AAV mini-dystrophin gene therapy for Duchenne muscular dystrophy: a phase 1b trial

Abstract

Gene therapy represents a promising approach for Duchenne muscular dystrophy (DMD), a rare X-linked genetic muscle disease. Fordadistrogene movaparvovec (PF-06939926) is an adeno-associated virus serotype 9 gene therapy containing a miniaturized dystrophin being developed for DMD, which aims to restore functional protein to muscle. We present 1-year data from ambulatory and nonambulatory participants in a phase 1b, multicenter, single-arm, open-label trial. Pediatric ambulatory male participants with a genetic DMD diagnosis and receiving stable glucocorticoids received a single intravenous low-dose (n = 3) or high-dose (n = 16) fordadistrogene movaparvovec. The primary endpoint was safety and tolerability at 1 year after dosing. In the ambulatory group, mean ± s.d. age at dosing was 8.6 ± 1.6 years. The most common treatment-emergent adverse events in the ambulatory group were vomiting (n = 15), nausea (n = 10), thrombocytopenia (n = 9), pyrexia (n = 9), decreased appetite (n = 8), fatigue (n = 7) and headache (n = 7). Three treatment-related serious adverse events occurred after dosing (dehydration, acute kidney injury, thrombocytopenia; all resolved within 15 days). In a small nonambulatory group (n = 3), mean ± s.d. age at dosing was 15.1 ± 1.0 years. The most common treatment-emergent adverse events were nausea (n = 3), vomiting (n = 3) and headache (n = 3); two severe treatment-related adverse events (hemolytic uremic syndrome and fatal cardiogenic shock) were observed. In the high-dose ambulatory group, the secondary endpoint of mini-dystrophin quantification showed robust expression. Mean (95% confidence interval) percent of mini-dystrophin-positive fibers for baseline, 2 months and 1 year were 0.1% (0.1-0.2), 20.3% (12.2-29.3) and 34.8% (21.1-49.8), respectively. At the 1-year time point of primary completion, fordadistrogene movaparvovec demonstrated an acceptable safety profile in the ambulatory population. Larger trials are needed to assess the efficacy of the gene therapy in DMD. ClinicalTrials.gov registration no. NCT03362502 .

Fig. 1. Participant disposition for ambulatory and nonambulatory participants.

a, Twenty-eight screenings were completed in ambulatory participants with 24 unique ambulatory participants (four participants were rescreened and met the enrollment criteria the second time). Five unique participants did not pass screening and were not assigned to treatment. Participants who met the enrollment criteria on being rescreened included two with positive anti-dystrophin T cell response on enzyme-linked immunosorbent spot (ELISpot) during the initial screen (this exclusion criterion was later removed from the protocol given the absence of myositis and myocarditis observed in this trial): one with positive hepatitis A virus IgM during the initial screen and one who was unable to complete the screening procedures during the first screen because of study enrollment pauses. b, Seven nonambulatory participants were screened with 3 enrolled. One participant who was screened twice was only counted once.

Fig. 2. Expression of dystrophin and distribution of mini-dystrophin in muscle biopsy samples from ambulatory participants assessed using LC–MS and automated image analysis of immunofluorescence, respectively.

a, LC-MS. b, Automated image analysis of immunofluorescence. n = 3 for low-dose fordadistrogene movaparvovec (FM) and n = 16 for high-dose fordadistrogene movaparvovec.

Fig. 3. One-year change in NSAA total score in ambulatory participants stratified according to age at study entry.

Individual values for participants in the low-dose (filled circles, n = 3) and high-dose (open circles, n = 16) fordadistrogene movaparvovec (FM) groups of the current study are shown along with box and whisker plots. The box plots display the interquartile range from the 25th to the 75th percentile. The line inside the box indicates the median value. The whiskers indicate the range within 1.5 times the interquartile range, with outliers shown as individual points. The small black dot (bottom left) represents an outlier in the external control cohort. The NSAA total score is based on assessment of 17 ambulatory actions and ranges from 0 to 34, with a higher score indicating greater functional ability. In the external control cohort (n = 59), the median NSAA total score at baseline was 28.0 in the 6–7-year-old group (n = 23), 28.0 in the 8-year-old group (n = 15), 26.0 in the 9-year-old group (n = 11) and 24.5 in the 10–12-year-old group (n = 10).

Extended Data Fig. 1. Expression of dystrophin and distribution of mini-dystrophin in muscle biopsy samples from non-ambulatory participants assessed by (A) LC-MS and (B) automated image analysis of immunofluorescence, respectively.

In (A) LC-MS (n = 2) and (B) automated image analysis of immunofluorescence (n = 2). High-dose (green open triangles = mean) groups. BL, baseline; LC-MS, liquid chromatography–mass spectrometry.

Extended Data Fig. 2. Plots of changes (from baseline to 1 year) in functional endpoints in ambulatory high-dose participants versus external control cohort by visit.

The external control cohort was derived from 156 placebo-treated participants from two previous interventional trials of DMD; 40 from Wagner et al., and 116 from Victor et al. Of these 156 external study participants, 59 met the eligibility criteria (ie, ages 4–12 years, rise from floor in ≤7 s, ability to walk 10 meters unaided, left ventricular ejection fraction [LVEF] ≥55%, stable steroid regimen for ≥6 months at screening), and had non-missing North Star Ambulatory Assessment (NSAA) total scores at 1 year. This group of 59 formed the external control cohort. A) Mean (95%) change from baseline in NSAA total score; B) Mean (95%) change from baseline in velocity of rise from floor; C) Mean (95%) change from baseline in velocity of run 10 m; D) Mean (95%) change from baseline in 4SC velocity; E) Mean (95%) change from baseline in 6MWD, F) Mean (95%) change from baseline in percent predicted forced vital capacity. At baseline, n = 16 for high dose and n = 59 for external control, except for panel F, n = 12 participants available at baseline in the high dose group. All other n numbers are given below each figure panel. 10 M w/r, time to walk/run 10 meters; 4SC w/r, four-stair climb walk/run; 6MWD, 6-minute walk distance; NSAA, North Star Ambulatory Assessment; SE, standard error.