Maintenance Of Clinical Response Research Articles

Maintenance of Clinical Response With Continued Risankizumab Treatment for Moderate-to-Severe Psoriasis Through 304 Weeks: Interim Analysis of the LIMMitless Open-Label Extension Study

Introduction: Interleukin (IL)-23 is a key regulator of plaque psoriasis pathogenesis. Risankizumab, a humanized immunoglobulin G1 monoclonal antibody that specifically inhibits IL-23 by binding to its p19 subunit, is approved for the treatment of moderate-to-severe plaque psoriasis in adults; however, additional data on long-term maintenance of efficacy with risankizumab treatment are needed. Here we report on the maintenance of clinical response through 304 weeks of continuous risankizumab treatment.
 Methods: In this interim analysis, we evaluated patients with moderate-to-severe plaque psoriasis who were randomized to receive risankizumab 150 mg at weeks 0, 4, and 16 and every 12 weeks thereafter during 2 double‑blind, phase 3, 52-week base studies (UltIMMa 1 [NCT02684370] and UltIMMa 2 [NCT02684357]) and enrolled in LIMMitless, an ongoing, phase 3, multicenter, single‑arm, open-label extension (OLE) study (NCT03047395) evaluating the long-term safety and efficacy of continuous risankizumab 150 mg treatment every 12 weeks for plaque psoriasis. Safety was assessed through ≤ 324 weeks by monitoring of treatment‑emergent adverse events through the data cutoff date (May 22, 2023). Efficacy was assessed by the proportion of patients who maintained ≥ 90% or 100% improvement from baseline in Psoriasis Area and Severity Index (PASI 90/100) during LIMMitless and mean improvement in PASI from baseline of the UltIMMa-1/2 study through 252 additional weeks in the LIMMitless study (total of 304 weeks). Missing efficacy data were imputed using modified nonresponder imputation (mNRI), last observation carried forward (LOCF), or observed cases (OC) methodology.
 Results: A total of 525 patients were randomized to receive risankizumab 150 mg treatment for 52 weeks in the UltlMMa‑1/2 studies and continued open-label risankizumab 150 mg treatment in the LIMMitless OLE study. Risankizumab was well tolerated through ≤ 324 weeks; no new safety concerns were reported in patients with moderate-to-severe plaque psoriasis. At OLE entry, most patients (451, 85.9%) achieved PASI 90; of those, 422 (93.6%) maintained PASI 90 through week 304 by mNRI (LOCF, 92.7%; OC, 93.8%). Of 320 patients (61.0%) who achieved PASI 100 at OLE entry, 209 (65.3%) maintained PASI 100 through week 304 by mNRI (LOCF, 80.6%; OC, 79.9%). Mean PASI improvement from baseline was generally consistent from OLE entry (95.6% for both LOCF and OC) through week 304 (LOCF, 95.9%; OC, 96.5%).
 Conclusion: In this 304-week interim analysis of continuous risankizumab treatment, the safety profile was consistent with previous interim analyses from the LIMMitless study. With continuous risankizumab treatment, most patients maintained PASI 90 or PASI 100 responses from OLE entry through 252 additional weeks in the LIMMitless study.

Effectiveness and Safety of Tofacitinib in the Management of Ulcerative Colitis: A Brazilian Observational Multicentric Study.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease which affects the colorectal mucosa with a relapsing-remitting pattern. The therapeutic options currently available for the medical management of UC include many options. Tofacitinib is an oral small molecule, Janus kinase (JAK) inhibitor, more selective for JAK1 and JAK3, which reduces the inflammatory process involved in the pathogenesis of UC. Retrospective observational multicentric study of patients with UC who used tofacitinib in any phase of their treatment. Clinical remission and response (according to Mayo score), mucosal healing, primary and secondary loss of response, discontinuation of the drug with possible causes, and the need for dose optimization or switching to biologicals, need for surgery and adverse events were evaluated. From a total of 56 included patients, clinical remission was observed in 43.6% at week 12, 54.5% at week 26, 57.9% at week 52, and 40% at the last follow-up visit. Clinical response was observed in 71.4%, 81.8%, 89.5%, and 61.8% at the same time periods, respectively. Mucosal healing rates were 50% and 17.8% needed colectomy. Tofacitinib was effective in induction and maintenance of clinical response and remission rates, compatible to other international real-word studies and meta-analyses.

