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

Study Overview
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Brief Summary
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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.

Detailed Description
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This study is a randomized, double-blind, placebo-controlled study which will be conducted in approximately 75 early manifest HD participants. After screening and baseline assessments are completed, participants will enter the Core Treatment Period which is double-blinded and placebo-controlled. The Core Treatment Period includes a Dose Range Finding (DRF) period of 17 weeks, followed by a Blinded Extension period of up to 53 weeks. Three cohorts will be enrolled in the Core Treatment Period, and data from each cohort will be evaluated for efficacy and safety before proceeding to a new cohort with a higher dose. The Core Treatment Period will serve to evaluate the safety, tolerability, pharmacokinetic(s) (PK) and pharmacodynamic(s) (PD) and to find the best dose(s) to use in future studies. After the dose(s) is determined at the end of the Core Treatment Period, participants will roll over into the Open Label Extension (OLE) and will be given branaplam for approximately 1 year and attend clinic visits every 4 weeks. At the end of the OLE, the study may be amended to provide open-label branaplam beyond 1 year or a separate extension study may be initiated.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled Dose Range Finding Study With Open-Label Extension to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of LMI070/Branaplam Administered as Weekly Oral Doses in Participants With Early Manifest Huntington's Disease

Conditions
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Early Manifest Huntington Disease

Intervention / Treatment
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* Drug: Branaplam
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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:

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The study design uses a staggered cohort approach, allowing safety and tolerability of lower doses to be assessed before randomizing subjects to higher doses. At the time of the Cohort Gating Assessments (CGAs), all available data will be reviewed from a safety and dose finding perspective by an independent Sponsor team to support the decision to open the next cohort. The independent Data Monitoring Committee (DMC) will review the data separately. The decision to open a new cohort will be made by the Sponsor in consultation with the DMC.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Arm A<br>Branaplam 56 mg oral solution once weekly | Drug: Branaplam<br>* messenger ribonucleic acid (RNA) splicing modifier<br>* Other names: LMI070;|
| Experimental: Treatment Arm B<br>Branaplam 112 mg oral solution once weekly | Drug: Branaplam<br>* messenger ribonucleic acid (RNA) splicing modifier<br>* Other names: LMI070;|
| Experimental: Treatment Arm C or X or Y<br>(C) Branaplam 154 mg oral solution once weekly, OR (X) Branaplam 84 mg oral solution once weekly OR (Y) Branaplam 28 mg oral solution once weekly | Drug: Branaplam<br>* messenger ribonucleic acid (RNA) splicing modifier<br>* Other names: LMI070;|
| Placebo Comparator: Placebo<br>Matching placebo oral solution once weekly | Drug: Placebo<br>* Matching placebo oral solution once weekly<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduction (%) of mHTT protein in cerebrospinal fluid (CSF) | To assess the dose-response relationship of branaplam administered over 16 weeks on mHTT protein change from baseline in cerebrospinal fluid (CSF) obtained via lumbar puncture. Treatment is administered for 16 weeks and assessments are done over a 17 week period. | Baseline up to Week 17 | 
| Number of treatment emergent adverse events and serious adverse events | The occurrence of adverse events will be sought by non-directive questioning of the participant at each visit during the study. Adverse events also may be detected when volunteered by the participant during or between visits or through physical examination findings, laboratory test findings, or other assessments. | Baseline up to approximately 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in Ventricular Volume, Caudate Volume and Total Brain Volume | Ventricular, Caudate and Total Brain Volume will be measured by structural magnetic resonance imaging (MRI) | Baseline up to approximately 2 years | 
| Concentrations of total HTT and mHTT protein in CSF | The concentrations of total HTT and mHTT protein will be measured in CSF samples obtained via lumbar puncture | Baseline up to approximately 2 years | 
| Change from baseline in the Unified Huntington's Disease Rating Scale (UHDRS) Total Functional Capacity (TFC) | The TFC focuses on the Investigator's assessment of the participant's capacity to perform a range of activities of daily living. The responses are derived from interview with the participant and/or companion, if applicable. Scores range from 0 to 13, with higher scores representing better functioning. | Baseline up to approximately 2 years | 
| Change from baseline in the Unified Huntington's Disease Rating Scale (UHDRS Total Motor Score (TMS) | The TMS is the cumulative sum of the individual motor ratings obtained during the administration of the motor assessment portion of the UHDRS. Scores range from 0 to 124; the higher score represents more significant impairment. | Baseline up to approximately 2 years | 
| Change from baseline in the Unified Huntington's Disease Rating Scale (UHDRS) Independence Scale (IS) | The IS represents the Investigator's assessment of the participant's level of independence, including topics of employment, finances, self-care and feeding. The scale has 19 discrete scores, from 10 (tube fed, total bed care) to 100 (no special care needed) with 5 point increments in between. | Baseline up to approximately 2 years | 
| Concentrations of total HTT and mHTT protein in plasma | The concentrations of total HTT and mHTT protein will be measured in plasma from blood samples. | Baseline up to approximately 2 years | 
| Concentrations of total HTT and mHTT protein in peripheral blood mononuclear cells (PBMCs) | The concentrations of total HTT and mHTT protein will be measured in PBMCs from blood samples. | Baseline up to approximately 2 years | 
| Area under the curve (AUC) of branaplam in plasma | AUC will be calculated by measuring concentrations of branaplam in blood samples | Baseline up to approximately 2 years | 
| Maximum concentration (Cmax) of branaplam in plasma | Cmax of branaplam will be calculated by measuring concentration in blood samples | Baseline up to approximately 2 years | 
| Time taken to reach Cmx (Tmax) of branaplam in plasma. | Tmax will be calculated by measuring concentrations of branaplam in blood samples | Baseline up to approximately 2 years | 
| Drug concentration observed at the last planned timepoint prior to dosing (Ctrough) of branaplam in plasma | Ctrough will be calculated by measuring concentrations of branaplam in blood samples | Baseline up to approximately 2 years | 
| Concentrations of branaplam in CSF | The concentration of branaplam will be measured in CSF samples collected via lumbar puncture | Baseline up to approximately 2 years | 
| Concentration ratio of branaplam in CSF/plasma. | Concentration ratio will be calculated by measuring branaplam in CSF samples collected via lumbar puncture and blood samples | Baseline up to approximately 2 years | 
| Area under the curve (AUC) of UFB112 in plasma | AUC will be calculated by measuring concentrations of UFB112 in blood samples | Baseline up to approximately 2 years | 
| Maximum concentration (Cmax) of UFB112 in plasma | Cmax of UFB112 will be calculated by measuring concentration in blood samples | Baseline up to approximately 2 years | 
| Time taken to reach Cmx (Tmax) of UFB112 in plasma. | Tmax will be calculated by measuring concentrations of UFB112 in blood samples | Baseline up to approximately 2 years | 
| Drug concentration observed at the last planned timepoint prior to dosing (Ctrough) of UFB112 in plasma | Ctrough will be calculated by measuring concentrations of UFB112 in blood samples | Baseline up to approximately 2 years | 
| Concentrations of UFB112 in CSF | The concentration of UFB112 will be measured in CSF samples collected via lumbar puncture | Baseline up to approximately 2 years | 
| Concentration ratio of UFB112 in CSF/plasma. | Concentration ratio will be calculated by measuring UFB112 in CSF samples collected via lumbar puncture and blood samples | Baseline up to approximately 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Early Manifest, Huntington Disease, Branaplam, LMI070, Dose Range Finding, Safety, HD, mHTT, Pharmacokinetics, oral, Adult