Market Overview

China FDA Approves Country's First All-Oral Regimen for Chronic Hepatitis C, Daklinza® (daclatasvir) in Combination with Sunvepra® (asunaprevir)

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Bristol-Myers
Squibb Company
(NYSE:BMY) announced today that the China Food and
Drug Administration (CFDA) has approved a direct-acting antiviral
regimen comprised of Daklinza® (daclatasvir) and Sunvepra®
(asunaprevir), for the treatment of treatment-naive or -experienced
patients, with or without compensated cirrhosis, infected with genotype
1b chronic hepatitis C virus (HCV). This is China's first all-oral,
interferon- and ribavirin-free HCV treatment regimen. In addition, Daklinza
has been approved in China for combination use with other agents,
including sofosbuvir, for adult patients with HCV genotypes 1-6
infection. This is the only all-oral pan-genotypic regimen recommended
by China's HCV Prevention and Treatment Guideline. Daklinza must
not be administered as monotherapy. Sofosbuvir is under review by the
CFDA, and is not currently licensed in China.

In more than 60 countries, Daklinza is approved as part of a
regimen with either Sunvepra or sofosbuvir. In China, Daklinza-based
regimens provide a shorter treatment duration (12 or 24 weeks) compared
to 48 weeks of treatment with previously approved regimens. The Daklinza
and Sunvepra regimen is already approved by regulatory
authorities in multiple countries across the Asia Pacific, Latin
America, and Eastern Europe regions. Sunvepra is not approved in
the United States.

"The burden of HCV in China is extremely high, and now for the first
time, we have an all-oral treatment option in the combination of Daklinza
and Sunvepra, which is a significant step forward for patients
and doctors alike," said Hui Zhuang, a professor at the Beijing
University Medical School and a member of the Chinese Academy of
Engineering. "This new option helps to address many of the unmet needs
for our HCV genotype 1b patients, and is also included in the latest
edition of China's HCV Prevention and Treatment Guideline."

The approval is based primarily upon results of the first completed
Phase 3 036 trial of the Daklinza and Sunvepra regimen for
HCV among Chinese patients, which was published in the November 2016
issue of the Journal of Gastroenterology and Hepatology. In the
trial, 91% (145/159) of genotype 1b patients who had been previously
interferon-ineligible or interferon-intolerant achieved sustained
virologic response ("SVR", or cure) at post-treatment week 24. The cure
rate was higher, at 99%, in patients without baseline NS5A
resistance-associated variants (RAVs; L31M or Y93H; n=137/139).

As detailed in the published Phase 3 trial, one death (0.6%), five
on-treatment serious adverse events (3%), and three grade 4 laboratory
abnormalities (2%) occurred on-treatment; none were considered related
to study drugs. Two patients (1%) discontinued due to adverse events
(AEs). The most common grade 1–4 on-treatment AEs (>5% of patients) were
platelet count decrease (14, 9%), upper respiratory tract infection (13,
8%), ALT increase (a diagnostic indication of liver disease or damage)
(11, 7%), neutrophil count decrease (11, 7%), monocyte (large white
blood cell) count decrease (10, 6%), white blood cell count decrease
(10, 6%), thrombocytopenia (decrease in the number of platelets in the
blood) (10, 6%), and pruritus (itchiness) (9, 6%); most were mild or
moderate in intensity. Treatment was generally well-tolerated regardless
of cirrhosis status.

"We are proud to build on our legacy, infrastructure and experience in
treating viral hepatitis throughout Asia by bringing Daklinza-based
regimens to patients in China," said Murdo Gordon, executive vice
president and chief commercial officer, Bristol-Myers Squibb. "Beginning
with our efforts to treat chronic hepatitis B, Bristol-Myers Squibb has
been committed to combating viral hepatitis in China for over a decade."

HCV represents a significant public health burden in China and is now
the fourth most commonly reported infectious disease countrywide, with
an estimated 10 million people currently living with the disease. Until
now, standard of care in China has been interferon- and
ribavirin-containing regimens which have left some patient groups with
unmet needs. The cure rate for interferon- and ribavirin- containing
regimens varies in a number of recent Chinese studies. In CCgenos, a
real-world observation study, the cure rate for interferon- and
ribavirin- containing regimens among GT-1b naïve patients is 62.4%.

