Evolution of Symptoms After Ustekinumab Induction Therapy in Patients With Crohn's Disease.

BACKGROUND & AIMS: Ustekinumab is an effective treatment of Crohn's disease (CD). Of interest to patients is knowing how soon symptoms may improve. We analyzed ustekinumab response dynamics from the ustekinumab CD trials. METHODS: Patients with CD received intravenous induction with ustekinumab ∼6 mg/kg (n = 458) or placebo (n = 457). Week 8 ustekinumab responders received subcutaneous ustekinumab 90 mg as the first maintenance dose or as an extended induction dose for nonresponders. Patient-reported symptom changes (stool frequency, abdominal pain, general well-being) within the first 14 days and clinical outcomes through week 44 were evaluated using the CD Activity Index. RESULTS: After ustekinumab infusion, stool frequency improvement was significantly (P < .05) greater than placebo on day 1 and for all patient-reported symptoms by day 10. In patients with no history of biologic failure or intolerance, cumulative clinical remission rates increased from 23.0% at week 3 to 55.5% at week 16 after the subcutaneous dose at week 8. Corresponding cumulative rates for patients with a history of biologic failure or intolerance increased from 12.9% to 24.1%. Neither change from baseline in CD Activity Index score nor week 8 ustekinumab pharmacokinetics were associated with week 16 response. Among all patients who received subcutaneous ustekinumab 90 mg q8w, up to 66.7% were in clinical response at week 44. CONCLUSIONS: Ustekinumab induction provided symptom relief by day 1 post-infusion. Following ustekinumab infusion and a subcutaneous 90 mg injection, clinical outcomes continued to increase through week 16 and up to week 44. Regardless of week 8 clinical status or ustekinumab pharmacokinetics, patients should receive additional treatment at week 8. CLINICALTRIALS: gov numbers, NCT01369329, NCT01369342, and NCT01369355.

[Cloning and functional characterization of two oxidosqualene cyclase genes from Siraitia grosvenorii].

Oxidosqualene cyclases(OSCs), belonging to a multigene family, can convert a common precursor 2,3-oxidosqualene into various types of triterpene skeletons. In this study, primers were designed according to the analysis of Siraitia grosvenorii transcriptome data, and two OSC genes SgAS1(GenBank No. QDO67189.1) and SgAS2(GenBank No. QDO67190.1) were cloned. The open reading frame(ORF) of SgAS1 was 2 262 bp, encoding 754 amino acids, and the ORF of SgAS2 was 2 289 bp, encoding 762 amino acids. Real-time quantitative PCR results demonstrated that the two SgOSCs genes showed different expression patterns in stems, leaves, and different stages of fruits. Phylogenetic analysis showed that both SgAS1 and SgAS2 were clustered with ß-amyrin synthases into a branch, but further functional characterization using yeast heterologous expression found that SgAS1 was inactive and SgAS2 could produce ß-amyrin as the sole product. Multiple sequence alignments revealed that SgAS2 had a conserved MWCYCR sequence related to ß-amyrin biosynthesis, while SgAS1 had an unusual LFCYTR sequence, for which the authors performed site-directed mutagenesis analysis of this sequence and found that tryptophan residue(W) was the key amino acid residue that affected the function of SgOSCs. In addition, the authors transformed the monofunctional ß-amyrin synthase SgAS2 into the chassis strain GH1, which was previously modified by the research group, and increased the yield of ß-amyrin to 44.05 mg·L~(-1). This study first reported the monofunctional ß-amyrin synthase SgAS2 from S. grosvenorii and conducted site-directed mutagenesis and synthetic biology investigation on it, providing a valuable resource for the directed biosynthesis of triterpenoids.

Ustekinumab versus adalimumab for induction and maintenance therapy in biologic-naive patients with moderately to severely active Crohn's disease: a multicentre, randomised, double-blind, parallel-group, phase 3b trial.

