Summary Basis of Decision for Harvoni

Clinical Pharmacology

The medicinal ingredients of Harvoni, ledipasvir (LDV) and sofosbuvir (SOF), are known to exhibit high potency and specificity as individual agents against the hepatitis C virus (HCV). When these two active pharmaceutical ingredients (LDV and SOF) are combined, they specifically target the HCV NS5A and NS5B proteins, respectively. The HCV NS5A protein is thought to play multiple roles in mediating viral replication, host-cell interactions, and viral pathogenesis. The HCV NS5B is involved in initiating HCV ribonucleic acid (RNA) replication that is critical for the viral replication cycle. Stopping the viral replication process leads to a rapid decline of HCV viral load and clearing of HCV levels in the body.

Studies evaluating QT prolongations have been conducted with the individual drugs, LDV and SOF. The effect of LDV 120 mg twice daily for 10 days on the QTc interval was evaluated in a randomized, multiple-dose, placebo-, and active-controlled (moxifloxacin 400 mg) three period crossover QT study in 59 healthy patients. The effects of SOF at the therapeutic dose (400 mg) and 3-fold above therapeutic dose (1,200 mg) on QTc interval were also evaluated in a randomized, single-dose, placebo-, and active-controlled (moxifloxacin 400 mg) four period crossover QT study in 59 healthy patients. Both these studies demonstrated a lack of effect of LDV or SOF on prolongation of the QTc interval based on the Fridericia correction method (QTcF). The upper bounds of the two-sided 90% confidence interval for the largest placebo-adjusted, baseline-corrected QT were below 10 ms.

Harvoni can be administered in patients with mild, moderate and severe hepatic impairment (Child-Pugh Class A, B or C).

Harvoni can be administered in patients with mild or moderate renal impairment. The safety of Harvoni has not been established in patients with severe renal impairment [estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m²] or end-stage renal disease (ESRD) requiring hemodialysis.

Phase III studies conducted in HCV-infected patients who received Harvoni with food or without food demonstrated that Harvoni can be administered without regard to food.

Based on population pharmacokinetic analyses, age, race, body mass index (BMI), treatment status (treatment-naive or treatment-experienced), the presence of ribavirin in the treatment regimen, or the presence or absence of cirrhosis had no clinically relevant effects on the exposure of SOF or LDV.

Safety and efficacy of Harvoni have not been established in patients with decompensated cirrhosis. Accordingly, a statement to this effect is reflected in the Warnings and Precautions and also in the Dosage and Administration sections of the Harvoni Product Monograph.

Drug-Drug Interactions

Ledipasvir and sofosbuvir (medicinal ingredients of Harvoni) are substrates of efflux drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Drugs that are potent P-gp inducers in the intestine (such as rifampin or St. John's wort) may decrease ledipasvir and sofosbuvir plasma concentrations leading to reduced therapeutic effect of Harvoni and potential loss of virologic response, and should not be used with Harvoni.

For further details on the clinical pharmacology, please refer to the Harvoni Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The efficacy of Harvoni was evaluated primarily in three Phase III studies: ION-1, ION-2, and ION-3. A total of 1,518 patients with genotype 1 chronic hepatitis C (CHC) were enrolled. All three studies evaluated the efficacy of Harvoni, with or without ribavirin (± RBV). The ION-1 and ION-2 studies also included a subset of patients with compensated cirrhosis (up to 20%).

ION-1 Study: Treatment-Naïve Patients with or without Cirrhosis

The ION-1 study, currently ongoing, is a Phase III, multicentre, randomized, open-label study which evaluated the efficacy of Harvoni ± RBV for treatment durations of 12 or 24 weeks, in treatment-naïve patients with genotype 1 CHC infection. All patients were to complete the post-treatment Week 4 and Week 12 visits regardless of treatment duration. Patients who had hepatitis C virus ribonucleic acid (HCV RNA) less than the lower limit of quantitation (LLOQ) at the post-treatment Week 12 visit were also to complete the post-treatment Week 24 visit unless a confirmed viral relapse occurred.

