.

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The most commonly reported side effects included rashes (36.4%), falls, pneumonia, and fever (31.8% each), headache (27.3%), upper respiratory tract infections (27.3%), and vomiting (22.7%).

Notably, participants initially assigned to Lumizyme and who switched to Nexviazyme’s high dose after six months showed no increased risk of safety concerns or side effects.

In addition, participants treated with Nexviazyme for two years showed stable or improved motor function, as assessed by several validated measures, and none showed signs of heart damage, a common complication of IOPD.

The trial design for the open-label, international Phase 3 Baby-COMET trial (NCT04910776) — which will assess the proportion of patients who are alive and free of invasive ventilation after one year of Nexviazyme treatment — also was shared at the symposium.

The study, currently enrolling in Europe and Taiwan, is evaluating Nexviazyme’s four-year safety and effectiveness in up to 16 previously untreated infants up to 6 months old with IOPD. The therapy’s pharmacokinetics, or its movement into, through, and out of the body, also will be assessed, along with its pharmacodynamics, or its effects on the body.

Data on the need for invasive ventilation from Baby-COMET will be compared with the results of an external group of Lumizyme-treated patients. Top-line data are expected in May 2024.