RESEARCH TRIANGLE PARK, N.C.—Virtually all drug discoveryand development concentrates on one of two classes of compounds—small moleculesthat are easy to administer but frequently not very good at binding to targets,or large molecules like proteins and peptides that provide highly specifictherapeutic action and very high binding potential but are expensive, unstablewith short half-lifes in vivo and seldomsuitable for oral administration. Tranzyme Pharma thinks macrocyclic moleculescan provide a third way—a "tweener" if you will—and Bristol-Myers Squibb hasbought into the idea by entering into a strategic collaboration agreement withthe company to discover, develop and commercialize novel macrocyclic compounds.
The collaboration will deploy Tranzyme's proprietary drugdiscovery technology, Macrocyclic Template Chemistry (MATCH), to identify anddevelop new drug candidates for multiple targets in diverse therapeutic areas.
Under the terms of the agreement, Tranzyme will be primarilyresponsible for early lead discovery, and Bristol-Myers Squibb will takeprimary responsibility for optimizing the identified lead compounds. BMS willbe solely responsible for completing preclinical and clinical development ofall products arising from the collaboration, and for their commercializationglobally. The company will provide an upfront payment of $10 million and anadditional $3 to $6 million in research funding to Tranzyme for an initialtwo-year term. Tranzyme will receive further funding if the agreement isextended beyond the initial term. In addition, Tranzyme is eligible to receivedevelopment and regulatory milestones and tiered royalties for each productresulting from the collaboration. Total milestone payments under the agreement,excluding royalties, could reach up to approximately $80 million for eachtarget program.
The goal of the collaboration is to explore the molecularchemistry space accessed by MATCH to discover novel bioactive macrocycles.These macrocycles represent a distinct and underexplored compound class thatdisplays favorable characteristics exhibited by large biomolecules, such ashigh potency and selectivity, while maintaining the benefits typicallyassociated with small-molecule drugs, such as high oral availability and lowcost of goods.
"Macrocyclic compounds are 'large small molecules,'"explains Dr. Vipin K. Garg, Tranzyme's president and CEO. "Being cyclicstretches the molecule and locks it in shape. This complexity and rigidityprevents the molecule from flip-flopping in space and increases affinity withthe target."
Macrocyclic drugs have been around a long time, henotes—cyclosporine, for example—but most of them were discovered in nature by ahit-or-miss discovery process, not synthesized in the lab. Using itshigh-throughput MATCH assay, Tranzyme has developed a library of between 25,000and 30,000 macrocyclics that provide the initial roadmap to indicate whether ornot there has been a good hit to a specific target, Garg says. After thisinitial phase, the molecule can be optimized.
Tranzyme Pharma's own pipeline is derived from its MATCHtechnology and targets two validated GPCR drug targets, ghrelin and motilin,explains Dr. Helmut Thomas, senior vice president of R&D. Two drugs are inthe clinic, with one nearing Phase III and the other in Phase II clinicaltrials.
"There are always concerns about safety, toxicity and oralbioavailability," notes Thomas, but so far all have proven to be good.
In addition to Tranzyme's current focus on gastrointestinal andmetabolic disease targets, Garg adds, MATCH has broad applicability in thetreatment of other diseases that involve hormones, peptides, ion channels orprotein-protein interaction pathways.