INDICATIONS
HARVONI IS INDICATED FOR THE TREATMENT OF CHRONIC HEPATITIS C (CHC) GENOTYPE 1 INFECTION IN ADULTS.
HOW SUPPLIED
DOSAGE FORMS AND STRENGTHS
HARVONI IS AVAILABLE AS AN ORANGE COLORED, DIAMOND SHAPED, FILM-COATED TABLET DEBOSSED WITH “GSI” ON ONE SIDE AND “7985” ON THE OTHER SIDE OF THE TABLET. EACH TABLET CONTAINS 90 MG LEDIPASVIR AND 400 MG SOFOSBUVIR.
STORAGE AND HANDLING
HARVONI TABLETS ARE ORANGE, DIAMOND-SHAPED, FILM-COATED, DEBOSSED WITH “GSI” ON ONE SIDE AND “7985” ON THE OTHER SIDE OF THE TABLET. EACH BOTTLE CONTAINS 28 TABLETS (NDC 61958-1801-1), A SILICA GEL DESICCANT, POLYESTER COIL, AND IS CLOSED WITH A CHILD-RESISTANT CLOSURE.
STORE AT ROOM TEMPERATURE BELOW 30°C (86°F).
DISPENSE ONLY IN ORIGINAL CONTAINER.
DO NOT USE IF SEAL OVER BOTTLE OPENING IS BROKEN OR MISSING.
MANUFACTURED AND DISTRIBUTED BY: GILEAD SCIENCES, INC. FOSTER CITY, CA 94404. ISSUED: MARCH 2015
DOSAGE AND ADMINISTRATION
RECOMMENDED DOSAGE IN ADULTS
HARVONI IS A TWO-DRUG FIXED-DOSE COMBINATION PRODUCT THAT CONTAINS 90 MG OF LEDIPASVIR AND 400 MG OF SOFOSBUVIR IN A SINGLE TABLET. THE RECOMMENDED DOSAGE OF HARVONI IS ONE TABLET TAKEN ORALLY ONCE DAILY WITH OR WITHOUT FOOD [SEE CLINICAL PHARMACOLOGY].
DURATION OF TREATMENT
RELAPSE RATES ARE AFFECTED BY BASELINE HOST AND VIRAL FACTORS AND DIFFER BETWEEN TREATMENT DURATIONS FOR CERTAIN SUBGROUPS [SEE CLINICAL STUDIES]. TABLE 1 BELOW PROVIDES THE RECOMMENDED HARVONI TREATMENT DURATIONS FOR TREATMENT-NAÏVE AND TREATMENT-EXPERIENCED PATIENTS AND THOSE WITH AND WITHOUT CIRRHOSIS [SEE CLINICAL STUDIES].
TABLE 1 : RECOMMENDED TREATMENT DURATION FOR HARVONI IN PATIENTS WITH CHC GENOTYPE 1
PATIENT POPULATION
RECOMMENDED TREATMENT DURATION
TREATMENT-NAIVE WITH OR WITHOUT CIRRHOSIS
12 WEEKS*
TREATMENT-EXPERIENCED** WITHOUT CIRRHOSIS
12 WEEKS
TREATMENT-EXPERIENCED** WITH CIRRHOSIS
24 WEEKS
* HARVONI FOR 8 WEEKS CAN BE CONSIDERED IN TREATMENT-NAÏVE PATIENTS WITHOUT CIRRHOSIS WHO HAVE PRE-TREATMENT HCV RNA LESS THAN 6 MILLION IU/ML [SEE CLINICAL STUDIES].
**TREATMENT-EXPERIENCED PATIENTS WHO HAVE FAILED TREATMENT WITH EITHER PEGINTERFERON ALFA + RIBAVIRIN OR AN HCV PROTEASE INHIBITOR + PEGINTERFERON ALFA + RIBAVIRIN.
SEVERE RENAL IMPAIRMENT AND END STAGE RENAL DISEASE
NO DOSE RECOMMENDATION CAN BE GIVEN FOR PATIENTS WITH SEVERE RENAL IMPAIRMENT (ESTIMATED GLOMERULAR FILTRATION RATE [EGFR] < 30 ML/MIN/1.73M²) OR WITH END STAGE RENAL DISEASE (ESRD) DUE TO HIGHER EXPOSURES (UP TO 20-FOLD) OF THE PREDOMINANT SOFOSBUVIR METABOLITE [SEE USE IN SPECIFIC POPULATIONS AND CLINICAL PHARMACOLOGY].
SIDE EFFECTS
CLINICAL TRIALS EXPERIENCE
BECAUSE CLINICAL TRIALS ARE CONDUCTED UNDER WIDELY VARYING CONDITIONS, ADVERSE REACTION RATES OBSERVED IN THE CLINICAL TRIALS OF A DRUG CANNOT BE DIRECTLY COMPARED TO RATES IN THE CLINICAL TRIALS OF ANOTHER DRUG AND MAY NOT REFLECT THE RATES OBSERVED IN PRACTICE.
THE SAFETY ASSESSMENT OF HARVONI WAS BASED ON POOLED DATA FROM THREE PHASE 3 CLINICAL TRIALS OF SUBJECTS WITH GENOTYPE 1 CHRONIC HEPATITIS C (CHC) WITH COMPENSATED LIVER DISEASE (WITH AND WITHOUT CIRRHOSIS) INCLUDING 215, 539, AND 326 SUBJECTS WHO RECEIVED HARVONI FOR 8, 12 AND 24 WEEKS, RESPECTIVELY [SEE CLINICAL STUDIES].
THE PROPORTION OF SUBJECTS WHO PERMANENTLY DISCONTINUED TREATMENT DUE TO ADVERSE EVENTS WAS 0%, < 1%, AND 1% FOR SUBJECTS RECEIVING HARVONI FOR 8, 12, AND 24 WEEKS, RESPECTIVELY.
THE MOST COMMON ADVERSE REACTIONS ( = 10%) WERE FATIGUE AND HEADACHE IN SUBJECTS TREATED WITH 8, 12, OR 24 WEEKS OF HARVONI.
TABLE 2 LISTS ADVERSE REACTIONS (ADVERSE EVENTS ASSESSED AS CAUSALLY RELATED BY THE INVESTIGATOR, ALL GRADES) OBSERVED IN = 5% OF SUBJECTS RECEIVING 8, 12, OR 24 WEEKS TREATMENT WITH HARVONI IN CLINICAL TRIALS. THE MAJORITY OF ADVERSE REACTIONS PRESENTED IN TABLE 2 OCCURRED AT SEVERITY OF GRADE 1. THE SIDE-BY-SIDE TABULATION IS TO SIMPLIFY PRESENTATION; DIRECT COMPARISON ACROSS TRIALS SHOULD NOT BE MADE DUE TO DIFFERING TRIAL DESIGNS.
TABLE 2 : ADVERSE REACTIONS (ALL GRADES) REPORTED IN = 5% OF SUBJECTS RECEIVING 8, 12, OR 24 WEEKS OF TREATMENT WITH HARVONI
HARVONI 8 WEEKS
N=215
HARVONI 12 WEEKS
N=539
HARVONI 24 WEEKS
N=326
FATIGUE
16%
13%
18%
HEADACHE
11%
14%
17%
NAUSEA
6%
7%
9%
DIARRHEA
4%
3%
7%
INSOMNIA
3%
5%
6%
LABORATORY ABNORMALITIES
BILIRUBIN ELEVATIONS: BILIRUBIN ELEVATIONS OF GREATER THAN 1.5XULN WERE OBSERVED IN 3%, < 1%, AND 2% OF SUBJECTS TREATED WITH HARVONI FOR 8, 12, AND 24 WEEKS, RESPECTIVELY.
LIPASE ELEVATIONS: TRANSIENT, ASYMPTOMATIC LIPASE ELEVATIONS OF GREATER THAN 3XULN WERE OBSERVED IN < 1%, 2%, AND 3% OF SUBJECTS TREATED WITH HARVONI FOR 8, 12, AND 24 WEEKS, RESPECTIVELY.
CREATINE KINASE: CREATINE KINASE WAS NOT ASSESSED IN PHASE 3 TRIALS OF HARVONI. ISOLATED, ASYMPTOMATIC CREATINE KINASE ELEVATIONS (GRADE 3 OR 4) HAVE BEEN PREVIOUSLY REPORTED IN SUBJECTS TREATED WITH SOFOSBUVIR IN COMBINATION WITH RIBAVIRIN OR PEGINTERFERON/RIBAVIRIN IN OTHER CLINICAL TRIALS.
