Efficacy and Safety Evaluation of Gemlapodect in Adult and Adolescent Tourette Syndrome: A Double-Blind, Placebo-Controlled, Phase IIb Study

The primary objective of this study is to evaluate the change in **tic severity score** using the Yale Global Tic Severity Scale-Revised (YGTSS-R) in adult and adolescent patients with **Tourette Syndrome**. This is clinically relevant as it aims to assess the efficacy of gemlapodect in reducing tic severity, which is a core symptom of Tourette Syndrome, potentially improving patient outcomes and quality of life.

Secondary objectives include:

• Impact on patient functioning
• Change in severity of illness
• Change in illness
• Change in Premonitory Urge for Tics Scale (PUTS)
• Change in ADHD assessment
• Impact on quality of life (QoL), including activities of daily living (ADL) and functioning
• Effect on metabolic safety
• Evaluation of safety and tolerability of gemlapodect, including suicidality
• Pharmacokinetics (PK)

These secondary objectives aim to provide a comprehensive evaluation of the treatment's impact on various aspects of patient health and safety, contributing to a holistic understanding of gemlapodect's therapeutic profile in the management of Tourette Syndrome.

The clinical trial involves a total of **50 participants** diagnosed with **Tourette Syndrome**. The study population includes both male and female subjects, with an age range starting from 12 years, contingent upon regional regulatory approval for adolescent inclusion, and extending to adults aged 18 years and older. Participants are required to have moderate to severe Tourette Syndrome as defined by DSM-5 diagnostic criteria. The trial population was selected based on specific inclusion criteria, including being treatment-naive or previously treated individuals in need of alternative treatment options. Participants must have a **BMI** within the range of 18 to 35 kg/m² and be capable of providing informed consent. Relevant lifestyle considerations include the discontinuation of all medications used to treat Tourette Syndrome for at least 14 days prior to randomization, while other psychotropic drugs, including stimulants, are permitted if stable for at least 30 days prior to randomization. The study also includes a vulnerable population, ensuring that all participants are fluent in the language of the investigator and study staff.

The clinical trial is a **randomized**, **double-blind**, **placebo-controlled** study designed to evaluate the efficacy and safety of **gemlapodect** in adult and adolescent patients with **Tourette Syndrome**. The trial is a Phase IIb, multi-center, twelve-week prospective study. Participants will be randomly assigned to receive either gemlapodect or a placebo, administered orally in the form of hard capsules. The primary objective is to assess the change in tic severity score using the Yale Global Tic Severity Scale-Revised (YGTSS-R) from baseline to day 85. Secondary endpoints include changes in various scales such as the Sheehan Disability Scale (SDS), Tourette Syndrome Clinical Global Impression-Severity (TS-CGI-S), and others, as well as assessments of body weight, blood glucose, lipids, and the incidence of adverse events.

The trial will commence with an inclusion (screening) visit to determine eligibility based on criteria such as age, severity of Tourette Syndrome, and medication history. Participants must discontinue all medications used to treat Tourette Syndrome at least 14 days prior to randomization. The study will include several follow-up visits to monitor the participants' progress and collect data on the primary and secondary endpoints. The end-of-study visit will occur at the conclusion of the twelve-week treatment period, where final assessments will be conducted.

The expected length of participant involvement is approximately twelve weeks, with the possibility of early termination if participants experience significant adverse events or fail to comply with the study protocol. The trial is estimated to start recruitment on March 21, 2024, and is expected to conclude by August 6, 2025. Participants will be required to adhere to the study's requirements, including regular visits and assessments, to ensure the integrity and validity of the trial results.

The clinical trial involves the administration of **Gemlapodect**, a novel PD10A inhibitor, as the experimental medication. **Gemlapodect** is provided in the form of a hard capsule, with a maximum daily dose of 15 mg. The route of administration is oral, and the treatment period extends up to 12 weeks. The active substance, **Gemlapodect**, is chemically synthesized and is also known by its synonyms, RO5545965 and NOE-105. The pharmaceutical product is manufactured by NOEMA PHARMA AG. Participants are required to adhere to the dosing schedule, and compliance is monitored throughout the study duration.

In addition to the experimental treatment, a placebo is utilized as a comparator in this double-blind, placebo-controlled study. The placebo is also provided in the form of hard capsules, ensuring blinding is maintained. The placebo capsules are indistinguishable from the active treatment capsules in appearance, ensuring the integrity of the study design. The administration of the placebo follows the same oral route and dosing schedule as the active treatment, with participant compliance similarly monitored.

The efficacy of the investigational product **Gemlapodect** in the treatment of Tourette Syndrome will be assessed through a series of primary and secondary endpoints. The primary endpoint is the change in the Yale Global Tic Severity Scale-Revised (YGTSS-R) total tic scores from baseline to Day 85, comparing **Gemlapodect** to placebo. Secondary endpoints include changes in the Sheehan Disability Scale (SDS), Tourette Syndrome Clinical Global Impression-Severity (TS-CGI-S) scale, and other relevant scales such as the Premonitory Urge for Tics Scale (PUTS) and ADHD Rating Scale (ADHD-RS) from baseline to Day 85. Additional assessments will include the Clinical Global Impression-Change (CGI-C) scale, Patient Global Impression-Change (PGI-C) scale, and the Child and Adolescent Gilles de la Tourette Syndrome-Quality of Life (C&A-GTS-QOL) subscale.

Measurements will be conducted at baseline and at the end of the treatment period (Day 85). The study will also monitor changes in body weight, blood glucose, and lipid levels, as well as the incidence and severity of adverse events (AEs), including serious adverse events (SAEs) and adverse events of special interest (AESI). Laboratory assessments, electrocardiogram (ECG) evaluations, vital signs, and suicidality assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS) will be part of the safety evaluations. Plasma concentrations of **Gemlapodect** will be measured to assess pharmacokinetics. The study is designed to confirm the efficacy and safety of **Gemlapodect** in reducing tics in adolescents and adults with Tourette Syndrome over a 12-week treatment period.