Acadia Seeks FDA Approval of Oral Trofinetide as Treatment for Rett

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by Patricia Inácio, PhD |

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Acadia Pharmaceuticals is asking the U.S. Food and Drug Administration (FDA) to approve its oral candidate trofinetide for the treatment of children and adults, ages 2 and older, with Rett syndrome.

Over the next two months, the FDA will determine whether Acadia’s new drug application (NDA) is acceptable for filing, and whether to grant it priority review — which could shorten trofinetide’s regulatory review from the usual 10 months to six.

The therapy was shown in clinical trials to ease fear/anxiety behaviors and improve communication in girls and young women with Rett.

“This is an important step forward for members of the Rett community who face a devastating disease with no approved therapies,” Steve Davis, the CEO of Acadia, said in a company press release.

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“We are grateful to the patients, their families and the physicians who have participated in the trofinetide clinical studies, including our pivotal Phase 3 Lavender study. We look forward to working with the FDA as it evaluates the NDA,” Davis added.

Trofinetide previously received orphan drug, fast track, and rare pediatric disease designations from the FDA for Rett syndrome. Each of these designations is meant to accelerate a therapy’s clinical development and regulatory review.

Should trofinetide be approved in the U.S., its orphan drug status provides a seven-year marketing exclusivity period for Acadia. Meanwhile, the rare pediatric disease designation makes the company eligible for a voucher redeemable for the priority review of an NDA for a different product.

Regulators in the European Union also have designated trofinetide an orphan drug.

Formerly called NNZ-2566, trofinetide was originally developed by Neuren Pharmaceuticals, which sold the therapy’s development and marketing rights in North America to Acadia in 2018.

It is a modified version of a protein fragment called glypromate, which is believed to lessen neuroinflammation and boost the number of connections between nerve cells in the brain — a phenomenon that is defective in Rett patients.

Trofinetide is meant to have better pharmacological properties, including easier storage, oral administration, and longer periods in the bloodstream than the original version of the medication.

A liquid solution, it is administered orally or through a gastrostomy tube at a dose based on a patient’s weight.

Trofinetide in clinical trials

The regulatory submission to the FDA was supported by promising data from the Phase 3 LAVENDER clinical trial (NCT04181723). That U.S.-based trial tested trofinetide against a placebo in 187 girls and young women, ages 5–20, with Rett syndrome.

Participants were randomly assigned to receive an oral solution of either trofinetide (30–60 mL) or a placebo, twice daily for 12 weeks, or about three months.

LAVENDER’s main goals included changes in key neurobehavioral symptoms based on scores in the Rett Syndrome Behaviour Questionnaire, a caregiver assessment, and in the Clinical Global Impression Scale-Improvement, which is a physician assessment of symptom changes.

Changes in communication skills, assessed with the caregiver-completed Communication and Symbolic Behavior Scales Developmental Profile Infant‑Toddler Checklist — Social Composite Score, was a key secondary goal.

Top-line data showed that the study met both its primary and secondary goals, with trofinetide found to be significantly better than the placebo at reducing neurobehavioral symptoms and improving communication in these patients.

Caregivers specifically reported the greatest reductions in behaviors such as fear/anxiety and body rocking/expressionless face.

The therapy was generally safe and well-tolerated, with the most frequent adverse events (side effects) being diarrhea and vomiting, which were mostly mild to moderate in severity.

Almost all patients who completed LAVENDER then enrolled in the LILAC open-label extension study (NCT04279314), in which all are receiving trofinetide for up to nine months.

Patients completing LILAC will be able to continue the treatment in a second extension trial, called LILAC-2 (NCT04776746). During that study, treatment will be maintained for more than 2.5 years.

Trofinetide also is being evaluated in 15 girls, ages 2 to 5, with Rett syndrome in the Phase 2/3 DAFFODIL trial (NCT04988867). The 12-week trial, involving seven clinical sites in the U.S., is expected to end in July 2023.