Trofinetide, Potential Rett Therapy, Not Seen to Be Affected by Food

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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A recent meal or snack does not affect the pharmacological profile of trofinetide, an experimental oral treatment for Rett syndrome, according to findings from a Phase 1 study in healthy adults.

Food can affect how a drug moves through a patient’s body, or its pharmacological profile, the researchers noted.

Results were detailed in the study, “A Phase 1, Open-Label Study to Evaluate the Effects of Food and Evening Dosing on the Pharmacokinetics of Oral Trofinetide in Healthy Adult Subjects,” published in the journal Clinical Drug Investigation.

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Acadia Seeks FDA Approval of Oral Trofinetide as Treatment for Rett

Trofinetide (previously called NNZ-2566) contains a modified version of the protein fragment glypromate, which is thought to improve the structure of connections between nerve cells in the brain and reduce inflammation. The therapy was originally developed by Neuren Pharmaceuticals, which gave Acadia Pharmaceuticals an exclusive license to develop and market the therapy in North America.

Trofinetide food study may help support regulatory review

Acadia previously sponsored a Phase 3 clinical trial called LAVENDER (NCT04181723), which enrolled 187 girls and young women with Rett syndrome, ages 5 to 20. Participants were given trofinetide (dosed according to weight) or a placebo, twice daily for 12 weeks.

Results from LAVENDER were announced late last year, and showed that participants given trofinetide had significant improvements in standardized measures of behavior and communication compared to those given a placebo.

These findings were met with excitement by the Rett community. “This is Really Big News. We are closer than ever to the first FDA-approved treatment for Rett syndrome,” Melissa Kennedy, CEO of the International Rett Syndrome Foundation, wrote in a foundation press release.

The U.S. Food and Drug Administration is considering whether to accept for review a recent application by Acadia requesting trofinetide be approved to treat Rett syndrome that is supported by LAVENDER trial findings.

Trofinetide is designed to be taken either by mouth or through a feeding tube as an oral solution. Whether a medication is taken with or without food, however, can have a substantial effect on its pharmacological profile. Here, scientists at Acadia conducted a small trial to test whether eating changes trofinetide’s pharmacological properties.

The trial enrolled 41 healthy adults, with a mean age of 32.9. Of this group, 35 people completed the study — reasons for discontinuation included participant choice and not following study protocols. One participant discontinued due to appendicitis, which was deemed unrelated to the treatment.

All who completed the study took three doses of trofinetide at 12 grams: one in the morning under fasting conditions, a second in the morning after a high-fat meal, and a third in the evening under fasting conditions. Of note, 12 g twice daily is the highest dose that was tested in the LAVENDER trial.

Pharmacological analyses broadly showed that the bioavailability of trofinetide — that is, how much of the medication was distributed in the body to reach its target areas — was generally similar across all three doses.

“In this study, the rate and extent of trofinetide absorption was comparable under morning fasted and evening fasted conditions,” the researchers concluded.

They noted a slight difference with food, but considered that “this small change is unlikely to be clinically meaningful and suggests that trofinetide can be taken with or without food.”

Safety data also were similar across all three conditions, and trofinetide was generally well tolerated. Ten treatment-related side effects were reported in eight participants; the most common were dizziness and POTS (postural orthostatic tachycardia syndrome), a condition characterized by a racing heart and lightheadedness upon standing up.

Acadia is running a Phase 2/3 trial called DAFFODIL (NCT04988867) to further investigate the safety, tolerability, and pharmacological properties of trofinetide given twice daily, with weight-based dosing, to children ages 2 to 5 with Rett syndrome. The open-label study is expected to conclude in July 2023.