”Improving Candidate Selection: Translating Molecules into Medicines.”

Allan B. Haberman, Ph.D

Bromodomain. A chromatin “reader” that is a target of PPI drug development. Source: WillowW at the English language Wikipedia.


Allan B. Haberman, Ph.D. was one of about 25 experts from pharmaceutical, biotechnology, and consulting firms who attended Aptuit’s  one-day think-tank event, ”Improving Candidate Selection: Translating Molecules into Medicines”. This was the third and final such networking and discussion symposium, which was held in downtown Boston, on December 4, 2017. The previous two events in this series had been held in San Francisco (18th & 19th Sept 2017) and in Hertfordshire, UK (22nd & 23rd Oct 2017). The Boston discussion session was preceded by a relaxed networking dinner on the evening of the 3rd.

Attendees and presenters at the Boston meeting were from Shire, Celgene, Forma Therapeutics, Roche, Amgen, Novartis, the Broad Institute, Warp Drive Bio, Mass General Hospital, EnBiotix, Yumanity, and Ra Pharma—among others—as well as from Aptuit and its parent company Evotec.

The focus of the meeting was on improving drug candidate selection in order to improve development success. Only about 10% of drug candidates make their way from first-in-humans trials to regulatory approval. The greatest amount of attrition occurs in Phase 2. Approximately half of candidates fail at that stage, mainly due to lack of efficacy.

One of the key issues discussed in the symposium was the role of the Lipinski Rule of Five—a set of physico-chemical properties that determine the “drug-likeness” of a clinical candidate; i.e., whether a compound is likely to be an orally active drug in humans. Some participants stated that these guidelines had been interpreted too rigidly, and have excluded many potentially good drugs from further development. They stated that the Lipinski rules are only guidelines, and do not replace thinking. (For a similar point of view, see Paul Leeson’s 2012 News and Views article in Nature.) For example, researchers should measure physical properties empirically, rather than inferring them.

The Lipinski rules also exclude whole classes of drug candidates—such as natural products and macrocyclic compounds—from consideration. Before the era of combinatorial chemistry and high-throughput screening, natural products were the mainstay of drug discovery and development.

The Haberman Associates website contains reports, articles, and links to reports that are useful in understanding the issues discussed in the Aptuit symposia. Links to most of these publications can be found on our Publications page. Notably, there is a 2009 report entitled Approaches to Reducing Phase II Attrition, which is available from Insight Pharma Reports. There is also a 2009 article (available on our website at no cost) based on that report, entitled “Overcoming Phase II Attrition Problem.”

Drug attrition numbers have not changed since our 2009 publications. However even back in 2009, pharmaceutical company researchers attributed high attrition rates due to lack of efficacy to companies’ addressing more complex diseases, with the need to discover and develop drugs that have novel mechanisms of action and/or address unprecedented targets. At the December 4 Aptiut symposium, participants similarly attributed high attrition rates to researchers’ tackling new classes of drugs. These included drug classes whose development involves working with premature technologies—e.g., protein-protein interactions (PPIs), gene therapy, RNAi, CAR-T therapies, cancer vaccines, , and combination immuno-oncology therapies.

Working on development of drugs based on premature technologies involves development of enabling technologies that will allow researchers to “move up the technology development curve” and thus to achieve increasing success in drug development. R&D in some of these fields—notably development of checkpoint inhibitors for use in immuno-oncology—has been moving up the technology curve, resulting in notable successes.

Although attrition rates have not changed since 2009, drug developers have been working with increasingly newer classes of drugs. Attrition thus continues to be a moving target.

Among the publications available on our website is our 2012 report—Advances in the Discovery of Protein-Protein Interaction Modulators. As the result of corporate restructuring, this report has not be available anywhere in recent years. However, with the permission of the publisher, Datamonitor Healthcare (a division of Informa), we are now hosting it on our website.

Aptuit’s “Translating molecules into medicines” symposia and improving drug discovery and development

The purpose of Aptuit’s symposia was “to discuss and learn from the experiences of those involved in working at the interface of discovery and development. These meetings were designed to give attendees the chance to build meaningful relationships, challenge their understanding of certain subjects and learn from leading members of their peer group in a non-commercialized setting.”

The organizers of the symposia ask whether “having the flexibility to think beyond established rules and adopting more collaborative development strategies will be just as important as the innovative science and technologies for drug discovery and development.” We at Haberman Associates look forward to assisting you in your efforts to move your drug discovery and development programs forward.


As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to your company, please contact us by phone or e-mail. We also welcome your comments on this or any other article on this blog.

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