ViroPharma Announces Publication of Cinryze(TM) (C1 Esterase Inhibitor [Human]) Phase 3 Trial Results in Hereditary Angioedema (HAE) in the New England Journal of Medicine
EXTON, Pa., Aug. 5 ViroPharma Incorporated (Nasdaq: VPHM) today announced that data from Phase 3 studies of Cinryze(TM) (C1 esterase inhibitor [human]) have been published in the August 5, 2010 issue of the New England Journal of Medicine. The paper entitled Nanofiltered C1 Inhibitor Concentrate for Treatment of Hereditary Angioedema by Dr. Bruce L. Zuraw et al. describes the safety and efficacy of Cinryze in treating and preventing attacks of hereditary angioedema. Cinryze is the first and only FDA-approved C1 esterase inhibitor therapy indicated for routine prophylaxis against angioedema attacks in adolescent and adult patients with hereditary angioedema (HAE), a rare, debilitating and potentially fatal disease; it is not approved by the FDA to treat acute angioedema attacks.
According to the publication, when used for prophylaxis, Cinryze significantly reduced the frequency of hereditary angioedema attacks (p<0.001), in addition to reducing the severity and duration of attacks, the need for open-label rescue therapy and the total number of days of swelling compared to patients receiving placebo. Patients administered Cinryze for acute angioedema attacks experienced a significant reduction in the time to unequivocal relief of symptoms versus those receiving placebo (p=0.02).
In addition, the authors stated that the incorporation of nanofiltration along with pasteurization in the Cinryze preparation provides an additional level of safety that may be particularly important for protecting against non-enveloped viruses and new infectious agents such as prions. With any blood or plasma derived product, there may be a risk of transmission of infectious agents, e.g. viruses and, theoretically, the CJD agent. With Cinryze, the risk of transmission of infectious material has been reduced by screening patients for prior exposure to certain virus infections and by manufacturing steps designed to reduce the risk of viral transmission including pasteurization and nanofiltration.
"Due to the lack of awareness about HAE, which is a rare, debilitating and potentially-life threatening disease, patients are often misdiagnosed and undergo unnecessary exploratory surgeries before receiving an accurate diagnosis," said Zuraw, professor of medicine and program director of the Allergy and Immunology Fellowship Program at the University of California at San Diego, and lead author and principal investigator of the study. "It is vital for healthcare providers to understand the disease and available prophylactic options so HAE patients can be effectively diagnosed and managed. Our hope is that published data like these, showing the safety and efficacy of an FDA-approved therapy such as Cinryze, will educate physicians and patients about the options now available to help prevent HAE attacks."
Cinryze Prophylaxis Study
According to the authors, the prophylaxis study employed a cross-over design to compare Cinryze with placebo in preventing attacks of angioedema during a 24-week period. The study consisted of two consecutive 12-week treatment periods during which subjects received prophylactic injections every 3 to 4 days. Subjects were randomized to receive either Cinryze (1000 U) or placebo during the first period. During the second period, each subject crossed over to receive whichever study medication he or she had not received during the first period. All acute angioedema attacks during the study were eligible for rescue treatment with open-label Cinryze.
The primary efficacy endpoint for each subject and for each treatment period was the number of attacks of angioedema that occurred during each period, normalized to 12 weeks. Secondary end points, reported for each period, included average severity of attacks, average duration of attacks, the number of open-label injections of Cinryze, and the total number of days of swelling. In addition, safety and changes from baseline in antigenic and functional levels of C1 inhibitor were evaluated.
Twenty-four patients were enrolled in the prophylaxis trial and randomized to one of two groups, 12 to placebo and 12 to Cinryze in the first of two 12 week periods. Twenty-two of 24 subjects (11 from each randomized group) completed the first treatment period and then crossed over to the second period, and were included in the end point analyses. Although included in the analysis, 2 of these 22 analyzed subjects (one from each group) failed to complete the second 12 week period.
