Daklinza in combination with sofosbuvir is
the first 12-week, all-oral therapy that offers SVR12 for the vast
majority of genotype 3 patients
Hepatitis C genotype 3 is one of the most
difficult-to-treat genotypes
Announcement marks the first approval of
Daklinza in the United States
Bristol-Myers Squibb Company (NYSE:BMY) announced today that
Daklinza™ (daclatasvir), an NS5A replication complex inhibitor, has
been approved by the U.S. Food and Drug Administration (FDA). This
approval marks the first time patients with chronic hepatitis C
virus (HCV) genotype 3 have a 12-week, once-daily, all-oral
treatment option. Daklinza is indicated for use with sofosbuvir for
the treatment of patients with chronic HCV genotype 3 infection.
Sustained virologic response (SVR) rates are reduced in HCV
genotype 3-infected patients with cirrhosis receiving this regimen.
The recommended dosage of Daklinza is 60 mg in combination with
sofosbuvir for 12 weeks.
“The U.S. approval of Daklinza means that chronic HCV genotype 3
patients may now complete treatment in just 12 weeks with an
all-oral, once-daily regimen,” said Chris Boerner, Head of U.S.
Commercial, Bristol-Myers Squibb. “We believe this
Daklinza-based regimen may be a solution to improving the standard
of care for these patients. This approval is the result of many
years of partnership with the HCV community to address the
complexities of genotype 3, and an important achievement in our
ongoing Daklinza development program, which focuses on patients
that are most challenging to treat.”
The pivotal Phase III open-label ALLY-3 clinical trial enrolled
152 patients with chronic HCV genotype 3 infection and compensated
liver disease (101 treatment-naïve patients and 51
treatment-experienced patients). The co-primary endpoints were
sustained virologic response rates 12 weeks after completing
therapy (SVR12) in each treatment group. The full study design is
outlined below. In the trial the Daklinza plus sofosbuvir regimen
demonstrated SVR12 in 90% of treatment-naïve and 86% of
treatment-experienced chronic HCV genotype 3 patients. SVR12 rates
were higher (96%) in genotype 3 patients without cirrhosis,
regardless of treatment history. In the more difficult-to-treat
patients with cirrhosis, SVR12 rates were reduced (63%). These
SVR12 rates were achieved with 12 weeks of therapy without the use
of ribavirin.
Daklinza is contraindicated in combination with drugs that
strongly induce CYP3A and, thus, may lead to lower exposure and
loss of efficacy of Daklinza. Daklinza also may be associated with
the risk of adverse reactions or loss of virologic response due to
drug interactions. In addition, there is a risk of serious
symptomatic bradycardia when coadministered with sofosbuvir and
amiodarone. Please see full Important Safety Information below for
more details.
In the pivotal Phase III trial, there were no treatment-related
serious adverse events (SAEs) and no discontinuations due to
adverse events (AEs). The most common treatment-related AEs at a
frequency of ≥5% were headache (14%), fatigue (14%), nausea (8%)
and diarrhea (5%).
“The treatment landscape for HCV has radically evolved in recent
years, and while we have achieved impressive SVR12 rates in
genotype 1, genotype 3 still represents a clinical challenge,” said
David R. Nelson, M.D., Professor of Medicine, Molecular Genetics
and Microbiology Director, UF Clinical and Translational Science
Institute, and Assistant Vice President of Research for the
University of Florida. “Not only are genotype 3 patients more
complicated to manage, but the aggressive nature of their disease
means there is a greater urgency to treat them. Daklinza in
combination with sofosbuvir gives healthcare providers a new option
to achieve a high overall SVR12 rate in this difficult-to-treat
patient population.”
Daklinza is an inhibitor of NS5A with dual modes of anti-viral
activity that inhibits both RNA replication and virion assembly. In
in vitro studies, Daklinza has shown anti-viral activity across
genotypes 1-6, with EC50 values from picomolar (pM) to low
nanomolar (nM) against wild type replicons.
Daklinza will be available and begin shipping within a week.
About the ALLY-3 Clinical Trial
The efficacy and safety of Daklinza in combination with
sofosbuvir were evaluated in the Phase III ALLY-3 clinical trial.
ALLY-3 was an open-label trial that included 152 patients with
chronic HCV genotype 3 infection and compensated liver disease who
were treatment-naïve (n=101) or treatment-experienced (n=51).
Patients received Daklinza 60 mg plus sofosbuvir 400 mg once
daily for 12 weeks and were monitored for 24 weeks post treatment.
