Principal Investigator Cassandra Newsom, Psy.D., director of the Translational Research Core in Autism and Neurodevelopment of Civitan International Research Center, has completed participation in Phase 2 Clinical Trials of a new drug, NNZ-2591, produced by Neuren Pharmaceuticals, that shows promising results for a devastating neurodevelopmental disorder called Pitt-Hopkins Syndrome (PTHS).
PTHS affects intellectual ability, speech, autism-like symptoms, and motor skills, as well as a range of medical issues and behavioral differences. The genetic neurological disorder is caused by a TCF4 mutation, a specific gene on chromosome 18 that is critical for early brain development.
Children with PTHS often have moderate-to-severe impairments. There are currently no approved treatments, despite its debilitating impact on patients and families.
NNZ-2591 yields positive outcomes
The successful drug trial showed that NNZ-2591, which targets IGF-1 receptors, offered significant improvements in participants, observed by both clinicians and caregivers. Specifically, improvements in communication, social interaction, cognition, and motor abilities were noted.
“The open-label Phase 2 trial involved 11 children aged 3 to 17 across five hospitals in the United States, including UAB,” said Newsom.
It focused on safety, tolerability, and pharmacokinetics over 13 weeks of treatment. “It showed that NNZ-2591 is safe and well-tolerated, with no serious or severe adverse events,” she explained.
The UAB site was the first to screen and enroll participants, and all four UAB participants who qualified for the study completed the trial.
Families from all corners of the country traveled to Birmingham, Alabama several times to participate in the clinical trial.
Equity in measurement
One exciting facet of the study is that caregiver ratings of improvement aligned with those of the clinicians. This parallel indicates the equity and utility of new outcome measurements that were created specifically for the trial.
Developed by Newsom and colleagues, the new measurements—PTHS Clinical Global Impression of Improvement (PTHS CGI-I) and the PTHS Clinical Global Impression of Severity (CGI-S)—are neurodevelopmental markers more sensitive to change than traditional measures, as the intellectual development differences are stark between typical developing children and those with Pitts Hopkins Syndrome.
“The lack of disease-specific outcome measures in rare disease has been a common problem in past clinical trials,” said Newsom, “and we are encouraged that the measure that we developed at UAB appears to overcome that hurdle and measures the types of change that are meaningful in this population.”
On the horizon
Newsom said the trial's promising result “offers hope for developing the first approved treatment for PTHS, potentially improving the quality of life for affected individuals and their families."
“Given the positive results and safety profile found in Phase 2, we are hopeful a larger Phase 3 double-blind, placebo-controlled trial will be approved, and we anticipate that UAB will again be a site,” she said.
“Additionally, the success of this trial highlights the potential of NNZ-2591 for other severe neurodevelopmental disorders, such as Phelan-McDermid, which has also found positive results and Angelman syndromes, which is currently in progress, with ongoing and future trials planned, such as Prader Willi, which will again include UAB as a site.”
An interdisciplinary success
Newsom explained that the success of the trial is attributed to the extensive collaboration on both national and international levels.
Study sites at UAB, University of California at San Francisco, Rush University, University of Texas Southwestern, and the University of Colorado played crucial roles in enrolling and supporting families through the trial.
“Partnerships between basic scientists, clinical researchers, and industry are vital in advancing drug discovery and providing new treatment options for families impacted by rare developmental genetic disorders,” said Newsom.
UAB collaborators on the study were many: Robert Tauscher, M.D., Lanning Klien, M.D., Dawn Decarlo, O.D., and Marissa Locy, O.D., from UAB Callahan Eye Center; Nathaniel Robin, M.D., Joy Dean, Ali Al Beshri, and Kristin Linscott from UAB Genetics; and Justin Schwartz, M.D. from UAB Pediatrics in Developmental Behavioral Pediatrics.
CCTS administrative research support was provided by Keenya Matthews, Brandon Bailey, Pamela Cunningham, and Tamara Howard.
Collaborators for measure development of the PTHS CGI included Sarah O’Kelley, Ph.D., Helen Root, (graduate student at the time of the study) and Emma Lewis (a recent graduate from the UAB bachelors’ program in Psychology).
Kimberly Goodspeed, M.D., a neurodevelopmental pediatric neurologist, also contributed to the study.
About Neuren Pharmaceuticals
Neuren Pharmaceuticals is dedicated to developing therapies for serious neurological disorders emerging in early childhood. Their programs are granted "orphan drug" designation in the U.S., encouraging development for rare diseases. Neuren's first drug, DAYBUE™ (trofinetide), is FDA-approved for Rett syndrome.