You are receiving this message as a subscriber to the FDA hepatitis electronic list serve. The purpose of the list serve is to relay important information about viral hepatitis-related products and issues, including product approvals, significant labeling changes, safety warnings, notices of upcoming public meetings and alerts to proposed regulatory guidances for comment.
Please do not reply to this message.
On November 22, 2013 FDA approved Olysio (simeprevir) 150 mg capsules for the treatment of chronic hepatitis C (CHC) infection, as a component of a combination antiviral treatment regimen. Below is a summary of the basis of approval and highlights from the prescribing information. Please refer to the full prescribing information for all the information needed to use OLYSIO safely and effectively.
INDICATIONS AND USAGE
OLYSIO is a hepatitis C virus (HCV) NS3/4A protease inhibitor indicated for the treatment of chronic hepatitis C (CHC) infection as a component of a combination antiviral treatment regimen.
OLYSIO efficacy has been established in combination with peginterferon alfa and ribavirin, in HCV genotype 1 infected subjects with compensated liver disease (including cirrhosis)
The following points should be considered when initiating OLYSIO for treatment of chronic hepatitis C infection:
OLYSIO must not be used as monotherapy
OLYSIO efficacy in combination with peginterferon alfa and ribavirin is influenced by baseline host and viral factors.
OLYSIO efficacy in combination with peginterferon alfa and ribavirin is substantially reduced in patients infected with HCV genotype 1a with an NS3 Q80K polymorphism at baseline compared to patients infected with hepatitis C virus (HCV) genotype 1a without the Q80K polymorphism. Screening patients with HCV genotype 1a infection for the presence of virus with the NS3 Q80K polymorphism at baseline is strongly recommended. Alternative therapy should be considered for patients infected with HCV genotype 1a containing the Q80K polymorphism.
OLYSIO efficacy has not been studied in patients who have previously failed therapy with a treatment regimen that includes OLYSIO or other HCV protease inhibitors.
Dosage and Administration
The recommended dose of OLYSIO is one capsule of 150 mg taken orally once daily with food. The type of food does not affect exposure to simeprevir. The capsule should be swallowed as a whole.
OLYSIO should be used in combination with peginterferon alfa and ribavirin. For peginterferon alfa and ribavirin specific dosage instructions, refer to their respective prescribing information.
| Duration of Treatment with OLYSIO, Peginterferon Alfa and Ribavirin | |||
|
| Treatment with OLYSIO, Peginterferon alfa and Ribavirin* | Treatment with Peginterferon alfa and Ribavirin* | Total Treatment Duration* |
| Treatment-naïve and prior relapser patients† including those with cirrhosis | First 12 weeks | Additional 12 weeks | 24 weeks |
| Prior non-responder patients‡ (including partial and null responders) including those with cirrhosis | First 12 weeks | Additional 36 weeks | 48 weeks |
| * Recommended duration of treatment if patient does not meet stopping rule (see Table 2). † Prior relapser: undetectable HCV RNA at the end of prior interferon‑based therapy and detectable HCV RNA during follow‑up ‡ Prior partial responder: prior on-treatment ≥ 2 log10 IU/ml reduction in HCV RNA from baseline at Week 12 and detectable HCV RNA at end of prior interferon‑based therapy. Prior null responder: prior on‑treatment < 2 log10 reduction in HCV RNA from baseline at Week 12 during prior interferon‑based therapy. |
Hepatic Impairment
No dose recommendation can be given for patients with moderate or severe hepatic impairment (Child‑Pugh Class B or C) due to higher simeprevir exposures. In clinical trials, higher simeprevir exposures have been associated with increased frequency of adverse reactions, including rash and photosensitivity
The safety and efficacy of OLYSIO have not been studied in HCV‑infected patients with moderate or severe hepatic impairment (Child‑Pugh Class B or C). The combination of peginterferon alfa and ribavirin is contraindicated in patients with decompensated cirrhosis (moderate or severe hepatic impairment). The potential risks and benefits of OLYSIO should be carefully considered prior to use in patients with moderate or severe hepatic impairment.
WARNINGS AND PRECAUTIONS
Photosensitivity
Photosensitivity reactions have been observed with OLYSIO in combination with peginterferon alfa and ribavirin, including serious reactions which resulted in hospitalization. Photosensitivity reactions occurred most frequently in the first 4 weeks of treatment with OLYSIO in combination with peginterferon alfa and ribavirin, but can occur at any time during treatment. Photosensitivity may present as an exaggerated sunburn reaction, usually affecting areas exposed to light (typically the face, "V" area of the neck, extensor surfaces of the forearms, and dorsa of the hands). Manifestations may include burning, erythema, exudation, blistering, and edema.
