Tricking Small Molecules
Akebia’s second lead compound, AKB-9778, is a “breakthrough therapy with no known competitors,” claims Dr. Gardner. The small molecule is designed to inhibit human protein tyrosine phosphatase beta (HPTPβ), the enzyme that regulates angiopoietin-1 and angiopoietin-2. Knowledge of these proteins is so new and evolving “that the science in this field in the past few years has taught us how to use the drugs. We’ve been remarkably fortunate.”
HPTPβ is only expressed in vascular endothelial cells, where the enzyme normally downregulates other enzymes associated with angiogenesis. Akebia’s approach is based on the concept that, by inhibiting a downregulator (or negative inhibitor) of a pathway, a desired product can be increased.
“Basically, we trick small molecules into having protein-like benefits to make them do what proteins would normally do.”
In the case of HPTPβ, AKB-9778 closely regulates Tie2, the signaling receptor for angiopoietin-2. “In almost all vascular conditions with profound vascular leakage, Tie2 is the bad actor,” continues Dr. Gardner.
Blood vessels are normally stabilized by angiopoietin-1 when the Tie2 receptor is phosphorylated. AKB-9778 prevents the dephosphorylation of the Tie2 receptor through inactivation of angiopoietin-2, an antagonist of angiopoietin-1. By restoring angiopoietin-1, the negative effects of angiopoietin-2 are suppressed.
Controlling vascular leakage could benefit patients with a variety of disorders, including sepsis, influenza, and cerebral edema. A proof-of-concept study is planned for patients with advanced melanoma and renal cell carcinoma, who are treated with IL-2 to stimulate their immune system to fight tumors. Unfortunately, IL-2 causes vascular leakage and the treatment must often be stopped early.
In preclinical models, AKB-9778 rescues animals from vascular damage 100% of the time. Akebia plans to file an IND for AKB-9778 in mid-2010 to prevent vascular damage caused by IL-2 therapy. A combination of AKB-9778 and IL-2 may allow cancer patients to tolerate longer courses of IL-2 and improve disease outcomes.
Additionally, animal models show that AKB-9778 prevents the spread of tumor cells.
“In three tumor types we found that stabilizing blood vessels around tumors prevents the tumor from metastasizing. This goes beyond what we imagined AKB-9778 could do,” says Dr. Gardner.
Many tumors secrete angiopoietin-2, which creates leaky localized environments. This allows sloughed off tumor cells to enter the vascular system and migrate through the body. AKB-9778 prevents tumor metastasis by stabilizing leaky blood vessels around tumors.
Akebia is looking for partners to carry out later clinical trials and marketing.
“We do not see ourselves becoming a fully integrated pharma company,” explains Dr. Gardner, who says a number of companies in Japan, the U.S., and Europe have shown an early interest in partnering with Akebia.