The future of pharma and health care: small molecule drugs

Rightful accolades to Moderna and Pfizer/BioNTech for the Covid-19 vaccines they created and developed in less than a year, along with plans to use their technologies to fight other infectious diseases, such as AIDS, and even to treat cancer, have renewed enthusiasm for complex therapies. But I believe that complex therapies, for all their wonders, represent only part of the future of medicine.

Modern medicines are split into two big families: biologics and small-molecule drugs.

Complex biologic drugs are isolated from natural sources (human, animal, or microbial cells), and are generally delivered by injection. In addition to the Covid-19 mRNA vaccines, biologics include therapies that activate the immune system, replace dysfunctional enzymes, and supply essential molecules the body has stopped making, like insulin. They’re big business: In 2021, companies developing biologic drugs received more than $20 billion in new funding, a stunning 250% increase over the previous year.

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By comparison, small-molecule drugs are medicines typically delivered in pill or tablet form. They generally haven’t excited investors as much, garnering less than 30% of biotech investments in 2021, even though they represent more than 90% of existing pharmaceutical drugs and more than 80% of drugs approved in 2021. Small molecule drugs include medicines like aspirin, penicillin, and the vast majority of pills and tablets that people take.

In theory, biologics can do things that small molecules can’t and have greater functionality. They are certainly popular with investors. Following the success of their vaccines, the stock prices of both Moderna and BioNTech rose more than 500% in two years. Investors are inevitably excited about companies developing more biologics.

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But society — and the biopharma industry — may be missing an even bigger opportunity: inventing small-molecule drugs with the functionality of complex biological molecules.

Imagine selectively editing a genetic abnormality in a particular organ with a simple pill. Or taking a pill to rejuvenate a failed organ. Or this possibility: a Covid-19 vaccine in a tablet that could be shipped to anyone’s home. Such advances could make it possible for people living in rural areas to take breakthrough cancer medications without having to travel hundreds of miles to a cancer center.

Small-molecule drugs can be 10,000 times tinier than biologic drugs and possess the unique ability to slip into cells and interact with almost any molecular target in the body. They generally work by turning proteins on or off, helping heal or eliminate diseased cells.

So far, small molecules have lacked the ability to achieve more complex functionality, like vaccines or cellular therapies. But that is rapidly changing.

New technologies have made possible the generation of rationally designed, high-functioning small-molecule medicines that can specifically and irreversibly target mutated cancer proteins — the cancer drug sotorasib is an example — or that induce novel functions that degrade or activate proteins, like proteolysis targeting chimeras (PROTACs). Advances in computation, chemistry, and biology have enabled ultra-high-throughput technologies that can explore vast libraries of molecules to more efficiently unearth high-functioning small molecules that possess the functionality of biologics.

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I’m bullish on the future of small-molecule drugs because that’s what my company, Totus Medicines, is focused on. But we aren’t alone. Other companies, including Arvinas, Kymera Therapeutics, Recursion Pharmaceuticals, Relay Therapeutics, Vividion Therapeutics, and others are also applying genomic insights and machine learning to generate small-molecule drugs that bridge the distinctions between them and biologics.

This new generation of small-molecule drugs would have tremendous advantages because they would combine what’s best about biologics — their exquisitely tuned capacity to influence any biological function — with what pharmaceutical companies always liked about simpler, traditional, small-molecule drugs: their price, ability to be taken by mouth, and ease of manufacturing and distribution.

These advantages would make small-molecule drugs a more equitable, democratic medicine compared to biological therapies, which are expensive and hard to make. Of the 10 most expensive drugs of 2021, all ten are biologics. Blincyto, an oncology drug for blood disorders made by Amgen, costs $712,000 a year. When the price was challenged, the drug maker could only respond, “The price … reflects the complexity of developing, manufacturing and reliably supplying innovative biologic medicines.”

Throughout history, simple solutions with complex functionality have repeatedly beaten more complex technologies. Think about the personal computer (and later the iPhone) versus minicomputers, or battery-powered electric vehicles versus internal combustion engines cars, or low-dose aspirin versus expensive blood thinners.

Yet highly innovative small-molecule companies still receive just one-third of the investment poured into companies developing biologics.

I believe the market’s assessment is wrong. Small-molecule drugs don’t have biologics’ limitations of distribution, delivery, and access. And small molecules, unlike approaches such as gene and cell therapy, can easily slip into cells to directly change the molecules inside them to treat disease. The opportunity of the future is to make small-molecule drugs into full-scale molecular machines that can exhibit any function.

Covalent drugs represent one of the most promising approaches for the near-term creation of such machines. These medicines can form irreversible bonds with their targets, enabling them to bind to and modify almost any gene in the body. Over the last 100 years, covalent drugs have saved hundreds of millions of lives, if not billions. Covalency has been used to create antibiotics like penicillin, early cardiovascular drugs like aspirin and statins, AZT to treat HIV/AIDS, and small-molecule pills for Covid-19 like Paxlovid, a covalent drug that reduces the risk of hospitalization or death by almost 90% among symptomatic patients.

Small-molecule drugs have traditionally been discovered serendipitously, and their covalency was understood only later. With the advent of new chemical and biological techniques such as high-throughput microscopy and nanoscale combinatorial chemistry, in combination with machine learning and data science, it will be possible to rationally design these drugs in weeks rather than years.

I see a future in which small molecular machines are the mainstay of therapeutics. They will likely be augmented by more complex biologic approaches, when appropriate. Hybrid therapies — small molecule medicines supplemented by complex biologics — could enable new combinatorial approaches to cancer, neurodegeneration, and even aging.

Academic and biopharma researchers should advance both, with urgency, to create a future in which currently now untreatable diseases are treatable.

Neil Dhawan is the CEO and cofounder of Totus Medicines.