Patients eligible for the study were randomized in a 1:1:1:1 ratio to one of the following four treatment groups:

• Group 1: Harvoni [90 mg ledipasvir (LDV)/400 mg sofosbuvir (SOF)] for 24 weeks;
• Group 2: Harvoni (90 mg LDV/400 mg SOF) + RBV [1,000 or 1,200 mg/day divided twice daily (BID)] for 24 weeks;
• Group 3: Harvoni (90 mg LDV/400 mg SOF) for 12 weeks;
• Group 4: Harvoni (90 mg/400 mg SOF) + RBV (1,000 or 1,200 mg/day divided BID) for 12 weeks.

The randomization schedule was stratified by genotype (1a, 1b, or mixed 1a/1b) and the presence or absence of cirrhosis at screening.

A total of 865 patients were randomized and dosed (approximately 200 patients in each group). Enrollment was managed so that approximately 20% of randomized patients had cirrhosis. Investigators and the sponsor were blinded to post-treatment HCV RNA results until the time of this interim analysis.

Patient enrollment occurred in two parts. Part A enrolled and randomized approximately 200 patients (50 patients per treatment group). Enrollment was halted in all four treatment groups once Part A was fully enrolled. Subsequently, once patients in Group 3 and Group 4 (12-week treatment groups) completed post-treatment Week-4, the data monitoring committee reviewed safety data from the first 12 weeks of dosing for all patients (Groups 1 to 4) and the sustained virologic response at week 4 (SVR4) for Groups 3 and 4. Part B commenced enrollment of approximately 600 additional patients (150 patients per group) after the predefined interim futility criteria was not met [that is (i.e.) to discontinue Groups 3 and 4]; therefore, Part B comprised all 4 Groups.

For this New Drug Submission (NDS), given the ION-1 study remained ongoing during filing of the NDS, for patients enrolled in Part A, all available efficacy data through the post-treatment Week 24 visit were finalized and included in the interim analysis. For patients enrolled in Part B, all available efficacy data through the end of treatment for Groups 1 and 2 and through the post-treatment Week 12 visit for Groups 3 and 4 were finalized and included in the interim efficacy analysis. A second final analysis will be conducted when all patients in all four treatment groups have completed the post-treatment Week 24 visit or prematurely discontinued from the study. This data will be reported in the final clinical study report to follow at a later date.

The primary endpoint for this study was determined as the antiviral efficacy of the combination treatment of Harvoni ± RBV as measured by the proportion of patients who achieved SVR at 12 weeks post-treatment (SVR12). The SVR was defined as HCV RNA less than the LLOQ of 25 IU/mL at 12 weeks after the end of treatment.

ION-1 Study Results

Study results from the ION-1 study demonstrated that both 12-week treatment groups met the primary efficacy endpoint with an SVR12 ≥90%. Furthermore, the overall SVR12 rates of Harvoni were found to be similar in the presence and absence of RBV for the week-12 treatment duration [97.7% versus (vs) 97.2%].

High SVR12 rates were also observed in patients with cirrhosis (94.1% vs 100.0% with or without RBV respectively), as well as in patients without cirrhosis (98.3% vs 96.7% with or without RBV respectively).

In the 12-week treatment groups, when comparing the HCV RNA (<LLOQ) at treatment week 4 to that of end of treatment week 12, similar SVR rates were noted, indicating that patients responded rapidly to Harvoni therapy once initiated.

In the Harvoni 12-week treatment group, only one patient relapsed and four patients did not have a post-treatment Week 12 visit and were classified as failures. The patient who relapsed had the IL28B TT allele, cirrhosis, and the baseline NS5A resistance-associated variant (RAV) L31M, and relapsed at the post-treatment Week 4 visit. In the Harvoni + RBV 12-week group, none of the patients relapsed. Six patients did not have a post-treatment Week 12 visit and were classified as failures.

The SVR rates for all patients enrolled in the 24-week treatment groups [Number of patients (n) = 434] were not available at the time of interim analysis. However, a total of 197 patients had both post-treatment Week 12 and 24 data available for a concordance analysis (47 patients in the Harvoni 12-week treatment group, 51 patients in the Harvoni + RBV 12-week treatment group, 49 patients in the Harvoni 24-week treatment group, and 50 patients in the Harvoni + RBV 24-week treatment group). Each of the 197 patients who achieved SVR12 also achieved SVR at Week 24, resulting in a positive predictive value of 100.0% for all groups.