Use sun protective measures and limit sun exposure during treatment with OLYSIO in combination with peginterferon alfa and ribavirin. Avoid use of tanning devices during treatment with OLYSIO in combination with peginterferon alfa and ribavirin. Discontinuation of OLYSIO should be considered if a photosensitivity reaction occurs and patients should be monitored until the reaction has resolved. If a decision is made to continue OLYSIO in the setting of a photosensitivity reaction, expert consultation is advised.
Rash
Rash has been observed in subjects receiving OLYSIO in combination with peginterferon alfa and ribavirin. Rash occurred most frequently in the first 4 weeks of treatment with OLYSIO in combination with peginterferon alfa and ribavirin, but can occur at any time during treatment. Severe rash and rash requiring discontinuation of OLYSIO have been reported. Most of the rash events in OLYSIO‑treated patients were of mild or moderate severity. Patients with mild to moderate rashes should be followed for possible progression of rash, including the development of mucosal signs (e.g., oral lesions, conjunctivitis) or systemic symptoms. If the rash becomes severe, OLYSIO should be discontinued. Patients should be monitored until the rash has resolved.
Sulfa Allergy
OLYSIO contains a sulfonamide moiety. In subjects with a history of sulfa allergy (n=16), no increased incidence of rash or photosensitivity reactions has been observed. However, there are insufficient data to exclude an association between sulfa allergy and the frequency or severity of adverse reactions observed with the use of OLYSIO.
ADVERSE REACTIONS
The most common reported adverse reactions (greater than 20% of subjects) in subjects receiving the combination of OLYSIO with peginterferon and ribavirin and occurring with at least 3% higher frequency compared to subjects receiving placebo in combination with peginterferon alfa and ribavirin during the first 12 weeks of treatment were: rash (including photosensitivity), pruritus and nausea.
DRUG INTERACTIONS
Potential for OLYSIO to Affect Other Drugs
Simeprevir does not induce CYP1A2 or CYP3A4 in vitro. Simeprevir is not a clinically relevant inhibitor of cathepsin A enzyme activity.
Simeprevir mildly inhibits CYP1A2 activity and intestinal CYP3A4 activity, but does not affect hepatic CYP3A4 activity. Co‑administration of OLYSIO with drugs that are primarily metabolized by CYP3A4 may result in increased plasma concentrations of such drugs. Simeprevir does not affect CYP2C9, CYP2C19 or CYP2D6 in vivo.
Simeprevir inhibits OATP1B1/3 and P‑glycoprotein (P‑gp) transporters. Co‑administration of OLYSIO with drugs that are substrates for OATP1B1/3 and P‑gp transport may result in increased plasma concentrations of such drugs.
Potential for Other Drugs to Affect OLYSIO
The primary enzyme involved in the biotransformation of simeprevir is CYP3A. Clinically relevant effects of other drugs on simeprevir pharmacokinetics via CYP3A may occur. Co‑administration of OLYSIO with moderate or strong inhibitors of CYP3A may significantly increase the plasma exposure of simeprevir. Co‑administration with moderate or strong inducers of CYP3A may significantly reduce the plasma exposure of simeprevir and lead to loss of efficacy. Therefore, co‑administration of OLYSIO with substances that are moderate or strong inducers or inhibitors of CYP3A is not recommended.
| Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen may be Recommended Based on Drug Interaction Studies or Predicted Interaction | ||
| Concomitant Drug Class Drug Name | Effect on Concentration of Simeprevir or Concomitant Drug | Clinical Comment |
| Antiarrhythmics | ||
| Digoxin* | ↑ digoxin | Concomitant use of OLYSIO with digoxin resulted in increased concentrations of digoxin due to inhibition of P‑gp by simeprevir. Routine therapeutic drug monitoring of digoxin concentrations is acceptable. |
| Amiodarone Disopyramide Flecainide Mexiletine Propafenone Quinidine | ↑ antiarrhythmics | Concomitant use of OLYSIO with these antiarrhythmics may result in mild increases in concentrations of these antiarrhythmics due to intestinal CYP3A4 inhibition by simeprevir. Caution is warranted and therapeutic drug monitoring for these antiarrhythmics, if available, is recommended when co‑administered with OLYSIO. |
| Anticoagulants | ||
| Warfarin* | ↔ warfarin | No dose adjustment is required when OLYSIO is co‑administered with warfarin. Routine monitoring of the international normalized ratio (INR) is acceptable. |