A145 EFFICACY AND SAFETY OF UPADACITINIB MAINTENANCE THERAPY IN PATIENTS WITH MODERATELY TO SEVERELY ACTIVE ULCERATIVE COLITIS: RESULTS FROM A RANDOMIZED PHASE 3 STUDY

BackgroundUpadacitinib (UPA), an oral selective and reversible JAK inhibitor, demonstrated significantly greater efficacy compared with placebo (PBO) for induction of remission in patients with moderately to severely active ulcerative colitis (UC) in two phase 3 induction trials.AimsEvaluate safety and efficacy of 52 weeks of UPA 15 mg QD (UPA15) and 30mg QD (UPA30) compared to placebo in patients achieving clinical response following UPA 45 mg treatment in the induction trials.MethodsThe primary analysis (n=451) evaluated efficacy and safety of UPA15 and UPA30 compared to PBO as maintenance therapy. The primary endpoint was clinical remission via adapted Mayo score at wk 52. Ranked secondary endpoints included endoscopic improvement, maintenance of clinical remission, corticosteroid-free clinical remission, maintenance of endoscopic improvement, endoscopic remission, maintenance of clinical response and Histologic-endoscopic mucosal improvement (HEMI).ResultsBaseline characteristics were similar between all treatment groups. Both UPA15 and UPA30 met the primary endpoint, and all secondary endpoints. Significantly greater percentages of patients receiving UPA15 and UPA30 vs. PBO achieved clinical remission (42.3% and 51.7%, vs. 12.1%), endoscopic improvement (48.7% and 61.6%, vs. 14.5%), maintenance of clinical remission (59.2% and 69.7%, vs. 22.2%), corticosteroid-free clinical remission (57.1% and 68.0%, vs. 22.2%), maintenance of endoscopic improvement (61.6% and 69.5%, vs. 18.9%), endoscopic remission, (24.2% and 25.9%, vs. 5.6%) and HEMI (34.8% and 49.3%, vs. 11.8%) (p<0.001 for all endpoints). UPA15 and UPA30 were both well-tolerated and no new safety signals were observed. Rates for serious adverse events (AEs) and AEs leading to treatment discontinuation were similar between UPA15 and UPA30 groups and lower compared to the PBO group. Most common AEs were nasopharyngitis and creatine phosphokinase elevation among UPA groups and UC exacerbation within the PBO group (30.2%). Herpes zoster was only reported in UPA groups (3.9%-4.1%). Similar rates of malignancy excluding NMSC were seen within all groups (0.7%-1.3%). MACE were only reported among patients receiving PBO (0.7%), while VTE were only found with UPA30 (1.3%).ConclusionsIn patients responding to UPA induction therapy, both UPA15 and UPA30 were safe and effective as maintenance treatment at 52 wk for all primary and secondary endpoints. Patients receiving UPA30 responded approximately 10% better for most endpoints compared to those receiving UPA15. Both doses were well-tolerated, with no new safety signals observed.Funding AgenciesAbbVie

DOP41 Efficacy and safety of extended induction treatment with upadacitinib 45 mg once daily followed by maintenance upadacitinib 15 or 30 mg once daily in patients with moderately to severely active Ulcerative Colitis

Abstract Background Upadacitinib (UPA), a selective and reversible Janus kinase inhibitor, has been shown to be safe and effective when administered at a dose of 45 mg once daily (QD) as 8-week induction therapy in moderate-to-severe Ulcerative Colitis (UC). This analysis evaluated outcomes following extended induction (45 mg QD for 16 weeks) followed by maintenance (15 or 30 mg QD) treatment with UPA in patients with UC who did not achieve a clinical response after 8 weeks’ induction. Methods Patients with moderate-to-severe UC who failed to achieve a clinical response (Adapted Mayo score decrease of ≥2 points and ≥30% from baseline, plus ≥1-point decrease in rectal bleeding score [RBS] or absolute RBS ≤1) to 8 weeks’ induction treatment with UPA 45 mg QD in the U-ACHIEVE Induction (NCT02819635) or U-ACCOMPLISH (NCT03653026) studies, continued to receive UPA 45 mg QD in an 8-week open-label extension. Responders at the end of the open-label extension entered the U-ACHIEVE Maintenance study and were randomised 1:1 to UPA 15 mg or 30 mg QD for 52 weeks. The efficacy endpoints were evaluated at Week 16 for the induction studies and at Week 52 for the maintenance study. Results In total, 125 patients who failed to achieve a clinical response after 8 weeks’ induction treatment received open-label UPA 45 mg for a further 8 weeks. Of these patients, 48.3% achieved a clinical response at Week 16 and were re-randomised to UPA 15 or 30 mg in U-ACHIEVE Maintenance. Among 16-week responders who entered the maintenance study, clinical remission, maintenance of clinical response, and endoscopic improvement, respectively, at Week 52 were achieved in 33.3% versus 19.0%, 66.7% versus 35.7%, and 37.5% versus 23.8% of those who received UPA 30 versus UPA 15 mg QD as maintenance treatment (Table 1). Adverse events of special interest were reported infrequently in the two maintenance treatment groups (Table 2). Conclusion In this analysis, prolonged induction treatment for a total of 16 weeks was beneficial in almost half of UC patients who failed to achieve a clinical response after 8 weeks’ induction with UPA 45 mg. The benefit of maintenance therapy in these delayed responders was further demonstrated, with UPA 30 mg providing greater benefit than UPA 15 mg QD.

