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The Incidence of Severe Liver Enzyme Abnormalities and Hepatic Adverse Events in the Maraviroc Clinical Development Programme
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Reported by Jules Levin
11th European AIDS Conference / EACS
Madrid, Spain, 24-27 October 2007
IM Hoepelman1, A Ayoub2, J Heera3, J Goodrich3, R Gulick4, I Huyghe5, E van der Ryst2, D Stevens6 and H Mayer3
1University Hospital Utrecht, Utrecht, The Netherlands; 2Pfizer Global Research and Development, Sandwich, UK; 3Pfizer Global Research and
Development, New London, USA; 4Weill Medical College of Cornell University, New York, USA; 5Pfizer Clinical Research Unit, Erasme, Brussels, Belgium;
6Veterans Affairs Medical Center, Boise, USA
AUTHOR CONCLUSIONS
Sporadic liver enzyme abnormalities were reported in the Phase 1/2a maraviroc programme but demonstrated no dose-relationship and no association with hyperbilirubinaemia.
In the 48-week, Phase 2b/3 studies, there was no evidence of an imbalance of severe liver enzyme abnormalities or severe hepatic adverse events in maraviroc versus comparator arms, unadjusted for longer time on therapy in the maraviroc arms of the MOTIVATE studies.
-- The same finding was reported in patients co-infected with HBV and/or HCV.
Patients potentially meeting the biochemical criteria for Hy's Law were few and evenly distributed between treatment groups.
Two subjects (one in Phase 1 and one in the discontinued MERIT QD arm) had severe elevations in liver enzymes. Although a contribution of maraviroc to these events cannot be excluded, other potential causes were present.
Data from the maraviroc clinical development programme suggest that hepatotoxicity may not be a CCR5-class safety issue.
BACKGROUND
Maraviroc (MVC; CelsentriŽ) is a recently approved oral CCR5 antagonist that demonstrated significantly greater virological and immunological efficacy and a similar safety profile when combined with optimized background therapy (OBT) compared with placebo + OBT in treatment-experienced patients with CCR5 tropic (R5) HIV-1 in the Phase 3 MOTIVATE 1 and 2 studies.1,2
The demonstration of concanavalin A-induced liver failure in CCR5-deficient mice3 combined with the discontinuation of the development of aplaviroc (another CCR5 antagonist) due to cases of hepatotoxicity in studies in ARV-naive and -experienced patients4,5 have led to concerns that hepatotoxicity may be a CCR5-class safety issue. However, there was no evidence of hepatotoxicity in a Phase 2b study in treatment-naive patients with the CCR5 antagonist vicriviroc (mean duration of follow-up 32 weeks).6
We therefore reviewed the incidence of liver enzyme abnormalities and cases of hepatotoxicity in the maraviroc development programme.
METHODS
Hepatic safety data were analysed from the MERIT, MOTIVATE 1 and 2 and A4001029 studies (48-week analysis), as well as Phase 1/2a and preclinical studies (Table 1).
-- The MERIT analysis excluded data from the discontinued maraviroc QD arm.
-- Data from the MOTIVATE studies were not adjusted for the longer duration of treatment exposure in the maraviroc QD (300 patient-years) and BID (309 patient-years) arms vs the placebo (111 patient-years) arms.
A review of the incidence of grade 3/4 liver enzyme abnormalities and cases of hepatotoxicity in the maraviroc development programme was conducted.
In the Phase 2b/3 studies, an analysis by HBV and/or HCV co-infection and by inclusion of tipranavir in patients' OBT was also performed.
Adverse events were assessed for causality by the investigator. All-cause safety data are presented throughout, except where indicated otherwise.
RESULTS
Preclinical studies
Toxicology studies in rats identified the liver as a target organ for maraviroc, with increased transaminases and necrosis observed at 1500 mg/kg and changes in the bile duct and hepatocytes with a no-observed-adverse-effect level (NOAEL) of 8-fold the therapeutic dose (Pfizer data on file).
Phase 1/2a studies
An extensive Phase 1/2a development programme that included more than 700 healthy volunteers and patients was carried out.
Clinically relevant elevations in transaminases occurred sporadically, with no dose relationship and no associated elevation in bilirubin.
