AASLD 2012: Simeprevir Safe and Effective for Hepatitis C Patients With Cirrhosis

The HCV protease inhibitor simeprevir (formerly TMC435) is generally safe and well-tolerated in people with advanced liver fibrosis or cirrhosis, and improves sustained response rates when added to pegylated interferon and ribavirin, researchers reported at the American Association for the Study of Liver Diseases Liver Meeting (AASLD 2012) last week in Boston. Related presentations showed that simeprevir is not implicated in drug-drug interactions with immunosuppressive agents or oral contraceptives.

The recent approval of the first direct-acting drugs targeting hepatitis C virus (HCV) has ushered in a new era of treatment. While many people with chronic hepatitis C look forward to interferon-free oral regimens, patients with advanced liver disease may not have time to wait, and will likely need to use direct-acting agents with pegylated interferon and ribavirin. As this group does not respond as well to interferon-based therapy and is less able to tolerate drug side effects, they need new add-ons that increase the likelihood of a cure with minimal extra toxicity.

Fred Poordad from Cedars-Sinai Medical Center in Los Angeles presented results from a subgroup analysis of participants with advanced liver fibrosis in the PILLAR and ASPIRE trials, a pair of Phase 2b randomized studies that assessed the safety and efficacy of simeprevir plus pegylated interferon and ribavirin in people with genotype 1 HCV.

TMC435 is a once-daily HCV NS3/4A protease inhibitor being jointly developed by Janssen Therapeutics (formerly Tibotec) and Medivir. Early studies showed that it has potent activity against HCV genotype 1, lesser activity against genotypes 2, 4, 5, and 6, and a favorable safety profile.

The PILLAR trial enrolled 386 treatment-naive genotype 1 chronic hepatitis C patients including people with advanced fibrosis (Metavir stage F3). Participants were randomly assigned to receive75 mg or 150 mg once-daily simeprevir or placebo in combination with pegylated interferon alfa-2a (Pegasys) and 1000-1200 mg/day weight-adjusted ribavirin for 12 or 24 weeks. Using a response-guided therapy (RGT) algorithm, people who achieved HCV suppression by week 4 and still had undetectable viral load from weeks 12 through 24 could stop treatment at that point; otherwise, they continued on pegylated interferon/ribavirin alone through week 48.

ASPIRE enrolled 462 treatment-experienced genotype 1 hepatitis C patients -- prior relapsers, partial responders, and null responders -- including people with advanced fibrosis or cirrhosis (Metavir stage 4). They were randomly assigned to receive100 mg or 150 mg once-daily simeprevir or placebo in combination with pegylated interferon/ribavirin for 12, 24, or 48 weeks; the 12- and 24-week arms continued on pegylated interferon/ribavirin alone through week 48.

As previously reported, the studies showed that adding simeprevir to pegylated interferon/ribavirin led to significantly higher sustained virological response rates for both treatment-naive patients in PILLAR and previously treated patients in ASPIRE. Simeprevir was generally safe and well tolerated, with the only notable added side effect being elevated bilirubin levels. The overall PILLAR and ASPIRE results were also presented in a poster at this year's Liver Meeting.

Poordad's presentation focused on findings from a post hoc analysis of the safety and efficacy of triple therapy among participants in the 2 trials who received 150 mg simeprevir -- the dose selected for further development. The pooled analysis included 26 treatment-naive people with stage F3 fibrosis from PILLAR, as well as 42 treatment-experienced participants with stage F3 fibrosis and 49 with stage F4 cirrhosis from ASPIRE.

A majority of participants (85% from PILLAR and about 65% from ASPIRE) were men, more than 90% were white, and the median age was about 52 years. Just over half had hard-to-treat HCV subtype 1a. People with very low platelet counts or decompensated cirrhosis were excluded.

Results

• Among previously untreated participants in PILLAR, 79% of those who received simeprevir triple therapy achieved sustained virological response 24 weeks after the end of treatment (SVR24), compared with 71% of those in the placebo arm.
• 16 of the 19 treatment-naive patients were eligible for response-guided therapy, and within this subgroup the SVR24 rate reached 94%.
• The difference in response was much greater for treatment-experienced people in ASPIRE.
• Among participants with stage F3 fibrosis, 56% who received triple therapy achieved SVR24, compared with just 4% -- that is, 1 prior partial responder -- who received pegylated interferon/ribavirin alone.
• Among people with stage F4 cirrhosis, 62% in the simeprevir arm, but none in the control group, achieved SVR24:

o   65% of previous relapsers;

o   67% of partial responders;

o   33% of null responders.

