Category: beta thalassaemia

Bluebird Bio’s decision to hit pause on the launch of Zynteglo for beta thalassaemia after two cases of cancer were seen in a clinical trial could see fears over the safety of viral vectors used to deliver gene therapies resurface. 

That’s the view of analysts at Jefferies, who suggest it could “re-ignite concerns over the use of lentiviral vectors and the risk of secondary (vector-mediated) cancer”.

Cancer is a perennial fear for therapies that involve altering DNA in cells, because of the risk that the viruses used to deliver genes into patient cells could inadvertently lodge in the wrong place on a chromosome, triggering a mutation or disrupting a mechanism that guards against a cell becoming cancerous.

Last week, Bluebird said it was pausing its Zynteglo (betibeglogene autotemcel) programme in Europe after a phase 1/2 trial in patients with sickle cell disease (SCD) – another red blood cell disorder – turned up two cases of blood cancers, one of acute myeloid leukaemia (AML) and another of myelodysplastic syndrome (MDS).

In addition to the pause on new treatments, the phase 1/2 study and another phase 3 trial of Zynteglo in SCD have been suspended as the company investigates whether the cancers could be related to the BB305 lentiviral vector used in the therapy.

If a causal link is shown, it could have “significant ramifications” on the use of lentiviral vectors, a type of self-inactivating virus that underpins both approved cell therapies like Novartis’ CAR-T Kymriah as well as a host of experimental therapies that involve genetic manipulation of cells.

One UK company that could be affected greatly by that is Oxford BioMedica, which has built a business around its LentiVector delivery platform used in Kymriah and other emerging therapies, according to Jefferies.

They note however that so far there have been no reported cases of secondary cancers to date with Kymriah, which has been available commercially for around three years.

Bluebird has said it hopes to have some data within the next few weeks that should explore the possibility of a causal link. That is concentrating on determining where the vector integrated into the chromosomes of the two patients with cancer, and if that has resulted in changes to gene expression in neighbouring areas.

The case comes just weeks after UniQure halted a trial of its haemophilia B gene therapy AMT-061 after an unexpected case of liver cancer. That therapy uses an adeno-associated virus (AAV) as a vector rather than a lentivirus, a vector type that features in approved gene therapies such as Roche’s Luxturna and Novartis’ Zolgensma.

Lentiviral vectors have become a popular alternative for some therapies because they can deliver larger gene sequences into target cells and are less likely to stimulate an immune response in the patient that could affect their safety and efficacy.

News of the pause came as UK cost-effectiveness watchdog NICE rejected Zynteglo for regular NHS use in first draft guidance, despite a confidential discount to its price tag of around €1.57 million in Europe.

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It’s back to the drawing board for bluebird bio and its discussions with NICE, which has rejected its beta thalassaemia gene therapy Zynteglo for regular NHS use in first draft guidance.

NICE is assessing Zynteglo (betibeglogene autotemcel), a one-off gene therapy for the condition, which can have life-threatening consequences and is associated with a curtailed life expectancy.

There is a curative treatment for people who rely on blood transfusions to survive and maintain their levels of red blood cells.

But haematopoietic stem cell transplantation is only possible when a donor with a matching human leukocyte antigen signature, within the correct age range, is available.

In this first draft guidance NICE raised a series of issues with Zynteglo, which bluebird has already agreed to supply at a confidential discount from its hefty price tag, which is around €1.57 million in Europe.

NICE said that data came from a small sample of patients and is using its standard discount rate of 3.5% to calculate the long-term benefits of the treatment.

The company has unsuccessfully pushed for a rate of 1.5%, which would attach more value to the long-term benefits of the therapy over a patient’s lifetime.

There was also a long list of other technical issues raised by NICE that count against Zynteglo in the assessment, including costs of fertility preservation and the number of simulated profiles in bluebird’s data.

Nicola Redfern, bluebird bio’s UK general manager, said the first step is to present a new analysis of data addressing issues raised by NICE before there are any discussions about lowering the price again.

She pointed out that the dossier presented to NICE was compiled in 2019 and the company now has six years’ worth of follow-up data.

Redfern also added that this is the first time that NICE had assessed a gene therapy using its single technology assessment process, which is used for medicines likely to be used more widely on the NHS.

However Redfern was still surprised the rejection given the discussions with NICE so far in the process.

She said: “Some of the specifics we thought we had covered off with them and discussed. The thing that baffled me most was the lack of understanding of this disease upon the people living with it.”

The UK Thalassaemia Society noted NICE’s citation of a UK patient reference report stating that 37% of respondents would immediately accept a referral to a transplant specialist and betibeglogene autotemcel if offered it.

Romaine Maharaj, executive director at UKTS, said: “Most of our members are very excited about the new therapy developments and are keen to explore these treatment options.

“Bone marrow transplant is only an option for a very small proportion of people with thalassaemia and so gene therapy offers a real potential alternative as a one-off resolution to this life-limiting condition.”

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bluebird bio has presented long-term data from its Zinteglo one-time gene therapy for the blood disorder beta-thalassaemia, as the company continues talks with payers in Europe to bring the ultra-pricey treatment to market.

The European Medicines Agency (EMA) has granted a conditional marketing authorisation for the drug that will be marketed as Zinteglo (betibeglogene autotemcel), meaning its licence must be renewed each year until confirmatory data is available.

Results announced at the American Society of Hematology could help bluebird make the case for the long-term use of the therapy as the treatment approaches the market in Europe.

