PTC to seek OK of AADC-deficiency gene therapy Upstaza in US

Therapy is already in use for patients in EU and UK

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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PTC Therapeutics plans to seek the U.S. approval this month of Upstaza (eladocagene exuparvovec), its one-time gene therapy that’s meant to address the root cause of aromatic L-amino acid decarboxylase (AADC) deficiency, the company announced.

The company met with the U.S. Food and Drug Administration (FDA) in December to review the data it plans to include in a biologics license application (BLA) package that’s part of the process to get Upstaza on the market, according to PTC’s 2023 annual report.

The gene therapy is already on the market for use by AADC deficiency patients, 18 months and older, in the European Union and the U.K., where it was approved in 2022 as the first disease-modifying therapy for the genetic condition.

AADC deficiency is caused by mutations in the DDC gene, which provides instructions to produce an AADC enzyme, which manufacture molecules such as dopamine and serotonin that are involved in nerve cell communication. Mutations in the DDC gene lead to reduced AADC activity, meaning nerve cells produce less dopamine and serotonin. This leads to a range of symptoms from developmental delays to weak muscle tone and difficulty moving.

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How does Upstaza work in AADC-deficiency?

Upstaza delivers a working version of the DDC gene to nerve cells. The working gene is packaged aboard a modified adeno-associated virus 2 (AAV2) that is harmless, meaning it’s not known to cause disease in humans.

Given as an infusion into the brain, it’s expected the virus will carry the working gene into nerve cells, enabling them to produce AADC on their own. This will increase dopamine and serotonin levels, thereby easing symptoms.

In clinical trials, a single Upstaza infusion helped children with a genetically confirmed diagnosis of AADC deficiency develop head control and the ability to sit unassisted. Besides helping children meet motor milestones for up to at least 10 years after dosing, Upstaza also led to cognitive gains.

The FDA said PTC hadn’t yet provided enough data to show the commercial version of the gene therapy was equivalent to the one used in clinical trials.

The agency did note that available data from an ongoing Upstaza Phase 2 trial (NCT04903288) in the U.S., Israel, and Taiwan could help support a BLA for accelerated approval based on biomarker data that reflects an increase in brain dopamine levels. An accelerated approval allows for an earlier approval of medications that treat serious diseases and fill an unmet medical need based on a surrogate biomarker, that is, a measure that’s thought to predict clinical benefit, but isn’t itself a measure of clinical benefit.

In such cases, full approval depends on further clinical trial data that supports the therapy’s clinical efficacy.

The Phase 2 study is evaluating Upstaza’s effects on the body and the safety of an MRI-compatible cannula to deliver it in three children with AADC deficiency for up to about five years after dosing.