BACKGROUND: Active-comparator trials are important to inform patient and physician choice. We aimed to evaluate the efficacy and safety of monotherapy with either ustekinumab or adalimumab in biologic-naive patients with moderately to severely active Crohn's disease. METHODS: We conducted a randomised, double-blind, parallel-group, active-comparator, phase 3b trial (SEAVUE) at 121 hospitals or private practices in 18 countries. We included biologic-naive patients aged 18 years or older with moderately to severely active Crohn's disease and a Crohn's Disease Activity Index (CDAI) score of 220-450, who had not responded to or were intolerant to conventional therapy (or were corticosteroid dependent) and had at least one ulcer of any size at baseline endoscopic evaluation. Eligible patients were randomly assigned (1:1; via an interactive web response system) to receive ustekinumab (approximately 6 mg/kg intravenously on day 0, then 90 mg subcutaneously once every 8 weeks) or adalimumab (160 mg on day 0, 80 mg at 2 weeks, then 40 mg once every 2 weeks, subcutaneously) through week 56. Study treatments were administered as monotherapy and without dose modifications. Patients, investigators, and study site personnel were masked to treatment group assignment. The primary endpoint was the proportion of patients who were in clinical remission (CDAI score <150) at week 52 in the intention-to-treat population (ie, all patients who were randomly assigned to a treatment group). This trial is registered with ClinicalTrials.gov, NCT03464136, and EudraCT, 2017-004209-41. FINDINGS: Between June 28, 2018, and Dec 12, 2019, 633 patients were assessed for eligibility and 386 were enrolled and randomly assigned to receive ustekinumab (n=191) or adalimumab (n=195). 29 (15%) of 191 patients in the ustekinumab group and 46 (24%) of 195 in the adalimumab group discontinued study treatment before week 52. There was no significant difference between the ustekinumab and adalimumab groups in the occurrence of the primary endpoint; at week 52, 124 (65%) of 191 patients in the ustekinumab group versus 119 (61%) of 195 in the adalimumab group were in clinical remission (between-group difference 4%, 95% CI -6 to 14; p=0·42). Safety for both groups was consistent with previous reports. Serious infections were reported in four (2%) of 191 patients in the ustekinumab group and five (3%) of 195 in the adalimumab group. No deaths occurred through week 52 of the study. INTERPRETATION: Both ustekinumab and adalimumab monotherapies were highly effective in this population of biologic-naive patients, with no difference in the primary outcome between the drugs. FUNDING: Janssen Scientific Affairs.

Ustekinumab Therapeutic Drug Monitoring-Impact on Clinical Practice: A Multicenter Cross-Sectional Observational Trial.

BACKGROUND AND AIMS: The value of ustekinumab (UST) therapeutic drug monitoring (TDM) in clinical practice remains unclear. This study examined the impact of UST TDM on clinical decision making in patients with Crohn's disease (CD). METHODS: A total of 110 consecutive UST-treated CD patients were enrolled in this multicenter, single-arm cross-sectional study. During a single study visit, clinical decisions, disease characteristics, and serum and fecal samples were obtained. The primary outcome was congruency of the actual and two hypothetical clinical decisions based on provision of UST TDM (with and without fecal calprotectin [FCP]) to participating clinicians. Decisions were compared against those of a review panel. A sub-study retrospectively measured the associations of clinical outcomes at the next follow-up visit with serum UST concentration [UST]. RESULTS: No differences in the pattern of decisions by clinicians were observed before and after provision of UST TDM (P = 1.0) or UST TDM + FCP (P = 0.86). However, 39% (TDM) and 50% (TDM + FCP) of hypothetical decisions differed from the initial decisions. The review panel's decisions differed with the addition of TDM + FCP (P = 0.0006), but not TDM alone (P = 0.16). The sub-study (n = 53) failed to detect an association between therapeutic serum [UST] at the initial study visit and clinical outcomes at the next visit. CONCLUSIONS: In consecutive CD patients treated with UST, the addition of TDM into routine clinical practice did not significantly impact clinical decisions and there was no association between short-term clinical outcomes and serum [UST]. Further studies are warranted before clinicians routinely implement UST TDM into clinical practice.

Combination Therapy With Infliximab and Azathioprine Improves Infliximab Pharmacokinetic Features and Efficacy: A Post Hoc Analysis.

BACKGROUND & AIMS: Among immunosuppressive- and biologic-naïve patients with moderately-to-severely active Crohn's disease (CD), a higher proportion of those treated with the combination of infliximab and azathioprine achieved corticosteroid-free remission at week 26 (CSFR26) than those given infliximab monotherapy; patients given the combination therapy also had higher serum concentrations of infliximab. Enhanced benefit of combination therapy may occur through synergistic modes of action or the influence of azathioprine on infliximab pharmacokinetics. METHODS: We analyzed data from 206 patients from whom week 30 serum samples were available: 97 received infliximab monotherapy (5 mg/kg, n = 97) and 109 received combination therapy (2.5 mg/kg/day; n = 109). Proportions of patients achieving CSFR26 and mucosal healing (absence of ulcers) at week 26 were calculated for each quartile of serum concentrations of infliximab, and exposure-response relationships were compared. RESULTS: Within quartiles of serum concentrations of infliximab, CSFR26 did not differ significantly between patients who received combination therapy vs monotherapy. However, among patients in the lowest quartile of serum concentration of infliximab, twice as many patients who received infliximab monotherapy achieved CSFR26 vs combination therapy. Anti-drug antibodies were detected only in the lowest quartile of serum concentrations of infliximab-in 35.9% of patients given monotherapy and 8.3% of patients given combination therapy. CONCLUSION: Among patients with CD and similar serum concentrations of infliximab, combination therapy with azathioprine was not significantly more effective than infliximab monotherapy. Combination therapy with azathioprine appears to improve efficacy by increasing pharmacokinetic features of infliximab. ClinicalTrials.gov, NCT00094458.

