Squibb Company (NYSE:BMY) announced today that Daklinza™
(daclatasvir, 60 mg), an NS5A replication complex inhibitor, has been
approved by the U.S. Food and Drug Administration (FDA) in combination
with sofosbuvir (with or without ribavirin) in genotypes 1 and 3. The
expanded label includes data in three additional challenging-to-treat
patient populations: chronic hepatitis C virus (HCV) patients with HIV-1
coinfection, advanced cirrhosis, or post-liver transplant recurrence of
HCV. The Daklinza plus sofosbuvir regimen is already available
for the treatment of chronic HCV genotype 3, and is currently the only
12-week, once-daily all-oral treatment option for these patients.
Sustained virologic response (SVR) rates are reduced in genotype 3
patients with cirrhosis receiving Daklinza and sofosbuvir for 12
weeks without ribavirin. The recommended dosage of Daklinza is 60 mg in
combination with sofosbuvir with or without (+/-) ribavirin for 12 weeks.
“The expanded indication for Daklinza offers an additional
treatment option for multiple subsets of patients who have genotype 1 or
3 chronic HCV,” said Chris Boerner, Head of U.S. Commercial,
Bristol-Myers Squibb. “HCV/HIV-coinfected patients and patients with
advanced cirrhosis or post-transplant recurrence of HCV still pose a
treatment challenge to physicians. As part of our commitment to the HCV
community, we have sought to make new treatment options available for
these and other targeted populations that have not yet been able to
fully benefit from currently available next-generation medicines.”
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 co-administered with sofosbuvir and amiodarone. Please
see full Important Safety Information below for more details.
The efficacy and safety of the Daklinza regimens were evaluated
in the Phase 3 ALLY-1 and ALLY-2 clinical trials.
ALLY-2 (Daklinza + sofosbuvir)
The ALLY-2 trial enrolled 153 treatment-naïve (n=101) and
treatment-experienced (n=52) HCV/HIV-coinfected patients treated with Daklinza
plus sofosbuvir for 12 weeks. Sustained virologic response was the
primary endpoint and was defined as HCV RNA below the LLOQ at
post-treatment week 12 (SVR12) in genotype 1 treatment-naïve patients.
(Genotypes 1 and 3)
12-week treatment duration
In ALLY-2, SVR12 rates were high regardless of baseline subgroup,
including Black/African-American (98%, n=50 in all genotypes studied),
and high baseline viral load (≥6,000,000 IU/mL) (97%, n=62 in all
genotypes studied). Rates of SVR12 were also similar among the
concomitant HAART (highly active antiretroviral therapy) regimens used,
which included protease inhibitors (97%, n=70 in all genotypes),
non-nucleoside reverse transcriptase inhibitors (100%, n=40 in all
genotypes), and integrase inhibitors (95%, n=39 in all genotypes).
Among the 153 patients in ALLY-2, 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% in ALLY-2 were fatigue (15%), nausea (9%), headache (8%) and
“The high SVR rates achieved with the daclatasvir-based (Daklinza)
regimen in HCV/HIV-coinfected patients are extremely encouraging for
potentially helping to address a serious health concern for individuals
with HIV,” said Kenneth Sherman, M.D., Ph.D., Gould Professor of
Medicine and Director, Division of Digestive Diseases, University of
Cincinnati College of Medicine. “Approximately a quarter of all HIV
patients in the U.S. are coinfected with HCV, and have historically been
particularly challenging to treat due to the complexities of the
overlapping therapeutic regimens used to treat each infection. New
options that allow for the treatment of HCV without altering HIV
medicines are still a significant need for these patients.” The dose of Daklinza
may need to be adjusted when used with some antiretroviral regimens.
ALLY-1 (Daklinza + sofosbuvir + ribavirin)
The ALLY-1 trial enrolled 113 patients with chronic HCV infection and
Child-Pugh A, B, or C advanced cirrhosis (n=60) or HCV recurrence after
liver transplant (n=53) treated with Daklinza plus sofosbuvir
with ribavirin for 12 weeks. The primary endpoint was SVR12 in each
Child-Pugh A, B or C Cirrhosis
Child-Pugh A cirrhosis
Child-Pugh B cirrhosis
Child-Pugh C cirrhosis
SVR12 rates were comparable between genotype 3 (5/6 with Child-Pugh B or
C cirrhosis and 10/11 post-liver transplant) and genotype 1 subjects
with or without decompensated cirrhosis.
