Keeping The Pipeline Moving
John Montana

Keeping The Pipeline Moving

Four chemistry tips during early discovery that might save time—and millions

By some estimates, it takes about $11 million a month—around the cost of a 90-second Super Bowl ad—to deliver a drug to market.

So anything that can be done to shorten the timetable—and produce high quality promising candidates—is golden. This is particularly true during the drug discovery phase, when the hunt for molecules, and ultimately development compounds that have a chance of advancing to the clinic, becomes critical.

While it is easy to make compounds, synthesizing the right molecule is another matter entirely, with the proof of success being the number of development candidates that get delivered, the amount of time it takes to deliver them and their success in the clinic.

The early discovery process begins with identifying potential hit compounds and it ends with modulating the winner to determine its pharmaceutical effect, and hopefully reaching the Investigational New Drug (IND) stage. These traditional approaches can be time-consuming and highly risky. For every 5,000 to 10,000 compounds that enter the pipeline, only one receives approval. Even therapies that reach clinical trials have only a 7% to 15% chance of being approved, according to recent publications.

So what can contract research organizations (CROs), which are being called upon more and more to do targeted segments of early discovery such as medicinal chemistry and in vitro and in vivo biology, do to accelerate this process? One option is to use bench scientists more strategically. During the later stages of lead optimization, CROs should also blend medicinal and process chemistry with formulation development capabilities to help ensure rapid transition of the development compound from discovery to development.

Here are four factors to help ensure the transition from discovery to development occurs in a time, cost and resource efficient manner.

  • Choose Your Target Engagement Biomarker Assays Early. Being confident that the mechanism of interest is effective and responsible for the physiological outcome in both in vitro and in vivo systems is essential. With this in mind, it's critical to establish, early on, in vitro target engagement biomarker assays that help ensure problems are identified early and dealt with quickly. One recent project that our group worked on, an oral receptor antagonist against a highly-competitive inflammation target, succeeded in identifying two key series of compounds in three months. Both binding and biomarker assays showed the project lead outperformed the competition even at this very early stage of the project. More importantly, we used the target engagement biomarker to correlate biochemical and cellular effects observed with the novel compound. This offered evidence of PK/PD effects in vivo and in the clinic, which in turn provided a lot of confidence that the mechanism would be clinically effective in Phase IIa efficacy studies.
  • Get Those Molecules to Behave. Face it, molecules that don't have the right physicochemical properties will bring your project to a screeching halt. So flagging issues as quickly as possible during early discovery is important. In the initial leads from that oral receptor antagonist project mentioned above, the solubility of the synthesized compounds was assessed and the series were progressed based on favorable physicochemical properties as well as potency. This meant that early novel compounds had far superior properties to the most advanced competitors, which along with other great properties (such as potency and DMPK) helped us to rapidly identify a 'Best in Class' development candidate and structurally differentiated back-up compound in 18 and 27 months respectively.
  • Appreciate the Value of Process Chemistry. In the earliest stages of drug discovery, medicinal chemists are invaluable in identifying high quality, novel compounds. But they aren't as spot-on when it comes time to synthesizing and scaling up key compounds for extensive in vivo and safety evaluation. Face it, medicinal chemists aren't trained to understand how to make large amounts of a material and they don't always know what to look for in order to provide an efficient and GMP-compliant synthesis. Moreover, using them for this purpose reduces valuable time they could be spending designing and making new compounds that move the project forward. A better choice would be to involve process chemists toward the end of the discovery phase. They can provide large quantities of key compounds for detailed in vivo evaluation, and when it comes time for nominating candidates process chemists can provide a scalable route for GMP transfer. How valuable is this approach? It can shave 6-9 months off the time it takes to get to IND – a savings of $70 to $100 million!
  • Involve formulation development. You can also save time and money by finding out, early on, whether you have suitable, stable, physical forms of your compounds of interest, and what the appropriate formulation is for downstream development for that short-list of potential candidates. Involving physical chemistry and formulation development during the later stages of lead optimization ensures that potential development compounds with a suitably stable, crystalline form are identified in a timely manner. As you get to that short list of compounds, that same group can also provide key data on API stability and excipient compatibility. Again, utilizing these skills in the discovery phase provides key data on the development candidate that can be passed on to the GLP formulation team to shorten the time to having a formulation suitable for clinical studies. It also ensures that no issues arise with physical form driven changes in DMPK properties that can result in lengthy delays and even project failure.

How to cite:

Montana, J. Keeping The Pipeline Moving. Eureka blog. Jun 30, 2015. Available: