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Press Releases

Take a look at a selection of our recent media coverage:

World-first approval for curative exa-cel gene therapy in sickle cell disease

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.

Life-long benefits in sickle cell disease

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.

Potential curative treatment found for sickle cell disease through stem cell gene therapy

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.

Sickle cell disease and CRISPR-Cas9 editing

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.‘

Hope for dystrophic epidermolysis bullosa sufferers after gene therapy approval

15th June 2023

Dystrophic epidermolysis bullosa is caused by a gene mutation, and the recent FDA approval of the corrective gene therapy VYJUVEK represents the first specific treatment to become available. Rod Tucker finds out more.

Dystrophic epidermolysis bullosa (DEB) is a rare genetic, blistering skin disorder that is usually present from birth. In addition to blistering, open wounds develop together with extra-cutaneous manifestations, affecting the eyes, oral cavity and many internal organ systems. Moreover, the disease places a huge burden on sufferers, caregivers and their families.

DEB occurs as a result of mutations in COL7A1, a gene encoding the alpha-1 chain of collagen type VII (C7) which form the anchoring fibrils of the skin and mucous membranes. Individuals with the disease have been referred to as ‘butterfly children’ due to the mechanical fragility of their skin which is analogous to that of a butterfly’s wings.

The FDA approval of VYJUVEK – also known as beremagene geperpavec or B-VEC – provides the first novel topical gene therapy. The treatment contains two copies of the COL7A1 coding sequence, encapsulated in a modified herpes simplex virus (HSV) type 1.

The delivery of the functional genes within B-VEC is achieved after outer shell viral proteins interact with proteins on the surface of skin cells to facilitate viral nucleocapsid entry. Once within the cell, the viral DNA is transcribed and translated into C7 and secreted into the extracellular space to assemble into anchoring fibrils.

Although yet to be officially approved by the European Medicines Agency (EMA), in 2018 the organisation granted B-VEC orphan drug designation, which will hopefully simplify the approval process. In addition, the UK’s National Institute for Health and Care Excellence is currently appraising the treatment.

But how effective is this novel topical therapy?

Efficacy of B-VEC in DEB

In an abstract abstract presented at the World Congress on Epidermolysis Bullosa in 2020, researchers described the use of B-VEC applied the wounds of two patients with recessive DEB in a phase 1 trial. It also detailed the findings of a phase 2 trial in which a total of 10 patients received the treatment. Overall, seven out of eight wounds treated with B-VEC closed completely within a median of 20.14 days.

Based on these early and positive findings, a phase 3, randomised, double-blind, placebo-controlled trial was initiated and published in the New England Journal of Medicine. The trial enrolled 31 patients, including children and adults, with DEB.

The trial used an intra-patient control design in which for each patient, the site investigator selected two wounds of similar size, anatomical region, and appearance. The wounds within each pair were then randomly assigned in a 1:1 ratio to receive either a weekly application of B-VEC or placebo for 26 weeks. The primary endpoint was complete wound healing at six months, whereas a secondary endpoint was complete wound healing after three months.

The results were remarkable. After six months, 67% of wounds treated with B-VEC were completely healed, compared to 22% of placebo-treated wounds (p = 0.002). Furthermore, complete healing of wounds after only three months occurred in 71% of those using B-VEC and 20% of placebo-treated wounds (p < 0.001). The researchers also examined the durability of the wound response in terms of sustained complete healing at both three and six months. This was seen in 50% of wounds treated with B-VEC but only 7% of placebo-treated wounds.

These positive findings in the phase 3 trial formed the basis of the FDA approval. But the results were important for a number of other reasons. Firstly, the successful use of a topical gene therapy over time bode well for not just DEB, but potentially for other genetic skin disorders. Secondly, the trial demonstrated the successful use a replication-defective HSV vector.

Thirdly, since B-VEC is formulated as a methylcellulose gel, it enables the patient or carer to apply the product themselves to existing wounds. Finally, because patients with epidermolysis bullosa are at an increased risk of squamous cell carcinoma (SCC), which can develop within chronic wounds, B-VEC may ultimately lower the risk of SCC.

Other potential treatments

But B-VEC is not the only therapeutic modality under investigation and there at least three other approaches being trialled. The first involves tautologous keratinocyte sheets containing full-length C7 using a retroviral vector and transplanted onto wound sites. In a phase 1/2 trial using this technique, researchers observed how wound healing exceeding 50% occurred in 95% of treated wounds compared to 0% in untreated control wounds.

