Two established biopharma execs and a repurposed drug with a wealth of safety data and promising efficacy in a randomized study netted startup Orbus Therapeutics Inc. $32.5 million in series A funding last year. That money is expected to take the Palo Alto, Calif.-based firm all the way to the unblinding of top-line data from the phase III STELLAR study, which just enrolled the first patient.

STELLAR is testing an oral version of eflornithine in anaplastic astrocytoma, a subtype of rare brain cancer anaplastic glioma that affects roughly 15,000 patients in the U.S. The open-label, controlled trial will include about 280 anaplastic astrocytoma patients whose cancer recurred following radiation and adjuvant chemotherapy, patients who face a particularly poor prognosis, with an estimated median survival of less than 12 months after recurrence.

They will be randomized, on a 1-to-1 ratio, to receive eflornithine plus alkylating agent lomustine vs. lomustine alone, with overall survival as the primary endpoint. Secondary endpoints will include progression-free survival and objective response rate.

Orbus anticipates completing enrollment in early 2018, said Bob Myers, president and CEO. Top-line data are expected in mid-2019, but the company plans to conduct two interim analyses: a futility analysis, likely in early 2018 based on current projections for enrollment and event rates, and a second analysis for superiority, probably around the middle of 2018.

Based on discussions with the FDA, positive data from STELLAR should be sufficient for Orbus to file for approval, Myers said.

Assuming a positive readout, Orbus – the name is derived from the Latin word meaning "orphan" – could look at commercializing eflornithine in anaplastic astrocytoma on its own. "There are only a few hundred treating physicians in the U.S.," Myers said. It's also likely larger firms will begin eying Orbus as a hot M&A prospect.

"The nice thing is that we have options," he told BioWorld Today.

For now, the firm operates using a virtual business model, Myers said, "though as we get closer to positive data, we'll look at scaling up."

Myers co-founded Orbus with Jason Levin, chief operating officer. Both had worked together previously at Jazz Pharmaceuticals Inc., a company Myers founded in 2003. Levin was one of the initial employees of Jazz and served as vice president of corporate development.

Series A investors Longitude Capital and Adams Street Partners were well-acquainted with Myers, having invested in Jazz. Joining them was H.I.G. Bioventures. "So we have a very strong investor base," Myers said.

Orbus also was fortunate to add Ernest Mario as chairman. A biopharma veteran, Mario currently heads the boards of Capnia Inc. and Chimerix Inc. and is a venture partner with Pappas Ventures. "Ernest is someone I've known for the last two decades," Myers said. "He has a wealth of pharma leadership and experience."

Drawing all to the table was a compound that has a long and interesting history.

A NEW MECHANISM OF ACTION

Known as the "resurrection drug" because of its ability to revive comatose patients with sleeping sickness, eflornithine first was discovered in the 1970s by scientists at the Merrell Research Institute in Strasbourg, France. The initial focus was cancer, based on the idea that it acted as a suicide inhibitor ornithine decarboxylase, an enzyme important for cell division and proliferation. But cancer studies, such as Ilex Oncology Inc.'s phase III trial in superficial bladder cancer, fell short of endpoints. (See BioWorld Today, Jan. 20, 2004.)

Meanwhile, eflornithine was showing tremendous success in the neglected tropical disease area, proving an effective treatment for African trypanosomiasis, or sleeping sickness, for which it is given intravenously. A later serendipitous discovery found the drug could inhibit an enzyme in hair follicles, and a topical cream version of eflornithine gained approval for hirsutism.

But interest in developing the drug against cancer remained.

"I wouldn't say [those earlier trials of eflornithine] failed," Myers explained. "This is a new mechanism of action. Cytotoxic agents kill cells; [eflornithine] is intended to stop cells from growing." So it made sense to look at combining eflornithine with a cytotoxic agent, such as lomustine.

Also, "10 to 12 years ago, we were looking at overall response rate – are tumors shrinking?" he added. "Stable disease is now becoming much more important."

In an earlier randomized study conducted by academic researchers – the largest in patients with newly diagnosed or recurrent anaplastic astrocytoma – data showed increased overall survival with eflornithine, both as a single agent and in combination with cytotoxic agents, Myers said.

Those data impressed the FDA, which granted breakthrough therapy designation in 2014. The drug also has orphan status for anaplastic glioma in the U.S. and for glioma in Europe.

So far, the primary and reversible side effects have been diarrhea and hearing loss observed in a small percentage of patients. Orbus also has the advantage of safety data accumulated from eflornithine's use in sleeping sickness and hirsutism.

Other indications could follow anaplastic astrocytoma. "We strongly believe the drug will have [benefit] elsewhere," Myers said. "But our current focus is on this pretty clear patient population."

Orbus appears to be the only company testing eflornithine as a treatment for cancer, though another firm, Cancer Prevention Pharmaceuticals Inc., is using a different approach, testing oral eflornithine (CPP-1X) in combination with sulindac, a nonsteroidal anti-inflammatory drug, as a pharmaco-prevention therapy designed to minimize the progression of polyps and tumors associated with familial adenomatous polyposis, a rare, genetic disease that nearly always progresses to colorectal cancer. A phase III program was launched in 2013, and the firm hit its target enrollment earlier this year. (See BioWorld Today, April 19, 2013.)