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First Gene Therapy for Haemophil­ia A Re­ceives Mar­ket­ing Au­tho­ri­sa­tion

The Committee for Advanced Therapies (CAT) at the European Medicines Agency (EMA), which is responsible for the evaluation of gene and cell therapies, recommended a conditional marketing authorisation on 17 June 2022 for the gene therapy product Roctavian (valoctocogene roxaparvovec) from the US company BioMarin for the treatment of adults with severe haemophilia A. The recommendation was endorsed by the Committee for Medicinal Products for Human Use (CHMP). Roctavian is the first gene therapy product for the treatment of haemophilia A to receive a marketing authorisation recommendation in the EU. The final decision on authorisation was taken by the European Commission on 24 August 2022.

Erythrocytes (Source: qimono/pixabay.com)

An Estimated 1 in 6,000 Men Are Affected by Haemophilia A

Haemophilia A is the most common form of the blood disease and occurs almost exclusively in men due to the underlying genetics. Individuals with haemophilia A have a defective factor VIII gene, which means no functional factor VIII proteins can be formed. The incidence is estimated to be about 1:6,000 among males. The treatment has hitherto consisted in the substitution of the missing coagulation factor VIII, which necessitates lifelong injections.

Missing Factor VIII Gene Transported into Liver Cells

Roctavian (valoctocogene roxaparvovec) is the first gene therapy for the treatment of haemophilia to apply for EU authorisation. The active substance in Roctavian is an AAV vector (non-proliferative adeno-associated virus) which does not multiply in humans and transfers the gene with the blueprint for the formation of the factor VIII protein to a few cells in the body. Gene therapy aims to introduce the factor VIII gene into some of the patient's liver cells after a single intravenous administration in order to provide a functional copy of the coagulation factor. This helps prevent bleeding or reduce bleeding episodes.

Use in Patients with Severe Haemophilia A

The field of application recommended by the CAT is the treatment of patients with severe haemophilia A who do not have factor VIII inhibitors due to previous factor VIII substitution therapy and do not have antibodies against AAV serotype 5, which is the serotype of the AAV vector used in the gene therapy. It is not yet known how long the treatment effect will last in an individual patient. However, in the majority of the 134 patients treated in the phase 3 trial, a significant reduction in bleeding and in the consumption of coagulation factors was observed two years after gene therapy compared to the pre-treatment period. In some patients, the clinical trial showed a positive treatment effect of up to five years after a single infusion.

The marketing authorisation recommendation from the CAT is based on the results of a single-arm, non-randomised phase 3 trial with 134 male patients with a history of haemophilia A without factor VIII inhibitors and without antibodies to AAV5. Two years after administration, efficacy data showed that the majority of patients experienced an increase in blood factor VIII levels after intravenous vector infusion. Bleeding rates decreased by 85% and most patients (128) no longer required factor VIII replacement therapy.

Clinical studies have shown that elevated liver test results are a common side effect of AAV-based gene therapies. An increase in the liver enzyme alanine aminotransferase (ALT) indicates incipient liver injury and has been observed following infusion of Roctavian. It can be successfully treated with corticosteroids. Patients with liver disease should not be treated with Roctavian. Other common and transient side effects are headache, joint pain and nausea. In order to be able to assess how long the effect of gene therapy lasts and whether additional adverse events will occur, the CAT has set a follow-up period of 15 years for patients.

Background – Conditional Marketing Authorisation

If the clinical data package is not considered to be comprehensive, but the data can be completed after authorisation, conditional marketing authorisation (CMA) is a way to allow market access for a medicinal product for which there is urgent need. The European regulatory framework provides for the possibility of conditional marketing authorisation for medicinal products if there is an unmet medical demand covered by the newly authorised medicinal product, if the treatment or prevention of life-threatening or severely debilitating diseases is involved or if the immediate availability of the medicinal product outweighs the risk that, owing to the lack of partial information, may exist at the time of conditional marketing authorisation. In order to convert the conditional authorisation into a full authorisation, it must be ensured that the applicant can provide additional data during the post-authorisation phase that is suitable to supplement the clinical data previously considered to be non-comprehensive

Background – CAT

The CAT at the EMA assesses the quality, safety and efficacy of advanced therapy medicinal products (ATMPs). The Committee is composed of experts from the EU Member States in the field of ATMPs – gene therapeutics, cell therapeutics and biotechnologically processed tissue products. The Paul-Ehrlich-Institut is a member of the CAT and is represented by Dr Jan Müller-Berghaus, his deputy Dr Egbert Flory and Dr Martina Schüßler-Lenz, chair of the CAT.

Updated: 05.09.2022