Written by Susan Courtney and Tom Garry
Reviewed by Dr. Barry A. Hendin, MSAA Chief Medical Officer
Researchers Continue to Suspect Epstein-Barr Virus as a Possible Factor in Developing MS
In an article published in Science (Bjornevik K, et al. 13 Jan 2022. Vol 375, Issue 6578. pp. 296-301.), “Longitudinal analysis reveals high prevalence of Epstein-Barr virus (EBV) associated with multiple sclerosis,” researchers present the results of a study that looks at a possible connection between these two conditions. These researchers analyzed EBV antibodies in blood serum from 801 individuals who developed MS among a cohort of more than 10 million people active in the United States military during a 20-year period (1993–2013).
According to the article, infection with the Epstein-Barr virus (EBV) has long been postulated to trigger multiple sclerosis. Prior analyses demonstrated increased serum antibodies to EBV in approximately 99.5% of individuals with MS, versus approximately 94% of healthy individuals. In the current study, all but 35 of the 801 MS cases were EBV seropositive. Eventually 34 of the 35 became infected with EBV prior to the onset of their MS. Only one individual was EBV seronegative at the time of MS onset.
According to the study authors, these findings provide compelling data that implicate EBV as a trigger for the development of MS. While nearly everyone is infected with EBV, only a small fraction develops MS, so other factors such as genetic susceptibility appear to be involved in MS pathogenesis. Multiple studies have identified EBV-infected B cells in the brains of people with MS. Researchers now look to understand how infection of B cells with EBV initiates the pathology seen in MS.
New ACTH Gel Available for Acute Exacerbations
People with MS have a new option for treating acute exacerbations with an adrenocorticotropic hormone (ACTH) preparation. ANI Pharmaceuticals, Inc. announced in late January 2022 that its Purified Cortrophin™ Gel (Repository Corticotropin Injection USP) 80 U/mL is commercially available in the United States.
ACTH is a hormone that stimulates the adrenal gland to secrete cortisol, corticosterone, and aldosterone, which can help ease exacerbations. Cortrophin Gel also is approved by the FDA for several other autoimmune conditions, including exacerbations of rheumatoid arthritis and psoriatic arthritis.
Positive Study Findings with Several Experimental Disease-Modifying Therapies for MS
ANK-700: Anokion SA, a Swiss biotechnology company with United States’ offices in Cambridge, Massachusetts, announced this month that it has initiated patient enrollment in the multiple-ascending dose portion of its MoveS-it trial. Multiple-ascending dose trials have separate groups of participants taking different initial doses of a medication, then doses are increased to assess if and when people experience side effects or have difficulty tolerating the therapy.
The MoveS-it trial is a randomized, double-blind, placebo-controlled Phase I trial of ANK-700 for the treatment of relapsing-remitting MS. In a press release, the company explained that ANK-700 is designed to “re-educate the immune system by introducing antigen-specific tolerance to myelin-based autoantigens in order to reduce neuroinflammation in the brain and spinal cord.” Initial results from the trial are expected in the second half of 2022.
Masitinib: An article first published online February 21, 2022 in Neurology: Neuroimmunology & Neuroinflammation, “Efficacy and Safety of Masitinib in Progressive Forms of Multiple Sclerosis” (Vermersch P, et al.), provided the results of a randomized, double-blind trial assessing two dose levels of masitinib versus placebo. The trial had 611 individuals with either primary-progressive MS or nonactive secondary-progressive MS and was conducted at 116 hospital clinics and specialized MS centers in 20 countries.
The article explains that Masitinib is a selective tyrosine kinase inhibitor, targeting innate immune cells (mast cells and microglia) that are involved in the pathophysiology of progressive multiple sclerosis (MS). Study AB07002 assessed oral masitinib in people with progressive MS who were progressing but not clinically active.
The primary end point was overall Expanded Disability Status Scale (EDSS) change from baseline using repeated measures. Looking at the primary end point, Masitinib showed significant benefit over placebo, with no elevated risk of infection.
NVG-291: NervGen Pharma announced in late December 2021 that it had received ethics board approval to proceed with the multiple ascending dose portion of the Phase I trial of its investigational therapy NVG-291. NervGen describes NVG-291 as a therapeutic peptide that mimics the activity of a cell surface receptor involved in regulating central nervous system repair.
The company, which is based in Vancouver, British Columbia, said, “In preclinical studies, NVG-291 has been demonstrated to promote repair mechanisms in the nervous system, including axonal regeneration, remyelination, and enhanced plasticity.”
PIPE-307: In March 2022, Pipeline Therapeutics announced that the U.S. Food and Drug Administration (FDA) cleared the company to initiate its Phase Ib/IIa clinical trial of PIPE-307 in patients with relapsing-remitting multiple sclerosis (RRMS). PIPE-307 is the company’s lead program for myelin restoration. It is an oral, highly selective antagonist of the muscarinic M1 receptor that is being developed for the treatment of MS.
According to Pipeline Therapeutics, multiple Phase I studies of PIPE-307 were recently completed in healthy volunteers. Results from the study, which used positron emission tomography (PET), demonstrate that doses tested in the Phase I study achieve a level of uptake in the human brain that have been associated with remyelination observed in preclinical studies.
The Phase Ib/IIa clinical trial of PIPE-307 will be conducted at multiple sites across the United States. Participants will receive daily oral dosing for three months.
Tolebrutinib: Tolebrutinib is an investigational medication that inhibits an enzyme called Bruton’s tyrosine kinase, or BTK. The enzyme affects the B cells and microglial cells believed to play a role in the development of MS, and researchers hope to modulate the neuroinflammation of MS through inhibiting BTK and, thus, targeting those immune system cells.
After a 12-week Phase II study of tolebrutinib showed encouraging results, researchers extended the trial of this oral medication. Although different doses were used initially, all 122 participants received 60 mg per day in the latter part of the study, which is also the dose being studied in the ongoing Phase III GEMINI 1 and GEMINI 2 trials (expected to be completed in 2023).
At Week 48, the mean number of new gadolinium-enhancing lesions seen on magnetic resonance imaging (MRI) remained low in people who had been on 60 mg since the initial study, and those who had switched to the 60 mg dose had a reduction in the number of gadolinium-enhancing lesions. The annualized relapse rate in people receiving 60 mg of tolebrutinib was 0.17, with 89.5% of patients having no relapses during the study period. No new safety signals emerged during the 48-week study.
Ublituximab: Reduction in lesion volume and number were seen on MRI following treatment with ublituximab in the ULTIMATE I and ULTIMATE II studies. T1-hypointense lesions seen on magnetic resonance imaging (MRI) of the brain and spinal cord are indicative of white matter destruction and axonal loss in people with MS. Recently presented data from two Phase III studies of ublituximab found that the investigational agent reduced those lesions to a greater extent than did the FDA-approved disease-modifying therapy Aubagio® (teriflunomide).
As noted, the data are from the ULTIMATE I and ULTIMATE II studies, which involved almost 1,100 people with relapsing MS. Those studies evaluated outcomes with intravenous infusions of ublituximab, a monoclonal antibody, relative to daily use of Aubagio, an oral medication, over the course of 96 weeks. In December 2021, the FDA accepted an application to consider approving ublituximab for the treatment of relapsing MS.