In the fight against spinal muscular atrophy (SMA), few treatments have reshaped the landscape like Zolgensma (onasemnogene abeparvovec). Priced at a staggering $2.1 million per patient for a one-time dose, it was the world’s most expensive drug at the time of its FDA approval in 2019. Although its innovative mechanism of action offers hope for those diagnosed with SMA, its price tag raises a critical question: how can one justify the cost?
What is SMA, and how does Zolgensma differ clinically?
SMA is a rare neuromuscular disorder, with a prevalence of approximately 1-2 per 100,000 persons or incidence around 1 in 10,000 live births. It is caused by mutations in the SMN1 gene, which produces the Survival Motor Neuron (SMN) protein essential for motor neuron survival. Without adequate levels of SMN protein, motor neurons degenerate, impairing their ability to transmit signals between the brain and muscles. This leads to progressive muscle weakness, paralysis, and, in severe cases, death [Figure 1]. The disease primarily affects infants and children, with symptoms ranging from life-threatening respiratory failure in SMA Type 1, with a median survival of about 2 years, to milder muscle weakness in SMA Type 4 with no major impact on life expectancy.
Figure 1: Pathophysiology overview of SMA.1) Mutation in the SMN1 gene leads to 2) deficiency in the SMN protein what causes 3) loss of motor neurons in the spinal cord, resulting in 4) progressive muscle weakness and atrophy.
Historically, SMA treatments focused on supportive care like physical therapy and respiratory support, which alleviated symptoms but didn’t target the root cause. A major breakthrough occurred in 2016 with the approval of Spinraza (nusinersen), the first medication to treat SMA. Nusinersen is an antisense oligonucleotide therapy that modifies the splicing of the backup SMN2 gene, enabling it to produce more functional SMN protein [Figure 2]. Following initial intrathecal injections, nusinersen requires ongoing administration every 4 months, making treatment a lifelong commitment.
Zolgensma represents a paradigm shift. Unlike other approaches, Zolgensma is a one-time gene therapy. It delivers a functional copy of the SMN1 gene directly to motor neurons, effectively addressing the root cause of SMA [Figure 2]. This mechanism allows motor neurons to resume producing SMN protein, halting disease progression.
Figure 2: Nusinersen vs Zolgensma Mechanism of Action. Spinal muscular atrophy (SMA) is caused by mutations in the SMN1 gene, which normally produces full-length SMN protein essential for motor neuron survival. The paralogous SMN2 gene differs by a C-to-T transition in exon 7, causing most SMN2 transcripts to skip exon 7 and produce a truncated, unstable SMN protein (Δ7-SMN). Only about 10% of SMN2 transcripts result in full-length SMN protein (FL-SMN2). 1)SMN2 Splicing Modulation: Antisense oligonucleotides (ASOs), such as Nusinersen, promote exon 7 inclusion in SMN2 mRNA, increasing the production of full-length SMN protein (FL-SMN2). 2)SMN1 Replacement: Gene therapy, such as AVXS-101 (Zolgensma), delivers a functional copy of the SMN1 gene via a self-complementary adeno-associated virus (scAAV9-SMN1), restoring production of full-length SMN protein (FL-SMN) to compensate for SMN1 loss. (Adapted from Parente and Corti, 2018)
Zolgensma has shown remarkable efficacy in multi-centre Phase 3 SPR1NT trial, where all 14 children were given the treatment at median age of 21 days of life. Childrenachieved the primary endpoint of independent sitting for at least 30 seconds at any visit up to 18 months of age. At the end of the study, 12 children retained this motor milestone at 18 months of age.
Following the trial, Novartis Gene Therapies SVP and CMO Shephard Mpofu stated: “When you consider these newborns would go on to develop severe symptoms of SMA Type 1, a devastating, progressive disease that robs children of the ability to talk, eat, sit up and even breathe, findings from the SPR1NT trial are nothing short of extraordinary.”
As of 2023, Zolgensma has been administered to over 3,000 patients worldwide, demonstrating its transformative potential in altering the natural course of SMA; however, its extraordinary cost remains a significant challenge for healthcare systems globally.
