There are (at least) two camps for drug repurposing, which can be usefully divided into the on-target and the off-target categories. ‘Off-target’ repurposing may be compared to the multi-facted roles for a mobile phone, wherein the same object has the attributes of a camera and a telephonic device. ‘On-target’ repurposing is akin to the adoption a single attribute (e.g. its camera) for multiple purposes, like taking snaps while on holiday or scanning documents while out of the office.
In our world, off-target drug repurposing is the identification of a new biological activity for an existing drug. Take for instance doxycycline. Long thought of as an antibiotic, it was in 1990 that researchers from SUNY funded by Johnson and Johnson filed patents on the anti-collagen destructive capacity of sub-antibiotic doses of tetracyclines. JnJ were one of the original investors in Collagenex, who licensed these patents and went on to commercialise Periostat for the treatment of periodontitis, a gum disease (later, in 2008, Collagenex were acquired by Galderma). In the FDA approval process, the lack of antibiotic power of the product was a crucial element, since the development of bacterial resistance was a concern of the agency.
Off-target discoveries are rare, particularly so in more modern substrates for repurposing. As drug discovery has progressed, the reliance on in vitro assessments of candidate efficacy has brought ever greater refinement to the biological specificity of the drugs that are eventually commercialised. Compounds which have been designed to bind specifically to a certain receptor subtype at nanomolar efficacy are proportionately less likely to have comparable serendipitous activity at another receptor site.
In times past, in vivo methods of assessment were far more likely to deliver drugs with polypharmaceutical properties. One needs to look no further than the history of the discovery and development of chlorpromazine to see that. Unfortunately, the greater biological promiscuity often comes alongside a greater propensity for undesirable side effects.
On-target drug repurposing conversely associates the same biological activity of a particular drug with a different therapeutic indication. A good example of this is milnacipran, which was known for its activity as a noradrenaline and serotonin reuptake inhibitor before Cypress Biomedical Inc (NASDAQ:CYPB) licensed it for North American markets from the private French company Pierre Fabre in 2001. Indeed, milnacipran had been approved and sold in France for the treatment of depression since 1997.
What Cypress did was to leave milnacipran’s propensity to act as an antidepressant aside, and to develop the product for the treatment of fibromyalgia syndrome (FMS), an indication marked by achy pain and stiffness in the body’s soft tissues — such as the muscles, tendons and ligaments. At the time, few treatments for FMS existed, despite a substantial patient population of around six million people in the United States. In re-directing the development, Cypress was still relying on the original pharmacology of milnacipran, but changing the associated therapeutic indication from depression to FMS.
In 2004, three years after completing the in-license deal, Cypress announced it had entered into an out-licensing agreement for the development and marketing for milnacipran with Forest Laboratories Inc. (NYSE:FRX). Under the terms of that agreement, Forest pledged to fund future developmental activities, and prospectively pay to Cypress upfront and milestone payments of between $200 and $250 million, as well as royalties on sales of product. Although Cypress also had its own milestone obligations to Pierre Fabre, SEC paperwork shows that the sub-license fees only amounted to about 5% of the Forest receipts.
On-target drug repurposing may involve relatively less by the way of scientific innovation compared to marketing expediency, yet the Cypress example clearly demonstrates the commercial advantage from this type of indication switch. By the time the drug had been submitted to the FDA, Pfizer had already gained approval for Lyrica (pregabalin), its alpha-2 delta ligand for the treatment of FMS. Yet, milnacipran seemed to offer a better profile than Lyrica, bringing less fatigue, better memory and no weight gain. The competence of the Cypress clinical team in demonstrating this trio of advantages should not be underestimated.
The on- and off-target discussion clearly shows how drug repurposing lies at the interface of scientific and commercial drug development. The fascination lies in the complexity of the problem.
…And yet this is a simplistic analysis. As we have seen the combination of therapeutic switching with new presentations and low-risk variants of known active agents turns this one-dimensional picture into three dimensions. Rather like the electronic world, where the next generation of mobile phones is smarter still, sophisticated drug repurposing can be tailored to produce ever greater value at marginal added risk: let’s say the iSwitch era has arrived!
