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MHRA races into the lead in authorising experimental gene therapies

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FIRST mRNA, then CRISPR. The Medicines and Healthcare products Regulatory Agency (MHRA), having acquired a taste for leading the world in authorising genetic therapies when it authorised the Pfizer/BioNTech mRNA genetic ‘vaccine’ in December 2020, is back to the business of enabling. On November 15 the MHRA became the first regulator in the world to issue a conditional marketing authorisation (CMA) for a therapy that involves editing the human genome.  It is called Casgevy and is designed to treat two rare genetically heritable conditions that afflict fewer than 16,000 people in the UK. It is based on an innovative gene-editing tool called CRISPR which won its inventors the Nobel Prize in 2020. 

But there’s a bigger story than Casgevy, the gene therapy in question; it’s one that has not been subjected to the scrutiny it warrants.  

In 2021 Sir John Bell, Regius Professor of Medicine at Oxford Universityand one of the authors of the UK’s 2021 Life Sciences Vision, declared that there was ‘a race on to determine which countries will lead this [gene therapy] sector over the next decade’ and that the prize both in terms of economic growth and human health was large.

Life sciences are a key element in what the World Economic Forum (WEF) calls the Fourth Industrial Revolution (4IR), a major component of which involves playing God for corporate profit through the genetic engineering of plants, animals and humans, all of which can be patented and add value to corporate intellectual property. 

The Life Sciences Vision, former Prime Minister Boris Johnson stated in the document’s foreword, is for the UK to ‘regain our status as a Science Superpower’. Key to the vision is the role planned for the MHRA to become the most ‘innovation friendly’ regulator in the world for advanced therapy medicines products (ATMPs) – medicines based on genes, tissues or cells. The NHS patient records will become a commodity to entice companies with, while the NHS provides them with experimental subjects.

The Life Sciences Vision outlines exactly what’s involved for the MHRA. It includes ‘utilising innovative clinical trial regulation to support earlier patient access to new treatments and technologies, novel approaches for surrogate marker detection, and adaptive licensing approaches that facilitate faster, safer access to potential new treatments and diagnostics’.

An examination of the MHRA’s decision to grant a CMA for Casgevy is a realisation of this plan and provides an example of how ‘utilising innovative clinical trial regulation to support earlier patient access to new treatments and technologies’ is expected to play out. 

Casgevy was developed by two companies, Vertex and CRISPR Therapeutics, for treating sickle cell anaemia (which affects people with African heritage) and β-thalassemia (which affects people with South Asian heritage), two rare and debilitating genetically inherited disorders of red blood cells which leave patients reliant on regular blood transfusions to relieve their symptoms. On December 8 the companies announced the US Food and Drug Administration (FDA) was following the MHRA and issuing an authorisation. The therapy utilises a 2020 Nobel Prize winning -based gene editing technology called CRISPR-CAS, discovered eight years earlier, which uses a cellular repair mechanism in the immune systems of bacteria.

The treatment requires a stem-cell transplant. The patient’s own stem-cells are removed and the CRISPR-Cas technique deletes the defective DNA sequence and repairs it by inserting new RNA into the DNA. The stem cells are transfused back into the body, enabling normal red blood cells to be produced. Stem-cell transplants are riskier in adults than in children, but the MHRA authorised Casgevy saying the risks of the procedure were similar to those associated with stem-cell transplants using their own stem-cells. 

John James OBE, chair of the Sickle Cell Society, welcomed the Casgevy announcement saying, ‘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.’

The MHRA has issued the CMA on the basis of what they say are promising but partial interim results from the phase 1 and phase 2 trials after another ‘rigorous assessment of safety, quality and effectiveness’ (my italics). The trials began in 2019 and involved 99 volunteers. The partial interim results upon which the authorisation was based encompass 29 of the 45 volunteers in the sickle cell cohort and 42 of 54 B-thalassemia cohort. It says that 12 months after treatment, 28 of the sickle cell cohort were free of severe pain crises, and 39 of the B-thalassemia cohort (representing 93 per cent) did not require any blood transfusions. 

The first flag is that with such small numbers the trial is statistically underpowered, particularly as there has thus far been no phase 3 trial. Given that the authorisation creates a precedent that eases the way for other gene-editing therapies, the evaluation period is very short, ringing some clear alarm bells. It raises the question of why it is being rushed through.

One reason is that genomics is being hyped as the key to preventive medicine. In September 2020, Lord Bethell (the minister who signed the temporary use authorisation for the Pfizer/BioNTech genetic vaccines on December 1, 2020) set out the government’s ambition for Genomic Healthcare saying, ‘We are committed to a future where genomics greatly improves the mental and physical wellbeing of the UK population and millions more worldwide.’

The thinking behind this approach is deterministic and largely ignores the greater contribution to good health made by nutrition, physical activity levels and reduced exposure to environmental toxins – the epigenetic lifestyle factors that activate or suppress genes. It’s a fair summation to say that even those with good genes can’t outrun a poor lifestyle. 

