Theravance Biopharma Announces Positive Top-Line Results from Phase 2b Dose-Ranging Study of its Investigational LAMA, TD-4208, for the Treatment of COPD
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. The lowest dose of 44 mcg produced a sub-therapeutic response of 52 mL that was not statistically different from placebo.
"For those COPD patients who depend on nebulized treatment to manage their COPD, currently available therapies require dosing more than once per day," said
Analyses of secondary endpoints were positive and consistent with the primary endpoint for doses of 88 mcg and above (all nominal p-values < 0.01 versus placebo). TD-4208 doses of 88, 175 and 350 mcg resulted in a placebo-corrected change from baseline on Day 28 in the 0 to 24-hour weighted mean FEV1 of 165, 162 and 174 mL, respectively. TD-4208 doses of 88 mcg and above showed a rapid onset of action as measured by a median time of 30 minutes to a 100 mL increase from baseline on Day 1. Doses of 88 mcg and above reduced the use of rescue medication by more than 1 puff per day, compared to placebo.
TD-4208 was generally well tolerated. Headache, shortness of breath and cough were the most common adverse events in the study, reported in 11 (3.1%), 10 (2.8%) and 7 (2.0%) subjects, respectively. Notably, there were minimal reports of side effects associated with anti-cholinergic treatment: there were only 2 reports of dry mouth, and no reports of blurred vision, constipation or urinary retention. Four subjects experienced serious adverse events, three of which were considered to be unrelated to study treatment by the blinded investigators, and the fourth was considered unlikely to be related to study treatment by the blinded expert reviewer. The overall withdrawal rate in the study was under 10%. A greater number of patients prematurely discontinued the study due to treatment-emergent adverse events in the two highest dose groups. Review of laboratory panels revealed no abnormal trends.
Commented Rick E Winningham, Chief Executive Officer: "We believe that TD-4208 has the potential to be a best-in-class single-agent product for COPD patients who require nebulized therapy. In addition, the therapeutic profile, together with the physical characteristics of TD-4208, suggest that this LAMA could serve as a foundation for several combination products and for delivery in metered dose inhaler and dry powder inhaler products. TD-4208 represents an important opportunity for our Company."
About the Phase 2b Study
The objectives of this randomized, double-blind, multicenter, placebo-controlled Phase 2b study were to characterize the FEV1 dose-response relationship, pharmacokinetics, safety and tolerability of multiple doses of TD-4208 in patients with moderate-to-severe COPD.
The study was conducted at 41 clinical sites in the US. A total of 355 patients were randomized to receive one of four doses of TD-4208 (44, 88, 175 or 350 mcg) or placebo once daily via a nebulizer in a 28-day, double-blind, parallel-group study design. Subjects had an average age of 62 years, a minimum of a 10 pack-year smoking history and an average FEV1 % predicted of 44%. Thirty-seven percent of subjects were on inhaled corticosteroids, and 35% of subjects had irreversible airways disease at screening.
The primary efficacy endpoint of the study was change from baseline in trough FEV1 after the last dose of treatment on Day 28. Secondary endpoints included trough FEV1 on Day 15, 16 and 28, weighted mean (area under the curve) assessments of FEV1 from 0 to 6 hours on Day 1 and 0 to 24 hours on Day 28, rescue medication use and peak expiratory flow.
Safety evaluations included adverse events, routine laboratory assessments, vital signs, 12-lead ECG tracings and 24-hour Holter ECG profiles. A subset of subjects in each treatment arm provided blood samples for pharmacokinetic evaluation.
About TD-4208 and the LAMA Program
TD-4208 is an investigational inhaled, long-acting muscarinic antagonist (LAMA) discovered by the team at
More than 12.5 million US adults are estimated to have COPD, and it is currently the third leading cause of death in the US, with more than 130,000 deaths annually. Smoking is the primary risk factor, and more than 80% of COPD deaths are caused by smoking. People who smoke are 12-13 times more likely to die from COPD than people who have never smoked. Other risk factors include air pollution, passive smoking, occupational exposure and genetic factors. More than 700,000 patients are admitted to hospitals annually in the US with worsening of their COPD. The costs of managing COPD in the US were estimated to be
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Rick E Winningham
Chief Executive Officer
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