Reductions in circulating B cell subsets and immunoglobulin G levels with long-term belimumab treatment in patients with SLE.

OBJECTIVE: To examine the long-term changes in circulating B cell subsets and IgG levels at 5+ years of continuous belimumab treatment and their correlations with efficacy and safety measures. METHODS: This was a post hoc analysis of a continuation study (BEL112233; NCT00724867) of eligible US patients who completed the 76-week BLISS-76 Study (BEL110751; NCT00410384), with up to eight calendar-years of follow-up and median (IQR) belimumab exposure of 310 (209, 364) weeks. From week 76, patients initially randomised to intravenous belimumab 1 mg/kg or 10 mg/kg every 4 weeks in BLISS-76 continued to receive the same dose in the continuation study, while those initially randomised to placebo received belimumab 10 mg/kg intravenous every 4 weeks during continuation. All patients continued to receive standard SLE therapy. Biomarker data were collected, and the effects on baseline and early changes (weeks 0-24 after starting belimumab) from baseline in biomarkers on SLE Responder Index (SRI-4) and infection rate were evaluated. RESULTS: Of the 819 patients from BLISS-76, 268 self-selecting patients entered BEL112233. Compared with baseline, B cell subset counts decreased by 40%-99% after 312 weeks (6 years), and serum IgG levels decreased by 28% after 284 weeks. Higher baseline naïve B cell counts were associated with greater SRI-4 response rates (p<0.05), whereas higher baseline SLE subset plasma and short-lived plasma B cell counts were associated with lower SRI-4 response rates (p<0.05). Elevated baseline IgG levels were associated with increased infection rates over the treatment period (p<0.05), and early greater decreases in IgG levels were associated with higher SRI-4 response rates (p<0.05). CONCLUSIONS: Belimumab treatment up to 312 weeks (6 years) resulted in substantial decreases in several circulating B cell subsets and IgG levels. Higher baseline naïve B cell counts and IgG levels were associated with improved SRI-4 response and increased infection rates, respectively.

Clinical, laboratory and health-related quality of life correlates of Systemic Lupus Erythematosus Responder Index response: a post hoc analysis of the phase 3 belimumab trials.

OBJECTIVE: Correlates of systemic lupus erythematosus (SLE) Responder Index (SRI) response with clinical trial end points were examined using pooled data from the Study of Belimumab in Subjects with SLE (BLISS) trials (N=1684). METHODS: Changes in clinical, laboratory and health-related quality of life measures from baseline at 52 weeks were compared between SRI responders (n=761) and non-responders (n=923). RESULTS: More SRI responders than non-responders had ≥4-point (100% vs 3.8%) and ≥7-point (40.3% vs 1.3%) Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index reductions, no new British Isles Lupus Assessment Group (BILAG) A and ≤1 new B scores (91.9% vs 35.9%), and a 25% reduction in corticosteroid dose decrease of 25% from >7.5 mg/d to ≤7.5 mg/d (25.5% vs 13.9%), and fewer had a corticosteroid increase from ≤7.5 mg/d to >7.5 mg/d (4.1% vs 21.3%; all p<0.001). More responders than non-responders had improved organ domains: Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (mean 1.45 vs 0.40), BILAG (2.00 vs 0.39), and greater improvement in Physician's Global Assessment (all p<0.001). Risks for developing any SLE flare or severe flare were reduced in responders by 42% and 87%, respectively (p<0.001). Responders reported greater improvements in Medical Outcomes Survey Short Form version 2 Physical and Mental Components and all domain scores, and Functional Assessment of Chronic Illness Therapy-Fatigue score compared with non-responders (all p<0.001). CONCLUSION: Overall, SRI response in patients with active, autoantibody-positive SLE was associated with improvements in clinical, laboratory and patient-reported outcome measures, indicating that SRI response was associated with a global benefit. TRIAL REGISTRATION NUMBER: NCT00424476; NCT00410384.

Disease control and safety of belimumab plus standard therapy over 7 years in patients with systemic lupus erythematosus.

