Bristol-Myers Gets Expanded Use for Daklinza (daclatasvir) for Additional Challenging-to-treat Patients with Genotype 1 or Genotype 3

FDA Hepatitis Update - Read changes to the Daklinza (daclatasvir) label expand indication outline by the FDA followed by Bristol-Myers Squibb’s press release. 

On February 5, 2016, FDA approved changes to the DAKLINZA (daclatasvir) label to expand the indication to include HCV genotype 1 infection and expand dosage recommendations to the following populations and to revise dosage recommendations for HCV genotype 3 subjects with compensated (Child-Pugh A) cirrhosis:

• HCV genotype 1 and 3 subjects co-infected with HIV-1
• HCV genotype 1 and 3 post-transplant subjects
• HCV genotype 1 subjects with compensated (Child-Pugh A) cirrhosis and decompensated (Child-Pugh B or C) cirrhosis
• HCV genotype 3 subjects with decompensated (Child-Pugh B or C) cirrhosis

Additionally, drug-drug interaction data regarding DAKLINZA coadministration with buprenorphine/naloxone, darunavir/ritonavir, dolutegravir, or lopinavir/ritonavir were included in the label.

The major revisions are summarized below.

1             INDICATIONS AND USAGE

DAKLINZA 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

2             DOSAGE AND ADMINISTRATION

2.1         Testing Prior to Initiation of Therapy

NS5A Resistance Testing in HCV Genotype 1a-Infected Patients with Cirrhosis: Consider screening for the presence of NS5A polymorphisms at amino acid positions M28, Q30, L31, and Y93 in patients with cirrhosis who are infected with HCV genotype 1a prior to the initiation of treatment with DAKLINZA and sofosbuvir with or without ribavirin

2.2 Recommended Dosage

The recommended dosage of DAKLINZA is 60 mg, taken orally, once daily, with or without food [.

Table 1 provides the recommended DAKLINZA-containing treatment regimens and duration based on HCV genotype and patient population. The optimal duration of DAKLINZA and sofosbuvir with or without ribavirin has not been established for HCV genotype 3 patients with cirrhosis or for HCV genotype 1 patients with Child-Pugh C cirrhosis.

For patients with HCV/HIV-1 coinfection, follow the dosage recommendations in Table 1

For specific dosage recommendations for sofosbuvir, refer to the prescribing information.

For HCV genotype 1 or 3 patients with Child-Pugh B or C cirrhosis or post-transplantation patients, the starting dose of ribavirin is 600 mg once daily, increasing up to 1000 mg daily as tolerated. The starting dose and on-treatment dose of ribavirin can be decreased based on hemoglobin and creatinine clearance.

For HCV genotype 3 patients with compensated cirrhosis (Child-Pugh A), the recommended dosing of ribavirin is based on weight (1000 mg for patients weighing less than 75 kg and 1200 mg for those weighing at least 75 kg administered orally in two divided doses with food).

Table 1:               Recommended Treatment Regimen and Duration for DAKLINZA in Patients with Genotype 1 or 3 HCV
	Patient Population	Treatment and Duration
Genotype 1	Without cirrhosis	DAKLINZA + sofosbuvir for 12 weeks
	Compensated (Child-Pugh A) cirrhosis
	Decompensated (Child-Pugh B or C) cirrhosis	DAKLINZA + sofosbuvir + ribavirin for 12 weeks
	Post-transplant
Genotype 3	Without cirrhosis	DAKLINZA + sofosbuvir for 12 weeks
	Compensated (Child-Pugh A) or decompensated (Child-Pugh B or C) cirrhosis	DAKLINZA + sofosbuvir + ribavirin for 12 weeks
	Post-transplant

Dosage Modification Due to Drug Interactions

Refer to the drug interactions and contraindications sections for other drugs before coadministration with DAKLINZA.

