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Biotech / Medical : Texas Biotech (TXB) -- Ignore unavailable to you. Want to Upgrade?

To: scaram(o)uche who wrote (819)	8/13/2001 4:26:41 PM
From: keokalani'nui	Read Replies (1) \| Respond to of 834

Re Bosentan, a few comments. Though I thought the ac would punt until after data from the ongoing P3 trial was available, in fact it had the data from the safety portion of the trial which was included to support the NDA--and that trial, ENABLE, continues blinded. I probably could have but didn't figure that out. The ac was very accepting of the toxicity issues, including anemia that I had not noticed before. After reading all of it, I have to say I really don't understand why Natrecor got such a hard time the first or second time around. Here are some excerpts from the Secondary Review: Use in patients with even mild hepatic impairment is contraindicated. Bosentan is a significant inducer of CYP 3A4 and 2C9, resulting in predictable effects on its own metabolism (50% reduction in steady-state plasma levels) and that of other drugs. Studies of pharmacokinetic interactions yielded results commensurate with the metabolism studies. Cyclosporine and ketoconazole significantly increased plasma levels of bosentan. Warfarin, simvastatin, and glyburide lowered plasma levels of bosentan. Digoxin, losartan, and nimodipine had no interactions with bosentan. Most of what is known about pharmacokinetics of bosentan came from studies of normal volunteers. Subjects with PPH had a clearance of 3.8 L/h, compared with 9 L/h in normal subjects. Very little difference can be expected from doses of 125 and 250 mg. Treatment with bosentan, while unequivocal in a large population, will not be discernible in an individual patient. Should bosentan be approved for the treatment of pulmonary arterial hypertension? To its credit, bosentan was shown to be effective in improving walking distance in two prospective studies, for which walking distance was the primary end point. The magnitude of effect on walking distance was probably clinically meaningful, and it was accompanied by positive trends in other measures of symptomatic benefit. On the other hand, symptomatic benefit is not an improvement in outcome. No trends with respect to outcome, positive or negative, can be discerned from the available data. Furthermore, inter- and intra-subject variability is large compared with the mean treatment effect, so physicians and patients will generally not be sure that changes in symptoms are attributable to treatment. The improvement in symptoms carries with it numerous risks. They include teratogenicity, P450 enzyme interactions affecting concomitant medications, hepatotoxocity, and anemia. Although these risks did not result in clearly worsened outcome, it is difficult to draw much comfort given the small size of the safety database and the likely less aggressive monitoring that occurs in clinical practice. The population studied with bosentan included primary pulmonary hypertension and pulmonary hypertension secondary to connective tissue or autoimmune diseases. The standards for approval should probably not be the same in these areas. Flolan (epoprostinol) is only indicated for treatment of primary pulmonary hypertension, where its considerable risks, primary related to mode of administration, do not overshadow a mortality benefit. One should consider whether bosentan delays the initiation of Flolan, and, if so, whether that is a good idea. There is no approved treatment for secondary pulmonary hypertension, so symptomatic improvement is clearly worth some risk. Clearly, a case can be made for approval. Bosentan is effective in improving the exercise capacity in patients with pulmonary hypertension of various etiologies. This benefit was manifest in other indices of symptomatic improvement. The drug will need close monitoring, but irreversible harm can probably be prevented by appropriate surveillance. A reasonable case can also be made against approval, particularly in primary pulmonary hypertension. Patients who receive the drug will never know whether their own symptoms are improved because of it, or how much worse they would feel off of it. They will incur real risks¾ from inadequate attention on the part of physicians to hepatic and hematologic effects or to drug interactions and from inadequate exploration of safety in the target population¾ for no certain gain. In terms of outcome¾ mortality or disease progression, the data say there is no benefit, but there may be irreversible harm in delaying the initiation of life-prolonging treatment. _________________ Wilder