Efficacy of Risankizumab versus Secukinumab in Patients with Moderate-to-Severe Psoriasis: Subgroup Analysis from the IMMerge Study.

IntroductionPatients with moderate-to-severe plaque psoriasis who experience poor clinical outcomes, including patients with obesity or prior treatment, need improved treatment options. Risankizumab specifically inhibits interleukin 23 and has demonstrated superior efficacy in active-comparator studies in patients with moderate-to-severe plaque psoriasis. We compared the efficacy of risankizumab with that of secukinumab across patient subgroups.MethodsSubgroup analyses using data from the phase 3 IMMerge study (NCT03478787) were performed. Efficacy in adults with moderate-to-severe psoriasis treated with risankizumab 150 mg and secukinumab 300 mg was assessed as the proportion of patients who achieved ≥ 90% improvement in Psoriasis Area Severity Index (PASI 90) at week 52 across demographics and disease characteristics. Post hoc analyses evaluated the proportion of patients who achieved PASI 90 and the least-squares mean percent PASI improvement from baseline at week 52 by body weight and body mass index (BMI), PASI 90 by prior treatment, and clinical response [PASI 90, PASI 100, and/or static Physician’s Global Assessment (sPGA) score of clear (0) or almost clear (1)] at week 16 and maintained particular response at week 52. Logistic regression analyses examined the effect of covariates (age, sex, BMI, baseline PASI, treatment) and potential interactions on PASI 90 at week 52.ResultsMore patients who received risankizumab (n = 164) compared with secukinumab (n = 163) achieved PASI 90 at week 52, regardless of demographics and disease characteristics (BMI, prior treatment, disease duration, and maintenance of clinical response at week 52). Improvements in PASI were greater in patients taking risankizumab than those taking secukinumab, regardless of weight or BMI. Results from logistic regression analysis showed treatment type had a significant impact on PASI 90 (risankizumab versus secukinumab, p < 0.0001).ConclusionRisankizumab showed consistently greater efficacy compared with secukinumab across different patient subgroups, and this was maintained through 52 weeks.Trial RegistrationClinicalTrials.gov identifier; NCT03478787.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13555-021-00679-6.

Five-year maintenance of clinical response and health-related quality of life improvements in patients with moderate-to-severe psoriasis treated with guselkumab: results from VOYAGE 1 and VOYAGE 2.

Psoriasis is a chronic disease requiring long-term therapy. Physician- and patient-reported outcomes were evaluated through week 252 in VOYAGE 1 and VOYAGE 2. In total, 1829 patients were randomized at baseline to receive guselkumab 100mg every 8weeks, placebo or adalimumab. Patients receiving placebo crossed over to guselkumab at week 16. Patients receiving adalimumab crossed over to guselkumab at week 52 in VOYAGE 1, and randomized withdrawal and retreatment occurred at weeks 28-76 in VOYAGE 2; all patients then received open-label guselkumab through week 252. Efficacy and health-related quality of life (HRQoL) endpoints were analysed through week 252. Safety was monitored through week 264. The proportions of patients in the guselkumab group who achieved clinical responses at week 252 in VOYAGE 1 and VOYAGE 2, respectively, were 84·1% and 82·0% [≥ 90% improvement in Psoriasis Area and Severity Index (PASI)]; 82·4% and 85·0% [Investigator's Global Assessment (IGA) 0 or 1]; 52·7% and 53·0% (100% improvement in PASI) and 54·7% and 55·5% (IGA 0). HRQoL endpoints were achieved as follows: 72·7% and 71·1% of patients (Dermatology Life Quality Index 0 or 1: no effect on patient's life); 42·4% and 42·0% [Psoriasis Symptoms and Signs Diary (PSSD) symptom score = 0] and 33·0% and 31·0% (PSSD sign score = 0). As measured in VOYAGE 2 only, approximately 45% of patients achieved ≥ 5-point reduction in Short Form-36 physical and mental component scores, and 80% reported no anxiety or depression (Hospital Anxiety and Depression Scale scores < 8). Similar findings were reported for adalimumab crossovers. These effects were maintained from week 52 in VOYAGE 1 and week 100 in VOYAGE 2. No new safety signals were identified. Guselkumab maintains high levels of clinical response and improvement in patient-reported outcomes through 5years in patients with moderate-to-severe psoriasis.