Karl Lintel, MD, President of Bristol-Myers Squibb (China) Investment
Co. Ltd and the Sino-American Shanghai Squibb Pharmaceutical Co.,
commented, "Today's approval of Daklinza and Sunvepra is
great news for patients in China, as we continue the global fight
against chronic hepatitis C. This milestone is testament to our ongoing
collaboration with multiple stakeholders, and aligning with government
policies to provide continuing support to HCV patients at the community
level."

Bristol-Myers Squibb is committed to working with stakeholders to seek
timely reimbursement for Daklinza and Sunvepra at the
national and provincial levels, to ensure patients have access to these
important products.

About the 036 Clinical Trial

In the multi-center Asian study, interferon-ineligible and -intolerant
patients with genotype 1b infection received Daklinza 60 mg
tablets once-daily plus Sunvepra 100 mg soft capsules twice-daily
for 24 weeks. Of the 159 patients enrolled, 127 were from mainland
China. The primary endpoint was SVR at post-treatment Week 24 (SVR24).

In the overall study population, the SVR24 was 91% (145/159) and was
similarly high in cirrhotic patients (47/52, 90%). SVR24 rates were
higher (137/139) [99%]) in patients without baseline NS5A RAVs (L31M or
Y93H), and lower in patients with baseline NS5A RAVs (8/19 [42%]).

Prevalence of baseline NS5A RAVs was 12% (19/159) overall, and 8% in
mainland China patients (10/127). HCV NS5A RAVs exist naturally (albeit
in lower prevalence vs wildtype) and can emerge after virologic response
failure. Screening for the presence of specific NS5A mutations can help
physicians determine the most suitable patients for treatment by
identifying those most likely to achieve cure with an NS5A-containing
regimen.

Data from other studies conducted outside of China investigating Daklinza
in combination with sofosbuvir were also considered as part of the
approval.

About the 114 Clinical Trial

In a multi-center study, treatment-naive patients with genotype 1b
infection received Daklinza 60 mg tablets once-daily plus Sunvepra
100 mg soft capsule twice-daily for 24 weeks. Of the total 206 patients,
161 were from mainland China. Patients were randomized 3:1 into two
treatment arms: an immediate Daklinza and Sunvepra
treatment group (n=155) or a placebo-deferred Daklinza and Sunvepra
treatment group (n=52). The primary endpoint was SVR at post-treatment
Week 12 (SVR12) in the immediate treatment arm, for comparison with the
historical SVR rate achieved with pegIFN/RBV (70%).

The SVR12 rate was 92% in treatment-naive patients with HCV genotype 1b
infection in the immediate treatment arm. Baseline NS5A-L31 or Y93H
polymorphisms were present in 11% (17/154) of these patients. The SVR12
rate was 96% (132/137) in patients without these baseline polymorphisms;
89% (17/19) with cirrhosis, 97% (115/118) without cirrhosis.

Discontinuations due to AEs were infrequent (1%). The most common AEs
(any grade, ≥5%) in the overall population were ALT increase, upper
respiratory tract infection, hypertension, AST elevation, INR elevation,
blood bilirubin elevation, and fatigue.

Bristol-Myers Squibb's Leadership in Viral Hepatitis

Bristol-Myers Squibb's heritage in virology in China began with Baraclude®
(entecavir), a market-leading oral treatment for patients suffering with
chronic hepatitis B virus (CHBV). Baraclude is indicated in China
for the treatment of chronic hepatitis B virus infection in adults with
evidence of active viral replication and either evidence of persistent
elevations in serum alanine aminotransferase (ALT) or histologically
active disease. Since its approval in China in 2005, Bristol-Myers
Squibb has worked to not only provide access to Baraclude, but
also to coordinate with government, local hospitals and physicians, and
NGOs to raise the standard of care and improve the quality of life and
survival of patients with HBV. In China, more than 1 million patients
have been treated with Baraclude, and Asia has accounted for more
than two-thirds of all Baraclude prescriptions.

