Forest COPD Combo Hits Roadblock En Route To NDA Filing
This article was originally published in Pharmaceutical Approvals Monthly
Executive Summary
Forest is delaying submission of an NDA for aclidinium/formoterol to resolve FDA concerns about the formulation’s chemistry, manufacturing and control specifications.
Forest Laboratories Inc. may be overtaken by competitors in the contest to get to market with the first chronic obstructive pulmonary disease product combining a long-acting beta2 agonist (LABA) with a long-acting muscarinic antagonist (LAMA). The company was set to file an NDA for its aclidinium/formoterol combination in the fourth quarter of 2013, but FDA concerns about the formulation have derailed its plans indefinitely.
Sponsors are working with FDA to resolve CMC issues with the combination formulation.
Forest and partner Almirall SA announced Aug. 14 that they decided to delay filing the NDA based on comments FDA made during a recent pre-NDA meeting. “The delay is related to resolving chemistry, manufacturing and control (CMC) specifications associated with the combination formulation,” they stated in a release. They said they are working with FDA “to determine the appropriate next steps.”
It is uncertain how long it will take to resolve these issues or what data the company may have to provide FDA, and Forest is not providing comment beyond the release.
Several COPD drugs are in development, including single-agent LABAs and LAMAs and the first fixed-dose combinations of these bronchodilators. Some companies predict that the LABA/LAMA combinations could become the new standard of care (Also see "COPD Market Snapshot: New Products, Limited Differentiation" - Pink Sheet, 6 May, 2013.).
GlaxoSmithKline PLC has an NDA pending for its LABA/LAMA combination Anoro Ellipta (vilanterol/umeclidinium), which has a PDUFA date of Dec. 18. Novartis AG’s indacaterol/glycophyronium combination is in a Phase III trial with a filing targeted for 2014. Boehringer Ingelheim GMBH’s olodaterol/tiotropium combination is also in Phase III development.
FDA approved Forest’s single agent COPD treatment Tudorza (aclidinium), which is marketed with Almirall’s Pressair inhaler, in July 2012 (Also see "Forest Tudorza Pressair Approval For COPD Includes Post-marketing CV Safety Study" - Pink Sheet, 23 Jul, 2012.). The company launched Tudorza in December and it had sales of $15.9 million for the three months ended June 30.
Tudorza Subject Of Department Of Justice Probe
The product also caught the attention of the Department of Justice. Forest noted in its May 23 10-K filing that it received a subpoena dated May 6 from the Office of the U.S. Attorney for the Southern District of New York requesting documents related to Tudorza. The company did not specify the nature of the inquiry. In 2010, Forest reached a $313 million settlement with DoJ for marketing Levothroid (levothyroxine) without FDA approval and to resolve allegations of off-label promotion of Celexa (citalopram) (Also see "Forest Admits To Knowingly Obstructing FDA Inspection In Guilty Pleas On Levothroid, Celexa Marketing" - Pink Sheet, 15 Sep, 2010.).
Forest announced positive topline results from two Phase III trials of aclidinium/formoterol in April and May.
The first study, a 24-week, randomized, double-blind trial, compared the 400/6 mcg and 400/12 mcg fixed-dose combinations to single agent aclidinium bromide 400 mcg, formoterol fumarate 12 mcg and placebo in 1,729 patients with moderate to severe COPD. Forest reported that both combinations demonstrated statistically significant improvements in the co-primary endpoints of change from baseline in morning pre-dose trough Forced Expiratory Volume (FEV1) versus formoterol 12 mcg and in FEV1 at one hour post-dose versus aclidinium 400 mcg at week 24. Both combinations also showed statistically significant improvements versus placebo in these variables.
The company said the second Phase III study, which evaluated the 400/12 mcg combination, also demonstrated statistically significant improvement in lung function.
The global market for COPD was nearly $9 billion in 2011 and is expected to grow at a steady annual rate of 4% between 2011 and 2021, when sales will reach almost $13.4 billion, according to the market research firm Decision Resources. The Centers for Disease Control & Prevention reports that chronic lower respiratory disease, primarily COPD, was the third leading cause of death in 2011 and that 15 million Americans have been diagnosed with COPD.