PTC now seeking US approval of one-time gene therapy Upstaza
Treatment already approved in EU, UK for patients 18 months and older
PTC Therapeutics has submitted its application seeking the approval of Upstaza (eladocagene exuparvovec) — a one-time gene therapy to correct the underlying cause of aromatic L-amino acid decarboxylase (AADC) deficiency — to the U.S. Food and Drug Administration (FDA).
“We are excited to bring Upstaza one step closer to children in the United States with the highly mortal and fatal disease of AADC deficiency. The data collected to date continue to demonstrate the transformative clinical benefits the gene therapy provides to patients,” Matthew B. Klein, MD, PTC Therapeutics‘ CEO, said in a company press release.
Upstaza already is approved in the European Union and in the U.K. to treat AADC deficiency patients, ages 18 months and older.
The submission of the biologics license application (BLA) to the FDA follows a December meeting between PTC and the agency to review data supporting the BLA. The FDA now will decide whether to accept or reject the submission. If accepted, a decision on whether or not to approve the gene therapy would typically be expected within 10 months.
If approved, Upstaza would become the first therapy in the U.S. for AADC deficiency.
If approved by FDA, Upstaza would be first US treatment for AADC deficiency
AADC deficiency is caused by mutations in the DDC gene, which lead to low levels of the AADC enzyme or the production of a faulty version. As a result in either case, nerve cells produce less dopamine and serotonin, two key neurotransmitters regulated by the activity of this enzyme. That, in turn, leads to physical and mental developmental delays. Neurotransmitters are chemical substances produced in response to nerve signals that allow these cells to communicate.
Upstaza delivers a healthy version of the DDC gene to nerve cells using a tweaked adeno-associated virus 2 (AAV2) as a vehicle. Commonly used in gene therapies, the AAV2 is modified to not cause disease in humans.
The gene therapy is administered directly into the brain, where the working gene is expected to allow nerve cells to produce AADC. This will increase dopamine and serotonin levels, thereby easing symptoms.
“The Upstaza BLA is the first filing for FDA approval of a treatment that addresses this devastating condition,” Jeremy Stigall, chief business officer at ClearPoint Neuro, a partner of PTC Therapeutics, said in a ClearPoint press release.
“Through our partnership with PTC, we are demonstrating our commitment to drive progress for the AADC deficiency community,” Stigall said.
The Upstaza BLA is the first filing for FDA approval of a treatment that addresses this devastating condition.
Data from clinical trials have shown that a single Upstaza infusion allowed children with AADC deficiency to develop head control. Children also were able to sit without the need of assistance. These motor benefits were maintained for up to 10 years, in parallel with cognitive gains.
In a first meeting the developer, the FDA had noted a lack of sufficient data supporting the equivalence of the version of the gene therapy used in the clinical trials to the commercial version.
The FDA agreed that biomarker data reflecting an increase in dopamine levels in a Phase 2 trial (NCT04903288), still ongoing in the U.S., Israel, and Taiwan, would help support a BLA seeking accelerated approval.
Accelerated approval is meant for medications for serious diseases with surrogate biomarker data, meaning the findings use a parameter believed to reflect the clinical benefit.
For a BLA approved under the accelerated approval process to be converted into a full approval, additional clinical trial data that support the therapy’s clinical efficacy are required.
The Phase 2 study is testing the effects of Upstaza in children with AADC deficiency. The safety of delivering the gene therapy using an MRI-compatible cannula also is being assessed. Both parameters will be evaluated for about five years after dosing.
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