Since 2002, the Bristol-Myers Squibb Foundation also has been leading
efforts at the community level in Asia in HBV and HCV awareness,
destigmatization, prevention, and care through the Delivering Hope
program. The multi-pronged program includes a variety of disease
education and vaccination efforts, including prevention of the most
common means of transmission, from mother to child. It also includes
capacity building, and training in partnership with local NGOs,
governments and healthcare workers. In China alone, more than 8 million
people at high risk of hepatitis infection across 28 provinces have
benefitted from these programs over the past decade. The Foundation has
committed more than $9.6 million (U.S.) in grants to a diverse group of
organizations for programs targeting specific populations.

About Daclatasvir

Daclatasvir, marketed as Daklinza, is a NS5A replication complex
inhibitor which targets the NS5A protein by directly disrupting its
normal function. The NS5A protein plays essential roles in the HCV viral
life cycle, including viral RNA replication and virion (viral particle)
assembly. Daklinza is approved by the U.S. Food and Drug
Administration (FDA) for use with sofosbuvir, with or without ribavirin,
for the treatment of patients with HCV genotype 1 or genotype 3
infection. Sustained virologic response (SVR12) rates are reduced in HCV
genotype 3-infected patients with cirrhosis receiving Daklinza in
combination with sofosbuvir for 12 weeks. Daklinza is approved by
the European Medicines Agency (EMA) for patients with HCV genotypes 1,
3, or 4.

Test all patients for evidence of current or prior hepatitis B virus
(HBV) infection before initiating treatment with Daklinza. HBV
reactivation has been reported in HCV/HBV coinfected patients who were
undergoing or had completed treatment with HCV direct acting antivirals
and were not receiving HBV antiviral therapy. Some cases have resulted
in fulminant hepatitis, hepatic failure, and death. Monitor HCV/HBV
coinfected patients for hepatitis flare or HBV reactivation during HCV
treatment and post-treatment follow-up. Initiate appropriate management
for HBV infection as clinically indicated. Please see full Important
Safety Information below for more details.

About Asunaprevir

Asunaprevir, marketed as Sunvepra, is an NS3 protease inhibitor,
an agent that binds to the NS3 protein of the HCV virus to block its
activity. The NS3/4A protease plays an essential role in the assembly of
the viral replication complex. Sunvepra is approved in 17
countries around the world, including in the Asia Pacific, Latin
America, and Eastern Europe regions; Sunvepra is not approved in
the United States. Sunvepra is approved as part of a regimen with Daklinza
for the treatment of HCV genotype 1b infection in adult patients. For
patients receiving Sunvepra-containing regimens, frequent
monitoring of liver enzymes (alanine aminotransferase (ALT), aspartate
aminotransferase (AST)) and bilirubin is required until completion of
therapy.

About Bristol-Myers Squibb in HCV

Bristol-Myers Squibb is focused on helping to eradicate hepatitis C
around the world, with a primary emphasis on difficult-to-treat
patients, including those millions in countries where population-based
HCV solutions remain a high unmet need.

In July 2014, Japan became the first country in the world to approve the
use of a daclatasvir-based regimen for the treatment of chronic
hepatitis C. Since then, daclatasvir-based regimens have been approved
in more than 60 countries across North, Central and South America,
Europe, the Middle East and the Asia-Pacific region.

U.S. Indication and Important Safety Information - Daklinza™
(daclatasvir)

INDICATIONS

Daklinza™ (daclatasvir) is indicated for use with sofosbuvir, with or
without ribavirin, for the treatment of patients with chronic hepatitis
C virus (HCV) genotype 1 or genotype 3 infection.

Limitations of Use:

  • Sustained virologic response (SVR12) rates are reduced in HCV genotype
    3-infected patients with cirrhosis receiving Daklinza in combination
    with sofosbuvir for 12 weeks.

