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Scientists react to NICE final draft guidance on Casgevy for the treatment of beta-thalassaemia.
Dr James Davies, Associate Professor of Genomics, Radcliffe Department of Medicine, University of Oxford, said:
“This is a very significant recommendation from NICE. Casgevy is the first treatment to be licensed based on genome editing. This is a completely new way of treating human disease in which the genome of cells is precisely modified. This technology has the potential to be used for treating many other genetic diseases, so this is a really important approval by NICE.
“People with thalassaemia have mutations in the haemoglobin genes, these make the main protein that carries oxygen in red blood cells. People with severe thalassaemia require blood transfusions every few weeks in order to survive.
“The treatment works by changing the DNA in the patient’s genome. It works by switching back on the haemoglobin genes that are used during fetal life which are normally turned off soon after birth. This allows patients with thalassemia to make normal blood cells with the ability to carry oxygen.
“In clinical trials, nearly all patients with thalassaemia, who required blood transfusions every few weeks did not require blood transfusions following treatment with Casgevy.
“However, the treatment requires chemotherapy in order for the genetically modified stem cells to take over blood cell production, which is not without risk. In addition, the long-term complications of these types of treatments are unlikely to be fully clear for many years.
“Worldwide there are large numbers of patients born each year with thalassaemia (around 40,000 births per year). It is particularly common in parts of the world with a high burden of malaria.”
Dr Alena Pance, Senior Lecturer in Genetics, University of Hertfordshire, said:
“This exciting strategy to potentially cure rather than treat genetic diseases causing deficiencies in B-globin was in fact approved in the UK for treatment of patients 12 years and over in November 2023, followed by approval in the US in December that year.
“This strategy, which represents a cure rather than treatment for Beta-Thalassemia and Sickle Cell Disease, because it consists in the modification of the patient’s own blood stem cells, giving a chance that these will generate functional red blood cells without need of transfusion nor immunosuppression. These diseases are caused by mutations in one of the genes that form haemoglobin in adults resulting in insufficient quantities or faulty proteins and dysfunction of the oxygen transport by the red blood cells. However, during development, specific foetal haemoglobin genes are expressed to cope with the lower oxygen levels in the womb, which are switched to the adult ones by another protein called BCL11A. This therapy uses genetic tools (CRISPR/Cas9) to modify blood stem cells of the patient to inactivate BCL11A and recover expression of the foetal globin gene, which then restores a functional haemoglobin. This strategy circumvents the problem that there are many different mutations that can cause the diseases, which can all be overcome with the same therapy. Using the patient’s own cells avoids immune incompatibilities and reactions and as the modification is in stem cells, these can potentially home themselves in the patient’s bone marrow and continue producing functional red blood cells for a long time or even forever, which is why this is potentially a cure.
“It is a positive development to see these innovative technologies being approved for wider use as it will surely open doors for similar approaches for the treatment of other genetic diseases. Even in the case of sickle cell anaemia and Beta-thalassemia, it will give an opportunity to study and follow the effectiveness of the approach further than the trial has achieved so far. Considering the all-around benefit of this recommendation for clinical use, the price tag seems quite extraordinary though.”
Dr Diana Hernandez, director of immune and advanced therapies at stem cell charity Anthony Nolan, said:
“Today’s landmark decision makes Casgevy the first CRISPR-Cas 9 therapy to be made available on the NHS – ushering in a new era of cell and gene therapies in the UK.
“Casgevy offers an effective cure for transfusion-dependent beta thalassaemia for people without a stem cell donor. The treatment involves removing the patient’s own blood stem cells and genetically modifying them so they produce healthy red blood cells. The modified stem cells are then infused back into the patient to permanently cure the disease.
“In the UK, beta-thalassaemia mainly affects people of Pakistani, Indian and Bangladeshi ethnic origin. These individuals are less likely to have a tissue-type matched donor on the stem cell register, making Casgevy the only viable option for this patient group.
“We are still waiting for this groundbreaking therapy to be funded for people with sickle cell, where it has huge promise and is desperately needed. Sickle cell largely affects patients from African and African-Caribbean backgrounds, who are less likely to have a matching stem cell donor, and this community has been waiting years for a new, effective treatment.”
Prof Laurence D Hurst, Professor of Evolutionary Genetics at The Milner Centre for Evolution, University of Bath, said:
“For many single gene genetic disorders gene therapy is now being actively researched and, in some cases, making it to clinic. To date the successful ones, have all taken the strategy of adding in a copy of the properly functioning version of the gene (as in recent gene therapies for haemophilia A and B). Casgevy is different as it involves editing not replacing genes.
