BMS-650032 (Asunaprevir)
BMS-790052  (Daclatasvir)

BMS-790052 is an investigational oral hepatitis C NS5A replication complex inhibitor. NS5A is one of the essential
components for HCV replication.BMS-650032 is an NS3 protease inhibitor, both in development for the treatment of chronic hepatitis C virus (HCV) infection

BMS-790052 and BMS-650032 were discovered by Bristol-Myers Squibb Research and Development. PEG-Interferon
lambda was discovered by ZymoGenetics, Inc., a wholly-owned subsidiary of Bristol-Myers Squibb.

April 7 2013
Daclatasvir/asunaprevir effective in difficult-to-treat HCV populations

Suzuki Y. J  Hepatol.  2013;58:655-662.
 
Most patients with chronic hepatitis C who had been ineligible for or  
nonresponsive to interferon-based treatment benefited from dual therapy with 
daclatasvir and asunaprevir in a recent study.

In an open-label, phase 2a study, researchers administered 24 weeks of dual
oral therapy with 60 mg NS5A  replication complex inhibitor daclatasvir (DCV)
once daily and 200 mg NS3 protease inhibitor asunaprevir (ASV) twice a day to 43
Japanese patients aged 20 to 75 years with chronic HCV genotype 1b.

The  cohort included 21 null responders and 22 who had been ineligible or
intolerant  to previous therapy with pegylated interferon-alfa and ribavirin  (PegIFN-a/RBV).
 Thirty-six  participants completed therapy. At 4 weeks, more patients in the  
intolerant/ineligible group had achieved undetectable HCV RNA levels than null 
responders, with mean RNA reductions of 5.4 log10 IU/mL among
intolerant/ineligible patients and 5.6  log10 IU/mL for null responders.

All  participants had undetectable HCV RNA levels after 8 weeks. Sustained virologic
response  (SVR) at 12 and 24 weeks after completion of treatment occurred in
76.7% of  the cohort (90.5% of null responders and 63.6% of intolerant/ineligible 
participants).

Virologic breakthrough occurred in three intolerant/ineligible participants,
along with four relapses after treatment. No null responders experienced relapse
or virologic  breakthrough. Investigators observed no associations between
breakthrough  or relapse and factors including gender, IL28B genotype,
age, HCV  RNA level at baseline, fibrosis stage and reasons for previous
treatment  ineligibility.

Common adverse events, all typically mild, included  headache,
nasopharyngitis, diarrhea and increases to ALT/AST. Five patients
experienced  serious events, and three discontinued treatment for
hyperbilirubinemia or  transaminase elevation.

“Dual  oral therapy with daclatasvir and asunaprevir elicited rapid clearance
of  detectable HCV RNA and achieved high rates of SVR in two difficult-to-treat 
patient populations,” the researchers concluded. “These results confirm initial 
findings that HCV genotype 1b infections can be cured with daclatasvir
combined  with asunaprevir, without PegIFN-a/RBV.

“Further research will assess the benefits of this and other [direct-acting
antiviral] combinations in larger and more diverse patient populations.”

Disclosure:
See the study for a full list of relevant disclosures.
http://www.healio.com/hepatology/chronic-hepatitis/news/online/%7B59F64758-CDD6-4495-AFEA-37F21060F831%7D/Daclatasvirasunaprevir-effective-in-difficult-to-treat-HCV-populations

Journal  of Hepatology-Volume  58, Issue 4 ,
Pages 655-662, 

April 2013

 Dual oral therapy with daclatasvir and asunaprevir for patients with HCV genotype 1b infection and limited treatment options
 
Suzuki Y , Ikeda K , F  Suzuki , Toyota J , Karino Y , K Chayama , KawakamiY , Ishikawa  H , H
Watanabe , Hu  W , Eley  T , F  McPhee , Hughes  E , Kumada  H .

Fonte Dipartimento di Epatologia, Toranomon Hospital,  Tokyo, Giappone. Indirizzo
elettronico: suzunari@interlink.or.jp Questo indirizzo email  è protetto dagli spambots. 
E' necessario abilitare JavaScript per vederlo.   .

Background & Aims 
Improved therapeutic options for chronic hepatitis C virus (HCV) infection
are needed for  patients who are poor candidates for treatment with current
regimens due to anticipated intolerability or low likelihood of  response.

Methods
In this open-label, phase 2a study of Japanese patients with chronic HCV genotype
1b infection, 21 null  responders (<2log10 HCV RNA reduction after 12weeks
of  peginterferon/ribavirin) and 22 patients intolerant to or medically  
ineligible for peginterferon/ribavirin therapy received dual oral treatment for  
24weeks  with the NS5A replication complex inhibitor daclatasvir (DCV)
and the NS3 protease inhibitor asunaprevir (ASV). The primary efficacy end
point was sustained virologic response at 12weeks post-treatment (SVR12).

Results
Thirty-six  of 43 enrolled patients completed 24weeks of therapy. Serum HCV
RNA  levels declined rapidly, becoming undetectable in all
patients on therapy  by week 8. Overall, 76.7% of patients achieved SVR12and
SVR24,

including 90.5% of null responders and 63.6% of ineligible/intolerant patients.  
There were no virologic failures among null responders. Three  
ineligible/intolerant patients experienced viral breakthrough and four relapsed  
post-treatment. Diarrhea, nasopharyngitis, headache, and ALT/AST increases,  
generally mild, were the most common adverse events; three discontinuations  
before week 24 were due to adverse events that included hyperbilirubinemia
and  transaminase elevations (two patients).

Conclusions
Dual  therapy with daclatasvir and asunaprevir, without peginterferon/ribavirin, was
well  tolerated and achieved high SVR rates in two groups of difficult-to-treat  
patients with hepatitis C virus genotype 1b  infection.

