Full Press Release Details
ANNOUNCES POSITIVE RESULTS FROM PIVOTAL PHASE 3 TRIAL OF DILTIAZEM (VEN 307) IN PATIENTS WITH ANAL FISSURES
Arms Show Significant Improvement
Over Placebo in Three Major Outcomes
Similar Between Treatment Arms and Placebo
Host Conference Call and Presentation Today, May 14, at 10:00 a.m. ET
NEW YORK, MAY 14, 2012 (GLOBE
NEWSWIRE) -- Ventrus Biosciences, Inc. (Nasdaq:VTUS) today reported positive results from its Phase 3, randomized,
double-blind, placebo-controlled clinical trial of diltiazem hydrochloride cream (VEN 307) in patients with anal fissures.
Ventrus' development partner, S.L.A. Pharma, has completed most of the outputs for the statistical analysis plan of the
Phase 3 trial, and Ventrus is pleased to communicate the data that they have generated.
The Phase 3 study randomized 465
subjects to diltiazem hydrochloride 4% or 2% w/w cream, or placebo, applied topically three times daily (TID) for 8 weeks,
followed by a 4 week blinded observation period. Both 4% and 2% diltiazem treatment arms demonstrated significant
improvements 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, 4%; 0.43, p=0.0134, 2%) and in the secondary endpoints of
overall anal-fissure-related pain (pain score 0.36, p=0.030, 4%; 0.40, p=0.0183, 2%) and anal fissure healing (32.7%,
p=0.0181, 4%; 31.2%, p=0.0359, 2%). Pain endpoints were assessed using an 11-point numerical pain rating scale (Likert-like
Adverse events (AEs) were similar for the
three treatment arms. Gastrointestinal Disorders were the most common. Reports of headaches were similar in the three arms (14.7%
of 4% diltiazem, 12.3% of 2% diltiazem, and 14.2% of placebo). There was one serious adverse event of surgery for hemorrhoid reported
in this trial. The study was conducted in 31 centers in Europe by S.L.A. Pharma, the product candidate's licensor. Ventrus
holds rights to diltiazem hydrochloride cream in North America.
Based on these results, Ventrus will request
a meeting with the U.S. Food and Drug Administration (FDA) to discuss the Phase 3 diltiazem study, as well as steps to move forward
toward a New Drug Application (NDA). Because diltiazem is approved in oral formulations for the treatment of angina and high blood
pressure, it is eligible for the FDA's 505(b)2 registration pathway. The Company is also preparing to initiate a second
pivotal Phase 3 study of VEN 307 in anal fissures in the second half of 2012.
"These results mark a watershed event for Ventrus,
in that they highlight the potential for VEN 307 to be a treatment of choice for anal fissures and set off a potentially transformative
period for the Company," said Russell H. Ellison, M.D., M.Sc., Chairman and Chief Executive Officer of Ventrus Biosciences,
Inc. "The outcome of this study exceeded our expectations, demonstrating an improvement in all three measures of efficacy
- pain on defecation, average daily pain and healing - results never before achieved in a single trial of a topical
drug in this disorder. We look forward to next steps in the clinical and regulatory process, and to bringing VEN 307, as expeditiously
as possible, to those suffering from anal fissures."
Dr. Ellison added: "We thank our
partners and colleagues at S.L.A. Pharma for conducting a high quality, well executed study, and for their timely reporting of
outcomes. These results come as Ventrus prepares for near-term pivotal data from a second pipeline product, VEN 309, in hemorrhoidal
disease. Combined, these product candidates may represent very significant advancements for two of the most prevalent and underserved
disorders in gastroenterology."
The study randomized 465 subjects
1:1:1 to three treatment arms, 4% or 2% diltiazem hydrochloride cream or placebo applied topically three times daily (TID) in
and around the anus for 8 weeks. To be eligible for the study subjects must have had an average baseline Numerical Rating
Scale (NRS), Likert Scale, score of 4 for worst pain associated with or following defecation during the 7 day screening
period. Baseline score for worst anal pain on defecation was the average of the last three NRS scores recorded during the 7
days prior to randomization; baseline score for the overall anal pain was the average of all recorded overall daily anal pain
scores during the 7 day screening period. Subjects used a telephone Interactive Voice Response System (IVRS) daily to report
There were 520 subjects screened, 465
randomized, and 440 subjects that completed the 12 week study period. Of the 25 subjects that discontinued, 15 were during
the first 4 weeks (5 per arm), 9 during weeks 5-8 (4% diltiazem: 3, 2% diltiazem: 1, and placebo: 5), and 1 during weeks 9-12
in the 2% arm. Three of the subjects that discontinued during the first 4 weeks were due to an adverse event (headache, anal
eczema, and pain in the anal region).
