2020-12-22| R&DTrials & Approvals

uniQure’s Hemophilia B Gene Therapy Put on Clinical Hold by the FDA

by Ruchi Jhonsa
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In yet another disappointment for the patients suffering from hemophilia, UniQure’s hemophilia B gene therapy program has been put on a clinical hold by the USFDA following safety concerns. This is the second hemophilia treatment this year after BioMarin’s gene therapy, which has suffered a regulatory setback. UniQure’s shares plunged 21% Monday morning following this news.

Patient safety in clinical trials is of utmost importance, and the FDA can put any study on hold if it finds any safety concerns. The clinical hold is a type of pause issued by the FDA to the sponsor of the study to delay a clinical investigation or to suspend an ongoing investigation. The hold on UniQure’s program was put after one patient of advanced age received a preliminary diagnosis of hepatocellular carcinoma (HCC), a form of liver cancer. The liver lesion came up during a routine checkup of the abdomen done after one year following the first dose of the therapy. UniQure informed the FDA of the situation in mid-December, which then led the agency to halt the program last week.

According to a statement, the patient has a history of multiple risk factors, which are associated with HCC, including hepatitis C infection, hepatitis B infection, and the presence of non-alcoholic fatty liver disease. Chronic infections with hepatitis C and B have been associated with approximately 80% of HCC cases. With so many possible causes also contributing to the development of liver cancer, it is difficult “to determine a possible causal relationship” right now due to insufficient data. “We will investigate whether there is a relationship to treatment,” which is “expected to be completed in early 2021,” said Ricardo Dolmetsch, President of R&D at UniQure.


Could this case of cancer be associated with gene therapy?

Gene therapies have become very popular with large pharmaceutical companies and smaller biotechs for treating genetic disorders. To date, however, the FDA has approved only two gene therapies for treating inherited disorders, which include Roche’s Luxturna and Novartis’ Zolgensma. The reason being that the FDA is very careful about the safety concerns, if any, raised in the report to the agency.

Gene therapies rely on certain viruses to transfer the genetic material inside the cell. Previously used viruses could transfer the genetic material made for therapy but also insert themselves into DNA near genes that cause cancer. This was a serious safety issue. However, the new ones called adeno-associated viruses or AAV were found safer as they rarely integrated into the human DNA. The cause of cancer in UniQure’s trial patient is unclear, but it is very unlikely because of the therapy.

Over the last 20 years, UniQure has administered gene therapy in 100 patients, including 54 in the hemophilia B trial. Some of them had gene therapy injected 10 years ago, and none of them so far have any liver cancer. Moreover, no cases of HCC have occurred in other AAV gene therapies. However, this case will be thoroughly investigated, and complete surgical resection of the lesion is scheduled for this week to confirm the HCC diagnosis. The full investigation will take one to three months to complete.


What happens to the trial now?

The HOPE-B trial had completed the dosing of the last patient in the trial this year in March and is not recruiting any new members. However, the ones that are already there “will continue to be monitored by their care teams” while the company gathers additional information as rapidly as possible,” stated Matt Kapusta, chief executive officer. The trial will be resumed once everything is clear. In spite of the investigation, UniQure will not delay paperwork for regulatory approval and expects to submit it by the second half of 2021.


Which other hemophilia trials are competing with UniQure’s?

As of October 2020, BioMarin’s valrox was the only gene therapy under development for hemophilia A, but its approval was turned down by the FDA due to lack of safety and efficacy data. It will now accumulate the data from the last patient in November 2021 and submit it for approval to the FDA in 2022. For hemophilia B, UniQure’s AMT-061 and Pfizer’s SPK-9001 are the two therapies that are currently in the phase 3 trial. Regeneron and Intellia are also working on CRISPR-based gene therapy to target the disease. However, it is still in the preclinical phase.

By Ruchi Jhonsa, Ph.D.

Related Article: uniQure’s Gene Therapy Impresses in Pivotal Trial Raising Hopes of a Hemophilia B Cure



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