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A Randomized, Placebo-Controlled Trial of Cenicriviroc for Treatment of Nonalcoholic Steatohepatitis with Fibrosis - CENTAUR Study
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"Greater CVC treatment benefits were observed in subjects with higher disease activity and fibrosis stage (ie, NAS ≥5, prominent hepatocellular ballooning, moderate-to-severe fibrosis); these observations help identify which patients are most likely to benefit from CVC treatment and are aligned with known risk factors of disease progression. The majority of subjects who achieved an improvement in fibrosis stage also achieved a reduction in collagen area by morphometry, supporting findings from secondary efficacy end points related to improvement in fibrosis."
EASL/2017: Hepatic Fibrosis is Associated With Histological Activity in Non-alcoholic Steatohepatitis: an Analysis From a Large Database of Screening Biopsies in the CENTAUR Trial - (09/08/17)
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A Randomized, Placebo-Controlled Trial of Cenicriviroc for Treatment of Nonalcoholic Steatohepatitis with Fibrosis
Hepatology Aug 2017
Abstract
The aim of this study was to evaluate cenicriviroc (CVC), a dual antagonist of C-C chemokine receptor types 2 and 5, for treatment of nonalcoholic steatohepatitis (NASH) with liver fibrosis.
A randomized, double-blind, multinational phase 2b study enrolled subjects with NASH, a nonalcoholic fatty liver disease activity score [NAS] ≥4, and liver fibrosis (stages 1-3, NASH Clinical Research Network) at 81 clinical sites. Subjects (N = 289) were randomly assigned CVC 150 mg or placebo. Primary outcome was ≥2-point improvement in NAS and no worsening of fibrosis at year 1. Key secondary outcomes were: resolution of steatohepatitis and no worsening of fibrosis; improvement in fibrosis by ≥1 stage and no worsening of steatohepatitis. Biomarkers of inflammation and adverse events were assessed.
Full study recruitment was achieved. The primary end point of NAS improvement in the intent-to-treat population and resolution of steatohepatitis was achieved in a similar proportion of subjects on CVC (N = 145) and placebo (N = 144) (16% vs 19%, P = 0.52 and 8% vs 6%, P = 0.49, respectively). However, the fibrosis end point was met in significantly more subjects on CVC than placebo (20% vs 10%; P = 0.02). Treatment benefits were greater in those with higher disease activity and fibrosis stage at baseline. Biomarkers of systemic inflammation were reduced with CVC. Safety and tolerability of CVC were comparable to placebo.
Conclusions: After 1 year of CVC treatment, twice as many subjects achieved improvement in fibrosis and no worsening of steatohepatitis compared with placebo. Given the urgent need to develop antifibrotic therapies in NASH, these findings warrant phase 3 evaluation.
Nonalcoholic fatty liver disease is now the most common cause of liver disease, with a prevalence of 25% globally.(1) Nonalcoholic steatohepatitis (NASH), the more severe form of the disease, is characterized by the presence of steatosis, lobular and/or portal inflammation, hepatocyte injury (ie, ballooning), and fibrosis.(2) The presence of liver fibrosis confers an increased risk of disease progression to cirrhosis, liver failure, and hepatocellular carcinoma, with a higher mortality.(3, 4) Fibrosis stage is the only histological feature of NASH independently linked to an increased likelihood of liver-related and all-cause (eg, cardiovascular disease) mortality in recent studies.(3-5) Therefore, reducing liver fibrosis is expected to improve the long-term clinical outcomes of patients with NASH.(6) Among pharmacological treatments currently undergoing evaluation, a number have reported improvement in histological features of NASH,(6-9) but only obeticholic acid improved fibrosis in a randomized clinical study in adults with noncirrhotic NASH.(10)
Cenicriviroc (CVC) is an oral, dual antagonist of C-C motif chemokine receptor types 2 and 5. Preclinical(11-14) and clinical evidence(15-17) support its anti-inflammatory and antifibrotic properties, which are mediated by C-C motif chemokine receptor types 2 and 5 blockade.
