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EMA recommends authorisation of first therapy to treat rare genetic disorder

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EMA has recommended granting a marketing authorisation in the European Union for Upstaza (eladocagene exuparvovec). This is a gene therapy for the treatment of adult and paediatric patients with severe aromatic L-amino acid decarboxylase (AADC) deficiency with a genetically confirmed diagnosis. The use of Upstaza to treat rare genetic disorder is now pending for European Commission decision to reach the European market.

AADC Deficiency

This nervous system deficiency is an ultra-rare, inherited genetic disease which typically manifests within the first year of life. It is caused by changes in the gene that produces the AADC enzyme which is needed to produce vital substances for the normal functioning of the brain and nerves, such as dopamine and serotonin.

Patients with AADC typically experience developmental delays, weak muscle tone, and inability to control the movement of the limbs. It is a long-term, debilitating, and life-threatening condition because it can lead to multiple organ failure. Patients also experience intellectual disability, show irritability and are at risk of death in the first decade of life. The condition affects to 1 in 118,000 people in the European Union, and there are no approved therapies for the treatment of AADC deficiency, and therefore, there is an unmet medical need for these patients.

For these reasons, Upstaza was designated as an Orphan medicinal product on November 2016.

Gene therapy

Upstaza consists of a modified virus (adeno-associated viral vector) containing a functional version of the AADC gene. When given to the patient by infusion into the brain, it is expected that the virus will carry the AADC gene into nerve cells enabling them to produce the missing enzyme. This will enable the cells to produce the substances they need to function properly, improving symptoms of the condition. The virus used in this medicine does not cause disease in humans.

As the active substance, the modified virus, contains a recombinant nucleic acid to add a genetic sequence, and the therapeutic effect is related to the product of the genetic expression of said sequence, this medicine is classified as a gene therapy medicinal product.

Clinical trial

EMA’s recommendation is based on the results of three trials including 28 children between the ages of 18 months and 8 years and 6 months with severe AADC deficiency. The main favorable effects attained by the participants were head control and the ability to sit unassisted. An expert group concluded that efficacy had been demonstrated and is clinically meaningful.

The majority of side effects reported were mild or moderate, being the most common ones raised body temperature (pyrexia) and involuntary, erratic movements (dyskinesia).

In the overall assessment, the Committee for Advanced Therapies (CAT) found that the benefits of Upstaza outweighed the possible risks in patients with AADC deficiency. EMA’s human medicines committee (CHMP) agreed with CAT’s assessment and positive opinion, and recommended approval of this medicine under exceptional circumstances.

Exceptional circumstances

A marketing authorisation under exceptional circumstances allows patients access to medicines that cannot be approved using a standard authorisation route as comprehensive data cannot be obtained under normal conditions of use, because there are only very few patients with disease, the collection of complete information on efficacy and safety would be unethical, or there are gaps in the scientific knowledge.

These medicines are subject to specific post-authorisation obligations and monitoring, such as 10-year follow-up on long-term efficacy and safety of the patients with rare genetic disorder enrolled in the clinical trials, and a registry-based safety study on patients treated globally.

If you want to know more, check out the official press release here.

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