Omoniyi J. Adedokun

Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis

BACKGROUND & AIMS Little is known about the efficacy of golimumab, a fully human monoclonal antibody to tumor necrosis factor (TNF) -α, for treatment of ulcerative colitis (UC). We evaluated subcutaneous golimumab induction therapy in TNF-α antagonist-naïve patients with moderate-to-severe UC despite conventional treatment. METHODS We integrated double-blind phase 2 dose-finding and phase 3 dose-confirmation trials in a study of 1064 adults with UC (Mayo score: 6-12; endoscopic subscore ≥ 2; 774 patients in phase 3). Patients were randomly assigned to groups given golimumab doses of 100 mg and then 50 mg (phase 2 only), 200 mg and then 100 mg, or 400 mg and then 200 mg, 2 weeks apart. The phase 3 primary end point was week-6 clinical response. Secondary end points included week-6 clinical remission, mucosal healing, and Inflammatory Bowel Disease Questionnaire (IBDQ) score change. RESULTS In phase 2, median changes from baseline in the Mayo score were -1.0, -3.0, -2.0, and -3.0, in the groups given placebo, 100 mg/50 mg, 200/100 mg, and 400/200 mg golimumab, respectively. In phase 3, rates of clinical response at week 6 were 51.0% and 54.9% among patients given 200 mg/100 mg and 400 mg/200 mg golimumab, respectively, vs 30.3% among those given placebo (both, P ≤ .0001). Rates of clinical remission and mucosal healing and mean changes in IBDQ scores were significantly greater in both golimumab groups vs the placebo group (P ≤ .0014, all comparisons). Rates of serious adverse events were 6.1% and 3.0%, and rates of serious infection were 1.8% and 0.5%, in the placebo and golimumab groups, respectively. One patient in the 400 mg/200 mg group died as a result of surgical complications of an ischiorectal abscess. CONCLUSIONS Treatment with subcutaneous golimumab induces clinical response, remission, and mucosal healing, and increases quality of life in larger percentages of patients with active UC than placebo. ClinicalTrials.gov Number: NCT00487539.

Subcutaneous Golimumab Maintains Clinical Response in Patients With Moderate-to-Severe Ulcerative Colitis

BACKGROUND & AIMS Subcutaneous golimumab, a fully human monoclonal antibody to tumor necrosis factor-α (TNFα), was evaluated as maintenance therapy in TNFα antagonist-naive adults with moderate-to-severe active ulcerative colitis, despite conventional therapy, who responded to golimumab induction therapy. METHODS We performed a phase 3, double-blind trial of patients who completed golimumab induction trials (Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment, eg, PURSUIT). Patients who responded to induction therapy with golimumab (n = 464) were assigned randomly to groups given placebo or injections of 50 or 100 mg golimumab every 4 weeks through week 52. Patients who responded to placebo in the induction study continued to receive placebo. Nonresponders in the induction study received 100 mg golimumab. The primary end point was clinical response maintained through week 54; secondary end points included clinical remission and mucosal healing at both weeks 30 and 54. RESULTS Clinical response was maintained through week 54 in 47.0% of patients receiving 50 mg golimumab, 49.7% of patients receiving 100 mg golimumab, and 31.2% of patients receiving placebo (P = .010 and P < .001, respectively). At weeks 30 and 54, a higher percentage of patients who received 100 mg golimumab were in clinical remission and had mucosal healing (27.8% and 42.4%) than patients given placebo (15.6% and 26.6%; P = .004 and P = .002, respectively) or 50 mg golimumab (23.2% and 41.7%, respectively). Percentages of serious adverse events were 7.7%, 8.4%, and 14.3% among patients given placebo, 50 mg, or 100 mg golimumab, respectively; percentages of serious infections were 1.9%, 3.2%, and 3.2%, respectively. Among all patients given golimumab in the study, 3 died (from sepsis, tuberculosis, and cardiac failure, all in patients who received 100 mg golimumab) and 4 developed active tuberculosis. CONCLUSIONS Golimumab (50 mg or 100 mg) maintained clinical response through week 54 in patients who responded to induction therapy with golimumab and had moderate-to-severe active ulcerative colitis; patients who received 100 mg golimumab had clinical remission and mucosal healing at weeks 30 and 54. Safety was consistent with that reported for other TNFα antagonists and golimumab in other approved indications. ClinicalTrials.gov number: NCT00488631.

Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease

BACKGROUND Ustekinumab, a monoclonal antibody to the p40 subunit of interleukin-12 and interleukin-23, was evaluated as an intravenous induction therapy in two populations with moderately to severely active Crohns disease. Ustekinumab was also evaluated as subcutaneous maintenance therapy. METHODS We randomly assigned patients to receive a single intravenous dose of ustekinumab (either 130 mg or approximately 6 mg per kilogram of body weight) or placebo in two induction trials. The UNITI-1 trial included 741 patients who met the criteria for primary or secondary nonresponse to tumor necrosis factor (TNF) antagonists or had unacceptable side effects. The UNITI-2 trial included 628 patients in whom conventional therapy failed or unacceptable side effects occurred. Patients who completed these induction trials then participated in IM-UNITI, in which the 397 patients who had a response to ustekinumab were randomly assigned to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 8 weeks or every 12 weeks) or placebo. The primary end point for the induction trials was a clinical response at week 6 (defined as a decrease from baseline in the Crohns Disease Activity Index [CDAI] score of ≥100 points or a CDAI score <150). The primary end point for the maintenance trial was remission at week 44 (CDAI score <150). RESULTS The rates of response at week 6 among patients receiving intravenous ustekinumab at a dose of either 130 mg or approximately 6 mg per kilogram were significantly higher than the rates among patients receiving placebo (in UNITI-1, 34.3%, 33.7%, and 21.5%, respectively, with P≤0.003 for both comparisons with placebo; in UNITI-2, 51.7%, 55.5%, and 28.7%, respectively, with P<0.001 for both doses). In the groups receiving maintenance doses of ustekinumab every 8 weeks or every 12 weeks, 53.1% and 48.8%, respectively, were in remission at week 44, as compared with 35.9% of those receiving placebo (P=0.005 and P=0.04, respectively). Within each trial, adverse-event rates were similar among treatment groups. CONCLUSIONS Among patients with moderately to severely active Crohns disease, those receiving intravenous ustekinumab had a significantly higher rate of response than did those receiving placebo. Subcutaneous ustekinumab maintained remission in patients who had a clinical response to induction therapy. (Funded by Janssen Research and Development; ClinicalTrials.gov numbers, NCT01369329 , NCT01369342 , and NCT01369355 .).

Association Between Serum Concentration of Infliximab and Efficacy in Adult Patients With Ulcerative Colitis

BACKGROUND & AIMS We analyzed data collected during the Active Ulcerative Colitis Trials (ACT-1 and ACT-2) to assess relationships between serum concentrations of infliximab and outcomes of adults with moderate-to-severe ulcerative colitis. METHODS We compared serum concentrations of infliximab with outcomes of 728 patients with moderately-to-severely active ulcerative colitis who participated in ACT-1 or ACT-2; efficacy data were collected at weeks 8, 30, and 54 (for ACT-1 only). Relationships between serum concentration of infliximab and efficacy outcomes were assessed using trend, logistic regression, and receiver operating characteristic curve analyses. We also evaluated factors that affected the relationship between exposure and response. RESULTS Median serum concentrations of infliximab at weeks 8, 30, and/or 54 were significantly higher in patients with clinical response, mucosal healing, and/or clinical remission than in patients who did not meet these response criteria. There were statistically significant relationships between quartile of infliximab serum concentration and efficacy at these time points (P < .01). Infliximab therapy was effective for a smaller proportion of patients in the lowest quartile, and these patients had lower serum levels of albumin and a higher incidence of antibodies to infliximab than patients in other quartiles. Although the relationship between exposure to infliximab and response varied among patients, approximate serum concentrations of 41 μg/mL infliximab at week 8 of induction therapy and 3.7 μg/mL at steady-state during maintenance therapy produced optimal outcomes in patients. CONCLUSIONS Serum concentrations of infliximab are associated with efficacy in patients with moderate-to-severe ulcerative colitis; however, complex factors determine the relationship between exposure to this drug and response. A prospective evaluation of the value of measuring serum concentrations of infliximab should be performed before these data can be included in patient management strategies. Clinicaltrials.gov numbers: NCT00036439 and NCT00096655.