Among all patients in ALLY-1, there were no treatment-related SAEs. Of
the 15 (13%) patients who discontinued study drug for adverse events, 13
(12%) patients discontinued ribavirin only and 2 (2%) patients
discontinued all study drugs. The most common treatment-related AEs at a
frequency of ≥5% in either cohort of ALLY-1 were headache (12%, 30%),
anemia (20%, 19%), fatigue (15%, 17%), nausea (15%, 6%), rash (8%, 2%),
diarrhea (3%, 6%), insomnia (3%, 6%), dizziness (0, 6%), and somnolence
(5%, 0) in the advanced cirrhotic and post-transplant treatment groups,
The ALLY-1 and -2 trials demonstrated that Daklinza is able to be
administered with the most commonly used medications for the treatment
of HIV and post-transplant immunosuppression. Based on the drug-drug
interaction profile, there is no need to change or adjust HAART
regimens, including darunavir-ritonavir, atazanavir-ritonavir,
lopinavir-ritonavir, efavirenz, raltegravir, dolutegravir, nevirapine
and rilpivirine. The dose of Daklinza was adjusted for some HAART
regimens. Daklinza is also compatible with many
immunosuppressive regimens, with no treatment-limiting drug-drug
interactions. The ALLY-1 trial studied most immunosuppressants:
cyclosporine, tacrolimus, sirolimus, everolimus, corticosteroids, or
“Post-liver transplant patients with HCV recurrence and patients with
advanced cirrhosis can be difficult to manage because of the potential
for drug-drug interactions associated with immunosuppressive treatments
and the complex conditions of liver disease,” said Fred Poordad, M.D.,
ALLY-1 Lead Investigator and Clinical Professor of Medicine, Chief,
Hepatology, University of Texas Health Science Center and VP, Academic
and Clinical Affairs, Texas Liver Institute. “Transplant patients need
to take a variety of immunosuppressive medications to prevent organ
rejection, and treatment with Daklinza plus sofosbuvir and
ribavirin allows patients to preserve their new liver by treating HCV
before its progression to more severe disease, while still maintaining
the critical regimens required to manage immunosuppression.”
Daklinza Regimens Dosing
Daklinza + sofosbuvir
Genotype 1 or Genotype 3 without cirrhosis
Genotype 1 with compensated cirrhosis (Child-Pugh A)
Daklinza + sofosbuvir + ribavirin
Genotype 3 with compensated cirrhosis (Child-Pugh A)
Genotype 1 or Genotype 3 with decompensated cirrhosis (Child-Pugh B
Genotype 1 or Genotype 3 post-transplant
For genotype 1a patients with cirrhosis, prior to the initiation of
treatment with Daklinza-based regimens, consider screening for
the presence of NS5A polymorphisms at amino acid positions M28, Q30,
L31, and Y93.
About the ALLY-2 Clinical Trial
ALLY-2 was an open-label trial that included 153 patients (genotypes 1-4i)
with chronic HCV and HIV coinfection. Patients received Daklinza
60 mg (dose-adjusted for concomitant antiretroviral use) plus sofosbuvir
400 mg once daily for 12 weeks and were monitored for 24 weeks
The 153 patients had a median age of 53 years (range, 24-71); 88% of the
patients were male; 63% were white, 33% were black, and 1% were Asian.
Most patients (80%) had baseline HCV RNA levels greater than or equal to
800,000 IU/mL. Sixty-eight percent of patients had HCV genotype 1a, 15%
had HCV genotype 1b, 8% had genotype 2, 7% had genotype 3, and 2% had
genotype 4. Daklinza is indicated in genotype 1 and genotype 3
only. Sixteen percent of all patients had compensated cirrhosis.
Concomitant HIV therapy included PI-based regimens (darunavir +
ritonavir, atazanavir + ritonavir, or lopinavir/ritonavir) for 46% of
patients, NNRTI-based regimens (efavirenz, nevirapine, or rilpivirine)
for 26%, integrase-based regimens (raltegravir or dolutegravir) for 26%,
and nucleoside-only regimens (abacavir + emtricitabine + zidovudine) for
1%. Two patients were not receiving treatment for HIV.
About the ALLY-1 Clinical Trial
ALLY-1 was an open-label trial that included 113 patients (genotypes
1-4, 6i) with chronic HCV infection and Child-Pugh A, B, or C
cirrhosis or HCV recurrence after liver transplant. Patients received Daklinza
60 mg plus sofosbuvir 400 mg once daily with ribavirin for 12 weeks and
were monitored for 24 weeks post-treatment. The recommended initial dose
of ribavirin was 600 mg or less daily with food and could be adjusted up
to 1000 mg per day if tolerated.
The 113 treated patients in ALLY-1 had a median age of 59 years (range,
19-82); 67% of the patients were male; 96% were white, 4% were black,
and 1% were Asian. Most patients (59%) were treatment-experienced, and
most (71%) had baseline HCV RNA levels greater than or equal to 800,000
IU/mL. Fifty-eight percent of patients had HCV genotype 1a, 19% had HCV
genotype 1b, 4% had genotype 2, 15% had genotype 3, 4% had genotype 4,
and 1% had genotype 6. Daklinza is indicated in genotype 1 and
genotype 3 only. Among the 60 patients in the cirrhosis cohort, 20% were
Child-Pugh class A, 53% were Child-Pugh class B, 27% were Child-Pugh
class C, and 35% had a Baseline Model for End-Stage Liver Disease (MELD)
score of 15 or greater. Most (55%) of the 53 patients in the
post-transplant cohort had F3 or F4 fibrosis (based on FibroSURE®
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 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 50 countries across Europe, Central and South America, the
Middle East and the Asia-Pacific region.
Indication and Important Safety Information - Daklinza™ (daclatasvir)
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.
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
-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.
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.
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.
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
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).
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.
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
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
Please click here
for the Daklinza full prescribing information.
i Genotypes 1-6 were eligible to enroll in ALLY-2 and ALLY-1.
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
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is defined in the Private Securities Litigation Reform Act of 1995
regarding the research, development and commercialization of
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including factors that could delay, divert or change any of them, and
could cause actual outcomes and results to differ materially from
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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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