Advances in Sickle Cell Disease Gene Therapies: Navigating the Evolving Landscape
Sickle cell disease (SCD) is a group of recessive genetic disorders affecting red blood cells, causing lifelong anaemia. SCD is characterised by sickle or crescent-shaped red blood cells resulting from abnormal haemoglobin. These deformed red blood cells have a shorter lifespan and can block blood flow through small blood vessels, causing pain (also referred to as vaso-occlusive crises, VOCs), organ damage and increased risk of infections. SCD affects 7.74 million people worldwide (1), with a higher prevalence among populations of African, Middle Eastern, South Asian, and Mediterranean descent. An estimated 80% of SCD cases are concentrated in sub-Saharan Africa (LMICs, lower-to-middle income countries) (2).
Treatment options for SCD remain limited, primarily offering supportive care rather than curative measures. Haematopoietic stem cell transplantation (HSCT) from an allogeneic human leukocyte antigen (HLA)-matched donor is currently the only curative option for patients. However, HSCT is infrequently performed due to a lack of available donors, graft rejection and graft-vs-host-disease, and the need for continuous lifelong immunosuppression. Despite the curative treatment having a 90-95% success rate (3), this treatment option implicates a significant treatment burden for patients through the associated risk of rejection. Symptom management for SCD involves medications such as hydroxyurea, l-glutamine and crizanlizumab to reduce the frequency of VOCs, antibiotics to prevent infections, and blood transfusions to alleviate anaemia.
SCD patients experience a substantial clinical burden (4) marked by frequent hospitalisations, chronic pain, organ damage, and reduced life expectancy. The chronic nature of SCD requires continuous medication management and hospitalisations for VOCs, diminishing patients’ quality of life. Organ damage from SCD can lead to long term complications and reduced life expectancy. Additionally, SCD imposes a considerable economic burden (4) including direct healthcare costs and indirect productivity losses as patients require frequent medical visits and specialised care. As SCD is a lifelong condition, healthcare resource utilisation (HCRU) costs persist over the long term. Management of SCD is a particularly large public health challenge in LMICs where patients face limited access to care and accurate prevalence estimates are hindered by an absence of newborn screening programs. Due to the significant burden of disease of SCD, there is a global need to overcome the hurdles of the current lack of accessibility and affordability of curative treatments and the limitations of allogenic HSCT. Addressing these will pave the way to allow better access and implementation of transformative, curative treatments such as gene therapies in areas of the world with the greatest need. Gene therapies present a promising curative treatment option, alleviating the need for frequent blood transfusion, improving quality of life of SCD patients, and reducing the burden of disease on society (5).
Gene therapies, which involve autologous (self) HSCT with genetically modified HSCs, in which the defective gene is replaced with a healthy gene, address these limitations, and have the potential to offer patients a viable curative treatment option (6). Two gene therapies for SCD treatment have been given regulatory approval to date; Vertex Pharmaceutical and CRISPR Therapeutics’ Casgevy and Bluebird Bio’s Lyfegenia.
Casgevy (Exagamglogene Autotemcel, Exa-cel), a cell-based gene therapy that utilizes CRISPR-Cas9, was approved by UK’s MHRA in November 2023, followed by the EMA CHMP (14 December 2023), and US FDA, which set a list price of $2.2 million for the one-time therapy. Casgevy was granted an orphan designation in January 2020 by the European Commission for the treatment of SCD. With the approved indication being “patients aged ≥12 years with severe SCD characterized by recurrent VOCs or TDT (transfusion-dependent beta thalassemia), for whom HSCT is appropriate and an HLA-matched related HSC donor is not available”, Vertex states that the approval makes the treatment available to more than 8,000 patients (7). This presents an opportunity for gene therapies to treat a larger patient population by inclusion of specific subgroups, theoretically implicating greater patient access. Access was granted for Casgevy for SCD treatment in the US upon approval and early access was granted by France’s HTA body, HAS, on 18 January 2024 for eligible TDT patients, ahead of the national reimbursement process.
Bluebird Bio’s Lyfegenia (Lovotibeglogene Autotemcel, Lovo-cel), a gene therapy that produces an anti-sickling hemoglobin (HbAT87Q), was also approved by the FDA in December 2023, with list price of $3.1 million. Notably, the label for Lyfgenia contains a black-box warning with information regarding the risk of haematologic malignancy in patients treated with the drug (8). This would lead to lifelong monitoring of malignancies, contributing to the patients’ experience of treatment burden.
