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)

Clinical Trials.gov identifier: NCT017117664

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.

Labels: , , , , ,