July 2012
Daclatasvir and asunaprevir—A potent interferon-free
regimen

Feb 2012
New Study Hailed as 'Watershed Moment' in Hep C  Research

Jan 7 2013
Asunaprevir (BMS-650032; Bristol-Myers Squibb, New York, NY) is a twice-daily protease inhibitor being developed in both IFN-containing and free regimens with daclatasvir, an NS5A inhibitor and BMS 791325, a non-nucleoside inhibitor.
Asunaprevir was initially studied at a dose of 600 mg twice per day, but was decreased to 200 mg twice per day because of increased liver enzymes. The combination of asunaprevir and daclatisvir was the first regimen to successfully cure HCV-infected patients without the use of IFN [14]. Despite potential approval in an IFN-free combination in genotype 1b patients and a potential quad regimen, asunaprevir is not likely to become the PI of choice for this second wave of PIs
because of the twice-per-day administration and potential association with hepatotoxicity...read more..

Jan 6 2013
Interferon free therapy with direct acting antivirals for HCV   
asunaprevir;daclatasvir;faldaprevir;simeprevir; NS5A inhibitors;NS5B polymerase inhibitors;
•protease inhibitors;ribavirin;sofosbuvir

November 2012

AASLD Updates-

AASLD-Quad Regimen of Daclatasvir and Asunaprevir Plus Interferon Alfa and Ribavirin Achieved SVR24 in 93% Geno 1a/b Null Responders

AASLD-Daclatasvir and Asunaprevir Achieved SVR12 in 78% of  Difficult-to-Treat Genotype 1b Prior Null Responders

A revolution in HCV treatment with direct-acting antivirals: From non-response to eradication

Journal of Hepatology
Volume 57, Issue 2 , Pages 455-457, August 2012

Hepatology  Department, AP-HP, University Paris Diderot 7 and INSERM U773, CRB3, Beaujon
Hospital, Clichy, France

Received 10 March 2012;  received in revised form 16 March 2012; accepted 18 March 2012. 
published online 28 March  2012.

COMMENTARY ON:

Preliminary study of two antiviral agents for hepatitis C genotype 1. Lok AS,
Gardiner DF, Lawitz E, Martorell C, Everson GT, Ghalib R, Reindollar R, Rustgi
V, McPhee F, Wind-Rotolo M, Persson A, Zhu K, Dimitrova DI, Eley T, Guo T,
Grasela DM, Pasquinelli C. N Engl J Med 2012 January 19;366(3):216–24. Copyrigth
(2012). Abstract reprinted with permission from the Massachusetts Medical
Society.

http://www.ncbi.nlm.nih.gov/pubmed/22256805

Abstract: Background: Patients with chronic hepatitis C virus (HCV) infection
who have not had a response to therapy with peginterferon and ribavirin may
benefit from the addition of multiple direct-acting antiviral agents to their
treatment regimen.


Methods: This open-label, phase 2a study included an exploratory cohort of 21
patients with chronic HCV genotype 1 infection who had not had a response to
previous therapy (i.e., had not had 2 log(10) decline in HCV RNA after 12weeks
of treatment with peginterferon and ribavirin). We randomly assigned patients to
receive the NS5A replication complex inhibitor daclatasvir (60mg once daily) and
the NS3 protease inhibitor asunaprevir (600mg twice daily) alone (group A, 11
patients) or in combination with peginterferon alfa-2a and ribavirin (group B,
10 patients) for 24weeks. The primary end point was the percentage of patients
with a sustained virologic response 12weeks after the end of the treatment
period.


Results: A total of 4 patients in group A (36%; 2 of 9 with HCV genotype 1a
and 2 of 2 with genotype 1b) had a sustained virologic response at 12weeks after
treatment and also at 24weeks after treatment. Six patients (all with HCV
genotype 1a) had viral breakthrough while receiving therapy, and resistance
mutations to both antiviral agents were found in all cases; 1 patient had a
viral response at the end of treatment but had a relapse after the treatment
period. All 10 patients in group B had a sustained virologic response at 12weeks
after treatment, and 9 had a sustained virologic response at 24weeks after
treatment. Diarrhea was the most common adverse event in both groups. Six
patients had transient elevations of alanine aminotransferase levels to more
than three times the upper limit of the normal range.

Conclusions: This preliminary study involving patients with HCV genotype 1
infection who had not had a response to prior therapy showed that a sustained
virologic response can be achieved with two direct-acting antiviral agents only.
In addition, a high rate of sustained virologic response was achieved when the
two direct-acting antiviral agents were combined with peginterferon alfa-2a and
ribavirin. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number,
NCT01012895.).

© European Association for the Study of the Liver. Published by Elsevier B.V.
All rights reserved.

Approximately 170 million people are infected with hepatitis C virus (HCV)
worldwide. Treatment of genotype 1 naïve chronic hepatitis C with peginterferon
alfa (PegIFN) and ribavirin (RBV) for 48weeks results in sustained virologic
response (SVR) in approximately 40% of patients. Retreatment of previous
non-responders to PegIFN/RBV therapy with triple therapy, a protease inhibitor
(telaprevir or boceprevir), PegIFN/RBV, results in an SVR in less than 30% of
cases [1], [2]. Direct-acting antivirals (DAAs) with different viral targets,
including NS3 protease inhibitors, nucleoside/nucleotide analogues and
non-nucleoside inhibitors of the RNA-dependent RNA polymerase, and NS5A
inhibitors are under development [3]. Gane and colleagues found that a
combination of two DDAs can suppress HCV RNA in genotype 1 non-responder
patients but the treatment with the DAAs combination was limited to 13days and
was followed immediately by treatment with PegIFN/RBV, thus preventing the
assessment of SVR with DAAs alone [4]. Studies of DAAs combinations in the
genotype 1 non-responder population are warranted.

Recently, Lok et al., in a preliminary study including patients with HCV
genotype 1 infection who were non-responders to prior therapy, showed that an
SVR could be achieved with two DAAs [5].

