Revefenacin (TD-4208) is an investigational nebulized therapy being developed as a once-daily treatment of chronic obstructive pulmonary disease (COPD). Revefenacin is a long acting muscarinic antagonist (LAMA), meaning it mediates bronchial smooth muscle contraction and release. It is designed to be a single-agent nebulized therapy.

The treatment is now in Phase 3 clinical trials after demonstrating positive results in Phase 2b studies of lung function in people with moderate-to-severe COPD, given the treatment once a day for 28 days.

Revefenacin is being co-developed by Theravance Biopharma and Mylan to treat COPD and other respiratory diseases.

Revefenacin (TD-4208) and clinical trials

The pharmacological profile of TD-4208 was compared to that of two other LAMA agents, tiotropium and glycopyrronium in preclinical in vivo studies in animals (dogs and rats). These studies were to determine the bronchoprotective potency of the drug to a LAMA receptor (subtypes M1 and M2), and to estimate lung selectivity. Results of these studies showed that TD-4208 had a bronchoprotective effect in both dogs and rats with a time suitable for a once daily use, or 24-hour potency. TD-4208’s lung selectivity is higher to that of the comparator drugs and results from its long M3 receptor residence time. The researchers concluded in their published study that “the in vivo preclinical profile suggests that TD-4208 has the potential to be a long-acting bronchodilator for once-daily treatment of respiratory diseases. Its greater functional selectivity for the lung in preclinical models may translate to an improved tolerability profile compared with marketed muscarinic receptor antagonists.”

Two Phase 2 clinical trials evaluated in COPD patients the pharmacodynamics, safety and tolerability and pharmacokinetics of TD-4208 at multiple doses (NCT01704404), and the safety and efficacy of once and twice daily doses (NCT02109172) of the drug using a jet nebulizer. In both studies, TD-4208 was compared to a placebo and treatment was given over seven days. Results from both studies supported TD-4208 as a “well-tolerated, once-daily inhaled treatment with limited systemic exposure.”

A Phase 2b study (NCT02040792) compared four doses of nebulized revefenacin (44, 88, 175 and 350 micrograms) to a placebo in people with moderate to severe COPD treated once daily for 28 days. Results of this study showed that the drug was well-tolerated, meeting the primary efficacy endpoint, FEV1, for doses of 88, 175 and 350 micrograms. Reported side effects included headache, shortness of breath, and cough.

A Phase 1 study (NCT02772159) was completed in 2016. In this study, a radioactive element (14C) was incorporated into TD-4208 to evaluate the drug’s absorption, distribution, metabolism and excretion (ADME). Healthy participants were given two treatments. In one, 20 micrograms of radiolabel TD-4208 were administered via intravenous (IV) route in a fasting state. A 38-day washout period followed before a second treatment, an oral dose of 200 micrograms of radiolabel TD-4208, again while fasting. Samples of blood, urine, feces and vomitus (if applicable) were collected and analyzed. Results of this ADME study, which ended in April 2016, have not been reported.

Two Phase 3 clinical trials (NCT02512510 and NCT02459080), both three-month efficacy studies involving more than 1,250 COPD patients and testing two doses (88 mcg and 175 mcg) of revefenacin inhalation solution, concluded in September 2016. Results from both trials demonstrated statistically and clinically relevant increases in trough FEV1 (forced expiratory volume in one second, a measure of lung health) after 12 weeks of once-daily dosing.

Another Phase 3 study is ongoing (NCT02518139), evaluating two doses of nebulized revefenacin (88 and 175 micrograms) and comparing its safety and tolerability to an active comparator (tiotropium 18 mcg). It is expected to end in May 2017.

Should results continue to be positive, Theravance to apply for regulatory approval of revefenacin as a COPD treatment with the U.S. Food and Drug Administration (FDA) in late 2017.

 

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