The second approach makes use of recombinant human collagen 7 replacement therapy, which is given intravenously. Results from a phase 2 open-label study showed that after 120 days, 69.2% of treated wounds achieved a pre-specified response of a >2-point improvement on a wound-specific assessment scale.

For the third approach, work with topical or intra-dermal gentamicin was seen to induce type VII collagen and anchoring fibril production at the dermal-epidermal junction of erosion sites in five patients with recessive dystrophic epidermolysis bullosa.

While the findings to date are promising, B-VEC is not a panacea. For instance, because the treatment does not penetrate through the skin, it is only able to treat existing wounds rather than preventing new ones from forming. Furthermore, it is likely to require life-long dosing and has no effect on the systemic disease manifestations.

The EMA estimates that epidermolysis bullosa affects up to 36,000 people across Europe and, despite its limitations, B-VEC has the potential to provide relief for the cutaneous symptoms of this burdensome disease, which will be welcomed by sufferers and carers alike.

Novel gene therapy reduces ischaemic burden in refractory angina

29th January 2023

A Phase II trial of an angina gene therapy has met all safety and efficacy objectives in patients with refractory angina

A novel angina gene therapy led to improvements in exercise capacity and a reduction in episodes of chest pain in those with refractory angina, according to the manufacturer XyloCor Therapeutics.

Patients with refractory angina continue to experience symptoms despite maximal drug therapy. Current treatment options for such patients include ranolazine with trial data suggesting that the drug improves exercise capacity and additional relief of anginal symptoms in those prescribed atenolol, amlodipine or diltiazem. Nevertheless, real-world data have been disappointing. For example, one study found that the drug failed to reduce the composite of ischaemia-driven revascularisation or hospitalisation without revascularisation in those with a history of chronic angina and who had incomplete revascularisation after percutaneous coronary intervention. Consequently, there remains an unmet need for patients with refractory angina.

The Phase II arm of the EXACT trial is designed to assess safety of XC001 (encoberminogene rezmadenovec), which represents an angina gene therapy which is administered by a transthoracic epicardial procedure, i.e., direct intramyocardial administration. It is anticipated that XCC01 will enable expression of human vascular endothelial growth factor and thus induce angiogenesis. In short, XC001 represents a one-time gene therapy with the aim of creating new blood vessels and thereby reducing ischaemic burden in the heart. In phase 1 of the trial, 12 participants with refractory angina, underwent mini thoracotomy with 15 epicardial injections of increasing doses.

While there are no actual data has currently been reported, XyloCor Therapeutics does indicate that the angina gene therapy reduced ischaemic burden and improved total exercise duration. In fact, six months after treatment, nearly half of the patients were able to undertake physical activity without this causing angina.

The company now hopes to continue work with XC001 and is currently finalising the design of an upcoming trial.

Fidanacogene elaparvovec gene therapy effective for haemophilia B

11th January 2023

Fidanacogene elaparvovec is a novel gene therapy which has been found to effective and well tolerated in adult males with haemophilia B

Pfizer has reported that its candidate gene therapy, fidanacogene elaparvovec, is effective in reducing the annualised bleeding rate (ABR) of total bleeds compared to a prophylaxis regimen with Factor IX (FIX) administered as part of usual care.

Haemophilia B is a rare, X-linked inherited bleeding disorders caused by mutations in the F9 gene, which results in missing or reduced production/function of clotting factor IX (FIX). The prevalence of haemophilia B is one in 40,000 live males although female carriers may also show some signs of bleeding.

An absence or reduced level of of FIX can result in spontaneous bleeding into the joints, muscles or brain causing serious complications. Currently, the mainstay of treatment for haemophilia B involves replacement of factor IX although adeno-associated viral (AAV)-based gene therapy is one of the most emerging treatment approaches. Fidanacogene elaparvovec is a novel, investigational vector that contains a bio-engineered AAV capsid (i.e. protein shell) and a high-activity human coagulation FIX gene.

The aim of such gene therapy is that once treated, individuals are able to produce FIX rather than having to regularly receive exogenous FIX. In a Phase 1/2a study, 15 adult haemophilia B patients were infused with 5 x 1011 vg/kg of fidanacogene elaparvovec and followed for at least one year. The study examined the ABR prior to and 52 weeks after the infusion. The results showed that the mean ABR during the first 52 weeks following fidanacogene elaparvovec infusion was 0.4 ± 1.1 compared to 8.9 ± 14.0 in the 52 weeks preceding infusion (p<0.001) and in fact, 12 patients reported zero bleeds in the 52 weeks post-infusion.

