Unravel Biosciences, Inc. ("Unravel") proposes to develop an orally administered, once daily novel treatment for the orphan drug indication of Pitt Hopkins syndrome. Unravel has utilized its proprietary drug discovery platform to identify drugs having potential therapeutic value for neurodevelopmental disorders caused by gene mutations shown to have a cascading effect on other genes. Unravel's platform combines human gene regulatory network-based computational drug prediction with in vivo screening in a population-level diversity, CRISPR-edited, Xenopus laevis tadpole disease model. Through use of Unravel's platform, the drug vorinostat ranked highly in predictive scoring for Pitt Hopkins syndrome. In work done for Rett syndrome, another orphan CNS disease with many molecular and phenotypic similarities to Pitt Hopkins syndrome, vorinostat broadly improved both CNS and non-CNS (e.g., gastrointestinal, respiratory, inflammatory) abnormalities in a pre-clinical mouse model of Rett syndrome. Vorinostat was the first treatment to demonstrate nonclinical efficacy across multiple organ systems when dosed after the onset of symptoms, and network analysis revealed a putative therapeutic mechanism for its cross-organ normalizing effects based on its impact on acetylation metabolism and post-translational modifications of microtubules, leading to the selection of vorinostat as a target candidate for further assessment in both Rett and Pitt Hopkins syndromes. The main hypotheses informing the goals and design of the study are as follows:
* Vorinostat is safe and tolerable when dosed in typical Rett patients at dose levels up to 160mg/m2/day
* At a molecular level, vorinostat mitigates the impact of the underlying TCF4 gene mutation in PTHS patients by restoring downstream mRNA synthesis, as measured by transcriptome data
* Vorinostat provides clinical benefit to Pitt Hopkins patients by reducing frequency and severity of clinical signs/symptoms and improving patient quality of life
The study is designed as an exploratory, proof of concept trial to investigate the study hypotheses as stated above and to achieve the primary goals of the trial. The study design adapts the well-known "n of 1" crossover study methodology (Guyatt, et.al., 1990, Kravitz, et.al., 2014), where each patient serves as their own control during comparative analyses of safety and efficacy. Up to 5 patients will be enrolled in the study to explore the hypothesis that vorinostat is a safe and potentially effective treatment for Pitt Hopkins syndrome. Each patient enrolled in the study will be exposed to a 4-week placebo study phase to generate baseline data that will serve as a control as well as two active drug phases with vorinostat treatment, starting at 80mg/m2/day dosing for 8 weeks, followed by dose escalation to 160mg/m2/day for 8 weeks. The study is designed to be single-blinded, where patients and their caregivers will not be aware of their treatment assignment in an attempt to minimize bias where practically possible, especially given the subjective nature of several of the endpoints being evaluated. Investigator, study staff, and sponsor will not be blinded to study treatment assignment.