The co-primary endpoints were defined as HCV RNA below the lower
limit of quantification (LLOQ) at post-treatment week 12 (SVR12) in
each treatment group. Most treatment-experienced patients had
failed prior treatment with peginterferon/ribavirin, but seven
patients had been treated previously with a sofosbuvir regimen and
two patients with a regimen containing an investigational
cyclophilin inhibitor. Previous exposure to NS5A inhibitors was
prohibited. The 152 treated patients in ALLY-3 had a median age of
55 years (range, 24-73); 59% of the patients were male; 90%
were white, 5% were Asian, and 4% were black. Most patients (76%)
had baseline HCV RNA levels greater than or equal to 800,000
IU/mL; 21% of the patients had compensated cirrhosis, and 40% had
the IL28B rs12979860 CC genotype.
About Hepatitis C Genotype 3
Genotype 3 is estimated to affect 12 percent of chronic HCV
patients in the U.S. and is the second most common hepatitis C
genotype globally after genotype 1. Hepatitis C genotype 3 is
considered one of the most difficult-to-treat genotypes.
About Bristol-Myers Squibb’s Patient Support Connect
Program
Bristol-Myers Squibb is committed to helping patients through
treatment with Daklinza. For patient support and financial
assistance, patients and physicians may call (844) 44-CONNECT
(844-442-6663). This number offers one-stop access to a range of
support services for patients and healthcare professionals alike,
including benefits investigation by care counselors, comprehensive
coverage research and emergency shipment for access-related
issues.
About Bristol-Myers Squibb in HCV
Bristol-Myers Squibb’s research efforts are focused on advancing
compounds to deliver the most value to HCV patients with high unmet
needs. At the core of our portfolio is daclatasvir, a NS5A complex
inhibitor which continues to be investigated in multiple treatment
regimens and in patients with co-morbidities. In addition to being
approved in combination with sofosbuvir for patients with genotype
3, daclatasvir is being investigated in other high unmet need
patients, such as pre- and post-transplant patients and HIV/HCV
coinfected patients, as part of the ongoing Phase III ALLY
Program.
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 HCV. Since then, daclatasvir-based regimens have been
approved across Europe, as well as numerous other countries in
Central and South America, the Middle East and the Asia-Pacific
region.
Indication and Important Safety Information - Daklinza™
(daclatasvir)
INDICATION
Daklinza™ (daclatasvir) is indicated for use with sofosbuvir for
the treatment of patients with chronic hepatitis C virus (HCV)
genotype 3 infection.
Limitations of Use:
- Sustained virologic response (SVR)
rates are reduced in HCV genotype 3-infected patients with
cirrhosis receiving Daklinza in combination with sofosbuvir for 12
weeks.
IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS
- 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 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 5.2 of the prescribing information.
- Bradycardia generally resolved after
discontinuation of HCV treatment.
- 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.
Adverse Reactions
- The most common adverse
reactions were (≥ 5%): headache (14%), fatigue (14%), nausea
(8%), and diarrhea (5%).
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 Section 7 of the Full Prescribing Information for
additional established and other potentially significant drug
interactions and related dose modification recommendations.
- Daklinza in Pregnancy: No data
with Daklinza in pregnant women are available to inform a
drug-associated risk. Animal studies of Daklinza at exposure above
the recommended human dose have shown maternal and embryofetal
toxicity. Consider the benefits and risks of Daklinza when
prescribing Daklinza to a pregnant woman.
- Nursing Mothers: Daklinza was
excreted into the milk of lactating rats; it is not known if
Daklinza is excreted into human milk. Consider the benefits and
risks to the mother and infant when breastfeeding.
Please click here
for the Daklinza full prescribing information
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, please visit http://www.bms.com or follow us
on Twitter at http://twitter.com/bmsnews.
Bristol-Myers Squibb Forward Looking Statement
This press release contains "forward-looking statements" as that
term is defined in the Private Securities Litigation Reform Act of
1995 regarding the research, development and commercialization of
pharmaceutical products. Such forward-looking statements are based
on current expectations and involve inherent risks and
uncertainties, including factors that could delay, divert or change
any of them, and could cause actual outcomes and results to differ
materially from current expectations. No forward-looking statement
can be guaranteed. Among other risks, there can be no guarantee
that Daklinza will become a commercially successful product.
Forward-looking statements in this press release should be
evaluated together with the many uncertainties that affect
Bristol-Myers Squibb's business, particularly those identified in
the cautionary factors discussion in Bristol-Myers Squibb's Annual
Report on Form 10-K for the year ended December 31, 2014 in our
Quarterly Reports on Form 10-Q and our Current Reports on Form 8-K.
Bristol-Myers Squibb undertakes no obligation to publicly update
any forward-looking statement, whether as a result of new
information, future events or otherwise.
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