Minimising risks: drug discovery practices for Chief Scientific Officers
Interview with Malcolm Weir, CEO of Heptares Therapeutics
Statistics seem almost stacked against developing a fitting drug for a target disease. Drug discovery is plagued by time consuming and costly processes, with extremely high failure rates. Improving some of the underlying processes strangling and stalling the drug discovery process has thus become a top priority for the industry. A speaker at the marcus evans Discovery Summit 2010 taking place in France, 22-24 March, Malcolm Weir, Founder and CEO of Heptares Therapeutics, shares his thoughts on the solutions to some of the issues troubling drug discovery scientists, the latest trends and building alliances.
What are the main discovery issues facing drug discovery companies right now?
Malcolm Weir: The biggest discovery issue right now is the chronic lack of productivity in the industry, especially on the small molecule front. There are difficulties in confidently producing New Chemical Entities (NCEs) with relatively low risk in later development. The solution is at least in part to produce better small molecules earlier on in the game, which will translate to a lower risk of failure. There should be a constant process of improving your chemistry and choosing the best targets to work on.
“The biggest discovery issue right now is the chronic lack of productivity in the industry…”
What are some of the challenges you are experiencing with drug discovery and what strategies are you implementing to overcome them?
Malcolm Weir: Our focus at Heptares Therapeutics is the G-protein-coupled receptor (GPCR) superfamily. This has been an immensely successful family, in fact the most successful from a drug discovery perspective. It still holds a great deal of promise for the future, as these receptors tend to be at controlling nodes in biological pathways and are often highly validated. A high proportion of pharmaceutical company targets are from this class, which contains over 370 members. The problem is that in the last decade, many of these targets have proven less tractable to traditional small molecule discovery approaches. The introduction of High Throughput Screening (HTS) and combinatorial chemistry has not dramatically changed that picture. It is particularly true for peptidergic receptors, but there are many other GPCRs for which there are selectivity problems, even though they may be relatively druggable. Our StaRTM platform for the first time enables structure-based and biophysical drug discovery approaches to be applied to GPCRs by stabilising them in pharmacologically-relevant conformations. This means that well-established powerful and precise molecular discovery techniques such as Surface Plasmon Resonance and X-ray crystallography, which are routinely used for soluble protein targets like kinases and nuclear receptors, can be deployed by Heptares on GPCRs. Engineering stabilised receptors also allows Heptares to approach agonist and antagonist GPCR therapeutic antibody discovery in new ways, both in vivo and in vitro – traditionally an area of difficulty in the industry.
What are some of the drug discovery trends emerging right now?
Malcolm Weir: I think there is a tendency of focusing on highly validated or precedented targets, and trying to find ways to crack those targets if they are proving intractable, because of the high failure of novel mechanisms in the clinic. That brings us back to the issue of the quality of small molecules entering pharmaceutical company pipelines. The trends are to focus on getting compounds into development that have a higher probability of success with better chemotypes and better properties, as well as having the necessary biological activity. There is also a trend for novel therapeutic modalities, such as antibody frameworks, biologicals in general, modified peptides, Small Interfering RNA (siRNA) knockdown, and improved delivery and pharmacokinetics of macrocycles and other ‘unconventional’ chemical classes.
Considering the current crisis, should more drug discovery experts build alliances? Why?
Malcolm Weir: I think partnering between companies is a very positive trend, when those companies have complementary assets. Providing the right deals can be struck and that sort of symbiosis is highly beneficial to the industry as a whole. The economics of reimbursement coupled to the likely fragmentation of traditional therapeutic areas due to pharmacogenomics and “right-drug-to-right-patient” is going to drive to more innovation. You cannot plan this in a single corporation, however large.
“I think partnering between companies is a very positive trend, when those companies have complementary assets.”
What are some of the promising opportunities in the industry right now?
Malcolm Weir: There is a superabundance of promise, with so many targets of varying degrees of validity and druggability, the problem is in making rational judgements about which are the right areas to concentrate upon. Great strides have been made in understanding what makes NCEs fail, based on decades of experience and analysis, and this has been capitalised on, through engineering more efficient small-molecules that are now moving through development. There is also a lot of promise in the wider application of antibody therapeutic approaches, with monoclonal antibodies being a well-precedented approach and other peptide and protein frameworks showing promise.
About the author:
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About the Discovery Summit 2010
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What do you see as the biggest challenges in drug discovery?