Genetic variation in UGT1A1 typical of Gilbert syndrome is associated with unconjugated hyperbilirubinemia in patients receiving tocilizumab.

OBJECTIVE: Tocilizumab, a monoclonal antibody to interleukin-6 receptor, was recently approved for the treatment of moderate-to-severe rheumatoid arthritis. Two patients during clinical development met laboratory, but not clinical, criteria for Hy's law with bilirubin elevations suspected as a result of genetic variation in uridine diphosphoglucose glucuronosyltransferase (UGT1A1) typical of Gilbert syndrome. METHODS: Genotyping of the two cases potentially meeting with Hy's law was performed using commercially available procedures. UGT1A1 single nucleotide polymorphism data were extracted from a genome-wide array database for 1187 patients from tocilizumab trials, and associations of UGT1A1 genotypes with bilirubin elevations were analyzed using logistic regression for associations with baseline and change from baseline in bilirubin levels as continuous variables. RESULTS: Bilirubin elevations were not associated with clinical adverse events. Both patients potentially meeting Hy's law carry homozygous UGT1A1*28 alleles and UGT1A1*60 alleles. UGT1A1*28 and three additional single nucleotide polymorphisms showed odds ratios greater than 25 for associations with elevated bilirubin. The presence of rs6742078 accounted for 32% of the total variance in bilirubin (P=2.2×10). CONCLUSION: Bilirubin increases occurring with tocilizumab appear to be related to anti-inflammatory effects extending to the liver. Thus, in the absence of other signs of hepatic dysfunction, bilirubin elevations after treatment with tocilizumab have a high probability of association with UGT1A1 polymorphism, which should alleviate concerns of serious hepatotoxicity. Our results underscore the value of genotyping in the clinical trial setting to avoid misinterpretations that could lead to terminating development of a promising new agent.

Coadministration of lorcaserin and phentermine for weight management: A 12-week, randomized, pilot safety study.

OBJECTIVE: To assess the short-term tolerability of lorcaserin alone or with two dose regimens of phentermine. METHODS: This was a 12-week, randomized, double-blind, pilot safety study of N = 238 nondiabetic patients with obesity or overweight with ≥1 comorbidity randomized to lorcaserin 10 mg twice daily (BID; LOR BID) alone or with phentermine 15 mg once daily (QD; LOR BID+PHEN QD) or 15 mg twice daily (LOR BID+PHEN BID). Patients reporting ≥ 1 of 9 potentially serotonergic adverse events (AEs), mean weight loss (WL), and ≥5% WL are reported. RESULTS: N = 238 were randomized, and N = 235 were treated. N = 94 reported potentially serotonergic AEs: 37.2% LOR BID, 42.3% LOR BID+PHEN QD, and 40.5% LOR BID+PHEN BID. AEs leading to discontinuation were reported approximately twice as often in the LOR BID+PHEN BID group versus the LOR BID group. Mean WL was 3.5 kg/3.3%, 7.0 kg/6.7%, and 7.6 kg/7.2% for LOR BID, LOR BID+PHEN QD, and LOR BID+PHEN BID, respectively. At least 5% WL was achieved by 28.2% LOR BID, 59.0% LOR BID+PHEN QD (P = 0.0002 vs. LOR BID), and 70.9% LOR BID+PHEN BID (P < 0.0001 vs. LOR BID) patients. CONCLUSIONS: Phentermine added to lorcaserin enhanced short-term weight loss but did not increase incidence of potentially serotonergic AEs; however, phentermine twice daily increased discontinuation compared to both lorcaserin alone and lorcaserin plus phentermine once daily.

Long-term efficacy and safety of twice-daily saquinavir soft gelatin capsules (SGC), with or without nelfinavir, and three times daily saquinavir-SGC, in triple combination therapy for HIV infection: 100-week follow-up.

