Phase 3 Clinical Trial Primary Endpoints for Huntington's Disease Drugs

By Rhizome Team

Huntington's disease (HD) is a progressive neurodegenerative disorder that presents unique challenges in clinical trial design. Selecting appropriate primary endpoints is crucial for demonstrating therapeutic efficacy and obtaining regulatory approval for new treatments.

Phase 3 clinical trials for Huntington's disease drugs require endpoints that comprehensively capture the multidimensional nature of the disease, including motor dysfunction, cognitive decline, and functional impairments. Understanding which endpoints are most commonly used and accepted by regulatory agencies helps guide trial design and development strategy.

Here we examine the primary endpoints used in recent Huntington's disease clinical trials, including clinical rating scales, biomarkers, and imaging measures. This analysis provides practical guidance for sponsors planning late-stage trials for HD therapeutics.

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What are good stage 3 clinical trial primary endpoints for a drug indicated for Huntington’s disease?

Answer

Good primary endpoints for stage 3 clinical trials of drugs indicated for Huntington’s disease (HD) should comprehensively capture the multidimensional nature of the disease, including motor, cognitive, and functional impairments, as well as biomarkers and structural changes associated with disease progression. Based on current evidence and prior studies, the following endpoints are considered appropriate:

1. Unified Huntington’s Disease Rating Scale (UHDRS):

Composite Unified Huntington’s Disease Rating Scale (cUHDRS):
The cUHDRS combines assessments of motor function, cognitive performance, and functional capacity, providing a comprehensive measure of disease progression. It has been widely used in trials, such as those evaluating RO7234292 (RG6042), where changes from baseline in cUHDRS scores were primary endpoints ²¹²¹⁴²⁷.
Total Functional Capacity (TFC):
The TFC subscale of the UHDRS evaluates functional abilities in daily activities, such as work, finances, and independence. It is a critical measure of functional decline and has been used as a primary endpoint in multiple trials, including those targeting early-stage HD ²¹⁴¹⁸²⁷.
Total Motor Score (TMS):
The TMS component of the UHDRS assesses motor symptoms such as chorea, dystonia, and bradykinesia. It is a key endpoint in trials focusing on motor symptom improvement, such as the PRIDE-HD study of pridopidine ³¹⁰¹⁸²⁶.

2. Cognitive and Functional Assessments:

Symbol Digit Modalities Test (SDMT):
This test evaluates cognitive processing speed and has been used as a primary endpoint in trials to assess cognitive decline ¹¹¹⁴¹⁸.
Stroop Word Reading Test:
This test measures executive function and cognitive flexibility, which are often impaired in HD. Changes in scores can serve as endpoints to evaluate cognitive improvement ¹⁴¹⁸.
Modified Physical Performance Test (mPPT):
This test assesses physical function and has been used as an efficacy endpoint to evaluate improvements in physical capabilities ¹⁷.

3. Biomarkers of Neuronal Injury:

Mutant Huntingtin Protein (mHTT):
Measuring changes in mHTT levels in cerebrospinal fluid (CSF) is a pharmacodynamic endpoint for therapies targeting the underlying pathology of HD ¹²¹⁴¹⁶²¹.
Neurofilament Light Chain (NfL):
NfL levels in CSF or blood are emerging as biomarkers of neuronal injury and disease progression. Changes in NfL levels have been used as endpoints to assess the biological impact of treatments ⁶¹¹¹⁴¹⁸²¹.
Tau Protein:
Tau levels in CSF are another biomarker of neuronal injury that has been explored in HD trials ¹¹¹⁴¹⁸.

4. Imaging-Based Endpoints:

Brain Atrophy (MRI):
MRI-based measures of brain atrophy, such as whole brain volume decline and caudate volume decline, are used to assess structural changes associated with HD. These endpoints help evaluate the neuroprotective effects of a drug ⁶¹¹¹²¹⁴¹⁸²².
Resting-State Functional MRI (fMRI):
fMRI and voxel-based morphometric studies can assess neural correlates of cognitive decline and may serve as exploratory endpoints in trials ⁶.

5. Chorea Severity:

Maximal Chorea Score:
This score, derived from UHDRS items 12a-12g, evaluates chorea severity and has been used as a primary endpoint in trials for drugs targeting motor symptoms, such as tetrabenazine ⁷²⁰.

6. Composite and Proportional Endpoints:

Composite Endpoints:
Combining motor, cognitive, and functional measures into a single progressive factor has been suggested as a comprehensive endpoint for early HD trials ²³.
Proportion of Patients with Clinically Meaningful Declines:
Trials may also use endpoints based on the proportion of patients experiencing specific declines, such as a decrease of at least 1 point in TFC or 1.2 points in cUHDRS, over the study period ²⁷.

7. Safety and Tolerability:

Monitoring adverse events, dose-limiting toxicities (DLTs), and other safety parameters is essential to ensure the drug’s safety profile is acceptable for long-term use ¹²²⁴.

Summary:

The choice of primary endpoints in stage 3 Huntington’s disease trials depends on the drug’s mechanism of action and therapeutic goals. Commonly used endpoints include the cUHDRS, TFC, TMS, cognitive tests (e.g., SDMT, Stroop), biomarkers (e.g., mHTT, NfL), and imaging measures (e.g., brain atrophy). These endpoints are well-suited for capturing the clinical and biological aspects of HD progression and are widely accepted by regulatory agencies like the FDA ²⁶¹¹¹²¹⁴¹⁸²¹²⁷.