“It relies on the fact that as foetuses our haemoglobin was different. Indeed, foetal haemoglobin is a little better than the adult version at extracting oxygen. Adult haemoglobin consists of two beta globins and two alpha globins. In foetuses we use gamma globin instead of beta globin. Shortly after birth a protein BCL11A helps in the switch from foetal to adult haemoglobin, from gamma to beta. Casgevy edits the gene for BCL11A and in so doing forces the cells to upregulate gamma globin so making more foetal haemoglobin.
“It does this by editing a part of the switch that turns the BCL11A gene on in developing blood cells. This causes BCL11A to not be made which in turn allows gamma globin to be produced, as BCL11A switches gamma globin off. As such – it is a CRISPR mediated gene edit – it is unlike the standard mode of gene therapy which involves addition of the correct gene.
“Given its mode of action, it is a potential therapy for any genetic disease involving badly functioning beta-globin, notably sickle cell disease and beta thalassemia.
“There are three questions remaining. First, is it a safe and effective therapy? Second, is it cost effective? Third, what are the long-term effects?
“Regarding the first, in trials for beta thalassemia it did well. As of November 2023, it was reported that of 42 patients in a trial long enough for early analysis over 90% didn’t require a red blood cell transfusion for at least 12 months after treatment, the others needing fewer. That producing gamma globin as an adult is not harmful is to be expected as there are indeed adults who still produce gamma globin and appear to be fine. We all produce a little of the foetal form and for sufferers of beta thalassemia and sickle cell disease the level of the foetal version is predictive of the severity of the disease (more foetal gamma globin, less severe). The evidence is convincing enough to permit authorization (different from NICE approval). The UK Medicines and Healthcare products Regulatory Agency (MHRA) authorised it as a therapy for sickle-cell disease and transfusion-dependent β-thalassemia on 16th November 2023, the US FDA approved it on 8th December 2023 and it was authorised on 28th February 2024 for use in the EU.
“The second issue is where NICE has had its biggest issues. As it is a “one-shot” medicine it has the potential to replace regular transfusions needed to treat thalassemia and to provide long term cure for that disease and for sickle cell anaemia. However, as a one-shot medicine it also doesn’t come cheap. This is a not uncommon problem with gene therapies. In 2012, a gene therapy for the rare disease lipoprotein lipase deficiency was approved in the EU but as it cost a million euros and was prescribed for only one patient, the treatment was withdrawn five years later. Most are extremely expensive (over a million dollars per treatment is normal). Indeed, on March 14th, 2024, NICE decided that Casgevy didn’t meet its cut offs for cost effectiveness for sickle cell disease. This new announcement of approval by NICE for beta thalassemia is therefore significant news for sufferers of transfusion-dependent beta thalassemia. The costs (and effects on life quality) of all of those transfusions needs to be weighed against their reduction enabled by Casgevy.
“While good news for such patients, we don’t know the answer to the third question, the longer term effects. Indeed, how long will the treatment last? This no doubt informed the choice to recommend the treatment for the Innovative Medicines Fund (IMF) with a limited patient pool (up to 460) so as to be able to collect the necessary data. If it passes these hurdles it has the potential to be a one shot cure, not simply a treatment, for this debilitating genetic disease.”
Yasmin Sheikh, Head of Policy and Public Affairs at stem cell charity Anthony Nolan, said:
“We’re delighted with this historic decision to approve the UK’s first ever CRISPR-based therapy. Casgevy offers an effective cure for transfusion-dependent beta thalassaemia – a debilitating condition that was previously incurable in patients who don’t have a stem cell donor.
“This groundbreaking therapy must also be funded for people with sickle cell, where it has huge promise and is desperately needed. The sickle cell community has been waiting for months for NICE and the manufacturer of Casgevy, Vertex, to come to an agreement over bringing this therapy to the NHS.
“We hope this approval for thalassaemia demonstrates a solution is possible, and urge NICE and Vertex to work together to deliver this treatment to patients with sickle cell as soon as possible.”
NICE’s final draft guidance on exagamglogene autotemcel for treating transfusion-dependent beta-thalassaemia was published at 00:01 UK time on Thursday 8th August 2024.
Declared interests
Prof Laurence D Hurst: His research involves using evolutionary insights to better design genes for gene therapy. He is a member of the Scientific Advisory Board of ExpressionEdits, a company that designs artificial genes for gene therapy and related protein production technology. He has a book in press at Princeton University Press (The Evolution of Imperfection) that considers the pros and cons of gene therapy as a solution to the high levels of genetic diseases in humans.
Yasmin Sheikh: No COI
Dr Diana Hernandez: No COI
Dr Alena Pance: I declare I do not have any conflict of interest regarding this work.
For all other experts, no response to our request for DOIs was received.