HSA approves Zolgensma: Pediatric spinal muscular atrophy gene therapy

Spinal muscular atrophy (SMA) is a rare genetic disease caused by a mutation in the survival motor neuron 1 (SMN1) gene. Affecting 1 in 10,000 newborns [1], this gene is responsible for the production of the survival motor neuron (SMN) protein, which is an essential protein used for the maintenance and function of specialised nerve cells – the motor neurons. Without SMN proteins, motor neurons die, resulting in muscles becoming weak and wasting away – with eventual loss of life functions such as breathing, swallowing, feeding or speaking. 

On 21 April 2023, the Health Sciences Authority (HSA) approved the first and only gene therapy – Zolgensma (onasemnogene abeparvovec-xioi) to treat spinal muscular atrophy (SMA), the most severe form of SMA, in children less than two years of age. If left untreated, SMA leads to death or the need for permanent ventilation by the age of two in more than 90% of cases [2]. 

Zolgensma contains the active ingredient onasemnogene abeparvovec, which is an adeno-associated virus vector-based gene therapy that targets the cause of SMA. The vector delivers a fully functional copy of the human SMN gene into the target motor neuron cells. By supplying a fully functional copy of the SMN gene, Zolgensma helps the body produce enough SMN protein, which improves muscle movement and function, increasing the survival chance of a child with SMA [3].

The approval of Zolgensma was based on hallmark trials – START and STR1VE-US. Trials were designed to evaluate the efficacy and safety of a single-dose IV infusion of Zolgensma, in symptomatic SMA Type 1 patients <6 months of age at dosing, who had one or two copies of the SMN2 backup gene, or two copies of the SMN2 backup gene, respectively [4,5]. 

Phase 1 START Trial and Long-term Follow-up Outcomes

START Phase 1 [4,7]

A 2-year study enrolled 15 patients with type 1 SMA. Symptomatic patients with the onset of clinical symptoms before 6 months of age were divided into 2 cohorts—a low-dose cohort (n=3) and a high-dose cohort (n=12). 

*In natural history, 0% of patients with SMA Type 1 were able to sit unassisted.
**Patients with SMA Type 1 in historical controls do not typically achieve CHOP INTEND scores ≥40.

START Long-term Follow-Up: Efficacy and Safety [5]

An ongoing, long-term follow-up study of Zolgensma-treated patients from the START clinical trial (N=13), is planned to last 15 years. A total of 13 patients, 10 from the high-dose cohort and 3 from the low-dose cohort, are enrolled in the study. The primary outcome measure was the incidence of serious adverse events (SAEs). As of June 2020 data cut, 100% (10/10) of patients in the high-dose cohort were alive and free of permanent ventilation.

STR1VE Phase 3 Trial Outcomes [6,7]

Phase 3 trial of symptomatic patients less than 6 months of age at the time of infusion, studied until 18 months of age (N=22). 

*In natural history, 0% of patients with SMA Type 1 were able to sit unassisted.
**In natural history, most patients with SMA Type 1 older than 12 months of age required feeding support.
***In natural history, most patients with SMA Type 1 required respiratory support by 12 months of age.
****Patients with SMA Type 1 in historical controls do not typically achieve CHOP INTEND scores ≥40.

In all trials, Zolgensma demonstrated rates of survival never seen in the natural history of the disease; significant motor function improvement, often within one month of dosing; and milestone achievement, including the ability to sit without support, a milestone never achieved in untreated patients.

Local Singaporean Physicians’ Commentary

While a single dose of Zolgensma can help correct the genetic defect and improve survival rates of SMA patients, the unique gene therapy does come with a hefty price tag of US$2.1 million. It is neither subsidized by the government, nor is SMA treatment covered by the Rare Disease Fund. With the approval of Zolgensma by HSA, doctors Ng Qin Xiang, Chan Hwei Wuen and Jeremy Lim feel that it is an opportunity to rethink how innovative, expensive gene therapies are financed. 

As Zolgensma could previously only be imported under the special access route, the approval signifies a major increase in accessibility of Zolgensma. However, parents have historically been turning to approaches such as crowdfunding, which are unsustainable solutions in the long run. 

The high cost of such innovative treatments are said to be mainly driven by the high investment costs, from discovery of basic molecules to clinical trials for safety and efficacy. Furthermore, many gene therapies, including those for rare diseases like SMA, are only applicable to small patient populations, which further limits the potential for economies of scale in terms of manufacturing, distribution and sales.

As such, beyond aggressively seeking pricing discounts from manufacturers, one proposed approach to cushion the heavy cost is to have staggered payment arrangements, combined with “value-based contracting” where the price of the drug is tied to how well it performs.

Dr Ng Qin Xiang is currently working towards becoming a Preventive Medicine specialist and pursuing a PhD at the NUS Saw Swee Hock School of Public Health. Dr Chan Hwei Wuen is a Consultant, Department of Ophthalmology and leads a dedicated Inherited Retinal Diseases service at the National University Hospital. Associate Professor Jeremy Lim is director of the Leadership Institute for Global Health Transformation at the NUS Saw Swee Hock School of Public Health.

References:

1. Centers for Disease Control and Prevention. (2023, March 8). Spinal muscular atrophy (SMA). Centers for Disease Control and Prevention.
2. Farrar MA, Park SB, Vucic S, et al. Emerging therapies and challenges in spinal muscular atrophy. Ann Neurol. 2017;81(3):355-368. doi:10.1002/ana.24864
3. Zolgensma Prescribing Information, Norvatis.
4. Mendell JR, Al-Zaidy S, Shell R, et al. Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy. N Engl J Med. 2017;377(18):1713-1722. doi:10.1056/NEJMoa1706198
5. Mendell JR, Al-Zaidy SA, Lehman KJ, et al. Five-Year Extension Results of the Phase 1 START Trial of Onasemnogene Abeparvovec in Spinal Muscular Atrophy. JAMA Neurol. 2021;78(7):834-841. doi:10.1001/jamaneurol.2021.1272
6. Day JW, Finkel RS, Chiriboga CA, et al. Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial. Lancet Neurol. 2021;20(4):284-293. doi:10.1016/S1474-4422(21)00001-6
7. WHO Multicentre Growth Reference Study Group. WHO Motor Development Study: windows of achievement for six gross motor development milestones. Acta Paediatr Suppl. 2006;450:86-95