Efficacy of Ustekinumab for Inducing Endoscopic Healing in Patients With Crohn's Disease.

BACKGROUND & AIMS: We evaluated the ability of ustekinumab, a monoclonal antibody against the p40 subunit of interleukins 12 and 23, to induce endoscopic healing in patients with moderate to severe Crohn's disease (CD). METHODS: We performed an endoscopy substudy of 334 patients with moderate to severe CD participating in 3 randomized controlled phase 3 studies to determine the safety and efficacy of ustekinumab induction and maintenance therapy. All patients underwent colonoscopy at baseline and week 8 of the induction studies and at week 44 of the maintenance study; all colonoscopies were assessed by a blinded central reader. During the induction studies, patients were randomly assigned to groups given intravenous ustekinumab (130 mg or 6 mg/kg) or placebo. At the baseline time point of the maintenance study (week 8 of the induction studies), patients with a clinical response to ustekinumab were randomly assigned to groups given subcutaneous ustekinumab (90 mg every 12 weeks or 8 weeks) or placebo. Additional maintenance analysis populations were patients who did not respond to ustekinumab or placebo during the induction studies, and patients who responded to placebo during the induction studies; we performed a post-hoc pooled analysis of randomly assigned and non-randomly assigned patients of the maintenance study. We analyzed data from patients with an ulcer in at least 1 segment at baseline of the induction studies. The primary end point was change in the Simplified Endoscopic Activity Score for Crohn's Disease (SES-CD), from baseline, at week 8. We also assessed the efficacy of maintenance therapy. RESULTS: Patients given ustekinumab had a greater reduction in SES-CD from the induction baseline time point until week 8 than placebo (reduction of 2.8 in patients given ustekinumab vs a reduction of 0.7 points in patients given placebo; P = .012). Results were similar among patients in different induction studies and patients given different doses of ustekinumab. At week 44, reductions in the SES-CD from the induction baseline were greater in patients given ustekinumab (for combined groups, a reduction of 2.5; P = .176 and for every 8 weeks, a reduction of 3.1; P = .107) than patients given placebo (reduction of 1.9 points). Maintenance results were similar for the larger pooled post-hoc analysis. CONCLUSIONS: In an analysis of data from 3 trials of patients with moderate to severe CD, ustekinumab (intravenous induction and subcutaneous maintenance) reduces SES-CD compared with placebo. We observed significant reductions in endoscopic disease activity at week 8 of induction therapy with ustekinumab. (ClinicalTrials.gov numbers, NCT01369329, NCT01369342, and NCT01369355).

The Effects of Ustekinumab on Health-related Quality of Life in Patients With Moderate to Severe Crohn's Disease.

BACKGROUND AND AIMS: We assessed the effect of ustekinumab on health-related quality of life [HRQOL] in adults with Crohn's disease [CD]. METHODS: Patients with moderately to severely active CD and inadequate response or intolerance to tumour necrosis factor antagonists [UNITI-1, n = 741], or conventional therapy [UNITI-2, n = 627] were randomised to placebo, ustekinumab 130 mg, or 6 mg/kg intravenous induction therapy. At Week 8, ustekinumab-treated responders (Crohn's Disease Activity Index [CDAI] reduction ≥100 or CDAI <150 points) were re-randomised to subcutaneous maintenance therapy [IM-UNITI, n = 388] with placebo, ustekinumab 90 mg every 12 weeks [q12w], or ustekinumab 90 mg every 8 weeks [q8w], for 44 additional weeks. Inflammatory Bowel Disease Questionnaire [IBDQ] and 36-item Short Form Health Survey [SF-36] physical component summary [PCS] and mental component summary [MCS] scores were completed at induction baseline and Week 8, and at maintenance Weeks 20 and 44. Clinically meaningful improvement in IBDQ and PCS and MCS scores were evaluated. For all HRQOL outcomes, each ustekinumab dose and placebo were compared. RESULTS: Induction baseline mean values of IBDQ, PCS, and MCS were similar across groups, but impaired relative to general population norms. At Week 8, ustekinumab induced greater improvement than placebo in both HRQOL scores. Significantly greater proportions of patients receiving ustekinumab 6 mg/kg or 130 mg had clinically meaningful IBDQ improvement [UNITI-1: 54.8%, 46.9% versus 36.5%, respectively; UNITI-2: 68.1%, 58.7% versus 41.1%, respectively; p <0.05, all comparisons]. Similarly, greater proportions of ustekinumab-treated patients in both studies had clinically meaningful improvements in PCS and MCS as compared with placebo. At Week 44, improvements in IBDQ, PCS, and MCS scores were maintained with ustekinumab. CONCLUSIONS: Ustekinumab improved HRQOL in patients with moderately to severely active CD.

