Speech for the inauguration of the Morningside Center for Innovative and Affordable Medicine, Emory University, Atlanta, November 14 2019

The Purpose and Repurposing of Drugs

By Gerald Chan

It gives me great pleasure to represent the Morningside Foundation to mark the establishment of the Morningside Center for Innovative and Affordable Medicine. The name of the Center was designed to draw attention to the world’s need for medicines that are at the same time innovative and affordable. It is a statement that innovation and affordability in medicine need not be mutually exclusive, but to prove this presumed exclusivity false, the pursuit of innovation must set out with the a priori constraint of affordability.

Even though the prophets of Silicon Valley are the most conspicuous peddlers of a techno-Utopian dream, nowhere is techno-Utopianism more indulged in America than in healthcare. Cost-agnostic innovations dangle the prospect of indefinite extension of life in the face of any sickness. In reality, the American people receive a poor scorecard for their health status and life expectancy even as their children’s future is mortgaged to pay for these poor outcomes. Technological feat alone can no longer merit the laurels for innovations in medicine if cost is prohibitive for their benefits to be broadly distributed to the populace.

The major approach to affordable innovation that the Morningside Center will advocate is drug repurposing. For those who are not familiar with drug development, I should first say a few words about what is drug repurposing. It is the exercise of demonstrating the efficacy of a drug in an indication other than the indication for which the drug was originally approved by the regulatory agency. In common usage, the term “repurposing” refers particularly to using the same drug for two indications which seem to share no obvious mechanistic commonality. Hence, it is different from the situation of Bevacizumab being used in oncology as Avastin and in ophthalmology as Lucentis because in both cases, the drug works by the common mechanism of stopping neo-vascularization by inhibiting vascular endothelial growth factor. A classic example of drug repurposing would be the drug thalidomide. The drug was first approved in Germany as a sedative and antiemetic for morning sickness in 1957. Four years later, thalidomide was withdrawn from the market due to its teratogenic effect. In 1998, thalidomide was approved by the FDA for treatment of erythema nodosom, a complication of leprosy. In 2006, the drug was repurposed and approved by the FDA for treating multiple myeloma. More recently, work done at Johns Hopkins University has shown thalidomide to be effective in treating intractable cough in patients with idiopathic pulmonary fibrosis.

I want to emphasize that successful cases of drug repurposing are not just flukes. If we should find it surprising that drugs can be repurposed, it is perhaps because our worldview of biology is too rigid compared to how nature operates. A common view in biology is that life functions by a series of chemical reactions each of which has exquisite lock-and-key specificity. These reactions are then organized into linear pathways each step of which has unique antecedents, unique effectors and unique outcomes. Specificity and uniqueness are seen as the cardinal principle governing how life functions.

While this is mostly true, there are nevertheless conspicuous clues in biology that nature is more cunning, more nuanced. A powerful example of non-uniqueness in nature is the codon degeneracy of tRNA. Rather than simply invoking a mathematical necessity to construct a formal explanation, there are now suggestions that codon degeneracy may in fact be used in directing protein folding. Nature never ceases to serve up inconvenient observations that challenge our neatly constructed models.

If we consider drug repurposing not as a utilitarian quest for therapeutics, but as an exercise in chemical biology, ie, the use of chemicals to introduce perturbations into living systems in order to elucidate biology, the picture that emerges is one of biological macromolecules having many shared features. Both uniqueness and shared features are part and parcel to life’s structure and function.

A most obvious manifestation of such shared features is that drugs have side effects. If nature operates strictly by uniqueness and specificity, no drugs would have any side effects. Such exactitude would also mean that we would have been successful in making very few drugs. The fact that hardly any drugs have no detectable side effects suggests that sharing of features among biologically relevant molecules is more of a rule than an exception. Chemical drugs tend to have side effects because of shared features at the molecular level. We call it off-target binding. Biologics such as antibodies, whilst having exquisite specificity in binding to their targets, still have side effects due to shared effectors among different molecular signaling pathways. One should hasten to note that not all side effects are deleterious. Drugs with good side effects are celebrated as wonder drugs that can confer multiple health benefits. Hardly a year goes by without some new study showing additional benefits for aspirin and the statins. In this light, drug repurposing is really an exercise in discovering beneficial side effects that are of sufficient potency to be clinically relevant as a therapeutic.

As of now, there are more than 2500 small molecule drugs that have been approved by the FDA. It is encouraging to see that this chemical library is now widely available and increasingly adopted by laboratory scientists who are making novel discoveries in biology. Many such discoveries are now published with hits from this collection of approved drugs. In many instances, the old drug was found to be effective for a new target at a concentration lower than what the drug was originally approved for. Safety is therefore even less of an issue. Such drugs can be brought directly into a Phase 2 clinical trial for the new indication. Even if a drug does not have adequate potency for the new activity in question, it is a promising starting point for molecular optimization. This affords savings in both time and cost.

We don’t know to what extent does this collection of FDA-approved drugs cover the entire space of chemical diversity that is of biological significance as there are still known biological targets that are thought to be undruggable. The Gates Foundation has supported the creation of a library of all molecules that have passed through Phase 1 clinical trial even if they subsequently failed to progress towards approval. In other words, their safety profiles have been established. This library will expand by four fold the space of chemical diversity that is available for drug repurposing endeavors.

