This month, Novartis’ pioneering gene therapy, Zolgensma (onasemnogene abeparvovec-xioi), for type 1 spinal muscular atrophy (SMA), was administered to its first patient in the UK following reimbursement approval from the National Institute for Health and Care Excellence (NICE) in early March. Type 1 SMA is a rare genetic condition that results in muscle weakness and movement difficulties in infants, with 90% of untreated patients dying before the age of two years.

The price of Zolgensma has proven to be a significant hurdle to achieving approval for reimbursement. With a list price of $2.47m, NICE has negotiated an undisclosed discounted price for the therapy, which is designed to be a single-dose therapy. Most of the challenges around pricing and reimbursement stem from the huge costs of manufacturing and drug development processes involved with gene therapies. GlobalData predicts that the approval for reimbursement of Zolgensma will likely provide a more well-defined pathway for the future approval for reimbursement of high-cost novel gene therapies currently in the pipeline for other rare diseases across the seven major markets (US, UK, France, Germany, Italy, Spain and Japan).

Zolgensma is a single-dose adeno-associated viral vector (AAV) gene therapy indicated for SMA, a condition caused by a defect in the survival motor neuron 1 (SMN1) gene, where the AAV delivers the SMN transgene into the motor neurons and produces full-length functional SMN protein. The SMN1 gene is responsible for a key protein essential to the survival of motor neurons, which regulate muscle function. The US Food and Drug Administration (FDA) approved the use of Zolgensma for patients younger than two years in May 2019, with the European Medicines Agency (EMA) also providing marketing authorisation for the drug last May, as well as similar approvals in the UK (NICE) in March and in Japan last March. These approvals demonstrate the possibility of a route to market for novel single-dose gene therapies likely to launch over the next decade for other rare monogenic disorders.

For example, lysosomal storage disorders (LSDs) are rare monogenic disorders with several AAV gene therapies currently in Phase I/II that are likely to be single-dose and potentially curative when they enter the market towards the end of this decade. More specifically, Fabry disease (FD) and Pompe disease (PD) are two types of LSDs with several gene therapies in Phase I/II that have early-stage clinical data demonstrating curative potential. Patients receiving treatment have begun to demonstrate long-term efficacy in terms of elevated enzyme levels or reduced levels of toxic metabolites up to 22 months after a single dose of gene therapy is administered, which has not been previously observed with the current regimen of enzyme replacement therapy. There is a critical need for gene therapies that are curative for both Fabry and Pompe diseases, as many patients do not respond well to current therapies.

In the case of SMA therapies, Spinraza was the first significantly disease-modifying and efficacious therapy and improved survival in children for the first time. Zolgensma presents significant advantages compared to Spinraza, however, with unprecedented efficacy in type 1 SMA patients. Zolgensma is also administered as a one-time infusion, whereas Spinraza requires multiple doses to be administered intrathecally. A significant clinical disadvantage to prescribing Spinraza is the administration through a lumbar puncture. This is difficult for those with spinal deformities, which require the institutional infrastructure and resources for the procedure to be carried out, as well as for post-procedural monitoring of patients.

The process by which Zolgensma was approved for reimbursement has proven useful for other gene therapies hoping to reach the market, such as those for Pompe and Fabry disease currently being developed by biotech companies Spark Therapeutics (SPK-3006) and 4D Molecular Therapeutics (4D-310). Zolgensma’s reimbursement approval, and the subsequent similar approval of future single-dose gene therapies, is based on the development of innovative reimbursement models that take into account the longer-term value these therapies have for patients, as well as the overall cost to the National Health Service (NHS). The reimbursement pathway that underscores Zolgensma will make reimbursement decisions after regulatory approval more predictable, as well as promoting the increasing clinical development of these novel gene therapies.

Significant challenges remain around the pricing and market access of gene therapies, however, as manufacturers have to present late-stage clinical data that demonstrate significant efficacy and even curative potential, in order to achieve approval for reimbursement for therapies with a high list price. In the case of Zolgensma, there had been several significant trials, including Phase I (START), Phase III (SPR1NT) and Phase I/II (STRONG) clinical trials, that demonstrated survival rates not seen in the natural history of the disease. In addition, patients demonstrated rapid developments in motor function skills and were able to sit upright with no support, all developing within one month of dosing.

If significant improvement in quality-adjusted life years (QALY) can be achieved, then, the approval and payer bodies across the major markets have demonstrated they will provide approval for reimbursement for these gene therapies. One barrier to the immediate market uptake of Zolgensma, however, is the lack of long-term safety and efficacy data. This also remains a significant challenge for gene therapies currently under development for other rare disease such as LSDs.

Other examples of novel cell and gene therapies with high list prices achieving reimbursement approval from across the major markets include CAR-T therapy KTE-X19 for mantle cell lymphoma marketed in the US and EU with the first full-access deal in Europe negotiated by NICE, and CAR-T therapy Kymriah for B-cell acute lymphocytic leukaemia, which has a ‘payment based on outcomes’ reimbursement model and is available in the US, EU and Japan. GlobalData predicts gene therapy will be a significant breakthrough for the rare metabolic disease market and that the approval for the reimbursement of Zolgensma will underscore the innovative reimbursement model that the NICE and the NHS have developed for the approval of future high-list-price single-dose gene therapies.

Cell & Gene Therapy Coverage on Pharmaceutical Technology supported by Cytiva.

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