UPDATED RESULTS FROM A NOVEL, LONGITUDINAL, MULTICENTER DISEASE MONITORING PROGRAM (DMP) OF VESTRONIDASE ALFA FOR THE TREATMENT OF MUCOPOLYSACCHARIDOSIS VII (MPS VII)

ABSTRACT

Background: MPS VII is an ultra-rare, autosomal recessive, debilitating, progressive lysosomal storage disease caused by beta-glucuronidase (GUS) enzyme deficiency. Vestronidase alfa (recombinant human GUS) enzyme replacement therapy is approved in the United States, Europe, and parts of Latin America for the treatment of MPS VII. Methods: The Disease Monitoring Program (DMP) is an ongoing, multicenter observational study collecting standardized real-world data from patients with MPS VII (N ≈ 35 planned) treated with vestronidase alfa or with any other management approach. Investigational sites are centers with expertise in mucopolysaccharidosis treatment. Data will be collected for up to 10 years and include demographics, clinical history, clinical characteristics, cognition, mobility, skeletal disease, pulmonary function, patient and caregiver-reported health-related quality of life, and long-term vestronidase alfa safety and effectiveness. Data are monitored and recorded in compliance with Good Clinical Practice guidelines. Annual individual patient reports will be provided to patients and caregivers. Results: As of 31 May 2021, 20 patients are enrolled 19 in the treated group and one in the untreated group. Of the 19 treated patients, 14 were treated with vestronidase alfa before DMP enrollment, and five were treated with vestronidase alfa during the DMP. Eleven patients (55%) are male, and 11 patients (55%) are Hispanic or Latino, reflecting that most patients (11 of 20) are enrolled in South America. Mean (SD [range]) age at MPS VII diagnosis was 4.47 (3.99 [0.1-12.0]) years and mean (SD [range]) age at DMP enrollment was 11.08 (7.21 [1.5-26.3]) years. Seven patients (35%) had a history of non-immune hydrops fetalis. For the 14 patients treated prior to DMP enrollment, mean (SD [range]) age at initiation of vestronidase alfa was 9.4 (6.3 [3.0-22.8]) years. For the five patients treated during the DMP, mean (SD [range]) age at initiation of vestronidase alfa was 6.1 (4.5 [2.5-11.5]) years. Three patients who reached two years of treatment in the DMP had an 88% and 75% reduction from baseline in the original (parent) clinical study in dermatan sulfate and chondroitin sulfate uGAG excretion, respectively. Four serious adverse events (SAEs) in two patients have been reported. One SAE, intermittent hypotension, was assessed as an infusion-associated reaction to vestronidase alfa;this SAE did not meet hypersensitivity criteria;this patient had a low positive anti-drug antibody (ADA) titer (180) prior to the first administration of vestronidase alfa but did not test ADA positive at any subsequent visit during the DMP. All SAEs were consistent with the known safety profile of vestronidase alfa. No deaths were reported. COVID-19 resulted in travel restrictions for many patients, but only one dose of vestronidase alfa was missed. Nine patients had ADA data analyzed at baseline;of these, four tested positive at initial baseline, but all four subsequently tested negative during the DMP, while three other patients had low positive ADA titers (range 110 to 1320). All patients with positive ADA samples tested negative for neutralizing ADA, and four had reductions of at least 80% in dermatan sulfate uGAG excretion from baseline in the original (parent) clinical study. Conclusions: Reductions in uGAG demonstrate ongoing effectiveness of vestronidase alfa at DMP Year 2. No new safety concerns were identified, and all patients continue on study. The MPS VII DMP continues to enroll patients and collect data to characterize MPS VII disease presentation, clinical heterogeneity, and progression.