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 Crohn's 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 Crohn's 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 Crohn's 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 .).

Long-term infliximab maintenance therapy for ulcerative colitis: the ACT-1 and -2 extension studies.

BACKGROUND: The aim was to evaluate long-term efficacy, quality of life, and safety in ulcerative colitis patients who received infliximab during the ACT-1 and -2 extension studies. METHODS: Adults with moderate-to-severely active ulcerative colitis in the 54-week ACT-1 and 30-week ACT-2 studies who achieved benefit from infliximab were eligible to participate in extension studies and receive up to 3 additional years of therapy. Patients received randomized study medication until all sites were unblinded; placebo-treated patients were discontinued. Patients receiving 5 or 10 mg/kg infliximab continued to receive open-label infliximab every 8 weeks. Patients receiving infliximab 10 mg/kg could decrease to 5 mg/kg; patients receiving infliximab 5 mg/kg could increase to 10 mg/kg if response was lost. RESULTS: A total of 229 of 484 infliximab-treated patients from the ACT-1 and ACT-2 main studies entered the long-term extensions. Overall, 70 (30.6%) patients discontinued infliximab infusions for adverse events (24 [10.5%]), lack of efficacy (11 [4.8%]), required a colectomy (1 [0.4%]), or for other reasons (34 [14.8%]). Proportions of patients whose Physician's Global Assessment scores were indicative of no or mild disease (score = 0 or 1) were maintained during the extension studies; 76.5% at Extension week 0 and ranged between 90.0% and 94.3% through Extension week 152. Improvement in Inflammatory Bowel Disease Questionnaire scores observed in the main studies was maintained. During the long-term extension, the infliximab safety profile was consistent with that of the main studies; no new or unexpected safety signals were observed. CONCLUSIONS: Long-term treatment with infliximab for up to 3 additional years was effective and well tolerated.

Early mucosal healing with infliximab is associated with improved long-term clinical outcomes in ulcerative colitis.

BACKGROUND & AIMS: In the Active Ulcerative Colitis Trial (ACT)-1 and ACT-2, patients with ulcerative colitis treated with infliximab were more likely than those given placebo to have a clinical response, undergo remission, and have mucosal healing. We investigated the association between early improvement (based on endoscopy) and subsequent clinical outcome. METHODS: Patients underwent endoscopic evaluations at weeks 0, 8, 30, and 54 (ACT-1 only), and were categorized into 4 subgroups by week 8 (Mayo endoscopy subscore, 0-3). The association of week 8 endoscopy subscores, subsequent colectomy risk, symptoms and corticosteroid use outcomes were analyzed. Mucosal healing was defined as a Mayo endoscopy subscore of 0 (normal) or 1 (mild). RESULTS: Infliximab-treated patients with lower week 8 endoscopy subscores were less likely to progress to colectomy through 54 weeks of follow-up evaluation (P=.0004). This trend was not observed among patients given placebo (P=.47). Patients with lower endoscopy subscores achieved better symptomatic and corticosteroid use outcomes at weeks 30 and 54 (P<.0001, infliximab; P<.01, placebo). Among patients who achieved clinical response at week 8, trends in subsequent clinical outcomes by week 8 endoscopy subscores were generally consistent with that for the overall patient population; no trends were observed among patients who achieved clinical remission. CONCLUSIONS: The degree of mucosal healing after 8 weeks of infliximab was correlated with improved clinical outcomes including colectomy. Similar trends were observed for all outcomes except colectomy among the subgroup with clinical response at week 8. The degree of mucosal healing at week 8 among those in clinical remission did not predict subsequent disease course.

Safety and efficacy of maintenance infliximab therapy for moderate-to-severe Crohn's disease in children: REACH open-label extension.

