As Edge Therapeutics Inc. sifted through the wreckage of its phase III trial with EG-1962 (nimodipine microparticles), analysts wanted an explanation of how the study could have passed the futility analysis – which just happened in December – by the data monitoring committee (DMC), and fail the interim peek.

Answers weren't coming. Shares of Berkeley Heights, N.J.-based Edge (NASDAQ:EDGE) plunged 91.6 percent, or $14.28, to close $1.31, as the market reacted to news from the Newton 2 study in adults with aneurysmal subarachnoid hemorrhage (aSAH). A pre-specified analysis performed on data from the day 90 visit of the first 210 subjects randomized and treated turned up a low probability that the drug would make a statistically significant difference compared to the standard of care: an oral form of nimodipine, a calcium channel blocker. The study's primary endpoint was a score at the 90-day mark of 6 to 8 on the extended Glasgow Outcome Scale, which is used to predict long-term functional outcome in patients with brain injuries. The DMC recommended the trial stop.

During a 10-minute, all-she-wrote-style conference call with the company, Credit Suisse analyst Martin Auster said he was "surprised by the abrupt turn in the study" since December. "I assume not too many additional samples are included between then and now," he said, estimating about 60 patients' worth of data. He asked if, based on separations between placebo and drug groups, the company had considered expanding patient enrollment at the time.

CEO Brian Leuthner replied that Edge "followed what the DMC instructed us to do at that time, which was to carry on with the study. The only thing we could do was listen to what their recommendation was, and that was to go forward."

Patients in the experimental arm of Newton 2 received a single 600-mg intraventricular injection of EG-1962 plus placebo capsules or tablets administered for up to 21 days. Patients in the active comparator arm were given a single dose of intraventricular normal saline and up to 21 days of oral nimodipine capsules or tablets. Along with the Glasgow score, neurocognitive outcome at day 90 was measured by the Montreal Cognitive Assessment method, as were safety (including delayed cerebral infarction at day 30) and health economic endpoints.

"The drug performed as we expected," Leuthner said. "What we didn't expect is the observed improvements in functional outcome in the control group," which tallied "higher than the response rate of any past clinical study, any data that we're aware of, and that's in a similar patient population," he said.

The company is figuring out what's next, but said cutbacks are likely in operations and in the workforce to spare cash. Edge reported $88.1 million in the bank at the end of last year. Chief Financial Officer Andrew Saik said the company has "been pretty consistent about giving guidance that our spend rate is around $4 million to $5 million per month. We've been spending at or about that level." He said the firm would provide further guidance in May.

An aSAH takes place when a brain aneurysm ruptures and causes bleeding into the compartment surrounding the brain, the subarachnoid space. Often the aneurysm heals over, bleeding stops and the person survives, but the condition can cause brain damage with paralysis, coma and death.

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Nimodipine is approved as an oral drug to be given six times per day for 21 days, but can cause hypotension. EG-1962 is designed to go directly into the brain, once, and achieve the same duration of exposure without such side effects. Edge had cause for optimism regarding Newton 2, as a phase I/II Newton study yielded good results. (See BioWorld Today, June 6, 2014.)

In 2013, the FDA cleared for marketing a liquid nimodipine solution, branded Nymalize by Atlanta-based Arbor Pharmaceuticals LLC. The compound previously had been available as liquid-filled gel capsules intended for oral use, but regulators got wind of serious and sometimes fatal consequences of using the capsules' contents intravenously. In August 2010, the FDA reminded doctors about the risks of such an approach, which had been the reason for a 2006 boxed warning on the capsules. Nymalize can be given by mouth, nasogastric tube or gastric tube, so there's no need for a needle, which is what caused problems before. The oral version of nimodipine originally was sold by Bayer AG, of Leverkusen, Germany, but has since become available as a generic drug. Last September, Arbor made Nymalize available in a 10-mL (30-mg) unit dose cup, designed for patients who require a dosage that is lower than the standard 20 mL (60 mg).

A condition related to aSAH made news earlier this month in connection with a separate, already approved compound for another indication, namely Kineret (anakinra), the interleukin-1 receptor antagonist from Stockholm-based Swedish Orphan Biovitrum AB, a rheumatoid arthritis therapy. Researchers at the University of Manchester and Salford Royal NHS Foundation Trust published findings in Stroke that show giving Kineret by injection reduces inflammation in ischemic stroke. Eighty participants in the study, who had a mean age of 72, were given six doses of the drug or a placebo over three days in a phase II trial. The first dose was given within six hours after the first stroke symptoms. In previous Manchester research, the drug proved similarly beneficial for aSAH patients.

Other research is ongoing to help people with aSAH. Idorsia Ltd., of Allschwil, Switzerland, has phase III-ready clazosentan, an endothelin receptor antagonist, in the works for vasospasms associated with aSAH. Idorsia was formed as a spin-out of Actelion Ltd.'s drug discovery capabilities, early stage assets and clinical pipeline as part of its acquisition by Johnson & Johnson, of New Brunswick, N.J., in June 2017. In the $30 billion takeover deal, J&J paid $280 cash per Actelion share to acquire its slate of commercial products and two late-stage clinical development assets. Actelion's shareholders retained ownership of the company's drug discovery and early clinical development operations in what was provisionally dubbed R&DNewco and later became Idorsia. (See BioWorld Today, Jan. 27, 2017.)