Gene therapy also becomes a reality for the treatment of severe haemophilia A characterized by congenital deficiency of Factor VIII. The European Commission has, in fact, granted the conditional marketing authorization (CMA) to valoctocogene roxaparvovec for adult patients with severe haemophilia A without a history of factor VIII inhibitors and without detectable antibodies to adeno-associated virus serotype 5 (AAV5). The European Commission has also decided to keep the orphan drug designation reserved for therapies for rare diseases.
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Preliminary studies
A study on the New England Journal of Medicine which showed the results from the GENEr8-1 clinical trial, which tested the efficacy of valoctocogene roxaparvovec gene therapy in 132 patients (men, because the disease essentially affects males by genetic characteristics) with severe haemophilia A. The drug, developed by the pharmaceutical company Biomarin, is the first gene therapy for the treatment of haemophilia A. The active ingredient, valoctocogene roxaparvovec, is based on a virus (adeno-associated virus or AAV) modified to prevent human disease.
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How gene therapy works
Drugs currently licensed for the treatment of haemophilia A mostly contain factor VIII, which replaces the missing protein. Available treatments require one or more injections per week or month and are lifelong. There is, therefore, an unmet medical need for new therapeutic approaches that can free patients from frequent injections. But how does this gene therapy work? The virus contains the factor VIII gene: once given to the patient as a single infusion, it is expected to carry the factor VIII gene into the liver cells, allowing them to produce the missing factor VIII. This helps the blood to clot more easily and prevent bleeding or reduce bleeding episodes without having to continue hemophilia prophylaxis, thus relieving patients of the burden of treatment compared to currently available therapies.
The impact of hemophilia A
Patients with haemophilia A are unable to produce factor VIII (a protein essential for blood clotting and stopping bleeding); they are more prone to bleeding and prolonged bleeding, for example after an injury or surgery. It is a rare and debilitating disease that affects around 0.7 in 10,000 people in the European Union. It is a lifelong disease and can be life-threatening when bleeding occurs in the brain, spinal cord, or intestines. “This European approval – he declared Johannes Oldenburg, director of the Institute of Experimental Hematology and Transfusion Medicine and of the Hemophilia Center at the University Clinic of Bonn, Germany – represents a medical breakthrough in the treatment of patients with severe haemophilia A, which broadens the conversation between patient and doctor about therapeutic choices, now including a single infusion that protects against bleeding for several years. It is exciting to envision the possibilities of this approved gene therapy, which has demonstrated a substantial and lasting reduction in bleeding for patients, who could potentially be freed from the burden of regular infusions. “
The duration of effectiveness
In Italy there are 4,109 patients with haemophilia A. Of the 8,000 adults with severe haemophilia A in the 24 countries covered by BioMarin’s approval today by the EMA, it is estimated that around 3,200 will be eligible for this gene therapy. It is currently unknown how long the therapeutic effect of this single infusion will last in a single patient. A positive therapeutic effect lasting up to two years after a single infusion was reported in approximately one hundred patients in the main study and up to five years in some patients in a supportive study conducted by the applicant. Longer-term follow-up tests may be needed to verify maintenance of a safe and effective response to the drug.
The registration studies
EMA’s recommendation is based on the results of a single-arm (pivotal), non-randomized Phase 3 study in 134 male patients with haemophilia A with no history of factor VIII inhibition and no pre-existing antibodies. Two years after administration, efficacy data showed that therapy significantly increased factor VIII activity levels in most patients. Bleeding rates were reduced by 85% and most patients (128) no longer needed factor VIII replacement therapy. For its part, the European Commission based its decision on a significant set of data from the clinical development program, including the two-year results of the global phase 3 GENEr8-1 study whose results demonstrated stable and lasting control. of bleeding, including a reduction in the mean annualized bleeding rate (ABR) and the mean annualized infusion rate of Factor VIII. In addition, the data includes five and four years of follow-up of the 6e13 vg / kg and 4e13 vg / kg dose cohorts, respectively.
The side effects
Hepatotoxicity (liver damage), a common side effect due to the immune reaction induced by these gene therapies and characterized to date by increased levels of a liver enzyme called alanine aminotransferase (ALT), has been reported with valoctocogene roxaparvovec. The condition can be successfully treated with corticosteroids. Other common side effects are headache, joint pain, and nausea. Patients treated with this therapy will be monitored for 15 years to ensure long-term efficacy and safety.