ISSUE: JUNE 2011 | VOLUME: 62:06
by Rosemary Frei
On the heels of data presented at the 46th annual meeting of the European Association for the Study of the Liver (EASL) meeting and this year’s Digestive Disease Week meeting came the FDA approval of two new drugs designed to boost the effectiveness of peginterferon-ribavirin therapy for patients with chronic hepatitis C virus (HCV) genotype 1 infection. On May 13, the FDA approved boceprevir (Victrelis, Merck) followed days later by the approval of telaprevir (Incivek, Vertex/Tibotec), marking an eagerly anticipated revolution in the management of patients with HCV.
Cascade of DataData on the new drugs have not been in short supply. An article published last year in The New England Journal of Medicine on the use of telaprevir for previously treated patients with chronic HCV genotype 1 infection brought this new class of agents—inhibitors of HCV protease—into the spotlight (McHutchison JG et al. 2010;362:1292-1303). The results of the randomized, double-blind phase II study—known as PROVE3 (Protease Inhibition for Viral Evaluation 3)—indicated that the addition of telaprevir for as few as 12 weeks significantly increased sustained virologic response (SVR).
Two Phase III studies published in March indicated that boceprevir also boosted efficacy in as few as 24 weeks. Results of the RESPOND-2 (Retreatment with HCV Serine Protease Inhibitor Boceprevir and Peginterferon/Rebetol 2) trial indicated that the three-drug cocktail nearly tripled SVR rates in previously treated patients (Bacon BR et al. N Engl J Med 2011;364:1207-1217). Furthermore, data from the SPRINT-2 (Serine Protease Inhibitor Therapy 2) trial also showed that SVR rates in treatment-naïve patients are boosted significantly with the addition of boceprevir (Poordad F et al. N Engl J Med 2011;364:1195-1206).
Final results from the Phase III REALIZE (Re-treatment of Patients with Telaprevir-based Regimen to Optimize Outcomes) trial also were presented at the EASL meeting. These data included all three major subgroups of patients who were not cured with a prior course of interferon-based therapy, including null responders.
All of the boceprevir studies were paid for by Merck, and the telaprevir studies were sponsored by Vertex and its collaborator, Tibotec.
Stephen H. Caldwell, MD, professor of medicine and director of hepatology, University of Virginia Health System, Charlottesville, pointed out that the emerging therapies for hepatitis C offer a significant increase in sustained viral eradication but also bring treatment complexity, side effects and expense.
“Emerging from the myriad of study names are new monitoring recommendations and prognostic indicators that will take time to really understand,” Dr. Caldwell said. “We should recall that the best-performed studies are closely monitored, often at a level unachievable in clinical practice. Clearly, the field has changed rapidly in a very short period of time. Careful assessment and thoughtful consideration will be key to optimizing success and minimizing failure,” he said.
Boceprevir Trials
In a poster presented at the EASL meeting, John M. Vierling, MD, and colleagues from Baylor College of Medicine in Houston analyzed the relationship between patients’ response during the lead-in period in the boceprevir trials and overall SVR rates. The investigators defined response during the lead-in period as at least a 1.0-log10 reduction in HCV RNA. Data from the SPRINT-2 and RESPOND-2 trials were combined for this study.
The researchers found a steady, stepwise increase in the percentage of patients achieving SVR after at least 24 weeks of triple-agent therapy based on the level of decrease in viral load after the four-week lead-in period with peginterferon-ribavirin alone. The pattern was particularly noticeable among non-black patients. Overall, the advantage of adding boceprevir was greatest for patients with less responsiveness to interferon.
“Patients in the boceprevir arms with a poor response to interferon had sufficiently high rates of SVR as compared with the control group. … [This] dispels concern that the addition of boceprevir to the treatment regimen would be the equivalent of functional monotherapy,” the investigators noted. “However, patients who have a poor response to the interferon may need to be monitored closely to determine who may benefit from better therapies, once they are available.”
They add that conversely, addition of boceprevir may not boost SVR rates among patients with undetectable HCV RNA levels after the lead-in period, but that “in the majority of these patients, total treatment duration is shortened to 28 weeks.”
The four most common treatment-related adverse events (AEs) in the RESPOND-2 and SPRINT-2 studies were fatigue, headache, nausea and anemia. In RESPOND-2, treatment discontinuation due to anemia occurred in 3% of boceprevir patients in 48-week treatment only. None of the controls discontinued due to anemia. The respective numbers for SPRINT-2 were 2%, 2% and 1%.
Erythropoietin was allowed for the treatment of anemia at the discretion of the investigators, and in RESPOND-2 was used by 41% and 46% of boceprevir patients in the response-guided and 48-week treatment arms, respectively, compared with 21% of patients in the control arm. In SPRINT-2, the respective numbers were 43%, 43% and 24%. (P values were not supplied.)