• Among PILLAR participants who experienced treatment failure on simeprevir, 1 (5%) had viral breakthrough and 2 (12%) relapsed after the end of treatment.
• Among ASPIRE participants with treatment failure, the corresponding proportions were 12% and 20%, respectively; 5 additional patients (7%) stopped treatment early due to futility rules.
• Simeprevir triple therapy was generally safe and well-tolerated in patients with advanced liver damage.
• Almost all participants in all study arms reported some side effects, the most common being fatigue, flu-like symptoms, itching, and rash.
• Grade 3/4 adverse events occurred in 43% of simeprevir recipients compared with 27% of those on pegylated interferon/ribavirin alone.
• Serious adverse event rates were 8% and 10%, respectively.
• 9% of patients taking triple therapy, but none in the control arm, stopped treatment early due to adverse events.
• 16% of simeprevir recipients and 27% of those on pegylated interferon/ribavirin alone developed at least moderate anemia, but none in either group had severe anemia.
• Grade 3 total bilirubin elevations occurred in 7% and 3%, respectively, but none had severe hyperbilirubinemia.
• Bilirubin changes were transient, generally mild or moderate, not associated with elevated ALT or AST, and rarely led to discontinuation.
• Frequencies of serious adverse events, laboratory abnormalities, and withdrawals were similar to those seen among participants with absent (stage F0), mild (stage F1), or moderate (stage F2) liver fibrosis receiving the same treatment assignments in the study as a whole.

In conclusion, the investigators reported "promising SVR rates with simeprevir 150 mg in HCV genotype 1-infected treatment-naive and -experienced patients." In particular, they emphasized the 33% response rate for prior null responders with advanced fibrosis/cirrhosis -- one of the most difficult groups to treat.

Simeprevir Drug Interactions

A pair of related presentations at the Liver Meeting reported findings from drug-drug-interaction studies with simeprevir.

People undergoing treatment for chronic hepatitis C often have co-existing conditions that require use of other medications, which can pose a risk of drug-drug interactions. When 2 or more drugs are processed by the same pathways, accelerated metabolism can lead to low drug levels with poor efficacy, or conversely, slowed metabolism can result in high drug levels with intensified side effects.

Sivi Ouwerkerk-Mahadevan and colleagues from Janssen looked at interactions between simeprevir and 2 immunosuppressive drugs, cyclosporine and tacrolimus. Hepatitis C patients may need these drugs to prevent organ rejection after a liver transplant.

Cyclosporine and tacrolimus are calcineurin inhibitors metabolized by the CYP3A4 enzyme and another pathway known as P-glycoprotein (P-gp). The 2 currently approved direct-acting HCV drugs -- boceprevir (Victrelis) and telaprevir (Incivek) -- significantly increase cyclosporine and tacrolimus levels through their effect on CYP3A4 activity in the liver, the researchers noted as background. Simeprevir is a weak inhibitor of P-glycoprotein and CYP3A4 in the gut, but not in the liver.

The Janssen team conducted a Phase 1 randomized crossover trial to evaluate pharmacokinetic interactions between 150 mg simeprevir and single doses of 100 mg cyclosporine or 2 mg tacrolimus in 28 healthy volunteers without hepatitis C. Participants were roughly evenly divided between men and women, all but 2 were white, and the median age was about 46 years.

Results

• The pharmacokinetic profile of simeprevir was comparable whether given alone or co-administered with cyclosporine or tacrolimus.
• When taken with simeprevir, maximum (Cmax) and overall (AUC) cyclosporine concentrations were 16% and 19% higher, respectively, than they were when taken alone.
• In contrast, maximum and overall levels of tacrolimus were 24% and 17% lower, respectively, when taken with simeprevir.
• Adverse events, especially headaches, were somewhat more common when drugs were combined.
• However, all side effects were mild to moderate, with no serious adverse events reported.

