A drug for gastrointestinal troubles shelved during Aryx Therapeutics Inc.'s 2011 demise is back in action at Renexxion LLC propelled by new FDA guidance setting aside the requirement for pre-approval cardiovascular safety outcome studies, the costly prospect of which scuttled the program's advancement at Aryx.

"We're very optimistic that we're looking at an NDA and a new drug out on the market by 2019 or maybe 2020," David Ryan, Renexxion's chief operating officer and general counsel told BioWorld Today. "Our focus now is very much on finding the optimum pathway to that approval."

Renexxion is exploring both chronic indications for which an oral formulation could work, such as chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C), and acute indications in which an intravenous formulation or single-dose oral solution would be more appropriate. Those include tube feeding, acute gastroparesis, short bowel syndrome and postoperative intestinal traffic-jams, or ileus.

The small Menlo Park, Calif.-based company will explore all potential avenues to move ahead, said Ryan, including licensing, a joint venture, a series A financing or even an eventual initial public offering, all ultimately serving to underwrite the estimated $50 million to $60 million cost of a phase III program.

"We believe we have a very clear pathway at this stage for phase III in CIC and IBS-C," Ryan said.

The regulatory breakthrough for Renexxion arrived during a recent meeting of the FDA's Division of Gastroenterology and Inborn Errors Products and a Center for Drug Evaluation and Research subcommittee dedicated to safety outcomes trials. During the meeting, "it was agreed that the necessary safety database for naronapride development for CIC and other functional GI disorders does not require statistical powering for cardiovascular outcomes," Renexxion said. The decision: Two randomized blinded placebo-controlled clinical trials of 1,000 subjects, each 12 weeks long, will be sufficient for filing of a new drug application for naronapride in CIC. Safety trials will be limited to 12 months total exposure in the 2,000 participants in addition to the 982 subjects already exposed to the drug during four positive phase II studies, conducted by former Aryx partner Procter & Gamble, which ultimately returned its rights to the drug in July 2008. (See BioWorld Today, July 13, 2006.)

In addition to Ryan, Renexxion is led in part by Aryx co-founders Peter Milner and Pascal Druzgala, both of which have funded the new company with Atheneos Capital. Milner is Renexxion's CEO while Druzgala is its chief scientific officer, a role he also holds at another Aryx descendant, Armetheon Inc. Ken Kengatharan, co-CEO of Armetheon is Renexxion's chair. (See BioWorld Today, Feb. 22, 2010, and April 15, 2013.)

Once a key candidate at Aryx, naronapride was derailed when the FDA put the brakes on approval of new 5HT-4 agonists – the class to which naronapride belongs – in the wake of concerns about heart safety risks that drove global market withdrawals of Propulsid (cisapride, Janssen Pharmaceutica NV) and Zelnorm (tegaserod, Novartis AG).

The problem for cisapride at least was cardiovascular toxicity due to a high affinity for the hERG channel, noted Druzgala. "Certain patients could literally drop dead all of a sudden (torsades de pointe, a lethal form of cardiac arrhythmia) if the blood concentration became too high," something that could happen when they were taking another drug that inhibited cisapride metabolism, he noted.

Though naronapride shares a class with cisapride, it is designed with very low affinity for the hERG channel and so that it is metabolized by metabolic pathways that are not common to other drugs, reducing the chances of other drugs interfering with its metabolism. Naronapride is also designed so that its main metabolite, ATI-7500, is inactive and rapidly eliminated from the body, he said.

Tegaserod on the other hand had problems with side effects due to affinity for serotonin receptors other than 5-HT4, specifically 5-HT2A and 5-HT2B, according to Druzgala. Naronapride was engineered to be specific for the 5-HT4 receptor, he said.