POSTMARKETING EXPERIENCE
THE FOLLOWING ADVERSE REACTIONS HAVE BEEN IDENTIFIED DURING POST APPROVAL USE OF HARVONI. BECAUSE POSTMARKETING REACTIONS ARE REPORTED VOLUNTARILY FROM A POPULATION OF UNCERTAIN SIZE, IT IS NOT ALWAYS POSSIBLE TO RELIABLY ESTIMATE THEIR FREQUENCY OR ESTABLISH A CAUSAL RELATIONSHIP TO DRUG EXPOSURE.
CARDIAC DISORDERS
SERIOUS SYMPTOMATIC BRADYCARDIA HAS BEEN REPORTED IN PATIENTS TAKING AMIODARONE WHO INITIATE TREATMENT WITH HARVONI [SEE WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS]
READ THE HARVONI (LEDIPASVIR AND SOFOSBUVIR TABLETS) SIDE EFFECTS CENTER FOR A COMPLETE GUIDE TO POSSIBLE SIDE EFFECTS
OVERDOSE
NO SPECIFIC ANTIDOTE IS AVAILABLE FOR OVERDOSE WITH HARVONI. IF OVERDOSE OCCURS THE PATIENT MUST BE MONITORED FOR EVIDENCE OF TOXICITY. TREATMENT OF OVERDOSE WITH HARVONI CONSISTS OF GENERAL SUPPORTIVE MEASURES INCLUDING MONITORING OF VITAL SIGNS AS WELL AS OBSERVATION OF THE CLINICAL STATUS OF THE PATIENT. HEMODIALYSIS IS UNLIKELY TO RESULT IN SIGNIFICANT REMOVAL OF LEDIPASVIR SINCE LEDIPASVIR IS HIGHLY BOUND TO PLASMA PROTEIN. HEMODIALYSIS CAN EFFICIENTLY REMOVE THE PREDOMINANT CIRCULATING METABOLITE OF SOFOSBUVIR, GS-331007, WITH AN EXTRACTION RATIO OF 53%.
CLINICAL PHARMACOLOGY
MECHANISM OF ACTION
HARVONI IS A FIXED-DOSE COMBINATION OF LEDIPASVIR AND SOFOSBUVIR WHICH ARE DIRECT-ACTING ANTIVIRAL AGENTS AGAINST THE HEPATITIS C VIRUS [SEE MICROBIOLOGY].
PHARMACODYNAMICS
CARDIAC ELECTROPHYSIOLOGY
THOROUGH QT STUDIES HAVE BEEN CONDUCTED FOR LEDIPASVIR AND SOFOSBUVIR.
THE EFFECT OF LEDIPASVIR 120 MG TWICE DAILY (2.67 TIMES THE MAXIMUM RECOMMENDED DOSAGE) FOR 10 DAYS ON QTC INTERVAL WAS EVALUATED IN A RANDOMIZED, MULTIPLE-DOSE, PLACEBO-, AND ACTIVE-CONTROLLED (MOXIFLOXACIN 400 MG) THREE PERIOD CROSSOVER THOROUGH QT TRIAL IN 59 HEALTHY SUBJECTS. AT THE DOSE OF 120 MG TWICE DAILY (2.67 TIMES THE MAXIMUM RECOMMENDED DOSAGE), LEDIPASVIR DOES NOT PROLONG QTC INTERVAL TO ANY CLINICALLY RELEVANT EXTENT.
THE EFFECT OF SOFOSBUVIR 400 MG (MAXIMUM RECOMMENDED DOSAGE) AND 1200 MG (THREE TIMES THE MAXIMUM RECOMMENDED DOSAGE) ON QTC INTERVAL WAS EVALUATED IN A RANDOMIZED, SINGLE-DOSE, PLACEBO-, AND ACTIVE-CONTROLLED (MOXIFLOXACIN 400 MG) FOUR PERIOD CROSSOVER THOROUGH QT TRIAL IN 59 HEALTHY SUBJECTS. AT A DOSE THREE TIMES THE MAXIMUM RECOMMENDED DOSE, SOFOSBUVIR DOES NOT PROLONG QTC TO ANY CLINICALLY RELEVANT EXTENT.
PHARMACOKINETICS
ABSORPTION
THE PHARMACOKINETIC PROPERTIES OF LEDIPASVIR, SOFOSBUVIR, AND THE PREDOMINANT CIRCULATING METABOLITE GS-331007 HAVE BEEN EVALUATED IN HEALTHY ADULT SUBJECTS AND IN SUBJECTS WITH CHRONIC HEPATITIS C. FOLLOWING ORAL ADMINISTRATION OF HARVONI, LEDIPASVIR MEDIAN PEAK CONCENTRATIONS WERE OBSERVED 4 TO 4.5 HOURS POST-DOSE. SOFOSBUVIR WAS ABSORBED QUICKLY AND THE PEAK MEDIAN PLASMA CONCENTRATION WAS OBSERVED ~0.8 TO 1 HOUR POST-DOSE. MEDIAN PEAK PLASMA CONCENTRATION OF GS-331007 WAS OBSERVED BETWEEN 3.5 TO 4 HOURS POST-DOSE.
BASED ON THE POPULATION PHARMACOKINETIC ANALYSIS IN HCV-INFECTED SUBJECTS, GEOMETRIC MEAN STEADY-STATE AUC0-24 FOR LEDIPASVIR (N=2113), SOFOSBUVIR (N=1542), AND GS-331007 (N=2113) WERE 7290, 1320, AND 12,000 NG•HR/ML, RESPECTIVELY. STEADY-STATE CMAX FOR LEDIPASVIR, SOFOSBUVIR, AND GS-331007 WERE 323, 618, AND 707 NG/ML, RESPECTIVELY. SOFOSBUVIR AND GS-331007 AUC0-24 AND CMAX WERE SIMILAR IN HEALTHY ADULT SUBJECTS AND SUBJECTS WITH HCV INFECTION. RELATIVE TO HEALTHY SUBJECTS (N=191), LEDIPASVIR AUC0-24 AND CMAX WERE 24% LOWER AND 32% LOWER, RESPECTIVELY, IN HCV-INFECTED SUBJECTS.
EFFECT OF FOOD
RELATIVE TO FASTING CONDITIONS, THE ADMINISTRATION OF A SINGLE DOSE OF HARVONI WITH A MODERATE FAT (~600 KCAL, 25% TO 30% FAT) OR HIGH FAT (~1000 KCAL, 50% FAT) MEAL INCREASED SOFOSBUVIR AUC0-INF BY APPROXIMATELY 2-FOLD, BUT DID NOT SIGNIFICANTLY AFFECT SOFOSBUVIR CMAX. THE EXPOSURES OF GS-331007 AND LEDIPASVIR WERE NOT ALTERED IN THE PRESENCE OF EITHER MEAL TYPE. THE RESPONSE RATES IN PHASE 3 TRIALS WERE SIMILAR IN HCV-INFECTED SUBJECTS WHO RECEIVED HARVONI WITH FOOD OR WITHOUT FOOD. HARVONI CAN BE ADMINISTERED WITHOUT REGARD TO FOOD.
DISTRIBUTION
LEDIPASVIR IS > 99.8% BOUND TO HUMAN PLASMA PROTEINS. AFTER A SINGLE 90 MG DOSE OF [14C]-LEDIPASVIR IN HEALTHY SUBJECTS, THE BLOOD TO PLASMA RATIO OF 14C-RADIOACTIVITY RANGED BETWEEN 0.51 AND 0.66.
SOFOSBUVIR IS APPROXIMATELY 61–65% BOUND TO HUMAN PLASMA PROTEINS AND THE BINDING IS INDEPENDENT OF DRUG CONCENTRATION OVER THE RANGE OF 1 ?G/ML TO 20 ?G/ML. PROTEIN BINDING OF GS-331007 WAS MINIMAL IN HUMAN PLASMA. AFTER A SINGLE 400 MG DOSE OF [14C]-SOFOSBUVIR IN HEALTHY SUBJECTS, THE BLOOD TO PLASMA RATIO OF 14C-RADIOACTIVITY WAS APPROXIMATELY 0.7.
METABOLISM
IN VITRO, NO DETECTABLE METABOLISM OF LEDIPASVIR WAS OBSERVED BY HUMAN CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, AND CYP3A4. EVIDENCE OF SLOW OXIDATIVE METABOLISM VIA AN UNKNOWN MECHANISM HAS BEEN OBSERVED. FOLLOWING A SINGLE DOSE OF 90 MG [14C]-LEDIPASVIR, SYSTEMIC EXPOSURE WAS ALMOST EXCLUSIVELY TO THE PARENT DRUG ( > 98%). UNCHANGED LEDIPASVIR IS THE MAJOR SPECIES PRESENT IN FECES.