OBJECTIVE: To evaluate the efficacy/safety of belimumab plus standard therapy in patients (n = 449) with active systemic lupus erythematosus (SLE) treated up to 7 years (n = 177 currently ongoing). METHODS: Patients (n = 345) who completed a double-blind, placebo-controlled, 52-week study of belimumab 1, 4, or 10 mg/kg and 24-week extension of belimumab (placebo switched to 10 mg/kg; belimumab same dose or switched to 10 mg/kg) could receive belimumab 10 mg/kg in an open-label continuation study (n = 296). Disease activity was analyzed in patients with active SLE at baseline of the initial study. Biomarker and SLE medication changes were evaluated, and adverse events (AE) were monitored throughout the study. RESULTS: Total belimumab exposure over 7 years (double-blind and open-label periods): 1746 patient-years. SLE Responder Index (SRI) response rates at Week 52 in autoantibody-positive patients: placebo, 29%; belimumab, 46% (p < 0.05). In the continuation study, 57% of auto-antibody-positive patients had an SRI response by Year 2 and 65% by Year 7; severe flares occurred in 19% with placebo and 17% with belimumab during the first year, with the annual rate declining to 2%-9% during years 2-7. Anti-dsDNA autoantibodies in patients positive for them at baseline had a progressive decline of 40%-60% from baseline over 2-7 years with belimumab. Corticosteroid use decreased over time with ≥ 50-55% reduction in median dose during years 5-7. Serious and overall annual AE rates, including infections, were generally stable or decreased during 7-year treatment. CONCLUSION: Disease control and safety profile were maintained in patients with active SLE taking belimumab plus standard therapy for up to 7 years. [ClinicalTrials.gov numbers: NCT00071487 and NCT00583362].

Improvements in health-related quality of life with belimumab, a B-lymphocyte stimulator-specific inhibitor, in patients with autoantibody-positive systemic lupus erythematosus from the randomised controlled BLISS trials.

OBJECTIVE: Assess the effects of belimumab treatment plus standard systemic lupus erythematosus (SLE) therapy on health-related quality of life (HRQOL) in patients with active, autoantibody-positive SLE. METHODS: Patients received standard therapy plus placebo or belimumab 1 or 10 mg/kg in two multicentre, randomised controlled trials of 52 (BLISS-52; N=865) and 76 (BLISS-76; N=819) weeks' duration. Responders were evaluated by SLE Responder Index at week 52. Patient-reported outcome assessments included SF-36, Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue, and EQ-5D. RESULTS: Mean SF-36 Physical Component Summary (PCS) scores at week 24 was a major secondary endpoint. Baseline SF-36 scores were 1.5 SDs below age-/sex-matched US norms with similar improvement at week 24 across treatment groups. Mean changes from baseline in PCS scores were significantly (p<0.05) greater with belimumab 1 mg/kg (4.20) and 10 mg/kg (4.18) versus placebo (2.96) in BLISS-52, week 52. In BLISS-76, significantly (p<0.05) greater improvements were seen with belimumab 1 mg/kg in PCS (belimumab 1 mg/kg=4.37, 10 mg/kg=3.41 vs placebo=2.85) and Mental Component Summary (MCS) scores (belimumab 1 mg/kg=3.14, 10 mg/kg=2.70 vs placebo=1.40) at week 52, and in MCS score at week 76 (belimumab 1 mg/kg=3.05, 10 mg/kg=2.28 vs placebo=1.36). In pooled analysis, significantly greater improvements in PCS, SF-36 vitality domain, and FACIT-Fatigue scores at week 52 were evident with both belimumab doses. CONCLUSIONS: The clinically meaningful improvements in HRQOL in autoantibody-positive patients with active SLE treated with belimumab and standard therapy are consistent with the reductions in disease activity observed in these trials. CLINICALTRIALSGOV NUMBER: NCT00424476, NCT00410384.

Baseline predictors of systemic lupus erythematosus flares: data from the combined placebo groups in the phase III belimumab trials.

