The article explores the MHRA and FDA's groundbreaking approval of Casgevy, the first gene therapy for sickle-cell disease and β-thalassaemia. Specialists express optimism, underlining its global significance and potential to impact patients' lives.

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The Medicines and Healthcare Products Regulatory Agency (MHRA), UK, has authorised a new treatment for sickle-cell disease and transfusion-dependent β-thalassaemia for patients aged 12 and over; MHRA rigorously assessed its safety, quality and effectiveness. The development was critically acclaimed by many specialists in relevant disciplines.

Researchers based Casgevy (exagamglogene autotemcel) on the innovative gene-editing tool CRISPR, which won its inventors the Nobel Prize in 2020. Both sickle cell disease and β-thalassaemia are genetic conditions caused by errors in the genes for haemoglobin, the molecule which the red blood cells use to carry oxygen around the body.

Centres for Disease Control and Prevention (CDC) describe sickle cell disease (SCD) as a group of inherited red blood cell disorders. It is particularly common in people with an African or Caribbean family background. The other disease-β-thalassaemia mainly affects people of Mediterranean, South Asian, Southeast Asian and Middle Eastern origin.

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Casgevy, first-of-its-kind gene-editing treatment

Julian Beach, Interim Executive Director of Healthcare Quality and Access at the MHRA noted that both sickle cell disease and β-thalassaemia are painful, life-long conditions that in some cases can be fatal. To date, bone marrow transplant – which must come from a closely matched donor and carries a risk of rejection – has been the only permanent treatment option.

"I am pleased to announce that we have authorised an innovative and first-of-its-kind gene-editing treatment called Casgevy, which in trials has been found to restore healthy haemoglobin production in the majority of participants with sickle-cell disease and transfusion-dependent β -thalassaemia, relieving the symptoms of the disease.”

He promised that 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.

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Two diseases with ‘simple chemistry and tragic results’

In his inimitable style, Dr Josh Bloom, the Director of Chemical and Pharmaceutical Science, at the American Council of Science and Health (ACSH) explains “the simple chemistry and tragic results” to describe sickle-cell disease(SCD) and transfusion-dependent β-thalassaemia.

"SCD is a genetic condition in which one single amino acid (out of 574) in haemoglobin – the protein responsible for transporting oxygen around the body – is replaced by another. In this case, a single genetic mutation causes the amino acid valine (molecular weight 117) to be replaced by glutamic acid (MW 147) – a difference of 30 atomic mass units in a protein with a molecular weight of 64,000.”

“You might think that a tiny difference in the molecular weight (0.047%) between the normal and mutant forms of haemoglobin would be insignificant. You would be wrong," he warned.

In people with sickle cell disease, this genetic error can lead to a series of serious health conditions such as attacks of very severe pain, life-threatening infections, and anaemia (whereby the patient’s body has difficulty carrying oxygen).

In people with β-thalassaemia, it can lead to severe anaemia. They often need blood transfusion every 3 to 5 weeks and injections and medicines throughout their lives.

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Consequences of impaired blood flow

Dr Henry Miller the Glenn Swogger Distiguished fellow at the American Council of Science and Health explained that these misshapen, inflexible, red blood cells get stuck in blood vessels, and the resulting impaired blood flow can lead to a variety of complications, including stroke, infection, episodes of pain called “pain crises,” and arthritis from haemorrhaging into joints.

He recalls how his MIT undergraduate advisor, Professor Vernon Ingram, had unravelled its molecular basis thus: “A mutation in DNA that causes a change in a single amino acid in the haemoglobin molecule. (Proteins are comprised of chains of amino acids.) The change occurs specifically at one site where normal haemoglobin has an amino acid called glutamic acid; those with SCD have valine, instead. This was the first description of the molecular abnormality in a genetic disease.”

His article details how the FDA approved the treatment for SCD and transfusion-dependent β-thalassaemia recently.

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Administration

The MHRA in its press release stated that Casgevy is designed to work by editing the faulty gene in a patient’s bone marrow stem cells so that the body produces functioning haemoglobin.

Physicians administer Casgevy by taking stem cells out of a patient’s bone marrow and editing a gene in the cells in a laboratory. Patients must then undergo conditioning treatment to prepare the bone marrow before the modified cells are infused back into the patient. After that, patients may need to spend at least a month in a hospital facility while the treated cells take up residence in the bone marrow and start to make red blood cells with the stable form of haemoglobin. The results have the potential to be life-long.

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Trial results

Trial results were notable and impressive: “In the clinical trial for sickle-cell disease, 45 patients have currently received Casgevy but only 29 patients have been in the trial long enough to be eligible for the primary efficacy interim analysis. Of these eligible patients, 28 (97%) were free of severe pain crises for at least 12 months after treatment.

In the clinical trial for transfusion-dependent β-thalassaemia, 54 patients have currently received Casgevy but only 42 patients have been in the trial long enough to be eligible for the primary efficacy interim analysis. Of these, 39 (93%) did not need a red blood cell transfusion for at least 12 months after treatment. The remaining three had more than a 70% reduction in the need for red cell transfusions.”