SOFOSBUVIR IS EXTENSIVELY METABOLIZED IN THE LIVER TO FORM THE PHARMACOLOGICALLY ACTIVE NUCLEOSIDE ANALOG TRIPHOSPHATE GS-461203. THE METABOLIC ACTIVATION PATHWAY INVOLVES SEQUENTIAL HYDROLYSIS OF THE CARBOXYL ESTER MOIETY CATALYZED BY HUMAN CATHEPSIN A (CATA) OR CARBOXYLESTERASE 1 (CES1) AND PHOSPHORAMIDATE CLEAVAGE BY HISTIDINE TRIAD NUCLEOTIDE-BINDING PROTEIN 1 (HINT1) FOLLOWED BY PHOSPHORYLATION BY THE PYRIMIDINE NUCLEOTIDE BIOSYNTHESIS PATHWAY. DEPHOSPHORYLATION RESULTS IN THE FORMATION OF NUCLEOSIDE METABOLITE GS-331007 THAT CANNOT BE EFFICIENTLY REPHOSPHORYLATED AND LACKS ANTI-HCV ACTIVITY IN VITRO. AFTER A SINGLE 400 MG ORAL DOSE OF [14C]-SOFOSBUVIR, GS-331007 ACCOUNTED FOR APPROXIMATELY > 90% OF TOTAL SYSTEMIC EXPOSURE.
ELIMINATION
FOLLOWING A SINGLE 90 MG ORAL DOSE OF [14C]-LEDIPASVIR, MEAN TOTAL RECOVERY OF THE [14C]-RADIOACTIVITY IN FECES AND URINE WAS APPROXIMATELY 87%, WITH MOST OF THE RADIOACTIVE DOSE RECOVERED FROM FECES (APPROXIMATELY 86%). UNCHANGED LEDIPASVIR EXCRETED IN FECES ACCOUNTED FOR A MEAN OF 70% OF THE ADMINISTERED DOSE AND THE OXIDATIVE METABOLITE M19 ACCOUNTED FOR 2.2% OF THE DOSE. THESE DATA INDICATE THAT BILIARY EXCRETION OF UNCHANGED LEDIPASVIR IS A MAJOR ROUTE OF ELIMINATION, WITH RENAL EXCRETION BEING A MINOR PATHWAY (APPROXIMATELY 1%). THE MEDIAN TERMINAL HALF-LIFE OF LEDIPASVIR FOLLOWING ADMINISTRATION OF HARVONI WAS 47 HOURS.
FOLLOWING A SINGLE 400 MG ORAL DOSE OF [14C]-SOFOSBUVIR, MEAN TOTAL RECOVERY OF THE DOSE WAS GREATER THAN 92%, CONSISTING OF APPROXIMATELY 80%, 14%, AND 2.5% RECOVERED IN URINE, FECES, AND EXPIRED AIR, RESPECTIVELY. THE MAJORITY OF THE SOFOSBUVIR DOSE RECOVERED IN URINE WAS GS-331007 (78%) WHILE 3.5% WAS RECOVERED AS SOFOSBUVIR. THESE DATA INDICATE THAT RENAL CLEARANCE IS THE MAJOR ELIMINATION PATHWAY FOR GS-331007. THE MEDIAN TERMINAL HALF-LIVES OF SOFOSBUVIR AND GS-331007 FOLLOWING ADMINISTRATION OF HARVONI WERE 0.5 AND 27 HOURS, RESPECTIVELY.
SPECIFIC POPULATIONS
PATIENTS WITH RENAL IMPAIRMENT: THE PHARMACOKINETICS OF LEDIPASVIR WERE STUDIED WITH A SINGLE DOSE OF 90 MG LEDIPASVIR IN HCV NEGATIVE SUBJECTS WITH SEVERE RENAL IMPAIRMENT (EGFR < 30 ML/MIN BY COCKCROFT-GAULT). NO CLINICALLY RELEVANT DIFFERENCES IN LEDIPASVIR PHARMACOKINETICS WERE OBSERVED BETWEEN HEALTHY SUBJECTS AND SUBJECTS WITH SEVERE RENAL IMPAIRMENT.
THE PHARMACOKINETICS OF SOFOSBUVIR WERE STUDIED IN HCV NEGATIVE SUBJECTS WITH MILD (EGFR = 50 AND < 80 ML/MIN/1.73M²), MODERATE (EGFR = 30 AND < 50 ML/MIN/1.73M²), SEVERE RENAL IMPAIRMENT (EGFR < 30 ML/MIN/1.73M²), AND SUBJECTS WITH ESRD REQUIRING HEMODIALYSIS FOLLOWING A SINGLE 400 MG DOSE OF SOFOSBUVIR. RELATIVE TO SUBJECTS WITH NORMAL RENAL FUNCTION (EGFR > 80 ML/MIN/1.73M²), THE SOFOSBUVIR AUC0-INF WAS 61%, 107%, AND 171% HIGHER IN MILD, MODERATE, AND SEVERE RENAL IMPAIRMENT, WHILE THE GS-331007 AUC0-INF WAS 55%, 88%, AND 451% HIGHER, RESPECTIVELY. IN SUBJECTS WITH ESRD, RELATIVE TO SUBJECTS WITH NORMAL RENAL FUNCTION, SOFOSBUVIR AND GS-331007 AUC0-INF WAS 28% AND 1280% HIGHER WHEN SOFOSBUVIR WAS DOSED 1 HOUR BEFORE HEMODIALYSIS COMPARED WITH 60% AND 2070% HIGHER WHEN SOFOSBUVIR WAS DOSED 1 HOUR AFTER HEMODIALYSIS, RESPECTIVELY. A 4 HOUR HEMODIALYSIS SESSION REMOVED APPROXIMATELY 18% OF ADMINISTERED DOSE [SEE DOSAGE AND ADMINISTRATION AND USE IN SPECIFIC POPULATIONS].
RACE: POPULATION PHARMACOKINETICS ANALYSIS IN HCV-INFECTED SUBJECTS INDICATED THAT RACE HAD NO CLINICALLY RELEVANT EFFECT ON THE EXPOSURE OF LEDIPASVIR, SOFOSBUVIR, AND GS-331007.
GENDER: POPULATION PHARMACOKINETICS ANALYSIS IN HCV-INFECTED SUBJECTS INDICATED THAT GENDER HAD NO CLINICALLY RELEVANT EFFECT ON THE EXPOSURE OF SOFOSBUVIR AND GS-331007. AUC AND CMAX OF LEDIPASVIR WERE 77% AND 58% HIGHER, RESPECTIVELY, IN FEMALES THAN MALES; HOWEVER, THE RELATIONSHIP BETWEEN GENDER AND LEDIPASVIR EXPOSURES WAS NOT CONSIDERED CLINICALLY RELEVANT, AS HIGH RESPONSE RATES (SVR > 90%) WERE ACHIEVED IN MALE AND FEMALE SUBJECTS ACROSS THE PHASE 3 STUDIES AND THE SAFETY PROFILES ARE SIMILAR IN FEMALES AND MALES.
PEDIATRIC PATIENTS: THE PHARMACOKINETICS OF LEDIPASVIR OR SOFOSBUVIR IN PEDIATRIC PATIENTS HAS NOT BEEN ESTABLISHED [SEE USE IN SPECIFIC POPULATIONS].
GERIATRIC PATIENTS: POPULATION PHARMACOKINETIC ANALYSIS IN HCV-INFECTED SUBJECTS SHOWED THAT WITHIN THE AGE RANGE (18 TO 80 YEARS) ANALYZED, AGE DID NOT HAVE A CLINICALLY RELEVANT EFFECT ON THE EXPOSURE TO LEDIPASVIR, SOFOSBUVIR, AND GS-331007 [SEE USE IN SPECIFIC POPULATIONS].
PATIENTS WITH HEPATIC IMPAIRMENT: THE PHARMACOKINETICS OF LEDIPASVIR WERE STUDIED WITH A SINGLE DOSE OF 90 MG LEDIPASVIR IN HCV NEGATIVE SUBJECTS WITH SEVERE HEPATIC IMPAIRMENT (CHILD-PUGH CLASS C). LEDIPASVIR PLASMA EXPOSURE (AUC0-INF) WAS SIMILAR IN SUBJECTS WITH SEVERE HEPATIC IMPAIRMENT AND CONTROL SUBJECTS WITH NORMAL HEPATIC FUNCTION. POPULATION PHARMACOKINETICS ANALYSIS IN HCV-INFECTED SUBJECTS INDICATED THAT CIRRHOSIS HAD NO CLINICALLY RELEVANT EFFECT ON THE EXPOSURE OF LEDIPASVIR [SEE USE IN SPECIFIC POPULATIONS].
