Potential for first once-daily nebulized LAMA in COPD

GEORGE TOWN, Grand Cayman—Theravance Biopharma, Inc. has presented additional positive data from its Phase 2b dose-ranging study of TD-4208, an investigational long-acting muscarinic antagonist (LAMA) in development for the treatment of chronic obstructive pulmonary disease (COPD). Previously released top-line study data demonstrated achievement of the study’s primary and key secondary efficacy endpoints for doses of 88 mcg and above. These latest trial results presented at the American Thoracic Society (ATS) 2015 International Conference held recently in Denver, Colorado, support the product’s potential to offer patients rapid and sustained therapeutic benefit from once-daily administration and to reduce the requirement for short-acting rescue medication.

The Phase 2b study evaluated four doses of TD-4208 (44, 88, 175 and 350 mcg) and placebo, administered once-daily for 28 days in a double-blind, parallel group study in a total of 355 patients with moderate-to-severe COPD. As previously reported, TD-4208 met the primary efficacy endpoint (change from baseline in trough FEV1 [forced expiratory volume in one second] following the last dose on Day 28) at once-daily doses of 88, 175 and 350 mcg, with statistically significant changes versus placebo (p<0.001) in trough FEV1 of 187 mL, 167 mL and 171 mL, respectively. TD-4208 was generally well tolerated in the study with headache (3.1 percent), shortness of breath (2.8 percent) and cough (2.0 percent) as the most common adverse events in the study.

In new data from the Phase 2b study reported at ATS, TD-4208 resulted in a rapid onset of action, with a median time to achieve a clinically relevant improvement in lung function (at least 100mL increase in FEV1) of 30 minutes for doses of 88 mcg and above. TD-4208 also reduced the requirement for short-acting inhaled rescue medication in a dose-dependent manner, with a mean reduction of more than one puff a day compared to placebo for doses of 88 mcg and above (p<0.001).

In a separate presentation at ATS, Theravance Biopharma announced new population pharmacokinetic analyses from three Phase 2 studies of TD-4208 that support the product’s profile as a well-tolerated, once-daily inhaled treatment with limited systemic exposure. Combined with safety and efficacy data from the Phase 2b dose ranging study, these findings reaffirm the sustained bronchodilator effects of TD-4208 in the lung and support the minimal antimuscarinic effects outside the lung at the intended clinical doses.

“The positive Phase 2b clinical study results with TD-4208 are encouraging, and particularly relevant in light of the fact that there are still limited treatment options for COPD patients who require long-acting nebulized bronchodilator therapy,” said Brett Haumann, M.D., senior vice president, clinical development at Theravance Biopharma. “Approximately 9 percent of COPD patients in the U.S. require or prefer nebulized therapy, but there are currently no once-daily bronchodilators of any class available via the nebulized route. We believe there is a compelling opportunity to provide these patients with access to a once-daily nebulized treatment. Importantly, data from our Phase 2b study of TD-4208 demonstrate a therapeutic profile that is consistent with once-daily dosing, an onset of action that provides prompt effect and the potential for a reduced dependence on short-acting rescue medication. We plan to evaluate these effects further in longer-term studies in Phase 3.”

Following end-of-Phase 2 discussions with the FDA, Theravance Biopharma is preparing to start the TD-4208 Phase 3 registrational program, which is anticipated to begin later this year. The Phase 3 registrational program will include two replicate three-month efficacy studies and a single twelve-month safety study. The studies will include approximately 2,300 patients and test two doses: 88 mcg and 175 mcg administered once-daily via nebulizer.

In February 2015, Theravance announced that it had entered into a partnership with Mylan Inc. and its affiliates for the development and, subject to FDA approval, commercialization of nebulized TD-4208 for COPD and other respiratory diseases. Under terms of the agreement, Theravance Biopharma will conduct development in the U.S. with all costs reimbursed by Mylan. Mylan is responsible for ex-U.S. development. Additionally, Theravance Biopharma is eligible to receive up to $220 million in development and sales milestone payments, as well as a profit-sharing arrangement with Mylan on U.S. sales and double-digit royalties on ex-U.S. sales. Theravance Biopharma retains worldwide rights to TD-4208 delivered through other dosage forms, such as a metered dose inhaler or dry powder inhaler, and the rights to nebulized TD-4208 in China.

According to the American Lung Association, COPD is a growing and devastating disease that is the third leading cause of death in the U.S. An estimated 12.7 million American adults are diagnosed with COPD and an almost equal number are believed to be undiagnosed. More than 700,000 patients are admitted to hospitals annually in the U.S. with worsening of their COPD. The costs of managing COPD in the U.S. were estimated to be $50 billion in 2010, including $29.5 billion in direct health care expenditures, $8.0 billion in indirect morbidity costs and $12.4 billion in indirect mortality costs. Once-daily LAMAs are currently the cornerstone of maintenance therapy for patients with COPD, but existing LAMAs are only available in handheld devices.

TD-4208 is an investigational, long-acting muscarinic antagonist (LAMA) in development for the treatment of COPD. In a statement Theravance said, “We believe that TD-4208 may become a valuable addition to the COPD treatment regimen and that it represents a significant commercial opportunity. Our market research indicates approximately 9 percent of the treated COPD patients in the U.S. either need or prefer nebulized delivery for maintenance therapy. LAMAs are a cornerstone of maintenance therapy for COPD, but existing LAMAs are only available in handheld devices that may not be suitable for every patient. TD-4208 has the potential to be a best-in-class once-daily single-agent product for COPD patients who require, or prefer, nebulized therapy. The therapeutic profile of TD-4208, together with its stability in both metered dose inhaler and dry powder device formulations, suggest that this LAMA could also serve as a foundation for novel handheld combination products.”

“Our pipeline of internally discovered product candidates includes potential best-in-class opportunities in underserved markets in the acute care setting, representing multiple opportunities for value creation. VIBATIV® (telavancin), our first commercial product, is a once-daily dual-mechanism antibiotic approved in the U.S. and Europe for difficult-to-treat infections. TD-4208 is an investigational long-acting muscarinic antagonist (LAMA) being developed as a potential once-daily, nebulized treatment for COPD. Axelopran (TD-1211) is an investigational potential once-daily, oral treatment for opioid-induced constipation (OIC). Our earlier-stage clinical assets represent novel approaches for potentially treating diseases of the lung and gastrointestinal tract and infectious disease.”