Across all four treatment groups, one patient in the Harvoni 24-week treatment group had an on-treatment virologic failure at Week 8 (breakthrough), associated with documented study drug non-compliance. Pharmacokinetic results for this patient showed that plasma concentrations were below the limit of quantitation at the Week 8 and 10 visits, supportive of study drug non-compliance at or around these visits.

Permanent discontinuations of treatment due to adverse events (AEs) were rare. Only 1.8% in the Harvoni 24-week treatment group, 2.8% in the Harvoni + RBV 24-week treatment group, and no patients in the 12-week treatment group permanently discontinued due to AEs.

ION-2 Study: Treatment-Experienced Patients with or without Cirrhosis

The ION-2 study was a Phase III multicentre, randomized, open-label study which evaluated the efficacy of Harvoni ± RBV, for treatment durations of 12 or 24 weeks, in treatment-experienced genotype 1 CHC-infected patients. The overall study design and primary endpoint were similar to that previously specified for the ION-1 study.

Randomization was also similar to the ION-1 study, with stratification by HCV genotype, the presence or absence of cirrhosis at screening, and response to prior HCV therapy (relapse/breakthrough or non-response) at screening. Approximately 400 patients were randomized (100 patients in each group). Enrollment was once again managed so that approximately 20% of randomized patients had compensated cirrhosis and approximately 50% of randomized patients had failed prior treatment with pegylated interferon plus ribavirin (PegIFN + RBV) or protease inhibitor plus pegylated interferon and ribavirin (PI + PegIFN + RBV) regimen.

ION-2 Study Results

Results from the ION-2 study were similar to those observed in the ION-1 study, with all four treatment groups having met the primary efficacy endpoint of an SVR12 rate. In addition, the overall SVR12 rates of Harvoni were found to be similar in the presence or absence of RBV for both the 12-week and 24-week treatment groups.

In the Harvoni 12-week treatment group, 93.6% of patients achieved SVR12 with seven patients relapsing. A similar SVR rate was observed with the Harvoni + RBV 12‑week treatment group who achieved SVR12 in 96.4% of the patients, with four patients relapsing.

In the Harvoni 24-week treatment group, SVR12 was achieved in 99.1% of the patients and with no patients relapsing. A similar rate was seen in the Harvoni + RBV 24-week treatment group who achieved SVR12 in 99.1% of the patients. Only one patient (0.9%) in the Harvoni + RBV 24-week treatment group experienced on-treatment virologic failure (rebound), which was associated with documented study drug non-compliance.

High SVR12 rates were also observed in patients with and without cirrhosis for both the 12 and 24-week treatment groups. In treatment-experienced patients with cirrhosis, the SVR12 rates were numerically lower in the 12-week groups with values of 86.4% with Harvoni and 81.8% with Harvoni + RBV when compared to the 24-week treatment groups who reported SVR12 of 100.0%. In the non-cirrhotic groups, the 12 and 24-week treatment groups, in the presence and absence of RBV, all produced high SVR12 rates (95 to 100%). The SVR rates in cirrhotic and non-cirrhotic patients who previously failed treatment with PegIFN/RBV or PI + PegINF/RBV were similar to the overall SVR12 of Harvoni 12-and 24-Week treatment duration in the presence and absence of RBV.

Although the addition of RBV to the Harvoni regimen did not enhance the observed SVR12 rate in both non-cirrhotic and cirrhotic patients, the extension of treatment duration of Harvoni from 12 to 24 weeks had a modest increase in non-cirrhotics and a numerically more significant increase in the cirrhotic group [for example (e.g.) increased from 86% to 100%]. On the basis of these results, a 24-week treatment duration was therefore recommended in the Harvoni Product Monograph for treatment-experienced cirrhotic patients in the absence of RBV.