The incidence of liver enzyme abnormalities for the Phase 1 multiple-dose studies are summarized in Table 2.
An analysis of laboratory abnormalities in Phase 1/2a studies (in which maraviroc doses ranged from 3 mg BID to1200 mg QD) revealed no dose relationship with liver enzyme abnormalities.7
There were very few subjects with an abnormal baseline liver enzyme value; these data are therefore not shown here.
overview of hepatotoxicity case in phase 1 study a40010668
A 27-year-old white female volunteer with sore throat and leukocytosis during placebo run-in was randomized to receive maraviroc 600 mg QD.
-- At Day 14 (i.e. 14 days after initiation of maraviroc) she reported flu-like symptoms with cervical/submaxillary lymphadenopathies; at Day 17 she developed orthostatic hypotension, mild thrombocytopenia, fever, rash and elevated ALT/AST/bilirubin; at Day 18 the presence of eosinophilia was documented; elevations in IgE and A-PTT/INR (indicating abnormalities in the coagulation pathway) also occurred.
All symptoms reversed following discontinuation of drug after Day 18.
All external consultants (two hepatologists and one expert in bacterial toxin production) believe the case to be possibly related to maraviroc but confounded.
Possible confounding factors include:
-- A pharyngeal culture was positive for Group A Streptococcus and antistreptolysin O (ASO) titre was elevated.
-- The S. pyogenes isolate was found to produce pyrogenic exotoxins (SpeA, SpeB, SpeC, SpeG, SpeJ and SmeZ).
-- Patient received at least 4-5 g of paracetamol.
-- Furthermore, hepatic synthetic function improved despite plasma concentrations of maraviroc remaining detectable.
Hepatic safety in ARV-experienced patients with R5 virus (MOTIVATE 1 and 2 studies)
The MOTIVATE 1 and 2 studies were designed to allow patients with limited treatment options and a degree of hepatic compromise access to maraviroc. Exclusion criteria of >5 x ULN for transaminases and >2.5 x ULN for bilirubin were used.
In the combined analysis of the MOTIVATE 1 and 2 studies, which enrolled treatment-experienced patients with only R5 virus at screening, no more than 1.5% of patients in the MVC QD arm had a grade 3 abnormality at baseline in AST, ALT or total bilirubin value, compared with no more than 1.2% and 0.1% in the MVC BID and placebo arms, respectively. Only one patient had a grade 4 baseline abnormality (AST, MVC QD).
Of patients receiving maraviroc (QD and BID) in the MOTIVATE 1 and 2 studies, approximately 30%, 26% and 13% had grade 1 or 2 elevations from baseline in AST, ALT and bilirubin levels, respectively, compared with 38%, 32% and 18% of patients receiving placebo.
Grade 3 or 4 liver enzyme abnormalities (without regard to baseline abnormality status) are summarized in Table 3.
The number of patients who experienced treatment-related grade 3 or 4 liver-related AEs in the maraviroc QD, maraviroc BID and placebo arms was 6 (1.5%), 11 (2.6%) and 3 (1.5%), respectively (unadjusted for exposure).
Overall, 14 patients discontinued due to hepatic AEs (Table 4): 6, 6 and 2 in the MVC QD, MVC BID and placebo arms, respectively.
Hepatic safety of MVC in ARV-naive patients with R5 virus (MERIT study)
Exclusion criteria of >3 x ULN for transaminases and >2 x ULN for bilirubin were specified for the Phase 2b/3 MERIT study in treatment-naive patients.
Grade 3 and 4 liver enzyme abnormalities (without regard to baseline abnormality status) are summarized in Table 5.
-- Three subjects in the maraviroc 300 mg BID arm experienced a grade 3 elevation in total bilirubin. All three patients had hyperbilirubinaemia that was not associated with transaminase elevations; in two patients it was associated with Gilbert's syndrome.
Grade 3: 5-10 x ULN for AST/ALT and 2.5-5 x ULN for total bilirubin; Grade 4: >10 x ULN for AST/ALT and >5 x ULN for total bilirubin
Six patients in the maraviroc (BID) arm experienced grade 3 or 4 treatment-related hepatic AEs compared with 11 in the efavirenz (QD) arm.
