At Sepracor, which focuses on the treatment of respiratory and central nervous system disorders, the split between external and internal med chem work is about 2:1. “Two-thirds of our research and budget goes outside to our global partners, in both biology and chemistry,” said Thomas Large, Ph.D., senior vp drug discovery at Sepracor. The company works with both academic and CRO partners, with all project leaders being internal staff.
Dr. Large emphasizes the importance of distinguishing between medicinal chemistry and synthetic chemistry. He describes “a big rush toward outsourcing of synthetic chemistry,” with the wave of outsourcing med chem activities progressing more slowly. Sepracor’s principal med chem partner is Scynexis.
“That experience has been overwhelmingly positive,” said Dr. Large. Many of the medicinal chemists in CROs come from the pharmaceutical industry as it scales back on core staff, he added. They bring with them “valuable drug-hunting medicinal-chemistry experience.”
If managed as a truly collaborative, intellectual partnership, “you can get to the point where it is a high functioning, integrated team,” in which the external partner has “a high sense of ownership” of the project.
“You don’t get to that point by chance, especially with medicinal chemistry,” Dr. Large explained. “You have to tell them everything: show them all the biology data, tell them all your ideas, get their feedback, and leverage their skills. If you did it as a transaction, I think by definition they would become synthetic chemists, not medicinal chemists.”
Millennium has entered into five significant collaborations with chemistry CROs—some successful and some not, according to Greenspan. The reasons some partnerships failed were because “the company didn’t provide the level of service we wanted, or we weren’t clear enough in our needs and expectations, or we didn’t understand clearly enough what our own needs were and how they could best be met in a cost-effective way.”
The two most common pitfalls in working with a CRO are unrealistic expectations and poor communication, asserted Greenspan. There is certainly truth to the adage “you get what you pay for” and expectations of quality, reliability, and service should take into account the relative price being paid.
Communication problems may include time delays, language difficulties, and cultural barriers—an example of the latter being a CRO partner’s reluctance to give bad news or to offer a contrary opinion when the company has unrealistic expectations. Good and open channels of communication are critical in medicinal chemistry outsourcing because it is “a day-to-day business,” said Greenspan. “You may be trying and troubleshooting new chemistries and making changes as you go. Direct communication with the chemist doing the work is important.” Work that proceeds along a path doomed to failure wastes valuable time and resources.
“Medicinal chemists like to talk about successful chemistries,” said Zimmermann, but you need your CRO partner “to talk the most and the loudest when things are going badly.”
When assessing a potential CRO partner, Zimmermann recommended evaluating the caliber of scientists the CRO hires—“would you hire these scientists to work as medicinal chemists in your company?” he asked. When Kalexsyn hires a medicinal chemist, it is looking for a synthetic chemist who has experience in multiple sciences.
“They understand pharmacology, ADME, toxicology, and physico-chemical parameters, in addition to their chemistry and molecular modeling skills.” They use all of these to weave together a structure-activity relationship strategy to advance hit-to-lead and lead optimization toward clinical candidates.”
He also recommended determining whether there is a philosophical and communications fit between the two companies. “These are inter-related and one without the other is a failure.”
The third critical factor is cost. Historically, cost was the first consideration, noted Zimmerman, but “pharma learned they have taken some bumps and bruises with that philosophy.” In a tenuous partnership, for example, the need for pharma to maintain on-site oversight throughout a project can become costly and greatly inflate the initial project price estimate.
Zimmermann further advised assessing a CRO’s analytical capabilities. A company “does not want to have to bring a compound back in-house and do a full characterization.” Before selecting a CRO partner he recommends hands-on site visits. “Invest in the relationship” and don’t assume anything, he said.