February 15, 2010 (Vol. 30, No. 4)
Akebia Therapeutics Sees Promise in the Oral Delivery Route
Drugs to treat chronic anemia constitute a multibillion dollar worldwide market, with injectable forms of recombinant erythropoietin (EPO) serving as the dominant type of therapeutic.
Currently, there are no oral small molecule drugs for chronic anemia, but researchers at Akebia Therapeutics are striving to change that by designing novel small molecules for anemia and vascular disorders.
The firm’s lead compound for anemia aims to replace injectable EPO with a once-daily oral drug. The company’s second lead compound not only treats vascular leakage, but also prevents some types of tumors from spreading, say company officials.
A medicinal chemist, Joseph Gardner, Ph.D., president and CEO of Akebia, founded the company in 2007 after a 20-year career at Procter & Gamble. Dr. Gardner left the corporate giant after it closed its discovery programs in 2006. He launched Akebia and licensed some of the most promising programs in the cardiovascular area from Procter & Gamble.
Akebia’s most advanced compound, AKB-6548, started Phase I trials last September. It inhibits hypoxia-inducible factor-prolyl hydroxylase (HIF-PH). HIFs are transcription factors that react to decreases in cellular oxygen, which can be stabilized or upregulated by inhibiting HIF-PH enzymes. This allows the body to better respond to reduced oxygen, injury, and infection. HIF pathways do not function optimally in anemia, fractures, wounds, and other conditions.
AKB-6548 increases the natural production of EPO, the hormone that directly stimulates the production of red blood cells in bone marrow. Anemia results from the reduced production of red blood cells. By inhibiting HIF-PH, AKB-6548 stabilizes HIF, which in turn, increases the expression of genes that make EPO.
AKB-6548 is designed to match the efficacy of injectable EPO given as standard therapy to dialysis patients. Akebia is also targeting predialysis patients and those with chronic renal disease, two patient groups who are undertreated for anemia because of the high costs and safety issue of injectable EPO. Among predialysis patients, one million people are estimated to be moderately anemic. They could benefit from anemia therapy if cheaper and safer alternatives were available.
Injections of EPO are expensive, with a year’s therapy for a dialysis patient costing up to $10,000. The Centers for Medicare & Medicaid Services is revising its payment schedule for drugs used at dialysis clinics.
“The price pressures on EPO are already intense and will become more so,” points out Dr. Gardner. The company believes its small molecule drug candidates will be more affordable and patient-friendly and safer than injectable EPO.
A few other firms are developing oral small molecule drugs to treat anemia, and these compounds are undergoing early clinical trials. “We all manipulate the same pathway,” says Dr. Gardner, who adds that public data suggests that Akebia’s AKB-6548 offers a better dosing regimen and safety advantages over its potential competitors.
Other compounds in the HIF-PH inhibitor series stimulate the immune system instead of erythropoiesis. Early tests show that some are powerful anti-infectives that kill antibiotic resistant strains of bacteria such as methicillin-resistant Staphylcoccus aureus (MRSA).
“The HIF-PH pathway has powerful and complicated biochemical mechanisms,” notes Dr. Gardner. Collaborations with Randall Johnson, Ph.D., an expert in HIF at the University of California, San Diego, are helping Akebia scientists to select compounds for different disease indications.
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.