SOURCE: Theravance Biopharma

Theravance Biopharma

March 09, 2016 07:30 ET

Theravance Biopharma Announces Positive Results Including Biomarker Data From Phase 1 Study of TD-0714, an Inhibitor of Neprilysin (NEP)

Study Demonstrates Maximal and Sustained Target Engagement, Low Levels of Renal Elimination and Favorable Safety and Tolerability Profile; Results Support Potential for Once-Daily Dosing With No Dose Adjustment in Subjects With Impaired Kidney Function

DUBLIN, IRELAND--(Marketwired - Mar 9, 2016) - Theravance Biopharma, Inc. (NASDAQ: TBPH) ("Theravance Biopharma" or the "Company") today announced positive results, including positive biomarker data, from its Phase 1 single-ascending dose (SAD) clinical trial of TD-0714, the lead molecule in the Company's neprilysin (NEP) inhibitor program for the treatment of a range of major cardiovascular and renal diseases. 

The trial in healthy volunteers was designed to assess the safety, tolerability and pharmacokinetics of TD-0714, as well as measure biomarker evidence of target engagement and the amount of the drug that is eliminated via the kidneys.

Key study findings included the following:

  • Evidence of biological effect, as shown by dose-related increases in the levels of cyclic GMP (cGMP, a well-precedented biomarker of NEP target engagement), with maximal effect demonstrated within the lower end of the dose range tested.

  • Sustained elevations of cGMP over 24 hours in both plasma and urine at all dose levels, supporting the drug's potential for once-daily dosing.

  • Low levels of renal elimination, with less than one percent of the total TD-0714 dose eliminated through the kidneys, as confirmed by intravenous microtracer testing technology.

  • A favorable safety profile following a single dose, with all doses being generally well-tolerated and with no serious adverse events reported. There were also no clinically significant changes noted in vital signs, laboratory measures or electrocardiograms at any of the doses tested.

These results met the Company's target product profile and provide confidence for future efficacy studies of TD-0714 in a broad range of cardiovascular and renal diseases, including in patients with compromised renal function. Theravance Biopharma is now conducting a Phase 1 multiple-ascending dose (MAD) study of TD-0714 that is designed to supplement the findings of the SAD study and support the ongoing clinical development of the molecule. The Company expects to complete the MAD study in the second half of this year.

"We are very encouraged by the data from this first clinical study of TD-0714. The data show a favorable safety and tolerability profile, dose-dependent kinetics and robust biomarker evidence of NEP inhibition that is sustained over 24 hours, supporting the potential for once-daily dosing. We were particularly pleased to see insignificant levels of renal clearance of TD-0714. The molecule is not dependent on the kidney for its elimination, therefore, it will not be necessary to adjust the dose in patients with low or variable renal function, in contrast to existing NEP-inhibitor-based therapy. This is important because a significant number of patients with cardiac and renal disease who may benefit from NEP inhibition have compromised renal function," said Brett Haumann, MD, Chief Medical Officer at Theravance Biopharma. "Furthermore, TD-0714 has the potential to be combined with a range of other therapies, including angiotensin receptor blockers and therapies with complimentary mechanisms of action, to treat patients with a range of cardiovascular and renal diseases."

"We set out to meet the difficult and specific challenge of designing a novel, once-daily, oral compound capable of clinically meaningful NEP inhibition with virtually no elimination of the drug through the kidneys," said Sharath S. Hegde, Ph.D., Senior Vice President, Research. "The data from this initial trial of TD-0714 provide clear evidence that we have achieved our goal and created a compound that possesses each of these critical attributes."

The Phase 1 clinical trial of TD-0714 was a randomized, double-blind, placebo-controlled, single-ascending dose study. The study investigated the safety and tolerability, pharmacokinetics, and pharmacodynamics of five ascending oral doses of TD-0714 (50, 100, 200, 400, and 600 mg) in 56 healthy volunteers.