Genomics also carries the baggage of 20th century eugenics. Rare disease research is less tainted by the stigma and is far less contentious than research on human embryos. It is the key to the Pandora’s box that is the intentional genetic engineering of humans, and the wedge being used to open it.

The groundwork was prepared for the Casgevy authorisation in advance, and it appears to have more to do with positioning the UK to reap economic rewards than anything else.In January 2021, the Department of Health published a document  signed off by Lord Bethell, the Parliamentary Under Secretary of State for Innovation at the Department of Health and Social Care, entitled the UK Rare Disease Framework. According to this, 7,000 rare diseases afflict around 3.5million people in the UK. Eighty per cent of these rare diseases have identified genetic origins, while 75 per afflict children, 30 per cent of whom will die before they are five years old.  

Shortly after the release of this paper, in March 2021 the MHRA announced the introduction of the Innovative Licensing and Access Pathway (ILAP) to ‘accelerate the time to market, facilitating patient access to medicines’. What they mean by this is high-value advanced therapy medical products (ATMPs) – medicines based on genes, tissues, or cells. The ILAP allows developers of these advanced medicines for ‘life threatening or seriously debilitating conditions’ or ‘public health needs’ (which likely means more genetic vaccines) to apply for ‘innovation passports’ for developmental products. Passports can be applied for at the earliest pre-clinical stage of development, following the model of the covid Vaccine Taskforce, while opportunities for ‘enhanced regulatory and other stakeholder input’ are provided.  Vertex applied for an ILAP in December 2022 which MHRA granted in January 2023. 

Once an ILAP is issued, according to the Life Science Vision, ‘it triggers the MHRA and partners to create the “Target Development Profile” (TDP). This “living document” will set out a unique product-specific roadmap towards patient access in the UK healthcare system’.

This is another key element of the strategy. Once a CMA is issued, the NHS can choose to make the therapy available to patients. On November 30, 2023, two weeks after the CMA was issued, the NHS announced that stem cell transplants for adult B-thalassemia patients, of whom there are about 600 in the UK, would be made available on the NHS. Stem cell transplants were previously only available to children due to more serious complications occurring in adults. 

The mRNA gene therapy ‘vaccine’ trials collapsed the tried and tested timescales for new drug development and authorisation; this innovation all but dispenses with phase 3 trials altogether. Patients taking up this offer via the NHS should be told that they will be taking on the role of a de facto phase 3 trial cohort. Many may consider the prospect of being free from the need for regular transfusions to be a benefit worth any risk from such a new therapy. The companies, who would ordinarily have to recruit volunteers and finance a phase 3 trial, also benefit as the UK taxpayer will presumably pay for treatments instead, while helpfully supplying the equivalent of a phase 3 cohort. 

Many of those afflicted with rare diseases will be considered vulnerable. What consideration has been given at this early stage to the ethics of offering them up as research candidates in this way in the pursuit of a competitive advantage? It is one of the darker aspects of 20th century eugenics that helped to so thoroughly discredit it. 

The NHS has been making other preparations with the Casgevy ILAP in mind. There are approximately 15,000 people in the UK with sickle cell disease. Just ahead of the ILAP application, in October 2022, the NHS issued an urgent call for more black blood donors saying that sickle cell disease was the fastest-growing genetic condition in the UK and that it now required 250 donors per day as opposed to the 150 daily donors required five years ago. In May 2023, it announced that it was introducing a world first genetic blood-matching programme for sickle cell and B-thalassemia patients to reduce the number of adverse reactions to blood transfusions. This creates a useful genetic database for the companies to access. So far there has been no announcement that any sickle cell patients are eligible for the Casgevy stem cell transplants. No doubt it will come. 

The chairman and chief executive officer of CRISPR Therapeutics, Samarth Kulkarni PhD, said, ‘I hope this represents the first of many applications of this Nobel Prize-winning technology to benefit eligible patients with serious diseases.’ 

Historically the biggest investor in CRISPR research is the US Defense Advanced Research Projects Agency, DARPA. https://www.darpa.mil/ Like mRNA vaccines, genetic engineering falls into its Super Soldier programme. In 2017 it invested $65million in a four-year project called Safe Genes, an investment intended to ‘develop countermeasures and prophylactic treatments against unwanted gene editing’.  The military has further interest in CRISPR’s potential for use in human augmentation, which is a double-edged sword as it has equal potential to be used as an engineered or even ethnically targeted bioweapon.

In the vision document Boris Johnson said, ‘The great opportunity before us now is to learn the lessons of this success [Covid vaccines] and make this exception the new norm, bottling the formula we have developed to tackle Covid and applying it to the search for life-changing breakthroughs against other diseases.’

Many will regard the ‘bottling’ of the formula to tackle Covid, in view of its unprecedented adverse events and unexplained excess deaths, as a UK production line too far.

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Paula Jardine
Paula Jardine
Paula Jardine is a writer/researcher who has just completed the graduate diploma in law at ULaw. She has a history degree from the University of Toronto and a journalism degree from the University of King’s College in Halifax, Nova Scotia.

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