In NovoBioJect, methotrexate (MTX) is the active pharmaceutical ingredient (API).

MTX is a small molecule that was first synthesized in 1948. In the 1980-ies Professors Joel Kremer and Michael Weinblatt demonstrated that MTX was an effective treatment of rheumatoid arthritis (RA).

Since then, MTX has become the gold standard treatment of RA and many other immune-mediated inflammatory diseases (IMIDs). 

Because of its original indication, many patients are worried when they are first prescribed MTX. However, in the dose range used to treat autoimmune diseases (5-30 mg per week) it is actually a very safe drug substance that is well-tolerated by the majority of the patients and can be taken chronically, by itself, or most often, in combination with other so-called Disease Modifying Anti-Rheumatic Drugs (DMARDs).

The major draw-back with MTX is that it only works well by itself in some patients. In most patients, however, other drug substance(s) must be added to the MTX treatment regime before the disease goes into remission - this is true for many of the DMARDs, including the biological ones.

Such add-on treatments add costs, side-effects and time needed to disease remission!

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For the longest time, researchers have tried to increase the therapeutic effect of MTX. Either by changing the molecular structure of MTX itself, or be changing the formulation of the MTX drug product (subcutaneous injections for example, instead of tablets). Researchers have also tried to add linkers to MTX so that more of the drug would enter the target cells. None of those approaches has led to a significant improvement of the clinical efficacy of MTX.

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Until we at Amplio Pharma turned the way to improve MTX up-side-down and around: instead of trying to get more MTX in the body and the cells (with higher doses, linkers, different formulations), why not slow down the elimination of MTX!?

Already 10 years ago, researchers found that MTX treatment effects were better in patients in whom one of the efflux proteins responsible for the elimination of methotrexate is defunct. It has also been known for many years that there is a clear correlation between intracellular retention and conversion of MTX into its active polyglutamated form and the efficacy of the treatment overall. In other words, the mode of action needed to get a more effective MTX is known. What has been lacking, is a safe way to achieve this with a so-called pharmacokinetic (PK) enhancer.

We have found the ideal PK enhancer for MTX: the natural compound Novobiocin.

In NovoBioJect, novobiocin (NOV) acts as the PK enhancer, with the function to boost the clinical effectiveness of the API methotrexate.

NOV is a natural small molecule that was first discovered in 1955. It is a fermentation product of a funges found in the soil. In the late 1950-ies and early 1960-ies it was used to treat S. aureus bacterial infections that were resistant to penicillin. By the early 1970-ies, better antibiotics had come to the market and the pharmaceutical companies that had been producing NOV took the no longer used drug products from the market.

The ABCG2 efflux protein was first described in 1998. The discovery of efflux proteins in the late 1990-ies was a scientific breakthrough - this was the mechanism behind the drug resistance that had often been encountered with cancer treatments. In fact, many drugs are substrates for efflux proteins. Unfortunately, only very few compounds are selective inhibitors of efflux proteins. It was only by chance that we discovered that NOV could block the ABCG2 protein at a concentration well below the dose levels needed for any clinical (side) effects. The second bit of luck came with the physical chemical properties of NOV: it is highly soluable in water making it suitable for subcutaneous administration together with MTX. The third bit that boosted our NovoBioJect development program is the availability of historical human data of NOV. This means that we can apply an abbreviated development program at a far lower risk. Our final advantage: NOV is available as GMP material.

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