Merck will market Daxas® (roflumilast), an investigational once-daily tablet for patients with chronic obstructive pulmonary disease (COPD). Here is this morning's Merck announcement. Right now the deal is for Canada and Europe. It may expand, though, if and when approved by FDA.
Here is a less sanguine view of the candidate, offered by MedPage Today:
. . . .Patients taking roflumilast experienced a number of adverse events: altogether, 14% of the patients in the trial discontinued the drug because of problems that included weight loss, psychiatric events including suicide, and the potential for cancer. Diarrhea and nausea were the leading causes of discontinuation.
Psychiatric adverse events were more common in roflumilast patients than in patients taking placebo (6% versus 3%), and roflumilast patients reported a two- to threefold greater incidence of insomnia, anxiety, and depression-related adverse events compared with placebo.
"Of significant concern are the occurrence of three completed suicides and two suicide attempts in COPD patients compared to no suicides/suicide attempts in patients receiving placebo," FDA reviewers wrote.
Also of concern was the greater incidence of cancer. A total of 218 cancer/tumor events were reported in 208 patients -- 60% of whom were in the roflumilast group,and 40% of whom were in the placebo group.
In Forest's briefing documents prepared for the advisory panel meeting, the company says six key studies "consistently demonstrated efficacy of 500 mcg roflumilast over placebo in reducing the rate of moderate to severe exacerbations and improving lung function."
Several months ago, Forest Research narrowed the proposed indication for the drug.
The company originally sought approval of roflumilast for maintenance treatment of COPD. Now, it is seeking approval for reducing exacerbations of COPD associated with chronic bronchitis in patients at risk of exacerbations.
"This change of indication six months into the review period and two months prior to the advisory committee meeting is problematic because it shifts the focus of the efficacy analysis, which was based upon the original indication." the FDA reviewers said. . . .
Paging Salmon. . . Batter, up! Salmon's commentary:
. . . .The 3 completed suicides and 2 attempts are of particular concern. It would be nice to know the denominator, the time frame post starting treatment and other signals of suicidality, e.g. thinking about harming yourself. Even the antidepressant and antipsychotic data that I am familiar with that raises the spectre of drug induced suicidality with those classes didn't have nearly that level of risk.
A 50% increase in cancer/tumors again is a major issue.
As for the change in indication. This is simply hand waving. All COPD treatments are designed to reduce exascerbations, either acutely during an acute attack or prophylacticly. If prophylacticly then by it's very nature it's a maintenence indication whether it uses that particular word or not.
I checked ClinTrials.gov and the primary objective for almost every study states reduction of exascerbations and the studies are typically for anywhere from 3 - 6 months. But even the few that don't say reduction of exascerbation are not for acute attacks so the change in indication is definitely simply handwaving and of no consequence clinically.
It's likely that this change in indication is for marketing purposes for comparison to the labeling for other treatments. If so it's likely designed to imply a reduction in severity of symptoms as compared to other available medications. This may allow them to get physicians to think the risk benefit balance is better than it is.
April 26, 2010 5:11 PM. . . .