OBJECTIVE: To identify predictors of moderate-to-severe systemic lupus erythematosus (SLE) flare in 562 patients treated with standard therapy alone in phase III belimumab trials, and to evaluate the impact of standard therapies on preventing flares. METHODS: Post hoc analysis assessed baseline demographics, disease activity, and biomarkers in patients with and those without flare at treatment weeks 24 and 52. Severe flare was defined by the modified SLE Flare Index (SFI) and the development of any new British Isles Lupus Assessment Group (BILAG) A domain score. Severe and moderate flare was defined by development of 1 new BILAG A domain score or 2 new BILAG B domain scores. Baseline characteristics associated with a ≥10% absolute difference or a ≥50% increase in flare rates were considered predictive. RESULTS: Frequencies of flares over 52 weeks according to the SFI, any new BILAG A domain score, and 1 new BILAG A domain score or 2 new BILAG B domain scores were 23.7%, 23.1%, and 32.0%, respectively. Flare predictors by univariate analysis on all 3 indices at weeks 24 and 52 were a score ≥12 on the Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index (SELENA-SLEDAI); anti-double-stranded DNA (anti-dsDNA) positivity; proteinuria (≥0.5 gm/24 hours); BILAG renal, vasculitic, and hematologic scores; elevated C-reactive protein levels; and B lymphocyte stimulator (BLyS) levels ≥2 ng/ml. Independent predictors by multivariate analysis at week 52 were SELENA-SLEDAI and/or BILAG renal involvement and anti-dsDNA ≥200 IU/ml (on all 3 indices); SELENA-SLEDAI and/or BILAG neurologic and vasculitic involvement (on 2 indices: any new BILAG A domain score and 1 new BILAG A domain score or 2 new BILAG B domain scores); BLyS levels ≥2 ng/ml (on 2 indices: the SFI and 1 new BILAG A domain score or 2 new BILAG B domain scores); and low C3 level (on the SFI). Baseline medications did not significantly decrease or increase moderate-to-severe SLE flare risk. CONCLUSION: Patients who were receiving standard SLE therapy and had renal, neurologic, or vasculitic involvement, elevated anti-dsDNA or BLyS levels, or low C3 had increased risk of clinically meaningful flare over 1 year. Hydroxychloroquine use was not predictive.

Efficacy and safety of belimumab in patients with rheumatoid arthritis: a phase II, randomized, double-blind, placebo-controlled, dose-ranging Study.

OBJECTIVE: To evaluate the efficacy/safety of belimumab in patients with rheumatoid arthritis (RA). METHODS: Patients fulfilling American College of Rheumatology (ACR) criteria for RA for ≥ 1 year who had at least moderate disease activity while receiving stable disease-modifying antirheumatic drug (DMARD) therapy and failed ≥ 1 DMARD were randomly assigned to placebo or belimumab 1, 4, or 10 mg/kg, administered intravenously on Days 1, 14, and 28, and then every 4 weeks for 24 weeks (n = 283). This was followed by an optional 24-week extension (n = 237) in which all patients received belimumab. Primary efficacy endpoint was the Week 24 ACR20 response. RESULTS: Week 24 ACR20 responses with placebo and belimumab 1, 4, and 10 mg/kg were 15.9%, 34.7% (p = 0.010), 25.4% (p = 0.168), and 28.2% (p = 0.080), respectively. Patients taking any belimumab dose who continued with belimumab in the open-label extension had an ACR20 response of 41% at 48 weeks. A similar ACR20 response (42%) at 48 weeks was seen in patients taking placebo who switched in the extension to belimumab 10 mg/kg. Greater response rates were observed in patients who at baseline were rheumatoid factor-positive, anticitrullinated protein antibody-positive, or tumor necrosis factor inhibitor-naive, or had elevated C-reactive protein levels, Disease Activity Score 28 > 5.1, or low B lymphocyte stimulator levels (< 0.858 ng/ml). Adverse event rates were similar across treatment groups. CONCLUSION: In this phase II trial, belimumab demonstrated efficacy and was generally well tolerated in patients with RA who had failed previous therapies. [ClinicalTrials.gov identifier NCT00071812].