Patients who were non-responders (Null, Partial) to prior HCV therapy had similar SVR12 response rates compared to patients who had a relapse/breakthrough prior to HCV therapy (91.8% - 100.0% vs 95.0% - 100.0%). Patients who had failed prior therapy with a PI+PegIFN+RBV regimen, for whom there are no other approved treatment options, also achieved very high response rates (93.9% -100.0%), similar to patients who had failed prior Peg-IFN+RBV therapy (93.0% - 100.0%).

In addition, the HCV RNA (<LLOQ) at treatment week 4 and at the end of treatment week 12 (EOT) results obtained in the ION-2 study were consistent with the SVR12 results; thus again demonstrating a rapid response rate from patients receiving Harvoni treatment. Furthermore, preliminary analysis of concordance between SVR12 and SVR24 also demonstrated 100% concordance.

Overall, the virologic failure rate was low (2.7%). No genotypic or phenotypic resistance to sofosbuvir was detected in virologic failure patients. Virologic failure was associated with single-class ledipasvir resistance.

A high SVR12 rate was also achieved in patients with baseline NS5A RAVs. Baseline NS3 RAVs and the Q80 polymorphism had no appreciable effect on SVR12 rates. Four out of 438 patients that had other nucleoside inhibitor (NI) RAVs at baseline (n = 3 L159F + C316N, n = 1 N142T) also achieved SVR12.

Also, no patients (n = 440) in any treatment group permanently discontinued study drug due to an AE.

ION-3 Study: Non-Cirrhotic Treatment-Naïve Patients without Cirrhosis

The ION-3 study was a Phase III multicentre, randomized, open-label study which evaluated the efficacy of Harvoni + RBV for 8 weeks and Harvoni without RBV for 8 and 12 weeks in treatment-naïve patients with genotype 1 HCV infection.

The primary endpoint of this study was the same as that specified in the ION-1 and ION-2 studies. In this study, approximately 600 patients were randomized in a 1:1:1 ratio to one of three treatment groups:

• Group 1: Harvoni (90 mg LDV/400 mg SOF) for 12 weeks;
• Group 2: Harvoni (90 mg LDV/400 mg SOF) + RBV (1,000 or 1,200 mg/day divided BID) for 8 weeks;
• Harvoni (90 mg LDV/400 mg SOF) for 8 weeks.

This study also enrolled a limited number of patients who were interferon (IFN) ineligible (6.3%) and had no other treatment options. The primary reasons for ineligibility were significant psychiatric disease and other reasons approved by the medical monitor (reasons reported in >1 patient included psoriasis and peripheral neuropathy).

ION-3 Study Results

Results from the ION-3 study were similar to those observed in the ION-1 and ION-2 studies, with all treatment groups having met the primary efficacy endpoint of an SVR12 rate.

The 8-week RBV-free treatment regimen was non-inferior to the 8-week treatment regimen + RBV and the 12-week Harvoni regimen, as demonstrated by the lower-bound 95.0% Confidence Interval (CI) of -3.9% and the lower bound 97.5% CI of -6.4%, respectively, based on the requirement that the lower bound of the CI of the difference between two treatment groups was greater than the pre-specified non-inferiority margin of -12%.

The overall SVR12 rates of Harvoni were found to be similar in the presence and absence of RBV for both the 8-week and 12-week treatment durations. In the Harvoni 8-week treatment group, 94.0% of the patients achieved SVR12 and eleven patients (5.1%) relapsed. Similar responses were seen in Harvoni + RBV 8-week group; 93.1% of the patients achieved SVR12 with nine patients (4.2%) relapsing. In the Harvoni 12-week treatment group, 95.4% of the patients achieved SVR12 but only three patients (1.4%) relapsed.

