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expert reaction to NICE final draft guidance on exagamglogene autotemcel (exa-cel) for severe sickle cell disease

Scientists comment on final draft guidance from NICE on the use of exagamglogene autotemcel (exa-cel) for severe sickle cell disease. 

 

Dr Diana Hernandez, director of immune and advanced therapies at UK stem cell charity Anthony Nolan, said:

“Today’s decision from NICE to grant access, on the NHS, to the UK’s first ever CRISPR-based therapy for some patients with sickle cell disease, represents a leap forward in the treatment of this debilitating and life-threatening condition. Sickle cell disease is caused by abnormally shaped red blood cells that can block blood vessels, causing fatigue, chronic pain and increased risk of infection. By modifying the DNA of the patient’s own stem cells so they produce healthy red blood cells, the treatment provides a ‘functional cure’ for people who otherwise have limited options.

“This treatment offers hope to thousands of patients in the UK, the majority of whom are from African and African-Caribbean backgrounds and have experienced years of feeling ignored, and is a glimpse into the exciting possibilities of gene therapies to treat diseases that have previously been considered incurable.”

 

Dr Alena Pance, Senior Lecturer in Genetics, University of Hertfordshire, said:

“Casgevy (exagamglogene autotemcel) is based on the innovative gene-editing tool CRISPR, which won its inventors the Nobel Prize in 2020

“This approach is a great medical advancement because gene-editing may represent a possible cure rather than a treatment of this inherited genetic disease and stem cell technology makes it possible to use patient-specific cells which avoid immunological issues.

“The background is that sickle cell disease is caused by mutation of one of the proteins that form haemoglobin. This is the main component of red blood cells that transports oxygen around the body. In adulthood, it consists of 4 globin proteins, 2 alpha and 2 beta, that form a tetramer with an iron core which binds the oxygen. During development however, the haemoglobin in the foetus is made with gamma globin instead of beta globin. This is because Gamma globin has higher affinity for oxygen, which is less abundant in the womb. At birth, there is a switch that silences Gamma globin which is no longer made and induces Beta globin to be made instead.

“When Beta globin is mutated long inflexible chains of haemoglobin form, called sickle haemoglobin that leads to a change in the morphology of the red blood cells which also become stiff and get stuck in small capillaries. This causes pain and loss of red blood cells or anaemia, which increases in situations of high need or use of oxygen, such as exercise or high altitude.

“What this therapy does is to switch off the factor that silences Gamma globin so that it can be produced in the red blood cells and substitute the faulty Beta globin. Because it is a blood disease, the gene-editing can be performed in the stem cells from the bone marrow from which all the cells in the blood originate. This means that the stem cells are extracted from the patient, modified and expanded in the lab and then put back into the patient where they will be able to reconstitute the blood. As a consequence, there is no immunological difference between the modified cells and the patient necessitating immunosuppressing medication for life and once the modified stem cells establish themselves in the bone marrow of the patient, they can repopulate the bone marrow and produce Gamma globin red blood cells technically for ever. An additional advantage this strategy has is that because it does not aim to correct the mutation (fix the faulty beta globin) it can be generally applied not just to sickle cell disease but also to beta-thalassemia. This is because there is a wide range of mutations in the beta globin gene and so fixing it would become patient-specific which would be even more costly and difficult.”

“There are some set backs to this approach and it is certain that the technology will continue improving, but at this moment in time, it is the greatest advance seen so far in the application of these technologies to health.”

 

Prof Ewan Birney, Deputy Director General of the European Molecular Biology Laboratory (EMBL) and Director of EMBL’s European Bioinformatics Institute (EMBL-EBI), said:

“This is an exciting development for practical CRISPR based gene therapy. After impressive clinical trials worldwide, the technology provides a way for certain sickle cell disease individuals to have a far better life. This CRISPR based therapy uses an interesting molecular mechanism, where the gene therapy acts on a different, related gene (fetal haemoglobin), boosting this gene’s expression in adulthood which mitigates the effect of the sickle cell changed adult haemoglobin. The mechanism was discovered by genetic studies in particular from cohorts in Sub-Saharan Africa and people with recent African ancestries.

“Looking ahead, this technology has the potential to treat many other rare diseases with precise genetic diagnoses.”