The average normalized attack rates for all 22 subjects during the two 12-week crossover periods were 6.26 and 12.73 for the Cinryze and placebo treatments, respectively. The estimated average difference in attack rates between Cinryze and placebo was 6.47 (95% CI 4.21 to 8.73; p<0.001). The mean score for the severity of attacks was significantly lower during Cinryze prophylaxis than during placebo (1.3 +/- 0.85 versus 1.9 +/- 0.36, p=0.001). The total duration of attacks was also shorter with Cinryze prophylaxis compared to placebo (2.1 +/- 1.13 versus 3.4 +/- 1.39 days, p=0.002). The number of subjects requiring open-label rescue therapy was less with Cinryze prophylaxis (11 versus 22), as was the total number of open-label injections (4.7 +/- 8.66 versus 15.4 +/- 8.41 injections, p<0.001) and the total number of days of swelling (10.1 +/- 10.73 versus 29.6 +/- 16.9 days; p<0.001).
Cinryze Acute Treatment Study
According to the authors, subjects experiencing attacks of moderate or severe intensity involving the abdomen, face, or external genitalia were eligible for randomized treatment. Eligible subjects were then randomized to receive either Cinryze (1000 U) or saline by intravenous push over 10 minutes. After 60 minutes, a second injection of the same study drug was administered if the subject had not reported symptoms to be either "absent" or "better" at the site of the most severe symptoms which had been designated as the "defining site". Symptom severity was assessed every 15 minutes starting from the initial injection and continuing until the subject reported "unequivocal relief," defined as three consecutive reports of improvement at the defining site. If four hours had elapsed without "unequivocal relief," trial assessments were discontinued and rescue therapy with open-label Cinryze was offered.
The primary end point was the time from study drug administration until the onset of unequivocal relief of symptoms at the defining site. Secondary efficacy measures included percentage of subjects who had unequivocal relief within four hours following treatment; time to complete resolution of the attack; and effects of treatment on C1 inhibitor antigenic and functional levels and C4 levels. Safety of Cinryze was also assessed.
Seventy-one eligible subjects were randomized into this study, 36 to Cinryze and 35 to placebo. After completion of study treatment, three subjects (one randomized to Cinryze and two randomized to placebo) were judged by an independent, blinded expert to have experienced episodes that were not true attacks of angioedema and were therefore excluded from the efficacy analysis.
The estimated median time to the onset of unequivocal relief was two hours in the Cinryze group as compared with more than four hours in the placebo group (estimated success ratio 2.41; 95% CI, 1.17 to 4.95; p=0.02). The onset of unequivocal relief occurred within four hours in 21 patients in the Cinryze group and in 14 patients in the placebo group (60 percent versus 42.4 percent; p=0.062). Median time to complete resolution was 12.3 hours in the Cinryze group and 25 hours in the placebo group (p=0.004) even though all subjects who did not have substantial improvement by the end of the four hour post-treatment assessment period were given open label Cinryze. C1 inhibitor antigenic and functional levels increased during treatment in the group given Cinryze, but not in the group given placebo (p<0.001 for both between-group comparisons). In contrast, C4 levels did not change significantly during the period of observation.
According to the authors, in the prophylactic treatment trial, 21 (88 percent) of subjects had one or more adverse events, the most common of which were upper respiratory tract infection, sinusitis, rash and headache. Three adverse events (pruritus and rash, lightheadedness, and fever) were classified as possibly related to the study drug. In the acute treatment trial, 6 subjects (17 percent) in the Cinryze group and 7 subjects (20 percent) in the placebo group experienced adverse events. Three of these events were classified as potentially related to study drug (tetany in one placebo treated subject, contact dermatitis in a placebo treated subject, and injection site rash in one Cinryze treated subject).
Open-Label Treatment Extension
After the two trials were completed, 88 subjects chose to enroll in an open-label extension study for the treatment of acute attacks. At a median of 11 months, 82 of the enrolled subjects had received open-label C1-inhibitor treatment for a total of 447 separate attacks, with the number of attacks per subject ranging from one to 57 (median 3). The median time to a response for the 447 attacks was 30 minutes, irrespective of whether a subject was given open-label treatment fewer than four times, four to nine times, or 10 times or more. The Kaplan-Meier estimate of the proportion of attacks that responded to treatment within four hours was 93 percent.
About Cinryze(TM) (C1 esterase inhibitor [human])
Cinryze is a highly purified, pasteurized and nanofiltered plasma-derived C1 esterase inhibitor product that has been approved by FDA for routine prophylaxis against angioedema attacks in adolescent and adult patients with HAE. C1 inhibitor therapy has been used acutely for more than 35 years in Europe in patients with C1 inhibitor deficiency.
