Updated label provides new treatment option
for patients with HIV-1 coinfection, advanced cirrhosis, and
post-liver transplant HCV recurrence
Bristol-Myers 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.
SVR12
(Genotypes 1 and 3)
12-week treatment duration
(n=137)
Genotype 1 97% (123/127) No cirrhosis
98% (103/105) Cirrhosis 91% (20/22) Genotype 3
100% (10/10)
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 diarrhea (7%).
“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 treatment cohort.
SVR12 Child-Pugh A, B or C Cirrhosis
(n=45)
Post-liver Transplant
(n=41)
Genotype 1 82% (37/45) 95% (39/41)
Child-Pugh A cirrhosis 91% (10/11) N/A
Child-Pugh B cirrhosis 92% (22/24) N/A
Child-Pugh C cirrhosis 50% (5/10) N/A
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, respectively.
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 mycophenolate mofetil.
“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
Regimen Patient Population Daklinza +
sofosbuvir
12 weeks
Genotype 1 or Genotype 3 without cirrhosis
Genotype 1 with compensated cirrhosis (Child-Pugh A)
Daklinza + sofosbuvir + ribavirin
12 weeks
Genotype 3 with compensated cirrhosis (Child-Pugh A)
Genotype 1 or Genotype 3 with decompensated cirrhosis
(Child-Pugh B and C) 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 post-treatment.
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® results).
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)
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.
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 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.-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.
NURSING MOTHERS:
- 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 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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term is defined in the Private Securities Litigation Reform Act of
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on current expectations and involve inherent risks and
uncertainties, including factors that could delay, divert or change
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should be evaluated together with the many uncertainties that
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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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