Evaluation of Tominersen Safety, Biomarkers, and Efficacy in Prodromal and Early Manifest Huntington's Disease: A Phase II Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this study is to evaluate the **safety** of tominersen compared with placebo in individuals with prodromal and early manifest Huntington's Disease. This will be assessed based on the incidence and severity of adverse events, with severity determined according to the Adverse Event Severity Grading Scale. Additionally, changes from baseline in clinical laboratory results, including cerebrospinal fluid (CSF) white blood cell (WBC) and protein levels, as well as safety magnetic resonance imaging (MRI), will be evaluated. The study will also assess CSF mutant huntingtin (mHTT) protein levels in response to tominersen compared with placebo at 9 months. Evaluating these parameters is clinically relevant as it provides insights into the potential risks and therapeutic effects of tominersen, which could inform treatment strategies for Huntington's Disease.

Secondary objectives include:

• Evaluating the safety of tominersen compared with placebo based on changes from baseline in vital signs, electrocardiogram (ECG) parameters, plasma clinical laboratory results, Montreal Cognitive Assessment (MoCA), and the proportion of participants with suicidal ideation or behavior as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS) score at each visit.
• Assessing the efficacy of tominersen compared with placebo based on changes from baseline at 16 months for the assessments of Total Functional Capacity (TFC) (non-U.S.)/composite Unified Huntington's Disease Rating Scale (cUHDRS) (U.S.), Symbol Digit Modalities Test (SDMT), Stroop Word Reading (SWR), and Total Motor Score (TMS).
• Evaluating changes from baseline in CSF neurofilament light chain (NfL) in response to tominersen compared with placebo at 16 months.
• Assessing the immune response to tominersen.

The clinical trial involves a total of **138 participants** diagnosed with **Prodromal and Early Manifest Huntington's Disease**. The study population includes both male and female subjects, aged between **25 and 50 years**. Participants were selected based on specific criteria, including being carriers of the Huntington's disease gene expansion mutation with a CAP score of 400-500. The trial population is characterized by individuals who are either in the prodromal stage of Huntington's disease, defined by a Diagnostic Confidence Level (DCL) of 2 to 3, or in the early manifest stage, defined by a DCL of 4. Participants are required to have an estimated glomerular filtration rate of at least 60 mL/min/1.73 m² and a body mass index within the range of 18-32 kg/m². The study also considers lifestyle factors such as total body weight, which must be greater than 40 kg. The trial includes a vulnerable population, and all participants have a study companion. The selection process ensures that the participants meet the necessary health and genetic criteria to evaluate the safety and efficacy of tominersen compared with placebo.

The clinical trial is a **Phase II**, randomized, double-blind, placebo-controlled, dose-finding study designed to evaluate the safety, biomarkers, and efficacy of **tominersen** in individuals with prodromal and early manifest **Huntington's disease**. The trial aims to assess the safety of tominersen compared to placebo by monitoring the incidence and severity of adverse events, changes in clinical laboratory results, and safety magnetic resonance imaging (MRI). Additionally, the study will evaluate cerebrospinal fluid (CSF) mutant huntingtin protein levels and the efficacy of tominersen based on changes in the composite unified Huntington's disease rating scale and total functional capacity over a period of 16 months.

The trial will involve a series of study visits, beginning with an inclusion (screening) visit to determine participant eligibility based on criteria such as age, gene expansion mutation carrier status, and health parameters. Participants will be randomly assigned to receive either tominersen or placebo via intrathecal bolus injection. Follow-up visits will occur at regular intervals to monitor safety, efficacy, and biomarker endpoints, including assessments of vital signs, electrocardiogram (ECG) parameters, and CSF neurofilament light chain levels. The end-of-study visit will conclude the trial, with a comprehensive evaluation of all collected data.

The expected duration of participant involvement is approximately 24 months, with the trial estimated to end by April 2027. Conditions that may lead to early termination from the study include the occurrence of severe adverse events, non-compliance with study procedures, or withdrawal of consent. The trial is not categorized as low intervention and is part of an ongoing development program for the investigational product.

The clinical trial involves the administration of **Tominersen**, an experimental medication, which is a **solution for injection**. The active substance, Tominersen, is an antisense oligonucleotide derived from nucleic acid. The pharmaceutical form is a solution intended for intrathecal administration via a bolus injection into the intrathecal space. The dosing regimen for Tominersen involves a maximum daily dose of 100 mg, with a total maximum dose of 500 mg over a treatment period of 24 months. The administration schedule is designed to ensure optimal therapeutic outcomes while monitoring for safety and efficacy. Participant compliance is monitored through regular assessments and adherence checks.

The study also includes a **placebo** group, which receives an inactive substance designed to mimic the appearance and administration route of the experimental medication. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments. This approach allows for an unbiased comparison of the safety and efficacy of Tominersen against the placebo. The placebo is administered following the same schedule and route as the active treatment to ensure consistency across the study arms.

The efficacy of **tominersen** in the clinical trial will be assessed through several primary and secondary endpoints. The primary efficacy endpoints include the percentage change from baseline in geometric means of cerebrospinal fluid (CSF) mutant huntingtin (mHTT) protein levels at Month 9, and the change from baseline in the composite unified Huntington's disease rating scale (cUHDRS) for non-U.S. participants and total functional capacity (TFC) for U.S. participants at 16 months. These measures will provide insights into the drug's impact on disease progression and functional capacity.

Secondary efficacy endpoints will include changes from baseline in various clinical parameters such as vital signs, electrocardiogram (ECG) parameters, plasma clinical laboratory results, and Montreal Cognitive Assessment (MoCA) scores. Additionally, the trial will assess the proportion of participants with suicidal ideation or behavior using the Columbia-Suicide Severity Rating Scale (C-SSRS) score at each visit, with a detailed focus on any severe cases. Other secondary measures include changes in CSF neurofilament light (NfL) levels at 16 months, and the incidence of anti-drug antibodies (ADAs) at specified timepoints relative to baseline prevalence, with titers determined if ADAs are identified.