Bioavailability, Pharmacokinetics, and Safety of Belimumab Administered Subcutaneously in Healthy Subjects.

This Phase 1 study evaluated the absolute bioavailability, pharmacokinetics (PK), tolerability, and safety of belimumab 200 mg/mL administered subcutaneously (SC) to healthy subjects as a single dose and as multiple doses up to 240 mg. In all, 118 subjects (age range 18-55 years; body weight 51-115 kg) were enrolled. Seventy-eight subjects received a single dose of belimumab 240 mg intravenously, or 2 × 120, 1 × 240, or 1 × 200 mg SC. Forty subjects received 4 weekly injections of belimumab 2 × 120 or 1 × 200 mg SC. Randomization was stratified by weight (<75 kg vs. ≥75 kg) and injection site (abdomen vs. thigh). Following single belimumab SC doses, bioavailability was 74-82%, indicating that belimumab SC was well absorbed, and bioavailability was similar among the three SC groups. Following 4 weekly belimumab SC doses, bioavailability was similar to that following single SC administration. Four subjects had persistent positive immune responses; neutralizing antibodies in these subjects were not detected and there was no apparent impact on PK. Belimumab was generally well tolerated after single and multiple SC dosing, and 200 mg SC weekly dosing is expected to provide an exposure similar to 10 mg/kg intravenously every 28 days.

Long-term safety profile of belimumab plus standard therapy in patients with systemic lupus erythematosus.

OBJECTIVE: To evaluate the safety profile of long-term belimumab therapy combined with standard therapy for systemic lupus erythematosus (SLE) in patients with active disease. METHODS: Patients who were randomized to receive intravenous placebo or belimumab 1, 4, or 10 mg/kg, plus standard therapy, and completed the initial 52-week double-blind treatment period were then allowed to enter a 24-week open-label extension phase. During the extension period, patients in the belimumab group either received the same dose or were switched to 10 mg/kg and patients in the placebo group were switched to belimumab 10 mg/kg. Patients who achieved a satisfactory response during the 24-week extension period were allowed to participate in the long-term continuation study of monthly belimumab 10 mg/kg. Adverse events (AEs) and abnormal laboratory results were analyzed per 100 patient-years in 1-year intervals. RESULTS: Of the 364 patients who completed the 52-week double-blind treatment period, 345 entered the 24-week extension, and 296 continued treatment with belimumab in the long-term continuation study. Safety data through 4 years of belimumab exposure (1,165 cumulative patient-years) are reported. Incidence rates of AEs, severe/serious AEs, infusion reactions, infections, malignancies, grades 3/4 laboratory abnormalities, and discontinuations due to AEs were stable or declined during 4-year belimumab exposure. The most common AEs included arthralgia, upper respiratory tract infection, headache, fatigue, and nausea. Serious infusion reactions were rare: only 1 occurred during the 4-year followup period. Rates of serious infection decreased from 5.9/100 patient-years to 3.4/100 patient-years, and no specific type of infection predominated. CONCLUSION: Belimumab added to standard therapy was generally well-tolerated over the 4-year treatment period in patients with SLE, which suggests that belimumab can be administered long term with an acceptable safety profile.

Effect of belimumab on vaccine antigen antibodies to influenza, pneumococcal, and tetanus vaccines in patients with systemic lupus erythematosus in the BLISS-76 trial.

