First therapy to treat rare genetic nervous system disorder AADC deficiency
EMA has recommended granting a marketing authorisation in the European Union (EU) for Upstaza (eladocagene exuparvovec), a therapy for the treatment of adult and paediatric patients with severe aromatic L-amino acid decarboxylase (AADC) deficiency with a genetically confirmed diagnosis.
AADC 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 certain substances vital for the normal functioning of the brain and nerves, including dopamine and serotonin. These substances are used by cells in the brain and the nervous system to send signals and are crucial for the development of motor functions.
Patients with AADC typically experience developmental delays, weak muscle tone and inability to control the movement of the limbs. AADC deficiency 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.
According to recent estimates, this condition affects 1 in 118,000 people in the EU. Currently, there are no approved therapies for the treatment of AADC deficiency. Patients are offered supportive treatments to manage the symptoms without addressing the underlying cause of the disease. Therefore, there is an unmet medical need for these patients.
Upstaza consists of a modified virus (adeno-associated viral vector) that contains 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 in turn is expected to enable the cells to produce the substances they need to function properly (such as dopamine and serotonin), thus improving symptoms of the condition. The virus used in this medicine does not cause disease in humans.
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 confirmed by a genetic diagnosis. All trials were conducted with an unblinded single arm and historic control data from published studies was used as a comparator.
The main favourable effects attained by the participants were head control and the ability to sit unassisted. An ad-hoc expert group was consulted to discuss the clinical relevance of the motor benefits of treatment and concluded that efficacy had been demonstrated and is clinically meaningful.
The most commonly reported side effects were raised body temperature (pyrexia) and involuntary, erratic movements (dyskinesia). The majority of side effects reported were mild or moderate.
In its overall assessment of the available data, the Committee for Advanced Therapies (CAT), EMA's expert committee for cell- and gene-based medicines, found that the benefits of Upstaza outweighed the possible risks in patients with AADC deficiency.
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, either because there are only very few patients with the disease, the collection of complete information on the efficacy and safety of the medicine would be unethical, or there are gaps in the scientific knowledge. These medicines are subject to specific post-authorisation obligations and monitoring.
The CHMP requested the applicant to submit data to further characterise the long-term efficacy and safety of patients enrolled in the clinical trials, on the basis of a 10-year follow-up, and a registry-based safety study on patients treated globally with the medicine. The studies will be conducted according to agreed protocols.
The opinion adopted by the CHMP is an intermediary step on Upstaza’s path to patient access. The CHMP opinion will now be sent to the European Commission for the adoption of a decision on the EU-wide marketing authorisation. Once a marketing authorisation has been granted, decisions about price and reimbursement will take place at the level of each Member State, taking into account the potential role/use of this medicine in the context of the national health system of that country.
- The applicant for Upstaza is PTC Therapeutics International Limited.
- Upstaza was designated as an orphan medicinal product for the treatment of Treatment of aromatic L-amino acid decarboxylase deficiency on 18 November 2016. The applicant for Upstaza received scientific advice from the Agency at various stages prior to submission of a marketing authorisation application.
- Following this positive CHMP opinion, the Committee for Orphan Medicinal Products (COMP) will assess whether the orphan designation should be maintained.