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.

Pharmacokinetics and Exposure Response Relationships of Ustekinumab in Patients With Crohn's Disease.

BACKGROUND & AIMS: Ustekinumab is a monoclonal antibody that binds with high affinity to the p40 subunit of human interleukin 12 (IL12 and IL23) that has been approved for treatment of patients with moderate to severe Crohn's disease (CD). However, there are few data on its pharmacokinetic properties or the relationship between drug exposure levels and patient response. We collected data from 2 Phase 3 induction studies and 1 maintenance study to determine ustekinumab's pharmacokinetic features, relationship between exposure and response, and optimal serum concentrations for efficacy. METHODS: We collected data on serum concentrations of ustekinumab and efficacy from induction studies of patients with moderate to severe CD given ustekinumab for 8 weeks following a single intravenous dose (either 130 mg or approximately 6 mg/kg). We collected the same data from a maintenance study of patients with a response to ustekinumab in the induction study who then received subcutaneous injections (90 mg) every 8 or 12 weeks for 44 weeks. At week 44 of the maintenance study (52 weeks after treatment began), patients were evaluated for the primary endpoint of clinical remission (defined as a CD activity index score below 150 points), endoscopic markers of efficacy, and serum level of C-reactive protein. Ustekinumab concentration data were categorized into quartiles and relationships between exposure and response were assessed. Optimal concentration cutoff values were evaluated using receiver operating characteristic curve analysis. RESULTS: Serum concentrations of ustekinumab over time were proportional to dose and did not differ significantly between the induction studies. In the maintenance study, ustekinumab concentration reached the steady state by the second maintenance dose; the median trough concentration was approximately threefold higher in patients given ustekinumab at 8-week intervals compared with 12-week intervals. Ustekinumab serum concentrations associated with rates of clinical remission and endoscopic efficacy endpoints, correlated inversely with level of C-reactive protein, and did not associate with use of immunomodulators. Trough concentrations of ustekinumab of 0.8 (or even up to 1.4 µg/mL) or greater were associated with maintenance of clinical remission in a higher proportion of patients than patients with lower trough concentrations. CONCLUSIONS: In an analysis of data from Phase 3 studies of patients with moderate to severe CD, we found serum concentrations of ustekinumab to be proportional to dose and associate with treatment efficacy. Concentrations of ustekinumab did not seem to be affected by cotreatment with immunomodulators. Clinicaltrials.gov no. NCT01369329 (UNITI 1), NCT01369342 (UNITI 2), and NCT01369355 (IM-UNITI).

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 .).

Ustekinumab induction and maintenance therapy in refractory Crohn's disease.

BACKGROUND: In patients with Crohn's disease, the efficacy of ustekinumab, a human monoclonal antibody against interleukin-12 and interleukin-23, is unknown. METHODS: We evaluated ustekinumab in adults with moderate-to-severe Crohn's disease that was resistant to anti-tumor necrosis factor (TNF) treatment. During induction, 526 patients were randomly assigned to receive intravenous ustekinumab (at a dose of 1, 3, or 6 mg per kilogram of body weight) or placebo at week 0. During the maintenance phase, 145 patients who had a response to ustekinumab at 6 weeks underwent a second randomization to receive subcutaneous injections of ustekinumab (90 mg) or placebo at weeks 8 and 16. The primary end point was a clinical response at 6 weeks. RESULTS: The proportions of patients who reached the primary end point were 36.6%, 34.1%, and 39.7% for 1, 3, and 6 mg of ustekinumab per kilogram, respectively, as compared with 23.5% for placebo (P=0.005 for the comparison with the 6-mg group). The rate of clinical remission with the 6-mg dose did not differ significantly from the rate with placebo at 6 weeks. Maintenance therapy with ustekinumab, as compared with placebo, resulted in significantly increased rates of clinical remission (41.7% vs. 27.4%, P=0.03) and response (69.4% vs. 42.5%, P<0.001) at 22 weeks. Serious infections occurred in 7 patients (6 receiving ustekinumab) during induction and 11 patients (4 receiving ustekinumab) during maintenance. Basal-cell carcinoma developed in 1 patient receiving ustekinumab. CONCLUSIONS: Patients with moderate-to-severe Crohn's disease that was resistant to TNF antagonists had an increased rate of response to induction with ustekinumab, as compared with placebo. Patients with an initial response to ustekinumab had significantly increased rates of response and remission with ustekinumab as maintenance therapy. (Funded by Janssen Research and Development; CERTIFI ClinicalTrials.gov number, NCT00771667.).