Analyses using a baseline HCV RNA cut-offs of < or >6 million IU/mL for treatment-naïve patients without cirrhosis revealed similar high SVR12 rates for the Harvoni ± RBV 8-week treatment groups (96-97%) and the 12-week treatment group of Harvoni (96%), all with low rates of relapse (about 2%) when the viral load was <6 million IU/mL. However, lower SVR12 rates (87-94%) were observed for all treatment groups (8-weeks Harvoni ± RBV and 12-weeks Harvoni) with higher relapse rates (8-10%) for the 8-week Harvoni ± RBV and a much lower relapse rate (1%) for the 12-week Harvoni when the baseline vial load cut-off was ≥6 million IU/mL. On the basis of these results, an 8-week treatment duration was recommended for treatment-naive patients without cirrhosis who have an HCV RNA baseline viral load <6 million IU/mL and 12-weeks of treatment duration for patients with viral load >6 million IU/mL.

Host and viral factors that have been traditionally predictive of or associated with lower rates of SVR [for example (e.g.) African-American race, high body mass index (BMI), genotype 1a, high viral load, non-CC IL28B allele] had no impact on SVR12 rates. A strong virologic response was observed in all groups.

Eleven patients who achieved SVR4 did not achieve SVR12. This included five patients in the Harvoni 8-week treatment group (three patients relapsed, one patient was lost to follow-up, and one patient withdrew consent), four patients in the Harvoni + RBV 8‑week treatment group (three patients relapsed, and one patient was lost to follow-up) and two patients in the Harvoni 12-week treatment group (two patients had visits that had not occurred at time of data cut off and were considered lost to follow-up).

The virologic response (HCV RNA levels, log₁₀ IU/mL) was strong in all treatment groups. After one week of treatment, mean changes from baseline across all groups ranged from -4.65 to -4.60 log₁₀ IU/mL, demonstrating that similar decreases in HCV RNA were observed in all groups, irrespective of inclusion of RBV in the treatment regimen. At Week 2, >88% of patients in each group had HCV RNA <LLOQ. At Week 4, 99.1% to 100% of patients in each treatment group had HCV RNA <LLOQ.

A total of 116 of 647 (17.9%) patients were identified as having at least one baseline NS5A RAV. Of these, 104 (89.7%) patients with baseline NS5A RAVs achieved SVR12 following 8-weeks of treatment with Harvoni ± RBV or 12-weeks treatment with Harvoni as follows:

• 34 of 38 (89.5%) patients in the Harvoni 8-week group;
• 32 of 38 (84.2%) patients in the Harvoni ± RBV 8-week group;
• 38 of 40 (95.0%) patients in the Harvoni 12-week group.

Of the 116 patients with baseline NS5A RAVs, 80 (69.0%) patients had at least one NS5A RAV conferring >100-fold reduced susceptibility to ledipasvir in vitro. Despite the presence of these NS5A RAVs, 69 of these 80 (86.3%) patients achieved SVR12.

A total of 23 patients relapsed. Of these patients, ten patients had NS5A RAVs at baseline; in nine patients, the NS5A RAV(s) were retained or enriched, and in one patient the NS5A RAV(s) were no longer detected at relapse. Thirteen patients had no baseline NS5A RAVs. In six of these 13 patients, NS5A RAVs emerged at relapse; in the remaining seven patients, no NS5A RAVs were detected at relapse.

The NS5B sequencing did not detect S282T in any of the 23 relapsed patients. However, in the Harvoni 12-week group, one patient with genotype 1a HCV infection had 2.5% L159F in NS5B together with >99% of NS5A Y93N; another patient with genotype 1a HCV infection had 1.1% V320A in NS5B without NS5A RAVs at relapse.

No resistance to ledipasvir or sofosbuvir (medicinal ingredients of Harvoni) were detected in 7 and 21 of the 23 relapsed patients, respectively. Virologic failure was associated with single class ledipasvir resistance in 16 (69.6%) of the relapse patients. The substitutions V320A and L159F in NS5B were each detected in one patient with genotype 1a HCV infection at low levels at relapse.

No patients in the Harvoni 8-week treatment group, 0.5% of patients in the Harvoni + RBV 8-week treatment group and 0.9% patients in the Harvoni 12-week treatment group, permanently discontinued treatment regimen due to an AE.