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 U.S. alone, there are six million patients diagnosed with chronic heart failure and approximately one million hospitalizations annually for acute heart failure.1

About Theravance Biopharma

Theravance Biopharma is a diversified biopharmaceutical company with the core purpose of creating medicines that make a difference in the lives of patients suffering from serious illness. Our pipeline of internally discovered product candidates includes potential best-in-class medicines to address the unmet needs of patients being treated for serious conditions primarily in the acute care setting. VIBATIV® (telavancin), our first commercial product, is a once-daily dual-mechanism antibiotic approved in the U.S., Europe and certain other countries for certain difficult-to-treat infections. Revefenacin (TD-4208) is a long-acting muscarinic antagonist (LAMA) being developed as a potential once-daily, nebulized treatment for chronic obstructive pulmonary disease (COPD). Our neprilysin (NEP) inhibitor program is designed to develop selective NEP inhibitors for the treatment of a range of major cardiovascular and renal diseases, including acute and chronic heart failure, hypertension and chronic kidney diseases such as diabetic nephropathy. Our research efforts are focused in the areas of inflammation and immunology, with the goal of designing medicines that provide targeted drug delivery to tissues in the lung and gastrointestinal tract in order to maximize patient benefit and minimize risk. The first program to emerge from this research is designed to develop GI-targeted pan-Janus kinase (JAK) inhibitors for the treatment of a range of inflammatory intestinal diseases. In addition, we have an economic interest in future payments that may be made by Glaxo Group Limited or one of its affiliates pursuant to its agreements with Innoviva, Inc. relating to certain drug development programs, including the Closed Triple (the combination of fluticasone furoate, umeclidinium, and vilanterol).

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THERAVANCE®, the Cross/Star logo, MEDICINES THAT MAKE A DIFFERENCE® and VIBATIV® are registered trademarks of the Theravance Biopharma group of companies.

This press release contains certain "forward-looking" statements as that term is defined in the Private Securities Litigation Reform Act of 1995 regarding, among other things, statements relating to goals, plans, objectives and future events. Theravance Biopharma intends such forward-looking statements to be covered by the safe harbor provisions for forward-looking statements contained in Section 21E of the Securities Exchange Act of 1934 and the Private Securities Litigation Reform Act of 1995. Examples of such statements include statements relating to: the Company's strategies, plans and objectives, the Company's regulatory strategies and timing and results of clinical studies, the potential benefits and mechanisms of action of the Company's product and product candidates and the Company's expectations for product candidates through development and commercialization. These statements are based on the current estimates and assumptions of the management of Theravance Biopharma as of the date of the press release and are subject to risks, uncertainties, changes in circumstances, assumptions and other factors that may cause the actual results of Theravance Biopharma to be materially different from those reflected in the forward-looking statements. Important factors that could cause actual results to differ materially from those indicated by such forward-looking statements include, among others, risks related to: delays or difficulties in commencing or completing clinical studies, the potential that results from clinical or non-clinical studies indicate the Company's product candidates are unsafe or ineffective, the feasibility of undertaking future clinical trials for our product candidates based on FDA policies and feedback, dependence on third parties to conduct clinical studies, delays or failure to achieve and maintain regulatory approvals for product candidates, risks of collaborating with third parties to discover, develop and commercialize product and product candidates and risks associated with establishing and maintaining sales, marketing and distribution capabilities with appropriate expertise and supporting infrastructure. Other risks affecting Theravance Biopharma are described under the heading "Risk Factors" contained in Theravance Biopharma's Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) on November 12, 2015. In addition to the risks described above and in Theravance Biopharma's other filings with the SEC, other unknown or unpredictable factors also could affect Theravance Biopharma's results. No forward-looking statements can be guaranteed and actual results may differ materially from such statements. Given these uncertainties, you should not place undue reliance on these forward-looking statements. Theravance Biopharma assumes no obligation to update its forward-looking statements on account of new information, future events or otherwise, except as required by law.

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