EP438: Ethical issues related to gene therapy with onasemnogene abeparvovec for spinal muscular atrophy type 1 in a developing country

Abstract

The 5-q linked spinal muscular atrophy (SMA) (OMIM#253300) or SMA type 1 is an autosomal recessive, neuromuscular degenerative disorder caused by deletion or variants of SMN1 gene. SMA type 1 had been the leading genetic cause of infant mortality and gene replacement therapy with onasemnogene abeparvovec (AVXS-101, Zolgensma) was approved by the Food and Drug Administration (FDA) in May 2019. We described our experience of the first four Malaysian patients with SMA type 1 who received compassionate treatment in University Malaya Medical Center (UMMC), Malaysia and explored the main ethical issue related to this therapy. In Malaysia, patients with SMA type 1 were offered compassionate care. Supportive therapy was provided and palliative treatment and genetic counselling were offered when it was available. In 2020, gene therapy with AVXS-101 zolgensma under Novartis global managed access program (GMAP) was offered on a compassionate basis for SMA type 1 patients under 2 years of age. Following multi-stakeholder meetings and discussion with parents of SMA patients, it was decided patients will be selected on the basis of the inclusion criteria involved. Four SMA type 1 patients who were on palliative care were selected and each patient has 0 copy of SMN1 gene with 2 or 3 copies of SMN2 gene, respectively. The parents were counselled and all consented to receive the therapy. The patients received the therapeutic dose of AVXS-101 therapy (1.1E14 vector genomes (vg)/kg) at 12-month, 15-month, 24-month and 19-month-old respectively. All 4 patients were negative for AAV-9 antibody and had normal liver function profile, serum troponin 1 levels and full blood counts. There were no complications during infusion. Post treatment, all patients showed raised serum transaminases and gamma-glutamyl transpeptidase (GGT), but none with clinical symptoms. Their liver function improved and normalized with a course of recommended dose of oral prednisolone. Asymptomatic thrombocytopenia occurred within 7 days post treatment and recovered without intervention. All patients experienced improvement in motor function with increase in CHOP-INTEND scores evaluated at 3 and 6-month post treatment. None of the patient was ventilator dependent although a patient received nocturnal non-invasive ventilatory support. With proper pre-treatment screening, immunization, respiratory and nutritional support, and post-gene transfer management, onasemnogene abeparvovec was safe and early efficacy was promising in 4 Malaysian children with SMA type 1. The future outcome and adverse effects could only be ascertained with long term follow-up and multi-disciplinary care. The main ethical issue relates to the high cost of the drug which is prohibitive in a developing country. Consequently, this had an impact regarding patient access to this drug and related life-saving orphan drugs in low and middle income countries. This will require further discussion with all stakeholders, support groups and governmental intervention to ensure equity of care and appropriate funding model for this severe neuromuscular condition.