| Anticonvulsants | ||
| Carbamazepine Oxcarbazepine Phenobarbital Phenytoin | ↓ simeprevir | Concomitant use of OLYSIO with carbamazepine, oxcarbazepine, phenobarbital or phenytoin may result in significantly decreased plasma concentrations of simeprevir due to strong CYP3A induction by these anticonvulsants. This may result in loss of therapeutic effect of OLYSIO. It is not recommended to co‑administer OLYSIO with these anticonvulsants. |
| Anti‑infectives | ||
| Antibiotics: Erythromycin* | ↑ simeprevir ↑ erythromycin | Concomitant use of OLYSIO with erythromycin resulted in significantly increased plasma concentrations of both erythromycin and simeprevir due to inhibition of CYP3A and P‑gp by both erythromycin and simeprevir. It is not recommended to co‑administer OLYSIO with erythromycin. |
| Antibiotics: Clarithromycin Telithromycin | ↑ simeprevir | Concomitant use of OLYSIO with clarithromycin or telithromycin may result in increased plasma concentrations of simeprevir due to CYP3A inhibition by these antibiotics. It is not recommended to co‑administer OLYSIO with clarithromycin or telithromycin. |
| Antifungals (systemic administration): Itraconazole Ketoconazole Posaconazole | ↑ simeprevir | Concomitant use of OLYSIO with systemic itraconazole, ketoconazole or posaconazole may result in significantly increased plasma concentrations of simeprevir due to strong CYP3A inhibition by these antifungals. It is not recommended to co‑administer OLYSIO with systemic itraconazole, ketoconazole or posaconazole. |
| Antifungals (systemic administration): Fluconazole Voriconazole | ↑ simeprevir | Concomitant use of OLYSIO with systemic fluconazole or voriconazole may result in increased plasma concentrations of simeprevir due to mild to moderate CYP3A inhibition by these antifungals. It is not recommended to co‑administer OLYSIO with systemic fluconazole or voriconazole. |
| Antimycobacterials: Rifampin*† Rifabutin Rifapentine | ↓ simeprevir ↔ rifampin, rifabutin, rifapentine | Concomitant use of OLYSIO with rifampin, rifabutin or rifapentine may result in significantly decreased plasma concentrations of simeprevir due to CYP3A4 induction by these antimycobacterials. This may result in loss of therapeutic effect of OLYSIO. It is not recommended to co‑administer OLYSIO with rifampin, rifabutin or rifapentine. |
| Calcium Channel Blockers | ||
| Amlodipine Diltiazem Felodipine Nicardipine Nifedipine Nisoldipine Verapamil | ↑ calcium channel blockers | Concomitant use of OLYSIO with calcium channel blockers may result in increased plasma concentrations of calcium channel blockers due to intestinal CYP3A4 and/or P‑gp inhibition by simeprevir. Caution is warranted and clinical monitoring of patients is recommended when OLYSIO is co‑administered with calcium channel blockers. |
| Corticosteroids | ||
| Systemic Dexamethasone | ↓ simeprevir | Concomitant use of OLYSIO with systemic dexamethasone may result in decreased plasma concentrations of simeprevir due to moderate induction of CYP3A4 by dexamethasone. This may result in loss of therapeutic effect of OLYSIO. It is not recommended to co‑administer OLYSIO with systemic dexamethasone. |
| Gastrointestinal Products | ||
| Propulsive: Cisapride | ↑ cisapride | Cisapride has the potential to cause cardiac arrhythmias. Concomitant use of OLYSIO with cisapride may result in increased plasma concentrations of cisapride due to intestinal CYP3A4 inhibition by simeprevir. It is not recommended to co‑administer OLYSIO with cisapride. |
| Herbal Products | ||
| Milk thistle (Silybum marianum) | ↑ simeprevir | Concomitant use of OLYSIO with milk thistle may result in increased plasma concentrations of simeprevir due to CYP3A inhibition by milk thistle. It is not recommended to co‑administer OLYSIO with milk thistle. |
| St. John's wort (Hypericum perforatum) | ↓ simeprevir | Concomitant use of OLYSIO with products containing St. John’s wort may result in significantly decreased plasma concentrations of simeprevir due to CYP3A induction by St. John’s wort. This may result in loss of therapeutic effect of OLYSIO. It is not recommended to co‑administer OLYSIO with products containing St. John’s wort. |
| HIV Products | ||
| Cobicistat‑containing product (elvitegravir/cobicistat/ emtricitabine/tenofovir disoproxil fumarate) | ↑ simeprevir | Concomitant use of OLYSIO and a cobicistat‑containing product (elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate) may result in significantly increased plasma concentrations of simeprevir due to strong CYP3A inhibition by cobicistat. It is not recommended to co‑administer OLYSIO with a cobicistat‑containing product. |
