Furiex Pharmaceuticals Inc.says its eluxadoline is well positioned in irritable bowel syndrome with diarrhea-predominant symptoms – a field with only one branded drug option – based on a top-line report from two positive Phase III trials.

In a Feb. 3 interview, the company said it is gearing up for a June FDA filing, as it was set to report positive top-line results for two studies of eluxadoline, which has Fast Track status with the FDA, in about 2,400 patients with IBS-d. In the 3001 and 3002 trials, the drug met primary composite endpoints based on simultaneous improvements in stool consistency and abdominal pain, satisfying both FDA and European Medicines Agency requirements, the company announced in a Feb. 4 investor call. And importantly for the safety-conscious space, the results do not appear to raise any safety red flags.

Furiex is targeting a June NDA filing for the locally-acting mu opioid receptor agonist/delta opioid receptor antagonist eluxadoline in IBS-d.

Eluxadoline is a twice-daily, locally acting drug with a dual mechanism of action, as a mu opioid receptor agonist and delta opioid receptor antagonist. Originally developed by Johnson & Johnson’s Janssen unit, the drug was in-licensed in 2011 by Furiex, a spin off of the contract research organization Pharmaceutical Product Development Inc.

Approval would be a major milestone in gastrointestinal disease. Currently only one drug is FDA-approved for IBS-d. GlaxoSmithKline PLC’s 5-HT3 antagonist Lotronex (alosetron) is cleared for women in restricted cases, following withdrawal from the market in 2000 and has a boxed warning. Loperamide, or Immodium, from McNeil Consumer Pharmaceuticals,is used over the counter, but has had the drawback side effect of constipation. Furiex has been betting that eluxadoline’s dual mechanism of action would offer efficacy with better tolerability Also see "J.P. Morgan Notebook: Thursday, January 16" - Pink Sheet, 17 January, 2014..

Some 18 million people in the U.S. have IBS-d, but the company’s target market would be focused on patients with more serious cases, who are likely to seek professional diagnosis and treatment. Furiex estimates the target market ranging from 2 million to 3 million patients in the U.S., with the same size market in Europe.

“One could argue that we have a wide open field for a drug that appears effective,” said Fred Eshelman, founding chairman of Furiex, during the call.

Two Trials, Two Different Endpoints

The two randomized controlled studies trials used different endpoints, in accordance with guidance from the FDA and EMA. The preferred U.S. measure for efficacy tests patients over 1-12 weeks compared to 1-26 weeks in Europe. Study 3002 had a total treatment period of 26 weeks, whereas Study 3001 assessed treatment over 52 weeks; the company explains that because the drug would be used chronically, it needed longer-term randomized data.

Both of the trials tested two doses of the drug – 75 mg twice daily vs 100 twice daily or placebo. To meet the pain efficacy endpoints, a patient would need to improve by 30% from the worst abdominal pain scores in the past 24 hours compared to baseline. The company reported that the effect on abdominal pain did contribute to the composite efficacy endpoint; however, as an individual secondary endpoint, this measure was numerically but not significantly improved. Furiex is looking to strike the right balance and market a dose that is the safest, and the jury is still out on what dose it will submit to FDA and come to market with, Eshelman said.

Key Phase III Efficacy Data For Eluxadoline, Intent-To-Treat Analyses

FDA composite endpoint (response over weeks 1-12)

EMA composite endpoint (response over weeks 1-26)

Study 3002

Eluxadoline 100 mg

*29.5%

*32.6%

Eluxadoline 75 mg

*28.9%

*30.4%

Placebo

16.2%

20.2%

Study 3001

Eluxadoline 100 mg

*25.1%

*29.3%

Eluxadoline 75 mg

*23.9%

23.4%

Placebo

17.1%

19%

*Denotes statistical significance

Eshelman pointed out in the interview that the top-line data are based on rigorous intention-to-treat analyses and that if the company were to look at those who actually had the drug and completed the study, the results might be even better. Furthermore, he said that the company believes that the results will support FDA approval, even though the pain improvement was not statistically significant on its own.

“FDA was quite clear with us that the criterion for approval is the co-primary composite endpoint. They told us that they would like to see trends in the secondary endpoints. Approval … is going to be based on the composite, which we hit quite handily,” Eshelman said.

Some clinician investigators in the field believe that because IBS is considered somewhat of a lifestyle disease, the safety bar is very high for new drugs to get approved Also see "Market Snapshot: Taking Constipation Seriously – Linaclotide Success Raises Hopes For Market Resurgence" - Pink Sheet, 4 July, 2011.. Furiex reported that eluxadoline had a favorable tolerability and safety profile; the most commonly reported side effects in the two studies were constipation (8.3% for 100 mg eluxadoline, 7.4% for 75 mg eluxadoline and 2.4% for placebo) and nausea (7.3% for 100 mg eluxadoline, 7.8% for 75 mg eluxadoline vs. 4.8% placebo). Investigators also reported a small rate of sporadic elevations of liver enzyme in both study arms, all of which resolved. Infrequent mild pancreatitis was reported in five patients who received eluxadoline (0.3%).

The drug acts locally, with very minimal systemic absorption, commented June Almenoff, chief medical officer. Those who drink heavily or have had their gall bladder out previously could have a risk of mild pancreatitis.

However, Alemenoff added, “we feel we have a very clear way to communicate with prescribers, so that should be quite manageable.”

The company said it is keeping its options open following the release of Phase III data with respect to plans to market or commercialize the drug on its own.

“With a post-Phase III asset in an area of high prevalence and unmet medical need, we are going to be surprised if we don’t get a fair amount of interest,” Eshelman said.

Furiex Makes Inroads In Tough-To-Treat IBS-d With Phase III Eluxadoline Data

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