RESEARCH TRIANGLE PARK, N.C.—Virtually all drug discovery and development concentrates on one of two classes of compounds—small molecules that are easy to administer but frequently not very good at binding to targets, or large molecules like proteins and peptides that provide highly specific therapeutic action and very high binding potential but are expensive, unstable with short half-lifes in vivo and seldom suitable for oral administration. Tranzyme Pharma thinks macrocyclic molecules can provide a third way—a "tweener" if you will—and Bristol-Myers Squibb has bought into the idea by entering into a strategic collaboration agreement with the company to discover, develop and commercialize novel macrocyclic compounds.

The collaboration will deploy Tranzyme's proprietary drug discovery technology, Macrocyclic Template Chemistry (MATCH), to identify and develop new drug candidates for multiple targets in diverse therapeutic areas.

Under the terms of the agreement, Tranzyme will be primarily responsible for early lead discovery, and Bristol-Myers Squibb will take primary responsibility for optimizing the identified lead compounds. BMS will be solely responsible for completing preclinical and clinical development of all products arising from the collaboration, and for their commercialization globally. The company will provide an upfront payment of $10 million and an additional $3 to $6 million in research funding to Tranzyme for an initial two-year term. Tranzyme will receive further funding if the agreement is extended beyond the initial term. In addition, Tranzyme is eligible to receive development and regulatory milestones and tiered royalties for each product resulting from the collaboration. Total milestone payments under the agreement, excluding royalties, could reach up to approximately $80 million for each target program.

The goal of the collaboration is to explore the molecular chemistry space accessed by MATCH to discover novel bioactive macrocycles. These macrocycles represent a distinct and underexplored compound class that displays favorable characteristics exhibited by large biomolecules, such as high potency and selectivity, while maintaining the benefits typically associated with small-molecule drugs, such as high oral availability and low cost of goods.

"Macrocyclic compounds are 'large small molecules,'" explains Dr. Vipin K. Garg, Tranzyme's president and CEO. "Being cyclic stretches the molecule and locks it in shape. This complexity and rigidity prevents the molecule from flip-flopping in space and increases affinity with the target."

Macrocyclic drugs have been around a long time, he notes—cyclosporine, for example— but most of them were discovered in nature by a hit-or-miss discovery process, not synthesized in the lab. Using its high-throughput MATCH assay, Tranzyme has developed a library of between 25,000 and 30,000 macrocyclics that provide the initial roadmap to indicate whether or not there has been a good hit to a specific target, Garg says. After this initial phase, the molecule can be optimized.

Tranzyme Pharma's own pipeline is derived from its MATCH technology and targets two validated GPCR drug targets, ghrelin and motilin, explains Dr. Helmut Thomas, senior vice president of R&D. Two drugs are in the clinic, with one nearing Phase III and the other in Phase II clinical trials.

"There are always concerns about safety, toxicity and oral bioavailability," notes Thomas, but so far all have proven to be good.