| Non‑Nucleoside Reverse Transcriptase Inhibitors (NNRTIs): Efavirenz* | ↓ simeprevir ↔ efavirenz | Concomitant use of OLYSIO with efavirenz resulted in significantly decreased plasma concentrations of simeprevir due to CYP3A induction by efavirenz. This may result in loss of therapeutic effect of OLYSIO. It is not recommended to co‑administer OLYSIO with efavirenz. |
| Other NNRTIs (Delavirdine, Etravirine, Nevirapine) | ↑ or ↓ simeprevir | Concomitant use of OLYSIO with delavirdine, etravirine or nevirapine may result in altered plasma concentrations of simeprevir due to CYP3A inhibition (delavirdine) or induction (etravirine and nevirapine) by these drugs. It is not recommended to co‑administer OLYSIO with delavirdine, etravirine or nevirapine. |
| Protease Inhibitors (PIs): Darunavir/ritonavir*‡ | ↑ simeprevir ↑ darunavir | Concomitant use of OLYSIO with darunavir/ritonavir resulted in increased plasma concentrations of simeprevir due to CYP3A inhibition by darunavir/ritonavir. It is not recommended to co‑administer darunavir/ritonavir and OLYSIO. |
| Protease Inhibitors (PIs): Ritonavir*# | ↑ simeprevir | Concomitant use of OLYSIO with ritonavir resulted in significantly increased plasma concentrations of simeprevir due to strong CYP3A inhibition by ritonavir. It is not recommended to co‑administer OLYSIO with ritonavir. |
| Other ritonavir‑boosted or unboosted HIV PIs, e.g., Atazanavir, Fosamprenavir, Lopinavir, Indinavir, Nelfinavir, Saquinavir, Tipranavir | ↑ or ↓ simeprevir | Concomitant use of OLYSIO with ritonavir‑boosted or unboosted HIV PIs may result in altered plasma concentrations of simeprevir due to CYP3A inhibition or induction by these HIV PIs. It is not recommended to co‑administer OLYSIO with any HIV PI, with or without ritonavir. |
| HMG CO‑A Reductase Inhibitors | ||
| Rosuvastatin* | ↑ rosuvastatin | Concomitant use of OLYSIO with rosuvastatin resulted in increased plasma concentrations of rosuvastatin due to inhibition of OATP1B1 by simeprevir. Initiate rosuvastatin therapy with 5 mg once daily. The rosuvastatin dose should not exceed 10 mg daily when co‑administered with OLYSIO. |
| Atorvastatin* | ↑ atorvastatin | Concomitant use of OLYSIO with atorvastatin resulted in increased plasma concentrations of atorvastatin due to inhibition of OATP1B1 and/or CYP3A4 by simeprevir. Use the lowest necessary dose of atorvastatin, but do not exceed a daily dose of 40 mg when co-administering with OLYSIO. |
| Simvastatin*
| ↑ simvastatin | Concomitant use of OLYSIO with simvastatin resulted in increased plasma concentrations of simvastatin due to inhibition of OATP1B1 and/or CYP3A4 by simeprevir. Titrate the simvastatin dose carefully and use the lowest necessary dose of simvastatin while monitoring for safety when co‑administered with OLYSIO. |
| Pitavastatin Pravastatin Lovastatin | ↑ pitavastatin, pravastatin, lovastatin | Concomitant use of OLYSIO with pitavastatin, pravastatin or lovastatin has not been studied. The dose of pitavastatin, pravastatin or lovastatin should be titrated carefully and the lowest necessary dose should be used while monitoring for safety when co‑administered with OLYSIO. |
| Immunosuppressants | ||
| Cyclosporine* | ↑ cyclosporine | No dose adjustment is required when OLYSIO is co‑administered with cyclosporine. Routine monitoring of blood concentrations of cyclosporine is acceptable. |
| Tacrolimus* | ↓ tacrolimus | No dose adjustment is required when OLYSIO is co‑administered with tacrolimus. Routine monitoring of blood concentrations of tacrolimus is acceptable. |
| Sirolimus | ↑ or ↓ sirolimus | Concomitant use of OLYSIO and sirolimus may result in mildly increased or decreased plasma concentrations of sirolimus. Routine monitoring of blood concentrations of sirolimus is acceptable. |
| Phosphodiesterase Type 5 (PDE‑5) Inhibitors | ||
| Sildenafil Tadalafil Vardenafil | ↑ PDE‑5 inhibitors | Concomitant use of OLYSIO with PDE‑5 inhibitors may result in mild increases in concentrations of PDE‑5 inhibitors due to intestinal CYP3A4 inhibition by simeprevir. No dose adjustment is required when OLYSIO is co‑administered with doses of sildenafil, tadalafil or vardenafil indicated for the treatment of erectile dysfunction. Dose adjustment of the PDE‑5 inhibitor may be required when OLYSIO is co‑administered with sildenafil or tadalafil administered chronically at doses used for the treatment of pulmonary arterial hypertension. Consider starting with the lowest dose of the PDE‑5 inhibitor and increase as needed, with clinical monitoring as appropriate. |
