Shares of Ventrus Biosciences Inc. (NASDAQ:VTUS) gained 14.8 percent Monday, closing at $12.58, after the company reported improvement in three measures of efficacy in a pivotal Phase III study of VEN 307 (diltiazem hydrochloride cream) in anal fissures.

Because anal fissures have largely been ignored by drug developers, gastroenterologists often prescribe specially compounded diltiazem or nitroglycerin, which has numerous side effects. VEN 307 would become the first FDA-approved treatment for pain associated with the condition.

A calcium channel blocker, diltiazem hydrochloride has been marketed in oral formulations for more than two decades to treat angina and high blood pressure. Applied perianally, the drug has been shown to normalize internal anal sphincter pressure and to reduce anal maximal resting pressure. Its vasodilator activity has the potential to improve blood supply, thus decreasing pain associated with anal fissures.

The condition – a tear in the lining of the anal canal characterized by severe pain during or following bowel movement – results in more than 1 million physician office visits annually. Poor vascular supply of the anal epithelium combined with increased activity of the internal anal sphincter smooth muscle often perpetuate ulceration, leading to surgery, explained Russell H. Ellison, chairman and CEO of New York-based Ventrus.

The placebo-controlled trial randomized 465 subjects to two doses of VEN 307 or placebo three times daily for eight weeks, followed by a four-week blinded observation period. Both the 4 percent and 2 percent diltiazem treatment arms demonstrated significant improvement compared to placebo in the primary endpoint of average of worst anal pain associated with or following defecation (pain score improvement 0.44, p = 0.0108 at 4 percent; 0.43, p = 0.0134 at 2 percent) and in the secondary endpoints of overall anal-fissure-related pain (pain score 0.36, p = 0.030 at 4 percent; 0.40, p = 0.0183 at 2 percent) and anal fissure healing (32.7 percent, p = 0.0181 at 4 percent; 31.2 percent, p = 0.0359 at 2 percent).

"To be honest, the outcome of this study exceeded our expectations," Ellison told BioWorld Today. "We got the two symptomatic endpoints in pain that matter the most to patients in addition to a very meaningful effect on healing. These three endpoints have never been shown in a single trial." The study was conducted in 31 centers in Europe by S.L.A. Pharma AG, a privately held pharmaceutical firm located outside Basel, Switzerland, with an operations arm in the UK, that licensed rights to the product from St. Mark's Hospital and Research Institute in London, which developed the drug's topical formulation and conducted proof-of-concept studies. In turn, Ventrus licensed rights to diltiazem hydrochloride cream in North America.

Ventrus is "pretty agnostic" about dose selection, Ellison said, and expects to receive guidance from the FDA when meeting to discuss the Phase III findings. Because diltiazem is approved in oral formulations for angina and high blood pressure, the compound is eligible for the FDA's 505(b)2 registration pathway.

In the meantime, Ventrus plans to initiate a second pivotal Phase III of VEN 307 in anal fissures, primarily in the U.S., in the second half of the year, with a new drug application (NDA) filing expected by the end of 2013.

"Given a standard PDUFA, we could commercialize in the second half of 2014," Ellison said.

Ventrus also is anticipating near-term data from lead compound VEN 309 (iferanserin ointment) in the larger indication of hemorrhoidal disease. The Phase III trial, under way at 74 U.S. sites, is fully enrolled, with data expected to report in late June or early July. Because the drug would be used in a chronic, recurrent, intermittent-use condition, positive findings would trigger additional carcinogenicity studies, a second pivotal trial and a double-blind recurrence trial similar to the Phase III TARGET 3 trial by Salix Pharmaceuticals Inc., of Raleigh, N.C., in patients with irritable bowel syndrome with diarrhea (IBS-D).

In the Salix study, subjects with IBS-D will be treated with Xifaxan (rifaximin), and those who respond to the initial course of treatment will be followed until symptoms recur. At that time, they will undergo double-blind randomization either to another course of Xifaxan or placebo. The primary endpoint is the proportion of subjects who responded to repeat treatment in both IBS-related abdominal pain and stool consistency compared to placebo during a four-week treatment-free follow-up period.

Salix plans to submit the analysis from TARGET 3 in response to the FDA's 2011 complete response letter on its supplemental new drug application for Xifaxan in IBS. (See BioWorld Today, Nov. 15, 2011, and Feb. 25, 2011.)

Ellison hopes for a smoother regulatory pathway for VEN 309, which has highly selective, antagonistic activity against peripheral 5-HT2A receptors involved in clotting and in the contraction of arteries and veins – events believed associated with hemorrhoid formation. By limiting 5-HT2A receptor activity, VEN 309 improves the flow of blood out of the dilated veins that comprise the hemorrhoid, thereby reducing bleeding, itchiness and pain

"There's never been an NDA for hemorrhoids," Ellison said. "There haven't even been well-designed, managed, controlled clinical trials. We've spent a lot of time working with FDA trying to figure out how to do the trial. We've been building it from the ground up, and you almost never get that chance these days."

The company expects to commercialize VEN 309 – to which it holds global rights – in the U.S., Europe and Japan and partner out the rest of the world after the pivotal data report. With $31.1 million in cash on hand as of March 31, that strategy should provide sufficient assets to complete the development and commercialization of VEN 307 and VEN 309, especially since Ventrus will target the small cadre of gastroenterologists and colorectal surgeons who specialize in anal fissures about one year before the hemorrhoid product likely would be launched.

Ventrus, which went public in 2010 through an initial public offering, has one additional product, VEN 308, a topical phenylephrine gel for fecal incontinence associated with ileal pouch anal anastomosis. (See BioWorld Today, Dec. 20, 2010.)

That candidate has FDA orphan drug designation, so "we're not burning exclusivity by waiting to develop it," Ellison said.