HCV Rx

Simeprevir: A New NS3/4A Protease Inhibitor

Several novel direct-acting antivirals are currently under development in the rapidly evolving field of hepatitis C virus treatment. The newest protease inhibitor, simeprevir, was approved for the treatment of HCV genotype 1 infection in November and appears to offer a significantly improved tolerability profile over the existing protease inhibitors boceprevir and telaprevir.

Clinical Pharmacology

Nonstructural proteins comprising the HCV replication complex have been identified as important targets of direct-acting antivirals. The NS3/4A serine protease enzyme is closely involved in viral replication and is inhibited by simeprevir (Olysio, Janssen Therapeutics). Although NS3/4A protease also is the target of the existing protease inhibitors boceprevir (Victrelis, Merck) and telaprevir (Incivek, Vertex), these agents are both ketoamides with structures distinctly different from simeprevir, which is a novel macrocyclic compound.

Leah Molloy

Simeprevir is supplied as a 150-mg capsule to be taken once daily with food, which increases bioavailability by more than 60% compared with administration without food. Simeprevir is almost completely protein bound to both albumin and alfa 1-acid glycoprotein, which is unchanged in the setting of end-organ dysfunction. It is metabolized via oxidation by CYP3A enzymes in the liver, and coadministration with strong inducers or inhibitors of CYP3A are, thus, not recommended. Simeprevir is a substrate and inhibitor of both CYP3A and P-glycoprotein; however, only intestinal, not hepatic, and CYP3A enzymes appear to be inhibited by simeprevir in vivo. This offers an important advantage over boceprevir and telaprevir, which are both potent inhibitors of hepatic CYP3A4/5, leading to significantly more drug-drug interactions.

The relatively slow absorption and elimination of simeprevir allow once-daily dosing. It has a delayed (3-4 hours) time to maximal serum concentration and a slow dissociation from the protease enzyme. Simeprevir has a plasma half-life of 41 hours and undergoes biliary elimination. The pharmacokinetics of simeprevir are markedly different from the other NS3/4A protease inhibitors allowing once-daily administration of one capsule compared with three tablets twice daily of telaprevir or four capsules three-times daily boceprevir.

Of note, simeprevir contains a sulfonamide group. Although the 16 sulfa-allergic patients who received simeprevir in trials did not develop any skin reactions characteristic of allergic reaction, sufficient data do not exist regarding the safety of simeprevir for patients with sulfa allergy.

Indications and Regimens

Simeprevir is indicated for the treatment of HCV genotype 1 combined with peginterferon alfa and ribavirin. All three agents are given together followed by continued therapy with peginterferon alfa and ribavirin without simeprevir. The duration of continued peginterferon alfa and ribavirin depends on patient history, as summarized in Table 1. Similar to other HCV regimens, criteria have been established for early termination of therapy for patients failing to respond, for whom continued treatment is anticipated to be futile.

 
 Table 1.

 

Clinical Study Data

The phase 3 studies QUEST-1 and 2, PROMISE, and CONCERTO-1, 2, 3 and 4 gave patients standard treatment of ribavirin and peginterferon alfa (RBV + PEG) with or without simeprevir, depending on the study. Patients randomly assigned to placebo instead of simeprevir completed 48 weeks of RBV + PEG, with coadministration of placebo for the first 12 weeks. All patients who received simeprevir completed at least 24 weeks of treatment, composed of 12 weeks of simeprevir plus RBV + PEG followed by 12 weeks of RBV + PEG (except for those patients in CONCERTO-2 randomly assigned to 24 weeks of simeprevir plus RBV + PEG). After the first 24 weeks, response-guided therapy used specific criteria (HCV RNA <25 IU/mL at week 4 and undetectable HCV RNA at week 12) to permit treatment discontinuation at 24 weeks. Patients not meeting response-guided therapy criteria continued RPV + PEG treatment for 24 more weeks to complete a total of 48 weeks of therapy. Studies are further summarized in Table 2.

Table 2.  

 

Study patients were categorized as treatment-naive, prior relapsers or prior nonresponders. The primary efficacy endpoint for all studies was the proportion of patients achieving sustained virologic response at 12 weeks after the end of treatment (SVR12).

The QUEST-1 and QUEST-2 trials compared simeprevir plus RBV + PEG (n=521) with placebo plus RBV + PEG (n=261) in treatment-naive patients. SVR12 was attained by 80% of patients given the simeprevir-containing regimen compared with 50% of those who did not receive simeprevir.

