Phase 1b/2a First‑in‑Human Randomized, Double‑Blind, Placebo‑Controlled, Multiple Ascending Intrathecal Dose Study of S233107 in Patients with Spinocerebellar Ataxia Type 3

The primary objective is to assess the safety and tolerability of multiple intrathecal administrations of S233107, compared with placebo in the dose‑escalation cohort and subsequently in an open‑label extension, in participants with spinocerebellar ataxia type 3; this evaluation is essential to determine the risk profile of a first‑in‑human intrathecal therapy for a rare neurodegenerative disorder. The secondary objective is to characterize the pharmacokinetic profile of S233107 in cerebrospinal fluid and plasma across both study parts, providing data on drug exposure and distribution that inform dose selection and therapeutic monitoring.

The trial enrolled twelve participants, both male and female, aged 18 to 65 years, who were medically stable and ambulatory without continuous use of a walking aid. All subjects had a genetically confirmed diagnosis of Spinocerebellar ataxia type 3 with an ATXN3 CAG repeat length of ≥60, met a total SARA score of ≥3 and a gait subscore between 1 and 4, and were either treatment‑naïve or on a stable regimen of symptomatic ataxia medication for at least three months. Stable non‑pharmacological interventions, such as physical therapy, speech therapy, or transcranial brain stimulation, had been maintained for a minimum of three months prior to baseline. Participants were selected based on these inclusion criteria and were assessed for overall health stability through medical history, physical examination, laboratory tests, and ECG. The cohort included individuals considered vulnerable, reflecting the disease’s rarity and impact.

The study is a first‑in‑human, multicentre, Phase 1b/2a trial evaluating intrathecal administration of S233107 in adults with spinocerebellar ataxia type 3. The protocol comprises two parts: Part 1 employs a randomized, double-blind, placebo-controlled design with multiple ascending dose cohorts, while Part 2 follows participants from Part 1 into an open-label extension to further assess safety, tolerability, and pharmacokinetics. Participants undergo a screening visit to confirm eligibility, including genetic confirmation of ATXN3 CAG repeat length and assessment of ambulatory status and SARA scores. Eligible subjects are then randomized and receive a series of intrathecal injections according to the assigned dose level, with scheduled follow‑up visits after each dosing interval for clinical evaluation, vital signs, ECG, laboratory tests, and adverse‑event monitoring. The study concludes with an end‑of‑study visit that includes final safety assessments and collection of pharmacokinetic samples. The overall trial recruitment period extends from September 2026 to October 2030, and individual participant involvement spans from the screening visit through the end‑of‑study visit, encompassing the dosing and follow‑up phases. Primary efficacy assessment focuses on the incidence and severity of adverse events and relevant clinical laboratory and ECG abnormalities, while secondary outcomes include concentrations and derived pharmacokinetic parameters of S233107 in cerebrospinal fluid and plasma.

The investigational product, S233107, is supplied as a intrathecal SOLUTION FOR INJECTION at two concentrations: 15 mg/mL and 4 mg/mL. Each concentration is administered via lumbar puncture directly into the cerebrospinal fluid. In Part 1 of the study, participants receive multiple ascending doses; the specific volume and total milligram dose per administration are determined by the predefined dose‑escalation cohort. Dosing is performed at scheduled intervals (e.g., every 4 weeks) as outlined in the protocol, and each administration is recorded in the source documentation. Compliance with the dosing schedule is monitored through site‑generated infusion logs and verification of drug accountability.

The second investigational formulation, also containing S233107 at a concentration of 4 mg/mL, follows the same administration route and schedule as the 15 mg/mL preparation. It is used in lower‑dose cohorts within the ascending‑dose sequence. Administration procedures, interval timing, and compliance monitoring are identical to those described for the higher‑concentration product, ensuring consistent data capture across dose levels.

The control arm utilizes a placebo that matches the appearance and volume of the active S233107 solutions. The placebo contains no active pharmaceutical ingredient and is administered intrathecally using the same schedule and procedural controls as the active arms. Blinding is maintained by identical packaging, and compliance is tracked in the same manner as for the active treatments.