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Upstaza Approved for AADC Deficiency in UK

The gene therapy was approved in the European Union earlier this year.

PTC Therapeutics’ Upstaza (eladocagene exuparvovec), a recombinant adeno-associated virus serotype 2 (AAV2)-based gene therapy intended to treat aromatic L–amino acid decarboxylase (AADC) deficiency with a severe phenotype, has received marketing authorization from the UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) for the treatment of children aged 18 months or older.1

Upstaza is delivered to the putamen via a 1-time treatment with a stereotactic surgical procedure and provides a functional copy of DDC, the disease-targeted gene. In clinical trials, treated participants who had not previously reached any developmental motor milestones mastered clinically meaningful motor skills including independent ambulation. Additionally, cognitive and language acquisition was achieved as early as 3 months after administration. Clinical benefits were shown to persist up to 10 years after administration. Additionally, reductions in symptoms that could lead to potentially fatal complications were observed.

"We are thrilled with the MHRA's rapid authorization of Upstaza," Stuart W. Peltz, PhD, chief executive officer, PTC Therapeutics, said in a statement regarding the news.1 "Patients in the UK with AADC deficiency are 1 step closer to having access to a much-needed disease modifying therapy. This is another milestone towards our commitment to advance innovative treatments and improve outcomes for people living with rare diseases."

The most common adverse events reported during Upstaza’s clinical trials included initial insomnia, irritability, and dyskinesia. Upstaza was previously approved in July of this year in all 27 European Union member states, Iceland, Norway, and Liechtenstein, approximately 12 years after the first patient was treated in a clinical trial in 2010.2 The approval came 2 months after the European Medicines Agency (EMA)’s Committee for Medicinal Products for Human Use (CHMP) issued a positive opinion based on results of 2 clinical trials for Upstaza (NCT01395641; NCT02926066) that were conducted in Taiwan.3 Upstaza is also approved in Northern Ireland.1 

"The approval of an AADC deficiency gene therapy in the UK will provide the opportunity to transform the prognosis for those born and living with this disease, and we are hopeful for access in the coming months,” Kirsty Hoyle, chief executive officer, Metabolic Support UK, added to the statement.1 “Without treatment, most children born with AADC deficiency will have difficulty with their development and many of the symptoms can be distressing and life-threatening. The impact on those living with AADC and their communities is significant, with children facing frequent hospitalizations, emergency visits, and requiring a multi-disciplinary team of highly trained specialists.”

Last month, PTC Therapeutics announced in a clinical and regulatory update that the company held a type C meeting with the FDA regarding a potential biologics license application (BLA) submission for Upstaza.4 It was noted that the FDA requested additional bioanalytical data to support comparability of the drug product evaluated in the clinical trials with commercial Upstaza. PTC Therapeutics mentioned in the press releasethat it is working to address the FDA’s request and that the company expects to make the BLA submission in the first half of next year.

CGTLive previously spoke with Paul Wuh-Liang Hwu, MD, PhD, professor of pediatrics, an investigator on the Taiwanese trials, about questions that remain regarding AADC deficiency. "In AADC deficiency, we’re working with patients, we’re working on mice, and trying to really dig into the pathogenesis, especially in younger patients, what exactly happens to the brain without dopamine...” Hwu told CGTLive during the interview. "We need to learn more about what separates responders from non-responders."

1. Upstaza gene therapy granted marketing authorization for AADC deficiency by UK's MHRA. News release. PTC Therapeutics, Inc. November 17, 2022. https://ir.ptcbio.com/news-releases/news-release-details/upstazatm-gene-therapy-granted-marketing-authorization-aadc 
2. Upstaza granted marketing authorization by European Commission as first disease-modifying treatment for AADC deficiency. News release. PTC Therapeutics. July 20, 2022. Accessed July 20, 2022. https://ir.ptcbio.com/news-releases/news-release-details/upstazatm-granted-marketing-authorization-european-commission 
3. PTC Therapeutics receives positive CHMP opinion for Upstaza for the treatment of AADC deficiency. News release. PTC Therapeutics. May 20, 2022. https://ir.ptcbio.com/news-releases/news-release-details/ptc-therapeutics-receives-positive-chmp-opinion-upstazatm 
4. PTC Therapeutics provides a corporate update and reports third quarter financial results. News release. PTC Therapeutics, Inc. October 27, 2022. https://ir.ptcbio.com/news-releases/news-release-details/ptc-therapeutics-provides-corporate-update-and-reports-third-0