Olysio (simeprevir) label revised‏

Information about FDA Hepatitis product approvals, safety warnings, medical product labeling changes, notices of upcoming public meetings, and notices about proposed regulatory guidances.
 On October 5, 2015 FDA approved revisions to the Olysio (simeprevir) label to include dosing recommendations for the treatment of HCV/HIV-1 coinfection and to expand the indications and usage to include genotype 4 infection.
The recommended dosage regimens and treatment duration for genotype 1 and HCV/HIV-1 co-infected patients was added to the following table:
Table 1: Recommended Dosage Regimens and Treatment Duration for OLYSIO, Peg IFN alfa, and RBV Combination Therapy for Treatment of CHC Infection in HCV Genotype 1 or 4 Mono infected and HCV/HIV 1 
Co infected Patients
Patient PopulationTreatment Regimen and Duration
Treatment naïve patients and prior relapsers* 
  • with or without cirrhosis, who are not co infected with HIV
12 weeks of OLYSIO in combination with Peg IFN alfa and RBV followed by an additional 12 weeks of Peg IFN alfa and RBV (total treatment duration of 24 weeks)†
  • without cirrhosis, who are co infected with HIV
with cirrhosis, who are co infected with HIV                               12 weeks of OLYSIO in combination with Peg-IFN-alfa and RBV followed by an additional 36 weeks of Peg IFN alfa and RBV (total treatment duration of 48 weeks)†
Prior non responders (including partial‡ and null responders#), with or without cirrhosis, with or without HIV co infection12 weeks of OLYSIO in combination with Peg-IFN-alfa and RBV followed by an additional 36 weeks of Peg IFN alfa and RBV (total treatment duration of 48 weeks)†                      
†HIV = human immunodeficiency virus.
* Prior relapser: HCV RNA not detected at the end of prior IFN based therapy and HCV RNA detected during follow up [see Clinical Studies (14)].
‡† Recommended duration of treatment if patient does not meet stopping rules (see Table 3).
#‡ Prior partial responder: prior on-treatment ≥ 2 log10 IU/mL reduction in HCV RNA from baseline at Week 12 and HCV RNA detected at end of prior IFN based therapy [see Clinical Studies (14)].
§# Prior null responder: prior on treatment < 2 log10 reduction in HCV RNA from baseline at Week 12 during prior IFN based therapy [see Clinical Studies (14)].
Section 6 Adverse Reactions was updated with the following information.
OLYSIO in combination with Peg IFN alfa and RBV was studied in 106 subjects with HCV genotype 1/HIV 1 co infection. The safety profile in HCV/HIV co-infected subjects was generally comparable to HCV mono infected subjects.
OLYSIO in combination with Peg IFN alfa and RBV was studied in 107 subjects with HCV genotype 4 infection. The safety profile of OLYSIO in subjects with HCV genotype 4 infection was comparable to subjects with HCV genotype 1 infection.
Azithromycin, bedaquiline and dolutegravir were added to the list of drugs without clinically significant interactions with OLYSIO (see section 7.4 of the label).
Section 12.3 Pharmacokinetics was updated to include the following statements.
Patients co infected with HIV 1
Simeprevir exposures were slightly lower in subjects with HCV genotype 1 infection with HIV 1 co infection compared to subjects with HCV genotype 1 mono infection. This difference is not considered to be clinically meaningful.
Section 12.4 Microbiology was updated to include data on genotype 4 as follows:
Chimeric replicons carrying NS3 sequences derived from HCV protease inhibitor treatment naïve genotype 4a-, 4d-, or 4r infected patients displayed median FC in EC50 values of 0.5 (IQR: 0.4 to 0.6; N=38), 0.4 (IQR: 0.2 to 0.5; N=24), and 1.6 (IQR: 0.7 to 4.5; N=8), compared to reference genotype 1b replicon, respectively. A pooled analysis of chimeric replicons carrying the NS3 sequences from HCV protease inhibitor naïve patients infected with other HCV genotype 4 subtypes, including 4c (N=1), 4e (N=2), 4f (N=3), 4h (N=3), 4k (N=1), 4o (N=2), 4q (N=2), or unidentified subtype (N=7) displayed a median FC in EC50 value of 0.7 (IQR: 0.5 to 1.1; N=21) compared to reference genotype 1b replicon.
In the RESTORE trial in genotype 4 infected subjects, 30 out of 34 (88%) subjects who did not achieve SVR had emerging amino acid substitutions at NS3 positions Q80, T122, R155, A156 and/or D168 (mainly substitutions at position D168; 26 out of 34 [76%] subjects), similar to the emerging amino acid substitutions observed in genotype 1 infected subjects.
Table 11: SVR12 Rates by IL28B rs12979860 Genotype in Adult Patients Receiving OLYSIO 150 mg Once Daily in Combination with Peg IFN alfa and RBV (Trials C212 and RESTORE)
Trial (Population)IL28B 
rs12979860 
Genotype
Treatment-
Naïve 
Subjects
% (n/N)
Prior 
Relapsers
% (n/N)
Prior Partial Responders
% (n/N)
Prior Null Responders
% (n/N)

