The presentations showed results of studies with AVL-291, a Bruton’s Tyrosine Kinase (“Btk”) inhibitor for the treatment of B cell malignancies, and CNX-222, a Pan-ErbB inhibitor that inhibits the ErbB family of targets, including EGFR and Her-2, for the treatment of breast and non-small cell lung cancer. With the compounds’ unique ability to covalently modify their protein targets, leading to irreversible inhibition and overcoming known resistance mechanisms, they may represent a best-in-class new therapeutic option for the treatment of many prevalent and aggressive cancers.
• AVL-291, an orally-available, novel Btk inhibitor, was shown to completely silence Btk through covalent inhibition, resulting in a prolonged duration of action. Btk plays a key role in cell signaling pathways that drive B cell malignancies such as Non-Hodgkin’s Lymphoma and B Cell Chronic Lymphocytic Leukemia.
• CNX-222, an orally-available novel Pan-ErbB inhibitor, was shown to completely and selectively silence the ErbB family of tyrosine kinases, including EGFR, Her-2 (also known as ErbB2), and their corresponding drug-resistant mutations. The ErbB family of tyrosine kinases is over-expressed in a wide variety of tumors including lung, breast and colorectal cancers.
• Furthermore, silenced proteins constitute novel biomarkers, and Avila has developed a unique covalent technology to measure directly and quantitatively the duration and extent of target silencing, thereby generating translational data to guide clinical treatment.
"These studies underscore the potential of our covalent drug platform to generate drugs that powerfully and irreversibly silence proteins, as well as Avila’s unique ability to measure and calibrate their effect in a dose- and time-dependent manner that is not possible with conventional drugs,” said Juswinder Singh, Ph.D., Chief Scientific Officer, Avila. "These data support clinical evaluation of our drugs in the treatment of cancer patients who no longer respond to existing targeted therapies, and we are aggressively advancing this class of drugs into late-stage preclinical studies with the goal of entering a candidate into clinical trials in 2010.”
In one study, “A novel platform-based approach to silencing cancer targets using small molecule drugs: Application to Bruton's tyrosine kinase” (Abstract #3739), data demonstrated that the orally available, novel Btk inhibitor, AVL-291, potently and selectively silences this important target in B cell cancers. Specifically, it was shown that AVL-291:
• Demonstrates exquisite selectivity compared to previously reported Btk inhibitors and does not inhibit other kinases, such as Lyn and Syk, that may cause toxicity;
• Inhibits Btk-dependent B cell receptor signaling potently and irreversibly for more than eight hours after a single brief exposure in vitro;
• Reduces the growth of human B lymphoma cells in vitro; and,
• Completely saturates Btk in vivo for several hours after a single dose in an animal model – a measurement made possible through the use of Avila’s translational covalent technology.
Btk plays a crucial role in the development and activation of B cells and contributes to the proliferation and survival of B cell lymphomas. Disruption of this signaling pathway results in cell death or decreased viability in several B cell lymphoma lines. AVL-291, with its ability to irreversibly inhibit and silence Btk, represents a new therapeutic option for the treatment of B cell related hematological cancers, such as non-Hodgkin’s lymphoma (NHL), B cell chronic lymphocytic leukemia (B-CLL), and other B cell-related diseases.
A second study, “A novel small-molecule drug platform to silence cancer targets: application to the pan-ErbB kinases” (Abstract #3746), demonstrated that the orally available, novel Pan-ErbB inhibitor, CNX-222, selectively silences the ErbB family of receptor tyrosine kinases. Specifically, it was shown that CNX-222:
• Inhibits potently and irreversibly EGFR, ErbB2, and a drug-resistant mutation of EGFR that no longer responds to current targeted therapies;
• Has exquisite selectivity compared to clinical ErbB inhibitors such as erlotinib and neratinib;
• Silences EGFR for >8 hours after compound removal in vitro;
• Reduces growth of ErbB-dependent tumors in vivo in animal models with greater efficacy than current targeted therapies.
The ErbB family of receptors is over-expressed in a wide variety of tumors and the therapeutic benefits of inhibiting them have been clinically validated in lung, breast and colorectal cancers. Current approaches to inhibiting the ErbB family of kinases are important therapies for patients; however, mutations in response to therapy create substantial drug resistance over time. CNX-222, with its ability to irreversibly silence the ErbB family of kinases and its clinically relevant mutations, may represent a best-in-class new therapeutic option for the treatment of many prevalent and aggressive cancers.
About Covalent Drugs
The covalent bonding mechanism of Avila Therapeutics’ drugs has unique properties to effectively ‘silence’ disease-causing proteins. Avila drugs establish a strong and enduring ‘bond’ – exceeding the more temporary ‘binding’ of conventional drugs – to completely shut down the activity of, and silence, a disease-causing protein. Avila’s covalent drugs have unique therapeutic benefits because they are exquisitely targeted, are effective against mutations and have long duration of action.
About Avila Therapeutics
Avila Therapeutics is the only biotechnology company developing a whole new therapeutic approach called 'protein silencing' based on a proprietary platform for developing covalent drugs that strongly and resiliently bond to disease-causing proteins, resulting in drugs that can be highly effective against diseases. Avila's covalent drugs have unique therapeutic benefits because they are highly targeted, are effective against mutations and have long duration of action. Avila is developing a pipeline of novel, protein silencing drugs with a current focus on viral infection, cancer, and autoimmune diseases. Avila was founded in 2007 and is based in Waltham, Massachusetts. For additional information, please visit http://www.avilatx.com.