Pharmacokinetic Properties of Infliximab in Children and Adults with Crohn's Disease: A Retrospective Analysis of Data from 2 Phase III Clinical Trials

BACKGROUND Infliximab is a chimeric monoclonal antibody against TNFα. The pharmacokinetic (PK) properties of infliximab have been studied in several adult patient populations, but a literature search identified no reported comparative population PK properties of this drug in pediatric patients. OBJECTIVES The current analysis applied population PK techniques to compare data on the PK properties of infliximab in pediatric and adult patients with moderately to severely active Crohns disease (CD) from 2 Phase III studies. METHODS This analysis used serum infliximab concentration data from 692 patients (112 children, 580 adults; age range, 6-76 years) from 2 Phase III clinical studies (REACH [A Randomized, Multicenter, Open-Label Study to Evaluate the Safety and Efficacy of Anti-TNF-α Chimeric Monoclonal Antibody in Pediatric Subjects with Moderate-to-Severe Crohns Disease] and ACCENT I [A Crohns Disease Clinical Trial Evaluating Infliximab in a New, Long-term Treatment Regimen]). PK models were developed separately for children, adults, and a combination of both. The combined population was used for establishing important covariates of infliximab PK properties in the combined CD population. Exploratory simulations using combined PK and covariate data were performed to expand the interpretation of the results in children. RESULTS Based on the findings, in a typical child (who, based on the median values in REACH, weighs 42 kg, has a baseline serum albumin concentration [SAC] 3.8 mg/dL, and has not developed antibodies to infliximab [ATIs]) who is receiving infliximab and an immunomodulator, PK estimates (typical value [SE]) were as follows: clearance (CL), 5.43 (0.15) mL/kg/d; V(d) in the central compartment (V(1)), 54.2 (1.15) mL/kg; V(d) in the peripheral compartment (V(2)), 29.2 (2.03) mL/kg; and intercompartmental clearance (Q), 3.52 (0.71) mL/kg/d. Corresponding properties in a typical adult (weight, 68 kg; SAC, 4.1 mg/dL) were CL, 5.39 (0.13) mL/kg/d; V(1), 52.7 (0.49) mL/kg; V(2), 19.0 (1.53) mL/kg; and Q, 2.15 (0.39) mL/kg/d. V(2) decreased as body weight increased, predicting a possible undercompensation for exposure with infliximab dosing per kg weight in lower-weight individuals. In pediatric and adult patients, CL was higher in those in whom ATIs developed or who had low baseline SAC. Concurrent immunomodulator use (purine antimetabolites or methotrexate) was associated with a 14% decrease in CL. In the pediatric and adult patients, observed trough serum infliximab concentrations, median infliximab t(1/2) (in children, 13.2 days; and in adults, 12.4 days), and exploratory PK simulations predicted infliximab PK properties to be comparable between children and adults. CONCLUSIONS Infliximab PK properties appeared to be comparable between pediatric and adult patients with CD. Specifically, in this select population using nonlinear mixed effects modeling, infliximab CL increased as SAC decreased. CL also increased with ATI formation but decreased with immunomodulator coadministration. Although weight affects infliximab PK properties (total CL and total Vd increased with total body weight while per kg CL and Vd decrease with total body weight), age was not found to influence infliximab PK in the age range tested (6-76 years).

