Market Access Considerations for the Future of Sickle Cell Disease Gene Therapies
Introduction
Building upon the introduction to gene therapies for sickle cell disease (SCD) in the first article, this discussion explores market access considerations surrounding the availability, affordability, and equitable distribution of gene therapies for a rare disease such as SCD. Given the geographic prevalence of SCD among people of African, Middle Eastern, South Asian, and Mediterranean descent, and the high cost-to-benefit-risk balance of gene therapies, distinct market access challenges emerge across various regions globally. In this article, we will explore key challenges associated with market access for gene therapies.
Challenge 1: Integrity and rigour of the clinical data package
The quality of the clinical evidence package is a key market access consideration for gene therapies targeting SCD, especially regarding the lingering uncertainties surrounding long-term safety and efficacy. Challenges arising from small sample sizes and limited follow up periods in pivotal trials raise significant concerns about the magnitude and durability of clinical benefits (1). Complicating matters further, clinical trials for gene therapies lack direct comparisons with appropriate comparators. This is especially true for late-line treatments, such as allogenic haemopoietic stem cell transplantation (HSCT), making it challenging to assess the relative efficacy and safety profiles of gene therapies (2). These uncertainties may require Health Technology Assessment (HTA) bodies to extrapolate the clinical benefits of gene therapies, by relying on scientific theory to assume long-term treatment effects. Recently, NICE negatively recommended Casgevy for SCD in draft guidance due to uncertainty from small patient numbers, lack of comparative data and evidence on long-term treatment effect. Following a brief analysis of European HTA evaluations (NICE, G-BA and HAS) for cell and gene therapies with single arm trials, HTAs are tending to be more lenient towards external control arms and indirect comparisons (e.g. HAS ASMR IV rating for Ebvallo in 2nd line for treatment of Epstein-Barr virus-positive post-transplant lymphomas (EBV+ PTLD)) (3).
Challenge 2: The need for international and national policies to ensure equitable access
Collaborative effort among global health organisations, pharmaceutical companies, funders, and SCD patient advocacy groups e.g. Sickle Cell Society, is essential to promote the implementation of policies that facilitate equitable access to gene therapies. Global health organisations such as WHO, in collaboration with national regulatory authorities in low-to-middle-income countries (LMICs), can ensure application of international regulations whilst taking the local clinical landscape into account. This presents an opportunity to harmonise regulatory frameworks for gene therapies in Africa, where many countries lack national guidelines (4).
On a national level, HTA bodies face the challenge of managing robust appraisal processes. This issue is exemplified by Casgevy, which is being evaluated by NICE (UK) under the Single Technology Appraisal (STA) process and also being considered by the Highly Specialised Technologies (HST) evaluation committee (5). There is a need for national HTA bodies to develop comprehensive frameworks to address the unique considerations posed by gene therapies, particularly regarding their cost-effectiveness.
Challenge 3: Cost-effectiveness and patient access
Another critical market access challenge for SCD gene therapies is achieving a favourable view of cost-effectiveness versus standard of care. The financial barriers associated with gene therapies pose significant challenges, especially in LMICs, where disease prevalence is greatest. The costs of innovative gene therapies are staggering, demonstrated by the $3.1 and $2.2 million price tag of bluebird bio’s Lyfgenia and Vertex-CRISPR’s Casgevy for SCD treatment, respectively. These challenges are evidenced by limited access to standard of care treatment of hydroxyurea, priced at just $100-300 per year, in sub-Saharan Africa (6). If standard of care treatment for SCD is deemed unaffordable by populations across the globe with the greatest need, how can equitable access to high-cost gene therapies be viewed as feasible?
Unfortunately, the significant financial burden on healthcare systems of LMICs extends beyond the product itself to include administration, hospitalisation expenses, and healthcare infrastructure. Accessibility to gene therapies in areas with high SCD prevalence, such as Africa where an estimated 85% of worldwide cases occur (7), is hindered by limited authorised treatment centres (ATCs) for gene therapy administration. Despite plans for expansion, Casgevy’s Vertex Pharmaceuticals has only established three ATCs in the European Union, with no public discussion on ATC accessibility outside Europe (8). Healthcare systems vary globally and while developing strategies for accessing costly treatments may be feasible in Europe or the US, other regions may struggle with the associated risks (2).
Building the cost-effectiveness case for SCD gene therapy is multifactorial, with clinical evidence playing a significant role. Lack of long-term clinical data and uncertainty in cost-effectiveness assumptions may lead to negative HTA recommendations, as published in the UK’s NICE draft guidance for Hemgenix, a $3.5 million haemophilia B gene therapy (9). Therefore, companies developing SCD gene therapies must carefully assess cost-effectiveness assumptions and accurately translate long-term clinical efficacy data to long-term cost-effectiveness, for a robust health economic case.
If access to gene therapies is achieved and products are deemed cost-effective, advanced healthcare systems still face considerable challenges in sustaining long-term access. Payers may struggle to cover these treatments where upfront payment precedes the payout of lifelong benefits. This challenge is particularly pertinent when patients switch insurers over time and the initial payer may not recuperate savings (10).
Enter value- and outcomes-based pricing agreements.
