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.