Daclatasvir (BMS-790052) is a first-in-class, highly selective HCV NS5A
replication complex inhibitor with picomolar potency in vitro [6]. NS5A is a
membrane-associated phosphoprotein present in basally phosphorylated (p56) and
hyperphosphorylated (p58) forms. It was previously reported that only
p58-defective mutants could be complemented in trans, and NS5A is involved in
HCV virion production, suggesting that different forms of NS5A exert multiple
functions at various stages of the viral life cycle. The N terminus of NS5A
(domain I) has been crystallized in alternative dimeric forms and contains both
zinc- and RNA-binding domains, properties that have been demonstrated in vitro.
Daclatasvir is active at picomolar concentrations in vitro towards replicons
expressing a broad range of HCV genotypes and acts in an additive to synergistic
way with interferon and other small molecule antiviral compounds [6], [7]. The
resistance profile of BMS-790052 reveals that inhibitor sensitivity maps to the
N terminus of domain 1 of NS5A [6], [7], [8]. In addition, it has been
demonstrated that NS5A inhibitors could block hyperphosphorylation of NS5A,
which is believed to play an essential role in the viral life cycle.

Asunaprevir (BMS-650032) is a highly active HCV NS3 protease inhibitor. NS3
serine protease is located at the N-terminal region of NS3. The NS3 serine
protease domain associates with the NS4A co-factor to cleave four specific
sites. This enzyme has been extensively characterized at the biochemical level
and its structure is known [9]. The serine protease activity of NS3 is an
attractive target for new drugs that could effectively block viral replication.
Protease inhibitors have high anti-viral efficacy and usually a low genetic
barrier. The genetic barrier to resistance is defined as the number of amino
acid substitutions required to confer full resistance to a drug. The genetic
barrier to protease inhibitors and NS5A inhibitors is usually low.

Both daclatasvir and asunaprevir produce marked declines in HCV RNA levels in
patients with HCV genotype 1 infection [10], [11] and administration of the two
drugs in combination did not produce a clinically meaningful pharmacokinetic
interaction [12].

In the study reported by Lok et al., patients with HCV genotype 1 infection,
with no response to previous treatment with PegIFN/RBV, were randomly assigned
to receive daclatasvir (60mg once daily) and asunaprevir (600mg twice daily)
alone (group A, 11 patients) or in combination with PegIFNα-2a and RBV (group B,
10 patients) for 24weeks [5]. A total of 4 patients in group A (36%; 2 of 9 with
HCV genotype 1a and 2 of 2 with genotype 1b) had an SVR 12weeks after treatment
and also 24weeks after treatment (Fig. 1). Six patients (all with HCV genotype
1a) had a viral breakthrough while receiving therapy, and resistance mutations
to both antiviral agents were found in all cases; 1 patient had a viral response
at the end of treatment but relapsed after the treatment period.

Fig. 1.
Virologic response.
(Group A) Four patients (36%)  had an SVR at 12weeks after the end of the treatment period, and all four  also had an SVR at week 24 after treatment. Six patients (all with HCV genotype  1a) had a viral breakthrough while receiving therapy; 1 patient had a viral  response at the end of treatment but relapsed after the treatment period. (Group  B) (1) 10/10 patients had undetectable HCV RNA by week 6 of therapy with no  viral breakthrough; (2) 10/10 patients achieved SVR12 and 9/10 achieved  SVR24; (3) 1  patient <LLOQ at week 24 post-treatment was undetectable on retesting, 1 and  3months later. Adapted from [5], with permission from the  Massachusetts Medical Society

Viral variants in the NS5A domain included Q30R, L31M/V, and Y93C/N; variants
in the NS3 protease domain included R155K and D168A/E/T/V/Y. The patient with a
viral relapse had a pre-existing NS3 protease resistance variant, R155K, at
baseline and at the time of viral relapse, whereas the NS5A resistance variant
Q30E was only detected at relapse. Although there were only 2 patients with HCV
genotype 1b infection in group A, the observation that both of the patients had
an SVR with two direct-acting antiviral agents alone may reflect a higher
resistance barrier for this combination of drugs in patients with HCV genotype
1b infection than in those with HCV genotype 1a infection. The high frequency of
resistance seen in patients with HCV genotype 1a infection who were treated with
DAAs alone suggests that studies of DAAs combinations without PegIFN/RBV in
patients with HCV genotype 1a infection should proceed carefully.

In group B,  the inclusion of Peg IFN/RBV with daclatasvir and asunaprevir provided
sufficient antiviral activity to suppress the emergence of resistance. All 10
patients in group B had an SVR 12weeks after treatment, and 9 had an SVR 24weeks after treatment.


It should be noticed that among the 14 patients who had an SVR 12weeks after treatment, a HCV RNA level of less than 25IU/ml was detected in 1 patient 24weeks after treatment and in 2 other patients 48weeks after treatment. All 3 patients had undetectable HCV RNA on re-testing. These data indicate that late relapse is unlikely to occur in patients who have an SVR with the DAAs combination, 12weeks after treatment as previously established with Peg IFN/RBV treatment [13].

The most common adverse events were diarrhea, fatigue, headache, and nausea.
Most adverse events were mild to moderate. There were no deaths, serious adverse
events, or discontinuations of study treatment due to adverse events. Diarrhea
was the most common adverse event in both groups. Six patients had transient
elevation of alanine aminotransferase levels to more than three times the upper
limit of the normal range.

Finally, Lok et al. reported interesting results with daclatasvir and
asunaprevir combination in HCV genotype 1 non-responders to previous treatment
with PegIFN plus ribavirin [5]. Similarly, Chayama et
al. reported impressive results in a pilot study of combination therapy with
asunaprevir and daclatasvir in 10 Japanese patients with HCV genotype 1b
infection and who had not responded to previous therapy with PegIFN/RBV: nine
patients achieved an SVR [14]. Several studies of DAA
combinations are ongoing with different HCV targets: [3], [5], [14], [15]. Preliminary results of
DAA combinations show increased antiviral efficacy, reduced resistance and a
good safety profile. It is important to note that some of these drugs have
pan-genotypic activity. This rapid progress strongly suggests that in the near
future, IFN-free short duration DAA combinations will make HCV the first chronic
viral infection to be eradicated worldwide.

