CASGEVY: CRISPR/Cas9 gene therapy now available in England following NICE recommendation

Vertex Pharmaceuticals announced a reimbursement agreement with NHS England for individuals 12 years or older with transfusion-dependent beta thalassemia ("TDT") to access the CRISPR/Cas9 gene-edited therapy, CASGEVY (exagamglogene autotemcel), from 8 August 2024. The agreement is limited to people living with TDT for whom a stem cell or bone marrow transplant is appropriate but no donor is available. NHS England confirmed that there are an estimated 460 people living with TDT in England that are potentially eligible for the therapy, with it being manufactured in the UK and offered at seven specialist NHS centres across the country in the coming weeks.

The reimbursement agreement resulted from the National Institute for Health and Care Excellence ("NICE") issuing guidance recommending such use of CASGEVY in the NHS. The drug carries a substantial list price of £1.65 million per course of the treatment; however, this will be subject to a confidential discount, which is likely to be significant.

CASGEVY and TDT

Beta thalassemia is an inherited and life threatening genetic disorder that, as a consequence of mutations in the beta-globin gene, is typified by dysfunctional production of adult haemoglobin. Haemoglobin is a protein that is essential for carrying oxygen in red blood cells. People living with beta thalassemia suffer from anaemia (a shortage of red blood cells or haemoglobin) that causes lethargy, shortness of breath and weakness. People living with TDT are a subset of people living with beta thalassemia who require regular transfusions. Affected individuals can also suffer from an enlarged spleen, liver and heart, as well as malformed bones and delayed puberty. Prior to CASGEVY, people living with TDT required frequent blood transfusions (even weekly in the most serious cases) and iron chelation therapy throughout their life, with many people living with TDT not expected to live far beyond the age of 50. While blood transfusions and bone marrow transplants also represent a potential treatment option, the lack of available donors has limited the efficacy of such modality.

As detailed further in the 11th issue of Bristows' Biotech Review of the Year, CASGEVY is a non-viral, autologous, ex vivo CRISPR/Cas9 gene-edited cell therapy, in which a person's own hematopoietic and progenitor (i.e. stem cells) are harvested from the person and edited to silence the gene that represses haemoglobin production. By "edited", we mean that a specific a double-strand break is introduced by an enzyme which acts as molecular scissors at a specific region of the BCL11A gene. This in turn changes the DNA sequence of the target cells, leading to reduced BCL11A expression (i.e. the gene which reduces production of haemoglobin). These modified stem cells are then transplanted back into the person, whereby the reduced BCL11A expression leads to an increase in production of foetal haemoglobin. In international clinical trials, it was reported that 93% of people living with TDT did not require a blood transfusion for at least one year following the treatment. It is hoped that CASGEVY could be a one-time use, lifetime cure.

CASGEVY approval

By way of background, the UK Medicines and Healthcare products Regulatory Agency ("MHRA") became the first health authority in the world to approve CASGEVY for the treatment of sickle cell disease ("SCD") and TDT in November 2023. The MHRA's EU and US counterparts (the European Medicines Agency and US Food and Drug Administration respectively) followed suit with approvals soon after.

Then, in draft guidance published in March 2024, NICE refused to recommend CASGEVY for treating SCD on grounds of the treatment being above the acceptable cost-effectiveness estimate as regards NHS resources. However, NICE's recommendation of CASGEVY for the treatment of eligible people living with TDT represents a landmark moment for people living with TDT in the UK, as well as for the cell and gene therapy ("CGT") space generally.

The treatment will be available through England's Innovative Medicines Fund ("IMF") - which has a fixed funding envelope of £340 million per year for funding early access to innovative non-cancer medicines - meaning that people living with TDT will have expedited access while further evidence on the benefits of the therapy to people living with TDT is gathered over the next five years. This makes CASGEVY the second treatment to be reimbursed within the IMF, following the reimbursement of CSL Behring's gene therapy, Hemgenix, under the IMF in June 2024.

What's next?

As of writing this article, the IMF's funding of CASGEVY only applies to people living with TDT living in England. It has been reported that Vertex is actively engaging with the NHS in Wales, Northern Ireland and Scotland regarding access to CASGEVY. Decisions on how NICE recommendations apply to these nations will be determined by the devolved bodies.[1]

Vertex has confirmed that it is continuing to work with: (i) NICE and NHS England to secure access to the treatment for eligible people living with SCD in England; and (ii) European reimbursement authorities to ensure that the treatment becomes available to eligible to people living with TDT and people living with SCD as soon as possible. We will monitor the progress of such negotiations.

The speed at which life-changing personalised medicine has advanced in recent history is nothing short of staggering. As Bristows previously reported in this article, and as evidenced by NICE's rejection of CASGEVY for treating SCD in March of this year, some CGTs have struggled to reach agreement with health authorities due to eye-watering price tags. Alongside pricing issues, manufacturing complexities have also imposed significant hurdles to the successful commercialisation of CGTs. CASGEVY now joins a select contingent of CGTs that, having successfully managed to circumvent such hurdles, can be deployed to change the lives of those in need.

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[1] The: (i) All Wales Medicines Strategy Group; (ii) Department of Health, Social Services and Public Safety; and (iii) Scottish Medicines Consortium, in Wales, Northern Ireland and Scotland respectively.