| Sedatives/Anxiolytics | ||
| Midazolam* (oral administration) | ↑ midazolam | Concomitant use of OLYSIO with orally administered midazolam resulted in increased plasma concentrations of midazolam due to mild inhibition of intestinal CYP3A4 by simeprevir. Caution is warranted when this drug, with a narrow therapeutic index, is co‑administered with OLYSIO via the oral route. |
| Triazolam (oral administration) | ↑ triazolam | Concomitant use of OLYSIO with orally administered triazolam may result in mild increases in concentrations of triazolam due to intestinal CYP3A4 inhibition by simeprevir. Caution is warranted when this drug, with a narrow therapeutic index, is co‑administered with OLYSIO via the oral route. |
| The direction of the arrow (↑ = increase, ↓ = decrease, ↔ = no change) indicates the direction of the change in PK. * These interactions have been studied in healthy adults with the recommended dose of 150 mg simeprevir once daily unless otherwise noted [see Clinical Pharmacology (12.3), Tables 6 and 7]. † The dose of OLYSIO in this interaction study was 200 mg once daily both when given alone and when co‑administered with rifampin 600 mg once daily. ‡ The dose of OLYSIO in this interaction study was 50 mg when co‑administered in combination with darunavir/ritonavir, compared to 150 mg in the OLYSIO alone treatment group. # The dose of OLYSIO in this interaction study was 200 mg once daily both when given alone and when co‑administered in combination with ritonavir 100 mg given twice daily. |
CLINICAL STUDIES
The efficacy of OLYSIO in patients with HCV genotype 1 infection was evaluated in two Phase 3 trials in treatment‑naïve subjects (trials QUEST 1 and QUEST 2), one Phase 3 trial in subjects who relapsed after prior interferon‑based therapy (PROMISE) and one Phase 2b trial in subjects who failed prior therapy with peginterferon (Peg‑IFN) and ribavirin (RBV) (including prior relapsers, partial and null responders) (ASPIRE). Prior relapsers were subjects who had undetectable HCV RNA at the end of prior IFN‑based therapy and detectable HCV RNA during follow‑up; prior partial responders were subjects with prior on‑treatment greater than or equal to 2 log10 reduction in HCV RNA from baseline at Week 12 and detectable HCV RNA at the end of prior therapy with Peg‑IFN and RBV; and null responders were subjects with prior on‑treatment less than 2 log10 reduction in HCV RNA from baseline at Week 12 during prior therapy with Peg‑IFN and RBV. Subjects in these trials had compensated liver disease (including cirrhosis), HCV RNA of at least 10000 IU/mL, and liver histopathology consistent with CHC.
In subjects who were treatment‑naïve and prior relapsers, the overall duration of treatment with Peg‑IFN‑alfa and RBV in the Phase 3 trials was response‑guided. In these subjects, the planned total duration of HCV treatment was 24 weeks if the following on‑treatment protocol‑defined response‑guided therapy (RGT) criteria were met: HCV RNA lower than 25 IU/mL (detectable or undetectable) at Week 4 AND undetectable HCV RNA at Week 12. Plasma HCV RNA levels were measured using the Roche COBAS® TaqMan® HCV test (version 2.0), for use with the High Pure System (25 IU/mL LLOQ and 15 IU/mL limit of detection). Treatment stopping rules for HCV therapy were used to ensure that subjects with inadequate on‑treatment virologic response discontinued treatment in a timely manner.
SVR (virologic cure) was defined as undetectable HCV RNA 24 weeks after planned end of treatment (SVR24) in the Phase 2b trial and was defined as HCV RNA lower than 25 IU/mL detectable or undetectable 12 weeks after the planned end of treatment (SVR12) in the Phase 3 trials.
Treatment‑Naïve Adult Subjects with HCV Genotype 1 Infection
The efficacy of OLYSIO in treatment‑naïve patients with HCV genotype 1 infection was demonstrated in two randomized, double‑blind, placebo‑controlled, 2‑arm, multicenter, Phase 3 trials (QUEST 1 and QUEST 2). The design of both trials was similar. All subjects received 12 weeks of once daily treatment with 150 mg OLYSIO or placebo, plus Peg‑IFN‑alfa‑2a (QUEST 1 and QUEST 2) or Peg‑IFN‑alfa‑2b (QUEST 2) and RBV, followed by 12 or 36 weeks of therapy with Peg‑IFN‑alfa and RBV in accordance with the on‑treatment protocol‑defined RGT criteria. Subjects in the control groups received 48 weeks of Peg‑IFN‑alfa‑2a or ‑2b and RBV.
