#ThinkSpeak & #CharcotProject: what I love about science is that you are always learning

Teriflunomide the dark horse of MS is getting more attention. #ThinkSpeak #CharcotProject #MSBlog

I am always learning. Two things happened to me last year that have me take two steps back and say: 'Wow, I didn't know that, how interesting, could it explain these observations, could the drug be working this way or that way, can we test this and that hypothesis, how soon can we start, ....'

At ECTRIMS I met a very bright group of basic scientists from Sanofi-Genzyme who simply made me aware of the published data on the anti-viral effects of teriflunomide. In parallel, the charming and very collaborative neurologist Dr Keith Edwards, from Albany New York, came to visit our centre. During his stay he explained to me that the reason why he was doing the natalizumab to teriflunomide switch study was because of teriflunomide's anti-viral activity against BK virus. BK virus is the sister virus to the JC virus and if teriflunomide was effective against BK virus it should also be effective against JCV. The hypothesis is that teriflunomide may work against JCV and hence be able to prevent, and possibly treat, PML. Independently, of the Sanofi-Genzyme scientists, Dr Edwards had discovered this whole parallel universe of data on the anti-viral properties of leflunomide (teriflunomide's pro-drug) and teriflunomide. 

Dr Keith Edwards
Multiple Sclerosis Center Of Northeastern New York

Independent of these events I have been receiving anecdotal reports from my colleagues in North America, both the USA and Canada, of how well their patients are doing on teriflunomide long-term. They are all saying that in real-life teriflunomide is performing much better than what you would expect from the pivotal trials. Why? In addition to this, teriflunomide is the only DMT that works significantly better second, or third, line than it does first-line (see figure below). Why is teriflunomide the outlier amongst the DMTs? Could all these observations be linked to teriflunomide's mode of action as an anti-viral agent? This is a possibility and needs to be explored. Therefore Professor Julian Gold and I are putting together a proposal under the Charcot Project banner to explore the anti-viral, in this case anti-EBV, effects of teriflunomide. In parallel we propose looking at its impact of teriflunomide on JCV in pwMS. I sincerely hope you the MS community will be as supportive of this project as you have been about our other viral hypotheses. The difference with teriflunomide, compared to other anti-viral drugs, is that we don't have to assess whether or not it is effective as a DMT in MS as it is already a licensed drug. All we have to do is demonstrate its anti-viral effect and then try and correlate this with its efficacy. I hope you are as excited about these events as we are. 

Josephson et al. Treatment of renal allograft polyoma BK virus infection with leflunomide. Transplantation. 2006 Mar 15;81(5):704-10.

BACKGROUND: Polyoma BK virus produces an aggressively destructive nephropathy in approximately 3% to 8% of renal allografts, is associated with graft loss within one year in 35% to 67% of those infected and there is no therapy of proven efficacy. Leflunomide is an immune suppressive drug with anti viral activity in vitro and in animals.

METHODS: We treated twenty-six patients with biopsy proven NK virus nephropathy (BKN) with either leflunomide alone (n=17) or leflunomide plus a course of cidofovir (n=9) and followed them for six to forty months. Leflunomide was dosed to a targeted blood level of active metabolite, A77 1726, of 50 microg/ml to 100 microg/ml (150 microM to 300 microM). Response to treatment was gauged by serial determinations of viral load in blood and urine (PCR), serum creatinine, and repeat allograft biopsy.

RESULTS: In the 22 patients consistently sustaining the targeted blood levels of active drug, blood and urine viral load levels uniformly decreased over time (P<.001). Mean serum creatinine levels stabilized over the first six months of treatment, and with 12 months or more of follow-up in 16 patients the mean serum creatinine has not changed significantly from base line. Four patients who did not consistently have blood levels of active drug (A77 1726) above 40 microg/ml did not clear the virus until these levels were attained or cidofovir was added.

CONCLUSIONS: Leflunomide inhibits Polyoma virus replication in vitro and closely monitored leflunomide therapy with specifically targeted blood levels appears to be a safe and effective treatment for Polyoma BK nephropathy.

Morita et al. Successful low-dose leflunomide treatment for ganciclovir-resistant cytomegalovirus infection with high-level antigenemia in a kidney transplant: A case report and literature review. J Clin Virol. 2016 Sep;82:133-8. doi: 10.1016/j.jcv.2016.07.015.

Ganciclovir-resistant cytomegalovirus infection is sometimes life-threatening for organ transplant recipients. Foscarnet is an alternative, although it may potentially worsen the preexistent impaired renal function. Here we report the case of a successful low-dose leflunomidetreatment in a kidney transplant recipient with very high viral replication, who underwent kidney transplantation 10 years before. Administering 10mg leflunomide daily for 5 months without a loading dose completely cleared the ganciclovir-resistant cytomegalovirus strains.

CoI: multiple

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