A Dose Range Finding Study With Open-Label Extension to Evaluate the Safety of Oral LMI070/Branaplam in Early Manifest Huntington's Disease

This is the first study of branaplam in adults with Huntington's Disease (HD) to determine the correct dose required to lower mutant huntingtin protein (mHTT) levels in the cerebrospinal fluid (CSF) to a degree expected to be efficacious over longer periods of time.

This study was a randomized, double-blind, placebo-controlled study with a variable duration (between approximately 17 weeks to approximately 53 weeks) for the core period and a one-year open label extension (OLE) in early-stage manifest Huntington's disease (HD) participants.

After screening period and baseline assessments, the following two Treatment Periods were planned:

• The core period consisted of a 17-week double-blind, placebo-controlled, Dose Range Finding (DRF) portion of the study, followed by a blinded extension (BE) of variable duration (up to approximately 53 weeks). The DRF Period was to evaluate the safety, tolerability, pharmacokinetivs (PK) and pharmacodynamics (PD) of branaplam, as well as determine the optimal dose(s) to explore in further clinical evaluations.

The core period was planned to consist of 3 treatment arms:

* Cohort 1: Treatment Arm A: branaplam 56 mg oral solution or matching placebo, once weekly
* Cohort 2: Treatment Arm B: branaplam 112 mg oral solution or matching placebo, once weekly
* Cohort 3:

Treatment Arm C: branaplam 154 mg oral solution or matching placebo, once weekly or Treatment Arm X: branaplam 84 mg oral solution or matching placebo, once weekly or Treatment Arm Y: branaplam 28 mg oral solution or matching placebo, once weekly

• The OLE was a one-year open-label extension to assess both long-term safety and tolerability, as well as the efficacy of the recommended optimal dose(s) for branaplam.

Due to safety concerns an urgent safety measure (USM) follow-up notification dated 06-Dec-2022 was issued to permanently discontinue the study treatment in all participants. At that point, only cohort 1 was enrolled. Therefore, only cohort 1 data is available for analysis (Treatment Arm A: branaplam 56 mg oral solution or matching placebo, once weekly). Participants who received active treatment (branaplam) were to remain in the study for follow-up for approximately one year following initial treatment discontinuation. The OLE part was not opened.

Eligibility Criteria:
Inclusion Criteria

* Signed informed consent must be obtained prior to participation in the study.
* Clinically diagnosed Stage 1 or 2 Huntington's disease with a diagnostic confidence level (DCL) = 4 and a United Huntington's Disease Rating Scale (UHDRS) Total Functional Capacity (TFC) \>8 at screening.
* Genetically confirmed Huntington's disease, with presence of ≥40 cytosine-adenineguanine (CAG) repeats in the huntingtin gene.
* Male and female participants between 25 to 75 years of age, inclusive, on the day of Informed Consent signature.

Exclusion Criteria

* Prior participation in clinical trial investigating a huntingtin-lowering therapy (unless participant received only placebo).
* Participants taking medications prohibited by the protocol.
* Any medical history, lumbar surgery or condition that would interfere with the ability to complete the protocol specified assessments.
* Participant has other severe, acute or chronic medical conditions including unstable psychiatric conditions, or laboratory abnormalities that in the opinion of the Investigator may increase the risk associated with study participation, or that may interfere with the interpretation of the study results.
* Any surgical or medical condition which might put the participant at risk in case of participation in the study. The Investigator should make this determination in consideration of the participant's medical history and/or clinical or laboratory evidence at the Screening visit.