OBJECTIVE: In patients with systemic lupus erythematosus (SLE), evidence suggests that most vaccines (except live-virus vaccines) are safe, although antibody response may be reduced. This substudy from the phase III, randomized, double-blind, placebo-controlled BLISS-76 trial evaluated the effects of belimumab on preexisting antibody levels against pneumococcal, tetanus, and influenza antigens in patients with SLE. METHODS: In BLISS-76, patients with autoantibody-positive, active SLE were treated with placebo or belimumab 1 or 10 mg/kg every 2 weeks for 28 days and every 28 days thereafter, plus standard SLE therapy, for 76 weeks. This analysis included a subset of patients who had received pneumococcal or tetanus vaccine within 5 years or influenza vaccine within 1 year of study participation. Antibodies to vaccine antigens were tested at baseline and Week 52, and percentage changes in antibody levels from baseline and proportions of patients maintaining levels at Week 52 were assessed. Antibody titers were also assessed in a small number of patients vaccinated during the study. RESULTS: Consistent with preservation of the memory B cell compartment with belimumab treatment, the proportions of patients maintaining antibody responses to pneumococcal, tetanus, and influenza antigens were not reduced. In a small group receiving influenza vaccine on study, antibody responses were frequently lower with belimumab, although titer levels were > 1:10 in all patients treated with 10 mg/kg and in the majority treated with 1 mg/kg. CONCLUSION: Treatment with belimumab did not affect the ability of patients with SLE to maintain antibody titers to previous pneumococcal, tetanus, and influenza immunizations. [ClinicalTrials.gov registration number NCT 00410384].

Belimumab reduces autoantibodies, normalizes low complement levels, and reduces select B cell populations in patients with systemic lupus erythematosus.

OBJECTIVE: To assess the effects of the B lymphocyte stimulator (BLyS)-specific inhibitor belimumab on immunologic biomarkers, including B cell and T cell populations, and maintenance of antibody titers to prior vaccines in autoantibody-positive systemic lupus erythematosus (SLE) patients. METHODS: Pooled data from 2 phase III trials, the Study of Belimumab in Subjects with SLE 52-week (BLISS-52) and 76-week (BLISS-76) trials, comparing belimumab 1 mg/kg or 10 mg/kg versus placebo (plus standard SLE therapy for each group) were analyzed for changes in autoantibody, immunoglobulin, and complement levels. BLISS-76 patients were also analyzed for changes in B cell and T cell populations and effects on prior vaccine-induced antibody levels. RESULTS: Belimumab-treated patients experienced significant sustained reductions in IgG and autoantibodies and improvement in C3/C4 levels, resulting in greater positive-to-negative conversion rates for IgG anti-double-stranded DNA (anti-dsDNA), anti-Sm, anticardiolipin, and anti-ribosomal P autoantibodies and normalization of hypergammaglobulinemia and low C3/C4 levels. Belimumab-treated patients experienced significant decreases in the numbers of naive and activated B cells, as well as plasma cells, whereas memory B cells and T cell populations did not decrease. Belimumab did not substantially affect preexisting antipneumococcal or anti-tetanus toxoid antibody levels. Post hoc analysis showed greater reductions in SLE disease activity and the risk of severe flares in patients treated with belimumab 10 mg/kg (P≤0.01) who were anti-dsDNA positive and had low C3/C4 levels at baseline. Normalization of the C3 or anti-dsDNA level by 8 weeks, irrespective of therapy, was predictive of a reduced risk of severe flare over 52 weeks. CONCLUSION: Belimumab appears to promote normalization of serologic activity and reduce BLyS-dependent B cell subsets in serologically and clinically active SLE. Greater serologic activity may predict a better treatment response to belimumab.

A phase II, randomized, double-blind, placebo-controlled, dose-ranging study of belimumab in patients with active systemic lupus erythematosus.