Table 2: Recommended DAKLINZA Dosage Modification with CYP3A Inhibitors and Inducers
Concomitant Drugs	DAKLINZA Dosage
Strong CYP3A inhibitors and certain HIV antiviral agents (see Drug Interactions (7.3) for a complete list)	30 mg once daily (one 30 mg tablet)
Moderate CYP3A inducers and nevirapine (see Drug Interactions (7.3) for a complete list)	90 mg once daily (three 30 mg tablets, or one 60 mg and one 30 mg tablet)
Strong CYP3A inducers (see Contraindications (4) for a complete list)	Contraindicated

6.1  Clinical Trials Experience

Approximately 2400 subjects with chronic HCV infection have been treated with the recommended dose of DAKLINZA in combination with other anti-HCV drugs in clinical trials. Six hundred seventy-nine subjects have received a DAKLINZA and sofosbuvir-based regimen. Safety experience from three clinical trials of DAKLINZA and sofosbuvir with or without ribavirin is presented.

DAKLINZA and Sofosbuvir

In the ALLY-2 trial, 153 treatment-naive and treatment-experienced subjects with HCV/HIV-1 coinfection were treated with DAKLINZA 60 mg once daily (dose-adjusted for concomitant antiretroviral use) in combination with sofosbuvir for 12 weeks. The most common adverse reaction (frequency of 10% or greater) was fatigue. The majority of adverse reactions were mild to moderate in severity. No subjects discontinued therapy for adverse events. Adverse reactions considered at least possibly related to treatment and occurring at a frequency of 5% or greater in ALLY-3 or ALLY-2 are presented in Table 4.

Table 4: Adverse Reactions (All Severity) Reported at ³5% Frequency, DAKLINZA + Sofosbuvir, Studies ALLY-3 and ALLY-2
Adverse Reaction	nALLY-3: HCV Genotype 3 n=152	ALLY-2: HCV/HIV-1 Coinfection n=153
Headache	21 (14%	8%
Fatigue	21 (14%	15%
Nausea	12 (8%	9%
Diarrhea	7 (5%	7%

DAKLINZA, Sofosbuvir, and Ribavirin

In the ALLY-1 trial, 113 subjects with chronic HCV infection, including 60 subjects with Child-Pugh A, B, or C cirrhosis and 53 subjects with recurrence of HCV after liver transplantation, were treated with DAKLINZA 60 mg once daily in combination with sofosbuvir and ribavirin for 12 weeks. The most common adverse reactions (frequency of 10% or greater) among the 113 subjects were headache, anemia, fatigue, and nausea. The majority of adverse reactions were mild to moderate in severity. Of the 15 (13%) subjects who discontinued study drug for adverse events, 13 (12%) subjects discontinued ribavirin only and 2 (2%) subjects discontinued all study drugs. During treatment, 4 subjects in the cirrhotic cohort underwent liver transplantation. Adverse reactions considered at least possibly related to treatment and occurring at a frequency of 5% or greater in either treatment cohort in ALLY-1 are presented in Table 5.

Table 5: Adverse Reactions (All Severity) Reported at ³5% Frequency in Either Treatment Cohort, DAKLINZA + Sofosbuvir + Ribavirin, Study ALLY-1
Adverse Reaction	Child-Pugh A, B, or C Cirrhosis n=60	Recurrence after Liver Transplantation n=53
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

Laboratory Abnormalities

Lipase Elevations: Selected Grade 3 and 4 treatment-emergent laboratory abnormalities observed in clinical trials of DAKLINZA in combination with sofosbuvir with or without ribavirin are presented in Table 6.

Table 6: Selected Grade 3 and 4 Laboratory Abnormalities in Clinical Trials of DAKLINZA + Sofosbuvir ±Ribavirin, Studies ALLY-3, ALLY-2, and ALLY-1
Parameter	Percent with Abnormality
		ALLY-3: HCV Genotype 3 DAKLINZA + Sofosbuvir n=152	ALLY-2: HCV/HIV-1 Coinfection DAKLINZA + Sofosbuvir n=153	ALLY-1: Child-Pugh A, B, or C with Cirrhosis and Post-transplant DAKLINZA + Sofosbuvir + Ribavirin n=113
Hemoglobin (£8.9 g/dL)		0	0	6%
Alanine aminotransferase (ALT) increased (³5.1 ´ ULN)		0	0	2%
Aspartate aminotransferase (AST) increased (³5.1 ´ ULN)		0	0	3%
Total bilirubin increased (>2.6 ´ULN)		0	5%a	8%
Lipase increased (³3.1 ´ ULN)		2%	4%	4%

^a  In the ALLY-2 trial, Grade 3 and 4 increases in total bilirubin were observed only in subjects receiving concomitant atazanavir.