Six patients in each of the maraviroc and efavirenz arms discontinued due to hepatic AEs.
-- Three patients in the maraviroc arm discontinued due to hepatic SAEs compared with four in the efavirenz arm.
overview of severe hepatotoxicity case in the discontinued QD arm of the MERIT study
A single case of life-threatening hepatotoxicity which resulted in hepatic transplantation was reported in the discontinued arm of study A4001026 in a patient randomized to receive 300 mg QD (administered dose 150 mg QD).
The subject had increasing liver function test (LFT) values between screening and baseline (prior to receiving maraviroc) while receiving concomitant isoniazid, co-trimoxazole and paracetamol.
The investigator concluded that hepatotoxicity was "possibly related" to maraviroc.
Hepatic safety of MVC + OBT in treatment-experienced patients with non-R5 virus compared with placebo + OBT (A4001029 study)
At 48 weeks, the number of patients who experienced grade 3 or 4 liver-related AEs reported in the maraviroc QD, maraviroc BID and placebo arms was 3, 1 and 2, respectively (unadjusted for exposure).
-- Of these, 1 event reported by a patient on maraviroc QD (abnormal LFTs) and a total of 3 events reported by two patients on placebo (hyperbilirubinaemia, and increased AST and ALT) were considered treatment related by the investigator.
No hepatic SAEs were reported by patients in this study.
Grade 3 or 4 LFTs (without regard to baseline abnormality status) are summarized in Table 6.
-- No more than one patient in each treatment arm had a grade 3 abnormality at baseline in AST, ALT or total bilirubin value. No patients had grade 4 liver enzyme values at baseline.
-- Of 14 patients who experienced grade 3/4 elevations in total bilirubin on treatment and who had no corresponding abnormality at baseline, one was receiving concomitant indinavir and the remaining 13 were receiving atazanavir in their OBT.
· There were no liver-related discontinuations in Study A4001029.
Hy's Law
Treatment-experienced patients potentially meeting the biochemical criteria for Hy's Law (defined as subjects with total bilirubin >2 x ULN, and AST and/or ALT >3 x ULN9) while on study drug in the Phase 3 studies were few and evenly distributed between treatment groups: seven (1.5%) on maraviroc QD, six (1.3%) on maraviroc BID and three (1.1%) on placebo.
In the MERIT study, only one treatment-naive patient (in the efavirenz arm) met the biochemical criteria for Hy's Law.
Hepatic safety evaluation in patients with other risk factors
hcv and hbv co-infected patients
Although allowed full access to the maraviroc Phase 3 trials, the number of HCV- and/or HBV-infected patients enrolled was relatively small. However subjects co-infected with HCV/HBV did not have an adverse outcome on maraviroc relative to those on placebo.
The number of ARV-experienced co-infected patients with a maximum on-treatment liver enzyme value of grade 3 or 4 in the Phase 3 trials is shown in Table 7. Co-infected patients were not at higher risk of increased liver enzyme abnormalities due to maraviroc in these trials or in the MERIT study.
24-week analysis of data from the MOTIVATE 1 and 2 and A4001029 studies, from patients diagnosed as co-infected with at least one on-drug follow up assessment
patients receiving concomitant tipranavir in obt
Adding maraviroc to an OBT containing tipranavir did not appear to increase the frequency of observed liver enzyme abnormalities (Table 8).
24-week analysis of data from the MOTIVATE 1 and 2 studies, from patients with at least one on-drug follow up assessment
References
1. Lalezari J, et al. 14th CROI 2007; Abstract 104bLB.
2. Nelson M, et al. 14th CROI 2007; Abstract 104aLB.
3. Moreno C, et al. Hepatology 2005; 42:854-862.
4. Ryan CT. AIDS Clin Care 2005; 17:107-108.
5. Crabb C. AIDS 2006; 20:641.
6. Greaves W, et al. 13th CROI 2006; Abstract 161LB.
7. McHale M, et al. 3rd IAS 2005; Abstract TuOa0204.
8. Mayer H, et al. 1st Int Wkshp Target HIV Entry 2005; Invited presentation.
9. Temple R. Pharmacoepidem Drug Saf 2006 ; 15:241-243.
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