Impact of Age and Motor Function in a Phase 1/2A Study of Infants With SMA Type 1 Receiving Single-Dose Gene Replacement Therapy

Abstract

Background: This study characterizes motor function responses after early dosing of AVXS-101 (onasemnogene abeparvovec) in gene replacement therapy in infants with severe spinal muscular atrophy type 1 (SMA1). Methods: This study is a follow-up analysis of 12 infants with SMA1 who received the proposed therapeutic dose of AVXS-101 in a Phase 1 open-label study (NCT02122952). Infants were grouped according to age at dosing and baseline Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders scores: (1) early dosing/low motor, dosed age less than three months with scores <20 (n ¼ 3), (2) late dosing, dosed at age three months or greater (n ¼ 6), and (3) early dosing/high motor, dosed age less than three months with scores 20 (n ¼ 3). Results: Early dosing/low motor group demonstrated a mean gain of 35.0 points from a mean baseline of 15.7, whereas the late dosing group had a mean gain of 23.3 from a mean baseline of 26.5. The early dosing/high motor group quickly reached a mean score of 60.3, near the scale maximum (64), from a mean baseline of 44.0. Despite a lower baseline motor score, the early dosing/low motor group achieved sitting unassisted earlier than the late dosing group (mean age: 17.0 vs 22.0 months). The early dosing/high motor group reached this milestone earliest (mean age: 9.4 months). Conclusions: The rapid, significant motor improvements among infants with severe SMA1 treated with AVXS-101 at an early age highlight the importance of newborn screening and early treatment and demonstrate the therapeutic potential of AVXS-101 regardless of baseline motor function.

“The Times They Are a-Changin’.” In reply to El-Zaidy et al.: AVXS-101 (Onasemnogene Abeparvovec) for SMA1: Comparative Study with a Prospective Natural History Cohort

“…Each scored 50 on the CHOP-INTEND at baseline, 17 points above the best performers of the control cohort. Since we know from previous reports of the study that these two patients are the patients who are walking today [4], the results of Al-Zaidy and colleagues nicely reinforce what L. Servais / Comparative Study with a Prospective Natural History Cohort most of clinicians already understood: Capturing patients post-symptom onset via the classical diagnosis pathways does not result in the best efficacy of these innovative therapies. Written between the lines of the article of Al-Zaidy et al is a plea for newborn screening, which is currently being implemented in more and more countries [5].…”

Sitting in patients with spinal muscular atrophy type 1 treated with nusinersen

“…In the clinical trial of the gene therapy onasemnogene abeparvovec, the baseline CHOP-INTEND score in conjunction with age was demonstrated to be a strong predictive factor of walking acquisition. 15 However, correlation was based on two infants who had very high baseline function at 1 month of age, who are not representative of the population of postsymptomatically identified patients. 16,17 SMN2 copy number was not significantly correlated with attainment of the sitting position.…”

Spinal muscular atrophy - onasemnogene abeparvovec and other therapeutic options

“…Wyniki te są istotne klinicznie [21,23]. Ponadto pacjenci, którzy otrzymali onasemnogene abeparvovec wcześnie (w wieku poniżej 3 miesięcy) osiągnęli poprawę funkcji motorycznych szybciej niż ci, którzy otrzymali lek później (w wieku powyżej 3 miesięcy) bez względu na wyjściowy stan zdrowia [24]. Porównanie wyników z dwóch grup wykazało zależność dawka-odpowiedź, która pozwala na kliniczne zastosowanie onasemnogene abeparvovec.…”