References

http://www.journal-of-hepatology.eu/article/S0168-8278(12)00235-8/fulltext

April 19, 2012
All-Oral Hepatitis C Virus Treatment with Bristol-Myers Squibb’s Investigational Compounds Daclatasvir and Asunaprevir Achieved Sustained Virologic Response in 77% of Difficult-to-Treat Patients.

• Dual oral therapy data demonstrates SVR24 in genotype 1b difficult-to-treat patients, including null responders and patients medically ineligible or intolerant to alfa and ribavirin
• Study confirms the sentinel cohort data reported at AASLD in 2011
• Data presented at The International Liver Congress in Barcelona

PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE: BMY) today announced results from a Phase II study in which treatment with an all-oral, dual direct-acting antiviral (DAA) regimen of daclatasvir, an investigational NS5A replication complex inhibitor, and asunaprevir, an investigational NS3 protease inhibitor, achieved undetectable viral load 24 weeks post-treatment (SVR24) in 77% (33/43) of difficult-to-treat genotype 1b hepatitis C (HCV) patients. Difficult-to-treat patients in this study included null responders, or patients who had previously not responded to treatment with peginterferon alfa and ribavirin (alfa/RBV), and patients who were medically ineligible or intolerant to previous treatment with alfa/RBV. In this study, serious adverse events (SAE) included three patients with fever (pyrexia), one with hypochondriasis, and one with hyperbilirubinemia which led to treatment discontinuation.

The study findings, presented in an oral session at the International Liver Congress (ILC), the 47th annual meeting of the European Association for the Study of the Liver (EASL) in Barcelona, Spain, confirmed the previously announced sentinel cohort data.
 
“Currently there are no treatments available for hepatitis C genotype 1 that can be administered without the concurrent use of alfa and ribavirin, which gives rise to a serious unmet need for patients who are ineligible or intolerant to alfa/ribavirin,” said principal investigator Fumitaka Suzuki, Toranomon Hospital, Tokyo, Japan. “The results of this Phase II study with Bristol-Myers Squibb’s daclatasvir and asunaprevir are encouraging as we study potential hepatitis C therapies for this difficult-to-treat patient population.”Study Results The primary endpoint of the study was the proportion of patients with sustained virologic response 12-weeks following treatment (SVR12). In this study, the patents were divided into two treatment groups: Group A consisted of 21 genotype 1b prior null responders and Group B consisted of 22 genotype 1b patients medically ineligible for alfa/RBV or with prior intolerance to alfa/RBV.

Overall, 77% (33/43) of patients achieved SVR12 and maintained virologic response through follow-up to SVR24. SVR24 was achieved by 91% (19/21) of patients in Group A and 64% (14/22) of patients in Group B. Of the 43 patients enrolled in the study, 39 completed 24 weeks of treatment. In this study, 94% (33/35) patients who achieved SVR4 remained undetectable SVR24, and 100% (33/33) of patients who achieved SVR12 remained undetectable at SVR24.

Viral breakthrough was observed in 7.0% (3/43) of patients and post-treatment relapse was observed in 9.3% (4/43) of patients in the study. All occurrences of viral breakthrough and post-treatment relapse took place in the alfa/RBV ineligible/intolerant arm. There were no viral breakthroughs and no post-treatment relapses in prior null responders.

Serious adverse events occurred in five patients. Three patients experienced Grade 2/3 fever (pyrexia), one patient developed Grade 2 hypochondriasis, and one patient developed Grade 4 elevated bilirubin levels (hyperbilirubinemia) that led to study discontinuation at week 2. There were three additional discontinuations due to adverse events: two transaminase elevations at weeks 12 and 16 and one lymphopenia at week 52 (off-study) in a patient with alfa/RBV added at week six. The most commonly reported on-treatment adverse events occurring in at least three patients were headache (14/43), nasopharyngitis (14/43), liver enzyme increases (12/43 ALT increase and 10/43 AST increase), diarrhea (Grade 1, 11/43), and fever (pyrexia, 8/43). There were no deaths in this study and no clinically relevant changes in electrocardiogram parameters.

About the Study
In this Phase II open-label clinical trial (AI447-017), an expanded cohort of 43 Japanese patients with chronic HCV genotype 1b infection with null response to prior alfa/RBV treatment (reduction in HCV RNA <2 log10 IU/mL with 12 weeks of alfa/RBV therapy) or patients ineligible for or intolerant to treatment with alfa/RBV were treated with daclatasvir 60 mg once daily and asunaprevir 200 mg twice daily, for 24 weeks. (Asunaprevir was initially dosed 600 mg twice daily in sentinel cohort of 10 null responders.) The primary efficacy endpoint was the proportion of patients with undetectable viral load (HCV RNA < 15 IU/mL) at 12 weeks post-treatment (SVR12). Patients were followed to 24 weeks post-treatment (SVR24).


Dual Oral Therapy with NS5A Inhibitor Daclatasvir (BMS-790052) and NS3 Protease Inhibitor
Asunaprevir (BMS-650032) in HCV Genotype 1b-Infected Null Responders or Patients Ineligible/Intolerant to  Peginterferon/Ribavirin

Reported by Jules Levin
Slides Provided By NATAP
 View-Coverage of the EASL @ NATAP

April
BMS-650032 (Asunaprevir)  BMS-790052 (Daclatasvir)-A revolution in HCV treatment with direct-acting antivirals: from non response to eradication
Both daclatasvir and asunaprevir produce marked declines in HCV RNA levels in patients with HCV genotype 1 infection [9-10] and administration of the two drugs in combination did not produce a clinically meaningful pharmacokinetic
interaction [11].

