The Committee for Advanced Therapies (CAT) of the European Medicines Agency (EMA), which is responsible for the evaluation of gene and cell therapies, recommended a conditional marketing authorisation on 9 December 2022 for the gene therapy drug Hemgenix (etranacogene dezaparvovec) from CSL Behring GmbH for the treatment of adults with severe and moderate haemophilia B who have no factor IX inhibitors. Factor IX inhibitors are antibodies produced by the immune system that reduce the effectiveness of factor IX drugs. The recommendation was endorsed by the Committee for Medicinal Products for Human Use (CHMP) on 15 December 2022. Hemgenix is the first gene therapy product for the treatment of haemophilia B to receive a marketing authorisation recommendation in the EU. The final decision on authorisation was taken by the European Commission on 20 February 2023.
Haemophilia B is a rare form of the blood disease and occurs almost exclusively in men due to the underlying genetics. Individuals with haemophilia B have a defective factor IX gene, which means no functional factor IX proteins can be formed. This protein is needed to form blood clots to stop bleeding. Prolonged bleeding in patients with haemophilia B can lead to serious complications, such as bleeding in joints, muscles or internal organs, including the brain. The incidence among males is estimated to be about 1 in 20,000 to 50,000 individuals. The treatment has hitherto consisted in the substitution of the missing coagulation factor IX, which necessitates lifelong injections.
Hemgenix (etranacogene dezaparvovec) is the first gene therapy for the treatment of haemophilia B in the EU authorisation process. The active substance in the gene therapy medicine Hemgenix is an AAV vector (non-proliferative adeno-associated virus) which does not multiply in the human body and transfers the gene with the blueprint for the formation of the factor IX protein to a few body cells. The body cells into which the factor IX gene has been transferred form the factor IX protein and release factor IX into the bloodstream. The gene therapy aims to introduce the factor IX gene into the patient's liver cells after a single intravenous administration in order to provide factor IX protein formed on the basis of the transferred, functional copy of the coagulation factor gene. This helps prevent bleeding or reduce bleeding episodes.
The CAT's marketing authorisation recommendation is based on the results of two prospective, open-label, single-arm, single-dose studies involving 57 male patients with moderate or severe haemophilia B. Bleeding rates decreased from 4.19 to 1.51 bleeds per year and most patients (96%) no longer required factor IX replacement therapy. In the first study, the positive treatment effects in the three patients were maintained for up to three years after the infusion. In the second study, the positive treatment effects in the 54 patients continued for up to two years after the infusion. It is not yet known how long the advantages of this single treatment will last. Patients treated with Hemgenix will therefore be followed for 15 years to monitor the long-term effectiveness and safety of this gene therapy.
The majority of adverse reactions observed in clinical trials were considered mild. Clinical studies have shown that an increase in liver function tests is a common side effect of AAV-based gene therapies. An increase in liver enzymes indicates incipient liver injury and has been observed following infusions of Hemgenix. It can be successfully treated with corticosteroids. Other common and transient adverse events are headache and flu-like symptoms.
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 need 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. It must be ensured that the marketing authorisation holder can provide additional data during the post-authorisation phase, which is suitable to supplement the clinical data previously considered to be non-comprehensive, in order to convert the conditional authorisation into a full authorisation.
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 medicines authorities of 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: 20.02.2023
