Treatment Arms Show Significant Improvement Over Placebo in Three Major Outcomes
Adverse Events Similar Between Treatment Arms and Placebo
Company to Host Conference Call and Presentation Today,
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 scale).
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
Based on these results, Ventrus will request a meeting with the
"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
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."
Results in Detail
I. Study Population
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 pain.
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
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.
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 placebo.
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 placebo: 45.2%). 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 were two subjects with an AE of cardiac disorder (palpitation); one in the 4% diltiazem arm and one in the placebo arm. There was one subject in the 2% diltiazem arm with an AE of hypotension.
There was one serious adverse event of surgery for hemorrhoid reported in this trial (4% diltiazem arm), which occurred during the post-treatment follow-up phase.
There was no difference in the skin irritation scores between arms.
Conference Call and Presentation
The Company is hosting a conference call and slide presentation to discuss results from the Phase 3 diltiazem (VEN 307) study today,
The call will be archived for replay on
About Anal Fissures
Anal fissure is a tear in the lining of the anal canal. It is a common anal disorder characterized by severe anal pain, associated with or after bowel movements. The pathogenesis of anal fissure is hypothesized to be initiated by the passage of a hard fecal bolus, resulting in a split in the epithelium of the anal canal. Along with poor vascular supply of the anal epithelium, increased activity (tone) of the internal anal sphincter smooth muscle further compromises the anodermal blood supply and contributes to the pain and ischemia of the anal epithelium, perpetuating ulceration and preventing healing.
In 2010, it was estimated by
About VEN 307: Diltiazem Hydrochloride cream
Diltiazem hydrochloride is a calcium-channel blocker that has been marketed in oral formulations for the treatment of angina and high blood pressure for over two decades. Diltiazem hydrochloride cream is applied perianally to treat pain related to anal fissure. It has been shown to normalize internal anal sphincter pressure and reduce anal maximal resting pressure, or MRP, and its vasodilator activity has the potential to improve blood supply, thereby decreasing the pain associated with anal fissures.
About S.L.A. Pharma
S.L.A. Pharma is a privately held pharmaceutical company located outside
Ventrus is a development stage pharmaceutical company focused on the development of late-stage prescription drugs for gastrointestinal disorders. Our lead products are: Iferanserin (VEN 309) for the topical treatment of hemorrhoidal disease, for which the first Phase 3 clinical trial began in
Please Note: The information provided herein contains estimates and other forward-looking statements regarding future events. Such statements are just predictions and are subject to risks and uncertainties that could cause the actual events or results to differ materially. These risks and uncertainties include, among others: the timing, cost and results of clinical trials and other development activities involving our product candidates; the unpredictability of the clinical development of our product candidates and of the duration and results of regulatory review of those candidates by the
Ventrus Biosciences, Inc. David Barrett646-706-5208 firstname.lastname@example.org Argot Partners David Pitts212-600-1902 email@example.com
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