Uniqure’s safety scare shakes haemophilia gene therapy

What a difference two weeks makes. Earlier this month, Uniqure was celebrating being one of the winners of this year’s Ash meeting following promising pivotal data on its haemophilia B gene therapy etranacogene dezaparvovec. Now the group has put trials of the project on hold after a case of liver cancer in its pivotal Hope-B study.

The company’s stock opened down 19% this morning, but the whole haemophilia gene therapy field will be crossing its fingers that the case does not turn out to be related to the therapy. For now, Uniqure hopes that it is not.

Underlying risk

The group suggested in its press release that the patient’s underlying risk factors might have led to the development of hepatocellular carcinoma: the subject in question had a long history of hepatitis C, as well as hep B and evidence of non-alcoholic fatty liver disease.

However, a key concern now is over insertional mutagenesis, namely that the vector-delivered gene had tampered with a target cell's chromosomal arrangement and in effect triggered a cancerous phenotype. Investigating the risk of this will clearly now be a major focus for Uniqure.

However, during a conference call today the company stressed the study participant's underlying risk factors, with chief executive Matt Kapusta saying Uniqure had not received any other reports of HCC across clinical trials of its gene therapies in over 100 subjects, some of whom had been followed for over 10 years.

Still, the company is taking the report “very seriously” and will carry out a full investigation into whether the adverse event is related to etranacogene dezaparvovec, the results of which should be available early next year.

The FDA is obviously proceeding cautiously too, and little wonder: the safety of gene therapies has been under the microscope since the death in 1999 of the clinical trial participant Jesse Gelsinger, who suffered an immune response to the adenoviral vector used in a gene therapy candidate for ornithine transcarbamoylase.

And a few years after that there were reports of leukaemia in two boys receiving a gene therapy for X-linked severe combined immune deficiency disorder. That one used a retroviral vector.

Since then, gene therapy has made a comeback, and newer projects largely use adeno-associated viral vectors, which are thought to be safer. But Uniqure’s hold could now raise concerns about all liver-directed gene therapies for haemophilia.

The group’s competitors in haemophilia B include Roche, whose fidanacogene elaparvovec, gained through the acquisition of Spark, is partnered with Pfizer, Sangamo, Takeda and Freeline (Freeline takes the haemophilia B gene therapy fight to Uniqure, December 15, 2020).

In haemophilia A contenders include Biomarin – whose valrox, like etranacogene dezaparvovec, uses an AAV5 vector – Pfizer/Sangamo, Roche and Bayer/Ultragenyx.

Today's development is also bad news for Uniqure’s partner CSL: Uniqure’s Mr Kapusta said during today’s call that CSL could not back out of the companies' deal unless there were antitrust concerns.

Filing on track?

Things could have been worse for Uniqure. The company has completed dosing in its studies of etranacogene dezaparvovec and does not plan to enrol additional patients. It claims that filing plans for the project remain on track, and hopes to submit the therapy to regulators in the second half of next year.

However, executives today admitted that they did not know exactly what the FDA would require to lift the clinical hold. And Uniqure's president of R&D, Ricardo Dolmetsch, added that it might "never be possible to completely discard some contribution of gene therapy".

Haemophilia is a sector where patient trust is already shaky after the contamination of blood products led to many patients contracting hepatitis and HIV. Perhaps this scare, even if it ends up being deemed unlikely to be related to treatment, could be enough to put some patients off gene therapies.