240 mg Achieved a Median Maximal Viral Load Decline of 4.9 Log10 IU/mL Following Three Daily Doses in Genotype 1a Patients
SOUTH SAN FRANCISCO, CA — (Marketwired) — 11/03/14 —
Theravance Biopharma (NASDAQ: TBPH), through its U.S. operating subsidiary, Theravance Biopharma US, Inc.,
today announced positive results from the first three cohorts of Study
0110, a Phase 1 proof-of-concept study of TD-6450, a next-generation
investigational NS5A inhibitor in development to treat patients with
hepatitis C virus infection (HCV).
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
“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 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 one of the principal investigators on the Phase 1 study.
“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 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
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 United States.
Hepatitis C, like all forms of hepatitis, 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
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 Today at 5:00 pm ET
Theravance Biopharma will hold a conference call today at 5:00 pm ET
to discuss the results of the Phase 1 study of TD-6450. To participate
in the live call by telephone, please dial (855) 296-9648 from the US,
or (920) 663-6266 for international callers. To listen to the conference
call live via the internet, please visit Theravance Biopharma’s web site at www.theravance.com,
under the Investor Relations section, Presentations and Events. To
listen to the live call and to download the slide presentation, please
go to Theravance Biopharma’s web site 15 minutes prior to its start to register, download, and install any necessary audio software.
A replay of the conference call 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.
About 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, please visit www.theravance.com.
THERAVANCE, the Cross/Star logo, MEDICINES THAT MAKE A
DIFFERENCE and VIBATIV are trademarks and/or registered trademarks of
the Theravance Biopharma group of companies.
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