Onasemnogene abeparvovec for the treatment of spinal muscular atrophy

Figures & data

Table 1. Types of spinal muscular atrophy [4,10,11].

SMA type	0	1	2	3	4
Approximate percentage of all SMA cases	<1%	45–60%	~20–30%	~15–20%	<1%
Typical SMN2 copies present	1 copy	2–3 copies	3 copies	3–4 copies	≥4 copies
Age at symptom onset	Prenatal	0–6 months	6–18 months	>18 months	20–30 years
Symptoms and typical features	Profound hypotonia Facial muscle weakness Inability to suck/swallow Respiratory failure at birth	Limb weakness Respiratory distress Weak cry Poor feeding Inability to sit unsupported Bell-shaped chest	May sit unsupported Poor crawling Limb weakness more profound in lower than upper limbs Some limitation of head and neck control Inability to stand or walk independently Impaired swallowing Ventilatory insufficiency Scoliosis	May stand or be able to walk independently Unable to run, jump, or climb Abnormal gait, foot deformity Able to eat independently	Ambulatory Mild, slowly progressive limb weakness
Support needed	Respiratory support beginning at birth	Respiratory and nutritional support by 5–6 months of age	Ventilatory support, feeding tube, wheelchair	Wheelchair or braces, physical and occupational therapy	Walking aids
Survival without disease-modifying treatment	Weeks	<2 years	Reduced life expectancy	Does not impact life expectancy	Does not impact life expectancy

SMA: spinal muscular atrophy; SMN2: survival motor neuron 2 gene.

Table 2. Future and ongoing clinical trials of onasemnogene abeparvovec.

	SMART (NCT04851873) [106]	STRONG (NCT03381729) [107,108]	STEER (NCT05089656) [109]
Purpose	To assess safety and tolerability over 12 months after administration of intravenous onasemnogene abeparvovec	To evaluate safety and tolerability of an intrathecal formulation of onasemnogene abeparvovec	To evaluate efficacy, safety, and tolerability of an intrathecal formulation of onasemnogene abeparvovec
Population	Patients who weigh ≥8.5 kg to ≤21 kg	Patients aged 6–50 months with three copies of SMN2	Patients with SMA type 2 and two to four copies of SMN2 who are aged 2–18 years
Estimated enrollment	24 patients	32 patients enrolled as of December 2019 interim analysis	125 patients
Design	Phase IIIb, open-label, single-arm multicenter study Motor-milestone achievement and function will be used to assess efficacy	Phase I, open-label, dose-comparison study The trial assessed three doses of onasemnogene abeparvovec administered via one-time intraspinal injection (Dose A: 6.0 × 10^13; Dose B: 1.2 × 10^14; Dose C: 2.4 × 10^14 vg).	Phase III, multicenter, randomized, sham-controlled, double-blind study
Preliminary results/notable findings to date		The US Food and Drug Administration halted the trial in October 2019 for safety concerns prompted by an animal study of intrathecal onasemnogene abeparvovec. The hold was lifted in August 2021. As of an interim analysis in December 2019, patients achieved clinically meaningful motor milestones in all dose groups and age groups. No deaths were reported, and no new safety signals were identified.
Expected completion	August 2023	No longer recruiting	October 2024

SMA: spinal muscular atrophy; SMN2: survival motor neuron 2 gene.

Table

Drug name (generic)	Onasemnogene abeparvovec
Phase (for indication under discussion)	Approved in the United States in 2019
Indication (specific to discussion)	Onasemnogene abeparvovec is an adeno-associated virus vector-based gene therapy indicated for the treatment of pediatric patients less than 2 years of age with spinal muscular atrophy (SMA) with biallelic mutations in the survival motor neuron 1 gene.
Pharmacology description/mechanism of action	Onasemnogene abeparvovec is a recombinant AAV9-based gene therapy designed to deliver a copy of the gene encoding the human SMN protein. SMA is caused by a biallelic mutation in the SMN1 gene, which results in insufficient SMN protein expression.
Chemical structure	Not available
Pivotal trial(s)	START, STR1VE-US, STR1VE-EU

Lally C, Jones C, Farwell W, et al. Indirect estimation of the prevalence of spinal muscular atrophy type I, II, and III in the United States. Orphanet J Rare Dis. 2017;12(1):175.

 PubMedGoogle Scholar

Bladen CL, Thompson R, Jackson JM, et al. Mapping the differences in care for 5,000 spinal muscular atrophy patients, a survey of 24 national registries in North America, Australasia and Europe. J Neurol. 2014;261:152–163.

 PubMed Web of Science ®Google Scholar

Butchbach MER. Copy number variations in the survival motor neuron genes: implications for spinal muscular atrophy and other neurodegenerative diseases. Front Mol Biosc. 2016; 3:7.

 PubMed Web of Science ®Google Scholar

Jena AB, Lakdawalla DN. Value frameworks for rare diseases: should they be different? Washington, DC: Health Affairs Blog, 2017 Apr 12. Available at: www.healthaffairs.org/do/10.1377/hblog20170412.059563/full/ [Last accessed 2021 Apr 12].

 Google Scholar

Ollendorf DA, Chapman RH, Pearson SD. Evaluating and valuing drugs for rare conditions: no easy answers. Value Health. 2018;21:547–552.

 PubMed Web of Science ®Google Scholar

Shih STF, Farrar M, Wiley V, et al. Newborn screening for spinal muscular atrophy with disease-modifying therapies: a cost-effectiveness analysis. J Neurol Neurosurg Psychiatry. 2021;92(12):1296–1304.

 PubMed Web of Science ®Google Scholar

Safety and efficacy of intravenous OAV101 (AVXS-101) in pediatric patients with spinal muscular atrophy (SMA) (SMART). clinicalTrials.gov identifier: NCT04851873. 2021 Apr 21. Available at: clinicaltrials.gov/ct2/show/NCT04851873 [Last accessed 2021 Nov 5]

 Google Scholar