Biomarkers play an essential role in overcoming challenges in clinical trials in muscle disease serve as diagnostic tools, indicators of disease progression, and measures of therapeutic efficacy. Biomarkers can be divided into disease-unspecific, shared-pathway, and disease-specific biomarkers.
Biomarkers like creatine kinase (CK) and myoglobin reflect shared pathomechanisms, such as muscle damage from increased cell membrane permeability. However, CK levels can decrease due to muscle mass loss or reduced muscle injury as a result of treatment, making it an unreliable biomarker for treatment response. myomiRs, classified as a unspecific, correlate better with treatment response as more established biomarkers. Biomarkers of specific pathways, as cytokines, proteins or growth factors, are specific for a disease group sharing a common pathogenic pathway, such the acquired myopathies, centronuclear myopathies, or mitochondrial disorders. Disease-specific biomarkers directly relate to specific disease pathogenic mechanisms, as expression of dystrophin in Duchenne Muscular Dystrophy (DMD) or DUX4 in Facioscapulohumeral Muscular Dystrophy (FSHD). In pharmacological trials targeting dystrophin expression in DMD or DUX4 suppression in FSHD, direct measurement of these biomarkers is indeed used as relevant response markers.
Overall, there are many promising biomarkers for muscle diseases. However, the main issue is to clarify the correlation between levels of a biological biomarker and changes in the disease state, due to natural progression or after treatment. To improve clinical trial design, combining biomarkers with imaging and functional assessments could enhance precision and reliability.
Key Points:
- Biomarkers are classified into disease-unspecific, shared-pathway, and disease-specific categories.
- Currently biomarkers are rarely used as primary endpoint in clinical studies on muscle diseases, however as surrogate endpoints they could detect disease exacerbations early, substitute clinical observations, and provide precise quantitative estimates.
- Specific biomarkers should be used in the evaluation of targeted therapies; general biomarkers are better for evaluating broader muscle damage treatments.
References:
Stemmerik MG, Tasca G, Gilhus NE, Servais L, Vicino A, Maggi L, Sansone V, Vissing J. Biological biomarkers in muscle diseases relevant for follow-up and evaluation of treatment. Brain. 2024 Oct 14:awae323. doi: 10.1093/brain/awae323. Epub ahead of print. PMID: 39397743.
Co-author:
Lorenzo Maggi, Neuroimmunology and Neuromuscular Disorders Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan MI, Italy
Publish on behalf of the Scientific Panel on Muscle and NMJ disorders