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14th February 2024
Exagamglogene autotemcel (exa-cel, brand name Casgevy) has been granted conditional marketing authorisation by the European Commission (EC) for severe sickle cell disease, its manufacturer Vertex Pharmaceuticals has announced.
The CRISPR/Cas9 gene-edited therapy is now approved for the treatment of patients aged 12 years and older who have severe sickle cell disease characterised by recurrent vaso-occlusive crises (VOCs) or transfusion-dependent beta thalassemia (TDT), for whom hematopoietic stem cell (HSC) transplantation is appropriate and a human leukocyte antigen matched related HSC donor is not available.
The EC approval follows the conditional marketing authorisation from the Medicines and Healthcare products Regulatory Agency in November 2023 for the same indication.
A genetically modified autologous CD34+ cell-enriched population, exa-cel contains human hematopoietic stem and progenitor cells edited ex vivo by CRISPR/Cas9 at the erythroid-specific enhancer region of the BCL11A gene.
The edited stem cells are then infused back into the patient to restore healthy haemoglobin production.
The EC approval was based on the results of the CLIMB-111 and CLIMB-121 clinical trials, for which Dr Locatelli is principal investigator.
Looking at exa-cel in both sickle cell disease and TDT, the trials met their respective primary outcome of becoming free from severe VOCs or transfusion independent for at least 12 consecutive months.
Once achieved, these benefits were potentially expected to be life-long.
Dr Franco Locatelli, principal investigator in the CLIMB-111 and CLIMB-121 studies, professor of pediatrics at the Catholic University of the Sacred Heart, Rome, and director of the Department of Pediatric Hematology and Oncology at the Bambino Gesù Children’s Hospital, said: ‘Sickle cell disease and transfusion-dependent beta thalassemia are debilitating, life-shortening diseases associated with significant burden on patients, families and health care systems.
‘Casgevy offers the potential of a functional cure, and it will be important to offer this therapeutic option to eligible patients as soon as possible.’
Exa-cel is the only genetic therapy approved for severe sickle cell disease and TDT patients in the European Union, and more than 8,000 patients are estimated to be eligible for treatment.
Vertex has secured early access for eligible TDT patients in France ahead of the national reimbursement process and is working closely with other national health authorities to secure prompt access for eligible patients.
The company is also seeking to establish a network of approximately 25 independently operated authorised treatment centres for the administration of exa-cel, of which there are currently three activated across Europe.
17th November 2023
The first-of-its-kind gene-editing treatment exagamglogene autotemcel (exa-cel, brand name Casgevy) has been granted conditional marketing authorisation by the Medicines and Healthcare products Regulatory Agency (MHRA) for the treatment of sickle cell disease and transfusion-dependent beta thalassemia (TDT).
Exa-cel is now approved for use in eligible patients aged 12 and over with sickle cell disease who have recurrent vaso-occlusive (VOC) crises, or TDT for whom a human leukocyte antigen-matched related hematopoietic stem cell donor is not available.
A genetically modified autologous CD34+ cell-enriched population, exa-cel contains human hematopoietic stem and progenitor cells edited ex vivo by CRISPR/Cas9 at the erythroid-specific enhancer region of the BCL11A gene.
The edited stem cells are then infused back into the patient to restore healthy haemoglobin production.
The innovative gene-editing tool CRISPR gained its inventors the Nobel Prize in 2020.
Professor Josu de la Fuente, professor of practice (cellular and gene therapy) at Imperial College London, and consultant haematologist at Imperial College Healthcare NHS Trust, said: ’This is a world-first and a significant moment for researchers, clinicians and, most of all, people with sickle cell disease and beta thalassaemia.
’These are inherited blood disorders which have a huge impact on people’s lives, including many people from our local community. This authorisation offers a new option for eligible patients who are waiting for innovative therapies.’
He added: ’I look forward to patients having access to this therapy as quickly as possible.’
The UK is the first country in the world to approve gene editing as a potential cure for these two inherited blood disorders. There are an estimated 2,000 patients eligible for Casgevy treatment across the country.
The MHRA approval was based on the results of two global clinical trials. Looking at exa-cel in both sickle cell disease and TDT, the trials met their respective primary outcome of becoming free from severe VOCs or transfusion independent for at least 12 consecutive months.
Once achieved, these benefits were potentially expected to be life-long.