OBJECTIVE: To assess the safety, tolerability, biologic activity, and efficacy of belimumab in combination with standard of care therapy (SOC) in patients with active systemic lupus erythematosus (SLE). METHODS: Patients with a Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score >/=4 (n = 449) were randomly assigned to belimumab (1, 4, or 10 mg/kg) or placebo in a 52-week study. Coprimary end points were the percent change in the SELENA-SLEDAI score at week 24 and the time to first SLE flare. RESULTS: Significant differences between the treatment and placebo groups were not attained for either primary end point, and no dose response was observed. Reductions in SELENA-SLEDAI scores from baseline were 19.5% in the combined belimumab group versus 17.2% in the placebo group. The median time to first SLE flare was 67 days in the combined belimumab group versus 83 days in the placebo group. However, the median time to first SLE flare during weeks 24-52 was significantly longer with belimumab treatment (154 versus 108 days; P = 0.0361). In the subgroup (71.5%) of serologically active patients (antinuclear antibody titer >/=1:80 and/or anti-double-stranded DNA [anti-dsDNA] >/=30 IU/ml), belimumab treatment resulted in significantly better responses at week 52 than placebo for SELENA-SLEDAI score (-28.8% versus -14.2%; P = 0.0435), physician's global assessment (-32.7% versus -10.7%; P = 0.0011), and Short Form 36 physical component score (+3.0 versus +1.2 points; P = 0.0410). Treatment with belimumab resulted in a 63-71% reduction of naive, activated, and plasmacytoid CD20+ B cells, and a 29.4% reduction in anti-dsDNA titers (P = 0.0017) by week 52. The rates of adverse events and serious adverse events were similar in the belimumab and placebo groups. CONCLUSION: Belimumab was biologically active and well tolerated. The effect of belimumab on the reduction of SLE disease activity or flares was not significant. However, serologically active SLE patients responded significantly better to belimumab therapy plus SOC than to SOC alone.

Novel evidence-based systemic lupus erythematosus responder index.

OBJECTIVE: To describe a new systemic lupus erythematosus (SLE) responder index (SRI) based on a belimumab phase II SLE trial and demonstrate its potential utility in SLE clinical trials. METHODS: Data from a randomized, double-blind, placebo-controlled study in 449 patients of 3 doses of belimumab (1, 4, 10 mg/kg) or placebo plus standard of care therapy (SOC) over a 56-week period were analyzed. The Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and British Isles Lupus Assessment Group (BILAG) SLE disease activity instruments, the Short Form 36 health survey, and biomarker analyses were used to create a novel SRI. Response to treatment in a subset of 321 serologically active SLE patients (antinuclear antibodies >/=1:80 and/or anti-double-stranded DNA antibodies >/=30 IU/ml) at baseline was retrospectively evaluated using the SRI. RESULTS: SRI response is defined as 1) a >/=4-point reduction in SELENA-SLEDAI score, 2) no new BILAG A or no more than 1 new BILAG B domain score, and 3) no deterioration from baseline in the physician's global assessment by >/=0.3 points. In serologically active patients, the addition of belimumab to SOC resulted in a response in 46% of patients at week 52 compared with 29% of the placebo patients (P = 0.006). SRI responses were independent of baseline autoantibody subtype. CONCLUSION: This evidence-based evaluation of a large randomized, placebo-controlled trial in SLE resulted in the ability to define a robust responder index based on improvement in disease activity without worsening the overall condition or the development of significant disease activity in new organ systems.

A Phase I/II study evaluating escalating doses of recombinant human albumin-interferon-alpha fusion protein in chronic hepatitis C patients who have failed previous interferon-alpha-based therapy.

Albumin-interferon-alpha (IFN-alpha) is a novel 85.7-kDa recombinant protein consisting of IFN-alpha that is genetically fused to human serum albumin. In this Phase I/II, multicentre, open-label study, we evaluated the safety and tolerability, pharmacokinetics and pharmacodynamics of albumin-IFN-alpha in IFN-alpha-experienced patients with chronic hepatitis C. Albumin-IFN-alpha was administered in 22 escalating doses (7-900 microg) in a single injection or in two injections 14 days apart. In the 119 patients studied, there were no discontinuations because of adverse events, and albumin-IFN-alpha had a favourable safety profile at doses up to 900 microg. The most common adverse events were headache (56%), fatigue (52%), injection site erythema (38%), arthralgias (32%) and pyrexia (27%). Reduced clearance resulted in a mean elimination half-life of 159 h, which supports dosing at 2- to 4-week intervals. Induction of the IFN-specific gene OAS1 was maintained for > or = 28 days following a single injection of albumin-IFN-alpha at doses of > or = 40 microg. Dose-dependent antiviral activity was observed in this IFN-alpha-experienced study population. Antiviral activity of > or = 1.0-log reductions in HCV RNA was observed in 47% (37/78) of patients in the 120- to 900-microg cohorts and in 59% (16/27) in the 400- to 900-microg double-injection cohorts. These results support further clinical studies of albumin-IFN-alpha for the treatment of patients with chronic hepatitis C.