In the pooled analysis for QUEST 1 and QUEST 2, demographics and baseline characteristics were balanced between both trials and between the OLYSIO and placebo treatment groups. In the pooled analysis of trials (QUEST 1 and QUEST 2), the 785 enrolled subjects had a median age of 47 years (range: 18 to 73 years); 56% were male; 91% were White, 7% Black or African American, 1% Asian, and 17% Hispanic; 23% had a body mass index (BMI) greater than or equal to 30 kg/m2; 78% had HCV RNA levels greater than 800000 IU/mL; 74% had METAVIR fibrosis score F0, F1 or F2, 16% METAVIR fibrosis score F3, and 10% METAVIR fibrosis score F4 (cirrhosis); 48% had HCV genotype 1a, and 51% HCV genotype 1b; 29% had IL28B CC genotype, 56% IL28B CT genotype, and 15% IL28B TT genotype; 17% of the overall population and 34% of the subjects with genotype 1a virus had the NS3 Q80K polymorphism at baseline. In QUEST 1, all subjects received Peg‑IFN‑alfa‑2a; in QUEST 2, 69% of the subjects received Peg‑IFN‑alfa‑2a and 31% received Peg‑IFN‑alfa‑2b.
Table 10 shows the response rates in treatment‑naïve adult subjects with HCV genotype 1 infection. In the OLYSIO treatment group, SVR12 rates were lower in subjects with genotype 1a virus with the NS3 Q80K polymorphism at baseline compared to subjects infected with genotype 1a virus without the Q80K polymorphism.
| Table 10: Treatment Outcome in Treatment‑Naïve Adult Subjects with HCV Genotype 1 Infection (Pooled Data QUEST 1 and QUEST 2; Intent‑to‑Treat Analysis) | ||
| Treatment Outcome | OLYSIO + PR N=521 % (n/N) | Placebo + PR N=264 % (n/N) |
| Overall SVR12 (genotype 1a and 1b) Genotype 1a Without Q80K With Q80K Genotype 1b | 80 (419/521) 75 (191/254) 84 (138/165) 58 (49/84) 85 (228/267) | 50 (132/264) 47 (62/131) 43 (36/83) 52 (23/44) 53 (70/133) |
| Outcome for all subjects without SVR12 | ||
| On‑treatment failure* | 8 (42/521) | 33 (87/264) |
| Viral relapse† | 11 (51/470) | 23 (39/172) |
| OLYSIO: 150 mg OLYSIO for 12 weeks with Peg‑IFN‑alfa‑2a or ‑2b and RBV for 24 or 48 weeks; Placebo: placebo for 12 weeks with Peg‑IFN‑alfa‑2a or ‑2b and RBV for 48 weeks. SVR12: sustained virologic response 12 weeks after planned EOT. * 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. Includes 4 OLYSIO‑treated subjects who experienced relapse after SVR12. |
In the pooled analysis of QUEST 1 and QUEST 2, 88% (459/521) of OLYSIO‑treated subjects were eligible for a total treatment duration of 24 weeks. In these subjects, the SVR12 rate was 88% (405/459).
Seventy‑eight percent (78%; 404/521) of OLYSIO‑treated subjects had undetectable HCV RNA at Week 4 (RVR); in these subjects the SVR12 rate was 90% (362/404), while 8% (32/392) with undetectable HCV RNA at end of treatment had viral relapse.
SVR12 rates were higher for the OLYSIO treatment group compared to the placebo treatment group by sex, age, race, BMI, HCV genotype/subtype, baseline HCV RNA load (less than or equal to 800000 IU/mL, greater than 800000 IU/mL), METAVIR fibrosis score, and IL28B genotype. Table 11 shows the SVR rates by METAVIR fibrosis score.
| Table 11: SVR12 Rates by METAVIR Fibrosis Score in Treatment‑Naïve Adult Patients with HCV Genotype 1 Infection (Pooled Data QUEST 1 and QUEST 2) | ||
| Subgroup | OLYSIO + PR % (n/N) | Placebo + PR % (n/N) |
| F0‑2 | 84 (317/378) | 55 (106/192) |
| F3‑4 | 68 (89/130) | 36 (26/72) |
| OLYSIO: 150 mg OLYSIO for 12 weeks with Peg‑IFN‑alfa‑2a or ‑2b and RBV for 24 or 48 weeks; Placebo: placebo for 12 weeks with Peg‑IFN‑alfa‑2a or ‑2b and RBV for 48 weeks. SVR12: sustained virologic response 12 weeks after planned EOT. |
SVR12 rates were higher for subjects receiving OLYSIO with Peg‑IFN‑alfa‑2a or Peg‑IFN‑alfa‑2b and RBV (88% and 78%, respectively) compared to subjects receiving placebo with Peg‑IFN‑alfa‑2a or Peg‑IFN‑alfa‑2b and RBV (62% and 42%, respectively) (QUEST 2).
Adult Subjects with HCV Genotype 1 Infection who Failed Prior Therapy
The PROMISE trial was a randomized, double‑blind, placebo‑controlled, 2‑arm, multicenter, Phase 3 trial in subjects with HCV genotype 1 infection who relapsed after prior IFN‑based therapy. All subjects received 12 weeks of once daily treatment with 150 mg OLYSIO or placebo, 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. Subjects in the control group received 48 weeks of Peg‑IFN‑alfa‑2a and RBV.