IMPORTANT SAFETY INFORMATION

WARNING: RISK OF HEPATITIS B VIRUS REACTIVATION IN PATIENTS
COINFECTED WITH HCV AND HBV

  • Test all patients for evidence of current or prior hepatitis B
    virus (HBV) infection before initiating treatment with Daklinza. HBV
    reactivation has been reported in HCV/HBV coinfected patients who were
    undergoing or had completed treatment with HCV direct acting
    antivirals and were not receiving HBV antiviral therapy. Some cases
    have resulted in fulminant hepatitis, hepatic failure, and death.
    Monitor HCV/HBV coinfected patients for hepatitis flare or HBV
    reactivation during HCV treatment and post-treatment follow-up.
    Initiate appropriate management for HBV infection as clinically
    indicated.

CONTRAINDICATIONS

  • When used in combination with other agents, the contraindications
    applicable to those agents are applicable to the combination regimen;
    refer to the respective prescribing information.
  • Drugs contraindicated with Daklinza: strong inducers of CYP3A
    that may lead to loss of efficacy of Daklinza include, but are not
    limited to: phenytoin, carbamazepine, rifampin, St. John's wort (Hypericum
    perforatum).

WARNINGS AND PRECAUTIONS

  • Risk of Hepatitis B Virus Reactivation in Patients Coinfected with
    HCV and HBV (additional information):
    HBV reactivation has also
    been reported in patients receiving certain immunosuppressant or
    chemotherapeutic agents; the risk of HBV reactivation may be increased
    in these patients.
  • Risk of Adverse Reactions or Loss of Virologic Response Due to Drug
    Interactions:
    Coadministration of Daklinza and other drugs may
    result in known or potentially significant drug interactions.
    Interactions may include the loss of therapeutic effect of Daklinza
    and possible development of resistance, dosage adjustments for other
    agents or Daklinza, possible clinically significant adverse events
    from greater exposure for the other agents or Daklinza.
  • Serious Symptomatic Bradycardia When Coadministered with Sofosbuvir
    and Amiodarone:
    Post-marketing cases of symptomatic bradycardia
    and cases requiring pacemaker intervention have been reported when
    amiodarone is coadministered with sofosbuvir in combination with
    another direct-acting antiviral, including Daklinza. A fatal cardiac
    arrest was reported with ledipasvir/sofosbuvir.
    • Coadministration of amiodarone with Daklinza in combination with
      sofosbuvir is not recommended. For patients taking amiodarone who
      have no alternative treatment options, patients should undergo
      cardiac monitoring, as outlined in Section 5.3 of the prescribing
      information.
    • Patients also taking beta blockers or those with underlying
      cardiac comorbidities and/or advanced liver disease may be at
      increased risk for symptomatic bradycardia with coadministration
      of amiodarone.
    • Bradycardia generally resolved after discontinuation of HCV
      treatment.
  • Risks Associated with Ribavirin Combination Treatment: If
    ribavirin is used as part of the regimen, the warnings and precautions
    for ribavirin, particularly the pregnancy avoidance warning, apply.
    See the ribavirin full prescribing information for complete
    information.

ADVERSE REACTIONS

  • In clinical trials (ALLY 2, 3) with the Daklinza and sofosbuvir
    regimen,
    the most common adverse reactions (≥5%) were,
    respectively: headache (8%, 14%), fatigue (15%, 14%), nausea (9%, 8%),
    diarrhea (7%, 5%).
  • In clinical trials (ALLY 1) with Daklinza, in combination with
    sofosbuvir and ribavirin,
    the most common adverse reactions (≥5%)
    were, in the cirrhosis cohort and the post-liver transplantation
    cohort, respectively: headache (12%, 30%), anemia (20%, 19%), fatigue
    (15%, 17%), nausea (15%, 6%), rash (8%, 2%), diarrhea (3%, 6%),
    insomnia (3%, 6%), dizziness (0, 6%), somnolence (5%, 0).

DRUG INTERACTIONS

  • CYP3A: Daklinza is a substrate. Moderate or strong inducers may
    decrease plasma levels and effect of Daklinza. Strong inhibitors
    (e.g., clarithromycin, itraconazole, ketoconazole, ritonavir) may
    increase plasma levels of Daklinza.
  • P-gp, OATP 1B1 and 1B3, and BCRP: Daklinza is an inhibitor, and
    may increase exposure to substrates, potentially increasing or
    prolonging their adverse effect.

