What is the role of Zolgensma (onasemnogene abeparvovec) in treating spinal muscular atrophy (SMA)?

From the Guidelines

Zolgensma (onasemnogene abeparvovec) is a crucial gene therapy for treating spinal muscular atrophy (SMA), offering a one-time treatment that can halt disease progression and improve patient prognosis, particularly when administered early in the disease course.

Key Points About Zolgensma

• Zolgensma works by replacing the malfunctioning survival motor neuron (SMN) gene with a functional variant, addressing the root cause of SMA - a deficiency in the survival motor neuron (SMN) protein 1.
• The treatment is most effective when given to children under 2 years of age, particularly before symptoms develop, and is administered as a one-time intravenous infusion.
• The standard dosage is 1.1 × 10^14 vector genomes per kilogram of body weight, and patients require liver function monitoring before and after treatment, as well as corticosteroid administration to manage potential immune responses.
• While Zolgensma is extremely expensive, it offers the potential for significant improvement in motor function and survival rates, particularly when administered early in the disease course, as seen in the development of Vitrakvi (larotrectinib) by Pfizer, which targets the neurotrophic tropomyosin receptor kinase (NTRK) gene fusion in different tumor types 1.

Considerations for Treatment

• Side effects may include elevated liver enzymes, vomiting, and potential risks of thrombocytopenia and cardiac events, requiring careful monitoring.
• The pharmaceutical industry is advancing the field of gene therapy through the integration of various technologies and methodologies to develop treatments tailored to the individual genetic and molecular profiles of patients, with Novartis leading in the gene replacement field with Zolgensma 1.
• The move towards personalized therapeutics, such as Zolgensma, alters the roles of health-care providers, patients, and payers, necessitating smaller, more adaptable, and tailored clinical trials, as well as the formulation of new endpoints and evidence 1.

From the FDA Drug Label

ZOLGENSMA is an adeno-associated virus (AAV) vector-based gene therapy indicated for the treatment of pediatric patients less than 2 years of age with spinal muscular atrophy (SMA) with bi-allelic mutations in the survival motor neuron 1 (SMN1) gene.

The role of Zolgensma (onasemnogene abeparvovec) in treating spinal muscular atrophy (SMA) is as a gene therapy to treat pediatric patients less than 2 years of age with SMA and bi-allelic mutations in the SMN1 gene.

• The indications for Zolgensma include treatment of pediatric patients with SMA and bi-allelic SMN1 gene mutations.
• Key considerations for Zolgensma administration include:
  • Patient age: less than 2 years
  • SMA diagnosis: bi-allelic SMN1 gene mutations
  • Administration: single-dose intravenous infusion 2 2 2

From the Research

Overview of Zolgensma

• Zolgensma (onasemnogene abeparvovec) is a gene therapy approved for the treatment of spinal muscular atrophy (SMA) 3, 4, 5, 6.
• It is administered as a one-time intravenous infusion, using the adeno-associated virus vector to deliver a functional copy of the human survival motor neuron (SMN) gene to motor neuron cells 3.

Mechanism of Action

• The SMN1 gene encodes survival motor neuron protein, which is responsible for the maintenance and function of motor neurons 3, 4.
• Onasemnogene abeparvovec provides a functional copy of the SMN1 gene, allowing for the production of SMN protein and improving motor function in patients with SMA 3, 4, 5.

Efficacy and Safety

• Clinical trials have shown that onasemnogene abeparvovec improves event-free survival, motor function, and motor milestone outcomes in patients with SMA, with these improvements maintained over the longer term (up to a median of ≈ 5 years) 3.
• The therapy has also been associated with rapid age-appropriate achievement of motor milestones and improvements in motor function in children with pre-symptomatic SMA, indicating the benefit of early treatment 3, 4.
• However, hepatotoxicity is a known risk of onasemnogene abeparvovec, which can generally be mitigated with prophylactic prednisolone 3, 4, 5.
• Long-term benefits and risks of the therapy have not been fully determined, but it appears to be a cost-effective treatment option compared to other therapies, such as nusinersen 4, 5.

Future Directions

• Research is ongoing to improve the therapeutic efficacy of onasemnogene abeparvovec, including the development of ubiquitination-resistant variants of the SMN protein 7.
• These variants have shown improved therapeutic effects in preclinical models, with increased lifespan, body weight, and motor function, as well as reduced liver toxicity 7.