THE PHARMACOKINETICS OF SOFOSBUVIR WERE STUDIED FOLLOWING 7-DAY DOSING OF 400 MG SOFOSBUVIR IN HCV-INFECTED SUBJECTS WITH MODERATE AND SEVERE HEPATIC IMPAIRMENT (CHILD-PUGH CLASS B AND C). RELATIVE TO SUBJECTS WITH NORMAL HEPATIC FUNCTION, THE SOFOSBUVIR AUC0-24 WERE 126% AND 143% HIGHER IN MODERATE AND SEVERE HEPATIC IMPAIRMENT, WHILE THE GS-331007 AUC0-24 WERE 18% AND 9% HIGHER, RESPECTIVELY. POPULATION PHARMACOKINETICS ANALYSIS IN HCV-INFECTED SUBJECTS INDICATED THAT CIRRHOSIS HAD NO CLINICALLY RELEVANT EFFECT ON THE EXPOSURE OF SOFOSBUVIR AND GS-331007 [SEE USE IN SPECIFIC POPULATIONS].
DRUG INTERACTION STUDIES
LEDIPASVIR AND SOFOSBUVIR ARE SUBSTRATES OF DRUG TRANSPORTERS P-GP AND BCRP WHILE GS-331007 IS NOT. P-GP INDUCERS (E.G., RIFAMPIN OR ST. JOHN'S WORT) MAY DECREASE LEDIPASVIR AND SOFOSBUVIR PLASMA CONCENTRATIONS, LEADING TO REDUCED THERAPEUTIC EFFECT OF HARVONI, AND THE USE WITH P-GP INDUCERS IS NOT RECOMMENDED WITH HARVONI [SEE WARNINGS AND PRECAUTIONS]. COADMINISTRATION WITH DRUGS THAT INHIBIT P-GP AND/OR BCRP MAY INCREASE LEDIPASVIR AND SOFOSBUVIR PLASMA CONCENTRATIONS WITHOUT INCREASING GS-331007 PLASMA CONCENTRATION; HARVONI MAY BE COADMINISTERED WITH P-GP AND/OR BCRP INHIBITORS. NEITHER LEDIPASVIR NOR SOFOSBUVIR IS A SUBSTRATE FOR HEPATIC UPTAKE TRANSPORTERS OCT1, OATP1B1, OR OATP1B3. GS-331007 IS NOT A SUBSTRATE FOR RENAL TRANSPORTERS, INCLUDING ORGANIC ANION TRANSPORTER OAT1 OR OAT3, OR ORGANIC CATION TRANSPORTER OCT2.
LEDIPASVIR IS SUBJECT TO SLOW OXIDATIVE METABOLISM VIA AN UNKNOWN MECHANISM. IN VITRO, NO DETECTABLE METABOLISM OF LEDIPASVIR BY CYP ENZYMES HAS BEEN OBSERVED. BILIARY EXCRETION OF UNCHANGED LEDIPASVIR IS A MAJOR ROUTE OF ELIMINATION. SOFOSBUVIR IS NOT A SUBSTRATE FOR CYP AND UGT1A1 ENZYMES. CLINICALLY SIGNIFICANT DRUG INTERACTIONS WITH HARVONI MEDIATED BY CYP OR UGT1A1 ENZYMES ARE NOT EXPECTED.
THE EFFECTS OF COADMINISTERED DRUGS ON THE EXPOSURE OF LEDIPASVIR, SOFOSBUVIR, AND GS-331007 ARE SHOWN IN TABLE 4 [SEE DRUG INTERACTIONS].
TABLE 4 : DRUG INTERACTIONS: CHANGES IN PHARMACOKINETIC PARAMETERS FOR LEDIPASVIR, SOFOSBUVIR, AND THE PREDOMINANT CIRCULATING METABOLITE GS-331007 IN THE PRESENCE OF THE COADMINISTERED DRUGA
NO EFFECT ON THE PHARMACOKINETIC PARAMETERS OF LEDIPASVIR, SOFOSBUVIR, AND GS-331007 WAS OBSERVED WITH THE COMBINATION OF ABACAVIR AND LAMIVUDINE, OR EMTRICITABINE, RILPIVIRINE, AND TENOFOVIR DF, OR RALTEGRAVIR.
LEDIPASVIR IS AN INHIBITOR OF DRUG TRANSPORTER P-GP AND BREAST CANCER RESISTANCE PROTEIN (BCRP) AND MAY INCREASE INTESTINAL ABSORPTION OF COADMINISTERED SUBSTRATES FOR THESE TRANSPORTERS. LEDIPASVIR IS AN INHIBITOR OF TRANSPORTERS OATP1B1, OATP1B3, AND BSEP ONLY AT CONCENTRATIONS EXCEEDING THOSE ACHIEVED IN CLINIC. LEDIPASVIR IS NOT AN INHIBITOR OF TRANSPORTERS MRP2, MRP4, OCT2, OAT1, OAT3, MATE1, AND OCT1. THE DRUG-DRUG INTERACTION POTENTIAL OF LEDIPASVIR IS PRIMARILY LIMITED TO THE INTESTINAL INHIBITION OF P-GP AND BCRP. CLINICALLY RELEVANT TRANSPORTER INHIBITION BY LEDIPASVIR IN THE SYSTEMIC CIRCULATION IS NOT EXPECTED DUE TO ITS HIGH PROTEIN BINDING. SOFOSBUVIR AND GS-331007 ARE NOT INHIBITORS OF DRUG TRANSPORTERS P-GP, BCRP, MRP2, BSEP, OATP1B1, OATP1B3, AND OCT1, AND GS-331007 IS NOT AN INHIBITOR OF OAT1, OCT2, AND MATE1. LEDIPASVIR, SOFOSBUVIR, AND GS-331007 ARE NOT INHIBITORS OR INDUCERS OF CYP OR UGT1A1 ENZYMES.
THE EFFECTS OF LEDIPASVIR OR SOFOSBUVIR ON THE EXPOSURE OF COADMINISTERED DRUGS ARE SHOWN IN TABLE 5 [SEE DRUG INTERACTIONS].
TABLE 5 : DRUG INTERACTIONS: CHANGES IN PHARMACOKINETIC PARAMETERS FOR COADMINISTERED DRUG IN THE PRESENCE OF LEDIPASVIR, SOFOSBUVIR, OR HARVONIA
NO EFFECT ON THE PHARMACOKINETIC PARAMETERS OF THE FOLLOWING COADMINISTERED DRUGS WAS OBSERVED WITH LEDIPASVIR OR SOFOSBUVIR: ABACAVIR, CYCLOSPORINE, DARUNAVIR/RITONAVIR, EFAVIRENZ, EMTRICITABINE, LAMIVUDINE, METHADONE, OR RILPIVIRINE.
MICROBIOLOGY
MECHANISM OF ACTION
LEDIPASVIR IS AN INHIBITOR OF THE HCV NS5A PROTEIN, WHICH IS REQUIRED FOR VIRAL REPLICATION. RESISTANCE SELECTION IN CELL CULTURE AND CROSS-RESISTANCE STUDIES INDICATE LEDIPASVIR TARGETS NS5A AS ITS MODE OF ACTION.
SOFOSBUVIR IS AN INHIBITOR OF THE HCV NS5B RNA-DEPENDENT RNA POLYMERASE, WHICH IS REQUIRED FOR VIRAL REPLICATION. SOFOSBUVIR IS A NUCLEOTIDE PRODRUG THAT UNDERGOES INTRACELLULAR METABOLISM TO FORM THE PHARMACOLOGICALLY ACTIVE URIDINE ANALOG TRIPHOSPHATE (GS-461203), WHICH CAN BE INCORPORATED INTO HCV RNA BY THE NS5B POLYMERASE AND ACTS AS A CHAIN TERMINATOR. IN A BIOCHEMICAL ASSAY, GS-461203 INHIBITED THE POLYMERASE ACTIVITY OF THE RECOMBINANT NS5B FROM HCV GENOTYPES 1B, 2A, 3A AND 4A WITH IC50 VALUES RANGING FROM 0.7 TO 2.6 ?M. GS-461203 IS NEITHER AN INHIBITOR OF HUMAN DNA AND RNA POLYMERASES NOR AN INHIBITOR OF MITOCHONDRIAL RNA POLYMERASE.
