Trofinetide may benefit patients with Rett syndrome

In pediatric patients with Rett syndrome, twice-daily 200-mg/kg doses of trofinetide improve symptoms such as repetitive behaviors, breathing problems, mood dysregulation, and ambulation. Furthermore, the treatment is safe and well tolerated, according to results published online ahead of print March 27 in Neurology.

“These are very promising data for the Rett community that is currently without any [Food and Drug Administration]–approved treatment option,” Daniel Glaze, MD, said in a press release from Acadia Pharmaceuticals, which is developing trofinetide.

In 2017, a phase 2 study indicated that the drug was safe and tolerable when administered in doses of 70 mg/kg b.i.d. to adolescent and adult females with Rett syndrome. The study also provided initial evidence of the drug’s efficacy. Dr. Glaze, professor of pediatrics and neurology at Baylor College of Medicine in Houston, and his colleagues decided to conduct a larger phase 2 study that examined higher doses and a longer treatment duration.

The researchers first enrolled 62 participants in the study, all of whom received placebo b.i.d. for 14 days. They next randomized participants in equal groups to placebo or one of three twice-daily doses of trofinetide (i.e., 50 mg/kg, 100 mg/kg, and 200 mg/kg). After a blinded review of safety and tolerability data, Dr. Glaze and his colleagues enrolled 20 more participants and randomized them in equal groups to placebo or 200 mg/kg b.i.d. of trofinetide. This modification in study design was intended to increase the likelihood of detecting a clinical benefit. Randomized, double-blind treatment lasted for 42 days. Participants presented for a final visit at approximately 10 days after the treatment period ended.

A total of 82 girls aged 5-15 years participated in the study. They all met the 2010 diagnostic criteria for classic Rett syndrome, had a documented pathogenic MECP2 variant, were in the postregression stage of the syndrome, and had been stable on pharmacologic and behavioral treatments for at least 4 weeks. The sample’s mean age was 9.7 years, 94% were white, and mean weight was 26.1 kg. The treatment groups’ demographic characteristics were balanced.

All three doses of trofinetide were safe and tolerable. One participant in the 200-mg/kg b.i.d. group was withdrawn from the study at her parents’ request. Serious adverse events occurred in one control participant, one receiving the 100-mg/kg b.i.d. dose, and one receiving the 200-mg/kg b.i.d. dose. These serious adverse events were considered unrelated to study medication and resolved by the study’s end. The most common adverse events were diarrhea, vomiting, upper respiratory tract infection, and pyrexia. Most were mild or moderate and considered unrelated to trofinetide.

The 200-mg/kg b.i.d. dose of trofinetide significantly improved outcomes on the Rett Syndrome Behavior Questionnaire (RSBQ), Clinical Global Impression Scale–Improvement (CGI-I), and Rett Syndrome Domain Specific Concerns (RTT-DSC), compared with placebo. The change of the median RTT-DSC score was 15%, and the change of the mean RSBQ score was 16%. More than 20% of participants receiving 200 mg/kg b.i.d. of trofinetide were rated much improved on the CGI-I, compared with less than 5% of controls.

“Overall, the observed clinical improvement in the present pediatric trial was more manifest than in the previous trial, with younger age (i.e., greater neuroplasticity), higher doses (i.e., higher drug exposure), and longer drug treatment duration (i.e., 28 days in Rett-001 vs. 42 days in Rett-002) as potential contributors,” said Dr. Glaze and his colleagues. “Future studies aiming at replicating the results of this pediatric trial would benefit from including the RSBQ as a primary endpoint and should also consider evaluating RSBQ subscales such as the General Mood.”

Neuren Pharmaceuticals and Rettsyndrome.org funded the study. Dr. Glaze is a consultant to Neuren Pharmaceuticals.

[email protected]

SOURCE: Glaze DG et al. Neurology. 2019 Mar 27. doi: 10.1212/WNL.0000000000007316.

In pediatric patients with Rett syndrome, twice-daily 200-mg/kg doses of trofinetide improve symptoms such as repetitive behaviors, breathing problems, mood dysregulation, and ambulation. Furthermore, the treatment is safe and well tolerated, according to results published online ahead of print March 27 in Neurology.

“These are very promising data for the Rett community that is currently without any [Food and Drug Administration]–approved treatment option,” Daniel Glaze, MD, said in a press release from Acadia Pharmaceuticals, which is developing trofinetide.

In 2017, a phase 2 study indicated that the drug was safe and tolerable when administered in doses of 70 mg/kg b.i.d. to adolescent and adult females with Rett syndrome. The study also provided initial evidence of the drug’s efficacy. Dr. Glaze, professor of pediatrics and neurology at Baylor College of Medicine in Houston, and his colleagues decided to conduct a larger phase 2 study that examined higher doses and a longer treatment duration.

The researchers first enrolled 62 participants in the study, all of whom received placebo b.i.d. for 14 days. They next randomized participants in equal groups to placebo or one of three twice-daily doses of trofinetide (i.e., 50 mg/kg, 100 mg/kg, and 200 mg/kg). After a blinded review of safety and tolerability data, Dr. Glaze and his colleagues enrolled 20 more participants and randomized them in equal groups to placebo or 200 mg/kg b.i.d. of trofinetide. This modification in study design was intended to increase the likelihood of detecting a clinical benefit. Randomized, double-blind treatment lasted for 42 days. Participants presented for a final visit at approximately 10 days after the treatment period ended.

A total of 82 girls aged 5-15 years participated in the study. They all met the 2010 diagnostic criteria for classic Rett syndrome, had a documented pathogenic MECP2 variant, were in the postregression stage of the syndrome, and had been stable on pharmacologic and behavioral treatments for at least 4 weeks. The sample’s mean age was 9.7 years, 94% were white, and mean weight was 26.1 kg. The treatment groups’ demographic characteristics were balanced.

