GIM-D-17-00410-R: "Efficacy, safety profile, and immunogenicity of alglucosidase alfa produced at 4000L scale in US children and adolescents with Pompe disease: ADVANCE, a phase IV, open-label, prospective study”, by Sihoun Hahn, MD, PhD and colleagues on behalf of the Pompe ADVANCE Study Consortium

Online Appendix 2. Baseline disease characteristics of patients who had clinical worsening at week 52

Notonly the most severe patients in ADVANCEdeclined or died; however, a majority of those who did so were severely affected at baseline. Ten of the 17 patients with clinical worsening at week 52 were nonambulatory, 10 tube-fed, 5 invasively and 1 noninvasively ventilated; for 9, caregivers reported pre-study motor decline at baseline. Two experienced high-sustained anti-rhGAA titers as defined by protocol (peak titer ≥25 600 and a last titer equal to or 1 dilution level lower than the peak titer). Later initiation of 160L rhGAA (first-ever-in-life enzyme therapy), greater disease involvement at baseline, and immunogenicity appeared related to clinical worsening, as detailed below

Thirteen of the clinically worsened patients had IOPD (3 of the 13 were atypical) and 4 LOPD (1 of the 4 had cardiac involvement, and 3 of the 4 lacked the common “adult” c.-32-13T>G GAA variant). Baseline motor function levels included 1 independent walker, 5 supported walkers, 6 supported standers, 1 sitter, and 4 with restricted antigravity movement.

Of the 13 total IOPD (classic and atypical) patients who clinically worsened, 9 were predicted from genotypes to be cross-reactive immunological material (CRIM)-positive, 2 CRIM-negative, 1 of unclear CRIM status (c.925G>A [p.Gly309Arg] in homozygosity has been reported as positive or negative in different reports), and 2 were missing genetic data.

Outcomes in patients who received immune modulation during the study are detailed in Supplementary Table S4. In brief, only 2 immunomodulation recipients clinically declined at Week 52.

In general, median ages of diagnosis and 160L initiation were lower in clinically stable or improved than in clinically worsened patients with classic or atypical IOPD: see the tables below.

Symptom Onset / Clinically Worsened / Clinically Stable / Improved
Classic IOPD / 0 – 6.63 mo (median 3.37 mo) / 0 – 8 mo (median 1.79 mo)
Atypical IOPD / 0 – 4.07 mo (median 1.17 mo) / 0 – 8.7 mo (median 6.2 mo)
LOPD / 0 – 14.47 mo (median 6.50 mo) / 0 –106.97 mo (median 11.20 mo)
Diagnosis / Clinically Worsened / Clinically Stable / Improved
Classic IOPD / 0.5 – 9.87 mo (median 5.27 mo) / Prenatal* – 10.73 mo(median 3.99 mo)
Atypical IOPD / 1.26 – 71.1 mo (median 17.07 mo) / 1– 31.87 mo (median 9.07 mo)
LOPD / 0 – 19.03 mo (median 15.50 mo) / 0.37 – 105.03 mo (median 19.67 mo)

*2 prenatally diagnosed classic IOPD patients were ascertained via elder sibs with Pompe disease.

160L Initiation / Clinically Worsened / Clinically Stable / Improved
Classic IOPD / 0.7 – 11.57 mo (median 11.57 mo) / 0.7 – 11.43 mo (median 4.00 mo)
Atypical IOPD / 18.2 – 126.63 mo (median 42 mo) / 2 – 132mo (median 24.03 mo)**
LOPD / 5 –22.17 mo (median 18.92 mo) / 0.93 – 126.67 mo (median 24.82 mo)

Disease durations (from symptom onset to 160L start) were 0 days to 10 yr 1 mo in stable/improved patients and 0–3740 days in clinically worsened patients. Seven of the 17 patients with clinical worsening at week 52 had been born and 4 diagnosed before 160L rhGAA approval in 2006. Their later access to rhGAA may have allowed more pre-treatment irreversible damage than in patients born or diagnosed after approval and treated promptly after diagnosis.