ANTIVIRAL ACTIVITY
IN HCV REPLICON ASSAYS, THE EC50 VALUES OF LEDIPASVIR AGAINST FULL-LENGTH REPLICONS FROM GENOTYPES 1A AND 1B WERE 0.031 NM AND 0.004 NM, RESPECTIVELY. THE MEDIAN EC50 VALUES OF LEDIPASVIR AGAINST CHIMERIC REPLICONS ENCODING NS5A SEQUENCES FROM CLINICAL ISOLATES WERE 0.018 NM FOR GENOTYPE 1A (RANGE 0.009–0.085 NM; N=30) AND 0.006 NM FOR GENOTYPE 1B (RANGE 0.004–0.007 NM; N=3). LEDIPASVIR HAS LESS ANTIVIRAL ACTIVITY COMPARED TO GENOTYPE 1 AGAINST GENOTYPES 4A, 5A, AND 6A, WITH EC50 VALUES OF 0.39 NM, 0.15 NM, AND 1.1 NM, RESPECTIVELY. LEDIPASVIR HAS SUBSTANTIALLY LOWER ACTIVITY AGAINST GENOTYPES 2A, 2B, 3A, AND 6E WITH EC50 VALUES OF 21–249 NM, 16–530 NM, 168 NM, AND 264 NM, RESPECTIVELY.
IN HCV REPLICON ASSAYS, THE EC50 VALUES OF SOFOSBUVIR AGAINST FULL-LENGTH REPLICONS FROM GENOTYPES 1A, 1B, 2A, 3A, AND 4A, AND CHIMERIC 1B REPLICONS ENCODING NS5B FROM GENOTYPES 2B, 5A, OR 6A RANGED FROM 14–110 NM. THE MEDIAN EC50 VALUE OF SOFOSBUVIR AGAINST CHIMERIC REPLICONS ENCODING NS5B SEQUENCES FROM CLINICAL ISOLATES WAS 62 NM FOR GENOTYPE 1A (RANGE 29–128 NM; N=67), 102 NM FOR GENOTYPE 1B (RANGE 45–170 NM; N=29), 29 NM FOR GENOTYPE 2 (RANGE 14–81 NM; N=15), AND 81 NM FOR GENOTYPE 3A (RANGE 24–181 NM; N=106). IN REPLICATION COMPETENT VIRUS ASSAYS, THE EC50 VALUES OF SOFOSBUVIR AGAINST GENOTYPES 1A AND 2A WERE 30 NM AND 20 NM, RESPECTIVELY. EVALUATION OF SOFOSBUVIR IN COMBINATION WITH LEDIPASVIR SHOWED NO ANTAGONISTIC EFFECT IN REDUCING HCV RNA LEVELS IN REPLICON CELLS.
RESISTANCE
IN CELL CULTURE
HCV REPLICONS WITH REDUCED SUSCEPTIBILITY TO LEDIPASVIR HAVE BEEN SELECTED IN CELL CULTURE FOR GENOTYPES 1A AND 1B. REDUCED SUSCEPTIBILITY TO LEDIPASVIR WAS ASSOCIATED WITH THE PRIMARY NS5A AMINO ACID SUBSTITUTION Y93H IN BOTH GENOTYPES 1A AND 1B. ADDITIONALLY, A Q30E SUBSTITUTION EMERGED IN GENOTYPE 1A REPLICONS. SITE-DIRECTED MUTAGENESIS OF THE Y93H IN BOTH GENOTYPES 1A AND 1B, AS WELL AS THE Q30E SUBSTITUTION IN GENOTYPE 1A, CONFERRED HIGH LEVELS OF REDUCED SUSCEPTIBILITY TO LEDIPASVIR (FOLD CHANGE IN EC50 GREATER THAN 1000-FOLD). HCV REPLICONS WITH REDUCED SUSCEPTIBILITY TO SOFOSBUVIR HAVE BEEN SELECTED IN CELL CULTURE FOR MULTIPLE GENOTYPES INCLUDING 1B, 2A, 2B, 3A, 4A, 5A, AND 6A. REDUCED SUSCEPTIBILITY TO SOFOSBUVIR WAS ASSOCIATED WITH THE PRIMARY NS5B SUBSTITUTION S282T IN ALL REPLICON GENOTYPES EXAMINED. SITE-DIRECTED MUTAGENESIS OF THE S282T SUBSTITUTION IN REPLICONS OF 8 GENOTYPES CONFERRED 2-TO 18-FOLD REDUCED SUSCEPTIBILITY TO SOFOSBUVIR.
IN CLINICAL TRIALS
IN A POOLED ANALYSIS OF SUBJECTS WHO RECEIVED HARVONI IN PHASE 3 TRIALS, 37 SUBJECTS (29 WITH GENOTYPE 1A AND 8 WITH GENOTYPE 1B) QUALIFIED FOR RESISTANCE ANALYSIS DUE TO VIROLOGIC FAILURE (35 WITH VIROLOGIC RELAPSE, 2 WITH BREAKTHROUGH ON-TREATMENT DUE TO DOCUMENTED NON-ADHERENCE). POST-BASELINE NS5A AND NS5B DEEP SEQUENCING DATA (ASSAY CUTOFF OF 1%) WERE AVAILABLE FOR 37/37 AND 36/37 SUBJECTS' VIRUSES, RESPECTIVELY.
OF THE 29 GENOTYPE 1A VIROLOGIC FAILURE SUBJECTS, 55% (16/29) OF SUBJECTS HAD VIRUS WITH EMERGENT NS5A RESISTANCE-ASSOCIATED SUBSTITUTIONS K24R, M28T/V, Q30R/H/K/L, L31M, OR Y93H/N AT FAILURE. FIVE OF THESE 16 SUBJECTS ALSO HAD BASELINE NS5A POLYMORPHISMS AT RESISTANCE-ASSOCIATED AMINO ACID POSITIONS. THE MOST COMMON SUBSTITUTIONS DETECTED AT FAILURE WERE Q30R, Y93H OR N, AND L31M.
OF THE 8 GENOTYPE 1B VIROLOGIC FAILURE SUBJECTS, 88% (7/8) HAD VIRUS WITH EMERGENT NS5A RESISTANCE-ASSOCIATED SUBSTITUTIONS L31V/M/I OR Y93H AT FAILURE. THREE OF THESE 7 SUBJECTS ALSO HAD BASELINE NS5A POLYMORPHISMS AT RESISTANCE-ASSOCIATED POSITIONS. THE MOST COMMON SUBSTITUTION DETECTED AT FAILURE WAS Y93H.
AT FAILURE, 38% (14/37) OF VIROLOGIC FAILURE SUBJECTS HAD 2 OR MORE NS5A SUBSTITUTIONS AT RESISTANCE-ASSOCIATED POSITIONS.
IN PHENOTYPIC ANALYSES, POST-BASELINE ISOLATES FROM SUBJECTS WHO HARBORED NS5A RESISTANCE-ASSOCIATED SUBSTITUTIONS AT FAILURE SHOWED 20-TO > 243-FOLD REDUCED SUSCEPTIBILITY TO LEDIPASVIR.
TREATMENT-EMERGENT NS5B SUBSTITUTIONS L159 (N=1) AND V321 (N=2) PREVIOUSLY ASSOCIATED WITH SOFOSBUVIR FAILURE WERE DETECTED IN THE PHASE 3 TRIALS. IN ADDITION, NS5B SUBSTITUTIONS AT HIGHLY CONSERVED POSITIONS D61G (N=3), A112T (N=2), E237G (N=2), AND S473T (N=1) WERE DETECTED AT LOW FREQUENCY BY NEXT GENERATION SEQUENCING IN TREATMENT FAILURE SUBJECTS INFECTED WITH HCV GT1A. THE D61G SUBSTITUTION WAS PREVIOUSLY DESCRIBED IN SUBJECTS INFECTED WITH HCV GT1A IN A LIVER PRE-TRANSPLANT TRIAL. THE CLINICAL SIGNIFICANCE OF THESE SUBSTITUTIONS IS CURRENTLY UNKNOWN.
THE SOFOSBUVIR-ASSOCIATED RESISTANCE SUBSTITUTION S282T IN NS5B WAS NOT DETECTED IN ANY FAILURE ISOLATE FROM THE PHASE 3 TRIALS. NS5B SUBSTITUTIONS S282T, L320V/I, AND V321I IN COMBINATION WITH NS5A SUBSTITUTIONS L31M, Y93H, AND Q30L WERE DETECTED IN ONE SUBJECT AT FAILURE FOLLOWING 8 WEEKS OF TREATMENT WITH HARVONI IN A PHASE 2 TRIAL.