Efficacy Conclusion

In sum, based on the data obtained from the three Phase III studies, ION-1, ION-2, and ION-3, Harvoni-containing regimens met their primary efficacy endpoint when compared to current standard-of-care regimens. Across the three studies, treatment with Harvoni did demonstrate high SVR12 rates in patients who had failed prior therapy with a PI+PegIFN+RBV regimen (94%) for whom there are no other approved treatment options and for patients who failed PegIFN alpha/RBV treatment (93%). Within these populations, SVR12 was achieved by 86-88% of patients with cirrhosis and 94-96% of patients without cirrhosis. Thus, previously treated patients with cirrhosis respond well to the new medication and, overall, the response rates in cirrhotic patients are much improved when compared to the current therapies.

In addition, a substantial number of genotype 1 HCV infected patients who were not able to receive PegIFN and/or RBV due to contraindications or were unwilling or intolerant to PegIFN, are now able to use an alternative medication which would be accompanied by greater compliance to medication with reduced treatment discontinuation due to safety or tolerability issues. Thus the absence of Peg-IFN and RBV in the new treatment regimen has substantial benefits by improving the tolerability, completion rates of the treatment regimen, and elimination of dose adjustment or interruptions.

Host factors that are known to be associated with poor response or relapse had no meaningful negative impact on SVR12 rates (i.e. the SVR12 rates were very high when compared to existing therapies). The SVR or cure rates in these groups of patients also represent significant treatment advances when compared to existing therapies.

Harvoni can also be administered either with or without food, thereby simplifying its administration.

As a result, Harvoni does offer another effective treatment option for either treatment naïve or treatment experienced HCV-infected patients.

For more information, refer to the Harvoni Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The overall safety profile of Harvoni was primarily established based on an integrated safety summary which includes data from the ION-1, ION-2, and ION-3 Phase III studies, previously described in the Clinical Efficacy section. A total of 1,952 patients were included in the overall safety data set. However, for the labeling of the Product Monograph, only 1,080 patients from the RBV-free treatment group were included (215 patients from the 8-Week RBV-free treatment group, 539 patients from the 12-Week RBV-free treatment group, and 326 patients from the 24-Week RBV-free treatment group).

ION-1 Study

In the ION-1 study, treatment regimens with Harvoni ± RBV for 12 or 24 weeks were well-tolerated. Patients experiencing any adverse event (AE) ranged from 79% to 92%. This observation, for the Harvoni + RBV treatment regimen, is consistent with that noted previously with sofosbuvir + RBV regimen and is expected for RBV use. Conversely, no specific safety signal associated with Harvoni was identified.

In regard to serious adverse events (SAEs), the majority of these events were determined by the investigator as unrelated to the study drug, with the exception of the following events: anemia (2 events in one patient who received RBV as a component of the treatment regimen); salpingitis; headache; factor VIII inhibition; and mesenteric vein thrombosis. All these SAEs occurred in 5 patients (0.3%). All SAEs were assessed at a Grade 3.

There were no treatment-emergent deaths, or Grade 4 (life threatening) AEs reported throughout the study. There was only one non-treatment-emergent death (Grade 4 liver failure) which occurred during conduct of the study.

Consistent with the absence of Peg-IFN and RBV, Grade 3 or 4 laboratory abnormalities were rare in the Harvoni treatment groups. No clinically meaningful changes from baseline in white blood cell (WBC), neutrophil, lymphocyte, hemoglobin, reticulocyte, and platelet values were observed. All Grade 3 or 4 increases in lipase values were transient and none of the patients with Grade 3 or 4 lipase elevations had an AE of clinical pancreatitis.

Addition of RBV to a Harvoni treatment regimen contributed substantially to the incidence of AEs and clinically significant laboratory abnormalities experienced by patients. This overall impact on morbidity was reflected in the on-treatment decreases in quality of life observed for RBV-containing groups, as measured by patient-reported outcomes. The addition of RBV increased the incidence of AEs by >5% which is typical of RBV (fatigue, insomnia, nausea, cough, pruritus, anemia, dyspnea, and dry skin) and increased by approximately 12% treatment-related AEs requiring medical intervention (e.g., required medication, hospitalization or prolongation of hospitalization, or other treatments).