 

Prof Felicity Gavins, Professor of Pharmacology and Royal Society Wolfson Fellow, Brunel University of London, said:

“The approval of Exa-cel for NHS use in England is a very exciting moment, not only because this marks the first approval of a CRISPR-based gene therapy for SCD in the NHS, but also because it offers a potentially curative treatment for eligible patients. By addressing the genetic cause of SCD, Exa-cel reduces or eliminates vaso-occlusive crises (VOCs), decreases hospitalisations, and improves quality of life.

“Of the 15,000 people in England with SCD, approximately 1,750 may be eligible for Exa-cel treatment. The therapy works by editing the patient’s BCL11A gene to reactivate fetal haemoglobin production, preventing red blood cells from sickling and blocking blood flow which cause VOCs and disease complications.

“However, while Exa-cel is a breakthrough, it is not a cure for all SCD patients, and uncertainties remain about its long-term effectiveness, safety and accessibility. It is critical to continue funding research to develop treatment that benefit the broader SCD population and address remaining challenges in care.”

 

Professor Laurence D. Hurst, Professor of Evolutionary Genetics, The Milner Centre for Evolution, University of Bath, said:

“The recommendation of exa-cel (alias Casgevy, alias Exagamglogene autotemcel) by NICE is a potential step change for sufferers (and their carers) of a common genetic disorder, sickle cell disease (SCD) that particularly affects UK individuals with a Caribbean and Black African ancestry. It will come as a very welcome reversal of a prior draft recommendation (March 2024) by many within the at-risk communities. 

“Part of NICE’s recommendation was based on the observation that the disorder is especially prevent in ethnic minority backgrounds and seeks to redress inequality in health access. This is a good news day for sufferers of severe SCD and for these communities.”

 

Why is there a need for a “cure” for sickle cell disease?

“Current treatments may be considered the equivalent of plastering over a wound repeatedly, rather than getting to the cause of the wound and curing it.

“SCD patients need regular blood transfusions and with that treatment to absorb excess iron. Some qualify for a drug therapy, Hydroxycarbamide, also used as in cancer chemotherapy, that reduces VOC rates. This increases rate of production of foetal globin and reduces red cell stickiness. There are very few treatments to stop symptoms and what is available often has intolerable side effects. A further issue is that while treatments may reduce VOC frequency they tend to increase pain associated with each VOC. They do not address the underlying cause.” 

“Stem cell transfusion – the best current “cure” – is potentially different as you are replacing the cells that make red blood cells in the patient with those from a donor who doesn’t have SCD.  However, only 15% of patients have a potential donor and this treatment can lead to immune rejection (graft versus host disease).

“Exa-cel is potentially a life-long cure – the patients can make their own non SCD inducing blood, thus immune rejection should not be an issue.”

 

How does this CRISPR therapy work?

“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 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).  Exa-cel is different as it involves “editing” your own DNA, not adding 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 carrying 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.  Exa-cel edits the gene for BCL11A preventing it from being made, 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. The treatment involve removing relevant cells from the patient, editing in the lab and replacing them into the patient.

“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.

“Importantly it is also likely that making gamma globin is safe – it is our own protein.  In addition, most of us fail to fully inactivate the foetal/gamma version and so well all have a bit of gamma globin.  Indeed, with conditions like SCD, the higher the level of gamma globin the lesser the symptoms.”

 

The therapy is life transforming

“The evidence for the efficacy and safety of Casgevy for SCD is good, although sample numbers are low. Base line the patients had 2.6 VOCs per year. Of 43 patients 29 were followed long enough. 28 of 29 had no VOCs for at least a year. None were hospitalised.

“There is a further issue, however, that it can be difficult to collect cells in patients with SCD and some of those not followed up were because the treatment couldn’t be given.

 

What is the new decision?

“This new decision is not a statement about safety and efficacy.  The therapy has been approved for use in the UK (late 2023), EU (spring 2024) and USA (late 2023) on safety and efficacy grounds. What is new is that NICE now recommends funding this with “managed access*” via the NHS as it is deemed adequately cost effective (or rather it was happy with the high level of uncertainty on cost effectiveness given the circumstances).  This is a reversal of its prior draft recommendation in March 2024.

“It is restricted to those for whom a stem cell transplant donor cannot be found and with severe SCD ie recurrent VOCs meaning 2 or more in the prior 2 years.

