Theravance Biopharma Announces Positive Results From Phase 1 Proof-of-Concept Study of TD-6450, an NS5A Inhibitor to Treat Hepatitis C
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 log10 IU/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," said
"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 vitro potency 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," said
About the Phase 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. The Company 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.
About Hepatitis C and the NS5A Inhibitor Class
Hepatitis C is an infectious disease of the liver. Worldwide, health experts estimate that 130 - 150 million people have chronic hepatitis C, with as many as four million of those cases in
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.
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Rick E Winningham
Chief Executive Officer
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