A Study to Investigate the Pharmacokinetics and Pharmacodynamics of RO7234292 (RG6042) in CSF and Plasma, and Safety and Tolerability Following Intrathecal Administration in Patients With Huntington's Disease

Study Overview
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Brief Summary
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Study BP40410 is an open-label, adaptive multiple-dose clinical study designed to characterize the PK of RO7234292 (RG6042) in plasma and CSF as well as the acute time course and recovery profile of CSF mHTT lowering in response to RO7234292 (RG6042) treatment after intrathecal (IT) administration of RO7234292 (RG6042) to patients with manifest Hungtington's disease (HD).

Official Title
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An Open-Label Adaptive Multiple-Dose Study to Investigate the Pharmacokinetics and Pharmacodynamics of RO7234292 in CSF and Plasma, and Safety and Tolerability Following Intrathecal Administration in Patients With Huntington's Disease

Conditions
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Huntingtons Disease

Intervention / Treatment
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* Drug: RO7234292 (RG6042)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Manifest HD diagnosis Independence Scale score of >=70. Genetically confirmed disease by direct deoxyribonucleic acid testing with a cytosine, adenine, and guanine base sequence found in DNA which is translated into glutamine (CAG) age product (CAP) score > 400. Ability to read the words red, blue, and green in the patient's native language. Ability to walk unassisted without a cane or walker and move about without a wheelchair on a daily basis as reviewed at screening and baseline visit. Ability to undergo and tolerate MRI scans. Exclusion Criteria: History of attempted suicide or suicidal ideation with plan (i.e., active suicidal ideation) that required hospital visit and/or change in level of care within 12 months prior to screening. Current active psychosis, confusional state, or violent behavior. Any serious medical condition or clinically significant laboratory, vital signs, or ECG abnormalities at screening that, in the Investigator's judgment, precludes the patient's safe participation in and completion of the study. Clinical diagnosis of chronic migraines or history of low pressure headache after lumbar puncture requiring hospitalization or blood patch. Treatment with investigational therapy within 4 weeks prior to screening or 5 drug elimination half-lives of investigational therapy, whichever is longer. Concurrent or planned concurrent participation in any interventional clinical study, including explicit pharmacological and non-pharmacological interventions. Observational studies are acceptable. Unable or unsafe to perform lumbar puncture on the patient. Previous lumbar surgery that is likely, in the opinion of the Investigator or surgical team, to make IT catheter insertion or IT injection unduly difficult or hazardous. Poor peripheral venous access. Scoliosis or spinal deformity making IT injection not feasible in the outpatient setting. Preexisting intra-axial or extra-axial lesions as assessed by a centrally read MRI scan during the screening period.

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 65 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose level 1 of RO7234292 (RG6042)<br>Participants will receive dose level 1 of RO7234292 (RG6042) intrathecally on Day 1 and Day 29. | Drug: RO7234292 (RG6042)<br>* RO7234292 (RG6042) will be administered in two IT doses of the same dose level at an interval of 28 days during the treatment period (Day 1 and Day 29). Each dose of RO7234292 (RG6042) will be administered as a single IT bolus injection.<br>* Other names: Tominersen;|
| Experimental: Dose level 2 of RO7234292 (RG6042)<br>Participants will receive dose level 2 of RO7234292 (RG6042) intrathecally on Day 1 and Day 29. | Drug: RO7234292 (RG6042)<br>* RO7234292 (RG6042) will be administered in two IT doses of the same dose level at an interval of 28 days during the treatment period (Day 1 and Day 29). Each dose of RO7234292 (RG6042) will be administered as a single IT bolus injection.<br>* Other names: Tominersen;|
| Experimental: Dose level 3 of RO7234292 (RG6042)<br>Participants will receive dose level 3 of RO7234292 (RG6042) intrathecally on Day 1 and Day 29. | Drug: RO7234292 (RG6042)<br>* RO7234292 (RG6042) will be administered in two IT doses of the same dose level at an interval of 28 days during the treatment period (Day 1 and Day 29). Each dose of RO7234292 (RG6042) will be administered as a single IT bolus injection.<br>* Other names: Tominersen;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concentrations of RO7234292 in CSF (cerebrospinal fluid) |  | Day 1, 2, 3, 4, 29, 43, 71, 127, and follow-up visit (6 months after last study drug administration) | 
| Concentrations of RO7234292 in Plasma |  | Day 1, 2, 3, 4, 5, 28, 29, 30, 43, 71, 127, and follow-up visit (6 months after last study drug administration) | 
| mHTT (mutant Huntingtin) Concentration in CSF |  | Days 1, 2, 3, 29, 43, 71, 127 and follow-up visit (6 months after last study drug administration) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and Severity of Adverse Events |  | Up to 6 months | 
| Percentage of Participants With Suicidal Ideation or Behavior, as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score | The Columbia-Suicide Severity Rating Scale (C-SSRS) is a structured tool to assess suicidal ideation and behavior. Four constructs are measured: severity of ideation, intensity of ideation, behavior, and lethality of actual suicide attempts. Binary (yes/no) data are collected for 10 categories, and composite endpoints based on the categories are followed over time to monitor patient safety. | Screening, Day -1, Day 28, Day 71, Day 127, and follow-up visit (6 months after last study drug administration) | 
| Incidence of Anti-Drug Antibodies (ADAs) |  | Day 1, Day 28, and follow-up visit (6 months after last study drug administration) | 
| Titer and Antibody Subtype, determined if ADAs are Identified |  | Day 1, Day 28, and follow-up visit (6 months after last study drug administration) | 
| Concentrations of RO7234292 in Urine |  | Up to 72 hours |