A phase 2 study to evaluate the antiviral activity, safety, and pharmacokinetics of recombinant human albumin-interferon alfa fusion protein in genotype 1 chronic hepatitis C patients.

BACKGROUND/AIMS: Recombinant human albumin-interferon alfa (alb-IFN) is a novel 85.7-kD recombinant protein consisting of interferon alfa-2b genetically fused to human serum albumin. METHODS: A phase 2, open-label, dose-ranging study was conducted in IFN-alfa-naïve patients with genotype 1 chronic hepatitis C to evaluate the antiviral activity, safety, and pharmacokinetics of alb-IFN. Fifty-six patients were enrolled to receive two subcutaneous injections of alb-IFN 14 days apart in five dose cohorts of 200, 450, 670, 900, and 1,200 microg. RESULTS: A 2 log(10) IU/mL or greater reduction in hepatitis C virus (HCV) RNA at Week 4 was observed in 69% (18/26) of patients who received the higher alb-IFN doses of 900 and 1,200 microg. The mean HCV RNA reduction at Week 4 in these two higher-dose cohorts was 3.2 log(10) IU/mL. Modeling of viral kinetics demonstrated a biphasic response that was dose dependent. Adverse events were mostly mild to moderate in severity. The most common adverse events were headache (73%), chills (63%), fatigue (61%), and arthralgia (55%). The median terminal half-life was 141 h consistent with previous alb-IFN data from IFN-alfa-experienced patients. CONCLUSIONS: Alb-IFN demonstrated significant antiviral activity and was well tolerated in patients with HCV genotype 1 infection.

A phase 1 study of PAmAb, a fully human monoclonal antibody against Bacillus anthracis protective antigen, in healthy volunteers.

BACKGROUND: Inhibition of the binding of Bacillus anthracis protective antigen (PA) to its cellular receptor can abrogate the downstream toxin-mediated deleterious effects of the anthrax toxin. A fully human monoclonal antibody against B. anthracis PA, PAmAb, was previously shown to provide a survival advantage in rabbit and monkey models of inhalational anthrax. METHODS: A randomized, single-blind, placebo-controlled, dose-escalation study with 105 healthy volunteers was conducted to evaluate the safety, pharmacokinetics, and biological activity of PAmAb. Subjects received PAmAb or placebo as a single intramuscular injection (11 subjects/cohort) or intravenous infusion (10 subjects/cohort). Three intramuscular dose levels (0.3, 1.0, and 3.0 mg/kg) and 5 intravenous dose levels (1.0, 3.0, 10, 20, and 40 mg/kg) were studied. Two separate intramuscular injection sites (gluteus maximus and vastus lateralis) were evaluated in the cohorts (hereafter, the "IM-GM" and "IM-VL" cohorts, respectively). RESULTS: PAmAb was well tolerated, with no dose-limiting adverse events. All adverse events were transient and mild to moderate in incidence and/or severity. The pharmacokinetics of PAmAb were linear within each route and site of administration but were significantly different between the IM-GM and IM-VL cohorts. The mean terminal elimination half-life ranged from 15 to 19 days. The bioavailability of PAmAb is approximately 50% for IM-GM injection and 71%-85% for IM-VL injection. The biological activity of PAmAb in serum, assessed using a cyclic adenosine monophosphate assay, correlated with serum concentrations. CONCLUSIONS: PAmAb is safe, well tolerated, and bioavailable after a single intramuscular or intravenous dose, which supports further clinical development of PAmAb as a novel therapeutic agent for inhalational anthrax.