The safety profile of 97 patients with SCD and TDT treated to date with Casgevy in these ongoing studies is generally consistent with the traditional treatments of myeloablative conditioning with busulfan and hematopoietic stem cell transplant.
Professor de la Fuente, who was also the chief national investigator of the UK arm and steering committee member of the two studies, said: ’I’m proud to have contributed to the development of the studies and be leading the UK arm. I am very grateful to my colleagues both at the Trust and the other centres involved in the trials and patient selection for their hard work, but most of all to the patients for their willingness to explore innovative therapies and their daily inspiration.’
Julian Beach, interim executive director of healthcare quality and access at the MHRA, added: ’Both sickle cell disease and beta thalassemia are painful, life-long conditions that in some cases can be fatal. To date, a bone marrow transplant – which must come from a closely matched donor and carries a risk of rejection – has been the only permanent treatment option.
He added: ’The MHRA will continue to closely monitor the safety and effectiveness of Casgevy, through real-world safety data and post-authorisation safety studies being carried out by the manufacturer.
’I would like to thank the patients with lived experiences who engaged with us as part of the assessment process and gave us valuable insight into their lives and the challenges of managing their condition.’
The manufacturer Vertex Pharmaceuticals is working closely with the National Institute for Health and Care Excellence to secure access for patients as soon as possible.
Exa-cel is also under review by the European Medicines Agency and other global regulators.
4th September 2023
The use of a stem cell gene therapy in sickle cell disease may offer a promising, curative treatment, according to a new study published in the New England Journal of Medicine.
Using OTQ923 – a clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9-edited CD34+ cell product – researchers have been able to cause targeted disruption of the HBG1 and HBG2 (γ-globin) gene promoters, thereby increasing foetal haemoglobin expression in red-cell progeny in patients with sickle cell disease.
The condition results from a single amino acid substitution in the gene encoding the β-globin subunit and polymerisation of deoxygenated sickle haemoglobin, resulting in reduced deformability of red blood cells.
Although elevated foetal haemoglobin levels in cells protect against the complications of sickle cell disease, during infancy, γ-globin gene transcription switches to β-globin. The overall effect of this transcriptional switch is a move away from production of foetal haemoglobin to adult haemoglobin within red blood cells.
An important question, is therefore whether it would be possible to reactivate expression of γ-globin and thus increase production of foetal haemoglobin, resulting in a clinical improvement in disease severity.
For the study, researchers used CRISPR-Cas9 to edit specific genes in stem cells taken from each patient. These edits led to an increased cellular production of foetal haemoglobin, which was able to replace the unhealthy adult sickled haemoglobin and protect against the complications of sickle cell disease.
A total of three participants with severe sickle cell disease received autologous OTQ923 after myeloablative conditioning and were followed for six to 18 months. At the end of the follow-up period, all the participants had stable induction of foetal haemoglobin, which was broadly distributed in red cells.
As a consequence of greater foetal haemoglobin, the occurrence of vaso-occlusive crises decreased without any detected off-target effects.
Senior author of the study, James LaBelle, director of the Pediatric Stem Cell and Cellular Therapy Program at UChicago Medicine and Comer Children’s Hospital, said: ‘The biggest take-home message is that there are now more potentially curative therapies for sickle cell disease than ever before that lie outside of using someone else’s stem cells, which can bring a host of other complications.‘
‘Especially in the last 10 years, we’ve learned about what to do and what not to do when treating these patients. There’s been a great deal of effort towards offering patients different types of transplants with decreased toxicities, and now gene therapy rounds out the set of available treatments, so every patient with sickle cell disease can get some sort of curative therapy, if needed.‘
16th December 2021
In patients with sickle cell disease, an early awareness of the risks associated with COVID-19 infection and acceptance of virtual appointments, resulted in a significant reduction in morbidity and mortality among those with the condition. This was the finding of a study by researchers from the Department of Haematology and Medical Oncology, Emory University School of Medicine and Georgia Comprehensive Sickle Cell Centre at Grady Health System, Atlanta, US presented at ASH 2021.