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Side effects

According to MHRA, the side effects from treatment were similar to those associated with autologous (from a person’s own cells) stem cell transplants, including (but not limited to) nausea, fatigue, fever and increased risk of infection.

Researchers did not identify any significant safety concerns during the trials. The MHRA and the manufacturer continue closely to monitor safety. MHRA said that both trials are ongoing and further results will be made available in due course.

The UK government’s independent scientific advisory committee, the Commission on Human Medicines, after a robust review of the available evidence, has endorsed the decision to authorise Casgevy.

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Experts comments

John James OBE, Chief Executive of the Sickle Cell Society noted that: "Sickle cell disorder is an incredibly debilitating condition, causing significant pain for the people who live with it and potentially leading to early mortality."

“There are limited medicines currently available to patients, so I welcome today’s news that a new treatment has been judged safe and effective, which has the potential to significantly improve the quality of life for so many,” he added.

Press release from Science Media Centre, London 

This release carried the views of specialists from many disciplines.

Dr Stephan Menzel, a Senior Lecturer at King’s College London recalled that the new therapeutic approach is based on their group’s discovery at King’s that the molecular regulator protein BCL11A is involved in switching between the foetal and the adult form of haemoglobin.

“The adult form is defective in sickle cell disease and beta thalassaemia, and the new therapy releases the BCL11A off-switch on the foetal form, which functions normally,” he clarified.

Professor David Rueda, Chair in Molecular and Cellular Biophysics, Imperial College London conceded that MHRA’s approval of Casgevy as the first gene therapeutic to treat beta-thalassaemia is excellent news for the patients and the gene therapy scientific community. He also noted that the published results of the clinical trial look very promising.

“However, it is well known that CRISPR can result in spurious genetic modifications with unknown consequences to the treated cells. It would be essential to see the whole-genome sequencing data for these cells before coming to a conclusion,” he raised an important concern.

“Nonetheless, this announcement makes me feel cautiously optimistic,” he said.

Prof Simon Waddington, Professor of Gene Therapy, at University College London (UCL), noted that current treatments for thalassaemia such as blood transfusions and chelating agents can have very unpleasant side effects.

“The approval of Casgevy is a tremendous advance in the treatment of beta thalassaemia, a disease caused by a mutation in one of our haemoglobin genes. When we are born, our blood switches from a foetal type of haemoglobin to a post-natal form. People with thalassaemia still have functional foetal haemoglobin even though it is switched off. Casgevy works by switching the foetal haemoglobin back on."

He observed that this treatment may not easily scale up to be able to provide treatments in low and middle-income countries, since it requires the technology to obtain a patient’s blood stem cells, deliver the genetic editor to these stem cells, and then reinjection of these cells. Therefore, it is not an “off-the-shelf” medicine that can be readily injected or taken in pill form.

“The patient also has to receive a type of medicine known as conditioning to kill off some of the bone marrow to make space for the corrected cells. This conditioning is known to have some side effects. Nevertheless, the current cure for thalassaemia, a bone marrow transplant from another person still requires conditioning and, unlike Casgevy, carries the risk of graft versus host disease.”

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R&D infrastructure in India for advanced medical treatments

I spoke to Dr Devashish Rath, Group Leader, CRISPR Biology Group, Applied Genomics Section, BARC about the R&D infrastructure in India for advanced medical treatments. The extracts of the interview:

Dr Parthasarathy: What is the possibility of India getting a foothold in advanced medical treatments?

Dr Devashish: India is a significant player in providing medical treatments, and generic drug manufacturing capabilities and is actively involved in research and development for various medical conditions. India has been making strides in biotechnology and life sciences, with a focus on research and development in areas such as genomics, personalised medicine, and biopharmaceuticals. India's effective response to the recent COVID-19 pandemic, evident in inpatient care, diverse treatment approaches, genome sequencing, and vaccine research and production, underscores its potential. The government has put in place a regulatory framework for medical therapies, stem cell research and clinical trials and is evolving to accommodate advancements in the field. The National Apex Committee for Stem Cell Research and Therapy is responsible for examining the scientific, technical, ethical, legal and social issues involving stem cell research and advanced medical therapies in India. ICMR and DBT have laid down guidelines for biomedical research to support research initiatives on cutting-edge treatment modalities. Achieving this goal will require coordinated efforts from all sectors. The future appears promising for India.

Dr Parthasarathy: Is there adequate infrastructure available in any institution?

Dr Devashish: India’s research infrastructure in the field of biotechnology and life sciences can support advanced therapeutic solutions. This includes cutting-edge laboratories, clean room facilities dedicated to cell and gene therapy manufacturing, sophisticated equipment for molecular biology and genetic engineering, and proficiency in regulatory compliance for clinical trials. A significant challenge is that these facilities are spread out and no single institute has everything needed. Advancing these therapies requires continuous efforts to consolidate essential skills in a unified space, subsequently scaling up to address the needs of a larger patient population. A notable example of this approach is the recently established Bangalore Life Science Cluster (BLiSC), where several premier institutes (NCBS, TIGS, InStem, C-CAMP) collaborate with each other and with reputed international institutes/universities to deepen their understanding of biology and enhance human health. Private pharmaceutical companies can contribute to this endeavour by actively participating and the recent rise in start-up culture in the life science field is giving it a boost. In FY 2022-2023, more than 900 startups in healthcare and biotech were registered, indicating significant progress in the field.

