With a mixed bag of clinical results in hand, ICOS-Texas Biotechnology LP outlined plans to move forward with development of sitaxsentan to treat pulmonary arterial hypertension (PAH).
"Based on the STRIDE results, we are very encouraged and have reinforced confidence in the importance of endothelial antagonism in the treatment of pulmonary arterial hypertension," Texas Biotechnology Corp. CEO and President Bruce Given said during a conference call. "We are encouraged by the data and look forward to meeting with the FDA, to hearing their views and discussing the next steps for sitaxsentan."
Formed more than two years ago, ICOS-Texas Biotechnology LP is a 50-50 limited partnership between Bothell, Wash.-based ICOS Corp. and Texas Biotechnology to develop endothelin receptor antagonists, including sitaxsentan, which selectively targets the endothelin A receptor. The joint venture deal, which included a $2 million up-front payment to Texas Biotechnology, could be worth up to $55.5 million to the Houston-based firm. (See BioWorld Today, June 7, 2000.)
Both ICOS and Texas Biotechnology expect a future FDA meeting to outline pivotal trial criteria for sitaxsentan.
Top-line results from the STRIDE (sitaxsentan to relieve impaired exercise in PAH) Phase IIb/III trial showed the small molecule met its primary endpoint at a higher dose, though in a lower-dose treatment group failed to achieve statistical significance. But the higher dose is more associated with liver abnormalities previously recognized as complications related to the endothelin antagonist class of drugs.
The 12-week, double-blind, placebo-controlled STRIDE trial was designed to assess the safety and efficacy of sitaxsentan in patients with New York Health Association Class II, III and IV PAH. The 178-patient trial randomized participants to sitaxsentan 100 mg, sitaxsentan 300 mg or placebo treatment once a day.
The 300-mg dose group met the trial's primary endpoint of change in percent of predicted peak VO2 from baseline to week 12, compared with placebo treatment (7 percent relative improvement). But the primary endpoint was not statistically significant for the 100-mg group.
That does not dissuade Given, though, who said he did not know of any PAH drug approvals based on peak VO2. Specific primary endpoint "p" values were not disclosed.
"The overall clinical effectiveness of the two sitaxsentan dose groups appears to be equivalent, suggesting that the 100- and 300-mg dose levels are at or near the top of the dose-response curve for efficacy," Given said. "Based on these assumptions, we also think it might be possible to use lower doses of sitaxsentan, and by doing so we might be able to further reduce the risk-benefit profile of the drug."
Specifically, the class of drugs could have negative consequences on a patient's liver.
The trial defined liver abnormalities as elevated serum aminotransferase values that were more than three times normal. Incidences of liver abnormalities, which reversed in all cases, were 2 percent for placebo, 0 percent for the 100-mg group and 10 percent for the 300-mg group. ICOS-Texas Biotechnology said that when data from the STRIDE trial are combined with data from the extension trial (patients were exposed to sitaxsentan for a maximum of 55 weeks in both studies combined), the incidences of liver abnormalities, which all were reversible, were 5 percent for the 100-mg group and 21 percent for the 300-mg group.
"Seeing a dose response for safety, in combination with believing that the 100-mg dose is at or near the top of the dose response curve for effectiveness, is important and may allow us to improve the risk benefit of sitaxsentan by studying lower doses," Given said. "As importantly, all patients developing liver abnormalities resolved with discontinuation of drug."
Industry observers agreed.
"For most observers of sitaxsentan clinical development, reported resolution of liver function likely eliminates excessive concern regarding a potential negative attribute of the drug," Leerink Swann and Co. analyst William Tanner wrote in a research note. "Most likely, the primary endpoint from the STRIDE trial would not be the same in future trials, and may not even be included for a variety of reasons (e.g., center familiarity, institutional variation, etc.). We would expect future primary endpoints to be focused on a clinical outcome, such as improvement in six-minute walk and NYHA class."
Both groups achieved statistical significance for a secondary endpoint, the change in six-minute walk distance from baseline to week 12 (for the low-dose group, p=0.006, and for the high-dose group, p=0.009). The clinical effectiveness in the two groups was equivalent (9 percent relative improvement).
New York Health Association class improvement was also statistically significant for both groups compared with placebo (for the low-dose group, p=0.018, and for the high-dose group, p=0.016).
"The secondary efficacy endpoints that we used in this trial were the more traditional measures used to support prior approvals in PAH," Given said, later adding that further trials may focus solely on such parameters, absent peak VO2 measurements.
The most frequent adverse events included headache, peripheral edema, nausea, nasal congestion and prolonged clotting time.
FDA meetings to plan further development could happen late this year or early next year, Given said. Texas Biotechnology's stock (NASDAQ:TXBI) fell 14 cents Monday to close at $1.98, while ICOS' shares (NASDAQ:ICOS) rose 58 cents to close at $25.49.
Separately, ICOS continues to develop Cialis in a similar joint venture arrangement with Indianapolis-based Eli Lilly and Co. Data presented four months ago at the America Urological Association meeting showed the erectile dysfunction drug gives men the ability to achieve an erection some 24 to 36 hours after taking it, longer than the eight-hour window provide by Viagra, developed by New York-based Pfizer Inc. (See BioWorld Today, May 29, 2002.)
Additional pharmacologic studies are being conducted as requested in an approvable letter received from the FDA in late April, with U.S. launch on track for the second half of next year.