On the national HTA-level, several European countries are evaluating Casgevy for treatment of SCD and/or TDT patients. In the UK, Casgevy has been submitted for a single technology appraisal (STA) to NICE, with an expected decision date of 1 May 2024. On 2 Feb 2024, Spain’s AEMPS announced that the HTA body will start development of the Therapeutic Positioning Report (TPR) based on the positive opinion of Casgevy from the CHMP in December 2023. However, other European markets are taking a cautious approach to securing approval for Casgevy. At its meeting on 1 Feb 2024, Germany’s Federal Joint Committee, G-BA plenary session decided to discontinue consultations on the requirement for application-related data collection and evaluations for Casgevy following an evaluation by IQWiG of the patient count in the clinical data submission. Similarly, as published on 18 Jan 2024, Italian AIFA’s CTS have stated their opinion to suspend the procedure for appraising Exa-cel for treatment of TDT.
Aside from Vertex and CRISPR Therapeutics, several other pharmaceutical companies are expanding their portfolio with pipeline gene therapy products for SCD treatment, with varying levels of success. For example, Novartis’s pipeline HIX-763 and OTQ-923 products were discontinued due to poor Phase 1/2 results. However, others are presenting with a hopeful outlook; Beam Therapeutics’ BEAM-101 product is expecting result output of Phase 2 studies, while Editas’ reni-cel product has two ongoing clinical trials. Despite pipeline development, it is of note that 88% of CRISPR drugs are in early development stages (9), and so another approval, as with Casgevy or Lyfgenia, does not carry a high likelihood.
The tentative stance that many markets are taking when considering market access of gene therapies for SCD treatment is reasonable given the significant challenges that accompany gene therapies.
In the next article, we will discuss the challenges of gene therapies for SCD including (1) the integrity and rigour of the clinical data package and evidence of long-term safety and efficacy, (2) cost-effectiveness and patient access in markets with high prevalence of SCD, particularly LMICs, and (3) policy to ensure equitable access to curative treatments across markets globally, and the resultant impact on gaining market access.
References:
1. GBD 2021 Sickle Cell Disease Collaborators. Global, regional, and national prevalence and mortality burden of sickle cell disease, 2000-2021: a systematic analysis from the Global Burden of Disease Study 2021. Lancet Haematol. 2023 Aug;10(8):e585-e599. doi: 10.1016/S2352-3026(23)00118-7. Epub 2023 Jun 15. Erratum in: Lancet Haematol. 2023 Aug;10(8):e574. PMID: 37331373; PMCID: PMC10390339.
2. Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. Lancet. 2010 Dec 11;376(9757):2018-31. doi: 10.1016/S0140-6736(10)61029-X. Epub 2010 Dec 3. PMID: 21131035.
3. Leonard A, Weiss MJ. Hematopoietic stem cell collection for sickle cell disease gene therapy. Curr Opin Hematol. Published online February 12, 2024. doi:10.1097/MOH.0000000000000807
4. Udeze C, Evans KA, Yang Y, Lillehaugen T, Manjelievskaia J, Mujumdar U, Li N, Andemariam B. Economic and Clinical Burden of Managing Sickle Cell Disease with Recurrent Vaso-Occlusive Crises in the United States. Adv Ther. 2023 Aug;40(8):3543-3558. doi: 10.1007/s12325-023-02545-7. Epub 2023 Jun 18. Erratum in: Adv Ther. 2023 Nov;40(11):5130. PMID: 37332020; PMCID: PMC10329958.
5. 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
6. Benz EJ Jr, Silberstein LE, Panepinto JA. Blood Spotlight Review on Gene Therapy for Sickle Cell Disease. Blood. Published online December 25, 2023. doi:10.1182/blood.2023021598
7. Vertex, European Commission Approves First CRISPR/Cas9 Gene-Edited Therapy, CASGEVY™ (exagamglogene autotemcel), for the Treatment of Sickle Cell Disease and Transfusion-Dependent Beta Thalassemia [News release, Online], Published online February 13, 2024. Available at: https://investors.vrtx.com/news-releases/news-release-details/european-commission-approves-first-crisprcas9-gene-edited
8. FDA, FDA Approves First Gene Therapies to Treat Patients with Sickle Cell Disease [News release, Online], Published online December 8, 2023. Available at: https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapies-treat-patients-sickle-cell-disease
9. Beaney, A. Trials to watch: CRISPR pipeline accelerates after milestone Casgevy approval. Clinical Trials Arena. Published online January 17, 2024, Available at: https://www.clinicaltrialsarena.com/features/trials-to-watch-crispr-pipeline-accelerates-after-milestone-casgevy-approval/?cf-view&cf-closed
Written by Ava Mair and Sophia McGovern
Decisive Dialogue 26th February 2024
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