FDA Grants Accelerated Approval to PTC Therapeutics’ Gene Therapy for AADC Deficiency

Matthew B. Klein, MD

(Credit: PTC Therapeutics)

According to a new announcement, the FDA has granted PTC Therapeutics’ gene therapy eladocagene exuparvovec-tneq an accelerated approval indicated for the treatment of patients aged 18 years and older with aromatic L-amino acid decarboxylase (AADC) deficiency, including the full spectrum of disease severity.¹ Marketed under Kebilidi, it becomes the first-ever gene therapy that is directly administered to the brain approved in the United States.¹

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. The company reported that launch preparations are progressing smoothly, with centers of excellence designated and surgeons already trained to administer the gene therapy.

"PTC has once again pioneered a new approach to treating highly morbid neurologic diseases," Matthew B. Klein, MD, chief executive officer at PTC Therapeutics, said in a statement.¹ "I am proud of our team's unwavering commitment to achieve this important regulatory milestone. We look forward to bringing this transformational gene therapy to children and adults with AADC deficiency in the United States."

In July 2022, the European Commission granted marketing authorization to eladocagene exuparvovec (where it is marketed as Upstaza) for the treatment of 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^.2

"[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 of PTC Therapeutics, said in a statement.² "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).

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).³

"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 of Teach RARE, whose daughter was treated as part of a clinical trial, said in a statement.² "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.⁴

REFERENCES
1. PTC Therapeutics Announces FDA Approval of AADC Deficiency Gene Therapy. News Release. PTC Therapeutics. Published November 13, 2024. Accessed November 13, 2024. https://ir.ptcbio.com/news-releases/news-release-details/ptc-therapeutics-announces-fda-approval-aadc-deficiency-gene
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://www.prnewswire.com/news-releases/upstaza-granted-marketing-authorization-by-european-commission-as-first-disease-modifying-treatment-for-aadc-deficiency-301589884.html
3. 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.
4. 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).