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Technology Stocks : Critical Therapeutics (CRTX) -- Ignore unavailable to you. Want to Upgrade?

To: tuck who wrote (3)	8/27/2004 12:13:49 PM
From: tuck	Read Replies (1) \| Respond to of 31

S-1 snip concerning safety of zileuton and zileuton CR: >>Zyflo is the only 5-lipoxygenase inhibitor drug to be approved for marketing by the FDA. In 1996, Zyflo was approved by the FDA as an immediate-release, four-times-a-day tablet for the prophylaxis and chronic treatment of asthma. Zyflo was launched in the United States in 1997. We are currently transferring the manufacturing technology used in the production of the API for Zyflo and the Zyflo tablets from Abbott to contract manufacturing sites. Once we complete this transfer, we expect to file an sNDA, which FDA regulations require in connection with a change of manufacturing sites. We expect that the FDA’s review of our sNDA will take approximately three months, but there is no legal requirement that the FDA complete its review in this timeframe. If the sNDA is approved within this timeframe, we would expect to begin marketing Zyflo in the first half of 2005. Dr. Paul Rubin, our President and Chief Executive Officer, led the development of Zyflo while he was employed by Abbott. The full clinical development program for Zyflo consisted of 21 safety and efficacy trials in an aggregate of approximately 3,000 patients with asthma. FDA approval was based on pivotal three-month and six-month safety and efficacy clinical trials in 774 asthma patients. The pivotal trials compared patients taking a combination of Zyflo and their usual asthma medications to patients taking a combination of placebo and their usual asthma medications. The results of the group taking Zyflo and their usual asthma medications showed: • rapid and sustained improvement for patients over a six-month period in objective and subjective measures of asthma control; • reduction of exacerbations and need for either bronchodilatory or steroid rescue medications; • acute bronchodilatory effect two hours after the first dose; and • greater airway response benefit in severe asthma patients with less than 50% of expected airway function, and a six-fold decrease in steroid rescues compared to placebo. In these double-blind, placebo-controlled clinical trials, 1.9% of patients taking Zyflo experienced ALT levels greater than or equal to 3xULN compared to 0.2% of patients receiving placebo. These enzyme levels returned to normal in both the patients who continued and those who discontinued the therapy. In addition, prior to FDA approval, a long-term, open-label safety surveillance trial was conducted in 2,947 patients. In this safety trial, 4.6% of patients taking Zyflo experienced ALT levels greater than or equal to 3xULN compared to 1.1% of patients receiving placebo. In 61.0% of the patients with ALT levels greater than or equal to 3xULN, the elevation was seen in the first two months of dosing. After two months of treatment, the rate of ALT levels greater than or equal to 3xULN stabilized at an average of 0.3% per month for patients taking a combination of Zyflo and their usual asthma medications compared to 0.11% per month for patients taking a combination of placebo and their usual asthma medications. This trial also demonstrated that ALT levels returned to normal in both the patients who continued and those who discontinued the therapy. The overall rate of patients with ALT levels greater than or equal to 3xULN was 3.2% in the approximately 5,000 patients who received Zyflo in placebo-controlled and open-label trials combined. In these trials, one patient developed symptomatic hepatitis with jaundice, which resolved upon discontinuation of therapy, and three patients developed mild elevations in the protein bilirubin. After reviewing the data from these trials, the FDA approved Zyflo in 1996 on the basis of the data submitted and we are not aware of any reports of serious liver damage in patients treated with Zyflo since its approval. Controlled-Release Formulation of Zileuton We believe that the controlled-release formulation of zileuton that we are developing will be more convenient for patients as a result of its twice-a-day dosing regimen than Zyflo’s current four-times-a-day dosing regimen and will increase patient drug compliance. Abbott completed Phase III clinical trials for this formulation in asthma, but did not submit an NDA. Based upon data provided to us, we believe this decision was not based upon the clinical efficacy or safety data generated during the program. We expect to submit an NDA based on safety and efficacy data generated from the two completed Phase III trials, a three-month efficacy trial and a six-month safety and efficacy trial. The results of these clinical trials were as follows: the three-month pivotal efficacy trial, in which 409 patients received either the controlled-release formulation of zileuton or placebo, generated similar efficacy results to those seen in the Zyflo pivotal trials. The trial demonstrated statistically significant improvements over placebo, in objective measures of asthma control, such as mean forced expiratory volume. The trial also showed a reduced need for bronchodilatory drugs as a rescue medication to alleviate uncontrolled symptoms; the efficacy component of the six-month trial included 757 patients and generated similar efficacy results to those seen in the Zyflo pivotal trials. The trial demonstrated statistically significant improvements over a combination of placebo and the patients’ normal asthma therapies, in objective measures of asthma control, such as mean forced expiratory volume. In the trial, the controlled-release formulation of zileuton also showed a reduced need for bronchodilatory drugs as a rescue medication to alleviate uncontrolled symptoms; and the safety data generated in a total of 1,335 patients from these two trials was comparable to safety data seen in the Zyflo pivotal trials. The incidence of ALT levels greater than or equal to 3xULN in patients receiving zileuton was 2.1% and in all cases ALT levels returned to normal in both the patients who continued and those who discontinued the therapy.<< Cheers, Tuck