Implementing value-based pricing agreements is increasingly essential for navigating cost-effectiveness complexities in healthcare and improving cost predictability with outcomes- or risk-based contracts. Traditional payment models are inadequate for one-time treatment gene therapies, as noted by Pfizer’s Angela Hwang (11). Bluebird bio’s Zynteglo for beta thalassemia treatment, has an outcomes-based agreement in the US, reimbursing up to 80% of therapy costs ($2.8 million) if a patient fails to remain transfusion-free up to two years post-therapy. A “no cure, no pay” agreement is being negotiated for Hemgenix with payers in the US. Even the Centers for Medicare and Medicaid Services (CMS), is proposing a model for multi-state outcomes-based agreements (10).
A new study conducted by the American College of Physicians specifically compared the cost-effectiveness of a gene therapy versus standard of care for treatment of SCD when a value-based price is considered. The results of the study found that gene therapy is beneficial and likely cost-effective if the price is below $2 million per person (6). Considering the current landscape of approved SCD gene therapies, the $2.2 million cost of Casgevy appears more feasible than the $3.1 million cost of Lyfgenia, although this is still $200k higher than the reported cost-effectiveness threshold, (Figure 1).
Figure 1: Product costs of Casgevy ($2.2 million) and Lyfgenia ($3.1 million) are above the $2 million cost-effectiveness threshold for gene therapies found in the 2024 Basu et al. study.
Options such as these may be plausible in high income countries (HICs), however, similar pricing agreements must also be considered internationally. A recent modelling analysis explored the prospect of value-based pricing for gene therapies for SCD across a wide range of settings (seven LMICs and six HICs) (12). The results are useful to inform the development of target product profiles and country-specific differential value-based pricing for SCD gene therapies, that account for the “heterogenous landscape of burden and affordability” globally (12).
Conclusion
The introduction of gene therapies for SCD promises to change the treatment landscape for patients by offering a cure. However, realising the full potential of gene therapies requires addressing numerous market access challenges. Issues such as cost-effectiveness, robust clinical evidence, and effective implementation of policies must be carefully navigated to ensure equitable access to these life-changing treatments for all patients, regardless of geography or socioeconomic status. By addressing these challenges, stakeholders can work towards a future of equitable access to gene therapies for SCD.
References
1. Nikitin, D., Beaudoin, F. L., Thokala, P., McKenna, A., Nhan, E., Rind, D. M., & Pearson, S. D. (2023). Gene therapies for sickle cell disease: Effectiveness and value. Journal of managed care & specialty pharmacy, 29(11), 1253–1259. https://doi.org/10.18553/jmcp.2023.29.11.1253
2. Raghuraman A, Lawrence R, Shetty R, et al. Role of gene therapy in sickle cell disease. Dis Mon. Published online February 6, 2024. doi:10.1016/j.disamonth.2024.101689
3. HAS (Haute Authorite de Sante, France), Ebvallo Transparency Commission Report, Published: Jun 7, 2023. Available at: https://www.has-sante.fr/upload/docs/evamed/CT-20229_EBVALLO_PIC_INS_AvisDef_CT20229.pdf
4. Munung, N.S., Nnodu, O.E., Moru, P.O. et al. Looking ahead: ethical and social challenges of somatic gene therapy for sickle cell disease in Africa. Gene Ther (2023). https://doi.org/10.1038/s41434-023-00429-7
5. NICE, GID-TA11259, Exagamglogene autotemcel for treating sickle cell disease [ID4016], Available at: https://www.nice.org.uk/guidance/indevelopment/gid-ta11249
6. Basu A, Winn AN, Johnson KM, et al. Gene Therapy Versus Common Care for Eligible Individuals With Sickle Cell Disease in the United States : A Cost-Effectiveness Analysis. Ann Intern Med. Published online January 23, 2024. doi:10.7326/M23-1520
7. Lugthart S, Ginete C, Kuona P, Brito M, Inusa BPD. An update review of new therapies in sickle cell disease: the prospects for drug combinations. Expert Opin Pharmacother. Published online February 12, 2024
8. Vertex Pharmaceutical, Press Release [online], Published: Feb 13, 2024. Available at: https://news.vrtx.com/news-releases/news-release-details/european-commission-approves-first-crisprcas9-gene-edited
9. NICE, GID-TA10699, Hemgenix - Etranacogene dezaparvovec for treating moderately severe or severe haemophilia B [ID3812], Draft Guidance, Available at: https://www.nice.org.uk/guidance/gid-ta10699/documents/draft-guidance
10. Adashi EY, Gruppuso PA, Cohen IG. CRISPR Therapy of Sickle Cell Disease: The Dawning of the Gene Editing Era. Am J Med. Published online January 4, 2024. doi:10.1016/j.amjmed.2023.12.018
11. Bloomberg, Angela Hwang interview, Published: Nov 7, 2019. Available at: https://www.bloomberg.com/news/videos/2019-11-07/pfizer-exec-on-biopharmaceuticals-breakthroughs-pipeline-video
Morgan G, Back E, Besser M, Hallett TB, Guzauskas GF. The value-based price of transformative gene therapy for sickle cell disease: a modeling analysis. Sci Rep. 2024;14(1):2739. Published 2024 Feb 1. doi:10.1038/s41598-024-53121-0
Written by Ava Mair and Sophia McGovern
Decisive Dialogue 26th March 2024
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