C212
(HIV 1 co infection)

C/C100 (15/15)100 (7/7)100 (1/1)80 (4/5)
C/T70 (19/27)100 (6/6)71 (5/7)53 (10/19)
T/T80 (8/10)0 (0/2)50 (1/2)50 (2/4)

RESTORE
(HCV genotype 4)

              
C/C100 (7/7)100 (1/1)--
C/T82 (14/17)82 (14/17)60 (3/5)41 (9/22)
T/T0 (8/10)00 (4/4)60 (3/5)39 (77/18)
SVR12: sustained virologic response 12 weeks after planned EOT.
Section 14 Clinical Studies was updated to include the trial results from the HCV/HIV- coinfected trial and the genotype 4 trial.
Subjects with HCV/HIV 1 Co Infection
C212 was an open label, single arm Phase 3 trial in HIV 1 subjects co infected with HCV genotype 1 who were treatment naïve or failed prior HCV therapy with Peg IFN alfa and RBV (including prior relapsers, partial responders or null responders). Non cirrhotic treatment naïve subjects or prior relapsers received 12 weeks of once daily treatment with 150 mg OLYSIO plus Peg IFN alfa 2a and RBV, followed by 12 or 36 weeks of therapy with Peg IFN alfa 2a and RBV in accordance with the protocol defined RGT criteria. Prior non responder subjects (partial and null response) and all cirrhotic subjects (METAVIR fibrosis score F4) received 36 weeks of Peg IFN alfa 2a and RBV after the initial 12 weeks of OLYSIO in combination with Peg IFN alfa 2a and RBV.
The 106 enrolled subjects in the C212 trial had a median age of 48 years (range: 27 to 67 years; with 2% above 65 years); 85% were male; 82% were White, 14% Black or African American, 1% Asian, and 6% Hispanic; 12% had a BMI greater than or equal to 30 kg/m2; 86% had HCV RNA levels greater than 800,000 IU/mL; 68% had METAVIR fibrosis score F0, F1 or F2, 19% METAVIR fibrosis score F3, and 13% METAVIR fibrosis score F4; 82% had HCV genotype 1a, and 17% HCV genotype 1b; 28% of the overall population and 34% of the subjects with genotype 1a had Q80K polymorphism at baseline; 27% had IL28B CC genotype, 56% IL28B CT genotype, and 17% IL28B TT genotype; 50% (n=53) were HCV treatment naïve subjects, 14% (n=15) prior relapsers, 9% (n=10) prior partial responders, and 26% (n=28) prior null responders. Eighty eight percent (n=93) of the subjects were on highly active antiretroviral therapy (HAART), with nucleoside reverse transcriptase inhibitors and the integrase inhibitor raltegravir being the most commonly used HIV antiretroviral. HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors (except rilpivirine) were prohibited from use in this study.
The median baseline HIV 1 RNA levels and CD4+ cell count in subjects not on HAART were 4.18 log10 copies/mL (range: 1.3 4.9 log10 copies/mL) and 677 × 106 cells/L (range: 489 1076 × 106 cells/L), respectively. The median baseline CD4+ cell count in subjects on HAART was 561 × 106 cells/mL (range: 275 1407 × 106 cells/mL).
Table 17 shows the response rates in treatment naïve, prior relapsers, prior partial responders and null responders.
Table 17: Response Rates in Adult Subjects with HCV Genotype 1 Infection and HIV 1 Co Infection (C212 Trial)
Response RatesTreatment Naïve Subjects
N=53
% (n/N)
Prior Relapsers
N=15
% (n/N)
Prior Partial Responders
N=10
% (n/N)
Prior Null Responders
N=28
% (n/N)
Overall SVR12 (genotype 1a and 1b)
Genotype 1a
Genotype 1b
79 (42/53)
77 (33/43)
90 (9/10)
87 (13/15)
83 (10/12)
100 (3/3)
70 (7/10)
67 (6/9)
100 (1/1)
57 (16/28)
54 (13/24)
75 (3/4)
Outcome for all subjects without SVR12
On treatment failure*9 (5/53)0 (0/15)20 (2/10)39 (11/28)
Viral relapse†         10 (5/48)                13 (2/15)                  0 (0/7)                 12 (2/17)         
150 mg OLYSIO for 12 weeks with Peg IFN alfa 2a and RBV for 24 or 48 weeks.
* On treatment failure was defined as the proportion of subjects with confirmed detectable HCV RNA at EOT (including but not limited to subjects who met the protocol specified treatment stopping rules and/or experienced viral breakthrough).
† Viral relapse rates are calculated with a denominator of subjects with undetectable HCV RNA at actual EOT and with at least one follow up HCV RNA assessment. Includes one prior null responder who experienced relapse after SVR12.
Eighty nine percent (n=54/61) of the OLYSIO treated treatment naïve subjects and prior relapsers without cirrhosis were eligible for a total treatment duration of 24 weeks. In these subjects, the SVR12 rate was 87%.
