AKB-4924 (to be changed to GB004) is a hypoxia-inducible factor-1 alpha (HIF-1 alpha) stabilizer. It works by blocking the prolyl-hydroxylase (PHD) enzymes, helping to stabilize HIF-1 alpha — a master regulator of the cellular response to hypoxia, a condition that happens when oxygen demand exceeds supply.
Other HIF stabilizers in clinical development are not specific for HIF-1 alpha and stimulate other pathways, such as the production of red blood cells (a process called erythropoiesis).
Studies have shown that inhibiting hydroxylase is protective in a mouse model of colitis, with later research suggesting that the protective effects of inhibiting PHDs were mediated through the protection of the intestinal barrier.
HIF was shown to promote the production of several factors and the regulation of intestinal mucosal immune responses, contributing to the protective immune environment of the intestinal mucosa.
In preclinical models of IBD, AKB-4924 was shown to improve intestinal inflammation and help restore intestinal barrier function.
The treatment candidate is being developed as a once-daily, oral treatment for IBD. In 2017, Aerpio completed its first human trial, a Phase 1 study (NCT02914262) that tested ascending doses of AKB-4924 in healthy male volunteers. The study found AKB-4924 to be safe and well-tolerated.
In May 2018, Aerpio initiated another Phase 1 multiple ascending dose study with 24 healthy volunteers to further assess the therapy’s safety and tolerability, as well as its pharmacokinetics (how the drug is processed in the body).
Study participants will be randomized to three dose cohorts or a placebo control group delivered orally once daily for eight days.
“Gossamer is the ideal partner to maximize the potential of GB004 [AKB-4924] in IBD,” Stephen Hoffman, an MD and PhD, the CEO of of Aerpio, said in a press release.
“The Gossamer team has a demonstrated track record of successful therapeutic development in IBD, specifically the development of Ozanimod in multiple sclerosis and IBD, as evidenced by the sale of Receptos to Celgene in 2015 for $7.2 billion,” Hoffman said.
“Our partnership allows us to focus our resources on our ophthalmology and diabetes programs currently in development at Aerpio,” he added.
Faheem Hasnain, Gossamer Bio’s chairman and CEO, said the biopharma is “pleased to have found GB004 after thoroughly assessing a substantial number of opportunities. This program represents an important addition to the Gossamer portfolio of drug candidates aiming to address unmet medical needs.”
“The HIF-1 alpha stabilization mechanisms represent truly novel biology with multiple putative benefits and a potential paradigm-changing approach to treating IBD patients,” added Sheila Gujrathi, MD, Gossamer Bio’s president and chief operating officer.
Under the terms of the licensing agreement, Gossamer will be responsible for the development, regulatory approvals, and commercialization of AKB-4924 (GB004), and all its financial expenses. In exchange, Gossamer paid Aerpio $20 million up front, and will pay Aerpio development, regulatory, and sales milestones of up to $400 million, along with royalties on global net sales.
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