CVC has demonstrated antifibrotic activity in animal models of liver and renal fibrosis.(11) These findings are supported in patients by improvements in noninvasive markers of hepatic fibrosis (aspartate aminotransferase-to-platelet ratio index, fibrosis-4, and enhanced liver fibrosis test) observed in post hoc analyses of a 48-week phase 2b study in HIV-infected subjects.(18, 19) Furthermore, extensive clinical experience using CVC, with over 1000 subjects treated to date, indicates a favorable safety profile including in subjects with cirrhosis and mild-to-moderate (Child-Pugh A or B) hepatic impairment.(17, 20)
CVC-mediated antagonism of C-C motif chemokine receptor type 2 is expected to reduce the recruitment, migration, and infiltration of pro inflammatory monocytes and macrophages at the site of liver injury.(14, 15) C-C motif chemokine receptor type 5 antagonism by CVC is
expected to additionally impair the migration, activation, and proliferation of collagen-producing activated hepatic stellate cells/myofibroblasts.(21) We designed the phase 2 CENTAUR study to test the efficacy and safety of CVC in adults with NASH and liver fibrosis; results from the year 1 primary analysis are reported here.
Subgroup Analyses for Key Secondary Fibrosis End Point
CVC provided antifibrotic benefits in both fibrosis strata (stages ≤2 and >2; Figure 2C and Figure 3). When subjects with baseline fibrosis stages 2 and 3 were pooled, CVC benefits were significant (P < 0.05; Figure 2D and Figure 3). CVC treatment benefits were consistent across prespecified subgroups; the greatest treatment benefits were in subjects with baseline NAS ≥5 and those with prominent hepatocellular ballooning, relative to those with baseline NAS =4 and few ballooned cells (Figure 2E, Figure 2F and Figure 3).
A post hoc analysis was conducted to evaluate the effect of biopsy length (<15 mm or ≥15 mm), in the modified intent-to-treat population (Supplementary Table S3). The majority of liver biopsies collected at baseline (78-83%) and year 1 (79-82%) had a length of ≥15 mm, a length above which sampling variability is expected to be lower.
A post hoc analysis of predictors of response determined that the factors most strongly associated with improvement in fibrosis stage and no worsening of steatohepatitis at year 1 were treatment (ie, receiving CVC), a higher fibrosis stage at baseline, mild or no portal inflammation at baseline, and a higher baseline body mass index (P < 0.050 for each, after adjustment for the other predictors). Although differences were observed in subgroups for gender, region, and presence of T2DM, these factors were not associated with response to CVC.
Safety and Tolerability
The safety population comprised all 288 subjects who were randomized and received at least one dose of study drug. The incidence of treatment-emergent adverse events was similar in both groups, and in general mild or moderate in severity (Supplementary Table S7).
Twenty-six treatment-emergent serious adverse events were reported (CVC, n = 16; placebo, n = 10). All serious adverse events but one (grade 2 arrhythmia; subject remained on blinded treatment) were considered not related to treatment. The incidence of treatment emergent grade 3 or 4 laboratory abnormalities was generally similar between groups. Grade 4 uric acid elevations, which occurred in subjects with increased baseline values, and asymptomatic grade 3 amylase elevations were observed more frequently in the CVC than placebo group (7.6% vs 4.2% and 4.2% vs 0.7%, respectively) (Supplementary Table S7). No treatment-emergent adverse events of pancreatitis were reported in subjects with grade 3 amylase elevations.
Discussion
NASH is highly prevalent globally and represents an unmet medical need, based on related morbidity and mortality burdens, and the lack of approved therapies.(1) CENTAUR prospectively analyzed and reported on composite clinical efficacy end points currently being evaluated in phase 3 NASH studies (NCT02548351, NCT02704403, NCT03028740; https://clinicaltrials.gov), and demonstrated a benefit on fibrosis in subjects with NASH after only 1 year of treatment. Although the primary outcome was not met, twice as many subjects on CVC than placebo achieved the clinically important key secondary outcome of improvement in fibrosis by ≥1 stage and no worsening of steatohepatitis. Fibrosis is the only histological feature that has been independently associated with clinical outcomes in longitudinal cohorts.(3-5) CENTAUR exclusively enrolled subjects with NASH and liver fibrosis; additionally, subjects were required to have active metabolic dysfunction (T2DM or metabolic syndrome), a well-known risk factor for disease progression. The primary outcome was chosen based on the standard established in prior phase 2 studies that assessed the efficacy of NASH therapies.(9, 10) Improvement in fibrosis by ≥1 stage and no worsening of steatohepatitis was selected as one of the two key secondary outcomes, both because of its association with clinical outcomes and to inform the phase 3 program. Greater CVC treatment benefits were observed in subjects with higher disease activity and fibrosis stage (ie, NAS ≥5, prominent hepatocellular ballooning, moderate-to-severe fibrosis); these observations help identify which patients are most likely to benefit from CVC treatment and are aligned with known risk factors of disease progression. The majority of subjects who achieved an improvement in fibrosis stage also achieved a reduction in collagen area by morphometry, supporting findings from secondary efficacy end points related to improvement in fibrosis.