7  DRUG INTERACTIONS

Table 7:   Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class: Drug Name	Effect on Concentrationa		Clinical Comment
HIV antiviral agents
Protease inhibitors:                Atazanavir with ritonavirb               Indinavir                Nelfinavir                Saquinavir	↑ Daclatasvir		Decrease DAKLINZA dose to 30 mg once daily.
Other antiretrovirals: Cobicistat-containing antiretroviral regimens Examples: atazanavir/cobicistat, elvitegravir/cobicistat/emtricitabine/ tenofovir disoproxil fumarate	↑ Daclatasvir		Decrease DAKLINZA dose to 30 mg once daily except with darunavir combined with cobicistat.
Non-nucleoside reverse transcriptase inhibitors (NNRTI):                Efavirenzb                Etravirine                Nevirapine	↓ Daclatasvir		Increase DAKLINZA dose to 90 mg once daily.
Strong CYP3A inhibitors (see also HIV antiviral agents)
Examples: clarithromycin, itraconazole, ketoconazole,bnefazodone, posaconazole, telithromycin, voriconazole	↑ Daclatasvir		Decrease DAKLINZA dose to 30 mg once daily when coadministered with strong inhibitors of CYP3A.
Narcotic Analgesic/Treatment of Opioid Dependence
buprenorphine buprenorphine/naloxone	↑ buprenorphine ↑ norbuprenorphine		For buprenorphine or buprenorphine/naloxone, no adjustment is needed, but clinical monitoring for buprenorphine-associated adverse events is recommended.

^a   The direction of the arrow (↑ = increase, ↓ = decrease) indicates the direction of the change in pharmacokinetic parameters.

^b   These interactions have been studied [see Clinical Pharmacology (12.3), Tables 9 and 10].

Drugs without Clinically Significant Interactions with DAKLINZA

Please see Section 12.3 (Pharmacokinetics) for information regarding anticipated interactions that are not clinically relevant.

Based on the results of drug interaction trials [see Clinical Pharmacology (12.3)], no clinically relevant changes in exposure were observed for cyclosporine, darunavir (with ritonavir), dolutegravir, escitalopram, ethinyl estradiol/norgestimate, lopinavir (with ritonavir), methadone, midazolam, tacrolimus, or tenofovir with concomitant use of daclatasvir. No clinically relevant changes in daclatasvir exposure were observed with cyclosporine, darunavir (with ritonavir), dolutegravir, escitalopram, famotidine, lopinavir (with ritonavir), omeprazole, sofosbuvir, tacrolimus, or tenofovir. No dosage adjustment for daclatasvir is necessary with darunavir/cobicistat or moderate CYP3A inhibitors, including atazanavir (unboosted), fosamprenavir, ciprofloxacin, diltiazem, erythromycin, fluconazole, or verapamil

No clinically relevant interaction is anticipated for daclatasvir or the following concomitant medications: peginterferon alfa, ribavirin, or antacids. No clinically relevant interaction is anticipated for daclatasvir with concomitant use of rilpivirine.

 CLINICAL STUDIES

Clinical Trials in HCV/HIV Coinfected Subjects (ALLY-2)

ALLY-2 was an open-label trial that included 153 subjects with chronic hepatitis C and HIV coinfection who received DAKLINZA and sofosbuvir for 12 weeks. Subjects with HCV genotype 1, 2, 3, 4, 5, or 6 infection were eligible to enroll. Subjects were HCV treatment-naive (n=101) or HCV treatment-experienced (n=52). Prior exposure to NS5A inhibitors was prohibited. The dose of DAKLINZA was 60 mg once daily (dose-adjusted for concomitant antiretroviral use) and the dose of sofosbuvir was 400 mg once daily [see Drug Interactions (7.3)].