In the study reported by Lok et al., patients with HCV genotype 1 infection with no response to previous treatment with PegIFN/RBV, were randomly assigned to receive daclatasvir (60 mg once daily) and asunaprevir
(600 mg twice daily) alone (group A, 11 patients) or in combination with PegIFN -2a and RBV (group B, 10 patients) for 24 weeks [5]. A total of 4 patients in group A (36%; 2 of 9 with HCV genotype 1a and 2 of 2 with genotype 1b) had a SVR
12 weeks after treatment and also 24 weeks after treatment (Fig. 1). Six patients (all with HCV genotype 1a) had a viral breakthrough while receiving therapy, and resistance mutations to both antiviral agents were found in all
cases; 1 patient had a viral response at the end of treatment but relapsed after the treatment period......Continue Reading

March 08, 2012 07:33 PM Eastern Daylight Time 
Bristol-Myers Squibb Posts Data Update on Daclatasvir, an NS5A Inhibitor in Phase III Development for the Treatment of Hepatitis C PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE:BMY) today posted an overview of new data on daclatasvir (or BMS-790052) on the company website. Daclatasvir is an NS5A replication complex inhibitor in Phase III development for the treatment of hepatitis C. These data were presented Thursday, March 8, at the Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle.

Feb 29, 2012
NEJM reports on two new drugs for hepatitis C
Last week's (January 19, 2012) New England Journal of Medicine delivered an intriguing, imperfect article on a new approach to treating hepatitis C (HCV). The paper's careful title, Preliminary Study of Two Antiviral Agents for Hepatitis C Genotype 1, seems right.

The analysis, with 17 authors listed, traces the response of 21 people with hepatitis C (HCV) who got two new anti-viral agents, with or without older drugs, in a clinical trial sponsored by Bristol-Meyers Squibb.The 21 study participants all had chronic infection by HCV genotype 1, a strain that's common in North America and relatively resistant to standard treatment. All subjects were between 18 and 70 years old, with a measurable level of HCV RNA in the blood, no evidence of cirrhosis, and no response to prior HCV treatment (according to criteria detailed in the paper). In the trial, 11 patients received a combination regimen of daclatasvir (60 mg once daily, by mouth) and asunaprevir (600 mg, twice daily by mouth) alone; the other 10 patients took the experimental drugs along with two older meds for HCV: Peginterferon (Pegasys, an injectible drug by Roche) and Ribavirin (Copegus, a pill, by Roche).

The main finding is that the 10 patients assigned to take four drugs all did strikingly well in terms of reducing detectable HCV in their blood over the course of 24 weeks. There was a dramatic response, also, in four of the 11 patients assigned to the new drugs only.

An accompanying editorial highlighted the work as a Watershed Moment in the Treatment of Hepatitis C. The medical significance is that they've demonstrated proof of principle: by "hitting" a resistant HCV strain with multiple anti-viral drugs simultaneously, they could reduce it to undetectable levels.

The first question you have to ask about this report is why the NEJM, the most selective of medical journals, would publish findings of an exploratory analysis of two new pills paired with two older drugs for HCV. The best answer, probably, is that the virus infects some 4 million people in the U.S. and approximately 180 million people worldwide, according to the study authors. HCV can cause liver damage, cirrhosis, liver cancer (which is usually fatal) and occasionally blood disorders.The new drugs derive from some interesting science.

This, maybe, also is a factor in why the article was published in the NEJM. Daclatasvir (BMS-790052) blocks a viral protein, NS5A, that's essential for HCV replication. The second new drug, asunaprevir (BMS-650032) inhibits a viral protease, NS3.I have several concerns about this report. One is that the researchers screened 56 patients for possible registration but enrolled only 21 on the trial; according to a supplementary Figure 1, 35 potential subjects (over half) didn't meet criteria for eligibility. This disparity makes any once-researcher wonder about bias in selecting patients for enrollment. If you're a pharmaceutical company and want to show a new drug or combo is safe, you're going to pick patients for a trial who are least likely to experience or display significant toxicity.

Toxicity seems like it could be problematic. Diarrhea, fatigue and headaches were common among the study subjects. Worrisome is that six patients (of 21, that would be 28.5% of those on the trial) had liver problems manifest by at least one enzyme (the ALT) rising over three times the normal limit.Further complicating the picture is there's no indication of how these new drugs mesh with the two drugs approved for HCV in 2011: Victrelis (boceprevir) and Incivek (telaprevir).Given all these limitations, you might wonder about Bristol-Meyers Squibb's influence at the NEJM or, more likely, the manuscript's peer reviewers.

The 17 study authors, and the editorialist, separately, disclose a host of industry ties.What I'm thinking, as much as I'm critical of this research work, is that this is probably the way of the future: smaller, pharma-funded studies of targeted new drugs in complicated combinations. Many will be authored by academics with ties to industry, if not put forth directly by company-employed researchers.

These quick-and-promising studies in select patient groups will be routine. And while advocates push for rapid publication of new clinical research in patients with resistant, disabling diseases, it'll be hard for physicians and patients to interpret these kinds of data.So these particular findings may turn out to be true and life-saving, or not.

The bigger concern is this: It would be helpful if the journals would take a really tough stance on full disclosure of authors and editors ties to industry. As Merrill Goozner has emphasized, the Physician Payment Sunshine Act, a small component of the 2010 health care reform legislation, has important implications for academic medicine and reporting of clinical research studies.

This post originally appeared at Medical Lessons, written by Elaine Schattner, ACP Member, a nonpracticing hematologist and oncologist who teaches at Weill Cornell Medical College, where she is a Clinical Associate Professor of Medicine. She shares her ideas on education, ethics in medicine, health care news and culture. Her views on medicine are informed by her past experiences in caring for patients, as a researcher in cancer immunology and as a patient who's had breast cancer.


Four-Drug Therapy Wiped Out Hepatitis C Virus in Most Cases
By Gene Emery
NEW YORK (Reuters Health) Jan 18 -

Study also Demonstrated 100% Sustained Virologic Response 12-Weeks Post Treatment with Quadruple Therapy

Null responders – patients whose virus did not respond to prior treatment with PEG-interferon alfa and ribavirin (HCV RNA decrease <2 log10 at 12 weeks).

Combining the experimental oral drugs asunaprevir and daclatasvir with the established treatment of peginterferon alfa-2a and ribavirin eliminated all traces of hepatitis C virus (HCV) in the blood of every volunteer, even after ribavirin-peginterferon alfa-2a treatment had already failed, in small phase II study released online today by the New England Journal of Medicine.