The PROMISE trial used the same regimens administered in the QUEST trials, but all patients were prior relapsers rather than treatment-naive. SVR12 was achieved by 79% of the 260 patients administered simeprevir plus RBV + PEG compared with 36% of the 133 patients administered placebo plus RBV + PEG.

CONCERTO-1 found greater SVR12 attainment among treatment-naive patients randomly assigned to simeprevir plus RBV + PEG (89%) compared with placebo plus RBV + PEG (69%).

CONCERTO-2 randomly assigned prior nonresponders to simeprevir plus RBV + PEG for 12 (SMV12) or 24 (SMV24) weeks. Patients in the SMV12 group then received 12 more weeks of RBV + PEG, and response-guided therapy criteria were used to assign additional therapy with RBV + PEG as needed in both study arms. Regardless of total treatment duration, more patients who received 12 weeks of simeprevir achieved SVR12 than did those who received 24 weeks of simeprevir (53% vs. 36%).

CONCERTO-3 was a single-arm, open-label study of prior relapsers (n=49) assigned simeprevir plus RBV + PEG for 12 weeks followed by another 12 weeks of RBV + PEG alone. Nearly all of the patients met response-guided therapy criteria to stop treatment after 24 weeks and, of those, 96% achieved SVR12.

In CONCERTO-4, prior relapsers, prior nonresponders and treatment-naive patients were administered 12 weeks of simeprevir plus RBV + PEG followed by 12 to 36 weeks of RBV + PEG (response-guided therapy for prior relapsers and treatment-naive patients only, all prior nonresponders took RBV + PEG for 36 weeks to complete a total 48 weeks of treatment). SVR12 was achieved by 92% of treatment-naive patients, 100% of prior relapsers and 39% of prior nonresponders.

Special Consideration: Q80K Polymorphism

Viral mutations appear to confer altered response to simeprevir treatment. Of greatest interest is the NS3 polymorphism Q80K described in HCV genotype 1a.

In QUEST-1, patients with this mutation had similar treatment response regardless of whether they were randomly assigned to simeprevir or placebo, suggesting inactivation of simeprevir in the presence of a Q80K mutation. Although this outcome was not replicated in QUEST-2 or PROMISE, both studies noted differences in response. QUEST-2 found that patients with the Q80K mutation administered simeprevir had better response than those with the mutation administered placebo, and patients in the PROMISE trial who received simeprevir and did not have the Q80K mutation had greater SVR12 attainment than those with the polymorphism.

Thus, product labeling advises clinicians to screen patients with HCV genotype 1a for the presence of the Q80K polymorphism and to consider alternative therapy options.

Cost and Acquisition

The wholesale acquisition cost of a 28-capsule bottle of simeprevir is $22,120, or approximately $66,360 for a 12-week treatment course. For payment assistance, Janssen has developed its Olysio Savings Program to provide financial aid to qualifying patients by limiting co-payments to $25.

References:
Forns X. Gastroenterology. 2014;doi:10.1053/j.gastro.2014.02.051.
Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2013.
Iskowitz M. Olysio simeprevir cost Hepatitis C New Drug Research and Liver Health. Nov. 26, 2013. Available at: http://hepatitiscnewdrugresearch.com/-olysiotrade-simeprevir-cost.html.
Izumi N. J Gastroenterol. 2014; [Published online ahead of print March 14].
Jacobson I. J Hepatol. 2013;58:S574.
Johnson & Johnson. Primary efficacy and safety findings from four phase 3 Japanese studies of simeprevir administered once daily demonstrate sustained virologic response in genotype 1 chronic hepatitis C adult patients. June 6, 2013. Available at: http://www.investor.jnj.com/releasedetail.cfmReleaseID=769679.
Manns M. J Hepatol. 2013;58:S578.
Olysio [package insert]. Titusville, NJ: Janssen Products, LP; 2013.
Victrelis [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2013.
For more information:
Leah Molloy, PharmD, is a clinical pharmacist, specialist in infectious diseases, at Children’s Hospital of Michigan, Detroit. She can be reached at Children’s Hospital of Michigan, Department of Pharmacy Services, 3901 Beaubien St., Detroit, MI 48201; email: lmolloy@dmc.org.
Disclosure: Molloy reports no relevant financial disclosures.

