Famciclovir Demonstrates Minimal Effect on EBV Activity, EBV Shedding in Multiple Sclerosis Pilot Study

Ruth Dobson, PhD

In a small phase 2a pilot study (NCT05283551) of patients with multiple sclerosis (MS) currently on natalizumab (Tysabri; Biogen), findings showed that treatment with famciclovir, an antiviral drug, did not impact salivary Epstein-Barr virus (EBV) shedding. The study, which had several noted limitations, provided an important proof-of-principle that examining for EBV shedding in saliva is feasible in the context of a clinical trial, with results to inform future designs of anti-EBV agents in MS.

Published in Multiple Sclerosis Journal, the proof-of-concept study included patients with MS (n = 30) who gave weekly saliva samples for 12 weeks before starting famciclovir 500 mg twice daily for 12 weeks. At the conclusion of the study, famciclovir failed to meet its primary end point of reducing the frequency of viral shedding, nor did it have a significant impact on either detectable viral DNA and overall copy number of EBV DNA detectable in saliva.

Led by Ruth Dobson, PhD, a consultant neurologist at Queen Mary University London, 29 patients received famciclovir and 24 completed the 12-week course. Coming into the study, the cohort’s median Expanded Disability Status Scale (EDSS) score was 3.5. Among the 5 participants who withdrew before completing the study, 2 were because of adverse events (AEs). No serious AEs were related to the study drug were reported.

Viral shedding was defined as a salivary EBV concentration greater than 5.8 copies/ul, with viral presence defined as any detectable EBV DNA in saliva. Among those with at least 1 usable saliva sample (n = 21), 10 (48%) participants had evidence of EBV shedding on at least 1 occation pre-drug, 7 (33.3%) during, and 5 (23.8%) post-drug (not significant; NS). When observing only those with evidence of viral shedding in at least 1 sample, a median of 1 of 12 samples pre-treatment, 2 of 12 samples on treatment, and 2.5 of 12 samples post-treatment showed evidence of viral shedding.

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"Without the development and testing of potentially effective anti-EBV interventions, understanding the role that EBV plays in MS remains challenging to study," Dobson et al wrote. "It remains a possibility that the dose used, 500 mg twice daily, was insufficient to inhibit EBV turnover. This dose was selected as it is the licensed prophylactic dose to prevent viral replication in people with herpes simplex; however, 500 mg four times daily is used for the treatment of active disease."

In terms of serological response, no significant differences were seen between pre- and post-treatment immunoglobulin titers against either EBNA-1 or VCA in serum. EBV DNA, detected in 86 of 181 samples prior to treatment, 74 of 183 samples taken during famciclovir, and 100 of 184 samples after treatment, did not significantly differ based on stages. Notably, a GLMM showed no change in EBV DNA copy number/ul through the study.

"It is also important to note that this was a small, pilot study, aimed to demonstrate proof of concept. Given the lower-than-expected rate of shedding in people on natalizumab, a small effect of famciclovir on EBV shedding cannot be excluded," the study authors wrote.

REFERENCE
1. Dobson R, Holden D, Giovannoni G, et al. A phase 2a open-label clinical trial to determine the effect of famciclovir on EBV activity as measured by EBV shedding in the saliva of patients with multiple sclerosis. Mult Scler J. Published online December 22, 2023. doi:10.1177/13524585231215268