Landmark drug trial shows promising results for Pitt-Hopkins syndrome

Written by: Mary Ashley Canevaro
Media contact: Jeff Hansen

This devastating neurodevelopmental disorder has no currently approved treatments.A completed Phase 2 clinical trial of a novel drug, directed by University of Alabama at Birmingham researchers, shows promising results for the devastating neurodevelopmental disorder Pitt-Hopkins syndrome, or PTHS. There are currently no approved treatments for this genetic neurological disorder, despite its debilitating impact on patients and families.

Pitt-Hopkins syndrome presents with autism-like symptoms and affects intellectual ability, speech and motor skills, causing a range of medical issues and behavioral differences. The disorder is caused by a mutation in TCF4, a specific gene on chromosome 18 that is critical for early brain development. Children with Pitt-Hopkins syndrome often have moderate to severe impairments.

Cassandra Newsom, Psy.D., director of the Translational Research Core of Civitan International Research Center at UAB, led the Phase 2 trials of the new drug NNZ-2591, produced by Neuren Pharmaceuticals, Camberwell, Australia. Trial results showed that NNZ-2591 offered significant improvements in the trial participants, as observed by both clinicians and caregivers. Specific improvements in communication, social interaction, cognition and motor abilities were noted.

"The open-label Phase 2 trial involved 11 children ages 3 to 17 across five hospitals in the United States, including UAB," Newsom said. The trial 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."

NNZ-2591 targets insulin-like growth factor 1 receptors, or IGF-1 receptors, which are found on the surface of cells and are key for the regulation of cell growth and metabolism.

UAB was the first site to screen and enroll drug trial 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.

A significant facet of the study was 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 by Newsom and colleagues.

The new measurements - the PTHS Clinical Global Impression of Improvement and the PTHS Clinical Global Impression of Severity - are neurodevelopmental markers more sensitive to change than traditional measures, as the intellectual development differences are stark between typically developing children and those with Pitt-Hopkins syndrome.

Cassandra Newsom, Psy.D."The lack of disease-specific outcome measures in rare disease has been a common problem in past clinical trials," Newsom said. "We are encouraged that the measure we developed at UAB appears to overcome that hurdle and measures the types of changes that are meaningful in this population."

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."

"Additionally, the success of this trial highlights the potential of NNZ-2591 for other severe neurodevelopmental disorders such as Phelan-McDermid syndrome, Angelman syndrome and Prader-Willi syndrome, which are in various phases of clinical trials."

Newsom says the success of the trial depended on extensive national and international collaboration. Study sites at UAB; the University of California, San Francisco; Rush University, Chicago, Illinois; the University of Texas Southwestern, Dallas, Texas; and the University of Colorado School of Medicine, Aurora, 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," Newsom said.

Many UAB researchers, clinicians, staff and students, including those at the Callahan Eye Hospital, Department of Genetics, Department of PediatricsDivision of Developmental-Behavioral Pediatrics, Department of Psychology, the Center for Excellence in Developmental Disabilities, and the Center for Clinical and Translational Science, collaborated in the study.

Genetics and Pediatrics are departments in the UAB Marnix E. Heersink School of Medicine, and Psychology is a department in the UAB College of Arts and Sciences.

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