First-Ever Consensus Framework Aims to Guide Charcot-Marie Tooth Clinical Trial Design

A coalition of Charcot-Marie-Tooth (CMT) disease organizations, clinicians, and pharmaceutical companies has published the first consensus clinical trial framework for CMT in the Journal of the Peripheral Nervous System. The framework, developed by a group called ToPIC: CMT (Together Patients, Industry and Clinicians), is intended to give drug developers a clearer, more consistent roadmap as they design trials and pursue FDA review for a disease that currently has no approved treatments.¹

CMT is genetically and clinically heterogeneous, with more than 100 identified causative genes and widely varying presentations even within the same subtype, factors that have historically complicated both trial design and natural history tracking. “Developing meaningful treatments for Charcot-Marie-Tooth disease requires collaboration across the entire research ecosystem,” Brian Lin, PhD, senior director of research at the Muscular Dystrophy Association (MDA), said in a statement.¹ “These recommendations provide greater clarity for sponsors developing therapies while keeping the needs and experiences of people living with CMT at the center of the process.”

Core recommendations

The framework's guidance spans 6 main areas:

• Flexible trial designs to limit placebo exposure. Because CMT is rare and progressive, the framework supports approaches such as single-participant designs and externally controlled trials, in which a treated cohort is compared against natural-history or historical-control data rather than a concurrent placebo arm. The goal is to reduce how many patients need to be exposed to placebo to generate persuasive evidence, a particular concern in a disease where symptom progression is often slow and enrollment pools are small.
• Enrollment by clinical phenotype rather than genetic subtype alone. Since many CMT subtypes share overlapping disease courses despite arising from different mutations, the framework recommends trial populations reflect shared clinical presentation when scientifically appropriate, rather than narrowly restricting enrollment by mutation. This is intended to speed enrollment in a field where some genetic subtypes may be limited to only a handful of known families, and to broaden the applicability of results once a mechanism is shown to act on a shared pathway rather than a single genetic cause.
• Disease-specific, function-based endpoints. The framework calls for endpoints capable of capturing meaningful change across a wide range of disease severity, from mildly to severely affected patients, rather than a single measure that may only be sensitive at one end of that spectrum. It highlights validated performance-based outcome assessments and patient-reported measures, including the CMT Health Index (CMT-HI), the CMT Functional Outcome Measure (CMT-FOM), and the CMT Neuropathy Score, as strong options that have already undergone prospective validation work.
• A defined role for biomarkers. Neurofilament light chain, PMP22 expression, and MRI-based muscle fat fraction are identified as tools that can support dose selection, prognosis, and, in some cases, serve as surrogate endpoints eligible for accelerated approval pathways. The framework frames this as particularly important for a disease that currently lacks a single validated, disease-defining biomarker, encouraging sponsors to incorporate multiple candidate measures rather than waiting for one gold standard to emerge.
• Support for early and lifelong treatment strategies. The framework encourages enrolling younger patients when scientifically and ethically justified, given that early intervention may preserve function before irreversible nerve damage occurs. At the same time, it emphasizes the need to study safety and efficacy across the full disease lifespan, recognizing that a therapy's risk-benefit profile may look different in a newly diagnosed child than in an adult who has lived with the disease for decades.
• Practical safety and labeling frameworks. This includes guidance on appropriately sized pediatric safety databases, considerations specific to gene therapy products, and a path for extrapolating benefit across CMT subtypes when scientifically justified, rather than requiring a separate, standalone trial for every genetic variant, an approach the framework's authors argue would be impractical given how many distinct CMT-causing genes have been identified.

Rationale behind the phenotype and pediatric guidance

The shift toward phenotype-based enrollment reflects mechanisms, like those targeting the neuromuscular junction, that may act on shared downstream symptom pathways rather than the specific gene causing a given CMT subtype. Susan Ruediger, co-founder and chief mission officer of the CMT Research Foundation (CMTRF) and a ToPIC: CMT steering committee member, pointed to an ongoing phase 2 program from NMD Pharma as an example: "If their physiology shows that it's a nerve problem and the nerve and the muscle isn't communicating, and this drug can come in and help that, does it matter what's causing that lack of communication?" she said. "Now that we're improving it, it could be relevant for all types."

The pediatric guidance was shaped in part by input from parents on the committee and a pediatrician with prior FDA review experience, reflecting a broader push toward earlier intervention. "If we can interfere or disrupt the progression of the disease earlier, people will have fewer or less symptoms or less impact from the symptoms," Ruediger said.

Disease and organizational background

CMTRF estimates roughly 3 million people worldwide are affected by CMT, a group of inherited peripheral neuropathies affecting motor and sensory nerve function; CMT1A, caused by a PMP22 gene duplication, accounts for roughly 60% of cases.^1,2 The framework was built in part on outcome measures validated through the Accelerate Clinical Trials in Charcot-Marie-Tooth Disease (ACT-CMT) study, an international, multicenter effort that examined the CMT-HI alongside other functional and biomarker measures in more than 200 adults with CMT1A.³

The publication reflects contributions from the CMT4B3 Research Foundation, Charcot-Marie-Tooth Association, CMTRF, Hereditary Neuropathy Foundation, and MDA, along with clinicians from institutions including the University of Illinois Chicago, University of Sydney, University of Colorado, University of Rochester, and University of Iowa, and pharmaceutical companies including Novartis, NMD Pharma, Armatus Bio, Applied Therapeutics, Thermo Fisher Scientific, Actio Biosciences, Alesta Therapeutics, and Elpida Therapeutics. To date, the MDA has invested more than $44 million in CMT research.¹

REFERENCES
1. Organizations Unite to Advance First-Ever Clinical Trial Framework for Charcot-Marie-Tooth Disease. News release. Muscular Dystrophy Association. August 5, 2026. Accessed August 19, 2026. https://www.mda.org/press-releases/organizations-unite-to-advance-first-ever-clinical-trial-framework-for-charcot-marie-tooth-disease
2. Abrams CK, Bruhn S, Burns J, et al. A unified clinical trial framework for Charcot-Marie-Tooth disease. J Peripher Nerv Syst. 2026;31(3):e70146. doi:10.1111/jns.70146
3. Rehbein N, et al. Patient-reported disease burden in the Accelerate Clinical Trials in Charcot-Marie-Tooth Disease Study. J Peripher Nerv Syst. 2024;29(4):487-493. doi:10.1111/jns.12662