566 Infliximab Concentration and Clinical Outcome in Patients With Ulcerative Colitis

Background: Infliximab (IFX), a chimeric mouse/human IgG1 monoclonal antibody against tumor necrosis factor alpha is successfully used in the treatment of Crohns disease and ulcerative colitis. Despite its beneficial effect, IFX can provoke an immunogenic response which can lead to loss of response to the drug. It is generally believed that, once elicited, an antibody response to a certain protein cannot be overcome. We hypothesised that in patients who elicit only low levels of antibodies to infliximab (ATI), these may disappear with dose optimisation and that patients may recapture response. Methods: In this retrospective analysis in 52 IFX-treated patients a total of 693 serum samples (average of 13.3 samples per patient) were analysed. Patients were selected based on ATIs detected on at least one time point during follow up with an in-house developed ELISA. All consecutive samples were then analysed for IFX trough levels (TLI; expressed in μg/ml; cut-off value: 0.91 μg/ ml) and ATIs (expressed in U/ml; cut-off value 7.95 U/ml) using a fluid phase mobility shift assay (Prometheus Laboratories, San Diego US). Treatment decisions to optimise and stop therapy were made on clinical grounds and CRP, without knowledge of ATI or TLI. Results: Patients developed ATIs after a median of 16 weeks (IQR 8-39) following initiation of IFX and after a median of 5 (IQR 3-7) infusions. In 14 (27%) patients ATIs disappeared over time whereas in 38 (73%) patients ATIs persisted. There was no difference in time to ATI onset between patients with transient or sustained ATIs. Patients with transient ATIs had significantly lower ATI levels (median 18.7 U/ml; IQR 10.6-31.5) compared to patients with sustained ATIs (median 22.1 U/ml; IQR 14.0-45.7; p<0.01; Mann-Whitney U test). Patients with sustained ATIs had a two-fold higher risk (RR 2.1; 95%CI 0.9-4.6; p<0.05) to suffer an acute infusion reaction compared to patients with transient ATIs. Concomitant immunomodulator (IMM) use was associated with lower ATI levels (median ATI level with IMM: 8.8 U/ml versus 15.5 U/ml without IMM; p<0.01; Mann-Whitney U test). In 8/14 patients (57%) ATIs disappeared following dose optimisation and in the other 6 patients (43%), ATIs disappeared spontaneously. Patients with sustained ATIs more often discontinued IFX treatment due to loss of response and/or hypersensitivity reactions compared to patients with transient ATIs (68% versus 14 % respectively; p<0.001; Fishers Exact test). Conclusion: Antibodies to infliximabmay be transient and can disappear after dose optimisation. Sustained high levels of ATIs lead however to permanent loss of response. When low or undetectable TLI are detected, knowledge of ATIs is therefore important as low titre ATIs can be overcome mostly with dose optimisation and high titre ATIs lead to a higher risk of adverse events and necessitate treatment stop.

Pharmacokinetics and Exposure-Response Relationship of Golimumab in Patients with Moderately-to-Severely Active Ulcerative Colitis: Results from Phase 2/3 PURSUIT Induction and Maintenance Studies

Background and Aims: To assess golimumab pharmacokinetics [PK] and exposure-response [ER] in adults with moderate-to-severe ulcerative colitis [UC] from the Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment [PURSUIT] studies. Methods: We analysed golimumab PK and ER data of patients with moderate-to-severe UC from the PURSUIT-subcutaneous induction [N = 1064] and maintenance [N = 464] studies. Induction analyses evaluated serum golimumab concentration [SGC] and efficacy data through Week [wk] 6 following subcutaneous doses at wk0 and wk2; maintenance analyses assessed data through wk54 following 4-weekly dosing. ER relationships were assessed using trend, logistic regression, and receiver-operating-characteristic curve analyses. Results: Median SGCs peaked at induction wk2 for golimumab 100/50mg, 200/100mg, and 400/200mg. Wk6 median SGCs were 0.78, 1.78, and 4.01 &mgr;g/ml, respectively. SGCs were sustained, reaching steady state approximately 8wks after golimumab maintenance commenced [wk14 of golimumab] regardless of induction dose. Median trough SGCs from maintenance wks8–44 ranged from 0.69 to 0.83 µg/ml [50 mg] and 1.33–1.58 µg/ml [100 mg]. SGCs were approximately dose proportional, and higher SGCs were associated with higher efficacy response rates during induction and maintenance. Factors associated with golimumab exposure were body weight, antibody-to-golimumab status, serum albumin, alkaline phosphatase, faecal markers, C-reactive protein, and pancolitis. SGCs of 2.5 µg/ml [induction wk6] and 1.4 µg/ml [maintenance steady-state trough] are potential target concentrations. Immunomodulators had no apparent impact on SGC with golimumab 100mg, whereas drug levels were slightly higher with golimumab 50mg with vs without immunomodulators. Conclusions: SGCs are approximately dose proportional, and a positive SGC-efficacy relationship exists during induction/maintenance golimumab treatment of adult UC patients. Optimal SGC targets require validation in prospective studies.

