Theravance Biopharma Announces Positive Results Including Biomarker Data from Phase 1 Multiple-Ascending Dose Study of TD-0714, an Inhibitor of Neprilysin (NEP)
Study results were consistent with data from the Company's previously completed single-ascending dose (SAD) trial of TD-0714, which showed robust and sustained inhibition of the NEP target over a 24-hour period. The biological effect was demonstrated by dose-related increases in the levels of cyclic GMP (a well-precedented biomarker of NEP target engagement). The 50 mg, 100 mg and 200 mg doses (including the elderly cohort) produced maximal increases, while 10 mg was sub-maximal, thereby providing a more complete assessment of the dose response for cGMP target engagement for TD-0714.
This trial also confirmed the low levels of renal elimination for TD-0714 reported in the SAD study, which showed that less than one percent of the total TD-0714 dose was eliminated through the kidneys.
All doses in the study were generally well-tolerated and no serious adverse events were reported at any dose in the study. One subject in the 10 mg dose group had a transient increase in certain liver function enzymes, and this subject's dosing was discontinued as a precaution. The same subject was subsequently re-dosed with 10 mg once daily for the full 14 days with no changes in liver enzymes, suggesting that factors other than treatment with TD-0714 were likely implicated in the initial findings. The subject remained asymptomatic during both dosing periods. There were no clinically relevant changes seen in any laboratory measures (including liver function enzymes) in any other subjects in the study.
"Consistent with our previously reported SAD data, these MAD study results met our target product profile for TD-0714. We are encouraged by the sustained levels of NEP inhibition after repeat dosing, which continues to build clinical support for the drug's potential for once-daily dosing. We have also confirmed that TD-0714 is not dependent on the kidney for its elimination, suggesting that dose adjustment may not be needed in patients with low or variable renal function and differentiating TD-0714 from current NEP-inhibitor-based therapy which is cleared by the kidneys and requires dose adjustment in these patients," said
About the Multiple-Ascending Dose Study
The Phase 1 clinical trial of TD-0714 was a randomized, double-blind, placebo-controlled, multiple-ascending dose study. The study investigated the safety and tolerability, pharmacokinetics, and pharmacodynamics (as defined by biomarker target engagement) of oral doses of TD-0714 (50, 100, 200 and 10 mg) administered once-daily for 14 days in 50 healthy adult and elderly volunteers. The study was designed to allow for the addition of the 10 mg dose group to characterize the bottom of the dose response curve for target engagement, once it had been confirmed that the 50, 100 and 200 mg doses produced maximal responses.
About Neprilysin (NEP) Inhibition
Neprilysin (NEP) is an enzyme that degrades natriuretic peptides. These peptides exert protective cardiac and renal effects including vasodilation, diuresis, natriuresis, reversal of maladaptive changes in heart, blood vessels and kidney, prevention of fibrosis, and prevention of end-organ damages. By elevating levels of natriuretic peptides, NEP inhibitors may have the potential to treat a range of major cardiovascular and renal diseases, including acute and chronic heart failure and chronic kidney disease. Roughly 26 million Americans suffer from chronic kidney disease, including diabetic nephropathy. In the
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Contact Information:
Renee Gala
Chief Financial Officer
650-808-4045
investor.relations@theravance.com
Tim Brons
646-319-8981
tbrons@vidasp.com
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