OBJECTIVE: Assess long-term effects of maintenance infliximab therapy in children with moderately-to-severely active Crohn's disease. RESEARCH DESIGN AND METHODS: One hundred twelve patients with a Pediatric Crohn's Disease Activity Index (PCDAI) score >30 received infliximab 5 mg/kg at weeks 0, 2, and 6 in the REACH study. Patients considered responders at week 10 were randomized to infliximab 5 mg/kg every 8 (q8w) or 12 (q12w) weeks. Patients who completed treatment through week 46, and who the investigator believed would benefit from continued treatment, could enter the open-label extension (OLE) and receive up to three additional years of infliximab. No hypothesis testing was performed. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov, identifier: NCT0020767. RESULTS: Sixty children entered the OLE: 33, 12, and 15 patients were receiving infliximab 5 mg/kg q8w, 5 mg/kg q12w, and 10 mg/kg q8w, respectively, at extension entry. Patients receiving infliximab for up to 3 years during the OLE maintained clinical benefit, with approximately 80% of patients consistently having no to mild disease activity per the physician's global assessment and very good to fair health in the past 2 weeks per the patient and parent/guardian global assessments. Patients with ≥1-year delay in bone age at baseline trended toward improvement in height during the OLE. Respiratory system disorders, most commonly upper respiratory infections, were the most prevalent adverse events reported; six (10%) patients had serious infections. CONCLUSIONS: Among children with moderately-to-severely active Crohn's disease who received infliximab for 46 weeks in REACH and then for up to 3 additional years in the REACH OLE, infliximab was effective in maintaining clinical benefit and was generally well-tolerated.

Relationship of C-reactive protein with clinical response after therapy with ustekinumab in Crohn's disease.

OBJECTIVES: Ustekinumab induction therapy was studied in a placebo-controlled trial of patients with Crohn's disease (CD; n=104). In patients receiving ustekinumab, 49% achieved clinical response at week 8 vs. 40% for placebo (P=0.34). In a subgroup of patients previously treated with infliximab (n=49), 59% receiving ustekinumab responded vs. 26% receiving placebo (P=0.02). METHODS: C-reactive protein (CRP) concentrations were analyzed from serum collected at baseline and at week 8. Change from baseline CRP concentration after treatment, the relationship between baseline CRP concentration and clinical response, and the relationship between baseline CRP concentration and disease location were investigated. RESULTS: Mean changes from baseline CRP at week 8 in the primary group were -0.3 and -3.1 mg/l after treatments with placebo (n=43) and ustekinumab (n=46), respectively (P=0.074). In the infliximab-experienced subgroup, the mean changes were +2.0 (placebo, n=23) and -2.6 mg/l (ustekinumab, n=20) (P=0.004). Patients with baseline CRP >or=10 mg/l tended to have lower placebo and a higher ustekinumab response. In addition, more extensive diseases associated with CD in the colon and ileum were reflected by higher CRP concentrations. CONCLUSIONS: The potential benefit of ustekinumab in CD is supported by serum CRP reductions. Evidence suggests that increased systemic inflammation as manifested by higher baseline CRP values leads to larger treatment effects with ustekinumab, especially in infliximab-experienced patients.

[Enhancement of a hepatitis B DNA vaccine potency using aluminum phosphate in mice].

OBJECTIVES: To study antibody response to a hepatitis B DNA vaccine by formulation with aluminum phosphate in mice. METHODS: An eukaryotic expression plasmid inserted HBsAg gene (pcDNA3.1-S) was constructed by cloning technique and the accuracy of the construct was confirmed by restriction enzyme digestion and DNA sequencing, then hepatitis B DNA vaccine formulations were prepared by mixing pcDNA3.1-S with various concentration of aluminum phosphate in 0.9% NaCl. HBsAg expressions were assayed by ELISA in vivo five days after intramuscular injection of pcDNA3.1-S with or without aluminum phosphate. And serum samples were obtained from individual immunized or control mice 6 weeks post injection. Then anti-HBs were assayed in mice sera by ELISA. RESULTS: Five days after intramuscular immunization, the levels of HBsAg expression of groups with aluminum phosphate showed no difference from those of control group in tibialis arterials muscles. In sera, HBsAg could not be detectable in all groups. Intramuscular immunization of BABL/C mice with pcDNA3.1-S mixed aluminum phosphate (0microg, 1microg, 10microg, 50microg, 100microg) 6 weeks later, the P/N values of anti-HBs in sera were 11.54+/-5.60, 11.00+/-6.62, 20.30+/-10.20, 49.18+/-24.40 and 48.68+/-27.78, respectively. It showed that pcDNA3.1-S mixing with aluminum phosphate could increase anti-HBs titers in mice. CONCLUSION: No increase of HBsAg expression was observed by mixing plasmid pcDNA3.1-S with various concentration of aluminum phosphate in vivo. But Intramuscular immunization of BALB/C mice with pcDNA3.1-S mixing aluminum phosphate adjuvant can increase anti -HBs titers. It seemed that aluminum phosphate would be valuable for further investigation as a potential adjuvant of hepatitis B DNA vaccines.