COMUNICADO: High Rates of SVR Demonstrated in Phase II Study with Investigational Triple DAA Regimen of Daclatasvir, Asunaprevir and

Actualizado 23/04/2013 14:36:33 CET

PRINCETON, New Jersey, April 23, 2013 /PRNewswire/ --

- This all-oral treatment regimen is being studied as an interferon-free and
ribavirin-free option

- Investigational regimen involves three different classes of direct-acting
antivirals (DAAs) - an NS5A replication complex inhibitor, an NS3 protease inhibitor
and an NS5B non-nucleoside polymerase inhibitor

- Phase III development as a fixed-dose combination is anticipated to begin
by late 2013

Bristol-Myers Squibb Company [ ] today announced additional, interim Phase II data demonstrating that 12- and 24-week Triple DAA treatment regimens of daclatasvir (DCV), asunaprevir (ASV) and BMS-791325 ('325) achieved high rates of sustained virologic response (SVR) of up to 94%, in treatment-naïve, genotype 1 chronic hepatitis C patients, at time points ranging from 4 to 36 weeks post-treatment depending on the treatment group. These data support the continued development of this interferon alfa-, ribavirin (RBV)- and ritonavir (RTV)-free regimen, with Phase III initiation anticipated to begin by late 2013.

The study results will be presented this week at the International Liver Congress, the 48th annual meeting of the European Association for the Study of the Liver (EASL), in Amsterdam.

Two serious adverse events (2/66), renal calculus and cerebral vasoconstriction, were reported in this study. The renal calculus was determined by the investigator to be unrelated to study drug. The cerebral vasoconstriction was associated with treatment intensification with peginterferon alfa and ribavirin following viral breakthrough in one patient. Headache was the most common adverse event in the study (27.3%, 18/66).

"The diversity of the hepatitis C patient population requires multiple treatment options that can enable a personalized approach to therapy. Effective and well-tolerated oral treatment regimens that are ribavirin-free remain an important unmet medical need in hepatitis C," said Brian Daniels [ ], MD, senior vice president, Global Development and Medical Affairs, Research and Development [ ], Bristol-Myers Squibb. "These data, which demonstrate comparable efficacy among the 12- and 24-week Triple DAA treatment groups, support the rapid Phase III development of this investigational Triple DAA regimen and provide further data on daclatasvir as an important component of DAA-based therapy."

Daclatasvir is the first NS5A replication complex inhibitor to be investigated in HCV clinical trials and is currently in Phase III development. Asunaprevir is an oral, NS3 protease inhibitor in Phase III development with daclatasvir. BMS-791325 is a non-nucleoside inhibitor of the NS5B polymerase, currently in Phase II development for hepatitis C as a component of daclatasvir-based treatment regimens.

Study Design and Results

This open-label, two-part Phase II study is designed to evaluate the safety and antiviral activity of the investigational hepatitis C treatment regimen of DCV, ASV and '325 in treatment-naïve patients with genotype 1a and 1b chronic hepatitis C infection. The primary endpoint of the study is viral load below the lower limit of quantitation (LLOQ; HCV RNA <25 IU/mL) at 12 weeks post-treatment (SVR12).

Part 1 of the study evaluated a treatment regimen of DCV 60 mg QD, ASV 200 mg BID and '325 75 mg BID for 24 or 12 weeks (Groups 1 and 2, respectively). Part 2 of the study evaluated the same DAA regimen for 24 or 12 weeks, with '325 dosed at 150 mg BID (Groups 3 and 4, respectively).

Interim results for Part 1 of the study were previously reported at the American Association for the Study of the Liver (AASLD) annual meeting in November 2012.

The study was expanded in November 2012, adding eight new treatment groups including the evaluation of this Triple DAA regimen in treatment-naïve patients with HCV genotype 4 and null responders with HCV genotype 1. Results from these treatment groups are not yet available.

Virologic Response

- 100% (28/28) of patients in Groups 1 and 2 (24- and 12-week treatment,
'325 75 mg) with post-treatment follow-up data achieved SVR24 and/or SVR36. There was
no viral breakthrough during treatment and no post-treatment relapse in either group.

- 91% (31/34) of patients overall in Groups 3 and 4 (24- and 12-week
treatment, '325 150 mg) achieved SVR4. Three out of the 34 patients experienced
virologic failure on or after treatment.

Group 1 Group 2 Group 3 Group 4
(n=16) (n=16) (n=16) (n=18)
BMS-791325 Dose 75 mg 75 mg 150 mg 150 mg
Treatment Duration 24 weeks 12 weeks 24 weeks 12 weeks
94%[a] 94%[b] 94% 89%[c],[d]
SVR4 (15/16) (15/16) (15/16) (16/18)
94%[a] 94%[b] 89%[c],[d]
SVR12 (15/16) (15/16) N/A* (16/18)
88%[a],[b] 94%[b]
SVR24 (14/16) (15/16) N/A N/A
SVR36 N/A (14/16) N/A N/A
6% 6%
Viral Breakthrough 0% 0% (1/16) (1/18)
Relapse 0% 0% 0% (1/18)

[a]Patient withdrewconsent; [b]One patient missed this visit but had achieved undetectable viral load at end of treatment or SVR at earlier endpoints;[c]One patient experienced viral breakthrough; [d]One patient relapsed; [e]Two patients missed this visit, but had achieved SVR at earlier endpoints

* N/A = data not available at time of analysis

On-Treatment Safety

There were no deaths and no patient discontinuations due to treatment intolerance or adverse events (AEs) related to BMS therapy. Two serious adverse events (SAEs) were reported in the study. One SAE, cerebral vasoconstriction, occurred in Group 3 during treatment intensification with peginterferon alfa and RBV following viral breakthrough and lead to treatment discontinuation; cerebral vasoconstriction is a known side effect of interferon alfa. The remaining SAE reported on-treatment, renal calculus, was observed in Group 2 and was determined by the investigator to be unrelated to study drug.

Most AEs were mild to moderate in severity. The most common AEs (greater than or equal to10% total) across all study groups were headache (27.3%, 18/66), asthenia (16.7%, 11/66), diarrhea (16.7%, 11/66), and nausea (13.6%, 9/66).

No Grade 3-4 elevations in liver enzymes (ALT/AST) or bilirubin were observed in this study. One grade 3 AE (headache) resolved after seven days with continued study treatment. One grade 3-4 laboratory abnormality was reported in this study. One case of lymphopenia was recorded in Group 2 at a single study visit concomitant with influenza. All other AEs were grade 1 or 2.

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