European Commission Passes Eladocagene Exuparvovec as First Approved Treatment for AADC Deficiency


In previous clinical studies, patients with AADC deficiency treated with the recombinant AAV2-based gene therapy achieved motor milestones, including head control and unassisted sitting.

Stuart Peltz, PhD, chief executive officer, PTC Therapeutics

Stuart Peltz, PhD

The European Commission has granted marketing authorization to PTC Therapeutics’ gene therapy eladocagene exuparvovec, marketed as Upstaza, for the treatment of aromatic L-amino acid decarboxylase (AADC) deficiency, becoming the first disease-modifying therapy approved for the rare disorder. The marketing authorization is applicable to all 27 European Union member states, as well as Iceland, Norway, and Liechtenstein.1

Approved for patients 18 years and older, eladocagene exuparvovec is recombinant adenoassociated virus serotype 2-based gene therapy delivered once in those with a clinical, molecular, and genetically confirmed diagnosis of AADC deficiency. AADC deficiency is a fatal, rare genetic disorder that typically causes severe disability and suffering from the first months of life, leading to decreased muscle tone, movement disorders, and disruption of the autonomic nervous system.

"[This] approval from the European Commission for Upstaza for the treatment of AADC deficiency is momentous for patients, for PTC, as well as for the larger gene therapy community,” Stuart Peltz, PhD, chief executive officer, PTC Therapeutics, said in a statement.1 "We are proud to bring this innovative therapy to the marketplace so that patients may benefit. Upstaza is the first and only approved disease-modifying treatment for patients living with AADC deficiency. We are ready to deliver this long-awaited treatment to patients as soon as possible."

The efficacy and safety of eladocagene exuparvovec has been demonstrated across clinical trials and compassionate use programs. One 2021 analysis included 3 major clinical trials that featured a total of 28 children with AADC deficiency treated at total doses of either 1.8 x 1011 vg (n = 21) or 2.4 x 1011 vg (n = 7).2 All told, the number of patients achieving full head control and sitting unassisted was significantly higher in those treated with the gene therapy than those in the Natural History Database (NHDB).

READ MORE: Treating Familial ALS at the Source: The Introduction of Gene Therapies

As early as 12 months after receiving the drug, 44% of patients achieved head control and 20% of subjects could sit unassisted. At 24 months after gene therapy, 64% of individuals achieved head control, 50% could sit unassisted, and 18% could stand without support. After 60 months of treatment, 75% of subjects achieved head control, 67% of patients could sit unassisted, 25% of the cohort could stand without support, and 8% of individuals could walk with support. In contrast, only 4% of the individuals from the NHDB (n = 49) achieved key milestones (P <.0001).2

"Before treatment, our daughter had not met any development milestones. She suffered from oculogyric crises that evolved into hours of pain, and we were told she would be bedridden for life," Richard Poulin, founder, Teach RARE, whose daughter was treated as part of a clinical trial, said in a statement.1 "After receiving Upstaza, she is now speaking, walking, running, and even riding horses. We're thrilled with the EMA approval and the hope that this milestone brings to other children and families impacted by AADC deficiency."

In May 2022, a post hoc analysis of the 3 trials showed that eladocagene exuparvovec improved body weight and reduced respiratory infections in patients with AADC deficiency.3 At baseline, 83.3% (20 of 24) of patients had body weight in the bottom third percentile; however, after 12 months of treatment, 95.9% maintained or gained weight relative to age- and gender-matched children without AADC deficiency; 42% (10 of 24) shifted to a higher percentile, and 54% (13 of 24) maintained the same percentile as at baseline. Additionally, the annual rate of upper respiratory tract infections and pneumonia decreased from 2.41 at 1 year after treatment to 0.31 at 5 years after treatment.3

1. 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.
2. Hwu P, Chien Y, Lee N, et al. 390 Efficacy of gene therapy with eladocagene exuparvovec in patients with AADC deficiency compared with natural history controls. Archives of Disease in Childhood. 2021;106:163-164.
3. Hwu P, Chien Y, Tseng S, Wang A, Schilling T, Tai C. Eladocagene exuparvovec improves body weight and reduces respiratory infections in patients with aromatic L-amino acid decarboxylase deficiency. Neurology. 2022;98(18 supplement).
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