Real-world experience with tofacitinib in ulcerative colitis: a systematic review and meta-analysis.

Background and aims:Tofacitinib is a Janus kinase inhibitor (JAKi) recently approved for the treatment of moderate to severe ulcerative colitis (UC) based on robust efficacy and safety data derived from OCTAVE clinical trials. Evidence on the outcomes of tofacitinib therapy in real-world UC patients is needed, as a number of these patients would be deemed ineligible for clinical trials. We have therefore summarised data derived from observational, real-world evidence (RWE) studies on the effectiveness and safety of tofacitinib in moderate to severe UC patients.Methods:We searched the PubMed, EMBASE, Scopus, Web of Science and Cochrane databases for observational studies on the use of tofacitinib in UC patients, published between 30 May 2018 and 24 January 2021. Pooled induction (8–14 weeks) and maintenance (16–26 weeks) clinical response and remission rates were calculated, as well as the proportion of reported adverse events using random effects models.Results:Nine studies were included, comprising 830 patients, of which 81% were previously treated with anti-tumour necrosis factor (TNF) and 57% with vedolizumab. Induction of clinical response and remission were achieved in 51% (95% confidence interval, 41–60%) and 37% (26–45%) of patients, after a median follow-up of 8 weeks. At the end of a median follow-up of 24 weeks, maintenance of clinical response and remission were met in 40% (31–50%) and 29% (23–36%) of patients, respectively. Thirty-two percent of the patients had at least one adverse event, the most commonly reported being mild infection (13%) and worsening of UC, requiring colectomy (13%). A third of the patients (35%) discontinued tofacitinib, most frequently due to primary non-response (51%).Conclusion:Tofacitinib is a safe and effective therapy in real-world UC patients, as previously reported by clinical trials.

Maintenance of clinical response and consistent safety profile with up to 3 years of continuous treatment with guselkumab: Results from the VOYAGE 1 and VOYAGE 2 trials

Long-term maintenance treatment is required for patients with psoriasis. To evaluate the efficacy and safety of guselkumab in patients with moderate to severe psoriasis through 3years of treatment. In 2 ongoing, phase 3 trials of guselkumab (VOYAGE 1 and VOYAGE 2), the proportions of patients achieving at least 90% and 100% improvement in the Psoriasis Area and Severity Index (PASI 90 and PASI 100, respectively) and Investigator's Global Assessment (IGA) scores of 0/1 and 0 were summarized for the guselkumab group (including placebo-to-guselkumab crossover). Patients who met treatment failure rules were considered nonresponders. Safety outcomes (rates/100 patient-years [PY]) were evaluated based on data pooled across studies through week 156. Three-year response rates for the guselkumab group in VOYAGE 1 and VOYAGE 2, respectively, were 82.8% and 77.2% for PASI 90, 50.8% and 48.8% for PASI 100, 82.1% and 83.0% for IGA score of 0/1, and 53.1% and 52.9% for IGA score of 0. Safety event rates across studies occurred through week 156 as follows: serious adverse events, 5.68/100 PY; serious infections, 1.15/100 PY; nonmelanoma skin cancers, 0.28/100 PY; malignancies other than nonmelanoma skin cancer, 0.47/100 PY; and major adverse cardiovascular events, 0.28/100 PY. Week 156 and week 100 rates were consistent. There was no comparator arm beyond 1year. Guselkumab shows durable efficacy and a consistent safety profile in patients with moderate to severe psoriasis treated for up to 3years.

