The Holy Grail of Drug Development: Small Molecules with the Power of Biologics
FDA new drug approvals hit a 16-year high with 39 drugs approved in 2012; the highest number since 1996 when 53 drugs were approved. Of those, 18 or slightly less than half, were biologics up from 12 in 2011 but still surprisingly low when you consider an industry report citing that nearly 40 percent of pharmaceutical industry pipeline programs/products currently involve biologics.
This raises the question: Why are so few biologics making it to the market and of those that have, why are they primarily smaller market (less than $1 billion) or orphan indications?
While there is probably not just one answer; it’s safe to assume that a significant reason for this disparity is because it’s really hard to successfully develop biologics, especially against certain highly valuable yet extremely challenging targets. More than ever before, what our industry needs are fresh, integrative approaches to drug discovery. After many years in which the pharmaceutical industry has had separate R&D silos for small molecules and biologics—neither of which has shown an ideal ability for addressing intracellular targets for protein-to-protein interactions—there now appears to be a middle space for drug discovery. This approach will be a topic of presentations and discussion at this week’s Molecular Med Tri Con 2013 conference in San Francisco.
One approach in this middle space is developing synthetic macrocycle therapeutics, which have a name that describes their cyclical structure. The distinctiveness of macrocycles goes beyond their structure to include their exceptional properties: –they are small molecules with the power of biologics because they are orally bioavailable and yet can access intracellular protein-protein interaction targets. Our company, Ensemble Therapeutics, has a proven technology platform for making millions of macrocycles, and our aim has been to make progress in this middle space between small molecules and biologics.
The Challenge of Protein-to-Protein Interactions
In recent years, the understanding of the human genome and the rapid growth of insight into cell function has revealed plenty of tantalizing targets for therapeutic intervention. The problem is, many of those compelling targets are protein-protein interactions that are not affected by the conventional small molecules that are favored in the pharmaceutical R&D world. Those protein surfaces are too large, flat and poorly functionalized to attract the attentions of conventional small molecules.
In a successful campaign to fight fire with fire, protein therapeutics such as antibodies and soluble receptors have been developed as injectable therapeutics and are revolutionizing the treatment of diseases such as rheumatoid arthritis osteoporosis, psoriasis and numerous types of cancer. But despite their great therapeutic potential, such large protein molecules cannot get into cells, and certainly can’t be given as oral pills.
Consequently, there are large numbers of intracellular disease targets with protein-protein interactions that remain stubbornly resistant to the best endeavors of drug discoverers. Furthermore, where biologics are available, they have to be administered by injection, a process that can be painful and inconvenient for the patient. We can therefore consider a ‘holy grail’ of drug discovery to be a drug molecule that can be taken by mouth, gets though cell membranes and can antagonize protein-protein interactions, both inside and outside of the cell.
Small Molecules with the Power of Biologics
Ensemble’s proprietary synthetic macrocycles have sufficient size and make enough molecular interactions to disrupt even the most refractory protein-protein interactions, but are lithe enough to squeeze through cell membranes. As such, they merit the description ‘small molecule oral biologics’ and present a radically new drug modality. The power of the Ensemble approach has recently been demonstrated with the discovery and development of antagonists of interleukin-17 (IL17) a cytokine that is central to a number of inflammatory diseases such as psoriasis, psoriatic arthritis and ankylosing spondylitis.
There are a number of biologics currently in clinical development that target the interaction of IL17 with its receptor – several of these have shown stunning activity against psoriasis and other inflammatory diseases. However, until very recently, there were no known small molecules with any affinity for the IL17 target – indeed most researchers would have argued that IL17 is in a category of target for which it would not be possible to make small molecule drugs. Macrocycles discovered at Ensemble bind to IL17 from multiple species (including man) with a high degree of affinity, they can be taken orally, and they have been found effective against inflammation in animals.
Macrocycles epitomize the concept of a small molecule biologic, as they present the most attractive aspects of both conventional small molecules and biologics. They have proven affinity for difficult-to-target protein-protein interactions and yet retain attractive drug-like small molecule properties including the ability to get inside cells, and be taken as oral pills.
Let’s hope that macrocycles are one of many novel approaches in the middle space between conventional small molecules and biologics that can continue to make positive steps in the clinic to carve out new spaces for medicines to help patients.