Co-administration of simeprevir with single doses of cyclosporine or tacrolimus was "generally safe and well tolerated in healthy volunteers," the researchers concluded. "Changes observed in [pharmacokinetic] parameters of cyclosporine and tacrolimus were not clinically relevant."

No dose adjustment of cyclosporine or tacrolimus would be required if administered with simeprevir, they suggested, but "concentrations of both immunosuppressive agents should be monitored according to standard clinical practice."

Ouwerkerk-Mahadevan noted that this study had been done in preparation for clinical trials of simeprevir in transplant recipients, but such studies are not yet underway.

At this year's Retrovirus conference in March, Ouwerkerk-Mahadevan reported findings from a drug-drug interaction study of simeprevir and widely used antiretroviral drugs in healthy volunteers, in preparation for clinical trials of simeprevir in HIV/HCV coinfected patients.

They concluded that no dose adjustments are needed when combining simeprevir with rilpivirine (Edurant), tenofovir (Viread), or raltegravir (Isentress), but co-administration with efavirenz (Sustiva) is not recommended.

Finally, a poster presentation by the Janssen team last week showed that simeprevir has no clinically relevantpharmacokinetic interactions with oral contraceptive pills containing ethinylestradiol and norethindrone, which are also metabolized by CYP3A4. This finding is important because women participating in hepatitis C treatment trials must use effective contraception because ribavirin can cause birth defects.

Interferon-free Simeprevir

While interferon-based therapy with new direct-acting agents remains necessary for many people with hepatitis C, excitement at the Liver Meeting largely focused on interferon-free regimens.

Simeprevir co-developer Medivir announced in September that a Phase 2 trial, now recruiting, is looking at an all-oral regimen of simeprevir plus the investigational non-nucleoside HCV polymerase inhibitor TMC647055 boosted with ritonavir, with or without ribavirin (www.clinicaltrials.gov/ct2/show/NCT01724086). This study will enroll treatment-naive patients with HCV genotype 1, as well as prior relapsers and null responders.

In a press release issued earlier this month, Medivir said that other Phase 2 trials in the works will test interferon-free oral regimens of simeprevir plus Bristol-Myers Squibb's NS5A inhibitor daclatasvir (www.clinicaltrials.gov/ct2/show/NCT01628692), Gilead Science'snucleotide analog polymerase inhibitor sofosbuvir (GS-7977), or Vertex’s nucleotide analog VX-135 (also known as ALS-2200), all in genotype 1 patients.

11/19/12

References

F Poordad, MW Fried, S Zeuzem,et al. Efficacy and tolerability of TMC435 150 mg once daily with peginterferon α-2a and ribavirin for treatment of HCV genotype 1 infection in patients with Metavir score F3 and F4 (PILLAR and ASPIRE trials). 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2012). Boston, November 9-13, 2012. Abstract 83.

MW Fried, F Poordad, S Zeuzem, et al. Safety and tolerability of TMC435 in combination with peginterferon α-2a and ribavirin for treatment of HCV genotype 1 infection in treatment-naive and -experienced patients (PILLAR and ASPIRE trials). 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2012). Boston, November 9-13, 2012. Abstract 769.

S Ouwerkerk-Mahadevan, A Simion, S Mortier, et al. No clinically significant interaction between the investigational HCV protease inhibitor TMC435 and the immunosuppressives cyclosporine and tacrolimus. 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2012). Boston, November 9-13, 2012. Abstract 80.

S Ouwerkerk-Mahadevan, M Beumont, KF Spittaels, et al. No pharmacokinetic interaction between the investigational HCV protease inhibitor TMC435 and an oral contraceptive containing ethinylestradiol and norethindrone. 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2012). Boston, November 9-13, 2012. Abstract 773.

Other Sources

Janssen Pharmaceuticals. Efficacy and Safety Data from Phase 2B Trials of Janssen’s Simeprevir in Hepatitis C Patients with Advanced Fibrosis of the Liver Presented at Annual Meeting of the American Association for the Study of Liver Diseases. Press release. November 10, 2012.

Medivir AB. Medivir announces a phase II all-oral study of Simeprevir (TMC435) and VX-135 for the treatment of Hepatitis C to be conducted by Janssen and Vertex. Press release. November 1, 2012.