An Exploratory Evaluation of the Safety and Efficacy of Vorinostat in Pitt Hopkins Syndrome

An Exploratory Evaluation of the Safety and Efficacy of Vorinostat in Pitt Hopkins Syndrome Using an "N of 1" Study Design

The study is an exploratory evaluation of the safety and efficacy of vorinostat in Pitt Hopkins syndrome. Each patient will be self-controlled in an adapted N-of-1 study design methodology with three treatment arms, including a 4-week placebo phase and two vorinostat dose arms, including every 8 weeks of daily dosing at a low dose of 80mg/m2/day and 8 weeks of a higher dose at 160mg/m2/day.

Key objectives of the study include:

• To confirm the safety and tolerability of oral vorinostat 80mg/m2/day and 160mg/ m2/day dose levels when administered to PTHS patients
• To identify the nature and magnitude of treatment response to vorinostat, as measured by changes in clinical and laboratory parameters indicative of trend towards benefit, as well as changes in mRNA expression (transcriptome response)
• Provide a data-driven justification for future study design and statistical analysis plan for subsequent clinical studies assessing safety and efficacy of vorinostat in PTHS

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.

Inclusion Criteria:

1. Subjects ≥3 years of age and ≤ 21 years of age at time of screening
2. Clinical diagnosis of PTHS with documented pathologic mutation in the TCF4 gene
3. At time of screening, is in a post-regression phase with no degradation of ambulation, hand function, speech or communication skills in the 4 months prior to screening
4. Has been on a stable regimen of medication or non-pharmacological treatment for at least 4 weeks prior to the baseline visit
5. Has had a stable pattern of seizure activity for 4 weeks before screening
6. Can swallow medication or can take it by gastrostomy tube
7. Can wear actigraphy data logging device on wrist or ankle
8. If of childbearing potential, must agree to use a highly effective method of contraception during the study and for 3 months after the last study drug administration (i.e., abstinence from sexual activity, hormonal contraceptives associated with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing system)
9. Subjects or their legally authorized representative must be able to provide an informed consent and have sufficient language skill to complete caregiver assessments in the language in which the study assessments are provided

Exclusion Criteria:

1. Has another clinically significant medical condition other than those related to their TCF4 mutation (e.g. diabetes mellitus, cardiovascular disease, renal disease, respiratory disease, hematological abnormalities, malignancy)
2. Has major surgery planned during the study period
3. Pregnant or nursing women
4. Has a history of brain injury, stroke, other cerebrovascular disease or hypoxic-ischemic encephalopathy
5. Has clinically significant abnormal vital signs at screening or baseline
6. Has an abnormal ECG at screening, including clinically significant QT prolongation
7. Has a clinically significant abnormal laboratory value at screening
8. Liver disease or transaminase levels > 1.5 times the upper limit of the normal range as determined during screening
9. Has a history of malignancy of any organ system within the past 5 years before screening
10. Is participating in or has participated in another clinical trial within 30 days prior to the screening visit
11. Has been treated with growth hormone, IGF-1, or insulin within 12 weeks of baseline
12. Is taking anticoagulant therapy or other HDAC inhibitors
13. Has had any change to their medication or non-pharmacological treatment within 4 weeks prior to the baseline visit
14. Life expectancy of less than 12 months.
15. Has a history of alcoholism or drug/chemical abuse within 2 years before screening.
16. In the investigator's opinion, is inappropriate for this study for any reason