Small Molecules: The Silent Majority of Pharmaceutical Pipelines


Xconomy Boston — 

The pharmaceutical industry is constantly evolving. There always seem to be new, innovative therapeutic approaches emerging that capture our imagination and advance our ability to make a difference in the lives of patients. Take, for example, T-cell therapy for cancer, microbiome therapies, and CRISPR-Cas9 gene editing, each of which could potentially have a significant impact on healthcare someday.

Yet despite these and other advances, I expect one thing won’t change: small, synthetic molecules will remain remarkably prevalent in both development pipelines and on the market. I think of them as a silent majority. They might not be grabbing the headlines, but they consistently deliver results.

This might sound surprising. After all, we’re talking about good old-fashioned organic chemistry with drugs that are made in chemical reactors rather than in cells or living tissues. But consider some of the following points before relegating these small molecules to obscurity.

Small molecule drugs still account for about 90 percent of the therapeutics in today’s pharmaceutical market. According to Medscape, in 2014 five of the top ten selling drugs were small molecule drugs: aripiprazole (Abilify, $7.2 billion), esomeprazole (Nexium, $6.3 billion), rosuvastatin (Crestor, $5.6 billion), fluticasone propionate (Advair Diskus, $5.0 billion), and sofosbuvir (Sovaldi, $4.4 billion). Nine of the top 10 (and 17 of the top 20) most prescribed drugs in the U.S. last year were small molecules. Medicare lists fluticasone and rosuvastatin as two of its top prescription drugs.

How are these numbers possible? How could small molecules still be so dominant and prevalent despite the emergence of ever-newer, ever more complex cutting-edge therapies? For one, we’re talking about an incredibly, almost unimaginably, diverse group of small chemical compounds that often share nothing in common with one another except for their small molecular size and the fact that they’re made from synthetic chemical reactions.

Just how diverse is this super-family? Consider three of them: aspirin, corticosteroids and ivacaftor (Kalydeco).

Aspirin is probably one of the oldest and most widely used therapeutics in the world, first sold under that brand in 1899. Nowadays, the world consumes more than 40,000 tons of aspirin every year. You can buy a bottle of 100 pills for $1 at your local pharmacy. And yet the potential benefits of aspirin are regularly in headlines as more and more uses continue to emerge. Aspirin is now used for a range of indications, from cardiovascular health, to Alzheimer’s disease, cancer treatment, pulmonary diseases, and of course, general everyday aches and pains. Amazingly, Bayer aspirin generated an estimated $998 million in sales worldwide in 2014. This for a drug that was originally patented under the Kaiser!

Then there are corticosteroids (such as cortisone), another example of a decades’ old, ubiquitous anti-inflammatory drugs. These drugs were first synthesized in 1949, and it’s almost impossible to think of any human on the planet who hasn’t used them at least once. These drugs are among the most potent anti-inflammatory drugs around (they mimic a hormone the body makes called cortisol) and can be formulated into almost any imaginable dosage; be it oral, topical, or injectable. Sadly, their side effects are often just as potent as their benefits, making them ill-suited for chronic therapy.

But “small molecule” doesn’t necessarily mean old drug. We see them featured in the newest, most cutting edge drugs; often tailored to fit very specific genetic subsets of patients.

A prime example is Vertex Pharmaceuticals’s ivacaftor. This is the first drug approved (in 2012) to treat a specific malfunctioning protein caused by the genetic defect in cystic fibrosis patients. Ivacaftor is currently approved for six percent of the 70,000 patients with CF worldwide. With its annual price of over $300,000, analysts estimate that ivacaftor will top $1 billion in sales by 2018 and possibly three to five times that when combined with other drugs to boost its reach.

These are just a few examples of the vast number of diverse types of small molecule drugs already on the market (let alone those currently in development). Here are a few reasons why I’m betting that small molecules will continue to dominate pharmaceutical pipelines:

1) It’s almost impossible to imagine just how many small molecules there are out there. Simply using the category “small molecules” is a misnomer. It lumps together molecules whose structure, function, medical usage, potency and safety profiles can be radically, and wonderfully, different.

2) Much of our biology is driven by small molecules, so it makes sense to use another small molecule to address any biological problems. For example, as a rule of thumb, nature likes to use “large molecules” such as proteins and sugars as building blocks and “small molecules” (such as cyclic AMP, which activates enzymes called kinases) for signaling and inhibition.

3) They’re relatively easy to make, scalable, and highly profitable. These are significant advantages. On average, a small molecule drug costs about $1/day to produce, with generics typically costing even less. By comparison, a biologics’ average cost is approximately $22/day or roughly $10,000/year.

Given all this, it shouldn’t come as a surprise that as we look at the therapeutic pipelines of pharma, many companies still continue to develop small molecules for almost every imaginable indication. Pharma giant Roche, after all, recently announced plans to restructure its small molecule manufacturing plant, a definitive nod to the significance of small molecule drugs.

So, with all due respect for the latest advances in our field from antibodies to genetic therapies, I’m going to stick my neck out and posit that this diverse, chaotic, illogical, and huge family we call “small molecules” will continue to play a significant role in the pharmaceutical industry for the foreseeable future.

This silent majority still has a lot to say.