The 153 treated subjects had a median age of 53 years (range, 24-71); 88% of subjects were male; 63% were white, 33% were black, and 1% were Asian. Sixty-eight percent of subjects had HCV genotype 1a, 15% had HCV genotype 1b, 8% had genotype 2, 7% had genotype 3, and 2% had genotype 4. Most subjects (80%) had baseline HCV RNA levels greater than or equal to 800,000 IU per mL; 16% of the subjects had compensated cirrhosis, and 73% had IL28B rs12979860 non-CC genotype. Concomitant HIV therapy included PI-based regimens (darunavir + ritonavir, atazanavir + ritonavir, or lopinavir/ritonavir) for 46% of subjects, 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.

SVR and outcomes in subjects with HCV genotype 1 without SVR12 in ALLY-2 are shown by patient population in Table 14. Available data on subjects with HCV genotype 2, 4, 5, or 6 infection are insufficient to provide recommendations for these genotypes; therefore, these results are not presented in Table 14. SVR12 rates were comparable regardless of antiretroviral therapy, HCV treatment history, age, race, gender, IL28B allele status, HCV genotype 1 subtype, or baseline HCV RNA level. For SVR outcomes related to baseline NS5A amino acid polymorphisms, see Microbiology (12.4).

No subjects switched their antiretroviral therapy regimen due to loss of plasma HIV-1 RNA suppression. There was no change in absolute CD4+ T-cell counts at the end of 12 weeks of treatment.

Table 14:             ALLY-2: SVR12 in Subjects with Genotype 1 and 3 HCV/HIV Coinfection Treated with DAKLINZA in Combination with Sofosbuvir for 12 Weeks
Treatment Outcomes	Total n=137
SVR12 Genotype 1	97% (123/127)
No cirrhosisa	98% (103/105)
With cirrhosis	91% (20/22)
Genotype 3b	100% (10/10)
Outcomes for genotype 1 subjects without SVR12
On-treatment virologic failurec	0.8% (1/127)
Relapsed	1.6% (2/126)
Missing post-treatment data	0.8% (1/126)

^a  Includes 5 subjects with inconclusive cirrhosis status.
^b  One subject with cirrhosis.
^c  One subject had detectable HCV RNA at end of treatment.
^d  Relapse rates are calculated with a denominator of subjects with HCV RNA not detected at the end of treatment.

Clinical Trials in Subjects with Child-Pugh A, B, or C Cirrhosis or with HCV Recurrence after Liver Transplantation (ALLY-1)

ALLY-1 was an open-label trial of DAKLINZA, sofosbuvir, and ribavirin that included 113 subjects with chronic HCV infection and Child-Pugh A, B, or C cirrhosis (n=60) or HCV recurrence after liver transplantation (n=53). Subjects with HCV genotype 1, 2, 3, 4, 5, or 6 infection were eligible to enroll. Subjects could be HCV treatment-naive or treatment-experienced, although prior exposure to NS5A inhibitors was prohibited. Subjects received DAKLINZA 60 mg once daily, sofosbuvir 400 mg once daily, and ribavirin for 12 weeks and were monitored for 24 weeks post treatment. Subjects received an initial ribavirin dose of 600 mg or less daily with food; the initial and on-treatment dosing of ribavirin was modified based on hemoglobin and creatinine clearance measurements. If tolerated, the ribavirin dose was titrated up to 1000 mg per day. A high proportion of reductions in ribavirin dosing occurred in the trial. By week 6, approximately half of the subjects received 400 mg per day or less of ribavirin. In total, 16 subjects (15%) completed less than 12 weeks and 11 subjects (10%) completed less than 6 weeks of ribavirin therapy, respectively. For the cohort of patients with cirrhosis (Child-Pugh A, B, or C), the median time to discontinuation of ribavirin was 43 days (range, 8-82, n=9). For the post-transplant cohort, the median time to discontinuation of ribavirin was 20 days (range, 3-57, n=7).

