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FDA Notes Suicides With Forest, Nycomed COPD Drug Daxas

From BioWorld Today (April 6, 2010)

WASHINGTON - The FDA’s concerns over suicides linked to Forest Laboratories Inc.’s chronic obstructive pulmonary disease (COPD) drug Daxas (roflumilast) had investors only somewhat worried Monday, with shares slipping just slightly.

In addition to the adverse events, which also included gastrointestinal toxicity, weight loss and the potential for cancer, regulators also noted that Daxas had only a modest effect in improving the lung function of patients with COPD in clinical testing.

In briefing documents released ahead of Wednesday’s FDA Pulmonary-Allergy Drugs Advisory Committee meeting, FDA drug reviewers also took issue with the late switch of Daxas’ proposed indication.

Swiss drug maker Nycomed GmbH, the firm that developed Daxas, had submitted the new drug application (NDA) to the agency last July with a proposed indication for the compound as a maintenance treatment of COPD associated with chronic bronchitis in patients at risk of exacerbations.

But New York-based Forest, which licensed Daxas from Nycomed under a deal potentially worth more than $500 million, submitted a new application in late January with what the FDA said were "substantial" changes, including a narrower indication and a new warning about neuropsychiatric events. (See BioWorld Today, Aug. 11, 2009.)

Forest tapered the indication to reduction in COPD exacerbations, which analysts said could be a more winnable indication. But the FDA said the change of indication six months into Daxas’ review and two months before the agency’s advisory committee meeting was "problematic," because it "shifts the focus of the efficacy analysis, which was based upon the original indication."

Regulators said the application would continue to be evaluated on the originally proposed indication.

The drug reviewers noted that the information in the briefing documents and the agency’s draft questions also remained focused on the initial broader indication.

The FDA, however, often changes its questions by the time advisory panel meetings roll around.

While Forest’s labeling changes may delay Daxas’ approval, in the end, the move could increase the likelihood of the drug getting the FDA’s OK, predicted Lazard Capital Markets analyst William Tanner.

Cowen & Co. analyst Ian Sanderson said a leading clinician and investigator in COPD he consulted called Forest’s move to the narrower indication a "good strategy." The consultant also said the advisory panel and the FDA would end up using the narrower indication, which Sanderson said would "preclude" the agency’s efficacy issues.

While Daxas had a statistically significant, "albeit quite modest," increase in prebronchodilator forced expiratory volume in 1 second, compared with placebo, the FDA said that increase "would not constitute a clinically meaningful benefit."

Although the concerns the FDA raised about gastrointestinal toxicity and weight loss were not a surprise, the suicides, which regulators called a "significant concern," could be perceived as a "negative surprise," said Baird & Co. analyst Thomas Russo.

He noted that the suicidality signal linked to Daxas was not highlighted in published research, nor is it in the labeling of established COPD agents, such as GlaxoSmithKline plc’s Advair (fluticasone and salmeterol) and Pfizer Inc.’s Spiriva (tiotropium bromide).

Regulators said none of the three men who committed suicide had a history of depression. In two of those cases, the patients had reportedly stopped taking Daxas about three weeks before the suicide event.

The two women who attempted suicide, however, had psychiatric histories, with depression in one patient and a previous suicide attempt in the other. Both women were receiving Daxas at the time of the suicide attempt.

But Cowen’s Sanderson said the suicidality signal may be just "noise." Nonetheless, he said it was something that likely would end up as a warning in the labeling.

Adverse psychiatric events were more common in patients taking Daxas 500 mcg compared with those who received the 250-mcg dosage or placebo, the FDA said. Of the three completed suicides, two received the 500-mcg dosage, with the third receiving the 250-mcg dosage.

Drug reviewers noted that there were 403 adverse psychiatric events reported in patients who received once-daily 500-mcg dosages, or 6 percent of study participants, compared with 190, or 3 percent, in the placebo group.

There were two-to-three times greater adverse events of insomnia, anxiety and depression in the Daxas 500-mcg dosage group, compared with placebo, the FDA said.

The percentage of patients in the COPD safety pool in the Daxas studies who experienced at least one adverse gastrointestinal event in the 500-mcg treatment groups was 22 percent, compared with 11 percent in placebo-treated patients.

Among the adverse GI events, about half experienced diarrhea and up to 25 percent experienced nausea.

While the adverse GI events, such as diarrhea and nausea, were the leading cause of early study termination in patients taking Daxas, a selective phosphodiesterase type 4 (PDE4) inhibitor, the FDA acknowledged that those events are known effects of that class of drugs.

The most severe adverse GI effects in patients taking Daxas were intractable diarrhea and pancreatitis. Two patients who developed acute pancreatitis died. Both were taking the 500-mcg dosage.

In the pivotal trial pool, 62.4 percent of Daxas-treated patients had measurable weight loss, compared with 37.7 percent in the placebo group. Regulators noted that only a fraction of the measured weight loss was reported as adverse events.

The FDA also raised concerns about the carcinogenic effects of Daxas in animal studies, which regulators called a "topic of special interest."

In the overall clinical development program, 60 percent of Daxas-treated patients reported cancer or tumor events, compared with 40 percent in the placebo group.

There were more lung and prostate cancers reported for patients treated with Daxas than in the placebo group, drug reviewers said, insisting that those differences could not be due to preferential dropout in the placebo group, since more patients receiving Daxas withdrew from clinical studies prematurely, compared with placebo.

Shares of Forest (NYSE:FRX) closed at $30.96, down 47 cents.


Posted: April 2010