Login to Your Account



Pharmaleads seeks funds for dual enkephalinase inhibitors

pharmaleads_may_17_2017.jpg

By Cormac Sheridan
Staff Writer

DUBLIN – Pharmaleads SAS is like the comeback kid who never went away. The French drug developer has spent a decade quietly focused on a novel drug mechanism in pain that was long disregarded by others in the field. The accrual of preclinical and early clinical data on its two lead drug candidates, combined with findings from other labs, have now brought it to the point where the rubber hits the road.

“Nobody really believed in this concept until we came up with some results,” Michel Wurm, director of corporate development at the Paris-based firm, told BioWorld Today.

The company aims to have readouts from three phase II trials by the end of 2018. Even one positive result would put it in pretty good shape. But it requires some cash to get to that point. “We need some fuel in the engine,” Wurm said.

The company’s scientific founders, Bernard Roques and Marie-Claude Fournié-Zaluski, pioneered a drug class called dual enkephalinase inhibitors, or “Denkis.” They are designed to inhibit the activities of two enkephalinases, neprilysin (NEP) and aminopeptidase N (APN), which are responsible for the breakdown of the enkephalins, endogenous ligands that bind opioid receptors and act as natural painkillers.

“They are the most potent pain modulators in the body,” Wurm said. “They are very rapidly degraded in order to maintain the alarm function of pain.” Delaying that process is the company’s goal. “The underlying concept is to increase their half-life and thereby increase their concentration, by inhibiting the two enzymes that degrade them.”

The approach is based on the idea that the drugs will only work where they are needed – as concentrations of the enkephalins and their inactivating enzymes are elevated at the site of nerve injury.

Roques and Fournié-Zaluski described the first such molecule more than three decades ago. But much of their focus was on building an academic understanding of the drug mechanism. Many early leads were not drug-like. Formal drug discovery started around a decade ago and yielded two clinical-stage candidates, PL-37 and PL-265, which share the same mechanism but not the same chemistry. Each is delivered as a prodrug, but PL-37 comprises two separate inhibitory activities that are joined by a disulphide bridge. Cleavage of that – in either the liver or intestinal mucosa – is required for activity. PL-265, in contrast, merely requires hydrolysis to become active, enabling it to be dosed locally or topically.

Their differing structures translate into differing pharmacokinetic profiles. PL-265 has a much longer duration of action, Wurm said, whereas PL-37 has a rapid onset of action but a short duration of activity. It can be taken orally but is also ideal for intravenous administration, he said.

It’s taken some time to understand their differing potentials: PL-37 has already been tested in patients with diabetic neuropathy in a short-duration phase IIa trial. The company has now decided to terminate its development in that indication, and to move PL-37 into breakthrough cancer pain and postoperative neuropathy instead. Migraine is another possibility for the drug, which would require reformulation, in order to take advantage of its ability to cross the blood-brain barrier.

“The goal is to be a substitute for morphine and injectable opiates,” Wurm said.

Meanwhile, the company is positioning PL-265 for neuropathy indications. It will conduct a European phase II trial in diabetic neuropathy and a U.S. trial in postsurgical neuropathic pain. “We will go for an American IND next year,” Wurm said.

PL-265 also has potential as a topical treatment for ocular pain indications. The company last week presented data in animal models of corneal injury and inflammatory pain and at the Association for Research in Vision and Ophthalmology 2017 meeting in Baltimore. The company is in talks with prospective partners about licensing out rights to the drug in ophthalmology, a move that would raise some cash to fund its other programs.

SYNERGY WITH NAV1.7 INHIBITORS

The company was buoyed by data published online in Nature Communications on Dec. 4, 2015, which suggested a causal association between elevated levels of enkephalin and the insensitivity to pain associated with loss-of-function mutations in the gene encoding the Nav1.7 sodium channel, one of the hottest targets in pain. The study was led by John Wood, of University College London, who was part of the original group of scientists who identified Nav1.7 as a target in a study involving members of a Pakistani family who shared an inherited insensitivity to pain. That original finding, reported in the Dec. 14, 2006, issue of Nature, has spurred a whole cluster of drug development programs. (See BioWorld Insight, Dec. 12, 2016.)

Not all of them have been successful, however. No drug, Wurm said, will capture the full effect of a deletion in SCN9A, the gene that encodes Nav1.7. The complexity of neuropathy dictates the necessity of drug combinations. Assuming at least some members of the Nav1.7 inhibitor class go all the way, Pharmaleads wants to position its drugs alongside them. “We have strong synergy with Nav1.7 inhibitors,” he said.

Pharmaleads is the only firm working on dual enkephalinase inhibitors, but Novartis AG’s heart failure drug, Entresto, comprises a 1-to-1 combination of the neprilysin inhibitor sacubitril and the angiotensin receptor blocker valsartan. Its approval helped to rehabilitate NEP inhibitors, which had been wrongly tainted by angioedema concerns around 15 years ago, Wurm said, following the failure of omapatrilat, a hypertension drug comprising a NEP inhibitor and an angiotensin-converting enzyme, which Bristol-Myers Squibb Co. had been developing. (See BioWorld Today, July 9, 2015.)

Most pain indications are notoriously difficult areas for drug development because of patients’ differing pain thresholds and the inherent variation in the experience of pain.

“An objective assessment is possible in postsurgical conditions, because you can measure the consumption of morphine,” Wurm said, but added that subjective pain assessment and large placebo effects have “ruined many, many trials in chronic pain.”

The company has obtained preliminary and tentative findings that some patterns of patient responses to the DN4 questionnaire, a standard diagnostic for diabetic neuropathy, identify nonresponders. If confirmed more robustly, that could help the company in setting inclusion criteria for future trials.