Efficacy and safety of biologic agents and tofacitinib in moderate-to-severe ulcerative colitis: A systematic overview of meta-analyses.

Ulcerative colitis (UC) is an inflammatory disease of the colon and rectum. Treatment options include biologics and tofacitinib. We aim to summarize the evidence on efficacy and safety of biologics and tofacitinib in moderate-to-severe UC. PubMed, Embase, Scopus, and the Cochrane Library were systematically searched to identify meta-analyses of randomized controlled trials assessing adalimumab, golimumab, infliximab, vedolizumab, and tofacitinib in UC. Efficacy outcomes included induction and maintenance of clinical response, clinical remission and mucosal healing. Safety outcomes included adverse events and serious adverse events. The overview involved 31 meta-analyses. All four biologics and tofacitinib were superior to placebo regarding efficacy. Indirect comparisons suggested that infliximab may be better than adalimumab and golimumab to induce clinical response and mucosal healing. Safety analyses indicated no increased rates of adverse events, except for infliximab. Biologics and tofacitinib are efficacious and safe for treating UC. These findings can support clinical decision-making.

Biologic drugs for induction and maintenance of remission in Crohn's disease: a network meta-analysis

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: We aim to conduct a systematic review and meta-analysis of all RCTs that compare biologic drugs (TNF-α antagonists, integrin antagonists, or ustekinumab) against placebo or an active comparator in adults with CD. Using frequentist network meta-analysis, we aim to assess the efficacy of biologic drugs to treat CD and generate a clinically useful ranking of available biological drugs according to efficacy in terms of: 1) Induction and maintenance of clinical remission in CD, defined as a Crohn's Disease Activity Index (CDAI) below 150; 2) Induction and maintenance of clinical response in CD, defined as a drop in the CDAI of at least 70 (CDAI-70) or 100 (CDAI-100) points compared to baseline; and 3) Induction of endoscopic remission in CD, defined as an absence of ulceration.

Efficacy of biological disease-modifying antirheumatic drugs: a systematic literature review informing the 2016 update of the EULAR recommendations for the management of rheumatoid arthritis

ObjectivesTo update the evidence for the efficacy of biological disease-modifying antirheumatic drugs (bDMARDs) in patients with rheumatoid arthritis (RA) to inform European League Against Rheumatism (EULAR) Task Force treatment recommendations.MethodsMEDLINE,...

Ustekinumab in treatment of Crohn's disease: design, development, and potential place in therapy.

Crohn’s disease is characterized by a dysregulation of both innate and adaptive immunity responses. Interleukin-12/23 (IL-12/23) pathway has been found to be a major driver of inflammation in adaptive immune responses. Ustekinumab is a fully human immunoglobulin G1 kappa monoclonal antibody that blocks the p40 subunit of IL-12 and IL-23 and prevents their interaction with their cell surface receptor and further cytokine activation. It is currently approved in the management of plaque psoriasis and psoriatic arthritis. Very promising data have emerged through phase II and phase III trials (UNITI-1, UNITI-2, and IM-UNITI) for both induction and maintenance of clinical response and remission in moderate-to-severe Crohn’s disease, resulting in approval by the Food and Drug Administration for this condition. This article reviews the immunology of the IL-12/23 pathway, available data regarding the initial designing of ustekinumab, drug development through clinical trials including pharmacokinetics, efficacy, and safety, and its potential place in the treatment of Crohn’s disease.

OC-003 Efficacy and Safety of Golimumab Induction for Moderate to Severe Ulcerative Colitis in the United Kingdom: Results from the Go-Colitis Study

