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Jan 15, 2010 (Vol. 30, No. 2)

Transforming Inflammatory Disease Therapies

Amira's Expertise Lies in Once-Daily Oral Therapies Targeting Bioactive Lipids

  • Click Image To Enlarge +
    Preclinical studies with AM966: healthy mouse lung tissue (left), lungs challenged with Bleomycin (center), and lungs challenged with Bleomycin and treated with AM966 (right).

    When Merck closed its San Diego operations in 2005, a team of about 20 scientists all experienced in developing drugs in the bioactive-lipid space, moved to the newly formed Amira Pharmaceuticals, founded by Peppi Prasit, Ph.D., Jilly Evans, Ph.D., and John Hutchinson, Ph.D. The Merck scientists played important roles in developing a number of anti-inflammatory drugs including Singular®. 

    Under the direction of Dr. Prasit, the CSO, Amira researchers design and test small molecule oral drugs to control asthma, other respiratory illnesses, and cardiovascular and fibrotic diseases. Amira has three programs that target bioactive lipids. The company’s lead program focuses on 5-lipoxygenase activating protein (FLAP) inhibitors and is in Phase II trials for asthma. GlaxoSmithKline licensed the FLAP technology in 2008.

    Another series of compounds are DP2 antagonists for asthma that are being tested in Phase I trials. Both drugs may also be potential therapies for chronic obstructive pulmonary disease (COPD). The newest project centers on lysophosphatidic acid (LPA), a bioactive lipid recently linked to idiopathic pulmonary fibrosis (IPF). This program is in late-stage preclinical testing.

  • Unmet Medical Need

    Finding a treatment for IPF fits with Amira’s goal to create therapies for unmet medical diseases. The only proven treatment for IPF is a lung transplant. An increasing number of first responders to the 9/11 World Trade Center attack are developing a similar grievous condition with a high death rate. “There’s a high unmet medical need and opportunity to bring new drugs forward to treat IPF and other fibrotic diseases,” reports CEO Bob Baltera, a 17-year veteran of Amgen.

    In 2008, Andrew Tager, M.D., and colleagues at Harvard Medical School discovered that LPA receptor 1 (LPA1) is the most highly expressed receptor in a mouse model for pulmonary fibrosis. They also showed that LPA1 knockout mice are protected from pulmonary fibrosis and death. Additionally, they found that lung fluid samples obtained from patients with IPF have elevated LPA and LPA1.

    Dr. Tager reported the results in Nature Medicine. When Dr. Prasit saw the data, he asked Dr. Tager to join the company’s scientific advisory board, and Amira scientists began a search for drug candidates aimed at LPA1. They have produced a number of small molecules that reduce lung fibrosis and inflammation up to 60% in preclinical animal models for IPF. The results are similar to those seen in LPA1 knockout mice. The small molecules also reduce kidney and liver fibrosis in animal models.

    “We are well on our way to developing an orally available antagonist. While a great deal of work remains, we believe this could be a novel first-in-class therapy,” says Dr. Prasit.

    The NIH estimates that there are 200,000 patients with IPF in the United States, and 50,000 new cases are diagnosed annually. If the LPA1 antagonists prove clinically successful, the company plans to develop and market a pill for IPF itself.

  • Home Run

    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.



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