OBJECTIVES: To evaluate the long-term efficacy and safety of saquinavir soft gelatin capsules (SQV-SGC) (Fortovase) in twice-daily, with or without nelfinavir (NFV), and three-times-daily regimens. This was an extension of a 48-week study, with follow-up to 100 weeks. DESIGN: Patients were randomized to one of three treatment arms: arm A, SQV-SGC 1200 mg three times daily plus two nucleoside reverse transcriptase inhibitors (NRTIs); arm B, SQV-SGC 1,600 mg twice daily plus two NRTIs; or arm C, SQV-SGC 1200 mg twice daily plus NFV 1250 mg twice daily plus one NRTI. At week 48, patients could either withdraw or continue in the study to the common study closure date. Antiretroviral activity was assessed by changes in HIV-1 RNA values and CD4 cell counts from 48 weeks until 100 weeks. RESULTS: In the modified intention-to-treat population, the proportion of patients with HIV-1 RNA values <400 copies/ml was statistically different between arms A and C (49 vs 28%, P=0.017), and arms B and C (48 vs 28%, P=0.027). Continued suppression of HIV-1 replication (HIV-1 RNA <400 copies/ml) was observed through 100 weeks in 83% (30/36), 73% (29/40) and 62% (16/26) of patients in treatment arms A, B and C, respectively, in the on-treatment (OT) population. At 100 weeks, sustained increases were achieved in mean CD4 cell counts of +361, +273 and +309 cells/mm3, respectively (OT population). No additional adverse events or increase in the proportion of patients reporting adverse events were observed from 48 weeks to 100 weeks. CONCLUSIONS: This study demonstrates the long-term efficacy and safety of SQV-SGC twice daily, with or without NFV, and three times daily, in triple combination therapy for HIV-1-infected patients. However, the evidence suggests that long-term treatment with SQV-SGC plus NFV may be less acceptable to patients.

Efficacy and safety of twice-daily versus three-times daily saquinavir soft gelatin capsules as part of triple combination therapy for HIV-1 infection.

OBJECTIVE: The objective of this study was to determine whether a triple therapy regimen incorporating twice-daily saquinavir is as effective as a three-times daily regimen. METHODS: This was an open-label, Phase III, multicentre, 48-week study involving 837 HIV-1-infected patients randomised to one of the following: saquinavir soft gel capsule (SGC) 1200 mg three-times daily, plus two nucleoside reverse transcriptase inhibitors (NRTIs) (arm A); saquinavir SGC 1,600 mg twice-daily, plus two NRTIs (arm B); saquinavir SGC 1,200 mg twice-daily and nelfinavir 1,250 mg twice-daily, plus a single NRTI (arm C). The primary outcome measure was the virological response in arm A versus B and in arm A versus C with respect to the percentage of patients whose plasma HIV-1 RNA levels fell below the level of quantification for the Amplicor assay (<400 copies/ml) at weeks 24 and 48. RESULTS: At 48 weeks, the percentage of patients with plasma HIV-1 RNA levels <400 copies/ml was 47.1% (arm A), 45.3% (arm B) and 42.7% (arm C) in the intention-to-treat analysis. The treatment difference between arm B-arm A was -1.8% (95% confidence intervals -10.1, 6.5) and for arm C-arm A was -4.5% (95% confidence intervals -12.7, 3.7) in the intention-to-treat analysis. These differences fell within the maximum allowable difference (+/- 12%) for arm B compared with arm A. At week 24, the percentage of patients with HIV-1 RNA levels <400 copies/ml was 59.6% (arm A), 57.6% (arm B) and 51.3% (arm C). CONCLUSIONS: A twice-daily triple therapy regimen incorporating saquinavir SGC plus two NRTIs was of equivalent efficacy to the three-times daily regimen studied. All regimens were generally well tolerated.

Longterm safety and efficacy of tocilizumab in patients with rheumatoid arthritis: a cumulative analysis of up to 4.6 years of exposure.

OBJECTIVE: To assess the longterm safety and efficacy of tocilizumab (TCZ) in patients with moderate to severe rheumatoid arthritis (RA). METHODS: Patient data were from 5 randomized controlled TCZ trials (n = 4211), their open-label extension phases (n = 3512), and a drug interaction study (n = 23). All randomly assigned patients, regardless of previous RA treatment, were analyzed. Measures of safety included number of adverse events (AE), serious AE (SAE), AE leading to treatment discontinuation, laboratory tests, and deaths. Efficacy measures included American College of Rheumatology (ACR) 20/50/70 responses, tender joint count (TJC), swollen joint count (SJC), ACR core set components, and low disease activity (LDA) or Disease Activity Score in 28 joints (DAS28) remission. ACR/European League Against Rheumatism (EULAR) disease remission was a posthoc exploratory analysis. RESULTS: Total duration of observation was 12,293 patient-years (PY). No new safety signals were identified; infections were the most common AE and SAE. The rate of serious infections was 4.5/100 PY. Improvements from baseline in clinical efficacy, measured as ACR20/50/70 responses, TJC, SJC, ACR core set components, and LDA and DAS28 remission, were generally sustained through at least 216 weeks of followup. ACR/EULAR disease remission was attained by 16.5% (Boolean) and 22.7% (index) of patients at Week 216. CONCLUSION: TCZ has to date been studied for up to 4.6 years (240 weeks) of treatment in patients with RA. Our analysis reveals a longer-term safety profile consistent with previous observations, no new safety signals, and durable efficacy of TCZ in a large clinical trial program.