Introduction Induction and maintenance of clinical response is a treatment goal for ulcerative colitis (UC). GO-COLITIS (NCT02092285; 2013–004583-56) is a UK phase 4, multicentre, open-label, single-arm trial evaluating the efficacy of golimumab (GLM) in induction and maintenance of clinical response in patients with moderate to severe UC. We report the results of an interim analysis of clinical response at the end of the GLM induction phase. Methods Anti-TNF naive patients (≥18 y) with UC ≥ 3 months and with moderate to severe disease (partial Mayo score 4–9 or Mayo score 6–12) at baseline, Mayo rectal bleeding subscore ≥1, and Mayo endoscopy subscore ≥2 (if full Mayo was used) were included. Patients received SC GLM on day 0 (200 mg) and day 14 (100 mg) during the 6 week induction phase, followed by GLM 50 or 100 mg every 4 weeks during the 48 week maintenance phase with 12 week follow-up, in line with the Summary of Product Characteristics. Clinical response and remission were summarised descriptively at the end of week 6. Clinical response was defined as decrease in partial Mayo score of ≥2 points and ≥30% from baseline, plus either a decrease in rectal bleeding subscore of ≥1 point or an absolute rectal bleeding score ≤1. Patients without scores were considered nonresponders. Clinical remission was defined as partial Mayo score ≤2 and no individual Mayo subscore >1. Results 205 patients were enrolled (mean [range] age, 39.3 [18–79] years; male, n = 123 [60%]). The mean baseline (SD) partial Mayo score was 6.4 (1.4). All patients received one or two doses of induction GLM. Clinical responses occurred in 141/205 patients (response rate, 68.8%; 95% CI, 62.0%–75.1%). Clinical remission occurred in 79/205 patients (remission rate, 38.5%; 95% CI, 31.8%–45.6%). The mean (SD) change from baseline in partial Mayo score (n = 198) was –3.2 (2.4). AEs (any cause) occurred in 37 (18%) patients. Serious AEs occurred in 17 (8%) patients: UC flare/worsening (n = 11), accidental overdose (n = 2), anaphylaxis (n = 1), constipation (n = 1), rectal fissure (n = 1), and respiratory tract infection (n = 1). Eight patients (4%) discontinued due to serious AEs. There were no fatal AEs. Conclusion During the GLM induction phase of GO-COLITIS, 68.8% of patients had a partial Mayo response and were eligible to continue to the 48 week maintenance phase. AEs were consistent with previous observations; no new safety signals were identified. Disclosure of Interest C. Probert Consultant for: Abbvie, MSD, Napp, Takeda, Speaker bureau with: Abbvie, Falk, Ferring, MSD, Shire, Takeda, Conflict with: Abbvie, Falk, MSD, Shire, Takeda, D. Gaya Speaker bureau with: Abbvie, Falk, Ferring, MSD, Shire, Takeda, Vifor, Conflict with: Abbvie, Falk, Ferring, MSD, Shire, Takeda, Vifor, P. Hamlin Speaker bureau with: Abbvie, Ferring, MSD, Takeda, Tillotts, Warner Chilcott, Conflict with: Abbvie, Falk, MSD, Tillotts, P. Irving Grant/research support from: MSD, Takeda, Consultant for: Abbvie, MSD, Takeda, Warner Chilcott, Vifor Pharma. Pharmacosmos, Topivert, Genentech, Hospira, Speaker bureau with: Abbvie, Falk Pharma, Ferring, MSD, Takeda, Warner Chilcott, Johnson and Johnson, Shire, S. Sebastian Grant/research support from: Abbvie, Ferring, Warner Chilcott, Consultant for: Falk Pharma, Ferring, MSD, Takeda, Warner Chilcott, Vifor Pharma, Speaker bureau with: Abbvie, Takeda, Warner Chilcott, G. Gillespie Shareholder of: MSD UK, Conflict with: Employment MSD UK, H. Tate Consultant for: MSD UK, C. Wheeler Shareholder of: MSD UK, Conflict with: Employment MSD UK

Discovery and development of surotomycin for the treatment of Clostridium difficile.

The primary challenge for treating Clostridium difficile infections (CDI) is maintenance of clinical response after the end of treatment (sustained clinical response). Disease recurrence following a positive clinical response occurs in approximately 6-25% of patients after the first episode and in up to 65% for subsequent recurrences. Surotomycin, a novel cyclic lipopeptide antibiotic with a core derived by Streptomyces roseosporus fermentation, disrupts C. difficile cellular membrane activity in both logarithmic and stationary phases and minimally disturbs normal gastrointestinal microbiota because of its lack of activity against Gram-negative anaerobes and facultative anaerobes. Preclinical and clinical evidence indicate that surotomycin has low oral bioavailability, allowing gastrointestinal tract concentrations to greatly exceed its minimum inhibitory concentration for C. difficile. Surotomycin is well tolerated and effective in hamster models of CDI. Phase 2 clinical evidence suggests that surotomycin (250mg twice daily) is an effective CDI treatment, with statistically lower recurrence rates than vancomycin.