The Grady Comprehensive Sickle Cell (SC) Center is the largest adult sickle cell centre in the US with the first 24/7 acute care unit for the management of sickle cell vaso-occlusive events (VOE). In 2019, the centre provided 3077 outpatient appointments for patients with sickle cell disease (SCD) and 3695 acute care visits. However, the arrival of the COVID-19 pandemic led to a huge drop in the number of both outpatient and acute care visits. But how the virus impacted on patients who were registered with the centre was the subject of the study presented by the Atlanta researchers at the ASH Conference 2021. The team made use of the Grady centre’s database, which was used for tracking the outcomes of registered patients during the COVID-19 pandemic and to date, represents the largest single-centre study on COVID-19 in people with SCD between March 2020 and March 2021.
Findings
From a total of 1343 patients in the database, 55 patients with average age of 28 years (51% female) contracted COVID-19. Among the 55 who tested positive for COVID-19, only 16 required treatment and of whom, 2 died.
In terms of COVID-19 symptoms, 58% experienced pain as the main symptom, followed by cough and fever (40%), dyspnoea (31%), and pneumonia with chest x-ray evidence (25%). Two patients developed acute respiratory distress syndrome (ARDS) and were intubated. Interestingly, the two deaths occurred early in the course of the pandemic in June and July 2020 when 20 total cases were diagnosed and there were no deaths recorded between October 2020 and March 2021. Due to the COVID-19 restrictions, the Grady centre quickly adopted virtual visits to deliver healthcare to their patients.
Commenting on their findings, the authors considered that the early adoption of virtual visits aided in protecting patients against COVID-19 as witnessed by the absence of any deaths during second peak in the winter of 2021. The authors felt that this indicated how patient’s diligence and awareness to stay home during the pandemic, proved to be crucial in reducing morbidity and mortality. They concluded that the option of virtual visits for healthcare delivery was key and should be utilised further in sickle cell care.
Citation
El Rassi F et al. COVID-19 Infection and Outcomes at a Comprehensive Sickle Cell Center. ASH Conference 2021
14th October 2021
NICE has approved crizanlizumab for the management of sickle cell crises in patients with sickle cell disease but only as part of a managed access agreement.
The term sickle cell disease describes a group of inherited red blood cell disorders that affect haemoglobin and which, according to the World Health Organization, approximately 5% of the world’s population carries trait genes for such disorders.
Sickle cell disease affects around 1 in 500 African American children and 1 in 36,000 Hispanic American children and is characterised by a change in the shape of red blood cells which become more ‘sickle-like”, reducing their flexibility of the cells.
These sickle-like red blood cells can lead to recurrent and unpredictable blockage of small blood vessels producing ischaemic pain, referred to as vaso-occlusion (VOC) or sickle cell crises.
In addition, activated and adherent leukocytes are the likely drivers of VOC in collecting venules and this process appears to be initiated by a transmembrane protein, P-selectin. Studies have shown that blockage of P-selectin appears to improve blood flow and thus reduce the risk of VOC and sickle cell–related pain crises.
The monoclonal antibody crizanlizumab binds to P-selectin blocking its action. The approval by NICE was based on data from the SUSTAIN trial. This double-blind, randomised, placebo-controlled, Phase II trial, assigned 198 patients to either a low-dose crizanlizumab (2.5 mg per kilogram of body weight), a high-dose crizanlizumab (5.0 mg per kilogram), or placebo and which were administered intravenously 14 times over a period of 52 weeks.
The primary outcome was the annual rate of sickle cell–related pain crises with high-dose crizanlizumab versus placebo. For the study, this was defined as acute episodes of pain caused by a VOC that resulted in a visit to a medical facility and treatment with pain relief medication.
The results showed that the median rate of crises per year was 1.63 with high-dose crizanlizumab versus 2.98 with placebo (p = 0.01). In addition, the median time to the first crisis was significantly longer with high-dose crizanlizumab than with placebo (4.07 vs. 1.38 months, p = 0.001),as was the median time to the second crisis (10.32 vs. 5.09 months, p=0.02).
In addition, the overall incidence of serious adverse event was comparable across the three arms.
NICE recognised that a limitation of the trial was the absence of longer term data on crizanlizumab such as mortality or among those who did not seek medical advice on VOCs. There was also no data on the prolonged treatment benefit and what happens when patients stop taking crizanlizumab.
While the appraisal document concluded that “Crizanlizumab is not recommended for routine use in the NHS“, the drug could be used where specific criteria are met. Thus, guidance notes that “crizanlizumab is recommended as an option for preventing recurrent sickle cell crises (vaso-occlusive crises) in people aged 16 or over with sickle cell disease only if the conditions in the managed access agreement are followed.”
Source. NICE 2021
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