Fred Poordad, MD, chief of hepatology and liver transplantation at the Comprehensive Transplant Center at Cedars-Sinai Medical Center in Los Angeles, and lead investigator of the SPRINT-2 trial, gave a talk at the EASL meeting outlining the utility of using an interleukin (IL)-28B polymorphism as a baseline predictor of four- and eight-week response to triple-agent therapy. Dr. Poordad and colleagues from the SPRINT-2 and RESPOND-2 trials examined on SVR rates in patients with three different IL-28B polymorphisms: cysteine–cysteine, thymine–thymine and cysteine–thymine. They determined that the cysteine–cysteine polymorphism is associated most strongly with SVR response; patients with this polymorphism may be eligible for short-duration therapy.
Dr. Poordad’s team also found that lead-in response is a stronger predictor of SVR than any other single baseline characteristic, including IL-28B polymorphism. They concluded that because IL-28B polymorphism status and lead-in response “are powerful predictors of SVR,” the optimal approach may be to use both.
“Taken together, these data showed that the addition of boceprevir to peginterferon and ribavirin achieved significantly higher SVR rates in patients with chronic HCV genotype 1 compared with peginterferon and ribavirin alone, and that nearly half of all patients were eligible to receive a shorter duration of therapy,” Dr. Poordad said.
Telaprevir Trials
The REALIZE trial was a randomized, double-blind, placebo-controlled study of people who were previously treated unsuccessfully for HCV infection.
Subjects were randomized 2:2:1 into two telaprevir-based treatment arms—a “lead-in” arm and a “simultaneous-start” arm—and a control arm, which comprised 48 weeks of treatment with peginterferon-ribavirin alone. The lead-in arm included a four-week lead-in period of treatment with peginterferon-ribavirin followed by the addition of telaprevir for 12 weeks, then followed by 32 weeks of treatment with peginterferon-ribavirin alone. The simultaneous-start arm involved 12 weeks of triple-combination therapy, followed by 36 weeks of peginterferon-ribavirin alone.
Forty-eight percent (316 of 662) of the patients had advanced liver fibrosis or cirrhosis, and 89% (586 of 662) had a high HCV RNA load (≥800,000 IU/mL) at study entry.
The primary end point in all three groups was SVR. The results were analyzed based on three subgroups of patients: patients with undetectable levels of HCV RNA during at least 42 weeks of prior treatment that later became detectable (prior relapsers); patients who achieved at least a 2-log10 decrease in HCV RNA by week 12 of treatment but who did not achieve undetectable levels by week 24 (prior partial responders); and, those who did not achieve a 2-log10 decrease in HCV RNA by week 12 of treatment (prior null responders).
SVR rates for all patients in the telaprevir treatment arms were significantly greater compared with patients in the control group (Table; P<0.001). This held true for patients in the two telaprevir-containing arms combined, among which 86% (245 of 286) of the prior relapsers achieved SVR, 57% (55 of 97) of prior partial responders had an SVR and 31% (46 of 147) of the prior null responders had an SVR.
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“We believe the data showed that an immediate start of a 12-week telaprevir-based regimen substantially improved viral cure rates in all three major subgroups of people who were not cured with currently available medicines,” said Robert Kauffman, MD, PhD, senior vice president and chief medical officer, Vertex Pharmaceuticals.
The most common AEs in the telaprevir studies were fatigue, pruritus, nausea, headache, rash and anemia. Anemia occurred in 36% of patients in the treatment lead-in arm, 30% of subjects in the simultaneous-start arm and 15% in the control arm; erythropoietin treatment was not allowed in the study. Rash was present in 36% of patients in the lead-in arm, 37% in the simultaneous-start arm and 19% of the control arm. Three percent of patients in the telaprevir-treatment arms discontinued all treatment because of anemia and 3% did so because of rash. (No P values were provided.)
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Retrospective analyses of IL-28B polymorphisms in patients treated with telaprevir also were presented at the EASL meeting. Data from the ADVANCE (A New Direction in HCV Care: A Study of Treatment-Naive Hepatitis C Patients with Telaprevir) trial, a Phase III study of treatment-naïve patients with HCV, indicated that the cysteine–cysteine variation of the IL-28B polymorphism is associated with the highest SVR rates, at 90% compared with 73% among patients with the thymine–thymine polymorphism and 71% among individuals with the cysteine–thymine polymorphism.
Retrospective analysis of data from REALIZE indicated that the cysteine–cysteine variant also is associated with the highest SVR rates, at 79% compared with 61% for the thymine–thymine polymorphism and 60% for the cysteine–thymine polymorphism.
Additionally, interim results from a Phase II study of treatment-naïve HCV patients with the combination of telaprevir, peginterferon-ribavirin and the polymerase inhibitor VX-222 (Vertex) also were presented at the meeting. Of patients who received a combination of the four agents, 90% had undetectable HCV RNA after 12 weeks. In another group of patients who received a combination of the four agents with a lower dose of VX-222, 83% showed undetectable levels of HCV RNA.
“Boceprevir and telaprevir will greatly improve our ability to eradicate hepatitis C from both treatment-naïve as well as treatment-experienced patients,” commented Donald M. Jensen, MD, professor of medicine and director of the Center for Liver Disease, University of Chicago Medical Center, who wrote an editorial accompanying the published results of RESPOND-2 and SPRINT-2 (N Engl J Med 2011;364:1272-1274). “However, this success will come at a cost—an increase in side effects and some increase in treatment complexity.”
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