Theravance Biopharma, through its U.S. operating subsidiary, South San Francisco, California-based Theravance Biopharma US, Inc., on Tuesday announced positive results from the first three cohorts of Study 0110 — a Phase 1 proof-of-concept study of the company’s TD-6450 next-generation investigational NS5A inhibitor in development for treatment of patients with hepatitis C virus infection (HCV).
In the study, TD-6450 was evaluated in three cohorts of eight genotype 1a (GT-1a) patients each at doses of 60, 120 and 240 mg, administered once-daily for three days. TD-6450 demonstrated dose-dependent antiviral activity with median maximal declines of HCV RNA of 3.87, 4.63 and 4.89 log10 IU/mL for doses of 60, 120 and 240 mg, respectively.
In the 120 and 240 mg dose groups, three days of once-daily oral treatment resulted in levels of serum HCV RNA below the limit of detection (LOD) in 43% (3/7) and 57% (4/7) of patients treated with TD-6450, respectively. Three of the seven LOD patients went on to show no measurable virus at Day 14, and two of these patients still had no measurable virus at Day 28. At a two-month time point in a long-term follow-up study, the viral load in these two patients was measurable, but both remained more than three logs below their baseline.
None of the patients in the three dose groups had virologic breakthrough during their three-day treatment course, and 100% of the treated GT-1a patients in the study achieved at least a three log10 IU/mL reduction of HCV RNA. At the 120 and 240 mg doses, 71% (5/7) and 86% (6/7) of treated patients achieved at least a four log10IU/mL reduction in HCV RNA, respectively.
All doses of TD-6450 were generally well tolerated after three doses and for the 28-day observation period. There were no serious adverse events and no patient discontinuations. There was no pattern of clinical adverse events or laboratory abnormalities related to treatment.
“We see diverse responses to direct antivirals in genotype 1 populations. Despite recent advances in HCV therapy, significant treatment challenges remain, including the required length of drug therapy. The robust activity of TD-6450 in genotype 1a patients suggests that this potentially best-in-class NS5A inhibitor could be a component of short and highly active combination therapy regimens,” says Eric Lawitz, MD, Vice President of Scientific and Research Development at the Texas Liver Institute and Clinical Professor of Medicine, The University of Texas Health Science Center San Antonio, and a principal investigator on the Phase 1 study in a Theravance Biopharma release.
“TD-6450, created using the principles of multivalent design, has a heterodimeric structure distinct from other NS5A inhibitors. We believe this unique structure allows it to bind asymmetrically across the NS5A protein interface, providing high in vitropotency against clinically encountered resistance-associated variants. We believe the potency of TD-6450 against both wild type virus and these resistance-associated variants enables the robust antiviral activity that we reported today,” says Mathai Mammen, MD Mathai Mammen, MD, Senior Vice President, Research and Development, Theravance Biopharma. “We look forward to analyzing the full set of results from this Phase 1 study and evaluating the next steps in the development strategy for TD-6450.” Dr. Mammen received his B.Sc. in Honours Chemistry and the Governor General’s Medal from Dalhousie University in Halifax, Nova Scotia in 1989, an M.D. from Harvard Medical School in 1998, and a Ph.D. in Chemistry from Harvard University, also in 1998.
Dr. Mammen says that the ideas elucidated in his doctoral thesis, entitled “Entropy and Electrostatics in Molecular Associations: Theory and Practice,” under the mentorship of Professor George Whitesides at Harvard University’s Department of Chemistry enabled him to write a business plan and co-found Theravance as a biotech startup with another physician Jim Tananbaum. The technology that formed the basis of Theravance Biopharma is called “Multivalent Drug Design,” which applies “a fundamentally different way to design medicines than is typical at modern-day biotechnology and pharmaceutical companies.” He notes that over the last twelve years the company has had tremendous success, with the discovery of nineteen new compounds that were entered into human clinical trials, and the Research and Early Clinical Development he oversees directly has a team of approximately 100 highly talented scientists and physicians.
The Phasorse 1 Proof-of-Concept Study (Study 0110)
This Phase 1 study is a double-blind, randomized, placebo-controlled, multiple-dose study to evaluate the safety, tolerability, pharmacokinetics and antiviral activity of orally administered TD-6450 in non-cirrhotic, treatment-naive patients with GT-1, 2, or 3 chronic HCV infection. The study includes seven cohorts. The first three cohorts enrolled eight GT-1a patients each (7 active; 1 placebo) and tested once-daily oral doses of 60, 120 or 240 mg, respectively. Patients were dosed for three days and followed for up to 28 days for viral load quantification. The limit of detection for the viral load quantification assay is 15 IU/mL.