Effect of Food on the Steady-State Pharmacokinetics of Delavirdine in Patients with HIV Infection.

OBJECTIVE: In a prior single-dose study that examined the effect of food on delavirdine pharmacokinetics in healthy volunteers, the absorption of delavirdine mesylate was delayed and the area under the curve was reduced by 26% in the presence of food. Since the complex, nonlinear pharmacokinetics of delavirdine do not permit a simple extrapolation of the results of a single-dose study to steady state, the present multiple-dose study was performed. PATIENTS AND STUDY DESIGN: Thirteen stable patients with HIV-1 infection (two females, 11 males; CD4 count range 124-588 cells/mm(3)) completed a randomised, crossover study in which subjects received two 14-day treatments with delavirdine mesylate 400mg every 8 hours. In treatment A, all delavirdine doses were administered on an empty stomach and in treatment B were taken with food. A pharmacokinetic evaluation was performed on day 14 of each treatment period. SETTING: An ambulatory AIDS research centre in an academic medical centre. INTERVENTIONS: Administration of delavirdine with and without food. MAIN OUTCOME MEASURES: Pharmacokinetic parameters for delavirdine. RESULTS: The maximum concentration (C(max)) [+/- standard deviation] in treatment A was 29.6 +/- 13.6muM and in treatment B it was 23.0 +/- 8.61muM (p = 0.037). The minimum concentrations (C(min)) were 9.45 +/- 6.7muM and 11.2 +/- 9.2muM, respectively (p > 0.05). The oral clearances (CL(oral)) were 17.8 +/- 41.6 L/h (treatment A) and 18.5 +/- 39.0 L/h (treatment B) [p > 0.05]. Similar patterns were observed for N-dealkylated delavirdine with a significant difference only in C(max) (4.13 vs 3.47muM [p = 0.022], treatment A vs B). CONCLUSIONS: These findings indicated that, in contrast to the increased CL(oral) noted in a prior single-dose study, food did not have a significant effect at steady state on the area under the plasma concentration-time curve or C(min). Although C(max) was significantly lower when the drug was taken taken with food, the clinical relevance of this parameter as compared with the trough concentration is unclear since the current focus for antiretrovirals is on maintaining trough concentrations in excess of in vitro inhibitory concentrations.

Multiple-Dose Pharmacokinetics of Delavirdine Mesylate and Didanosine in HIV-Infected Patients.

BACKGROUND: Delavirdine is a non-nucleoside reverse transcriptase inhibitor with pH-dependent absorption characteristics that has received accelerated approval for the treatment of patients with HIV-1 infection. In a prior single-dose study concurrent administration of delavirdine mesylate and didanosine (buffered formulation) resulted in up to a 31% decrease in the area under the plasma delavirdine concentration versus time curve (AUC) compared with when both drugs were taken separately. OBJECTIVE: To evaluate the interaction of these two agents at steady state. STUDY DESIGN AND PATIENTS: A total of 11 HIV-infected subjects who were previously stabilised on didanosine were enrolled into a randomised, open-labelled crossover study. Nine subjects continued to receive their prescribed dose and schedule of didanosine, with each dose of didanosine taken either together with or 1 hour after delavirdine mesylate (400mg every 8 hours). Pharmacokinetic studies at baseline, day 14 and day 28 were conducted and the plasma concentrations of delavirdine and didanosine were determined. RESULTS: A lower delavirdine maximum plasma concentration (C(max)) [22.4 +/- 11 vs 35.5 +/- 17muM; p = 0.045] was noted when delavirdine and didanosine were taken together. However, no significant difference was noted for delavirdine AUC (114 +/- 56 muM.h compared with 153 +/- 79 muM.h [p = 0.181]). In addition, no differences were noted for didanosine pharmacokinetic parameters between treatments. CONCLUSION: These data indicate that patients receiving didanosine and delavirdine as part of a combination regimen during long-term therapy can be instructed to take them together in an attempt to enhance adherence to treatment with both antiretroviral agents.