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REPAIR-MS: 31P-MRS imaging to assess the effects of CNM-Au8 in MS

 

Recent advancements have seen a wide variety of efficacious disease-modifying therapies become available for the treatment of multiple sclerosis (MS). While these have been revolutionary in the prevention and management of relapses, particularly in younger patients, they have demonstrated limited benefits in patients with progressive MS. Therefore, successful neuroprotective and neuro-reparative treatments are needed.

Nanocatalysts are a novel drug class using nano-sized crystals of therapeutic metals that have the potential to meet this need.1 CNM-Au8 is the leading drug under investigation in this class; an aqueous suspension of clean surfaced pure gold nanocrystals, able to cross the blood-brain barrier and drive bioenergetic reactions in the central nervous system (CNS), fundamental to neuronal survival, repair, and function.

In patients with MS, bioenergetic failure in the CNS plays a significant role in disease pathogenesis. Preclinical findings in animal models have demonstrated the neuroprotective and remyelination capacity of CNM-Au8.2 Additionally, studies in neuronal cultures have demonstrated its ability to decrease reactive oxygen species levels, improve neuron survival and increase mitochondrial capacity in response to cellular stress.2

Robert Glanzman, MD, FAAN, Clene Nanomedicine Inc, Salt Lake City, UT, discusses the interim results from the ongoing Phase II REPAIR-MS trial (NCT03993171), investigating the metabolic effects of CNM-Au8 in patients with MS treated for a minimum of 12 weeks.2 Two dose levels of CNM-Au8 are under investigation, using high-resolution magnetic resonance spectroscopy (31P-MRS) to assess its target engagement. 2

 

Comparisons of bioenergetic metabolites at baseline, prior to and after CNM-Au8 treatment show bioenergetic improvements in total nicotinamide adenine dinucleotide (NAD) levels, NAD+/NADH ratio, and normalization of adenosine triphosphate (ATP) levels attributable to CNM-Au8. These results demonstrate the drug’s catalytic effects on key central nervous system metabolic markers, providing promising evidence that the drug enters the brain and has significant target engagement. Its homeostatic effects could reverse bioenergetic failure in MS, resulting in neuroprotective effects. Full analyses are expected later in 2021.

Serum neurofilament light chain levels as a biomarker in MS

 

Sensitive, quantitative biomarkers to predict disease course, monitor progression and guide treatment decisions are lacking in MS. Magnetic resonance imaging (MRI) is used to give an insight into a patient’s disease – but its inability to detect clinically silent disease and spinal cord lesions, inconvenience, and snapshot nature make it far from the optimal MS biomarker.3 MS is a heterogeneous and unpredictable disease, emphasizing the importance of developing a clinically applicable biomarker, without which identification of and response to disease activity is hindered.

 

Serum neurofilament light chain (sNfL) as a novel blood-based biomarker was highlighted as an emerging concept in MS at ACTRIMS 2021. Neurofilaments are neuronal-specific cytoskeletal proteins thought to have a critical role in axon growth and stability.4 They are found in the cerebrospinal fluid and serum following neuronal injury. Observations of increased sNfL have been reported in brain trauma cases and numerous neurodegenerative disorders, including MS. Previous studies have linked sNfL levels in MS to measures of disease activity, disability worsening, and brain atrophy.5

Elias Sotirchos, MD, Johns Hopkins University School of Medicine, Baltimore, MD, discusses a real-world, multicenter cohort study of almost 7000 patients and 201 healthy controls enrolled in the MS PATHS network, designed to assess the associations of sNfL with disease features in MS.5Assessments of serum samples found sNfL levels to be elevated in 17.2% of patients. Raised sNfL was associated with progressive MS (OR=1.63, 95% CI=1.38-1.92), as well as comorbidities such as diabetes (OR=1.89, 95% CI=1.42-2.49) and smoking status (current vs never smoker, OR=1.49, 95% CI=1.20-1.85). Additionally, patients with high sNfL MS showed significantly worse neurological function, lower brain parenchymal fraction, lower thalamic volume, and higher T2 lesion volume (p<0.001 for all).

This study demonstrates the utility of sNfL as a valuable biomarker that, with further validation, could be used in disease prognostication and monitoring of MS disease activity.

Leukocyte telomere length and disability in MS

 

Chronological age has long been recognized as an impactful factor in the disease course of multiple sclerosis (MS). Older age is associated with an increased rate of non-relapse-related disability accumulation, independent of disease duration.6 A clear connection with chronological age brings into question the extent to which biological aging plays a role in MS progression.

