Pharmacology

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.

Clinical trials

In a phase 1/2 open-label study (NCT02122952) of onasemnogene abeparvovec for spinal muscular atrophy type 1, twelve infants were grouped according to age at dosing and baseline Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders scores. At follow-up analysis this study showed that 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 (07). Despite a lower baseline motor score, the early dosing/low motor group achieved sitting unassisted earlier than the late dosing group, indicating the importance of early screening and treatment of spinal muscular atrophy type 1. A further study of health outcomes of treatment of infants with spinal muscular atrophy type 1 in this trial was associated with reduced pulmonary and nutritional support requirements, improved motor function, and decreased hospitalization rate over the follow-up period, which contrasts with the natural history of progressive respiratory failure and reduced survival (01). The results suggest an overall improved quality of life following gene replacement therapy.

Because there is no head-to-head comparison, onasemnogene abeparvovec trial (NCT02122952) and nusinersen clinical trial (ENDEAR; NCT02193074) were indirectly compared using frequentist and Bayesian approaches (02). Results suggest that onasemnogene may have an efficacy advantage relative to nusinersen for overall survival, independent from permanent assisted ventilation, motor function, and motor milestones.

STR1VE-US is a part of the global phase 3 STR1VE clinical program that includes open-label, single-arm, single-dose, multicenter trials (STR1VE-US in the United States, STR1VE-EU in Europe, and STR1VE-AP in Asia Pacific) designed to evaluate the efficacy and safety of a single, 1-time intravenous infusion of onasemnogene in symptomatic patients with spinal muscular atrophy type 1 who are less than 6 months of age at the time of gene therapy, with 1 or 2 copies of the SMN2 backup gene and who have biallelic SMN1 gene deletion or point mutations (NCT03306277). At the close of the 2-year study, all 12 patients in cohort 2 (targeted therapeutic dose) were alive and free of permanent ventilation. Without treatment, most of these patients would not have survived past the age of 2 or would require permanent ventilation. At data cutoff on June 11, 2020, 13 patients treated in START were assessed for serious adverse effects after a 5-year extension study as a part of 15-years follow-up of infants afflicted with spinal muscular atrophy treated with onasemnogene (09). Analysis of data showed that onasemnogene continued to have a monitorable and manageable safety profile with no serious adverse events for up to 6.2 years after dosing.

Results of a phase 3, open label, multicenter trial of onasemnogene abeparvovec showed statistical superiority and clinically meaningful responses when compared with observations from the natural history cohort (03). The favorable benefit-risk profile shown in this study supports the use of onasemnogene abeparvovec for treatment of symptomatic patients with genetic or clinical characteristics predictive of infantile-onset spinal muscular atrophy type 1.

SPR1NT is an ongoing phase 3, open-label, single-arm, multicenter trial designed to evaluate the safety and efficacy of a 1-time intravenous infusion of onasemnogene in presymptomatic patients with spinal muscular atrophy and 2 or 3 copies of SMN2 who are at least or over 6 weeks of age (NCT03505099). Estimated study completion date is July 26, 2021.

Indications

Onasemnogene is a 1-time treatment approved by the Food and Drug Administration for spinal muscular atrophy patients less than 2 years of age who possess mutations in both copies of the SMN1 gene.

Goals and duration of treatment

Onasemnogene targets the genetic root cause of spinal muscular atrophy and the goal of treatment has been advanced beyond event-free survival and motor milestone achievement to maintain the ability to thrive. Hundreds of patients now treated, including some more than 5 years posttreatment, further confirm the profound benefit a 1-time dose of onasemnogene has on spinal muscular atrophy patients without any serious adverse effects.

Dosing

The recommended dose of onasemnogene for pediatric patients is 1.1 × 1014 vector genomes per kg of bodyweight, administered as a single intravenous infusion over 60 minutes.

Special considerations

Precautions. The following precautions are recommended:

Lactation. There is no information on whether breastfeeding should be restricted in mothers of infants who may be seropositive for anti-AAV9 antibodies.

Pediatrics. Administration of onasemnogene to premature neonates before reaching full-term gestational age is not recommended because concomitant treatment with corticosteroids may adversely affect neurologic development. Onasemnogene infusion should be delayed until the corresponding full-term gestational age is reached.

Interactions

A patient’s vaccination schedule should be adjusted a to accommodate concomitant corticosteroid administration prior to and following onasemnogene because some vaccines, such as MMR and varicella, are contraindicated for patients on a substantially immunosuppressive steroid dose.

Adverse effects

Cumulative safety data from patients treated with intravenous onasemnogene in clinical trials and the RESTORE global registry show that adverse events were monitorable and manageable and the overall benefit-risk safety profile remains favorable. The most common adverse effects of onasemnogene are elevated liver enzymes and vomiting. Only 1 case of acute liver injury was reported in clinical trials.