The ten patients treated with all four drugs all had undetectable viral levels 12 weeks after treatment stopped, and nine still had undetectable levels after 24 and 48 weeks.Another 11 patients received only asunaprevir and daclatasvir, and four of them had a sustained virologic response at 12 and 24 weeks after treatment.

"This is a watershed moment in the annals of HCV therapy because it shows that a sustained virologic response can be achieved without interferon," Dr. Raymond T. Chung of Massachusetts General Hospital wrote in an editorial in the January 19 issue.

Dr. Anna Lok of the University of Michigan and chief author of the study told Reuters Health that the cure rate for the peginterferon/ribavirin regime is low. "It's only 36%. But considering that these are difficult patients to treat, 36% is not too bad," she said.All 21 patients in the current study had genotype 1 HCV, the most common in the U.S., and all had failed to respond to peginterferon plus ribavirin (i.e., they had not had at least a 2 log10 decline in HCV RNA after at least 12 weeks of treatment).

The response was far better when the four drugs were used. By the end of treatment, at week 24, all 10 patients in that group had undetectable levels of HVC RNA. Forty-eight weeks after the end of therapy, only one had any trace of the virus, and the amount was too small to quantify, according to the researchers.

About 4.1 million people in the United States and 180 million worldwide are infected by hepatitis C, with its associated risk of cirrhosis and liver cancer.In the randomized phase II study, where patients knew what treatment they were getting, everyone received 600 mg of asunaprevir twice daily and 60 mg of daclatasvir once daily for 24 weeks.

Both are made by Bristol-Myers Squibb, which paid for the trial.Ten of the 21 also got 180 mcg of Pegasys brand peginterferon alfa-2a each week and Copegus brand ribavirin, where the daily dose was 1,000 mg for those weighing less than 75kg and 1,200 mg for those weighing more.

Both are Roche products.After 24 weeks of therapy, all 10 patients getting the four-drug regimen and five of the 11 patients receiving the non-interferon regimen had no trace of virus in their blood.The six patients in the non-interferon group who had viral breakthrough during the treatment period all had HCV genotype 1a. Another patient in that group had viral recurrence after treatment ended.

By 24 weeks after treatment ended, the virus had returned in one of the 10 getting all four drugs. But that one person was retested 13 days after recurrence and levels of HCV RNA were undetectable, a phenomenon that was seen in other patients, said Dr. Lok. "Because it was not persistent, we believe 100% actually maintained virus clearance all the way to week 48."

"To be able to get to 90% or 100% is very remarkable," she said. "On the other hand, we all know that a lot of patients can't handle interferon and ribavirin because of the side effects. What we hear from the patients is that they hate interferon. They prefer not to get treatment. Everyone is looking for when can we have an interferon-free regimen."In the new study, the side effects were similar in the two experimental groups.

The three most common were diarrhea, fatigue and headache, reported by 45% to 73% of patients. Six patients had transient elevations of alanine aminotransferase to more than 3 times the upper limit of normal.

Side effect rates were complicated by the fact six of the 11 volunteers randomized to receive only daclatasvir and asunaprevir received rescue therapy with interferon and ribavirin after a viral breakthrough.None of the 21 dropped out because of the side effects.

Dr. Lok said 48 weeks of peginterferon and ribavirin usually costs about $40,000. Adding a protease inhibitor as a third drug costs another $50,000, and new biologicals often go for a comparable amount.The eventual price of the experimental drugs is not known, assuming they are approved.Thus, a four-drug regimen would add to the cost, Dr. Lok said, but "if this pans out, it's only 24 weeks of treatment. And if you get a cure once and for all, you don't have to worry about managing the complications of cirrhosis, liver transplant, liver cancer down the road.
"SOURCE: http://bit.ly/A5JnBy N Engl J Med 2012; 366:216-224.

Hepatitis C Pills Clear Virus Without Injections

PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE: BMY) today announced the full results, published in the New England Journal of Medicine, from a Phase II clinical trial in patients with hepatitis C virus (HCV) genotype 1 who had not responded to prior therapy with PEG-interferon alfa and ribavirin (‘null responders’1). The study demonstrated that its primary endpoint of the achievement of sustained virologic response 12-weeks post-treatment (SVR12) is possible with a direct-acting antiviral (DAA)-only combination containing daclatasvir and asunaprevir (4/11 patients, including two of two patients infected with HCV genotype 1b). This study was the first study to demonstrate the possibility that hepatitis C can be cured (defined as sustained virologic response 48 weeks post-treatment or SVR48) without the use of interferon. The study also demonstrated that 100 percent (10/10) of these difficult-to-treat patients dosed with quadruple therapy containing daclatasvir and asunaprevir in combination with PEG-Interferon alfa and ribavirin achieved SVR12. In this study there were no serious adverse events on treatment or discontinuations due to adverse events. Diarrhea was the most common adverse event in both groups (73% and 70%).

“Even with the recent approval of two protease inhibitors, treatment of hepatitis C patients who have not responded to PEG-interferon alfa and ribavirin has limited success. Because of this high unmet medical need, there is a necessity for new combination regimens that can increase response rates in null responders,” said lead investigator Anna Lok, MD, FRCP, director of clinical hepatology and professor in the department of internal medicine at the University of Michigan Medical School in Ann Arbor. “The data seen in this study with Bristol-Myers Squibb’s investigational DAAs daclatasvir and asunaprevir, either as DAA-only therapy or as part of quadruple therapy, are encouraging as we work to advance hepatitis C therapy for this difficult-to-treat patient population. This study also shows for the very first time that sustained viral responses can be achieved without the use of interferon and ribavirin.”

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 investigational, oral, selective NS3 protease inhibitor.

Study Results

Viral Response: Dual DAA Therapy with daclatasvir and asunaprevir (Group A)

Eleven patients were randomized to receive dual DAA therapy for 24 weeks. Seven of the 11 patients (64%) in Group A achieved undetectable viral load by week four, and five patients remained undetectable at the end of treatment. Of these 11 patients, one patient relapsed at four (4) weeks post treatment while four patients (36%) had sustained virological response at 12 weeks post-treatment (SVR12). In follow-up to 48-weeks post treatment, no additional cases of viral relapses were observed.