Demographics and baseline characteristics were balanced between the OLYSIO and placebo treatment groups. The 393 subjects enrolled in the PROMISE trial had a median age of 52 years (range: 20 to 71 years); 66% were male; 94% were White, 3% Black or African American, 2% Asian, and 7% Hispanic; 26% had a BMI greater than or equal to 30 kg/m2; 84% had HCV RNA levels greater than 800000 IU/mL; 69% had METAVIR fibrosis score F0, F1 or F2, 15% METAVIR fibrosis score F3, and 15% METAVIR fibrosis score F4 (cirrhosis); 42% had HCV genotype 1a, and 58% HCV genotype 1b; 24% had IL28B CC genotype, 64% IL28B CT genotype, and 12% IL28B TT genotype; 13% of the overall population and 31% of the subjects with genotype 1a virus had the NS3 Q80K polymorphism at baseline. The prior IFN‑based HCV therapy was Peg‑IFN‑alfa‑2a /RBV (68%) or Peg‑IFN‑alfa‑2b/RBV (27%).
Table 12 shows the response rates for the OLYSIO and placebo treatment groups in adult subjects with HCV genotype 1 infection who relapsed after prior interferon‑based therapy. In the OLYSIO treatment group, SVR12 rates were lower in subjects infected with genotype 1a virus with the NS3 Q80K polymorphism at baseline compared to subjects infected with genotype 1a virus without the Q80K polymorphism.
| Table 12: Treatment Outcome in Adult Subjects with HCV Genotype 1 Infection who Relapsed after Prior IFN‑Based Therapy (PROMISE; Intent‑to‑Treat Analysis) | ||
| Treatment Outcome | OLYSIO + PR N=260 % (n/N) | Placebo + PR N=133 % (n/N) |
| Overall SVR12 (genotype 1a and 1b) Genotype 1a Without Q80K With Q80K Genotype 1b | 79 (206/260) 70 (78/111) 78 (62/79) 47 (14/30) 86 (128/149) | 37 (49/133) 28 (15/54) 26 (9/34) 30 (6/20) 43 (34/79) |
| Outcome for all subjects without SVR12 | ||
| On‑treatment failure* | 3 (8/260) | 27 (36/133) |
| Viral relapse† | 18 (46/249) | 48 (45/93) |
| OLYSIO: 150 mg OLYSIO for 12 weeks with Peg‑IFN‑alfa‑2a and RBV for 24 or 48 weeks; Placebo: placebo for 12 weeks with Peg‑IFN‑alfa‑2a and RBV for 48 weeks. SVR12: sustained virologic response 12 weeks after planned EOT. * 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 5 OLYSIO‑treated subjects who experienced relapse after SVR12. |
In PROMISE, 93% (241/260) of OLYSIO‑treated subjects were eligible for a total treatment duration of 24 weeks. In these subjects, the SVR12 rate was 83% (200/241).
Seventy‑seven percent (77%; 200/260) of OLYSIO‑treated subjects had undetectable HCV RNA at Week 4 (RVR); in these subjects the SVR12 rate was 87% (173/200), while 13% (25/196) with undetectable HCV RNA at end of treatment had viral relapse.
SVR12 rates were higher for the OLYSIO treatment group compared to the placebo treatment group by sex, age, race, BMI, HCV genotype/subtype, baseline HCV RNA load (less than or equal to 800000 IU/mL, greater than 800000 IU/mL), prior HCV therapy, METAVIR fibrosis score, andIL28B genotype. Table 13 shows the SVR rates by METAVIR fibrosis score.
| Table 13: SVR12 Rates by METAVIR Fibrosis Score in Adult Patients with HCV Genotype 1 Infection who Relapsed after Prior Interferon‑Based Therapy (PROMISE) | ||
| Subgroup | OLYSIO + PR % (n/N) | Placebo + PR % (n/N) |
| F0‑2 | 82 (137/167) | 41 (40/98) |
| F3‑4 | 73 (61/83) | 24 (8/34) |
| OLYSIO: 150 mg OLYSIO for 12 weeks with Peg‑IFN‑alfa‑2a and RBV for 24 or 48 weeks; Placebo: placebo for 12 weeks with Peg‑IFN‑alfa‑2a and RBV for 48 weeks. SVR12: sustained virologic response 12 weeks after planned EOT. |
The ASPIRE trial was a randomized, double‑blind, placebo‑controlled, 7‑arm, Phase 2b trial in subjects with HCV genotype 1 infection, who failed prior therapy with Peg‑IFN‑alfa and RBV (including prior relapsers, partial responders or null responders). Subjects received 12, 24 or 48 weeks of 100 mg or 150 mg OLYSIO in combination with 48 weeks of Peg‑IFN‑alfa‑2a and RBV, or 48 weeks of placebo in combination with 48 weeks of Peg‑IFN‑alfa‑2a and RBV.