Vedolizumab for the Treatment of Adults with Moderate-to-Severe Active Ulcerative Colitis: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of its single technology appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer of vedolizumab (Takeda UK) to submit evidence of the clinical effectiveness and cost effectiveness of vedolizumab for the treatment of patients with moderate-to-severe active ulcerative colitis (UC). The Evidence Review Group (ERG) produced a critical review of the evidence for the clinical effectiveness and cost effectiveness of the technology, based upon the company's submission to NICE. The evidence was derived mainly from GEMINI 1, a Phase 3, multicentre, randomised, double-blinded, placebo-controlled study of the induction and maintenance of clinical response and remission by vedolizumab (MLN0002) in patients with moderate-to-severe active UC with an inadequate response to, loss of response to or intolerance of conventional therapy or anti-tumour necrosis factor (TNF)-α. The clinical evidence showed that vedolizumab performed significantly better than placebo in both the induction and maintenance phases. In the post hoc subgroup analyses in patients with or without prior anti-TNF-α therapy, vedolizumab performed better then placebo (p value not reported). In addition, a greater improvement in health-related quality of life was observed in patients treated with vedolizumab, and the frequency and types of adverse events were similar in the vedolizumab and placebo groups, but the evidence was limited to short-term follow-up. There were a number of limitations and uncertainties in the clinical evidence base, which warrants caution in its interpretation--in particular, the post hoc subgroup analyses and high dropout rates in the maintenance phase of GEMINI 1. The company also presented a network meta-analysis of vedolizumab versus other biologic therapies indicated for moderate-to-severe UC. However, the ERG considered that the results presented may have underestimated the uncertainty in treatment effects, since fixed-effects models were used, despite clear evidence of heterogeneity among the trials included in the network. Results from the company's economic evaluation (which included price reductions to reflect the proposed patient access scheme for vedolizumab) suggested that vedolizumab is the most effective option compared with surgery and conventional therapy in the following three populations: (1) a mixed intention-to-treat population, including patients who have previously received anti-TNF-α therapy and those who are anti-TNF-α naïve; (2) patients who are anti-TNF-α naïve only; and (3) patients who have previously failed anti-TNF-α therapy only. The ERG concluded that the results of the company's economic evaluation could not be considered robust, because of errors in model implementation, omission of relevant comparators, deviations from the NICE reference case and questionable model assumptions. The ERG amended the company's model and demonstrated that vedolizumab is expected to be dominated by surgery in all three populations.

Maintenance of clinical response with long-term brodalumab (AMG 827) therapy for psoriasis: Week 144 results from an open-label extension study

Maintenance of clinical response with long-term brodalumab (AMG 827) therapy for psoriasis: Week 144 results from an open-label extension study

Adalimumab monotherapy versus combination therapy with immunomodulators in patients with Crohn's disease: A systematic review and meta-analysis

Background and aimsCombination therapy with infliximab and azathioprine has been shown to be superior to either treatment alone in Crohn's disease (CD). However, the benefit of combining adalimumab with an immunomodulator remains controversial.The aim of this study was to compare the efficacy of adalimumab monotherapy with combination therapy for induction and maintenance of response and remission in CD using a meta-analysis of the current literature. MethodsWe performed a systematic literature search using Medline, Embase, Cochrane and several other databases. Prospective randomized controlled trials, retrospective cohort and case-controlled studies were included. The primary outcomes included induction of response and remission (up to week 12), maintenance of clinical response and remission (1year) and the need for dose escalation. Several subgroup and sensitivity analyses were performed. ResultsEighteen out of 2743 retrieved studies were included. A meta-analysis of 7 studies assessing induction of remission (n=1984) showed that ADA monotherapy was inferior to combination therapy [OR=0.78 (0.64–0.96), p=0.02]. A meta-analysis of 4 studies revealed that combination therapy was not statistically different from ADA for maintenance of remission [OR=1.08 (0.79–1.48), p=0.48]. Combination therapy was also not different from ADA monotherapy in terms of requirement for dose escalation [OR=1.13 (0.69–1.85), p=0.62]. ConclusionsCombination therapy with ADA and immunomodulator was mildly superior to ADA monotherapy for induction of remission in CD. The rate of remission at 1year and the need for dose escalation were similar in both groups. These findings should be interpreted with caution in view of possible confounders and should be further validated by randomized controlled trials.

