Tuesday, 16 June 2015

RHB-104 in RRMS - the "chameleon circuit" of drug re-purposing in pharma research

Proof of Concept Study of RHB-104 as Add-on Therapy to Interferon Beta-1a in Relapsing Remitting Multiple Sclerosis (RRMS)(CEASE-MS)

The investigators hypothesize that Mycobacterium avium paratuberculosis positive Relapsing Remitting MS subjects will have a greater response to Interferon beta-1a therapy plus RHB-104 than from Interferon beta-1a alone.

Relapsing Remitting Multiple SclerosisDrug: RHB-104Phase 2

Study Type:Interventional
Study Design:Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title:A Phase IIa Proof of Concept Study to Assess the Efficacy and Safety of Fixed Dose Combination RHB-104 as Add-On Therapy to Interferon Beta-1a in Patients Treated for Relapsing Remitting Multiple Sclerosis
Drug re-purposing is the redirection of clinically advanced or marketed drugs into certain diseases from its initially intended indications. So RHB-104 (95mg clarithromycin, 45mg rifabutin, and 10mg clofazimine) was originally perused as treatment for Crohn's disease (currently in Phase III) based on a controversial link between Mycobacterium paratuberculosis (MAP, which normally affects cows) and Crohn's. 

The quote from the pharmaceutical director of clinical operations is as follows: "The CEASE-MS study was initiated following four successful pre-clinical studies and is based on the hypothesis that a bacterially induced dysregulated immune system plays a role in the pathogenesis of multiple sclerosis" - I obtained this quote from  multiplesclerosisnewstoday.com, as I was unable to find any reference to RHB-104 in the regular academic press sites.

An interesting hypothesis, but why MS, why not Parkinson's disease, or Alzheimer's disease? Surely, a certain percentage of the world's  population should test positive for MAP? To try to answer this question I looked back at the ingredients in the mix - 1) clarithromycin, has activity against rapidly growing mycobacteria but resistance is an issue; 2) rifabutin, we know from our tuberculosis patients has poor CNS penetrance (maximum concentrations around 30% of plasma); and 3) Clofazimine, originally used in the treatment of leprosy (Mycobacterium leprae), but also an effective immunosuppressant - aah the penny drops. 

Clofazimine can inhibit macrophages, neutrophil motility and lymphocyte transformation. It's a shame its currently discontinued and only available by obtaining an investigational new drug (IND) exemption.

And there you have it, the possible logic behind RHB-104 in RRMS. It is also why the trial is only 24 weeks duration (traditionally mycobactrium trials are 6 months - 1 year since mycobacteria are docile and divide slowly), and the outcome measures include active lesions, cytokine panel, T2 hyperintense lesions and T1 post-gadolinium lesions.


  1. So Neuro Doc Gnanapavan the effect of RHB 104 would be the immunosuppressive action of Clofazimine? Because I have read many publications regarding a possible interaction of gut microbiome with MS...

  2. Hi Cinara, the trial is too short to test this hypothesis. If there was an effect in the gut system the effects may not be apparent neurologically until at least 6 months (the lead time for treatment effect given at time 0 to have an effect through immunomodulation). I feel they should do a larger study of greater duration to look into this in greater detail.


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