All three doses of trofinetide were safe and tolerable. One participant in the 200-mg/kg b.i.d. group was withdrawn from the study at her parents’ request. Serious adverse events occurred in one control participant, one receiving the 100-mg/kg b.i.d. dose, and one receiving the 200-mg/kg b.i.d. dose. These serious adverse events were considered unrelated to study medication and resolved by the study’s end. The most common adverse events were diarrhea, vomiting, upper respiratory tract infection, and pyrexia. Most were mild or moderate and considered unrelated to trofinetide.

The 200-mg/kg b.i.d. dose of trofinetide significantly improved outcomes on the Rett Syndrome Behavior Questionnaire (RSBQ), Clinical Global Impression Scale–Improvement (CGI-I), and Rett Syndrome Domain Specific Concerns (RTT-DSC), compared with placebo. The change of the median RTT-DSC score was 15%, and the change of the mean RSBQ score was 16%. More than 20% of participants receiving 200 mg/kg b.i.d. of trofinetide were rated much improved on the CGI-I, compared with less than 5% of controls.

“Overall, the observed clinical improvement in the present pediatric trial was more manifest than in the previous trial, with younger age (i.e., greater neuroplasticity), higher doses (i.e., higher drug exposure), and longer drug treatment duration (i.e., 28 days in Rett-001 vs. 42 days in Rett-002) as potential contributors,” said Dr. Glaze and his colleagues. “Future studies aiming at replicating the results of this pediatric trial would benefit from including the RSBQ as a primary endpoint and should also consider evaluating RSBQ subscales such as the General Mood.”

Neuren Pharmaceuticals and Rettsyndrome.org funded the study. Dr. Glaze is a consultant to Neuren Pharmaceuticals.

[email protected]

SOURCE: Glaze DG et al. Neurology. 2019 Mar 27. doi: 10.1212/WNL.0000000000007316.

In pediatric patients with Rett syndrome, twice-daily 200-mg/kg doses of trofinetide improve symptoms such as repetitive behaviors, breathing problems, mood dysregulation, and ambulation. Furthermore, the treatment is safe and well tolerated, according to results published online ahead of print March 27 in Neurology.

“These are very promising data for the Rett community that is currently without any [Food and Drug Administration]–approved treatment option,” Daniel Glaze, MD, said in a press release from Acadia Pharmaceuticals, which is developing trofinetide.

In 2017, a phase 2 study indicated that the drug was safe and tolerable when administered in doses of 70 mg/kg b.i.d. to adolescent and adult females with Rett syndrome. The study also provided initial evidence of the drug’s efficacy. Dr. Glaze, professor of pediatrics and neurology at Baylor College of Medicine in Houston, and his colleagues decided to conduct a larger phase 2 study that examined higher doses and a longer treatment duration.

The researchers first enrolled 62 participants in the study, all of whom received placebo b.i.d. for 14 days. They next randomized participants in equal groups to placebo or one of three twice-daily doses of trofinetide (i.e., 50 mg/kg, 100 mg/kg, and 200 mg/kg). After a blinded review of safety and tolerability data, Dr. Glaze and his colleagues enrolled 20 more participants and randomized them in equal groups to placebo or 200 mg/kg b.i.d. of trofinetide. This modification in study design was intended to increase the likelihood of detecting a clinical benefit. Randomized, double-blind treatment lasted for 42 days. Participants presented for a final visit at approximately 10 days after the treatment period ended.

A total of 82 girls aged 5-15 years participated in the study. They all met the 2010 diagnostic criteria for classic Rett syndrome, had a documented pathogenic MECP2 variant, were in the postregression stage of the syndrome, and had been stable on pharmacologic and behavioral treatments for at least 4 weeks. The sample’s mean age was 9.7 years, 94% were white, and mean weight was 26.1 kg. The treatment groups’ demographic characteristics were balanced.

All three doses of trofinetide were safe and tolerable. One participant in the 200-mg/kg b.i.d. group was withdrawn from the study at her parents’ request. Serious adverse events occurred in one control participant, one receiving the 100-mg/kg b.i.d. dose, and one receiving the 200-mg/kg b.i.d. dose. These serious adverse events were considered unrelated to study medication and resolved by the study’s end. The most common adverse events were diarrhea, vomiting, upper respiratory tract infection, and pyrexia. Most were mild or moderate and considered unrelated to trofinetide.

The 200-mg/kg b.i.d. dose of trofinetide significantly improved outcomes on the Rett Syndrome Behavior Questionnaire (RSBQ), Clinical Global Impression Scale–Improvement (CGI-I), and Rett Syndrome Domain Specific Concerns (RTT-DSC), compared with placebo. The change of the median RTT-DSC score was 15%, and the change of the mean RSBQ score was 16%. More than 20% of participants receiving 200 mg/kg b.i.d. of trofinetide were rated much improved on the CGI-I, compared with less than 5% of controls.

“Overall, the observed clinical improvement in the present pediatric trial was more manifest than in the previous trial, with younger age (i.e., greater neuroplasticity), higher doses (i.e., higher drug exposure), and longer drug treatment duration (i.e., 28 days in Rett-001 vs. 42 days in Rett-002) as potential contributors,” said Dr. Glaze and his colleagues. “Future studies aiming at replicating the results of this pediatric trial would benefit from including the RSBQ as a primary endpoint and should also consider evaluating RSBQ subscales such as the General Mood.”

Neuren Pharmaceuticals and Rettsyndrome.org funded the study. Dr. Glaze is a consultant to Neuren Pharmaceuticals.

[email protected]

SOURCE: Glaze DG et al. Neurology. 2019 Mar 27. doi: 10.1212/WNL.0000000000007316.