Randomised clinical trial: a placebo‐controlled study of intravenous golimumab induction therapy for ulcerative colitis

Tumour necrosis factor alpha (TNFα)‐antagonism effectively treats ulcerative colitis (UC). The golimumab clinical programme evaluated subcutaneous (SC) and intravenous (IV) induction, and SC maintenance regimens, in TNFα‐antagonist‐naïve patients with moderate‐to‐severe active UC despite conventional treatment.

Pharmacokinetics of infliximab in children with moderate-to-severe ulcerative colitis: results from a randomized, multicenter, open-label, phase 3 study.

Background:To assess infliximab pharmacokinetics in pediatric ulcerative colitis (UC). Methods:This phase 3, randomized, open-label multicenter study enrolled 60 children (6–17 yr) with moderate-to-severely active UC (Mayo score, 6–12; endoscopic subscore, ≥2), despite conventional therapy. Patients received infliximab 5-mg/kg induction infusions at weeks 0, 2, and 6. Week 8 clinical responders (n = 45) were randomized to infliximab 5 mg/kg given every 8 weeks (q8w) through week 46 or every 12 weeks (q12w) through week 42. Patients losing response during maintenance infliximab were eligible to increase the dose (5→10 mg/kg) and/or shorten the dosing interval (q12w→q8w). Blood samples were collected for infliximab concentration and pharmacokinetic determinations. Results:Infliximab pharmacokinetics were not influenced by age (6–11 yr versus 12–17 yr), baseline immunomodulator use, or the extent of UC. At week 8, higher serum infliximab concentrations (≥41.1 &mgr;g/mL) were associated with greater proportions of patients achieving efficacy endpoints (clinical response, 92.9%; mucosal healing, 92.9%; and clinical remission, 64.3%) versus those with lower serum concentrations (<18.1 &mgr;g/mL; 53.9%, 53.9%, and 30.8%, respectively). At week 30, higher median trough serum infliximab concentrations were observed with infliximab 5 mg/kg q8w (1.9 &mgr;g/mL) versus q12w (0.8 &mgr;g/mL) and with infliximab 10 mg/kg (2.9 &mgr;g/mL) versus 5 mg/kg (1.1 &mgr;g/mL) among patients who are regimen adjusted. Conclusions:Infliximab pharmacokinetics/exposure–response relationship in patients with UC aged 6 to 17 years were generally comparable with those observed in reference adult UC populations, supporting using infliximab 5 mg/kg at weeks 0, 2, and 6 followed by maintenance dosing with 5 mg/kg q8w in these patients. A positive relationship was noted between serum infliximab level and clinical effect following induction therapy similar to adults.

Confirmatory population pharmacokinetic analysis for bapineuzumab phase 3 studies in patients with mild to moderate Alzheimer's disease

The population pharmacokinetics of bapineuzumab, a humanized monoclonal IgG1 antibody that was generated from a murine monoclonal antibody and binds specifically to amino acids 1 to 5 of the free N‐terminus of human amyloid‐beta peptide, were characterized in patients with mild‐to‐moderate alzheimers disease in two Phase 3 studies (ELN115727‐301 and ELN115727‐302). A total of 8,040 serum concentration measurements were analyzed from 1,458 patients who received 6 doses of bapineuzumab intravenously once every 13 weeks. A confirmatory analysis was conducted using a prespecified two‐compartment model with first‐order elimination. After the primary covariate effect assessment, a reduced model was obtained. Based on the reduced model, the typical population values for clearance (CL) and volume (Vc) from the central compartment in a Caucasian subject with a standardized body weight of 70 kg were 0.17 L/day and 3.13 L, respectively. Bapineuzumab CL and Vc increased with body weight. Furthermore, CL was 15% higher in non‐Caucasian subjects; however, this was not considered clinically relevant. None of the other evaluated covariates had a meaningful impact on CL. The median terminal elimination half‐life was estimated to be approximately 29 days. Sensitivity analyses and bootstrapping results supported model stability.