Safety evaluations include monitoring for adverse events, routine laboratory assessments, vital signs and 12-lead ECG tracings.
In cohorts 4 through 6, patients with GT-1b, GT-2 and GT-3 are dosed once-daily at 240 mg. An additional cohort (cohort 7) of GT-1a patients is dosed twice daily with 240 mg. Data generation and analysis of results for cohorts 4 through 7 is ongoing. An interim analysis of those cohorts showed antiviral activity for GT-1b similar to that for GT-1a, but minimal antiviral activity for GT-2 and GT-3.
The company anticipates presenting further data on all cohorts at a future scientific conference.
TD-6450 is an internally discovered multivalent NS5A inhibitor designed to have improved antiviral activity against GT-1 resistance-associated variants (RAV) resistant to first generation NS5A inhibitors. TD-6450’s heterodimeric structure permits an asymmetric binding mode to NS5A relative to structurally symmetric inhibitors. TD-6450 has demonstrated additive activity with other classes of anti-HCV agents in replicon assays, and no cross-resistance with RAVs that confer resistance to other anti-HCV agents. Theravance Biopharma believes that the antiviral activity of TD-6450, in combination with other antivirals, may help improve cure rates and/or reduce treatment times for appropriate patients.
TD-6450 was previously evaluated in a single-ascending dose and a 14-day multiple-ascending dose study in healthy subjects (study 0094). This randomized, double-blind, placebo-controlled study evaluated the safety, tolerability and pharmacokinetics of TD-6450. Single doses (up to 500 mg) and multiple doses of TD-6450 (up to 240 mg daily for 14 days) were evaluated in healthy subjects. Following single and multiple doses, TD-6450 was generally well-tolerated and no subjects discontinued due to adverse events. Headache was the most commonly reported adverse event following multiple doses (n=4). TD-6450 pharmacokinetics were linear up to 240 mg following single and multiple doses and its long half-life supports once-daily dosing.
Hepatitis C and the NS5A Inhibitor Class
Hepatitis C is a serious and potentially deadly infectious disease of the liver. It is estimated that some 130 – 150 million people have chronic hepatitis C, with as many as four million of those cases in the United States. Like all forms of hepatitis, Hepatitis C can damage the liver. Of people infected, 55 to 85 percent will develop chronic infection, and 75 percent of those with chronic infection will develop chronic liver disease.
The hepatitis C non-structural 5A (NS5A) protein of HCV has emerged as an attractive drug target and inhibitors of NS5A have a central role in all-oral HCV therapy. The multi-functional NS5A protein is required for ribonucleic acid (RNA) replication and virion assembly, and a number of investigational and approved NS5A inhibitors have shown antiviral efficacy in HCV-infected patients.
Conference Call Replay Available
A replay of Theravance Biopharma’s November 4 conference call discussing the results of the Phase 1 study of TD-6450 will be available on Theravance Biopharma’s web site for 30 days through December 3, 2014. An audio replay will also be available through 11:59 p.m. ET on November 10, 2014 by dialing (855) 859-2056 from the US, or (404) 537-3406 for international callers, and entering confirmation code 28908270.
Theravance Biopharma is a biopharmaceutical company focused on the discovery, development and commercialization of small molecule medicines across a number of therapeutic areas, including respiratory disease, bacterial infections, central nervous system (CNS)/pain, and gastrointestinal (GI) motility dysfunction. Theravance Biopharma has one approved product, VIBATIV (telavancin), which was discovered and developed internally, a pipeline of internally discovered product candidates and strategic collaborations with pharmaceutical companies.
In addition, the Company has an economic interest in future payments that may be made by GlaxoSmithKline plc (GSK) pursuant to its agreements with Theravance, Inc. relating to certain drug programs, including the combination of fluticasone furoate (FF), umeclidinium (UMEC), and vilanterol (VI) (FF/UMEC/VI), the combination of the bifunctional muscarinic antagonist-beta2 agonist (MABA) GSK961081 (‘081) and FF (‘081/FF), and MABA monotherapy. By leveraging its proprietary insight of multivalency to drug discovery, the Company is pursuing a best-in-class strategy designed to discover superior medicines in areas of significant unmet medical need.
Theravance Biopharma is a publicly-held corporation, with U.S. headquarters located in South San Francisco, California, and trades on the NASDAQ Global Select Market under the symbol TBPH. For additional information, visit: http://www.theravance.com
University of Texas Health Science Center San Antonio
University of Texas Health Science Center San Antonio