The 113 treated subjects in ALLY-1 had a median age of 59 years (range, 19-82); 67% of the subjects were male; 96% were white, 4% were black, and 1% Asian. Most subjects (59%) were treatment-experienced, and most (71%) had baseline HCV RNA levels greater than or equal to 800,000 IU per mL. Fifty-eight percent of subjects 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, 77% had IL28B rs12979860 non-CC genotype. Among the 60 subjects in the cirrhosis cohort, 20% were Child-Pugh A, 53% were Child-Pugh B, and 27% were Child-Pugh C, and 35% had a Baseline Model for End-Stage Liver Disease (MELD) score of 15 or greater. Most (55%) of the 53 subjects in the post-transplant cohort had F3 or F4 fibrosis (based on FibroSURE^Ò results).

SVR12 and outcomes in subjects without SVR12 in ALLY-1 are shown for subjects with HCV genotype 1 by patient population in Table 15. Available data on subjects with HCV genotype 2, 4, 5, or 6 infection are insufficient to provide recommendations; therefore, these results are not presented in Table 15.

SVR12 rates were comparable regardless of age, gender, IL28B allele status, or baseline HCV RNA level. For SVR12 outcomes related to baseline NS5A amino acid polymorphisms, see Microbiology (12.4). No HCV genotype 1 or genotype 3 subjects with Child-Pugh C cirrhosis had baseline resistance-associated NS5A amino acid polymorphisms. 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.

Table 15:  ALLY-1: SVR12 in Genotype 1 Subjects with Child-Pugh A, B, or C Cirrhosis or with HCV Genotype 1 Recurrence after Liver Transplantation Treated with DAKLINZA in Combination with Sofosbuvir and Ribavirin for 12 Weeks
Treatment Outcomes	Child-Pugh A, B, or C Cirrhosis n=45	Post-Liver Transplant n=41
SVR12
Genotype 1	82% (37/45)	95% (39/41)
Child-Pugh A	91% (10/11)	-
Child-Pugh B	92% (22/24)	-
Child-Pugh C	50% (5/10)	-
Genotype 1a	76% (26/34)	97% (30/31)
Genotype 1b	100% (11/11)	90% (9/10)
Outcomes for subjects without SVR12
On-treatment virologic failure	2% (1/45)a	0
Relapseb	16% (7/44)	5% (2/41)

^a  One subject had detectable HCV RNA at end of treatment.

^b  Relapse rates are calculated with a denominator of subjects with HCV RNA not detected at end of treatment.

Effect of Baseline HCV Amino Acid Polymorphisms on Treatment Response

Genotype 1a NS5A polymorphisms: In HCV genotype 1a-infected subjects with cirrhosis, the presence of an NS5A amino acid polymorphism at position M28, Q30, L31, or Y93 (defined as any change from reference identified by population-based nucleotide sequencing) was associated with reduced efficacy of DAKLINZA and sofosbuvir with or without ribavirin for 12 weeks in the ALLY-1 and ALLY-2 trials (see Table below). Due to the limited sample size, insufficient data are available to determine the impact of specific NS5A polymorphisms at these positions on SVR12 rates in subjects with cirrhosis. Six of 54 subjects (11%) with cirrhosis had one of the following specific NS5A polymorphisms at baseline: M28V/T (n=2), Q30R (n=1), L31M (n=2), or Y93N (n=1); 2 subjects with M28V or Q30R achieved SVR12 while 4 subjects with M28T, L31M, or Y93N did not achieve SVR. Eleven of 112 subjects (10%) without cirrhosis had one or more of the following specific NS5A polymorphisms at baseline: M28T/V (n=3), Q30H/L/R (n=5), L31M (n=1), and Y93C/H/S (n=4); all noncirrhotic subjects with these baseline NS5A polymorphisms achieved SVR12. Based on an analysis of 1026 HCV genotype 1a NS5A amino acid sequences from pooled clinical trials, the prevalence of polymorphisms at these positions was 11% overall, and 11% in the U.S.

