Individual heat map assessments demonstrate vestronidase alfa treatment response in a highly heterogeneous mucopolysaccharidosis VII study population

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.

Clinical effect and safety profile of pegzilarginase in patients with arginase 1 deficiency

“…Baseline abnormalities and key mobility assessments were displayed using a heat map‐like display. 14 Given the absence of any previous reports of clinical outcome assessment use in ARG1‐D, baseline deficits and clinical response definitions were based on literature insights from other relevant mobility impacting conditions and expert opinions. Baseline deficits were defined as: 6MWT: below the lower fifth percentile; GMFM‐D: <35 of 39; GMFM‐E: <68 of 72; ABAS‐3: ≤85.…”

“…AEs, vital signs, and laboratory tests including PD assessments were summarized. Baseline abnormalities and key mobility assessments were displayed using a heat map‐like display 14 . Given the absence of any previous reports of clinical outcome assessment use in ARG1‐D, baseline deficits and clinical response definitions were based on literature insights from other relevant mobility impacting conditions and expert opinions.…”

Intravenous Enzyme Replacement Therapy in Mucopolysaccharidoses: Clinical Effectiveness and Limitations

“…Two studies on MPS I and MPS II identified the amelioration of ROM as the main cause of improvements in ADL and consequently in QoL [34,45]. Improvement in mobility was seen in 6 of 12 MPS VII patients treated with vestronidase alfa and 6 out of 12 patients showed fine motor issues and self-care improvement [21,157]. Conversely, Cox-Brinkman et al did not find any ROM improvement in MPS I after one year of treatment with laronidase [94] and Guarany et al did not see any difference between treated and not-treated patients with different MPSs [95].…”

Open-label phase 1/2 study of vestronidase alfa for mucopolysaccharidosis VII

“…Vestronidase alfa concentrations declined multi-exponentially following infusion, and there was no evidence of accumulation with QOW dosing. A pharmacokinetic-pharmacodynamic modelling study that included subjects in this study supported the vestronidase alfa dosing regimen of 4 mg/kg QOW [ 5 , 6 , 8 , 9 , 12 ].…”

“…Vestronidase alfa (recombinant human β-glucuronidase) is an enzyme replacement therapy approved in the United States for the treatment of MPS VII in children and adults, in Europe for non-neurological manifestations of MPS VII, and in Brazil [ [5] , [6] , [7] ]. In a randomized, placebo-controlled, phase 3 study (N = 12), vestronidase alfa 4 mg/kg administered intravenously every other week (QOW) for 24 weeks significantly reduced urinary GAG (uGAG) excretion, and most subjects with MPS VII exhibited improvement in other clinical and patient-reported outcomes [ 8 , 9 ]. In the open-label, long-term extension, reductions in uGAG excretion were sustained, and treatment was well tolerated [ 10 ].…”