Subcutaneous ustekinumab for the treatment of anti-TNF resistant Crohn's disease—The McGill experience

BackgroundUstekinumab is a fully human IgG1κ monoclonal antibody that blocks the biologic activity of interleukin-12/23. Ustekinumab is approved for treatment of plaque psoriasis and has been shown to be effective for induction and maintenance of clinical response in anti-TNF resistant Crohn's disease (CD). The aim of the study was to describe the real-life experience with open-label use of ustekinumab in anti-TNF resistant CD patients. MethodsA retrospective observational open-label study. Clinical response was defined by physician's global assessment combined with decision to continue therapy. The clinical response was evaluated at 3, 6, 12months and last follow-up. ResultsThirty-eight patients were included in the study. Initial clinical response was achieved in 28/38 (73.7%) of the patients. Among the initial responders, 80% with follow-up data maintained their response for 6months. At 12months of follow-up, 88.9% of patients responding at 6months maintained their response. At the last follow-up (7.9±5.2 mo) 27/38 (71%) of the patients were responding, and 73.3% were able to discontinue corticosteroids. Dose escalation was required in 47.7% of the patients and was successful in 61.1% of them. SummaryIn this real-life cohort of severe anti-TNF resistant CD, an initial clinical response to subcutaneous ustekinumab was observed in 73.7% of the patients. The initial response was successfully maintained in the majority of patients for up to 12months. Subcutaneous ustekinumab is an effective therapeutic option in this challenging patient cohort. The optimal dosing and injection schedule remain to be established in future studies.

Su1400 Impact of Patient Weight on Adalimumab Efficacy in Crohn's Disease -A Pilot Study

Introduction: Ustekinumab is a fully human IgG1κ monoclonal antibody that blocks the p40 subunit of interleukin-12/23, inflammatory cytokines implicated in the pathogenesis of Crohn's disease (CD). Ustekinumab is approved for treatment of plaque psoriasis. It was reported to be effective for induction and maintenance of clinical response in anti-TNF resistant CD only Aim: To describe a real-life experience with open -label use of subcutaneous ustekinumab in anti-TNF resistant CD patients, in a tertiary referral center setting. Methods: A retrospective observational study. Clinical response was defined by physician's global assessment combined with decision to continue therapy. Clinical endpoints were over 12 months of follow-up or discontinuation of ustekinumab. The primary outcome was clinical response by 3 months. Secondary outcomes included clinical response at 6 and 12 months and steroid-free response at each time-point. Results: Patient characteristics: 37 patients were treated with subcutaneous ustekinumab between 2/2011 to 7/2013 (median follow up: 5 (3-12) months). The demographic and clinical characteristics of the patients were as follows: male50%, age37 (21-62), age at diagnosis20.5 (2-54) years. The disease characteristics were as follows: location ileal 16.2% , colonic 18.9%, ileocolonic 64.9%; disease phenotype: luminal 46%; penetrating 43.2%, structuring 10.8%; 40.5% had perianal involvement; 27.5% had previously undergone total proctocolectomy. Previous treatment included at least one biologic in all patients, two biologics in 86.7% and three biologics in 18.9 %. A loading dose was administered in 89% of the patients: 90 mg at weeks 0,1,2 80%; 45 mg at weeks 0 and 4 -12% , 90 mg at weeks 0 and 4 8% of the patients. Initial maintenance dosing included: 90 mg q8 wk73%, 90 mg q4 wk -21.6% , 45/ 90 mg q12wk 12 5.2% of the patients. The mean duration of follow-up was 6.1 ± 3.9 months. Follow-up data was available for 37, 24 and 16 patients at 3, 6, and 12 months, respectively. Treatment outcomes: Clinical response at 3 months was achieved in 22/37 (59.5%) of the patients; 11 (50%) of these patients were steroid-dependent at treatment onset, 7/11 (63.6%) were able to discontinue corticosteroids and 18.2% to decrease the dose by at least 50%. At 6 months, among the 15 patients with follow-up data available 11 (73%) were still responsive; 3 additional patients were non-responders at 3 months but responded at 6 months. At 12 months, follow-up data was available for 9/25 of earlier responders; 6/9 (66%) maintained their response; all were steroid-free. Summary: In this cohort of severe anti-TNF resistant CDpatients, initial response to subcutaneous ustekinumab resulted in clinical response in almost 60% of patients, with the majority of responders sustaining the benefit for 6-12 months.

Maintenance of clinical response with long-term brodalumab (AMG 827) therapy for psoriasis: Week 96 results from an open-label extension study

Maintenance of clinical response with long-term brodalumab (AMG 827) therapy for psoriasis: Week 96 results from an open-label extension study