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Archive for August, 2010

Inspire Pharmaceuticals’ Denufosol for cystic fibrosis

Posted by lifetech on August 26th, 2010

There is ongoing discussion as to how the cystic fibrosis mutation causes lung disease. The “low airway volume” is a widely accepted hypothesis. It proposes that depletion of “airway surface liquid” impairs ciliary beat and causes the retention of thickened mucus, which predisposes to lung infections. Thus there is considerable interest in developing therapeutic interventions that restore airway surface volume. That is what Inspire is trying to accomplish with denufosol, an agent that may restore airway hydration by activating an alternative ion channel (the P2Y2 receptor). The first denufosol phase III trial (TIGER-1) was technically positive, as it met the study’s primary endpoint. However, clinical results as a whole were not that impressive over 24 weeks, and pulmonary exacerbation results were of particular concern. Favorably, the trial’s open label extension suggests that denufosol may work slowly and steadily – but this observation needs confirmation in a controlled trial. This may be achieved with the second ongoing phase III trial (TIGER-2), which treats a larger number of patients for a longer period of time. Besides considerations of denufosol’s clinical worthiness, TIGER-2 needs to do better than TIGER-1 to avoid regulatory and commercial challenges from other approved and late-stage development airway hydrating agents as well as agents from other classes such as CFTR repair therapies (discussed in our Vertex report). The latter target the basic defect that causes CF, and could dramatically change the CF treatment paradigm in the medium future. Thus, a lot is at stake for TIGER-2. We refer you to our denufosol report for an in-depth discussion of clinical, regulatory and commercial challenges.


Ironwoods’, Forest Laboratories’ and Almirall’s linaclotide for constipation

Posted by lifetech on August 10th, 2010

The legions of individuals who suffer from chronic idiopathic constipation or constipation-predominant irritable bowel syndrome (IBS-C) may soon have another therapy with which to address their discomfort. Ironwood Pharmaceuticals and its partners, Forest Laboratories and Almirall are developing linaclotide. It is an oral peptide that acts through GCC receptors in the intestinal tract — the same receptors activated by the bacterial toxins implicated in E coli diarrhea. Via this unique mechanism, linaclotide increases intestinal fluid secretion, thereby relieving constipation.

The companies have reported positive results for two phase III chronic constipation trials. The two pivotal phase III trials in IBS-C should complete soon and results should be released in Q4. The data so far are fairly encouraging, however there are some key questions. For example, are available results clinically relevant even if statistically significant? Does the program meet new standards for IBS therapies that FDA has just released? Will there be overhang from FDA’s experience with other IBS therapies withdrawn from the market due to postmarketing safety issues (think Zelnorm)? And most important, how will linaclotide fare in the marketplace against Amitiza? Check our latest report for an in-depth discussion of these questions.