Capturing the Elusive: Why Multi-Protein Biomarkers Tests Are the Future of Measuring MS Progression

While disease activity in multiple sclerosis (MS) can be measured using imaging, clinical symptoms, and more recently, objective fluid biomarker tests, measuring disease progression—the driver of long-term disability—has remained elusive. The goal is to develop a multi-marker test for progression that will help clinicians better manage their patients. 

Here, I discuss how proteomics and precision biomarkers could capture the elusive by quantifying the biology of progression so we can meet our goal and continue to reshape the standard of MS care.

Current challenges in measuring disease progression

Compared with MS disease activity, disease progression is more insidious and more challenging to assess. Progression is defined by the accrual of disability over time and evaluated on the Expanded Disability Status Scale (EDSS), a crude and subjective measure based largely on the patient’s ambulatory status. Issues with cognition, fatigue, bladder/bowel, and dexterity can also help assess progression, but these are largely subjective measures as well.

An added complexity is that there are two mechanisms of progression. Relapse-associated worsening (RAW) involves the accumulation of damage from relapses, eventually leading to disability. Progression independent of relapse activity (PIRA) occurs in the absence of relapses. It represents the neurodegenerative component of MS, the silent accumulation of disability driven by underlying chronic inflammation, axonal loss, and neurodegeneration rather than acute demyelinating attacks. PIRA demonstrates there are biological processes underlying progression that are distinct from RAW.

Addressing the complex biology of progression is a major challenge in managing patients. It is also the next frontier for therapeutic advancement in MS, and I am excited by the promise of blood-based biomarker tests to advance the space.

Quantitating MS biology with protein biomarkers

The future of progression management lies in multi-protein biomarker tests, because biological signals are closest to the underlying “truth.” It can provide quantitative, objective insights into the biology of the disease that routine imaging and symptoms cannot.

Multi-protein biomarker tests are ideal for measuring progression for three reasons. First, they can capture the breadth of disease heterogeneity across patient populations by providing an objective biological window into different types of damage happening at once. Second, they can capture the disease heterogeneity within an individual patient, as their biology changes in response to manifestations of the disease, natural processes such as aging and disease-modifying therapies. Third, they can offer prognostic power that enables a personalized medicine approach.

These tests are now an achievable reality, thanks to major advances in proteomics technology in terms of the number of proteins that can be measured simultaneously and the sensitivity of these measurements. The latter is particularly important for detecting protein biomarkers in the periphery (e.g., blood) for a disease affecting the central nervous system (CNS). 

From research to multi-marker assay

Octave Bioscience already offers a clinically validated multi-protein biomarker test to measure disease activity in MS, and we’re developing a complementary multi-marker test for disease progression. 

To do this, we leverage our partnerships with academic centers that have run natural history studies of MS. These centers have patient blood samples on which we run proteomics assays, as well as annotated clinical and radiological data that allow us to correlate proteomics data with disease state. 

We start by casting a wide net, evaluating over 5,000 proteins as potential biomarkers of progression. We evaluate each potential biomarker in two ways: First, we look for statistical associations between a single protein—or a set of several proteins—with endpoints of progression, such as the EDSS or brain atrophy. Next, we examine the biological relevance of the protein to MS in terms of the disease pathways, mechanisms, and cell types where that protein operates. By bringing together correlation and probable causation, we can select a panel of proteins that represent the complexity and heterogeneity of progression and will be generalizable to the MS population.

Validation and utility

From here, we rigorously validate the multi-protein assay in samples from numerous patient cohorts across disparate patient populations, focusing on reproducibility to ensure the test will be generalizable, precise, and reliable every time it’s used. 

Utility is also critical. For clinicians, the test results must translate to improved patient management and outcomes. For pharma, the test output must be associated with a measure of drug efficacy or a surrogate marker of response in a clinical trial. For both groups, ideally, the test should be agnostic to the various therapies patients may receive.

MS progression must be addressed if patients are to have better outcomes. The development of therapies for progression and biomarker-based tests that objectively measure it, go hand-in-hand toward those better outcomes. Clinical laboratories will play a central role in translating this science into practice. As multi-protein tests for MS progression mature, lab professionals will be instrumental in ensuring data quality, analytical consistency, and integration into clinical workflows. Together, we can transform how neurologists and patients understand progression—turning what was once invisible into measurable, actionable insight. Octave is grateful for the generous grant from the Valhalla Foundation that will help us move the needle in that direction for physicians and patients.