The hepatitis C protease inhibitor simeprevir (formerly TMC435) was generally safe and well tolerated in people with advanced liver fibrosis or cirrhosis and improved sustained response rates when added to pegylated interferon and ribavirin, researchers reported at The Liver Meeting 2012, the 63^rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) last week in Boston. Two related reports showed that simeprevir is not implicated in drug-drug interactions.

The recent approval of the first direct-acting hepatitis C drugs has ushered in a new era of treatment. Whilst many people with hepatitis C look forward to interferon-free oral regimens, patients with advanced liver disease may not have time to wait and will need to use direct-acting agents with pegylated interferon/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, two phase 2b randomised 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 favourable 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 receive 75 or 150mg once-daily simeprevir or placebo in combination with pegylated interferon alfa-2a (Pegasys) and 1000-1200mg/day weight-adjusted ribavirin for 12 or 24 weeks. Using a response-guided therapy algorithm, people who achieved HCV suppression by week 4 and remained undetectable from weeks 12 to 24 could stop treatment at that point; otherwise they continued on pegylated interferon/ribavirin alone through week 48.

ASPIRE enrolled about 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 receive 100 or 150mg once-daily simeprevir or placebo with pegylated interferon/ribavirin for 12, 24 or 48 weeks; the 12- and 24-week arms then continued on pegylated interferon/ribavirin alone through week 48.

Overall, as previously reported, both studies found that adding simeprevir to pegylated interferon/ribavirin led to significantly higher sustained virological response rates after completion of treatment. Simeprevir was generally safe and well tolerated, with the only notable added side-effect being elevated bilirubin. (Overall PILLAR and ASPIRE results were presented in a poster at this year’s Liver Meeting.)

Poordad’s presentation reported findings from a post hoc analysis of the safety and efficacy of triple therapy amongst participants with advanced liver damage in the two trials who received 150mg simeprevir – the dose selected for further development. The pooled analysis included 26 treatment-naive people with F3 fibrosis from PILLAR as well as 42 treatment-experienced participants with F3 fibrosis and 49 with 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 in the early fifties. Just over half had hard-to-treat HCV subtype 1a. People with very low platelet counts or decompensated cirrhosis were excluded.

Amongst the 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. Sixteen of the nineteen patients were eligible for response-guided therapy, and within this subgroup the SVR₂₄ rate reached 94%.

Amongst the PILLAR participants who experienced treatment failure on simeprevir, one (5%) had viral breakthrough and two (12%) relapsed. Amongst the ASPIRE participants, the corresponding proportions were 12 and 20%, respectively; in addition five people (7%) stopped treatment early because they met futility rules.

Simeprevir triple therapy was generally safe and well tolerated in these 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, but these were mostly mild or moderate in intensity.

Grade 3/4 adverse events occurred in 43% of simeprevir recipients and 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 for this reason.

Turning to laboratory abnormalities, 16% of simeprevir recipients and 27% of those on pegylated interferon/ribavirin alone developed at least moderate anaemia, but none in either group had severe anaemia.

Grade 3 total bilirubin elevations occurred in 7 and 3%, respectively, but again none had severe hyperbilirubinemia. The researchers noted that bilirubin changes were transient, generally mild or moderate, were not associated with elevated ALT or AST (enzymes signalling liver inflammation) and rarely led to discontinuation.

Reassuringly, the frequencies of serious adverse events, laboratory abnormalities and withdrawals amongst people with advanced fibrosis or cirrhosis were similar to those seen amongst participants with absent (stage F0), mild (stage F1) or moderate (stage F2) liver fibrosis receiving the same treatment assignments in the study populations as a whole.

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

Two 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 two 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 two 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 metabolised by the CYP3A4 enzyme and another pathway known as P–glycoprotein, or P-gp.  The two currently approved direct-acting HCV drugs, boceprevir (Victrelis) and telaprevir (Incivo), were found to significantly increase cyclosporine and tacrolimus levels through their effect on CYP3A4 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 randomised crossover trial to evaluate pharmacokinetic interactions between 150mg simeprevir and single doses of 100mg cyclosporine or 2mg tacrolimus in 28 healthy volunteers without hepatitis C. Participants were divided roughly evenly between men and women, all but two were white and the median age was about 46 years.

The pharmacokinetic profile of simeprevir – or how levels changed in the body after administration – was comparable whether given alone or with cyclosporine or tacrolimus. When taken with simeprevir, maximum (C_max) 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.

Side-effects, especially headaches, were somewhat more common when drugs were combined, but all were mild to moderate with no serious adverse events reported.

The researchers concluded that co-administration of simeprevir with single doses of cyclosporine or tacrolimus was “generally safe and well tolerated in healthy volunteers”. “Changes observed in [pharmacokinetic] parameters of cyclosporine and tacrolimus were not clinically relevant,” they added.

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 said that this study was 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 co-infected patients.

A poster presentation by the Janssen team at the Liver Meeting showed that simeprevir also has no clinically relevant pharmacokinetic interactions with oral contraceptive pills containing ethinylestradiol and norethindrone, which are also metabolised by CYP3A4 enzyme. This finding is important because women taking part in hepatitis C treatment trials must use effective contraception as ribavirin can cause birth defects.

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

Simeprevir co-developer Medivir recently announced 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 (Norvir), with or without ribavirin. 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 studies in the works will test interferon-free oral regimens of simeprevir plus Bristol-Myers Squibb’s NS5A inhibitor daclatasvir, Gilead Science’s nucleotide analogue polymerase inhibitor sofosbuvir (GS-7977) or Vertex’s nucleotide analogue VX-135 (also known as ALS-2200), all in genotype 1 patients.