Onasemnogene is the intravenous gene therapy to directly provide survival motor neuron 1 (SMN1) gene to produce SMN protein (11). It consists of a nonreplicating recombinant AAV9 containing the complimentary DNA of the human SMN gene under the control of the cytomegalovirus enhancer/chicken-β-actin-hybrid promoter. The adeno-associated virus inverted terminal repeat has been modified to promote intramolecular annealing of the transgene, thus forming a double-stranded transgene ready for transcription.
Pharmacodynamics. There are no clinically relevant pharmacodynamics data but the mechanism of action of onasemnogene is described briefly. Following 1-time intravenous administration, onasemnogene delivers a copy of SMN gene in a self-complementary adeno-associated viral serotype 9, which induces SMN expression in motor neurons and peripheral tissues to counter the effects of spinal muscular atrophy. Initially tested in a murine model of spinal muscular atrophy, it extended the average survival from approximately 2 weeks to 1 month with a low dose and to more than 250 days with higher doses of the vector (04; 05; 12).
Clinical findings confirm those in preclinical studies. Comparison of the results of the low-dose cohort to the results of the high-dose cohort shows a dose-response relationship that supports the effective of onasemnogene. Functional replacement of the mutated gene encoding SMN1 in patients with spinal muscular atrophy type 1, a single intravenous infusion of adeno-associated viral vector containing DNA coding for SMN, resulted in longer survival, superior achievement of motor milestones, and better motor function than in historical cohorts (10). No waning of effect or clinical regression in motor function was reported in follow-up to 2 years.
Pharmacokinetics. Following systemic administration, onasemnogene affects multiple systems, eg, cardiovascular system, skeletal muscles, and autonomic as well as enteric nervous systems, which may be advantageous because spinal muscular atrophy type 1 affects multiple systems and SMN protein is ubiquitously expressed. It crosses the blood-brain barrier and targets neurons in all regions of the spinal cord.
Vector shedding after infusion with onasemnogene was investigated at multiple time points during a clinical trial. Vector DNA is shed in saliva, urine, and stool after infusion of onasemnogene, with much higher concentrations of vector DNA found in the stools than in saliva. Biodistribution studies show that highest levels of vector DNA are found in the liver. Vector DNA is also detected in the spleen, heart, pancreas, inguinal lymph node, skeletal muscles, peripheral nerves, kidney, lung, intestines, spinal cord, brain, and thymus. Immunostaining for SMN protein shows generalized SMN expression in spinal motor neurons, neuronal and glial cells of the brain, and in the heart, liver, skeletal muscles, and other tissues evaluated.
Routes of administration. Onasemnogene is administered as a suspension by intravenous infusion. An intrathecal formulation, onasemnogene abeparvovec abeparvovec-xioi, is in clinical development in the United States but the FDA placed a partial hold on the clinical trial (NCT03381729) in 2019, which is based on findings in animals suggesting an association with dorsal root ganglia mononuclear cell inflammation, sometimes accompanied by neuronal cell body degeneration or loss. The manufacturer is working with the FDA to resolve this issue.
Pharmaco-economics. Because of the high price of gene therapy products, cost-effectiveness studies are being done. The treatment costs of onasemnogene abeparvovec for 1 patient is over $2 million given as 1-time infusion over 1 hour, making it the most expensive dose of a drug ever. However, it will favorably compete against nusinersen, a splice-modulating antisense oligonucleotide, which needs to be given every 4 months to maintain improvement, with a cost of $750,000 for the first year and $350,000 per year after that.
A Markov model has been used to estimate the incremental cost-effectiveness ratio expressed as cost/quality-adjusted life year of onasemnogene abeparvovec versus nusinersen over a lifetime (08). Expected survival over a lifetime predicted by the model was 37.20 life years for onasemnogene and 9.68 for nusinersen. The average lifetime single dose onasemnogene cost per patient was $4.2 to $6.6 million for onasemnogene and $6.3 million for nusinersen, indicating that onasemnogene was cost-effective compared to chronic nusinersen for spinal muscular atrophy type 1 patients.