Small molecules need love too

There are plenty of new areas to explore in therapeutic options for all diseases and conditions that vex us, but are we straying too far from reliable ground and ignoring good options in the process?

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Science follows fashion. Life-sciences research trends in recent decades have sharply moved toward biological solutions to biological problems. Cells and proteins as therapeutic approaches are in ascendancy. Augmentation via genetic editing is at the tip of the spear.
Innovation deserves the excitement. After all, these approaches show potential for cures, well beyond reducing disease progression or only treating symptoms. At my age, regenerative medicine appeals. The promise of finally addressing many unmet, or poorly met, needs in human disease is driving the cash as well as the buzz. We have many new tools to drill deeper into the cell. Their cost and performance go up. The excitement for future results drives out some less cutting-edge science that is known to work.
Our patent system modulates the science and the cash. We share ideas with others in trade for a period of exclusivity. That’s fair and it works, although we argue and scheme to extend exclusivity. A second bargain involves grandfathering drug approval regulations—not holding older therapies to the new standards of both safety and efficacy. Being exempt from new drug development standards has the fairness advantage of not requiring, or even encouraging, more work after new tools allow for greater insights. Otherwise, drug approval would become hopelessly chaotic and we would never safely know when our IND-enabling studies were done or our NDA/BLA filings would be complete.
We can argue about process improvements occurring concurrently with development projects, but we are not going back. Relooking at what could now be done with a drug approved three decades back is not economically feasible. Why not?
We devote little capital when the promise of a return is miniscule vs. alternative uses. Once exclusivity is lost, pricing power has often eroded 90 percent. Oncology, for example, has driven resources away from antibiotics, depression and hypertension. What’s wrong with that? I say quite a lot. Older drugs often disappoint in both efficacy and safety. The unknown unknowns in the past have become known unknowns today. Many drugs are ineffective in a high percentage of people for whom they are prescribed at the dose recommended. Let me arbitrarily define high as 20 percent. For some antidepressants it is closer to 70 percent. These patients and their insurance companies do not get their money back. Older drugs interact with each other and with newer compounds in ways that vary person to person.
We learn from qualitative observations (aka bad experiences), but most often we measure absolutely nothing. Older drugs do get some attention from academic toxicologists and ADME folks, but while contributing to knowledge, these are not GLP studies. The latter are unfundable.
Why is this important? In the last few years, scripts written for generic drugs passed 90 percent of the total. Counting dollars vs. scripts, the percent is much smaller. The cost for a single antibody therapy could pay for a month of antibiotics or antidepressants for the entire population of a small town. Our aging population experiences more and more unstudied drug-drug interactions.
Furthermore, ethical reasons and science drive polypharmacy to hedge bets, combining the standard-of-care generic along with the experimental drug. For example, 5-fluorouracil might well be used along with an antibody. This highly toxic drug is approaching six decades old and not appearing close to retirement. The exposure varies significantly patient to patient and dosing is generally based on mg/m^2 of body surface area. There are multiple API manufacturers and 1,998 clinical studies of 5-FU listed in at this writing, and many are studies of drug combinations. While it is well established in the literature that measurement of drug exposure improves efficacy and reduces toxicity with 5-FU, this is all too often not done. Why not?
There are many other examples of grandfathered (grandpersoned?) drugs that cause trouble, the NSAIDS and acetaminophen being the prototypes. No member of PhRMA will put resources into going backward, and NIH is also far fonder of supporting something new. As a result, very little is being done to optimize dosing in individual patients with older drugs, alone or in combination. Pediatrics and geriatrics are special cases, given that neither were considered in trials many decades ago. The possibilities for improvement are clear from papers in the top clinical pharmacology journals. The development of new measurement tools such as clinical mass spectrometry are not quite ready for the world beyond medical schools. Very little of the published science reaches clinical practice. Implementing clinical research is costly, and the profit motive is absent.
In recent years, experts report that repurposing approved drugs, or drugs that failed for efficacy or human toxicity, suggests redeploying some old molecules and exploring them with the new tools. The idea makes sense, just as off-label use makes sense. For approved OMEs (old molecular entities), there is a notion that costly toxicity studies can be avoided as new uses and combinations are explored. Several “de-risked” repurposing libraries of well-documented candidates have been assembled.
The history of repurposing success is well known, but the few examples were from chance observations and not the deliberate process now ongoing. Here, too, the effort is limited by the patent system. The challenge of safely protecting innovative uses in the face of many generic suppliers is real.
Small molecules are here to stay. They have substantial advantages in safety, manufacturing cost, stability, delivery to patients and availability in low- to middle-income countries. They are also likely to be partners with their big sisters. Patients could benefit from applying new tools with old drugs, improving efficacy and reducing harm. Physicians could be guided with help from clinical decision support tools in electronic health records—long discussed, but not yet real. We know what to do but can’t afford to do it while proteins keep vacuuming up so many resources.

Peter T. Kissinger (who can be reached at is professor of chemistry at Purdue University, chairman emeritus of BASi and a director of Chembio Diagnostics, Phlebotics and Prosolia.

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