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AASLD: Once-Daily HCV Protease Inhibitors Show Early Promise
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MedPage Today
November 03, 2009
BOSTON -- Two investigational drugs targeting the hepatitis C virus (HCV) protease enzyme helped patients clear the virus with once-daily dosing, contrasting with the three-times-per-day schedule needed for similar drugs in development, researchers reported here in separate studies.
At least 85% of patients adding narlaprevir (formerly called SCH 900518) to pegylated interferon-alfa-2b (PEGIntron) and ribavirin (Rebetol) after four weeks achieved rapid virological responses, compared with no patients receiving only interferon and ribavirin, according John Vierling, MD, of Baylor College of Medicine in Houston.
Early virologic responses, defined as viral clearance after 12 weeks of treatment, also occurred in 85% to 87% of patients receiving narlaprevir after the interferon-ribavirin lead-in, versus 17% of patients in the control arm.
Comparable results were reported for another investigational compound, BI 201355, by Mark Sulkowski, MD, of Johns Hopkins University. The drug, also given once daily with interferon-ribavirin, led to HCV RNA becoming undetectable by week 12 in up to 90% of patients.
Action Points
* Explain to interested patients that narlaprevir and BI 201355 are not FDA approved for any purpose and are only available in a clinical trial setting.
* Note that these studies were published as abstracts and presented at a conference. These data and conclusions should be considered preliminary until published in a peer-reviewed journal.
Vierling and Sulkowski reported interim results from ongoing Phase II trials of the two drugs here in a late-breaking abstract session at the American Association for the Study of Liver Disease's annual meeting.
Narlaprevir
By itself, narlaprevir is eliminated rapidly from circulation, as are boceprevir and telaprevir, the HCV protease inhibitors farthest along in development (now in Phase III testing). Those drugs must be given three times daily. Vierling said the multiple dosing schedule is a source of compliance problems for HCV-infected patients.
But co-administering narlaprevir with 100 mg of the anti-HIV drug ritonavir -- one-twelfth the dose normally given to HIV patients -- interferes with narlaprevir's metabolism by the CYP3A4 enzyme, prolonging its half-life enough that a single daily dose is feasible, Vierling said.
In the current study, called NEXT-1, several permutations of the narlaprevir-ritonavir and interferon-ribavirin combinations are being tested.
The study has enrolled 111 patients, all with HCV genotype 1.
Three dose levels of narlaprevir (200 or 400 mg once daily or 100 mg twice daily), combined with 100 mg of ritonavir, were initiated simultaneously with pegylated interferon and ribavirin at standard doses.
Two other treatment arms were established in which the two once-daily doses of narlaprevir plus ritonavir were started after patients had been on the interferon-ribavirin combination for four weeks.
A sixth group took only interferon and ribavirin, which is the current standard of care for HCV antiviral treatment.
In the five groups receiving narlaprevir, the drug was given for 12 weeks, with interferon and ribavirin continued for an additional 12 or 36 weeks, depending on patients' virologic responses after the first four weeks of treatment.
In the two arms involving delayed narlaprevir, virologic clearance within four weeks occurred in 85% to 87% of patients, Vierling reported.
Starting narlaprevir and ritonavir simultaneously with interferon and ribavirin appeared to be a less successful strategy, with 58% to 75% of patients in those arms achieving rapid virologic responses.
Vierling said that dosing narlaprevir twice daily actually reduced its efficacy, presumably because maximal plasma levels of the drug were about half those seen with the once-daily administration of higher doses.
Mild to moderate anemia and mild neutropenia were the main adverse events that appeared to be related to the narlaprevir-ritonavir treatment. Vierling said no patients discontinued treatment because of anemia, and the neutropenia had no clinical consequences.
Dizziness was also seen more often with narlaprevir, but also was relatively mild, Vierling said.
Other adverse effects, such as fatigue, nausea, headache, and skin rashes occurred in the control arm and with narlaprevir.
BI 201355
The other once-daily protease inhibitor described here, BI 201355, does not require co-administration of another agent to keep it active for a full day.
Sulkowski reported that the drug led to rapid virological responses in most patients, with 62% to 77% showing viral clearance within four weeks of starting the drug.
Unlike narlaprevir, however, a four-week lead-in with interferon and ribavirin did not boost BI 201355's effectiveness. The highest response rates at weeks four and 12 were seen with 240 mg of the drug started simultaneously with interferon-ribavirin, at 77% and 90%, respectively.
Response rates among patients receiving the same dosage of BI 201355 with the four-week lead-in were 62% and 80%, respectively.
Approximately 450 patients took part in the four-arm trial, which also included a control group receiving only interferon and ribavirin. Viral clearance after four and 12 weeks in the control group was seen in 4.2% and 42% of patients, respectively, significantly lower than in the groups taking BI 201355 (P<0.05).
As in the NEXT-1 trial, all patients had HCV genotype 1.
Sulkowski said skin rashes were the chief adverse effects of concern with the drug. Most cases were mild and patients were able to stay on the drug. But 27% to 33% of patients in the higher-dose BI 201355 groups developed rashes, compared with about 13% of the control group.
Jaundice was also seen in up to 20% of patients treated with BI 201355. Less than 2% of the control patients developed the condition.
Scott Friedman, MD, of Mount Sinai School of Medicine in New York City, who was not involved in the study, said he was skeptical about the need for once-daily dosing in HCV infected patients.
He said his experience is that most patients understand the importance of keeping to their dosing schedules.
"The patients I see, they get it," Friedman said.
But he added that compliance may be more of a problem with new patients, compared with those who have been on therapy for a while.
The narlaprevir study was funded by Schering-Plough.
The BI 201355 study was funded by Boehringer Ingelheim.
Vierling reported relationships with Schering-Plough, Abbott, Bristol-Myers Squibb, Gilead, Roche, Salix, Vertex, Hepa-Life Technologies, Arbios Systems, Axcan, Indenix, Novartis, Wyeth, GlobeImmune, Zymogenetics, Ocera, Intercept, Conatus, Pharmasset, and Pfizer.
Several co-authors were employees of Schering-Plough.
Sulkowski reported relationships with Boehringer Ingelheim, Roche, Schering, Merck, Human Genome Sciences, Gilead, Vertex, Tibotec, Bristol-Myers Squibb, Pfizer, Medarex, Peregrine, Debiopharm, and Abbott. Several co-authors were employees of Boehringer Ingelheim.
Friedman reported relationships with Exalenz, sanofi-aventis, Axcan, Angion, Intercept, 7TM, Stromedix, and Celera.
Primary source: American Association for the Study of Liver Diseases
Source reference:
Vierling J, et al "Once daily narlaprevir (SCH 900518) in combination with PEGINTRON (peginterferon alfa-2b)/ribavirin for treatment-naïve subjects with genotype-1 CHC: Interim results from NEXT-1, a Phase 2a study" AASLD 2009; Abstract LB4.
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