CROSS RESISTANCE
LEDIPASVIR WAS FULLY ACTIVE AGAINST THE SOFOSBUVIR RESISTANCE-ASSOCIATED SUBSTITUTION S282T IN NS5B WHILE ALL LEDIPASVIR RESISTANCE-ASSOCIATED SUBSTITUTIONS IN NS5A WERE FULLY SUSCEPTIBLE TO SOFOSBUVIR. BOTH SOFOSBUVIR AND LEDIPASVIR WERE FULLY ACTIVE AGAINST SUBSTITUTIONS ASSOCIATED WITH RESISTANCE TO OTHER CLASSES OF DIRECT-ACTING ANTIVIRALS WITH DIFFERENT MECHANISMS OF ACTIONS, SUCH AS NS5B NON-NUCLEOSIDE INHIBITORS AND NS3 PROTEASE INHIBITORS. NS5A SUBSTITUTIONS CONFERRING RESISTANCE TO LEDIPASVIR MAY REDUCE THE ANTIVIRAL ACTIVITY OF OTHER NS5A INHIBITORS. THE EFFICACY OF LEDIPASVIR/SOFOSBUVIR HAS NOT BEEN ESTABLISHED IN PATIENTS WHO HAVE PREVIOUSLY FAILED TREATMENT WITH OTHER REGIMENS THAT INCLUDE AN NS5A INHIBITOR.
PERSISTENCE OF RESISTANCE-ASSOCIATED SUBSTITUTIONS
NO DATA ARE AVAILABLE ON THE PERSISTENCE OF LEDIPASVIR OR SOFOSBUVIR RESISTANCE-ASSOCIATED SUBSTITUTIONS. NS5A RESISTANCE-ASSOCIATED SUBSTITUTIONS FOR OTHER NS5A INHIBITORS HAVE BEEN FOUND TO PERSIST FOR > 1 YEAR IN SOME PATIENTS.
EFFECT OF BASELINE HCV POLYMORPHISMS ON TREATMENT RESPONSE
ANALYSES WERE CONDUCTED TO EXPLORE THE ASSOCIATION BETWEEN PRE-EXISTING BASELINE NS5A POLYMORPHISMS AT RESISTANCE-ASSOCIATED POSITIONS AND RELAPSE RATES. IN THE POOLED ANALYSIS OF THE PHASE 3 TRIALS, 23% (370/1589) OF SUBJECTS' VIRUS HAD BASELINE NS5A POLYMORPHISMS AT RESISTANCE-ASSOCIATED POSITIONS (ANY CHANGE FROM REFERENCE AT NS5A AMINO ACID POSITIONS 24, 28, 30, 31, 58, 92, OR 93) IDENTIFIED BY POPULATION OR DEEP SEQUENCING.
IN TREATMENT-NAÏVE SUBJECTS WHOSE VIRUS HAD BASELINE NS5A POLYMORPHISMS AT RESISTANCE-ASSOCIATED POSITIONS IN STUDIES ION-1 AND ION-3, RELAPSE RATES WERE 6% (3/48) AFTER 8 WEEKS AND 1% (1/113) AFTER 12 WEEKS OF TREATMENT WITH HARVONI. RELAPSE RATES AMONG SUBJECTS WITHOUT BASELINE NS5A POLYMORPHISMS AT RESISTANCE-ASSOCIATED POSITIONS WERE 5% (8/167) AFTER 8 WEEKS AND 1% (3/306) AFTER 12 WEEKS TREATMENT WITH HARVONI.
IN TREATMENT-EXPERIENCED SUBJECTS WHOSE VIRUS HAD BASELINE NS5A POLYMORPHISMS AT RESISTANCE-ASSOCIATED POSITIONS, RELAPSE RATES WERE 22% (5/23) AFTER 12 WEEKS AND 0% (0/19) AFTER 24 WEEKS OF TREATMENT WITH HARVONI.
THE SPECIFIC BASELINE NS5A RESISTANCE-ASSOCIATED POLYMORPHISMS OBSERVED AMONG SUBJECTS WITH RELAPSE WERE M28T/V, Q30H, Q30R, L31M, H58P, Y93H, AND Y93N IN GENOTYPE 1A, AND L28M, A92T, AND Y93H IN GENOTYPE 1B. SUBJECTS WITH MULTIPLE NS5A POLYMORPHISMS AT RESISTANCE-ASSOCIATED POSITIONS APPEARED TO HAVE HIGHER RELAPSE RATES.
SVR WAS ACHIEVED IN ALL 24 SUBJECTS (N=20 WITH L159F+C316N; N=1 WITH L159F; AND N=3 WITH N142T) WHO HAD BASELINE POLYMORPHISMS ASSOCIATED WITH RESISTANCE TO NS5B NUCLEOSIDE INHIBITORS. THE SOFOSBUVIR RESISTANCE-ASSOCIATED SUBSTITUTION S282T WAS NOT DETECTED IN THE BASELINE NS5B SEQUENCE OF ANY SUBJECT IN PHASE 3 TRIALS BY POPULATION OR DEEP SEQUENCING.
ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY
SOFOSBUVIR: HEART DEGENERATION AND INFLAMMATION WERE OBSERVED IN RATS FOLLOWING GS-9851 (A STEREOISOMERIC MIXTURE CONTAINING APPROXIMATELY 50% SOFOSBUVIR) DOSES OF 2,000 MG/KG/DAY FOR UP TO 5 DAYS. AT THIS DOSE, AUC EXPOSURE TO THE PREDOMINANT CIRCULATING METABOLITE GS-331007 IS APPROXIMATELY 17-FOLD HIGHER THAN HUMAN EXPOSURE AT THE RECOMMENDED CLINICAL DOSE. NO HEART DEGENERATION OR INFLAMMATION WAS OBSERVED IN MICE, RATS, OR DOGS IN STUDIES UP TO 3 MONTHS, 6 MONTHS, OR 9 MONTHS AT GS-331007
AUC EXPOSURES APPROXIMATELY 24-, 5-, OR 17-FOLD HIGHER, RESPECTIVELY, THAN HUMAN EXPOSURE AT THE RECOMMENDED CLINICAL DOSE. IN ADDITION, NO HEART DEGENERATION OR INFLAMMATION WAS OBSERVED IN RATS FOLLOWING SOFOSBUVIR DOSES OF UP TO 750 MG/KG/DAY IN THE 2-YEAR CARCINOGENICITY STUDY AT GS-331007 AUC EXPOSURE APPROXIMATELY 9-FOLD THE EXPOSURE IN HUMANS AT THE RECOMMENDED CLINICAL DOSE.
CLINICAL STUDIES
OVERVIEW OF CLINICAL TRIALS
THE EFFICACY OF HARVONI WAS EVALUATED IN THREE PHASE 3 TRIALS OF 1518 SUBJECTS WITH GENOTYPE 1 CHRONIC HEPATITIS C (CHC) WITH COMPENSATED LIVER DISEASE:
STUDY ION-3: NONCIRRHOTIC TREATMENT-NAÏVE SUBJECTS [SEE CLINICAL TRIALS IN TREATMENT-NAÏVE SUBJECTS],
STUDY ION-1: CIRRHOTIC AND NONCIRRHOTIC TREATMENT-NAÏVE SUBJECTS [SEE CLINICAL TRIALS IN TREATMENT-NAÏVE SUBJECTS], AND
STUDY ION-2: CIRRHOTIC AND NONCIRRHOTIC SUBJECTS WHO FAILED PRIOR THERAPY WITH AN INTERFERON-BASED REGIMEN, INCLUDING REGIMENS CONTAINING AN HCV PROTEASE INHIBITOR [SEE CLINICAL TRIALS IN SUBJECTS WHO FAILED PRIOR THERAPY].
ALL THREE PHASE 3 TRIALS EVALUATED EFFICACY OF HARVONI (ONE FIXED-DOSE TABLET OF 90 MG OF LEDIPASVIR AND 400 MG OF SOFOSBUVIR ADMINISTERED ONCE DAILY) WITH OR WITHOUT RIBAVIRIN. TREATMENT DURATION WAS FIXED IN EACH TRIAL. SERUM HCV RNA VALUES WERE MEASURED DURING THE CLINICAL TRIALS USING THE COBAS TAQMAN HCV TEST (VERSION 2.0), FOR USE WITH THE HIGH PURE SYSTEM. THE ASSAY HAD A LOWER LIMIT OF QUANTIFICATION (LLOQ) OF 25 IU/ML.
SUSTAINED VIROLOGIC RESPONSE (SVR) WAS THE PRIMARY ENDPOINT AND WAS DEFINED AS HCV RNA LESS THAN LLOQ AT 12 WEEKS AFTER THE CESSATION OF TREATMENT. RELAPSE WAS A SECONDARY ENDPOINT, WHICH WAS DEFINED AS HCV RNA GREATER THAN OR EQUAL TO LLOQ WITH 2 CONSECUTIVE VALUES OR LAST AVAILABLE POST-TREATMENT MEASUREMENT DURING THE POST-TREATMENT PERIOD AFTER ACHIEVING HCV RNA LESS THAN LLOQ AT END OF TREATMENT.