Present to defend chromosomal DNA against degradation, telomeres are nucleotide repeats located at the end of chromosomes. With each cell division, a small portion of telomeric DNA is routinely lost, making telomere shortening a reliable marker of cellular aging. Shorter telomere lengths are seen in several age-related and autoimmune diseases such as dementia, systemic lupus, and arthritis.6

The repercussions of biological age in MS have been highlighted as an important research question. As part of the ‘Spectrum of MS across the lifespan’ session at ACTRIMS 2021, Jennifer Graves, MD, PhD, MAS, University of California San Diego School of Medicine, San Diego, CA, discusses an investigation into the influence of leukocyte telomere length (LTL) in MS, recently published in Annals of Neurology.6 The study examined a large cohort of patients with MS with over 10 years of follow-up, to improve understanding of the relationship between cellular age and clinical disability in MS.6 LTL, a measure representative of system-wide telomere shortening, was measured from DNA samples of over 500 participants. Expanded Disability Status Scale (EDSS) evaluation and 3D T1-weighted brain magnetic resonance imaging were performed at baseline and follow-up.

 

Baseline analyses demonstrated that independent of age, reduced LTL was associated with higher EDSS scores (95% CI=0.13–0.42, p<0.001) and reduced brain volume (95% CI=0.10–14.7, p=0.047), differences that were maintained over the 10-year follow-up. In a subset of patients with LTL monitored over time, LTL decrease was associated with EDSS worsening (95% CI=0.08–0.61, p=0.012). Mediation analyses attributed 15% of the overall effect of chronological age on disability to telomere length.

Further investigation of cellular aging in MS progression is warranted. Variability in biological aging could explain some of the heterogeneity seen in MS disease course and therefore, targeting aging-related mechanisms may be of therapeutic importance in MS.

Novel B-cell targeting approaches in MS

 

Growing use of anti-CD20 therapies that selectively target B-cells in MS has shed light on the influence of B-cells in disease pathogenesis. While the role of CNS antibodies in MS activity has long been recognized, there is a growing understanding of the non-antibody dependent functions of B-cells in this context. B-cells appear to be a valuable target in MS as evidence suggests that abnormal pro-inflammatory B-cells can overstimulate peripheral immune cells, leading to relapse upon CNS infiltration, as well as contribute to non-relapsing progressive disease through CNS-compartmentalized inflammation when residing in the CNS.7

 

Anti-CD20 monoclonal antibodies such as ocrelizumab, ofatumumab, and rituximab effectively deplete peripheral inflammatory B-cells and CD20-expressing T-cells in MS. Therefore, approval of these agents has led to successful prevention of relapses from new local inflammatory lesion formation, but questions remain over whether CNS B-cells can be targeted.

There remains a notable unmet need for treatments targeting non-relapsing progressive MS. Amit Bar-Or, MD, FRCPC, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, discusses the current approaches under investigation that may extend the use of B-cell-targeted therapies. A new area of interest is Bruton’s tyrosine kinase (BTK) inhibitors. With BTK comprising an essential component of BCR- and FcRγ-associated receptor-signaling, these small molecules can target B-cells and myeloid cells, both identified as important drivers of MS development.8 BTK inhibitors could target progressive disease as well as relapses, as they can not only target infiltrating immune cells in the periphery but can also access the CNS to target resident B-cells and microglia.

Written by Juliet Lawrence

References

  1. Clene Nanomedicine Inc. Clene Nanomedicine Presents Updated Interim Data from Phase 2 Multiple Sclerosis Programs at ACTRIMS Forum 2021 [Press release]. Feb 2021.
  2. R Glanzman, J Rin, B Greenberg, et al. Effects of Nanocatalysis on CNS Bioenergetic Markers in Patients Treated with CNM-Au8: Interim Results from Two Phase 231Phosphorous Imaging Studies [Conference presentation abstract]. ACTRIMS Forum 2021, 25-27 Feb 2021. https://www.abstractsonline.com/pp8/#!/9245/presentation/266
  3. S Thebault, G Bose, R Booth, et al. Serum neurofilament light in MS: The first true blood-based biomarker? Mult Scler. Feb 2021.
  4. T Plavina, C M Singh, D Sangurdekar, et al. Association of Serum Neurofilament Light Levels With Long-term Brain Atrophy in Patients With a First Multiple Sclerosis Episode. JAMA Netw Open. Nov 2020; 3(11): e2016278.
  5. E Sotirchos, K Fitzgerald, M Smith, et al. Associations of Serum Neurofilament Light Chain with Clinical and Radiological Measures in a Large Real World MS Population [Conference presentation abstract]. ACTRIMS Forum 2021, 25-27 Feb 2021.
  6. K Krysko, R Henry, B Cree, et al. Telomere Length Is Associated with Disability Progression in Multiple Sclerosis. Ann Neurol. Nov 2019; 86(5): 671–682.
  7. R Li, K Patterson, A Bar-Or. Reassessing B cell contributions in multiple sclerosis. Nat Immunol. Jul 2018; 19(7):696-707.
  8. E Contentti, J Correale. Bruton’s tyrosine kinase inhibitors: a promising emerging treatment option for multiple sclerosis. Expert Opin Emerg Drugs. Sep 2020; 25(4): 377-381.
The content of VJNeurology is intended for healthcare professionals