“The defence for the opening of access was based on the health inequalities faced by people with SCD, the technology being innovative and the fact that prior decision had failed to capture the quality of life of the carers.

“Earlier this year NICE approved the same therapy for beta thalassemia -also owing to beta glogin issues- for a restricted number of patients.”

 

What does the treatment cost?

“The treatment is a one-off procedure. The headline cost per treatment £1,651,000 but the actual cost to the NHS is a commercial secret.”

 

What are the uncertainties?

“There are two main uncertainties:

“First, being a new treatment how long it will last is unknown. Why the treatment might revert is unclear but only time will tell.

“The second is whether there are downstream side effects.  CRISPR as an application for example involves send a molecule to cut DNA at a designated site in our DNA.  Sometimes, however, the cuts also happen at sites we didn’t want to have cut. These are so-called “off-target” effects.  The early data from the research team behind found no evidence for such off-target effects but they remain a possibility. More classical forms of gene therapy – involving adding genes to our DNA – have been associated with induction of cancer and so the field is naturally cautious.”

 

What is SCD?

“Sickle cell disease is a genetic disease associated with a different form of a gene and its derived protein that make up part of the molecular that transports oxygen from the lungs to the body, heamoglobin, in our red blood cells.  The affected gene/protein is “beta globin”.

“Sufferers have pain 4 days out of every seven and unpredictable episodes of severe pain, termed vaso-occlusive crises [VOCs] that can require hospitalization.  Over 2 years about 2/3 of sufferers need emergency care 2 to 3 times and about a quarter spend 1-2 weeks in hospital.  Higher rates of both define severe SCD. It causes ongoing anaemia (lack of red blood cells) and widespread organ damage. Even with access to medical support, life expectancy is typically around 50 years.”

 

Why is SCD so prevalent in ethnic minorities?

“Globally locations with endemic malaria have higher rates of the disorder.  This is because individuals with a mix of beta globin genes (we all have two versions, one inherited from mother one from father) are less likely to die young from malaria.  This selection favouring individuals with a mix of beta-globins maintains the two versions of the beta globin gene at relatively high frequencies.  However, it also means that the rate at which individuals will inherit two of the SCD causing version of the gene is also high – if mum and dad were both carriers a quarter of their kids will get SCD.  Having two SCD versions is needed for the full blown SCD. In sub-Saharan Africa up to 1-3% of the population suffer SCD making it a remarkably prevalent genetic disease.”

 

Professor David Rees, Professor of Paediatric Sickle Cell Disease, King’s College London, said:

“It is encouraging that Exa-cel has been approved for use to treat patients with sickle cell disease in England, particularly as it is based on discoveries made at King’s College London by Dr Stephan Menzel and Professor Swee Lay Thein. The treatment uses CRISPR gene editing technology to increase the level of fetal haemoglobin in people with sickle cell disease, which has a major effect in reducing the severity of the condition. The treatment is not curative in the traditional sense of the word, in that the patients still have some features of sickle cell disease, but early studies suggest that successfully treated patients have very few symptoms of the condition, at least in the medium term.

“Exa-cel has been approved for patients getting episodes of acute pain over the age of 12 years, and potentially more than 5000 people with sickle cell disease may be eligible for this in the UK. However, it is difficult to know how many people will actually benefit, because of the very high cost and potential toxicity of the treatment. Exa-cel treatment still requires very strong chemotherapy, similar to having a bone marrow transplant, which causes problems with reduced fertility and sometimes more serious complications, and it seems likely that it will most benefit patients with severe and progressive problems caused by sickle cell disease.

“Despite these concerns, the availability of Exa-cel is a major advance and offers a really important new treatment option for some patients with sickle cell disease. Excitingly, advances in gene editing are happening very rapidly at the moment and it seems likely that cheaper, safer and more effective forms of gene editing will emerge for sickle cell disease over the coming years, offering the prospect of a curative treatment which is universally applicable, even in low income countries where the majority of patients live.”

 

 

NICE’s final draft guidance on Exagamglogene autotemcel for treating severe sickle cell disease in people 12 years and over was published at 00:01 UK time on Friday 31 January 2025. 

 

 

Declared interests

Professor David Rees: “I don’t think I have any significant conflicts of interest.”

Prof Ewan Birney: No conflict of interest.

Dr Alena Pance: No conflicts.

For all other experts, no response to our request for DOIs was received.

 

 

 

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