In Methotrexate Forte, methotrexate is the active pharmaceutical ingredient (API).

Methotrexate is a small molecule that was first synthesized in 1948. In the 1990-ies it was discovered that methotrexate could be used to treat autoimmune diseases like rheumatoid arthritis. Since then, it has become the gold standard and first line drug to treat many immune-mediated inflammatory diseases. 

Although many patients are worried when they are first prescribed methotrexate, it is a very safe drug substance that is well-tolerated by the majority of the patients and can be taken chronically.

The draw-back with methotrexate is, that it works well for only a part of the patient population. In the majority of the patient population, other drug substance(s) must be added to the treatment before the disease goes into remission. These add-on treatments add costs, side-effects and time!

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For the longest time, researchers have tried to increase the therapeutic effect of methotrexate. Either by changing the molecular structure of methotrexate itself. Or be changing the formulation of methotrexate. Researchers tried to add linkers that would increase the uptake of methotrexate in the target cells. None of those approaches resulted in a significant improvement of the clinical efficacy of methotrexate.

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Until we at Amplio Pharma turned the question around: instead of trying to get more methotrexate in the body (higher doses, targeting linkers, local administration), why not slow methotrexate down from leaving the target cells and the circulation?

Research shows a better treatment effect in patients in whom one of the efflux proteins responsible for the elimination of methotrexate is defunct. Research also shows a clear correlation between intracellular retention and conversion of methotrexate into its polyglutamated form and efficacy of the treatment overall. In other words, the mode of action needed to get a more effective methotrexate is known. What has been lacking, is a safe candidate molecule to achieve this effect in patients. We have found that in novobiocin.

In Methotrexate Forte, novobiocin acts as the PK enhancer, with the function to boost the clinical effectiveness of the API methotrexate.

Novobiocin is a small molecule that was first discovered in 1955. It is a natural fermentation product of a bacterium that lives in the soil. In the late 1950-ies and 1960-ies it was used to treat bacterial infections that were resistant to penicillin. In the 1970-ies, better antibiotics were brought to the market and the pharmaceutical companies that had been producing novobiocin took the no longer used drug product from the market.

The ABCG2 efflux protein was first described in 1998. The discovery of this family of efflux proteins in the late 1990-ies was a breakthrough as it was discovered to be responsible for a large portion of the drug resistance that had been observed in chronic disease and cancer treatments. Indeed, many of today's drugs are substrates for these efflux proteins. Unfortunately, only few compounds are suitable to just inhibit the activities of ABC transporters. It was only by chance that we discovered that novobiocin could block the ABCG2 protein at a dose level far below the dose level needed for a clinical effect. The second bit of luck followed with the physical chemical properties of novobiocin: it is highly soluable in water making it suitable for subcutaneous administration together with Methotrexate. The third finding that boosted our development program is the availability of  human pharmacokinetic data of novobiocin after intramuscular or intravenous administration. Our final advantage: novobiocin is available as GMP material.

All in all, Amplio Pharma is in the ideal situation to develop Methotrexate Forte.