Long-term Safety and Efficacy of Avalglucosidase Alfa in Patients With Late-Onset Pompe Disease

Abstract

Background and objectives: Pompe disease is a rare, progressive neuromuscular disorder caused by deficiency of lysosomal acid α-glucosidase (GAA) and subsequent glycogen accumulation. Avalglucosidase alfa, a recombinant human GAA enzyme replacement therapy designed for increased cellular uptake and glycogen clearance, has been studied for long-term efficacy and safety in patients with late-onset Pompe disease (LOPD). Here, we report up to 6.5 years' experience with avalglucosidase alfa during the NEO1 and NEO-EXT studies.

Methods: NEO1 participants with LOPD, either treatment naive (Naive Group) or receiving alglucosidase alfa for ≥9 months (Switch Group), received avalglucosidase alfa (5, 10, or 20 mg/kg every other week [qow]) for 6 months before entering NEO-EXT and continued their NEO1 dose until all proceeded with 20 mg/kg qow. Safety and efficacy, a prespecified exploratory secondary outcome, were assessed; slopes of change for efficacy outcomes were calculated from a repeated mixed-measures model.

Results: Twenty-four participants enrolled in NEO1 (Naive Group, n = 10; Switch Group, n = 14); 21 completed and 19 entered NEO-EXT; in February 2020, 17 participants remained in NEO-EXT, with data up to 6.5 years. Avalglucosidase alfa was generally well tolerated during NEO-EXT, with a safety profile consistent with that in NEO1. No deaths or treatment-related life-threatening serious adverse events occurred. Eighteen participants developed antidrug antibodies without apparent effect on clinical outcomes. No participants who were tested developed immunoglobulin E antibodies. Upright forced vital capacity %predicted remained stable in most participants, with slope estimates (95% CIs) of -0.473 per year (-1.188 to 0.242) and -0.648 per year (-1.061 to -0.236) in the Naive and Switch Groups, respectively. Six-minute walk test (6MWT) %predicted was also stable for most participants, with slope estimates of -0.701 per year (-1.571 to 0.169) and -0.846 per year (-1.567 to -0.125) for the Naive and Switch Groups, respectively. Improvements in 6MWT distance were observed in most participants aged <45 years at NEO1 enrollment in both the Naive and Switch Groups.

Discussion: Avalglucosidase alfa was generally well tolerated for up to 6.5 years in adult participants with LOPD either naive to alglucosidase alfa or who had previously received alglucosidase alfa for ≥9 months.

Classification of evidence: This study provides Class IV evidence of long-term tolerability and sustained efficacy of avalglucosidase alfa in patients with LOPD after up to 6.5 years.

Trial registration information: NCT01898364 (NEO1 first posted: July 12, 2013; clinicaltrials.gov/ct2/show/NCT01898364); NCT02032524 (NEO-EXT first posted: January 10, 2014; clinicaltrials.gov/ct2/show/NCT02032524). First participant enrollment: NEO1-August 19, 2013; NEO-EXT-February 27, 2014.

Figure 1. Participant Disposition

^aNaive to alglucosidase alfa therapy. ^bPrior alglucosidase alfa therapy for ≥9 months. ^cSerious adverse events (SAEs) of respiratory distress and chest discomfort occurring during the ninth avalglucosidase alfa infusion; these SAEs were considered to be infusion-associated reactions. In NEO1, participants received 5, 10, or 20 mg/kg of avalglucosidase alfa every other week (qow) for 6 months. On entering NEO-EXT, they continued their current assigned NEO1 dose of avalglucosidase alfa for 104–156 weeks prior to all participants proceeding to receive 20 mg/kg qow of avalglucosidase alfa.

Figure 2. Upright FVC %Predicted Over Up to 6 Years of Avalglucosidase Alfa Treatment (All Participants Ever Received 20 mg/kg Dose)

Black lines are trend lines for the slope, derived from a linear mixed-effects model. Individual participant trajectories are color coded to enable the FVC %predicted (Figure 2) and 6MWT distance (Figure 3) for individual participants to be compared. Naive group: 83-year-old participant (turquoise line): worsening aortic aneurysm at week 156, underwent surgery, and presented at week 169 with infusion-associated reaction of fever and shivering during subsequent avalglucosidase alfa infusion (ADA: 12,800; peak titer 51,800; NAb enzyme uptake positive); week 208: chronic inflammatory demyelinating polyneuropathy (ADA: 6,400; NAb enzyme uptake positive; last available sample ADA: 6,400; NAb negative). Naive group: 43-year-old participant (red line): week 208 exanthema and swelling at the infusion site (ADA: 100; peak titer 1,600; NAb enzyme uptake positive; last available sample ADA: 200; NAb negative). Switch group: 68-year-old participant (yellow line): medical history of left upper lobectomy for upper left lobe lung cancer and developed right upper lobe lung cancer, rib cage pain, and right renal cell carcinoma (ADA: negative; peak titer 200; NAb negative). Switch group: 39-year-old participant (olive green line): medical history of anxiety, car accident at week 168, events of sinus infection, influenza, and cold until last available visit (ADA: negative; peak titer <100; NAb negative). Switch group: 49-year-old participant (lime green line): medical history of depression, seasonal allergies, asthma, pain, fatigue, arthritis, and muscle soreness (ADA: negative; peak titer 1,600; NAb negative); recovery of FVC may be due to the change to 20 mg/kg dose from initial 5 mg/kg dose. 6MWT = 6-minute walk test; ADA = antidrug antibody; FVC = forced vital capacity; NAb = neutralizing antibody.

Figure 3. 6MWT Distance %Predicted After Up to 6 Years of Avalglucosidase Alfa Treatment (All Participants Ever Received 20 mg/kg Dose)

Black lines are trend lines for the slope, derived from a linear mixed-effects model. Individual participant trajectories are color coded to enable the FVC %predicted (Figure 2) and 6MWT distance (Figure 3) for individual participants to be compared. Naive group: 83-year-old participant (turquoise line): worsening aortic aneurysm at week 156, underwent surgery, and presented at week 169 with infusion-associated reaction of fever and shivering during subsequent avalglucosidase alfa infusion (ADA: 12,800; peak titer 51,800; NAb enzyme uptake positive); week 208: chronic inflammatory demyelinating polyneuropathy (ADA: 6,400; NAb enzyme uptake positive; last available sample ADA: 6,400; NAb negative). Naive group: 43-year-old participant (red line): week 208 exanthema and swelling at the infusion site (ADA: 100; peak titer 1,600; NAb enzyme uptake positive; last available sample ADA: 200; NAb negative). Switch group: 68-year-old participant (yellow line): medical history of left upper lobectomy for upper left lobe lung cancer and developed right upper lobe lung cancer, rib cage pain, and right renal cell carcinoma (ADA: negative; peak titer 200; NAb negative). Switch group: 64-year-old participant (royal blue line): history of gout, Bell palsy, episodes of acute diverticulosis and Clostridium difficile, and chronic hip/back pain (ADA: negative; NAb negative). Switch group: 73-year-old participant (turquoise line): history of degenerative disc disease, back pain, and arthritis (ADA: 6,400; peak titer 12,800; NAb negative; last available sample ADA: 1,600; Nab negative). 6MWT = 6-minute walk test; ADA = antidrug antibody; FVC = forced vital capacity; NAb = neutralizing antibody.

Figure 4. 6MWT Distance by Age at First (Baseline) and Last Assessment (Up to Week 312) for Individual Participants Who Ever Received Avalglucosidase Alfa 20 mg/kg Dose

6MWT = 6-minute walk test.