FLAP is an early key component in the leukotriene pathway, a complex signaling process that controls inflammation, immunity, and other biological processes. Excessive production of leukotrienes exacerbates inflammatory diseases such as asthma. The FLAP gene is also linked to inflammation in heart disease. Amira’s lead FLAP inhibitors, AM803 and AM103, bind to FLAP and block the synthesis of leukotrienes to control inflammation. Both compounds are licensed to GlaxoSmithKline, and the lead compound is performing well in Phase II trials in asthma patients. “We hit a home run with FLAP inhibitors,” says Dr. Prasit.
In August 2009, Amira submitted an IND application for AM461, an oral drug antagonist of the receptor DP2 involved in the arachidonic acid pathway. DP2, also known as CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 lymphocytes), regulates allergic inflammation. The submission of the IND for AM461 followed just four months after Amira started clinical testing for AM211, another DP2 antagonist currently in Phase I trials.
Additionally, in June 2009, Amira released interim results from a Phase I trial of AM211 showing that a single dose brings sustained pharmacodynamic effects, and the drug has a good safety profile. There is strong scientific rationale to target the arachidonic pathway in a variety of respiratory diseases, and a weak DP2 antagonist is approved for allergic rhinitis in Japan. Oral DP2 antagonists may become novel therapies for COPD, allergic rhinitis, and asthma. Amira is talking with potential partners who are interested in advancing the DP2 antagonists.
Amira scientists started from scratch to create their small molecule programs. “In 2005, our pipeline was only an idea and nothing was seeded to us from Merck,” says Dr. Prasit. Rather than concentrating their efforts on one molecule, Amira researchers create a series of small molecules with similar properties to test. The small molecules all target the same pathway, but their chemical structures are very different.
This approach provides quick backup molecules if one proves ineffective or unsafe. Rather than putting all their eggs in one basket, “we assume the first compounds we test will fail, so we have multiple compounds in our basket,” Dr. Prasit explains.
In addition to biologists and chemists on the Amira team, Dr. Prasit also includes drug-metabolism experts. “The key to designing a successful once-a-day, small molecule pill is drug metabolism, and it is not a trivial point,” he adds. Many small companies don’t seriously consider how a drug degrades and where it goes in the body, a process that can doom new drugs. “Our view is beautiful in its simplicity. We are good at oral, once-a-day drug design, and we stick to bioactive lipid pathways,” adds Baltera.