About a year after its IPO, Akebia Therapeutics Inc. is raising $60 million in a follow-on offering to support phase III testing of its lead candidate, the renal anemia drug AKB-6548, and phase I development of the cancer-focused AKB-6899. Both drugs are hypoxia inducible factor-prolyl hydroxylase (HIF-PH) inhibitors.

Underwriters UBS Securities LLC and Morgan Stanley & Co. LLC priced the 7.3 million shares (NASDAQ:AKBA) offered at $8.25 each. JMP Securities is acting as lead manager. Needham & Co. and Brean Capital LLC are acting as co-managers.

Net proceeds from the offering are expected to be about $56.1 million, prior to accounting for underwriters' potentially exercising a 30-day option to buy an additional 1.1 million shares. Akebia shares, first offered to investors last year for $17 each, fell to a 52-week low of $8.11 shortly after the offering priced. By Friday's market close, shares were down 36 cents, to $8.31. (See BioWorld Today, Feb. 19, 2014, and March 21, 2014.)

Shares in the Procter & Gamble Co. spin-off have struggled ever since October, when it released top-line results from a phase IIb study of AKB-6548 in nondialysis patients with anemia related to chronic kidney disease (CKD). Investigators in that study recorded an imbalance in serious adverse events (SAEs), with a higher incidence of SAEs in the active treatment group (23.9 percent) vs. the placebo group (15.3 percent). At the time, the Cambridge, Mass.-based company said one SAE was considered probably related to active treatment and two were possibly related, including one death.

Digging deeper into the data since, Akebia President and CEO John Butler told BioWorld Today that the imbalance was driven "virtually completely" by SAEs related to natural progression of trial subjects' kidney disease. "These were significantly ill patients," he said, noting that nearly three-quarters were in stage IV or stage V of the disease, meaning their disease was considered either severe or end-stage.

Since the trial's conclusion, Akebia has met with two different regulatory authorities in Europe and had a type C meeting with the FDA, which had the full data in hand. There was "no expression of concern around the data at all," said Butler. "As I've walked the people on the Street through it, we got them to a place where they understood that there isn't a safety signal here. Our perspective is that the drug is ready to move into phase III and those are the conversations we're having with regulators now."

The company is now planning two phase III studies of AKB-6548 in patients with anemia secondary to CKD that will probably include a total of 3,000 patients. They will be outcomes-focused trials with major adverse cardiac events as an endpoint. Butler said the company has taken for granted that it will have to run a cardiovascular outcomes study.

Akebia is working to secure buy-in from regulators for a harmonized study that can meet both U.S. and European requirements. It's also working to schedule an end-of-phase II meeting with the FDA by the end of the second quarter and a scientific advice meeting with the EMA in the third quarter. Coming out of those meetings, the company hopes to have a definitive trial design that would allow it to dose the first patient with AKB-6548 before the end of this year.

Like any race worth running, Akebia isn't alone in pursuit of HIF-PH inhibition for treating CKD-linked anemia. Tokyo-based Astellas Pharma Inc. and partner Fibrogen Inc., of San Francisco, are making tracks, too, having reported just last month that they reached agreement on final protocols and are enrolling seven phase III trials of the HIF-PH inhibitor roxadustat (also known as ASP1517/FG-4592) for anemia in CKD in the U.S., Europe and Asia Pacific, excluding Japan and China. That program is expected to enroll about 7,300 dialysis and pre-dialysis patients. Work to submit regulatory filings in 2016 for China and 2018 for the U.S. remains on track, Fibrogen said.

BROADER HORIZONS

The second major goal of Akebia's follow-on offering is to fund development for AKB-6899, a small-molecule HIF-PH inhibitor with potential benefits in oncology and ophthalmology. Akebia has yet to file an investigational new drug application for the preclinical candidate, but is busily advancing studies to support filing this year, with hopes of kicking off a phase I study later this year or early in 2016 in solid tumors.

So far, AKB-6899 has demonstrated the ability in vitro to reduce vascular endothelial growth factor levels in the presence of hypoxia, which isn't appropriate for treating kidney disease, but is perfect for going after cancer, since cancer cells tend to be hypoxic cells. In preclinical mouse models, it has been active in reducing tumor growth and development of metastases.

"It's an anti-angiogenic product that could have a significantly improved toxicity profile vs. standard of care," said Butler, adding that it could also be used in combination with currently approved therapies with very little added toxicity.

The company is also expecting to complete preclinical proof-of-concept studies of the candidate in ophthalmology in early 2016 with the goal of potentially delivering the drug's anti-angiogenic effect in an eye drop. That, said Butler, could ultimately lead to an alternative therapy to Avastin (bevacizumab, Genentech Inc./Roche AG) or Lucentis (ranibizumab, Genentech Inc./Roche AG), sparing patients the current injection they undergo now. "Obviously, if we're pleased with what we see, we would accelerate that program into phase I as fast as we can," he said.