Will “Reusable Drugs” Truly Be a Worthwhile Exercise?

Researchers at the Stanford University School of Medicine recently announced that they have developed a computer program designed to find new uses for already approved drugs.  As reported by Amy Dockser Marcus in The Wall Street Journal, researchers Atul Butte, Joel Dudley and Marina Sirota believe that their technology allows them to screen rapidly genomic databases in such a way that they can identify examples where a drug creates a change in gene activity opposite to the gene activity caused by a disease.  Such an observation allows researchers to identify uses for drugs that they were not initially designed for.
At the outset, let me say that I firmly support all efforts to find new uses for drugs.  And hopefully, this new approach will yield a breakthrough.  But I am not convinced that this will be a bountiful source of new products.

It is interesting that whenever researchers look to repurpose old drugs for new uses, they always use sildenafil (tradename, Viagra) as their poster child, as it was serendipitously discovered as an agent to treat erectile dysfunction (ED), even though that wasn’t the specific use it was designed for.  However, this discovery was not so accidental.  Sildenafil was designed as a potent inhibitor of an enzyme known as PDE-5.  The interest in PDE-5 inhibitors stemmed from the fact that inhibition of this enzyme should result in elevation of nitrous oxide (NO) in vascular tissue beds.  NO is well known to be a vasodilator.  Pfizer scientists hoped that by blocking PDE-5 in the heart vasculature, arteries would dilate and the result would be enhanced blood flow in patients with cardiac disease like congestive heart failure.

Sildenafil did, in fact, cause vasodilation.  However, this vasodilation was first observed in the penis and not the heart.  Instead of being a breakthough medication for heart disease, sildenafil became a major treatment for ED.  So, yes, this was a biological consequence that was not initially envisioned.  The key in all of this is that Pfizer scientists designed and synthesized a safe and effective PDE-5 inhibitor that could be tested in clinical trials to determine what the utility of such an agent would be.  Sildenafil was, in fact, designed as a vasodilator.  Its effects, however, were manifest in an organ other than the heart.

When a new mechanism is found to be effective in patients, scientists often explore where else such an agent may be of use.  Pfizer researchers were also interested in learning whether sildenafil would cause vasodilation in other parts of the body.  One theory was that the small arteries in the lung might also be sensitive to sildenafil’s effects.  Patients with primary pulmonary hypertension (PHT) suffer from arterial constriction which is extremely debilitating, and people with this disorder have trouble breathing.  Clinical trials showed that sildenafil was very effective in treating PHT, and it is marketed for this condition as Revatio.

Another example is Pfizer’s tofacitinib, an inhibitor of the enzyme JAK-3.  This orally effective drug was initially designed to be used as an agent to prevent organ transplant rejection.  However, when the impressive early clinical data first came in, researchers began to envision other uses for a drug that acted by this mechanism, including rheumatoid arthritis and psoriasis.  Tofacitinib is now in late stage clinical trials for these and other indications.

These two examples illustrate two important points.  The first is that, while serendipity is always appreciated in any research program, for any pharmaceutical research program to be successful, you need to have a safe compound which targets a specific biological process.  Once in the clinic, you may find that the mechanism for which the drug was originally designed does not prove to be the optimum use for the new drug (there is also a downside to this – sometimes the new mechanism may have a mechanistically related side-effect that turns out to kill the drug).  But you don’t go blindly into clinical trials with the hope that a PDE-5 inhibitor might do something beneficial in people.  Rather, you must connect the mechanism to a biological effect.

The second point is that when a mechanistically exciting drug shows beneficial effects in a disease, the news spreads rapidly throughout a research organization.  Scientists will share these results and then hypothesize where else such a compound may be effective.  This leads to many other experiments to explore the new exciting finding and potentially, new uses for this drug in medicine.

The Stanford scientists have raised a lot of hopes that their new approach will uncover new uses for existing medications.  Hopefully, they will have success. But casting a broad net with the hope of finding something new will be very challenging.  As the understanding of the causes of diseases grows, and should a compound that would be expected to interact in this specific pathway already exist, chances are that the company that developed the drug is already onto this new potential use.