The most common adverse reactions observed have been upper respiratory infection, sinusitis, rash and headache. No drug-related serious adverse events (SAEs) have been observed in clinical trials. Severe hypersensitivity reactions may occur. Thrombotic events have occurred in patients receiving high dose off-label C1 inhibitor therapy well above the approved treatment dosage regimen. Monitor patients with known risk factors for thrombotic events. With any blood or plasma derived product, there may be a risk of transmission of infectious agents, e.g. viruses and, theoretically, the CJD agent. The risk has been reduced by screening patients for prior exposure to certain virus infections and by manufacturing steps to reduce the risk of viral transmission including pasteurization and nanofiltration.
Cinryze is for intravenous use only. A dose of 1000 Units of Cinryze can be administered every 3 or 4 days for routine prophylaxis against angioedema attacks in HAE patients. Cinryze is administered at an injection rate of 1 mL per minute.
About Hereditary Angioedema (HAE)
HAE is a rare, severely debilitating, life-threatening genetic disorder caused by a deficiency of C1 inhibitor, a human plasma protein. This condition is the result of a defect in the gene controlling the synthesis of C1 inhibitor. C1 inhibitor maintains the natural regulation of the contact, complement, and fibrinolytic systems, that when left unregulated, can initiate or perpetuate an attack by consuming the already low levels of endogenous C1 inhibitor in HAE patients. Patients with C1 inhibitor deficiency experience recurrent, unpredictable, debilitating, and potentially life threatening attacks of inflammation affecting the larynx, abdomen, face, extremities and urogenital tract. Patients with HAE experience approximately 20 to 100 days of incapacitation per year. There are estimated to be at least 6,500 people with HAE in the United States.
For more information on HAE, visit the U.S. HAE Association's website at: www.haea.org.
About ViroPharma Incorporated
ViroPharma Incorporated is an international biopharmaceutical company committed to developing and commercializing innovative products for physician specialists to enable the support of patients with serious diseases for which there is an unmet medical need, and providing rewarding careers to employees. ViroPharma commercializes Cinryze(TM) (C1 esterase inhibitor [human]) for routine prophylaxis against angioedema attacks in adolescent and adult patients with hereditary angioedema (HAE). ViroPharma commercializes VancocinŪ (Vancomycin Hydrochloride, USP), approved for oral administration for treatment of antibiotic-associated pseudomembranous colitis caused by Clostridium difficile and enterocolitis caused by Staphylococcus aureus, including methicillin-resistant strains (for prescribing information on ViroPharma's commercial products, please download the package inserts at http://www.viropharma.com/Products.aspx). ViroPharma currently focuses its drug development activities in diseases including C1 esterase inhibitor deficiency and C. difficile infection.
ViroPharma routinely posts information, including press releases, which may be important to investors in the investor relations and media sections of our company's web site, www.viropharma.com. The company encourages investors to consult these sections for more information on ViroPharma and our business.
Certain statements in this press release contain forward-looking statements that involve a number of risks and uncertainties. Forward-looking statements provide our current expectations or forecasts of future events. Forward-looking statements in this press release include statements regarding the therapeutic indication and use, safety, efficacy, tolerability and potential of Cinryze and our focus, goals, strategy, research and development programs, and ability to develop compounds, commercialize drugs and execute on our plans. Our actual results could differ materially from those results expressed in, or implied by, these forward-looking statements. The development and commercialization of pharmaceutical products is subject to risks and uncertainties. The data that were discussed in the New England Journal article are subject to different interpretations and may not be predictive of the results of any future testing or of how Cinryze performs in commercial usage. These factors, and other factors, including, but not limited to those described in our annual report on Form 10-K for the year ended December 31, 2009 and 10-Qs for the quarters ended March 31, 2010 and June 30, 2010 filed with the Securities and Exchange Commission, could cause future results to differ materially from the expectations expressed in this press release. The forward-looking statements contained in this press release are made as of the date hereof and may become outdated over time. ViroPharma does not assume any responsibility for updating any forward-looking statements. These forward looking statements should not be relied upon as representing our assessments as of any date subsequent to the date of this press release.
SOURCE ViroPharma Incorporated
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