CLINICAL TRIALS IN TREATMENT-NAÏVE SUBJECTS
TREATMENT-NAÏVE ADULTS WITHOUT CIRRHOSIS
ION-3 (STUDY 0108) ION-3 WAS A RANDOMIZED, OPEN-LABEL TRIAL IN TREATMENT-NAÏVE NON-CIRRHOTIC SUBJECTS WITH GENOTYPE 1 CHC. SUBJECTS WERE RANDOMIZED IN A 1:1:1 RATIO TO ONE OF THE FOLLOWING THREE TREATMENT GROUPS AND STRATIFIED BY HCV GENOTYPE (1A VS 1B): HARVONI FOR 8 WEEKS, HARVONI FOR 12 WEEKS, OR HARVONI + RIBAVIRIN FOR 8 WEEKS.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS WERE BALANCED ACROSS THE TREATMENT GROUPS. OF THE 647 TREATED SUBJECTS, THE MEDIAN AGE WAS 55 YEARS (RANGE: 20 TO 75); 58% OF THE SUBJECTS WERE MALE; 78% WERE WHITE; 19% WERE BLACK; 6% WERE HISPANIC OR LATINO; MEAN BODY MASS INDEX WAS 28 KG/M² (RANGE: 18 TO 56 KG/M²); 81% HAD BASELINE HCV RNA LEVELS GREATER THAN OR EQUAL TO 800,000 IU/ML; 80% HAD GENOTYPE 1A HCV INFECTION; 73% HAD NON-C/C IL28B ALLELES (CT OR TT).
TABLE 6 PRESENTS THE RESPONSE RATES FOR THE HARVONI TREATMENT GROUPS IN THE ION-3 TRIAL AFTER 8 AND 12 WEEKS OF HARVONI TREATMENT. RIBAVIRIN WAS NOT SHOWN TO INCREASE THE RESPONSE RATES OBSERVED WITH HARVONI. THEREFORE, THE HARVONI + RIBAVIRIN ARM IS NOT PRESENTED IN TABLE 6.
TABLE 6 : STUDY ION-3: RESPONSE RATES AFTER 8 AND 12 WEEKS OF TREATMENT IN TREATMENT-NAÏVE NON-CIRRHOTIC SUBJECTS WITH GENOTYPE 1 CHC
HARVONI 8 WEEKS
(N=215)
HARVONI 12 WEEKS
(N=216)
SVR
94% (202/215)
96% (208/216)
OUTCOME FOR SUBJECTS WITHOUT SVR
ON-TREATMENT VIROLOGIC FAILURE
0/215
0/216
RELAPSEA
5% (11/215)
1% (3/216)
OTHERB
1% (2/215)
2% (5/216)
SVR BY GENOTYPEC
GENOTYPE 1A
93% (159/171)
96% (165/172)
GENOTYPE 1B
98% (42/43)
98% (43/44)
A THE DENOMINATOR FOR RELAPSE IS THE NUMBER OF SUBJECTS WITH HCV RNA < LLOQ AT THEIR LAST ON-TREATMENT ASSESSMENT.
B OTHER INCLUDES SUBJECTS WHO DID NOT ACHIEVE SVR AND DID NOT MEET VIROLOGIC FAILURE CRITERIA (E.G., LOST TO FOLLOW-UP).
C ONE SUBJECT WITHOUT A CONFIRMED SUBTYPE FOR GENOTYPE 1 INFECTION WAS EXCLUDED FROM THIS SUBGROUP ANALYSIS.
THE TREATMENT DIFFERENCE BETWEEN THE 8-WEEK TREATMENT OF HARVONI AND 12-WEEK TREATMENT OF HARVONI WAS –2.3% (97.5% CONFIDENCE INTERVAL –7.2% TO 2.5%). AMONG SUBJECTS WITH A BASELINE HCV RNA < 6 MILLION IU/ML, THE SVR WAS 97% (119/123) WITH 8-WEEK TREATMENT OF HARVONI AND 96% (126/131) WITH 12-WEEK TREATMENT OF HARVONI.
RELAPSE RATES BY BASELINE VIRAL LOAD ARE PRESENTED IN TABLE 7.
TABLE 7 : STUDY ION-3: RELAPSE RATES BY BASELINE VIRAL LOAD AFTER 8 AND 12 WEEKS OF TREATMENT IN TREATMENT-NAÏVE NON-CIRRHOTIC SUBJECTS WITH GENOTYPE 1 CHC
HARVONI 8 WEEKS
(N=215)
HARVONI 12 WEEKS
(N=216)
NUMBER OF RESPONDERS AT END OF T REATMENT
215
216
BASELINE HCV RNAA
HCV RNA < 6 MILLION IU/ML
2% (2/123)
2% (2/131)
HCV RNA = 6 MILLION IU/ML
10% (9/92)
1% (1/85)
A HCV RNA VALUES WERE DETERMINED USING THE ROCHE TAQMAN ASSAY; A SUBJECT'S HCV RNA MAY VARY FROM VISIT TO VISIT.
TREATMENT-NAÏVE ADULTS WITH OR WITHOUT CIRRHOSIS - ION-1 (STUDY 0102)
ION-1 WAS A RANDOMIZED, OPEN-LABEL TRIAL THAT EVALUATED 12 AND 24 WEEKS OF TREATMENT WITH HARVONI WITH OR WITHOUT RIBAVIRIN IN 865 TREATMENT-NAÏVE SUBJECTS WITH GENOTYPE 1 CHC INCLUDING THOSE WITH CIRRHOSIS. SUBJECTS WERE RANDOMIZED IN A 1:1:1:1 RATIO TO RECEIVE HARVONI FOR 12 WEEKS, HARVONI + RIBAVIRIN FOR 12 WEEKS, HARVONI FOR 24 WEEKS, OR HARVONI + RIBAVIRIN FOR 24 WEEKS. RANDOMIZATION WAS STRATIFIED BY THE PRESENCE OR ABSENCE OF CIRRHOSIS AND HCV GENOTYPE (1A VS 1B). THE INTERIM PRIMARY ENDPOINT ANALYSIS FOR SVR INCLUDED ALL SUBJECTS ENROLLED IN THE 12-WEEK TREATMENT GROUPS (N=431). SVR RATES FOR ALL SUBJECTS ENROLLED IN THE 24-WEEK TREATMENT GROUPS (N=434) WERE NOT AVAILABLE AT THE TIME OF INTERIM ANALYSIS.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS WERE BALANCED ACROSS THE TREATMENT GROUPS. OF THE 865 TREATED SUBJECTS, THE MEDIAN AGE WAS 54 YEARS (RANGE: 18 TO 80); 59% OF THE SUBJECTS WERE MALE; 85% WERE WHITE; 12% WERE BLACK; 12% WERE HISPANIC OR LATINO; MEAN BODY MASS INDEX WAS 27 KG/M² (RANGE: 18 TO 48 KG/M²); 79% HAD BASELINE HCV RNA LEVELS GREATER THAN OR EQUAL TO 800,000 IU/ML; 67% HAD GENOTYPE 1A HCV INFECTION; 70% HAD NON-C/C IL28B ALLELES (CT OR TT); AND 16% HAD CIRRHOSIS.
TABLE 8 PRESENTS THE RESPONSE RATES FOR THE TREATMENT GROUP OF HARVONI FOR 12 WEEKS IN THE ION-1 TRIAL. RIBAVIRIN WAS NOT SHOWN TO INCREASE RESPONSE RATES OBSERVED WITH HARVONI. THEREFORE, THE HARVONI + RIBAVIRIN ARM IS NOT PRESENTED IN TABLE 8.
TABLE 8 : STUDY ION-1: RESPONSE RATES AFTER 12 WEEKS OF TREATMENT IN TREATMENT-NAÏVE SUBJECTS WITH GENOTYPE 1 CHC WITH AND WITHOUT CIRRHOSIS
HARVONI 12 WEEKS
(N=214)
SVRA
99% (210/213)
OUTCOME FOR SUBJECTS WITHOUT SVR
ON-TREATMENT VIROLOGIC FAILUREA
0/213
RELAPSEA,B
< 1% (1/212)
OTHERA,C
1% (2/213)
A EXCLUDING ONE SUBJECT WITH GENOTYPE 4 INFECTION.
B THE DENOMINATOR FOR RELAPSE IS THE NUMBER OF SUBJECTS WITH HCV RNA < LLOQ AT THEIR LAST ON-TREATMENT ASSESSMENT.