Six patients, all with HCV genotype 1a, experienced viral breakthrough on dual DAA therapy, and analysis of HCV sequences following breakthrough confirmed resistance to both antivirals. With the addition of PEG-interferon alfa and ribavirin to their regimen (rescue therapy), four of the six patients achieved undetectable viral load. Two of these patients relapsed following the treatment period and two remained undetectable, one with 14 weeks and one with 42 weeks of post treatment follow-up. Two of the six patients did not achieve undetectable HCV RNA and treatment was discontinued.

Viral Response: Quadruple Therapy with daclatasvir, asunaprevir and PEG-Interferon alfa and ribavirin (Group B)

Ten patients were randomized to receive quadruple therapy for 24-weeks. Six of the 10 patients (60%) in Group B achieved undetectable HCV RNA by week four. Ten of the 10 patients (100%) were undetectable by the end of treatment, and all 10 achieved SVR12. No patients experienced viral relapse during 48 weeks of post-treatment observation.

Safety

In the study, there were no serious adverse events on treatment, no deaths, and no treatment discontinuations due to adverse events. Most adverse events were mild to moderate, and the most common AEs were diarrhea (group A: 8/11, 73%; group B: 7/10, 70%), fatigue (group A: 6/11, 55%; group B: 7/10, 70%), headache (group A: 5/11, 45%; group B: 5/10, 50%), and nausea (group A: 2/11, 18%; group B: 5/10, 50%).

Six patients (four from group A, including two receiving rescue therapy, and two from group B) experienced elevated liver enzymes [ALT >3x upper limit of normal (ULN)] which did not require treatment discontinuation or dose interruptions, and all patients stabilized or improved with continued therapy. Six patients, all of whom received PEG-interferon alfa and ribavirin, experienced Grade 3 or 4 neutropenia, a blood disorder characterized by an abnormally low number of white blood cells.

About the Study

This open-label, phase IIa study evaluated the antiviral activity and safety of the combination of daclatasvir and asunaprevir with and without PEG-Interferon alfa and ribavirin in 21 HCV genotype 1 null responders. Patients in the study were randomized to receive one of two treatment regimens for 24 weeks. The 11 patients in Group A received dual-DAA therapy with daclatasvir 60 mg once daily and asunaprevir 600 mg twice daily, both taken orally. The 10 patients in Group B received quadruple therapy with daclatasvir 60 mg once daily, asunaprevir 600 mg twice daily, PEG-interferon alfa 180 µg once weekly, and ribavirin 1000-1200 mg daily (according to body weight) in two divided doses. The primary study objective was to determine the proportion of patients achieving undetectable viral load (HCV RNA <10 IU/mL) 12 weeks post-treatment (SVR12). This dual-DAA combination is now in Phase III development.

January 13, 2012
Bristol-Myers Squibb Begins Tender Offer to Acquire Inhibitex, Inc.

2011

AASLD-2011 PDF
Dual Oral Combination Therapy with the NS5A Inhibitor Daclatasvir (DCV; BMS-790052) and the NS3 Protease Inhibitor Asunaprevir (ASV; BMS-650032)
Achieved 90% Sustained Virologic Response (SVR12) in Japanese HCV Genotype 1b-Infected Null Responders

Interferon-free regimen  
Data Presented at the March 2011 EASL showed that Bristol-Myers two investigational oral hepatitis C drugs BMS-790052 and BMS-650032, cured 4/11 people without interferon and ribavirin. These patients failed prior HCV therapy  deemed as null-responders (the most difficult to treat). 

The Collaboration;  PSI-7977, Pharmasset’s and Bristol-Myers  BMS-790052

Pharmasset and Bristol-Myers Squibb  clinical collaboration agreement

In January of 2011 Pharmasset and Bristol-Myers Squibb announced  that the companies have entered into a clinical collaboration agreement to evaluate the utility of BMS-790052, Bristol-Myers Squibb’s NS5A replication complex inhibitor, in combination with PSI-7977, Pharmasset’s nucleotide polymerase inhibitor, for the treatment of chronic hepatitis C virus (HCV). This proof of concept study will evaluate the potential to achieve sustained viral response 24 weeks post treatment with an oral, once-daily treatment regimen in patients across HCV genotypes. Specifically, the study will assess the safety, pharmacokinetics and pharmacodynamics of BMS-790052 in combination with PSI-7977, with and without ribavirin, in treatment-naïve patients chronically infected with HCV genotypes 1, 2, and 3. The study is planned to start in the first half of 2011. This collaboration represents the first cross-company collaboration combining two oral agents to address a significant unmet medical need in the treatment of HCV.  

In May 2010 Pharmasset and Bristol-Myers begin combined study for hepatitis C Pharmasset (VRUS) initiated a Phase 2a trial investigating the combination of Pharmasset's PSI-7977, a nucleotide polymerase inhibitor, and BMS-790052, Bristol-Myers Squibb's (BMY) NS5A replication complex inhibitor, for the treatment of chronic hepatitis C. The primary endpoint of the trial is sustained virologic response. This trial is the result of a clinical collaboration agreement between Pharmasset and Bristol-Myers Squibb announced in January.

About PSI-7977
PSI-7977 is a uracil nucleotide analog inhibitor of the NS5B polymerase being developed for the treatment of chronic HCV infection. Nucleotide analog polymerase inhibitors work by acting as alternative substrates that block the synthesis of HCV RNA, which is essential for the virus to replicate. PSI-7977 has been studied in combination with peginterferon and ribavirin for up to 12 weeks in genotype 1, 2 or 3 patients and is currently in two Phase 2b studies, one of which is investigating an interferon sparing regimen in genotype 2 or 3 patients. PSI-7977 is also being investigated in a 14-day combination study with PSI-938, a guanine nucleotide analog.