The safety and tolerability of NASH therapies are paramount, as the condition is typically asymptomatic and patients are often being treated for comorbidities including T2DM and cardiovascular disease. In CENTAUR, the incidence of treatment-emergent adverse events and laboratory abnormalities was comparable between CVC and placebo. The most frequently reported treatment-emergent adverse events of at least moderate severity (i.e., fatigue, diarrhea, and headache) were consistent with the extensive clinical experience with CVC in prior studies.(16, 17, 22) Changes in fasting metabolic parameters from baseline were relatively small and comparable between groups, indicating that CVC is not likely to worsen pre-existing metabolic disease in NASH patients. The results of CENTAUR are potentially paradigm-shifting, as they challenge the common assumption that the antifibrotic effects of NASH agents can only be observed by improving the underlying metabolic liver disease. Instead, the beneficial impact of CVC on fibrosis without affecting the histological features of steatohepatitis at year 1 reinforces the rationale for directly targeting inflammatory and fibrotic mechanisms. The antifibrotic activity of CVC observed here is consistent with findings in several animal models of chronic liver injury.(11)
While the study didn't meet the primary end point at year 1, it nonetheless underscores the evolving principles of clinical-trial design that increasingly look to assign end points that are aligned with the mechanism of action.
Based on its mechanism of action, the lack of effect of CVC on lobular inflammation was unexpected and will need to be further explored. One possible explanation may be that the impact of CVC on the composition of immune cells in the inflamed lobule, as well as the noncellular components of inflammation (ie, chemokines and soluble mediators), cannot be fully characterized by the H&E stain alone (used to grade the degree of lobular inflammation). Detailed characterization of immune cell subsets will be valuable in the future to further clarify the impact of CVC on hepatic inflammation. Although the NAS has been widely used to evaluate early treatment effects in phase 2 studies, it does not distinguish targeted effects of CVC on C-C motif chemokine receptor type 2-expressing monocyte-derived macrophages, as previously demonstrated in models of liver injury.(12, 14) Specifically, activities of chemokine signaling, including intrahepatic monocyte and macrophage recruitment, and fibrogenesis, occur downstream of liver-cell injury and metabolic dysregulation in the pathophysiology of NASH; therefore, they may not be reflected in the traditional histological features of the NAS, including steatosis, lobular inflammation, and hepatocellular ballooning. Therefore, further evaluation using cell-specific markers will be required to elucidate the effects of CVC on immune cells in patients.
Importantly, a broad mechanistic impact of CVC on inflammatory signaling is underscored by reductions in circulating markers of systemic inflammation (ie, high-sensitivity C-reactive protein, interleukin-6, fibrinogen) and soluble cluster of differentiation 14 (a marker of monocyte activation), which is consistent with previous studies in subjects with HIV infection.(17, 22)
In this study in subjects with NASH, a large histological data set of 252 paired biopsies was available for year 1 evaluation in the modified intent-to-treat population. All liver biopsies were read centrally by a single pathologist, thereby reducing reader variability. Limitations of our study include: differences in responses among subgroups (eg, region, sex, and T2DM) that may reflect the multifactorial nature of the disease; the study sample size; and the inherent variability of liver biopsy sampling,(23) which will require further investigation in subsequent studies.
Improvement in fibrosis stage has been reported in phase 2 NASH randomized clinical trials, as early as 24 weeks.(10, 24, 25) These and similar studies have also demonstrated that a small but significant proportion of subjects, up to approximately 20%,(8-10) will have spontaneous improvement on placebo. This improvement has often been attributed to increased clinical monitoring, motivation, and compliance to diet and lifestyle changes of subjects participating in such trials. Therefore, the observation that some placebo subjects improved in the CENTAUR study is neither unexpected nor out of line with other reported results.
In conclusion, CVC showed a significant antifibrotic benefit at year 1 and was well tolerated. Although the primary end point of the study was not met, the fact that the CENTAUR year 1 study results showed that CVC provided clinically meaningful benefits and resulted in twice as many subjects achieving 'improvement in fibrosis by ≥1 stage and no worsening of steatohepatitis' as compared with placebo, suggests that the study did in fact show proof of concept, warranting phase 3 development of CVC. If this benefit is corroborated by the continued follow-up over the planned second year of treatment, and subsequent confirmatory trials, CVC will represent an important advance in the treatment of liver fibrosis in patients with NASH.
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