Abstract
Mucopolysaccharidosis (MPS) VII is an ultra‐rare, progressively debilitating, life‐threatening lysosomal disease caused by deficiency of the enzyme, β‐glucuronidase. Vestronidase alfa is an approved enzyme replacement therapy for MPS VII. UX003‐CL301 was a phase 3, randomized, placebo‐controlled, blind‐start study examining the efficacy and safety of vestronidase alfa 4 mg/kg intravenously administered every 2 weeks to 12 patients with MPS VII. Due to the rarity of disease, broad eligibility criteria resulted in a highly heterogeneous population with variable symptoms. For an integrated view of the diverse data, the changes from baseline (or randomization for the placebo period) in clinical endpoints were grouped into three functional domains (mobility, fatigue, and fine motor + self‐care) and analyzed post‐hoc as subject‐level heat maps. Mobility assessments included the 6‐minute walk test, 3‐minute stair climb test, Bruininks‐Oseretsky test (BOT‐2) gross motor function subtests, and patient‐reported outcome assessments (PROs) related to movement, pain, and ambulation. Fatigue assessments included the Pediatric Quality of Life Multidimensional Fatigue Scale and other fatigue‐related PROs. Fine motor + self‐care assessments included BOT‐2 fine motor function subtests and PROs for eating, dressing, hygiene, and caregiver assistance. Most subjects showed improvement in at least one domain. Two subjects improved in two or more domains and two subjects did not show clear improvement in any domain. Both severely and mildly affected subjects improved with vestronidase alfa in clinical assessments, PRO results, or both. Heat map analysis demonstrates how subjects responded to treatment across multiple domains, providing a useful visual tool for studying rare diseases with variable symptoms.
Highlights
Mucopolysaccharidosis (MPS) VII is an ultra-rare, autosomal recessive, debilitating, and life-threatening lysosomal disease caused by a deficiency of the β-glucuronidase (GUSB) enzyme that aids in the degradation of glycosoaminoglycans (GAGs)
Most patients with MPS VII die before the second or third decade of life due to progressive organ dysfunction, with a median age of survival for patients postnatally diagnosed of 42 months
Mobility assessments included: 2- and 6-minute walk test (2MWT, 6MWT)14; 3-minute stair climb test (3MSC)15; Bruininks-Oseretsky test of motor proficiency (BOT-2) running speed and agility and balance16; clinical problem evaluation (CPE) walking and running; MPS health assessment questionnaire (MPS HAQ) walking, stairs, and movement17; and PROMIS health assessment questionnaire (PROMIS) pain or childhood health assessment questionnaire (CHAQ) pain depending on the age of the subject
Summary
Mucopolysaccharidosis (MPS) VII ( known as Sly syndrome) is an ultra-rare, autosomal recessive, debilitating, and life-threatening lysosomal disease caused by a deficiency of the β-glucuronidase (GUSB) enzyme that aids in the degradation of glycosoaminoglycans (GAGs). As a result, GAGs such as dermatan, chondroitin, and heparan sulfate, accumulate in a wide variety of tissues and cause organ dysfunction. Clinical endpoints for each subject were grouped into three functional domains—mobility, fatigue, and fine motor + selfcare—and analyzed as subject-level heat maps These domains were selected because they allowed for similar clinical efficacy results to be assessed in aggregate for each subject according to major areas of known disease impairment such as, walking/hip pain, lack of energy, and limited dexterity or independence in daily care. By including both physical assessments and patientreported outcome assessment scores, an integrated heat map analysis allowed us to assess the totality of response in each domain
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