Consistent with the expected toxicity profile of RBV, decreases in hemoglobin and increases in reticulocytes, platelets, and bilirubin were observed in both Harvoni + RBV groups for the duration of active treatment. No patients in the RBV-free groups met the criteria for clinically significant anemia.

ION-2 Study

In the ION-2 study, treatment with Harvoni ± RBV for 12 or 24 weeks, were also generally safe and well-tolerated. Patients experiencing any AE ranged from 67% to 90%. No specific safety signals associated with Harvoni were identified. Additionally, no treatment-related SAEs occurred. No deaths or pregnancies were reported. Only one patient (in the Harvoni 24-week group) had a Grade 4 AE (unstable angina), which was reported as serious and not related to study drug.

Grade 3 or 4 laboratory abnormalities were rare in the Harvoni treatment groups, consistent with the absence of Peg-IFN and RBV. No clinically meaningful changes from baseline in WBC, neutrophil, hemoglobin, reticulocyte, lymphocyte, or platelet values were observed. The most common Grade 3 or 4 chemistry laboratory abnormalities across treatment groups were increased serum glucose (all patients had a history of diabetes, were taking diabetic medication, or had glucose intolerance at screening) and increased lipase. No on-treatment trends in lipase were observed. Grade 3 and 4 lipase elevations were not sustained. None of the patients with Grade 3 or 4 lipase elevations had an AE of clinical pancreatitis.

The addition of RBV to Harvoni increased the incidence of AEs and clinically significant laboratory abnormalities that were consistent with the known side-effects of RBV.

The percentage of patients experiencing AEs was higher in the 24-week treatment groups compared with the 12-week treatment groups.

ION-3 Study

In the ION-3 study, treatment regimens with Harvoni ± RBV for 8-weeks or Harvoni for 12-weeks were, like that observed in the ION-1 and ION-2 studies, generally safe and well-tolerated. Patients experiencing any AE ranged from 67% to 76%. Again, no specific safety signals associated with Harvoni were identified.

The 8- and 12-week treatment groups with Harvoni, in the absence of RBV and PegIFN alpha, managed to eliminate many of the AEs and laboratory abnormalities associated with RBV and the need for laboratory monitoring. No patients in the Harvoni 8-week treatment group, 0.5% of patients in the Harvoni + RBV 8-week treatment group and 0.9% patients in the Harvoni 12-week treatment group, permanently discontinued treatment regimen due to an AE.

No trends in SAE type or onset time were observed amongst the ten patients reporting SAEs. All SAEs were considered by the investigator as unrelated to the study drug. In addition, no deaths were reported.

In comparison, the addition of RBV to the Harvoni treatment regimen contributed substantially to the incidence of AEs and clinically significant laboratory abnormalities experienced by patients. This impact was also indirectly reflected in the on-treatment decreases in quality of life observed for the Harvoni + RBV 8-week treatment group, as measured by patient-reported outcomes.

Grade 3 or 4 laboratory abnormalities were also rare in the Harvoni treatment groups, consistent with the absence of Peg-IFN and RBV. The most common Grade 3 or 4 chemistry laboratory abnormalities across treatment groups were transient levels of increased lipase and increased serum glucose. None of the patients with lipase elevations had an AE of clinical pancreatitis or developed treatment-emergent clinical events of pancreatitis. The patients with Grade 3 or 4 increased serum glucose all had a history of diabetes, were taking diabetic medication, or had glucose intolerance at screening.

Safety Conclusion

In conclusion, the addition of RBV to the Harvoni treatment regimen showed an increase in the incidence of AEs and also that of clinically significant laboratory abnormalities. This conclusion is consistent with the known side-effects of RBV. In comparison, the development of an IFN- and RBV-free regimen treatment option, that of Harvoni, appears to improve the AE profile associated with CHC therapy and also simplifies treatment management by eliminating the need for dose reduction/discontinuation of RBV following the occurrence of RBV-associated AEs. As a result, the development of Harvoni for the treatment of chronic HCV infection has the potential to have a major impact on the global incidence, prevalence, and management of CHC infection.

For more information, refer to the Harvoni Product Monograph, approved by Health Canada and available through the Drug Product Database.