May 26

PSI-7977 and BMS-790052 interferon-free trial for Geno 1,2 and 3 initiated

Collaboration between Pharmasset and Bristol-Myers Squibb   By Pharmasset, Inc. Published: Thursday, May. 26, 2011 - 3:55 am
PRINCETON, N.J., May 26, 2011 -- /PRNewswire/ -- Pharmasset, Inc. (Nasdaq: VRUS) announced today the initiation of a Phase 2a trial investigating the combination of Pharmasset's PSI-7977, a nucleotide polymerase inhibitor, and BMS-790052, Bristol-Myers Squibb Company's (NYSE: BMY) NS5A replication complex inhibitor, for the treatment of chronic hepatitis C (HCV).  This trial is the result of a clinical collaboration agreement between Pharmasset and Bristol-Myers Squibb announced in January 2011.

"We are happy to announce the initiation of this important combination trial," stated William Symonds, Pharmasset's Senior Vice President of Clinical Pharmacology and Translational Medicine. "Recent data from Bristol-Myers Squibb's combination study demonstrated that individuals with HCV can be cured without the traditional interferon and ribavirin, but only if two potent DAAs are used and drug resistance is avoided. We believe Pharmasset's nucleotide analogs have demonstrated potent antiviral activity and a high barrier to resistance and therefore have the potential to be the future backbone of interferon-free treatment."

About the Trial
This Phase 2a trial is planned to enroll approximately 84 patients with chronic HCV genotypes 1, 2 or 3 who have not been treated previously. The primary endpoint of the trial is sustained virologic response (SVR). The trial will be conducted in the U.S. Subjects will be randomized equally across each of the following arms:

• PSI-7977 400mg QD for 7 days, then add BMS-790052 60mg QD for further 23 weeks in genotype 1 subjects;
• PSI-7977 400mg QD for 7 days, then add BMS-790052 60mg QD for further 23 weeks in genotype 2 or 3 subjects;
• PSI-7977 400mg QD and BMS-790052 60mg QD for 24 weeks in genotype 1 subjects;
• PSI-7977 400mg QD and BMS-790052 60mg QD for 24 weeks in genotype 2 or 3 subjects;
• PSI-7977 400mg QD, BMS-790052 60mg QD and ribavirin for 24 weeks in genotype 1 subjects;
• PSI-7977 400mg QD, BMS-790052 60mg QD and ribavirin for 24 weeks in genotype 2 or 3 subjects.

Additional details can be found at  http://clinicaltrials.gov

Parallel, Open-Label, Randomized Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of PSI-7977 in Combination With BMS-790052 With or Without Ribavirin in Treatment Naive Subjects Chronically Infected With Hepatitis C Virus Genotypes 1, 2, or 3

March 2011 EASL

 BMS-790052, PEG-interferon alfa and ribavirin treatment-naïve patients infected with genotype 1

Bristol-Myers Squibb Company (NYSE: BMY - News) presented encouraging data from a phase II study (n=48) which evaluated its candidate BMS-790052 as a combination therapy for treating patients suffering from the hepatitis C virus (HCV). Bristol-Myers presented data from the mid-stage study at the 46th annual meeting of the European Association for the Study of the Liver in Germany.

The double-blind study evaluated BMS-790052 at three doses (3 mg, 10 mg or 60 mg) in treatment-naïve patients infected with genotype 1 chronic HCV. Results from the study revealed that the rate of SVR12 (sustained virologic response – absence of detectable HCV at 12 weeks post treatment ) achieved by patients treated with a combination of BMS-790052, PEG-interferon alfa and ribavirin (the standard of care) was higher across all evaluated doses than those receiving placebo in combination with PEG-interferon alfa and ribavirin. The patients were divided equally into four groups.

Patients in the 10 mg arm achieved the highest rate (92%) of SVR12. 83% and 42% patients achieved SVR12 in the 60 mg and 3 mg arms of BMS-790052 respectively. Adverse events and serious adverse events were found to be consistent with those in the PEG-Interferon alfa and ribavirin arm across all 3 doses of BMS-790052.

See Slides From NATAP; First Report of SVR12 for a NS5A Replication Complex Inhibitor, BMS-790052, in Combination With PegIFNα-2a and RBV: Phase IIA Trial in Treatment-Naive HCV Genotype 1 Subjects - (03/31/11)

Press Release EASL; BMS-790052 Plus PEG-Interferon Alfa/Riba Achieved Up to 92% SVR-Naïve Geno1 HCV Patients


Quadruple treatment study

BMS Phase 2B Study including 4 drug regimen of NS5A BMS-790052 + protease BMS-650032 + Peglambda/Rbv:    
 In Bristol-Myers quadruple treatment study, HCV patients were given four drugs in combination; pegylated Interferon-alpha, ribavirin ; and two different direct-acting antivirals (DAAs) BMS-650032 (an HCV NS3 protease inhibitor) and BMS-790052 (an HCV NS5A replication complex inhibitor). Patients suppressed the emergence of "resistant variants" and resulted in a 100% rate of sustained virological response - undetectable HCV RNA - 12 weeks after therapy, deemed (SVR12).

See All Slides At  NATAP; Quadruple Therapy With BMS-790052, BMS-650032 and Peg-IFN/RBV for 24 Weeks Results in 100% SVR12 in HCV Genotype 1 Null Responders: "HCV infection can be cured without interferon & ribavirin: 2 orals BMS790052+BMS650032" 


 (AASLD), 2010
BMS-790052 (NS5A inhibitor) and BMS-650032 (NS3 inhibitor)
BMS-790052 is an NS5A inhibitor and BMS-650032 is an NS3 protease inhibitor, both in development for the treatment of chronic hepatitis C virus (HCV) infection
American Association for the Study of Liver Diseases (AASLD), 2010

PEG-Interferon Lambda
A novel and potential first-in-class interferon in development for the treatment of hepatitis C virus (HCV) infection
American Association for the Study of Liver Diseases (AASLD), 2010

(EASL), April 2010

BMS-790052
Once-Daily NS5A Inhibitor Leads to High Rates of Extended Rapid Virologic Response in Treatment-Naïve HCV-Genotype 1 Subjects When Combined with Peginterferon and Ribavirin: A Phase 2a Trial
European Association for the Study of the Liver (EASL), April 2010