Ventrus Could Start Pivotal Trial For Rx Hemorrhoid Therapy Mid-Year

Ventrus Biosciences Inc. is ready to take its lead candidate iferanserin, a novel compound aimed at arresting hemorrhoid symptoms rather than soothing them, into Phase III studies after the micro-cap biotech's late-December initial public offering brought in $20 million to support the program.

For such a small company, "there's a certain noise level you've got to rise above, and we got lucky there because it's an interesting story of a late-stage product in a market where nobody's done anything for about 70 years," CEO Russell Ellison said in an interview. "I think [the success of the IPO] had a lot to do with getting our story out to a broader audience."

A noteworthy aspect of the IPO is that the shareholders are largely retail as opposed to institutional investors, Ellison pointed out, adding that many who bought stock are physicians. "This is a tremendous retail story and a huge participation in the IPO was in fact retail, something we haven't seen since the '90s," Ellison said.

On Dec. 23, Ventrus announced it had closed an offering of 2.9 million shares, and then on Jan. 7 came news that the underwriters of the IPO, Rodman & Renshaw LLC and National Securities Corp., had exercised in full their over-allotment option to purchase an additional 435,000 shares of stock at $6 per share. Including the over-allotment, a total of 3.335 million shares were sold, grossing about $20 million.

New York-based Ventrus has plenty of cash to take both iferanserin and a second late-stage compound, diltiazem cream for anal fissures, to Phase III study endpoints "and have runway to do something about it," Ellison said during a presentation Feb. 14 at the BIO CEO & Investor Conference in New York.

New SPA Endpoints Make For A Stronger Label

Ventrus has been working with FDA on a trial design and endpoints to test prescription hemorrhoid products, since iferanserin (VEN 309) would be the first to market if approved. "It's been really great working with the GI division. They've been incredibly transparent and thoughtful," Ellison said.

Contingent on a revised special protocol assessment, which Ventrus hopes to hear on by mid-May, the first Phase III trial is shaping up to be about 400 patients at 60 U.S. sites randomized to drug plus ointment versus ointment alone. The ointment is applied using a single-use applicator twice daily for two weeks.

The company got feedback from the agency on the endpoint definitions in its proposed protocol in mid-March that could "provide a much stronger label" that would encourage faster and broader adoption of the therapy, the firm said. Ventrus has amended the protocol and resubmitted it.

The study is still on track to launch mid-year, with enrollment completed by the end of December and results from the double-blinded phase reporting in the first quarter of 2012.

The endpoints are unambiguously tied to cessation of symptoms, Ellison said in the interview. "This is very important because both FDA and the company wanted endpoints that were very clinically meaningful and incontrovertible. No worries about scale validation, etc. You really have to stop having symptoms."

The primary endpoint now is proportion of patients with cessation of bleeding by the end of day seven that persists for the remainder of the treatment period (through day 14). A key secondary endpoint is proportion of patients with cessation of pain and/or itching by the end of day seven that persists for the remainder of the treatment period (through day 14).

Having clear evidence of clinically meaningful benefit from the study endpoints will be important for the company. Instead of turning to over-the-counter products, "patients are going to have to pay a copay here, and they have to believe it's worth it," Ellison said. He didn't expect that intra-anal steroids, the only prescription alternative, could meet the same endpoints. "I would be very surprised if they could. Who knows? There's no data."

Enrollment criteria are two days of consecutive bleeding at randomization with two days of either pain or itching, and hemorrhoids that "pretty much do not require surgery," Ellison said.

The treatment period is two weeks, with a two-week follow-up, and then patients who complete the 28 days have access to the drug open label for a year for treatment of recurrence. Recurrence is important to FDA, stressed Ellison. One thing Ventrus hopes to determine is what a recurrence rate might look like with an effective drug treatment for hemorrhoids, because one has never been approved.

Because a patient could have as many as 12 retreatments in a lifetime, Ventrus has to do a full chronic use NDA with 1,500 patients exposed, as well as the accompanying animal carcinogenicity and toxicology studies.

Because the product will entail chronic use, Ventrus is planning a second Phase III trial in recurrent patients.

A second Phase III, in recurrent patients, will be planned based on the results of the first study. "We'll probably want that in our filings because this is seen as a chronic use drug," Ellison said.

Iferanserin works by blocking the 5HT2a receptor, which is involved in clotting and contraction of arteries and veins. Once the receptor is under control, blood flow out of the dilated hemorrhoidal area is improved, and itching and pain are relieved. The science underlying the drug's mechanism was discovered in the 1990s but has never been published.

The compound is less than 10% bioavailable and very specific only to 5HT2a receptors, and it is administered at too low a dose to cross the blood-brain barrier, Ellison explained at the BIO CEO Conference in reference to serious adverse events seen with 5HT2 receptors and weight-loss drugs.

A Repurposed Compound To Treat Anal Fissures

The other advanced candidate, diltiazem cream (VEN 307), is a topical treatment for the relief of pain associated with anal fissures, small tears or cuts in the skin that lines the anus. There also are no FDA-approved drugs for this indication, though Cellegy/ProStrakan have spent more than seven years trying to gain approval for nitroglycerin ointment Rectogesic (formerly Cellegesic).

Currently, according to Ventrus, gastroenterologists order diltiazem from compounding pharmacists individually for each patient.

Ventrus will likely be able to use the 505(b)(2) pathway to seek approval of diltiazem for anal fissures.

Diltiazem, used for decades for hypertension and angina, dilates the blood vessels supplying the region, reduces anal sphincter tone and thereby decreases pain. Much data is available on the molecule, and it is likely Ventrus will seek approval via the 505(b)(2) NDA pathway (Also see "Ventrus Biosciences Inc." - Scrip, 1 Jan, 2010.).

SLA Pharma AG, Ventrus' partner for the compound outside of North America, began a European Phase III study of the anal fissure product in November, with data possible in the second quarter of 2012. The study is enrolling 465 patients at 30 sites, randomized to one of two strengths of the test drug or placebo.

A third candidate may be progressed in 2012, phenylepherine gel (VEN 308) for fecal incontinence, depending on the readouts from the first two products, Ellison said. The gel has had clinical proof of concept studies, and there are quite a few investigator-initiated trials in the prospectus, but it still needs a Phase IIb to get the dose right and possibly some formulation work, he said.

By Shirley Haley