Extended long-term efficacy and safety of velmanase alfa treatment up to 12 years in patients with alpha-mannosidosis

Abstract

Enzyme replacement therapy (ERT) using velmanase alfa previously showed promising efficacy and safety outcomes for up to 4 years of therapy in patients with alpha-mannosidosis. This pooled analysis from two multicenter, open-label phase IIIb extension trials rhLAMAN-07 (N = 13; NCT01908712) and rhLAMAN-09 (N = 8; NCT01908725) evaluated the long-term effects of velmanase alfa. Sixteen patients who previously completed phase I-III rhLAMAN-02/-03/-04/-05/-08 trials and five ERT-naïve patients were enrolled. Patients received 1 mg/kg velmanase alfa once weekly. Endpoints included changes from treatment baseline (before initial dose of velmanase alfa in any trial) in serum oligosaccharides, 6-minute walk test (6MWT), 3-minute stair climb test (3MSCT), pulmonary function (forced vital capacity [FVC], % predicted), serum immunoglobulin G (IgG) levels, and adverse events. The overall cohort comprised 21 patients, divided by age at treatment baseline into pediatric (n = 14) and adult subgroups (n = 7). Distance walked according to 6MWT increased or stabilized in pediatric patients, while in adults either stabilization or slight decline was observed. Similarly, pediatric patients performed better in the 3MSCT. Changes in FVC, % predicted, were comparable in both subgroups up to ~6 years of observation, diverging thereafter. Overall, sustained serum oligosaccharide clearance and serum IgG level increase was observed upon treatment initiation and persisted until last common observation. Velmanase alfa treatment was generally well tolerated, with the majority of reported adverse events being of mild-to-moderate intensity. With follow-up of up to 12 years, long-term efficacy and safety outcomes indicate continued benefits of velmanase alfa in patients with alpha-mannosidosis.

Keywords: alpha‐mannosidosis; enzyme replacement therapy; long‐term efficacy and safety; lysosomal storage disorder; recombinant enzymes; velmanase alfa.

FIGURE 1

Overview of rhLAMAN‐07 and rhLAMAN‐09 treatment periods of individual patients. Overall, 21 patients were included in the pooled analysis of rhLAMAN‐07 and rhLAMAN‐09, of which 13 patients could be followed for up 12 years (Panel A). Overall exposure to velmanase alfa during participation in any rhLAMAN trial, which corresponds to the observation period for the pooled analyses from treatment baseline to study end, is shown in Panel (B) for individual patients. Thus, the observation periods included treatment periods in previous studies, except for four patients from the placebo arm of rhLAMAN‐05 (marked with an asterisk), and five patients who did not receive enzyme replacement therapy (ERT) prior to the start of rhLAMAN‐07 (ERT‐naïve patients). Two patients from the parental phase III (rhLAMAN‐05) trial withdrew consent after ~54 months of treatment in rhLAMAN‐07 and ~1 month of treatment in rhLAMAN‐09, respectively. A further six patients entered the study after 2019, five of whom were treatment‐naïve.

FIGURE 2

6MWT, 3MSCT, and forced vital capacity (FVC) outcomes. Mean ± SE changes are shown from treatment baseline, defined as the last available value before the first dose of velmanase alfa in the parental study, as the last available value before the first dose in rhLAMAN‐07/‐09 for patients in the placebo arm of rhLAMAN‐05, and as Visit 1 for treatment‐naïve patients in rhLAMAN‐07. X‐axes display the median of each time interval. 3MSCT, 3‐minute stair climb test, 6MWT, 6‐minute walk test; SE, standard error.

FIGURE 3

Serum oligosaccharides. Mean ± SE changes are shown from treatment baseline, defined as the last available value before the first dose of velmanase alfa in the parental study, as the last available value before the first dose in rhLAMAN‐07/‐09 for patients in the placebo arm of rhLAMAN‐05, and as Visit 1 for treatment‐naïve patients in rhLAMAN‐07. The decrease of the mean values between 38.7 and 60.8 months is due to data of only one pediatric patient being available for these time points; this patient had a higher value at treatment baseline and a stronger decrease following treatment than the other patients (Supplementary Figure S1a). X‐axes display the median of each time interval. SE, standard error.

FIGURE 4

Serum IgG. All four patients (three pediatric patients, one adult) were treatment‐naïve when they were enrolled in rhLAMAN‐07/‐09. Mean ± SE changes are shown from treatment baseline at Visit 1 in rhLAMAN‐07 (treatment baseline values were not available for the remaining 17 patients of the pooled cohort). IgG, immunoglobulin G; SE, standard error.