There were 465 subjects randomized to the
study, 156, 154, and 155 subjects randomized to the 4% diltiazem, 2% diltiazem, and placebo arms respectively in the Intent to
Treat (ITT) population as well as the Safety population. There were 402 subjects in the per-protocol population, 132, 134, and
136 to the 4% diltiazem, 2% diltiazem, and placebo arms respectively. The majority of the subjects were randomized in Romania with
309, 86 Bulgaria, 30 Germany, 17 Lithuania, 14 UK, and 9 from Spain. Mean age ranged from 42.5 to 44.2 years, with 56.6% females
and 43.4% males. All subjects were Caucasian in the study except one Asian subject in the placebo arm.
The primary endpoint was change from baseline
in average of worst anal pain associated with or following defecation ("worst anal pain") for Week 4 (7 treatment days
preceding the Week 4 visit). The secondary endpoints included: Change from baseline in average of daily overall anal fissure (AF)
-related pain ("daily overall anal pain") for each week, proportion of subjects who have complete healing of AF by
Week 8, percentage of subjects achieving an average of 30% reduction from baseline in the NRS for worst anal pain for Week
4, and Patient Global Impression of Improvement (PGI-I) by Week 4.
All randomized subjects were included in
the analysis (ITT). Missing NRS scores were baseline observation carried forward (BOCF) for all missing pain scores due to discontinuation
for AE or loss of efficacy (n=4) and last observation carried forward (LOCF) for all other missing pain scores. Mean baseline NRSs
were balanced across the three treatment arms (4% diltiazem: 6.40, 2% diltiazem: 6.21, and placebo: 6.38). There was no treatment-by-center
interaction for the primary endpoint analysis. The primary endpoint of Week 4 change in NRS for worst anal pain was analyzed using
a model that included treatment, center, mean baseline NRSs and previous failure with GTN (glycerine trinitrate).
Both 4% and 2% diltiazem treatment arms
demonstrated statistically significant improvement over placebo for change in Week 4 NRS for worst anal pain. Reduction in pain
score was 0.44 (p=0.0108) and 0.42 (p=0.0134), for 4% and 2% diltiazem, respectively. The significant response started at Week
3 for both arms and continued to Week 8, with a reduction in pain score of 0.51 (p=0.006) and 0.41 (p=0.022) for 4% and 2% respectively
at Week 8. As a sensitivity analysis, BOCF was used for all missing pain data, results were essentially unchanged with reduction
in pain scores at Week 4 of 0.39 (p=0.017) and 0.41 (p=0.0118), for 4% and 2% diltiazem, respectively.
Secondary Endpoints:
The secondary endpoint of overall daily
AF-related anal pain for Week 4 was significant for both the 4% and 2% diltiazem arms vs. placebo with a reduction in pain
score of 0.36 (p=0.030) and 0.40 (p=0.0183) respectively. Mean baseline NRS were balanced across the three treatment arms (4% diltiazem:
5.84, 2% diltiazem: 5.93, and placebo: 6.04). The significant response started at Week 2 for the 2% diltiazem arm and continued
to Week 8, with a reduction in pain score of 0.63 (p=0.001) at Week 8. The significant response started at Week 4 for the 4% diltiazem
arm and continued to Week 8, with a reduction in pain score of 0.55 (p=0.004) at Week 8.
Healing at Week 8 was significantly improved
for both 4% and 2% diltiazem arms compared to placebo, 32.7% (p=0.0181) and 31.2% (p=0.0359) vs. 23.9%, respectively. There was
no significant difference from placebo in healing at Week 4.
Subjects were classified as responders
if their Week 4 reduction in worst anal pain NRS was 30% reduction from baseline. 56% of subjects on 4% diltiazem and 47% of
subjects on placebo were classified as responders (p=0.048). There was no difference in the response rate in the 2% diltiazem and
There was no difference in the overall
daily anal pain between arms for 30% reduction in NRS from baseline to Week 4.
The PGI-I showed a significant difference
between 2% diltiazem vs. placebo at Week 4 and 8 with p=0.0106 and 0.0328 respectively. There were no significant differences in
the PGI-I with 4% diltiazem and placebo.
Analgesic usage was not increased in either
active treatment arm compared to placebo. The average number of days/week for analgesic use was significantly lower for weeks 1-4
for the 2% diltiazem arm vs. placebo (p=0.034).
Safety and Tolerability:
Adverse events (AEs) were similar for the
three treatment arms. Gastrointestinal Disorders were the most common (4% diltiazem: 65.4%, 2% diltiazem: 59.1%, and placebo: 54.2%).
The majority of the Gastrointestinal Disorders were anal pain recorded as an AE (4% diltiazem: 42.3%, 2% diltiazem: 41.6%, and