Within the next month, the US Food and Drug Administration (FDA) is set to review a landmark gene therapy product, Zolgensma (onasemnogene abeparvovec), touted by its developer (AveXis, a Novartis subsidiary) as a potential one-off cure for a rare inherited neuromuscular condition, spinal muscular atrophy (SMA). Zolgensma has been designed to overcome the genetic mutation in SMA type-1, the most common subtype, which is associated with a high infant mortality rate and is severely debilitating.

While the launch of this product has been hotly anticipated by patient groups and physicians, there has also been much animated discussion over its expected US price tag – estimated at well over a million dollars per patient. Opinion is divided on whether such high prices are sustainable within the US healthcare system, and conversely, whether it would be ethical to deny patients access to a lifesaving treatment purely on grounds of cost.

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Does it work, and is it safe?

Certainly, the supporting clinical evidence has been working in Zolgensma’s favor so far. Most recent data from the STRIVE trial in 22 infants with SMA-1 revealed “early and rapid” improvements in neuromuscular function and motor milestones, following a single Zolgensma infusion. This supported previous data from the START trial, which had created a stir when Novartis announced “unprecedented” positive developments such as rolling over and unaided sitting at the 24-month mark. It should be remembered that untreated SMA-1 generally results in mortality or a requirement for permanent ventilation in 90% of untreated cases, by two years of age.

Regarding safety, reports so far have been generally favorable – with the most common adverse event being a (manageable) increase in serum aminotransferase levels. However, the picture was clouded recently by reports of two infant deaths during trials. One of these has already been considered by an independent monitor to be non-treatment-related, although a second, from a severe respiratory infection with neurological complications, remains open, with investigations continuing. Novartis’s most recent statement indicated that the company did not predict this event to have a negative impact on the timing or outcome of the FDA’s decision.

The problematic question of pricing

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In bringing such a treatment to SMA patients, a balance clearly needs to be struck between avoiding unnecessary delays (especially in a fatal condition) and spending a large portion of the entire healthcare budget on only one drug. This dilemma is especially acute in the field of gene therapy, where there is little precedent on which to base a pricing decision.

With such considerations in mind, last November Novartis pitched a tentative US price point at around USD4-5 million per patient, as a “cost-effective” estimate for the one-off treatment, although more recent communications have broadened the range downwards. In April, CEO Vas Narasimhan stated in an analyst call that he would consider USD4-5 million per-patient a cost-effective price if a cut-off value of USD500,000 per quality-adjusted life year (QALY) were used but could consider values down to USD1.5 million in the case of a USD150,000 per QALY threshold. The actual price point will remain to be seen once the treatment is approved.

It is noteworthy that these company estimates chime closely with expected threshold prices for cost-effectiveness quoted only last month by the US Institute for Clinical and Economic Review (ICER) advisory body – and this may well work in favor of acceptance. Indeed, ICER recently endorsed Novartis’s pricing of another gene therapy product, the chimaeric antigen receptor T-cell (CAR-T) therapeutic Kymriah for cancer, at USD475,000 per patient for a one-off treatment – although sustainability of payments for such expensive treatments will still need to be carefully re-evaluated over time.

How does it line up against Spinraza?

No discussion on SMA would be complete without considering Biogen‘s rival product Spinraza (nusinersen) – which was the first-ever SMA product to reach the market, back in December 2016. While Spinraza also addresses the underlying mutation of SMA, and has also shown clear effectiveness in improving motor function, it has the disadvantage of being a small molecule requiring multiple lifelong dosing, and carries a hefty reported US price tag of USD750,000 per patient for the first year, followed by USD375,000 per year (according to our PharmOnline International [POLI] – Pharmaceutical Pricing & Reimbursement Database).

While the price estimates for Zolgensma appear likely to be much higher, it must be remembered that it this is for a one-off treatment, whereas Spinraza requires repeated lifelong repeated administration, compounding costs over time – a factor which has restricted its reimbursement in several key markets. Indeed, ICER’s recent study ruled that it considered Spinraza a “low long-term value for money” option at current prices, and that it would require an 83% discount to meet the USD150,000 per QALY threshold. Once Zolgensma hits the market, Biogen will have to re-evaluate their pricing package carefully, if it is to compete effectively with a one-off gene therapy.

The next month will be crucial both for Zolgensma and its rival Spinraza. Certainly, if Zolgensma lives up to its advance publicity, and is approved this month with pricing at a level which could be considered sustainable, it has the potential to out-compete Spinraza – unless any long-term efficacy, patient acceptance or safety issues emerge over time. With gene therapy still in its infancy as a strategy, this long-awaited event for SMA groups still carries its risks, both in practical and financial terms.