C OTHER INCLUDES SUBJECTS WHO DID NOT ACHIEVE SVR AND DID NOT MEET VIROLOGIC FAILURE CRITERIA (E.G., LOST TO FOLLOW-UP).
RESPONSE RATES FOR SELECTED SUBGROUPS ARE PRESENTED IN TABLE 9.
TABLE 9 : STUDY ION-1: SVR RATES FOR SELECTED SUBGROUPS AFTER 12 WEEKS OF TREATMENT IN TREATMENT-NAÏVE SUBJECTS WITH GENOTYPE 1 CHC WITH AND WITHOUT CIRRHOSIS
HARVONI 12 WEEKS
(N=214)
GENOTYPEA
GENOTYPE 1A
98% (142/145)
GENOTYPE 1B
100% (67/67)
CIRRHOSISB
NO
99% (176/177)
YES
94% (32/34)
A ONE SUBJECT WITHOUT A CONFIRMED SUBTYPE FOR GENOTYPE 1 INFECTION AND ONE SUBJECT WITH GENOTYPE 4 INFECTION WERE EXCLUDED FROM THIS SUBGROUP ANALYSIS.
B SUBJECTS WITH MISSING CIRRHOSIS STATUS WERE EXCLUDED FROM THIS SUBGROUP ANALYSIS.
CLINICAL TRIALS IN SUBJECTS WHO FAILED PRIOR THERAPY
PREVIOUSLY-TREATED ADULTS WITH OR WITHOUT CIRRHOSIS
ION-2 (STUDY 0109) ION-2 WAS A RANDOMIZED, OPEN-LABEL TRIAL THAT EVALUATED 12 AND 24 WEEKS OF TREATMENT WITH HARVONI WITH OR WITHOUT RIBAVIRIN IN GENOTYPE 1 HCV-INFECTED SUBJECTS WITH OR WITHOUT CIRRHOSIS WHO FAILED PRIOR THERAPY WITH AN INTERFERON-BASED REGIMEN, INCLUDING REGIMENS CONTAINING AN HCV PROTEASE INHIBITOR. SUBJECTS WERE RANDOMIZED IN A 1:1:1:1 RATIO TO RECEIVE HARVONI FOR 12 WEEKS, HARVONI + RIBAVIRIN FOR 12 WEEKS, HARVONI FOR 24 WEEKS, OR HARVONI + RIBAVIRIN FOR 24 WEEKS. RANDOMIZATION WAS STRATIFIED BY THE PRESENCE OR ABSENCE OF CIRRHOSIS, HCV GENOTYPE (1A VS 1B) AND RESPONSE TO PRIOR HCV THERAPY (RELAPSE/BREAKTHROUGH VS NONRESPONSE).
DEMOGRAPHICS AND BASELINE CHARACTERISTICS WERE BALANCED ACROSS THE TREATMENT GROUPS. OF THE 440 TREATED SUBJECTS, THE MEDIAN AGE WAS 57 YEARS (RANGE: 24 TO 75); 65% OF THE SUBJECTS WERE MALE; 81% WERE WHITE; 18% WERE BLACK; 9% WERE HISPANIC OR LATINO; MEAN BODY MASS INDEX WAS 28 KG/M² (RANGE: 19 TO 50 KG/M²); 89% HAD BASELINE HCV RNA LEVELS GREATER THAN OR EQUAL TO 800,000 IU/ML; 79% HAD GENOTYPE 1A HCV INFECTION; 88% HAD NON-C/C IL28B ALLELES (CT OR TT); AND 20% HAD CIRRHOSIS. FORTY-SEVEN PERCENT (47%) OF THE SUBJECTS FAILED A PRIOR THERAPY OF PEGYLATED INTERFERON AND RIBAVIRIN. AMONG THESE SUBJECTS, 49% WERE RELAPSE/BREAKTHROUGH AND 51% WERE NON-RESPONDER. FIFTY-THREE PERCENT (53%) OF THE SUBJECTS FAILED A PRIOR THERAPY OF PEGYLATED INTERFERON AND RIBAVIRIN WITH AN HCV PROTEASE INHIBITOR. AMONG THESE SUBJECTS, 62% WERE RELAPSE/BREAKTHROUGH AND 38% WERE NON-RESPONDER.
TABLE 10 PRESENTS THE RESPONSE RATES FOR THE HARVONI TREATMENT GROUPS IN THE ION-2 TRIAL. RIBAVIRIN WAS NOT SHOWN TO INCREASE RESPONSE RATES OBSERVED WITH HARVONI. THEREFORE, THE HARVONI + RIBAVIRIN ARMS ARE NOT PRESENTED IN TABLE 10.
TABLE 10 : STUDY ION-2: RESPONSE RATES AFTER 12 AND 24 WEEKS OF TREATMENT IN SUBJECTS WITH GENOTYPE 1 CHC WITH OR WITHOUT CIRRHOSIS WHO FAILED PRIOR THERAPY
HARVONI 12 WEEKS
(N=109)
HARVONI 24 WEEKS
(N=109)
SVR
94% (102/109)
99% (108/109)
OUTCOME FOR SUBJECTS WITHOUT SVR
ON-TREATMENT VIROLOGIC FAILURE
0/109
0/109
RELAPSEA
6% (7/108)
0/109
OTHERB
0/109
1% (1/109)
A THE DENOMINATOR FOR RELAPSE IS THE NUMBER OF SUBJECTS WITH HCV RNA < LLOQ AT THEIR LAST ON-TREATMENT ASSESSMENT.
B OTHER INCLUDES SUBJECTS WHO DID NOT ACHIEVE SVR AND DID NOT MEET VIROLOGIC FAILURE CRITERIA (E.G., LOST TO FOLLOW-UP).
AMONG THE SUBJECTS WITH AVAILABLE SVR12 AND SVR24 DATA (206/218), ALL SUBJECTS WHO ACHIEVED SVR12 IN THE ION-2 STUDY ALSO ACHIEVED SVR24.
RESPONSE RATES AND RELAPSE RATES FOR SELECTED SUBGROUPS ARE PRESENTED IN TABLES 11 AND 12.
TABLE 11 : STUDY ION-2: SVR RATES FOR SELECTED SUBGROUPS AFTER 12 AND 24 WEEKS OF TREATMENT IN SUBJECTS WITH GENOTYPE 1 CHC WHO FAILED PRIOR THERAPY
HARVONI 12 WEEKS
(N=109)
HARVONI 24 WEEKS
(N=109)
GENOTYPE
GENOTYPE 1A
95% (82/86)
99% (84/85)
GENOTYPE 1B
87% (20/23)
100% (24/24)
CIRRHOSISA
NO
95% (83/87)
99% (85/86)
YES
86% (19/22)
100% (22/22)
PRIOR HCV THERAPY
PEG-IFN + RBV
93% (40/43)
100% (58/58)
HCV PROTEASE INHIBITOR + PEG-IFN + RBV
94% (62/66)
98% (49/50)
RESPONSE TO PRIOR HCV THERAPY
RELAPSE/BREAKTHROUGH
95% (57/60)
100% (60/60)
NONRESPONDER
92% (45/49)
98% (48/49)
A SUBJECTS WITH MISSING CIRRHOSIS STATUS WERE EXCLUDED FROM THIS SUBGROUP ANALYSIS.
TABLE 12 : STUDY ION-2: RELAPSE RATES FOR SELECTED SUBGROUPS AFTER 12 AND 24 WEEKS OF TREATMENT IN SUBJECTS WITH GENOTYPE 1 CHC WHO FAILED PRIOR THERAPY
HARVONI 12 WEEKS
(N=109)
HARVONI 24 WEEKS
(N=109)
NUMBER OF RESPONDERS AT END OF T REATMENT
108
109
CIRRHOSISA
NO
5% (4/86)B
0% (0/86)
YES
14% (3/22)
0% (0/22)
PRESENCE OF BASELINE NS5A RESISTANCE-ASSOCIATED POLYMORPHISMSC
NO
2% (2/85)
0% (0/90)
YES
22% (5/23)
0% (0/19)
IL28B STATUS
C/C
0% (0/10)
0% (0/16)
NON-C/C
7% (7/98)
0% (0/93)
A SUBJECTS WITH MISSING CIRRHOSIS STATUS WERE EXCLUDED FROM THIS SUBGROUP ANALYSIS.
B THESE 4 NON-CIRRHOTIC RELAPSERS ALL HAD BASELINE NS5A RESISTANCE-ASSOCIATED POLYMORPHISMS.
C NS5A RESISTANCE-ASSOCIATED POLYMORPHISMS INCLUDE ANY CHANGE AT NS5A POSITIONS 24, 28, 30, 31, 58, 92, OR 93.