Drug Discovery is expensive and many pharmaceutical companies make sure that the process is followed through all the steps including the ability to get their investment back from drug discovery. Janssen just got the FDA approval for tuberculosis. However, their motive was very different. There are only few hundred patients with drug resistant TB (tuberculosis) in the US, so that is not the main motive for them – they are going in the wrong direction for making money. World-wide they probably expect to make only a few $100M. They have given away the rights to the drug to TB alliance for distribution to the rest of the world and obviously will not make any money to recover any of their costs. So why did they do it?
Why?: It turns out the development of treatment was the interest of the founder of Janssen, Paul Janssen and his motivation came from sister who died of this disease. This lead to the development of Bedaquiline: tradename – Sirturo. Based on the profile of the drug and the need in the world, this was approved by FDA in record time of 6 months. This potentially makes a great drug since it works against drug-resistant-tuberculosis bacteria too. However there are a few worrying things:
Worrying: The drug caused the death of higher number of patients than the control group (11.4% compared to 2.5%) and caused QT prolongation of the heart. The report is available here:
Phenotypic discovery: Sirturo is an inhibitor ATP Synthase. Typically, ATP Synthase inhibitors are not good targets since ATP Synthase in mitochondria may be cross reactive and will be responsible for unbelievably bad toxicity since that enzyme is responsible for generation of energy. This compound was discovered by phenotypic screening rather than search for a specific target and then discover the molecule that binds it. In this case, the compound was discovered first and the mechanism of action was discovered much later. Fortunately, it turned out that the compound was very specific to the TB ATP synthase rather than the human form of the enzyme.
Model for others?: This serves as a good model for future drug discovery since if all you are looking for a specific effect on bacteria then that is what you screen for – this has been the typically way of drug discovery for most antimicrobials. The reason that works well is that with anti-microbials it is possible to get great model systems but with other disorders that are more eukaryotic based, it may be difficult to have a good model system even if you did want to set up a phenotypic drug discovery assay.
However, since we do not understand all the pathways it does make one question the process in almost all pharmaceutical companies that use high throughput assays to screen for inhibitors in isolated biochemical systems. These systems are typically separated from cells and even if you do find an inhibitor, it may not quite work as you imagined as a drug… as the recent phase III drug failures have shown. Cell based phenotypic drug discovery may be the route that we want to develop that is a good compromise with complex systems and high throughput screening.