Small Molecules Evolve
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BIO is the world’s largest trade association representing biotechnology companies, academic institutions, state biotechnology centers and related organizations across the United States and in more than 30 other nations.
Small molecule drugs make up most of the drugs we take conveniently as pills, including painkillers like ibuprofen (Advil), antibiotics like penicillin and amoxicillin, or cholesterol-lowering drugs like atorvastatin (Lipitor). The biotechnology revolution allowed scientists to create drugs through genetic engineering and related biological processes, creating a new category of drugs known as “biologics.” These biologic drugs are generally administered by injection and include arthritis treatments like Humira, cosmetic drugs like Botox, and cancer drugs like Keytruda, which famously reversed Jimmy Carter’s brain metastases. The rapid advances in biologic drugs have inadvertently created a misperception that small molecules may not be as challenging, innovative, or impactful – and nothing could be further from the truth.
The small molecules drugs of today look nothing like the molecules of the 1970s. Thanks to decades of Nobel Prize-winning advances in chemistry, modern pharmaceutical scientists are now able to build far more complex molecules than ever before to tackle today’s healthcare crises. For example, AZT, the first drug to treat AIDS, was approved in 1987 (green box at the top of Figure 1, below). While its commercialization was an inflection point in humanity’s fight against HIV, the molecule is much less chemically complex than the drugs being approved today.
Whereas AZT has only 32 atoms (C10H13N5O4), the recently approved HIV medication lenacapavir has a whopping 96 atoms (C39H32ClF10N7O5S2). The increased molecular size and complexity are also reflected in the amount of time and effort required to synthesize the molecule. Whereas AZT requires only 3-4 steps to make from readily purchasable materials (Figure 1, top), lenacapavir requires at least 20 total steps (Figure 2, bottom).
The chemical complexity of lenacapavir is reflective of the increased difficulty in finding modern drugs that satisfy all the requirements to be impactful. It took at least 16 years from the start of the research program at Gilead Sciences to the approval of lenacapavir by the FDA in 2022 for the treatment of HIV. Whereas AZT has numerous side effects including a black box warning for hematological toxicity, myopathy, and lactic acidosis, must be taken several times a day, and can be overcome by drug-resistant HIV mutants, lenacapavir only needs to be dosed twice a year, is better tolerated, and fights all known strains of HIV, including previously drug-resistant strains of HIV.
Lenacapavir doesn’t reflect a single cherry-picked example from HIV. You can find examples of small molecule innovation in every therapeutic area. Figure 2 visually highlights a few more contrasts between earlier generations of drugs and recently approved or investigational drugs in trials now.
From the commonly prescribed painkiller ibuprofen to the emerging migraine-fighting atogepant, the established cancer chemotherapy anchor cyclophosphamide to the modern targeted therapy, venetoclax, or the often-prescribed cholesterol-lowering statins to cholesterol-lowering drugs like MK-0616 that are showing signs of working when statins don’t, it is clear from inspection that the drugs of today are in a new class of their own. Modern molecules are bigger, tougher, and harder to make and discover, all while serving patients in ways we never figured out how to until now. Atogepant is helping patients who suffer from debilitating migraines that don’t respond to other treatments live with a better quality of life, venetoclax has been responsible for many leukemia patients becoming cancer free after multiple rounds of chemotherapy failed, and emerging drugs like MK-0616 are likely to prevent heart attacks and stroke in thousands of people should they make it to approval.
Unfortunately, the lack of awareness about the innovation in small molecule drugs over the decades has manifested not just a hostility to the biotech and pharmaceutical industries making these advances, but also in recent legislation that penalizes companies that choose to make investments in small molecule research over other areas. For example, the Inflation Reduction Act’s drug price setting provisions handicap small molecule research programs relative to other areas of healthcare investment, possibly out of a perception that small molecules are less innovative or less important than other areas of healthcare. Such legislation may have the unintended consequence of making healthcare even more expensive in the long run, by reducing industry investment in the class of drugs with the longest track record of delivering patient-friendly and economical solutions to healthcare challenges.
About the Biotechnology Innovation Organization (BIO)
BIO is the world’s largest advocacy association representing member companies, state biotechnology groups, academic and research institutions, and related organizations across the United States and in 30+ countries.