Other than offering drugs with known safety profiles, drug repurposing also offers a methodological diversification to drug development. It is taken for granted now that the starting point of modern drug development is a novel laboratory finding in biology. Chemistry is then brought in followed by pre-clinical and then clinical development. The starting point of this exercise is reductionist molecular biology. In contrast, drug repurposing often began with astute clinical observations. For example, patients being treated with a drug for one condition experienced improvement in another unrelated morbidity. Since the drug is FDA approved and physicians have the latitude for off-label use after proper ethical review, the physician can conduct a clinical study to validate the second efficacy. This journey is therefore one that originates from the clinic rather than the laboratory and goes back into the clinic, either directly or via the laboratory for mechanistic elucidation. Dr. Sukhatme’s work with ketorolac and cancer recurrence is a beautiful example of such a journey.

We would do well to remember that some of the most widely used drugs today were developed before molecular biology came of age. James Black who received the Nobel Prize for discovering beta blockers for treating cardiovascular diseases and histamine H2 receptor antagonists for treating stomach ulcer was emphatic in using only physiological functional assays. The same can be said for David Jack who developed the asthma drug albuterol, the topical corticosteroids beclomethasone and fluticasone, and the migraine drug sumatriptan. Philosophically, drug repurposing is kindred to this tradition. At times, the complexity of life does elude reductionism but is nevertheless still susceptible to pharmacologic intervention.

Two bottlenecks remain in the practice of drug repurposing. One has to do with discovering the unanticipated co-efficacies of a drug for multiple indications. Recognizing the role of serendipity in such cases, astute clinical observations are needed which should all the more be encouraged now against the pressure towards a practice of medicine that is increasingly protocol and reimbursement driven. Another solution is data mining; this presupposes that the data sets are large and complete enough to reveal statistically significant associations.

Then there is the perennial question of funding. The biggest impediment to wider adoption of drug repurposing remains a financial one. Drug developers seek novelty not only as a badge of honor, but also for the financial reward which in turn relies on patent protection against knockoffs. By definition, a repurposed drug cannot have composition-of-matter patent protection; only weaker patent protection such as a use patent or a formulation patent is possible. Coupled with the fact that for a repurposed drug to gain regulatory approval for a new indication, full-fledged Phase 2 and Phase 3 clinical trials are still required, the most expensive parts of the drug development process, it is not surprising that there is little interest among the pharmaceutical companies to support drug repurposing.

I have seen a number of cases of a scientist having discovered a new activity for an old drug. Unable to raise funding to go through clinical trial, he then tweaks the drug molecule to make it a patentable new chemical entity. Such exercises are driven not by pharmacologic consideration but purely by financial ones. The result is additional cost and time delay due to the new chemical entity needing clearance through preclinical development and Phase 1 clinical trial for human safety.

This dilemma brings us back to asking the question of what is the purpose of developing drugs in the first place. A more penetrating question we must ask is what is the purpose of the financial capital that supports drug development. As long as this capital has financial return as its sole purpose, the behavior of the sector will be to only develop expensive drugs, or to price drugs as expensively as the market can bear. The continuing price increase of the biologic drugs and certain vaccines long after expiration of patent protection points to a market failure. The pricing practices of pharmaceutical companies make mockery of their own marketing material that purports the welfare of patients as preeminent in their mission. It is no wonder that in a Gallup poll published two months ago of the American people’s favorableness towards 25 different industries, the pharmaceutical industry came in dead last, lower than the federal government which ranked number 24 and the healthcare industry which ranked number 23, and much lower than the big tech companies of Silicon Valley with all their depravities.

An article that appeared in the Financial Times a few weeks ago has this poignant title – Novo Nordisk Walks Ethical Tightrope As Critics Blast Sector Over Drug Cost. This ethical tightrope has always been part and parcel to a capitalistic economic system; finding a sustainable balance on this tightrope is the crisis of capitalism in the twenty-first century. It is no longer possible for big corporations to hide behind the dictum of Milton Friedman and ignore the cost to society of a single-minded pursuit of profits for shareholders. A new balance must be struck between what is good for shareholders and what is good for society. Either pharmaceutical companies become more self-aware or there will be political backlash as is already evident in the run up to the next presidential election in this country. In the UK, the specter of patent revocation for very expensive drugs has already appeared.

As one who works in science, albeit not in an academic setting, I am an advocate for the potential of science to bridge the divergent interests of patients and shareholders provided that our conduct of science, and our funding of science in drug development have in view both the objectives of innovation and affordability. To this end is the Morningside Center dedicated.

As a conclusion to my comments, I was hoping that two of my younger colleagues can come and tell their story. Regrettably, or happily, they are unable to come today because of clinical trial data readout. As undergraduates at Brown University, these two young men met in a pharmacology course. Their brainstorming led them to hypothesize that two old drugs can be disease-modifying for patients with ALS, or Lou Gehrig’s disease. From their dorm rooms, they bootstrapped their way into a Phase 2 clinical trial led by the Massachusetts General Hospital. A few people helped along the way, such as the late Henry Termeer, the founder of Genzyme, and the Nobel laureate Wally Gilbert who is by pedigree my scientific grandfather as I trained under his former student. When the annals of business history is written, this drug repurposing endeavor should occupy a nobler position than the other business started from a dorm room in Harvard the name of which is a F word.

It is not for me to talk about the data of this trial now, suffice it to say that I am confident their two repurposed drugs will make a significant difference in the course of disease progression in ALS patients. In preparation for my talk this evening, I called to remembrance a book I had not touched for almost two decades. It is the book Tuesdays with Morrie, sub-titled An Old Man, A Young Man and Life’s Greatest Lesson. Some twenty years ago, that book put ALS on the map in the public’s awareness. Today, we still know precious little about the disease and can do little for ALS patients. I have witnessed two young men repurposing two old drugs and having a shot at radically altering the course of this disease for patients. Their work is an affirmation that properly directed, science can still offer hope for innovative and affordable medicines.

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