Demographics and baseline characteristics were balanced between the OLYSIO and placebo treatment groups. The 462 subjects enrolled in the ASPIRE trial had a median age of 50 years (range: 20 to 69 years); 67% were male; 93% were White, 5% Black or African American, and 2% Asian; 25% had a BMI greater than or equal to 30 kg/m2; 86% had HCV RNA levels greater than 800000 IU/mL; 63% had METAVIR fibrosis score F0, F1, or F2, 19% METAVIR fibrosis score F3, and 18% METAVIR fibrosis score F4 (cirrhosis); 41% had HCV genotype 1a, and 58% HCV genotype 1b; 18% had IL28B CC genotype, 65% IL28B CT genotype, and 18% IL28B TT genotype (information available for 328 subjects); 12% of the overall population and 27% of the subjects with genotype 1a virus had the NS3 Q80K polymorphism at baseline. Forty percent (40%) of subjects were prior relapsers, 35% prior partial responders, and 25% prior null responders following prior therapy with Peg‑INF‑alfa and RBV. One hundred ninety‑nine subjects received OLYSIO 150 mg once daily (pooled analysis) of which 66 subjects received OLYSIO for 12 weeks and 66 subjects received placebo in combination with Peg‑IFN‑alfa and RBV.
Table 14 shows the response rates for the OLYSIO and placebo treatment groups in prior relapsers, prior partial responders and prior null responders.
| Table 14: Treatment Outcome in Adult Subjects with HCV Genotype 1 Infection who Failed Prior Peg‑IFN‑alfa and RBV Therapy (ASPIRE Trial, Prior Partial and Null Responders) | |||
| Treatment Outcome | 150 mg OLYSIO 12 Weeks + PR N=66 % (n/N) | Pooled 100 mg and 150 mg OLYSIO 12 Weeks + PR N=132 % (n/N) | Placebo + PR N=66 % (n/N) |
| SVR24 | |||
| Prior relapser | 77 (20/26) | 83 (44/53) | 37 (10/27) |
| Prior partial responders | 65 (15/23) | 67 (31/46) | 9 (2/23) |
| Prior null responders | 53 (9/17) | 45 (15/33) | 19 (3/16) |
| Outcome for all subjects without SVR24 | |||
| On‑treatment virologic failure* | |||
| Prior relapser | 8 (2/26) | 6 (3/53) | 22 (6/27) |
| Prior partial responders | 22 (5/23) | 20 (9/46) | 78 (18/23) |
| Prior null responders | 35 (6/17) | 36 (12/33) | 75 (12/16) |
| Viral Relapse† | |||
| Prior relapser | 13 (3/23) | 8 (4/49) | 47 (9/19) |
| Prior partial responders | 6 (1/17) | 8 (3/36) | 50 (2/4) |
| Prior null responders | 18 (2/11) | 20 (4/20) | 25 (1/4) |
| 150 mg OLYSIO: 150 mg OLYSIO for 12 weeks with Peg‑IFN‑alfa‑2a and RBV for 48 weeks; Placebo: placebo with Peg‑IFN‑alfa‑2a and RBV for 48 weeks. SVR24: sustained virologic response 24 weeks after planned EOT. * On‑treatment virologic failure was defined as the proportion of subjects who met the protocol‑specified treatment stopping rules (including stopping rule due to viral breakthrough) or who had detectable HCV RNA at EOT (for subjects who completed therapy). † Viral relapse rates are calculated with a denominator of subjects with undetectable HCV RNA at EOT and with at least one follow‑up HCV RNA assessment. |
In prior partial responders, SVR24 rates in subjects receiving OLYSIO with Peg‑IFN‑alfa and RBV were 47% and 77% in subjects with HCV genotype 1a and 1b, respectively, compared to 13% and 7%, respectively, in subjects receiving placebo with Peg‑IFN‑alfa and RBV. In prior null responders, SVR24 rates in subjects receiving OLYSIO with Peg‑IFN‑alfa and RBV were 41% and 47% in subjects with HCV genotype 1a and 1b, respectively, compared to 0% and 33%, respectively, in subjects receiving placebo with Peg‑IFN‑alfa and RBV.
SVR24 rates were higher in the OLYSIO‑treated subjects compared to subjects receiving placebo in combination with Peg‑IFN‑alfa and RBV, regardless of HCV geno/subtype, METAVIR fibrosis score, and IL28B genotype.
The complete label will be available soon at Drugs@FDA
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
Manage your FDA Subscriptions:
- Update your preferences or unsubscribe
- Questions about this service? Please visit subscriberhelp.govdelivery.com
- Other inquiries? webmail@oc.fda.gov