See Sections 4, 7, and 12.3 of the Daklinza Full Prescribing
Information for additional established and other potentially significant
drug interactions and related dose modification recommendations.
Refer
to the prescribing information for other agents in the regimen for drug
interaction information.

DAKLINZA IN PREGNANCY

  • No adequate human data are available to determine whether or not
    Daklinza poses a risk to pregnancy outcomes. Animal studies of
    Daklinza at exposure above the recommended human dose have shown
    maternal and embryofetal toxicity.
  • If Daklinza and sofosbuvir are administered with ribavirin, the
    information for ribavirin with regard to pregnancy testing,
    contraception, and infertility also applies to this combination
    regimen.
    Refer to the ribavirin prescribing information.

LACTATION

  • It is not known whether Daklinza is present in human milk, affects
    human milk production, or has effects on the breastfed infant.
    Daklinza was present in the milk of lactating rats. The development
    and health benefits of breastfeeding should be considered along with
    the mother's clinical need for Daklinza and any potential adverse
    effects on the breastfed child from Daklinza or from the underlying
    condition.
  • When Daklinza is administered with ribavirin, the nursing
    mothers' information for ribavirin also applies to this combination
    regimen. Refer to the nursing mothers' information in the ribavirin
    prescribing information.

Please see Full Prescribing Information, including Boxed WARNING here.

U.S. Indication and Important Safety Information - BARACLUDE®
(entecavir):

INDICATION

BARACLUDE (entecavir) is indicated for the treatment of chronic
hepatitis B virus (HBV) infection in adults and pediatric patients 2
years of age or older with evidence of active viral replication and
either evidence of persistent elevations in serum aminotransferases (ALT
or AST) or histologically active disease.

The following points should be considered when initiating therapy with
BARACLUDE:

  • In adult patients, this indication is based on clinical trial data in
    nucleoside-inhibitor treatment-naïve and lamivudine-resistant subjects
    with HBeAg-positive and HBeAgnegative HBV infection and compensated
    liver disease and a more limited number of subjects with decompensated
    liver disease.
  • In pediatric patients 2 years of age and older, this indication is
    based on clinical trial data in nucleoside-inhibitor-treatment-naïve
    and in a limited number of lamivudine experienced subjects with
    HBeAg-positive chronic HBV infection and compensated liver disease.

IMPORTANT SAFETY INFORMATION

WARNINGS: SEVERE ACUTE EXACERBATIONS OF HEPATITIS B, PATIENTS
CO-INFECTED WITH HIV AND HBV, and LACTIC ACIDOSIS AND HEPATOMEGALY

  • Severe acute exacerbations of hepatitis B have been reported in
    patients who have discontinued anti-hepatitis B therapy, including
    entecavir. Hepatic function should be monitored closely with both
    clinical and laboratory follow-up for at least several months in
    patients who discontinue anti-hepatitis B therapy. If appropriate,
    initiation of anti-hepatitis B therapy may be warranted.
  • Limited clinical experience suggests there is a potential for the
    development of resistance to HIV (human immunodeficiency virus)
    nucleoside reverse transcriptase inhibitors if BARACLUDE is used to
    treat chronic HBV infection in patients with HIV infection that is not
    being treated. Therapy with BARACLUDE is not recommended for HIV/HBV
    co-infected patients who are not also receiving highly active
    antiretroviral therapy (HAART).
  • Lactic acidosis and severe hepatomegaly with steatosis, including
    fatal cases, have been reported with the use of nucleoside analogues,
    alone or in combination with antiretrovirals.

Warnings and Precautions

  • Before initiating BARACLUDE therapy, HIV antibody testing should be
    offered to all patients. BARACLUDE has not been studied as a treatment
    for HIV infection and is not recommended for this use.
  • Lactic acidosis with BARACLUDE use has been reported, often in
    association with hepatic decompensation, other serious medical
    conditions, or drug exposures. Patients with decompensated liver
    disease may be at higher risk for lactic acidosis. BARACLUDE should be
    suspended in any patient who develops clinical or laboratory findings
    suggestive of lactic acidosis or pronounced hepatotoxicity.