Several novel direct-acting antivirals are currently under development in the rapidly evolving field of hepatitis C virus treatment. The newest protease inhibitor, simeprevir, was approved for the treatment of HCV genotype 1 infection in November and appears to offer a significantly improved tolerability profile over the existing protease inhibitors boceprevir and telaprevir.

Clinical Pharmacology

Nonstructural proteins comprising the HCV replication complex have been identified as important targets of direct-acting antivirals. The NS3/4A serine protease enzyme is closely involved in viral replication and is inhibited by simeprevir (Olysio, Janssen Therapeutics). Although NS3/4A protease also is the target of the existing protease inhibitors boceprevir (Victrelis, Merck) and telaprevir (Incivek, Vertex), these agents are both ketoamides with structures distinctly different from simeprevir, which is a novel macrocyclic compound.

Leah Molloy

Simeprevir is supplied as a 150-mg capsule to be taken once daily with food, which increases bioavailability by more than 60% compared with administration without food. Simeprevir is almost completely protein bound to both albumin and alfa 1-acid glycoprotein, which is unchanged in the setting of end-organ dysfunction. It is metabolized via oxidation by CYP3A enzymes in the liver, and coadministration with strong inducers or inhibitors of CYP3A are, thus, not recommended. Simeprevir is a substrate and inhibitor of both CYP3A and P-glycoprotein; however, only intestinal, not hepatic, and CYP3A enzymes appear to be inhibited by simeprevir in vivo. This offers an important advantage over boceprevir and telaprevir, which are both potent inhibitors of hepatic CYP3A4/5, leading to significantly more drug-drug interactions.

The relatively slow absorption and elimination of simeprevir allow once-daily dosing. It has a delayed (3-4 hours) time to maximal serum concentration and a slow dissociation from the protease enzyme. Simeprevir has a plasma half-life of 41 hours and undergoes biliary elimination. The pharmacokinetics of simeprevir are markedly different from the other NS3/4A protease inhibitors allowing once-daily administration of one capsule compared with three tablets twice daily of telaprevir or four capsules three-times daily boceprevir.

Of note, simeprevir contains a sulfonamide group. Although the 16 sulfa-allergic patients who received simeprevir in trials did not develop any skin reactions characteristic of allergic reaction, sufficient data do not exist regarding the safety of simeprevir for patients with sulfa allergy.

Indications and Regimens

Simeprevir is indicated for the treatment of HCV genotype 1 combined with peginterferon alfa and ribavirin. All three agents are given together followed by continued therapy with peginterferon alfa and ribavirin without simeprevir. The duration of continued peginterferon alfa and ribavirin depends on patient history, as summarized in Table 1. Similar to other HCV regimens, criteria have been established for early termination of therapy for patients failing to respond, for whom continued treatment is anticipated to be futile.

 
 Table 1.

 

Clinical Study Data

The phase 3 studies QUEST-1 and 2, PROMISE, and CONCERTO-1, 2, 3 and 4 gave patients standard treatment of ribavirin and peginterferon alfa (RBV + PEG) with or without simeprevir, depending on the study. Patients randomly assigned to placebo instead of simeprevir completed 48 weeks of RBV + PEG, with coadministration of placebo for the first 12 weeks. All patients who received simeprevir completed at least 24 weeks of treatment, composed of 12 weeks of simeprevir plus RBV + PEG followed by 12 weeks of RBV + PEG (except for those patients in CONCERTO-2 randomly assigned to 24 weeks of simeprevir plus RBV + PEG). After the first 24 weeks, response-guided therapy used specific criteria (HCV RNA <25 IU/mL at week 4 and undetectable HCV RNA at week 12) to permit treatment discontinuation at 24 weeks. Patients not meeting response-guided therapy criteria continued RPV + PEG treatment for 24 more weeks to complete a total of 48 weeks of therapy. Studies are further summarized in Table 2.

Table 2.  

 

Study patients were categorized as treatment-naive, prior relapsers or prior nonresponders. The primary efficacy endpoint for all studies was the proportion of patients achieving sustained virologic response at 12 weeks after the end of treatment (SVR12).

The QUEST-1 and QUEST-2 trials compared simeprevir plus RBV + PEG (n=521) with placebo plus RBV + PEG (n=261) in treatment-naive patients. SVR12 was attained by 80% of patients given the simeprevir-containing regimen compared with 50% of those who did not receive simeprevir.