In the US, Zinteglo has hit a speed-bump with the FDA, which is asking for more information about production facilities before a review of clinical data can begin.

Of the 10 patients enrolled in the ongoing long-term study (LTF-303) from a phase 3 programme, 9/10 (90%) were transfusion independent (TI) and all these patients remain transfusion independent.

David Davidson, chief medical officer at bluebird, said: “All of the patients in our phase 3 studies who achieved transfusion independence have maintained it, with the durability of the treatment effect underscored by patients from our earlier studies reaching their five-year anniversaries of freedom from transfusions. “

In a group of patients aged under 18 from the Northstar-2 and Northstar-3 phase 3 studies, 87% (13 out of 15) achieved TI and remained so.

In a long-term follow-up 53% of patients who achieved TI and restarted iron chelation have since stopped and 30% who achieved TI now receive phlebotomy to reduce iron levels.

Davidson added: “Transfusion independence has been observed in paediatric, adolescent and adult patients and across genotypes – suggesting outcomes with this gene therapy may be consistent regardless of age or genotype.”

In Europe bluebird has set a price of up to $1.58 million euros for a single shot.

This is paid in instalments, with 315,000 euros paid up front and four additional payments due only if the treatment continues to be effective.

Zinteglo is already launched in Germany and is nearing the end of its year of free pricing.

But it’s fair to say that the therapy won’t come cheaply even though most member states will likely end up negotiating a lower price

In England, cost-effectiveness body NICE is reviewing Zinteglo and is due to publish draft document early in the new year.

Although it’s too early to say how the review will go, NICE will be looking for more certainty on the long-term effects of the therapy.

The latest data won’t be part of the submission to NICE, but the company hopes that an ongoing review of the cost-effectiveness body’s methodology will help novel gene therapies get to market.

Nicola Redfern, general manager of bluebird bio UK, is hopeful that NICE will refine its existing Quality Adjusted Life Year (QALY) and find better ways to deal with uncertainties in clinical data.

“How we deal with uncertainties is going to be fundamentally important,” she said.

Another issue to address is the discount rate NICE uses to calculate the value of medicines and their long-term impact on patients’ lives.

The 3.5% discount rate currently used means that these benefits reduce quickly over time in the view of NICE and Redfern agrees with NICE’s own proposals to adopt the 1.5% discount rate used by the Treasury.

“We agree with NICE that there is already evidence to bring it in line with the rate in the Treasury Green Book.”

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A gene-editing drug developed by CRISPR Therapeutics and Vertex Pharma has achieved “remarkable” improvements in patients with beta thalassaemia and sickle cell disease in an early-stage trial reported at the American Society of Haematology (ASH) annual meeting.

The data with the CRISPR/Cas9 drug CTX001 is still very early-stage, coming from just seven thalassaemia patients and three with SCD, but provide further evidence that it may be possible to use the gene-editing technology as a one-shot treatment for serious diseases.

All seven thalassaemia patients were seriously ill, requiring regular blood transfusions to control symptoms at enrolment into the study, but all were transfusion-independent three to 18 months after receiving CTX001 as a single infusion.

Similarly, three SCD patients suffered none of the characteristic painful attacks – known as vaso-occlusive crises (VOCs) – in the three to 15-month follow-up period after the treatment.

The trials are the first to test a CRISPR/Cas9 gene editing therapy in humans for a genetic disease, according to the partners.

The only available cure for both diseases is a bone marrow transplant from a closely related donor, an option that is not available for the vast majority of patients because of the difficulty in finding a suitable match, the high cost of the procedure, and the risk of potentially life-threatening complications.

CTX001 is an ‘ex vivo’ application of gene-editing, in which the technology is used to modify a patient’s own cells outside the body.

It uses CRISPR/Cas9 to make a patient’s haematopoietic stem cells produce high levels of foetal haemoglobin (HbF) in red blood cells, by introducing a gene known as BCL11A which down-regulates the production of the adult form of the oxygen-carrying molecule.

Reverting to HbF in thalassaemia and SCD patients produces normal, healthy red blood cells, rather than the misshapen cells produced by faulty haemoglobin in the two disorders. Patients remain in the hospital for approximately one month following the infusion.

“What we have been able to do through this study is a tremendous achievement,” said investigator Haydar Frangoul of the Sarah Cannon Research Institute, who presented the results at ASH.

“By gene editing the patient’s own stem cells we may have the potential to make this therapy an option for many patients facing these blood diseases,” he added.

The success of the study is a shot across the bows of companies trying to develop other genetic therapies for thalassaemia and SCD.

That includes Bluebird Bio, which already has approval in Europe for Zynteglo, its gene therapy for thalassaemia, and is due to file its related therapy LentiGlobin for SCD next year.

Bluebird suffered a setback last month in the US, however, after the FDA asked for more manufacturing data on Zynteglo which could delay the programme by up to a year, allowing CRISPR and Vertex to narrow its lead.

CRISPR and Vertex’s two phase 1/2 studies in thalassaemia and SCD – called CLIMB-111 and CLIMB-211, respectively – have now recruited 19 patients. They are due to enrol 45 apiece, and are scheduled to readout next year.

If positive, the results could lead to regulatory filings, and analysts at EvaluateVantage have suggested that CTX001 could become a $1.3 billion product if it gets approved for both indications.

In October, CRISPR Therapeutics co-founder Emmanuelle Charpentier and Intellia co-founder Jennifer Doudna shared the 2020 Nobel Prize in Chemistry for their work on CRISP/Cas9.

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