To illustrate this, 2022 data from the WHO Global Health Expenditure Database was analyzed. Zolgensma’s list price of $2.1 million was compared to the per capita health expenditure of 10 selected countries [Figure 3].
Figure 3: Number of citizens required to sacrifice their health budget to fund a single course of Zolgensma treatment. Values were calculated by dividing Zolgensma's list price by individual 2022 health expenditures per capita (in USD) of each country.
The findings reveal that funding a single course of Zolgensma would require the equivalent of tens of thousands of citizens to sacrifice their annual health budgets in low and lower-middle income countries, as defined by the World Bank. This creates immense financial pressure on governments in less developed nations, exacerbating global inequities in access to life-saving treatments. In 2020, Poland created a separate Medical Fund with a dedicated 4 billion PLN (~1 billion USD) in new legislation to enable annual funding and reimbursement for highly expensive, innovative treatments like Zolgensma. However, such legislative changes are not possible all over the globe.
What is the estimated value of Zolgensma?
The Institute for Clinical and Economic Review (ICER) estimated that Zolgensma's price of $2.1 million far exceeds value-based thresholds. ICER suggested a value-aligned price for Zolgensma would range between $310,000 and $900,000 for SMA Type 1 indication. This discrepancy highlights the challenges of pricing innovative therapies for rare diseases, where unmet needs are significant, but costs are high.
Given its high price, the NHS faced significant challenges in making Zolgensma accessible to patients in the UK while balancing its public healthcare budget. In March 2021, the NHS reached a confidential agreement with Novartis Gene Therapies to provide Zolgensma to eligible infants with SMA Type 1. Although the exact details of the deal remain undisclosed, the NHS has historically employed certain financial instruments to enable access to high-cost treatments. These include outcome-based pricing where payments are linked to the real-world results or structured payment plans where the payment is split across several months or years. In case of gene therapies, such risk-sharing instruments are a great option for the payers, given the early therapeutic timing which allows to monitor treatment’s performance in the forthcoming years [Figure 4].
Figure 4: Therapeutic timing of Zolgensma compared to CAR-T. Monitoring real-world effectiveness and incorporating it within outcome-based pricing is much more favourable option for gene therapies as opposed to expensive oncology treatments, often given as a last line of treatment when patient’s life-expectancy is months not years.
In the UK, access is restricted to babies up to 6 months of age or to babies between 7-12 months of age if “the treatment will give them at least a 70% chance of being able to sit independently”, according to NICE. To mitigate this, the NHS has invested in enhancing diagnostic pathways to support earlier identification of SMA.
A pilot study at Oxford was launched to detect presymptomatic SMA. Treatment within days of birth is critical, as studies have shown that Zolgensma is most effective when administered early, before significant motor neuron damage occurs. Consequently, access to the treatment is restricted in many countries to exclude older children. However, new 2024 data from the SMART study shows that older, previously treated children can also benefit from Zolgensma.
What should we think of all of this?
Zolgensma’s clinical effectiveness is undeniable. It has transformed the lives of many children who would otherwise have not had a chance of breathing, sitting and walking independently, if not for the treatment. From an economics perspective, it’s clear the price is very high. This drives global inequalities in access to the treatment as no African country will ever sacrifice tens of thousands of allocated health expenditures per patient to fund a few courses of Zolgensma treatment per year. However, before we are quick to criticise the manufacturers let’s ask ourselves – when developing highly innovative treatments where should this risky R&D investment come from? One may argue that nowadays we are observing a shift from early in-house drug development to small bio-tech acquisitions to outsource innovation and mitigate the risk, however clinical trials are still required and are still a risky part of R&D.
Isn’t the innovation a result of investment – and, within the pharma industry, a highly risky investment at that? Are we not further stirring the innovation for patients in other disease areas? As usual in economics, we observe a trade-off – here a balance between affordability and innovation. Let’s seek this balance and spark meaningful discussions about equally accessible healthcare.
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