Seventy-one percent (n=37/52), 93% (n=14/15), 80% (n=8/10) and 36% (n=10/28) of OLYSIO treated treatment naïve subjects, prior relapsers, prior partial responders and prior null responders had undetectable HCV RNA at week 4 (RVR). In these subjects the SVR12 rates were 89%, 93%, 75% and 90%, respectively.
Table 18 shows the SVR rates by METAVIR fibrosis scores.
Table 18: SVR12 Rates by METAVIR Fibrosis Score in Adult Subjects with HCV Genotype 1 Infection and HIV 1 co Infection (C212 Trial)
SubgroupTreatment Naïve 
Subjects % (n/N)
Prior 
Relapsers
% (n/N)
Prior Partial Responders
% (n/N)
Prior Null Responders
% (n/N)
F0 289 (24/27)78 (7/9)50 (1/2)57 (4/7)
F3 457 (4/7)100 (2/2)67 (2/3)60 (6/10)
Two subjects had HIV virologic failure defined as confirmed HIV 1 RNA ≥ 200 copies/mL after previous < 50 copies/mL; these failures occurred 36 and 48 weeks after end of OLYSIO treatment.
Adult Subjects with HCV Genotype 4 Infection
RESTORE was an open label, single arm Phase 3 trial in subjects with HCV genotype 4 infection who were treatment naïve or failed prior therapy with Peg IFN alfa and RBV (including prior relapsers, partial responders or null responders). Treatment naïve subjects or prior relapsers received once daily treatment with 150 mg OLYSIO plus Peg IFN alfa 2a and RBV for 12 weeks, followed by 12 or 36 weeks of therapy with Peg IFN alfa 2a and RBV in accordance with the protocol defined RGT criteria. Prior non responder subjects (partial and null response) received once daily treatment with 150 mg OLYSIO plus Peg IFN alfa 2a and RBV for 12 weeks, followed by 36 weeks of Peg IFN alfa 2a and RBV.
The 107 enrolled subjects in the RESTORE trial with HCV genotype 4 had a median age of 49 years (range: 27 to 69 years; with 5% above 65 years); 79% were male; 72% were White, 28% Black or African American, and 7% Hispanic; 14% had a BMI greater than or equal to 30 kg/m2; 60% had HCV RNA levels greater than 800,000 IU/mL; 57% had METAVIR fibrosis score F0, F1 or F2, 14% METAVIR fibrosis score F3, and 29% METAVIR fibrosis score F4; 42% had HCV genotype 4a, and 24% had HCV genotype 4d; 8% had IL28B CC genotype, 58% IL28B CT genotype, and 35% IL28B TT genotype; 33% (n=35) were treatment naïve HCV subjects, 21% (n=22) prior relapsers, 9% (n=10) prior partial responders, and 37% (n=40) prior null responders.
Table 19 shows the response rates in treatment naïve, prior relapsers, prior partial responders and null responders. Table 20 shows the SVR rates by METAVIR fibrosis scores.
Table 19: Response Rates in Adult Subjects with HCV Genotype 4 Infection (RESTORE Trial)
Response RatesTreatment Naïve Subjects
N=35
% (n/N)
Prior Relapsers
N=22
% (n/N)
Prior Partial Responders
N=10
% (n/N)
Prior Null Responders
N=40
% (n/N)
Overall SVR1283 (29/35)86 (19/22)60 (6/10)40 (16/40)
Outcome for all subjects without SVR12
On treatment failure*9 (3/35)9 (2/22)20 (2/10)45 (18/40)
Viral relapse†9 (3/35)5 (1/22)20 (2/10)15 (6/40)
150 mg OLYSIO for 12 weeks with Peg IFN alfa 2a and RBV for 24 or 48 weeks.
* On treatment failure was defined as the proportion of subjects with confirmed detectable HCV RNA at EOT (including but not limited to subjects who met the protocol specified treatment stopping rules and/or experienced viral breakthrough).
† Viral relapse rates are calculated with a denominator of subjects with undetectable (or unconfirmed detectable) HCV RNA at actual EOT.
Table 20: SVR12 Rates by METAVIR Fibrosis Score in Adult Subjects with HCV Genotype 4 Infection (RESTORE Trial)
SubgroupTreatment Naïve Subjects
% (n/N)
Prior Relapsers
% (n/N)
Prior Partial Responders
% (n/N)
Prior Null Responders
% (n/N)
 
F0-285 (22/26)91 (10/11)100 (5/5)47 (8/17)
F3-478 (7/9)82 (9/11)20 (1/5)35 (7/20)
You will be able to view the complete label at drugs@fda or dailymed.
Richard Klein
Office of Health and Constituent Affairs
Food and Drug Administration
Kimberly Struble
Division of Antiviral Products
Food and Drug Administration
Steve Morin
Office of Health and Constituent Affairs
Food and Drug Administration
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