The BENEGENE-2 study was a single arm trial, designed to evaluate the efficacy and safety of fidanacogene elaparvovec in adult male participants with moderately severe to severe haemophilia B (defined by a Factor IX circulating activity of 2% or less). The primary outcome was the ABR for total bleeds from week 12 to month 15 post-infusion. In the trial, 45 eligible participants completed at least six months of routine exogenous FIX prophylaxis therapy during the study lead-in before receiving a single intravenous dose of fidanacogene elaparvovec (5e11 vg/kg).

Fidanacogene elaparvovec and annualised bleeding rate

The mean ABR for all bleeds was 1.3 for the 12 months from week 12 to month 15 compared to an ABR of 4.43 during the lead-in six months pre-treatment period, giving in a 71% reduction in ABR (p<0.0001) after a single dose of fidanacogene elaparvovec. 

For secondary endpoints, there was a 78% reduction in treated ABR (p=0.0001) and a 92% reduction in the annualised infusion rate (p<0.0001). The mean FIX activity was 27% after 15 months and 25% at 24 months and the mean steady-state FIX concentration was significantly higher than the pre-specified threshold of 5% (p<0.0001).

Fidanacogene elaparvovec has been granted breakthrough regenerative medicines advance therapy (RMAT) and orphan drug designations from the US Food and Drug Administration, as well as PRIority MEdicines (PRIME) and orphan drug designation from the European Medicines Agency.

Gene therapy induces sustained and normalised levels of factor IX in haemophilia B

29th July 2022

Gene therapy use in a Phase II trial for patients with haemophilia B induced sustained increases in factor IX levels in virtually all patients

Gene therapy with FLT180a given to patients who have haemophilia B resulted in elevation of factor IX levels to within the normal range and which was sustained for many months according to the findings of a small, Phase II trial by UK and US researchers.

Haemophilia is an inherited bleeding disorder where the blood fails to clot properly and can lead to spontaneous bleeding. There are two forms of haemophilia – A and B – both of which occur as a result of deficiency or dysfunction of blood clotting factors.

Haemophilia A is due to factor VIII dysfunction and haemophilia B due to factor IX dysfunction and because the genes for these two factors are located on the X chromosome, haemophilia occurs primarily in males.

The prevalence of haemophilia (per 100,000 males) has been estimated to be 17.1 cases for all severities of haemophilia A, 3.8 cases for all severities of haemophilia B and 1.1 cases for severe haemophilia B.

The current treatment for haemophilia B involves intravenous infusions of factor IX either regularly, i.e., prophylactic therapy, or ‘on demand’ and while the latter is highly effective at stopping bleeding, it cannot fully reverse the long-term damage that follows after a bleed. In recent years, studies have suggested that gene therapy with FLT180a has the the potential to deliver a durable, functional cure for haemophilia B.

FLT180a is an adeno-associated virus gene therapy that carries the factor IX gene and enters liver cells and produces factor IX protein.

For the present study, researchers described the efficacy and safety of FLT180a in patients with severe haemophilia B, defined as factor IX levels < 1% of the normal range (50 to 150IU/dl) and administered four different doses. In addition, all patients received glucocorticoids with or without tacrolimus to reduce the risk of a vector-related immune response.

The researchers set two primary endpoints as safety (based on adverse events) and efficacy, assessed in terms of the level of factor IX induced by FLT180a after 26 weeks. Secondary endpoints included the change in annualised bleeding rates and consumption of factor IX concentrate.

Gene therapy with FLT180a and factor IX levels

Ten male patients were administered a single dose of gene therapy and completed the 26-week trial and were then enrolled in a long-term follow-up. The study provides an individual assessment of each patient and after a median of 27.2 months, sustained factor IX levels were observed in nine patients, with one resuming factor IX prophylaxis. Overall, five patients had normal factor IX levels (ranging from 51% to 78%), three had levels ranging from 23 to 43% and one had a level of 260%.

In terms of safety, none of the patients withdrew because of toxic effects and 10% of all adverse events were deemed to be related to FLT180a although all patients had at least one adverse event related to immunosuppressant therapy.

Among all patients, the mean annualised bleeding rate at baseline was 2.93 events/year which reduced to 0.71 after gene therapy. In addition, the annualised factor IX consumption per patient also decreased from 226,026IU/year to to a mean of 9723 IU/year after treatment.

The authors concluded that normal factor IX levels can be achieved after the use of FLT180a gene therapy in patients with severe or moderately severe haemophilia B.

Chowdary P et al. Phase 1–2 Trial of AAVS3 Gene Therapy in Patients with Hemophilia B. N Engl J Med 2022