Another hurdle is the scarcity of trained clinical professionals who, in collaboration with researchers in labs, can administer these advanced treatment regimens. The long-term follow-up and documentation required for these therapies can also pose challenges, particularly in the context of the substantial disease burden.

Dr Parthasarathy: Is BARC collaborating with ICMR or other institutions in medical applications?

Dr Devashish: The BARC focuses on fundamental and applied research to better understand diseases and host factors through advanced genetic, molecular, and cell biology techniques. Many projects are being conducted in collaboration with institutes such as Tata Memorial Centre (TMC), Radiation Medicine Centre (RMC), ACTREC, and others to investigate various aspects of cancer biology, including treatment and disease progression, synthesising different organic compounds and evaluating them for potential activity against certain types of cancer and or for radioprotection, the anti-microbial potential of the CRISPR approach, particularly for tuberculosis, and diagnostics of infectious and non-infectious diseases.

Dr Parthasarathy: How does bone marrow transplant compare with the new method approved by MHRA in treating sickle cell disease and thalassaemia?

Dr Devashish: These are two distinct approaches for treating sickle cell disease and other hemoglobinopathies. In bone marrow transplant, healthy bone marrow is transplanted from a compatible donor (usually a sibling or close relative) into the patient with the disease. The bone marrow contains hematopoietic stem cells, which can give rise to healthy blood cells, including red blood cells and thus alleviate the symptoms of defective haemoglobin. The main challenges in bone marrow transplant are finding a suitable donor, severe immune reactions and side effects from chemotherapy given before the transplant. On the other hand, MHRA approved Casgevy therapy based on CRISPR systems which makes precise genome modifications. In this therapy, fetal haemoglobin production is switched on by inactivating its inhibitor gene BCL11A in the patient's own hematopoietic stem cells. This therapy would enable the production of normal fetal haemoglobin, preventing the formation of abnormal, sickle-shaped red blood cells in diseased conditions.

The key differences in both therapies are the source of cells (donor vs self); Approach (Bone marrow transplant replaces the entire bone marrow, while CRISPR targets specific genetic changes at molecular levels); and Risks and challenges (graft-versus-host disease in bone marrow transplant or off-target effects in CRISPR-based therapies).

Presently, bone marrow transplant is the only long-term therapeutic option for sickle cell disease that has been thoroughly explored and optimised. CRISPR-based approaches provide a solution that restores function through precise alterations with significantly fewer constraints; but, their long-term consequences, efficacy, and availability to a large number of patients must be reviewed and addressed.

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The disease prevalence in India

A 2023 report by DKMS BMST, a non-governmental organisation dedicated to eradicating blood cancer states that about 20 million people in India are diagnosed with SCD or sickle cell disease.

India ranks second globally. Each year, around 150,000 to 200,000 children are born with sickle cell disease in India; 50-80 per cent of children diagnosed with SCD struggle to reach the age of five.

In the 'Guidelines for National Programme for Prevention & Management of Sickle Cell Disease' prepared by the National Sickle Cell Anaemia Elimination Mission 2023, the Prime Minister noted that, "The tribal populations in India share a disproportionate burden of sickle cell disease. We will usher in a social revolution against this disease and bring in the most advanced science and technology to tackle it. We are committed to improving the quality of life of people with sickle cell disease and ensure future generations are safe from it.”

Rightly, the current emphasis is prevention and management of the disease. While India has the potential to carry out appropriate research and development in advanced medical disciplines, equitable absorption of their benefits by all, rich and poor needs the development of innovative funding models.

In the press release from Science Media Centre, London, Steve Bates, CEO of the UK Bioindustry Association, pointed out that the UK already has in place the National Health Service (NHS) innovative medicine fund as an explicit policy route to enable rapid absorption of innovation.

In the same press release, Dr Sara Trompeter, Consultant Haematologist, UCLH and NHS Blood and Transplant, PI NIHR BioResource and Clinical Lead Sickle Cell Diverse Data Genomics England said that they are looking forward to National Institute for Health and Care Excellence (NICE) approval so that this treatment can be delivered free of charge to patients in the NHS.

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

Dr K S Parthasarathy is a former Secretary of the Atomic Energy Regulatory Board and a former Raja Ramanna Fellow, Department of Atomic Energy. A Ph. D. from the University of Leeds, UK, he is a medical physicist with specialisation in radiation safety and regulatory matters. He was a Research Associate at the University of Virginia Medical Centre, Charlottesville, USA. He served the International Atomic Energy Agency as an expert and member in some of its Technical and Advisory Committees.