Genotype 1b NS5A polymorphisms: In a pooled analysis of 43 subjects infected with HCV genotype 1b with available baseline nucleotide sequence data in ALLY-1 and -2, virus from 21% (n=9) of subjects receiving DAKLINZA and sofosbuvir with or without ribavirin had one of the following baseline NS5A amino acid polymorphisms: R30K/M/Q (n=4), L31M (n=2), or Y93H (n=3). All 9 subjects with NS5A polymorphisms achieved SVR12, including 5 who were noncirrhotic and 4 who were in the post-transplant period.

Genotype 3 NS5A polymorphisms: In the ALLY-3 trial in which HCV genotype 3-infected subjects received DAKLINZA and sofosbuvir for 12 weeks, the presence of an NS5A Y93H polymorphism was associated with a reduced SVR12 rate (see Table below). In a pooled analysis of 175 subjects infected with HCV genotype 3 with available baseline nucleotide sequence data in the ALLY-1, -2, and -3 trials, virus from 7% (13/175) of subjects had the NS5A Y93H polymorphism, and all 13 of these subjects were in the ALLY-3 trial. Phylogenetic analysis of NS5A sequences indicated that all genotype 3 subjects with available data in the ALLY-1, -2, and -3 trials (n=175) were infected with HCV subtype 3a.

Impact of NS5A Amino Acid Polymorphisms on SVR12 Rates in Subjects with HCV Genotype 1a or Genotype 3 Infection in Phase 3 Trials of DAKLINZA + Sofosbuvir ± Ribavirin
NS5A Polymorphisms	SVR12 Rates after 12 Weeks of Treatment with DAKLINZA + Sofosbuvir ± Ribavirina
	With NS5A Polymorphism(s) % (n/N)	Without NS5A Polymorphism(s) % (n/N)b
HCV genotype 1a-infected subjects: M28,c Q30,cL31,c or Y93c	76% (13/17)	95% (142/149)
Without cirrhosisd	100% (11/11)	99% (100/101)
With cirrhosis (Child-Pugh A, B, or C)	33% (2/6)	88% (42/48)
HCV genotype 3-infected subjects: Y93H	54% (7/13)	92% (149/162)
Without cirrhosisd	67% (6/9)	98% (125/128)
With cirrhosis (Child-Pugh A, B, or C)	25% (1/4)	71% (24/34)

^a   HCV genotype 1a-infected subjects received DAKLINZA + sofosbuvir ± ribavirin for 12 weeks in the ALLY-1 and ALLY-2 trials. HCV genotype 3-infected subjects received DAKLINZA + sofosbuvir for 12 weeks in the ALLY-3 trial; no data on the impact of Y93H are available for HCV genotype 3-infected subjects treated with DAKLINZA + sofosbuvir ± ribavirin in ALLY-1 and ALLY-2 trials.

^b  None of the 11 subjects with Child-Pugh C cirrhosis had an indicated NS5A polymorphism; 5 achieved SVR (genotype 1a: 4/9; genotype 3a: 1/2).

^c  Any change from genotype 1a reference.

^d  Includes subjects who were post-transplant with undefined cirrhosis status.

Daklinza is a product of Bristol-Myers Squibb. The complete labeling will be posted at Drugs@FDA, and DailyMed.

Richard Klein
Office of Health and Constituent Affairs
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

Steve Morin
Office of Health and Constituent Affairs
Food and Drug Administration

Press Release:
U.S. FDA Approves Expanded Use of Bristol-Myers Squibb’s Daklinza (daclatasvir) for Additional Challenging-to-treat Patients with Genotype 1 or Genotype 3 Chronic Hepatitis C
Updated label provides new treatment option for patients with HIV-1 coinfection, advanced cirrhosis, and post-liver transplant HCV recurrence

February 05, 2016 12:47 PM Eastern Standard Time

PRINCETON, N.J.--(BUSINESS WIRE)--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.

#MEDIA Bristol-Myers Squibb receives expanded FDA approval to treat additional GT1 or GT3 chronic #HepC patients Tweet this

“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 ofDaklinza 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
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. 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.