Adverse Reactions

  • In clinical trials in patients with compensated liver disease, the
    most common (≥3%) adverse reactions of any severity with at least a
    possible relation to study drug for BARACLUDE-treated subjects were
    headache, fatigue, dizziness, and nausea. In these trials, the most
    common adverse reactions of moderate to severe intensity (grades 2-4)
    were diarrhea, dyspepsia, nausea, vomiting, fatigue, headache,
    dizziness, somnolence, and insomnia.
  • In the decompensated liver disease trial, the most common adverse
    reactions of any severity among patients treated with BARACLUDE,
    regardless of causality, included: peripheral edema (16%), ascites
    (15%), pyrexia (14%), hepatic encephalopathy (10%), and upper
    respiratory infection (10%). In this trial, 18% (18/102) of BARACLUDE
    patients and 20% (18/89) of adefovir patients died during the first 48
    weeks of therapy. The majority of those deaths were due to liver
    related causes.

Drug Interactions

  • BARACLUDE (entecavir) is primarily eliminated by the kidneys;
    therefore coadministration of BARACLUDE with drugs that reduce renal
    function or compete for active tubular secretion may increase serum
    concentrations of either entecavir or the coadministered drug.
    Patients should be monitored closely when receiving BARACLUDE with
    other renally-eliminated drugs.

Pregnancy and Nursing Mothers

  • There are no adequate and well-controlled studies of BARACLUDE in
    pregnant women. BARACLUDE should be used during pregnancy only if the
    potential benefit justifies the potential risk to the fetus.
  • There are no studies on the effect of BARACLUDE on transmission of HBV
    from mother to infant. Therefore, appropriate interventions should be
    used to prevent neonatal acquisition of HBV.
  • It is not known whether BARACLUDE is excreted into human milk;
    however, many drugs are excreted into breast milk. Due to the
    potential for serious adverse reactions in nursing infants from
    BARACLUDE, risks and benefits should be considered when deciding
    whether to discontinue breast-feeding or discontinue BARACLUDE in
    nursing women.

Pediatric Use

  • The adverse reactions observed in pediatric patients who received
    treatment with BARACLUDE were consistent with those observed in
    clinical trials of BARACLUDE in adults. Adverse drug reactions
    reported in greater than 1% of pediatric patients included abdominal
    pain, rash events, poor palatability ("product taste abnormal"),
    nausea, diarrhea, and vomiting.
  • Due to limited data, in lamivudine-experienced pediatric patients,
    Baraclude should be used only if the potential benefit justifies the
    potential risk to the child. Consideration should be given to the
    impact of BARACLUDE on future treatment options.

Renal Impairment

  • Dosage adjustment of BARACLUDE is recommended for patients with a
    creatinine clearance <50 mL/min, including those on hemodialysis or
    continuous ambulatory peritoneal dialysis. There is insufficient data
    to recommend specific dosage adjustments of BARACLUDE in pediatric
    patients with renal impairment, however dosage adjustments similar to
    those for adults should be considered.

Liver Transplant Recipients

Renal function must be carefully monitored both before and during
treatment with BARACLUDE in a liver transplant recipient who has
received or is receiving an immunosuppressant that may affect renal
function, such as cyclosporine or tacrolimus.

Duration of Therapy

  • The optimal duration of treatment with BARACLUDE for patients with
    chronic HBV infection and the relationship between treatment and
    long-term outcomes such as cirrhosis and hepatocellularcarcinoma are
    unknown.

Additional Information

BARACLUDE is not a cure for HBV. Patients should be advised that
treatment with BARACLUDE has not been shown to reduce the risk of
transmission of HBV to others through sexual contact or blood
contamination.

Please click here
for the BARACLUDE full prescribing information, including Boxed WARNINGS.

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global biopharmaceutical company whose mission
is to discover, develop and deliver innovative medicines that help
patients prevail over serious diseases. For more information about
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