The PROMISE trial used the same regimens administered in the QUEST trials, but all patients were prior relapsers rather than treatment-naive. SVR12 was achieved by 79% of the 260 patients administered simeprevir plus RBV + PEG compared with 36% of the 133 patients administered placebo plus RBV + PEG.

CONCERTO-1 found greater SVR12 attainment among treatment-naive patients randomly assigned to simeprevir plus RBV + PEG (89%) compared with placebo plus RBV + PEG (69%).

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CONCERTO-2 randomly assigned prior nonresponders to simeprevir plus RBV + PEG for 12 (SMV12) or 24 (SMV24) weeks. Patients in the SMV12 group then received 12 more weeks of RBV + PEG, and response-guided therapy criteria were used to assign additional therapy with RBV + PEG as needed in both study arms. Regardless of total treatment duration, more patients who received 12 weeks of simeprevir achieved SVR12 than did those who received 24 weeks of simeprevir (53% vs. 36%).

CONCERTO-3 was a single-arm, open-label study of prior relapsers (n=49) assigned simeprevir plus RBV + PEG for 12 weeks followed by another 12 weeks of RBV + PEG alone. Nearly all of the patients met response-guided therapy criteria to stop treatment after 24 weeks and, of those, 96% achieved SVR12.

In CONCERTO-4, prior relapsers, prior nonresponders and treatment-naive patients were administered 12 weeks of simeprevir plus RBV + PEG followed by 12 to 36 weeks of RBV + PEG (response-guided therapy for prior relapsers and treatment-naive patients only, all prior nonresponders took RBV + PEG for 36 weeks to complete a total 48 weeks of treatment). SVR12 was achieved by 92% of treatment-naive patients, 100% of prior relapsers and 39% of prior nonresponders.

Special Consideration: Q80K Polymorphism

Viral mutations appear to confer altered response to simeprevir treatment. Of greatest interest is the NS3 polymorphism Q80K described in HCV genotype 1a.

In QUEST-1, patients with this mutation had similar treatment response regardless of whether they were randomly assigned to simeprevir or placebo, suggesting inactivation of simeprevir in the presence of a Q80K mutation. Although this outcome was not replicated in QUEST-2 or PROMISE, both studies noted differences in response. QUEST-2 found that patients with the Q80K mutation administered simeprevir had better response than those with the mutation administered placebo, and patients in the PROMISE trial who received simeprevir and did not have the Q80K mutation had greater SVR12 attainment than those with the polymorphism.

Thus, product labeling advises clinicians to screen patients with HCV genotype 1a for the presence of the Q80K polymorphism and to consider alternative therapy options.

Cost and Acquisition

The wholesale acquisition cost of a 28-capsule bottle of simeprevir is $22,120, or approximately $66,360 for a 12-week treatment course. For payment assistance, Janssen has developed its Olysio Savings Program to provide financial aid to qualifying patients by limiting co-payments to $25.

References:
Forns X. Gastroenterology. 2014;doi:10.1053/j.gastro.2014.02.051.
Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2013.
Iskowitz M. Olysio simeprevir cost Hepatitis C New Drug Research and Liver Health. Nov. 26, 2013. Available at: http://hepatitiscnewdrugresearch.com/-olysiotrade-simeprevir-cost.html.
Izumi N. J Gastroenterol. 2014; [Published online ahead of print March 14].
Jacobson I. J Hepatol. 2013;58:S574.
Johnson & Johnson. Primary efficacy and safety findings from four phase 3 Japanese studies of simeprevir administered once daily demonstrate sustained virologic response in genotype 1 chronic hepatitis C adult patients. June 6, 2013. Available at: http://www.investor.jnj.com/releasedetail.cfmReleaseID=769679.
Manns M. J Hepatol. 2013;58:S578.
Olysio [package insert]. Titusville, NJ: Janssen Products, LP; 2013.
Victrelis [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2013.
For more information:
Leah Molloy, PharmD, is a clinical pharmacist, specialist in infectious diseases, at Children’s Hospital of Michigan, Detroit. She can be reached at Children’s Hospital of Michigan, Department of Pharmacy Services, 3901 Beaubien St., Detroit, MI 48201; email: lmolloy@dmc.org.
Disclosure: Molloy reports no relevant financial disclosures.