Mirikizumab: A New Therapeutic Option for the Treatment of Ulcerative Colitis.

OBJECTIVE: To review the pharmacologic and clinical profile of mirikizumab in the treatment of moderate to severe ulcerative colitis (UC). DATA SOURCES: A PubMed search was performed from inception to December 2023 using keywords mirikizumab, interleukin-23 inhibitor, and UC. Information was also obtained from package inserts as well as published abstracts. STUDY SELECTION AND DATA EXTRACTION: Phase 3 studies plus relevant literature on mirikizumab pharmacologic and clinical profile were reviewed. DATA SYNTHESIS: Mirikizumab approval was based on LUCENT-1 and LUCENT-2. In the phase 3 studies involving patients with moderate to severe UC, mirikizumab, when compared to placebo, resulted in clinical remission in a significantly higher proportion of patients in both the induction and maintenance phase. In addition, mirikizumab met the secondary endpoints of alternate definition of clinical remission, endoscopic remission, glucocorticoid-free clinical remission, histologic-endoscopic mucosal remission, and improvement in bowel urgency status, bowel-urgency remission, and maintenance of clinical remission. Common adverse events noted include infection (15.1%), injection-site reaction (8.7%), nasopharyngitis (7.2%), and headache (3.3%). RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON TO EXISTING AGENTS: Mirikizumab is the first selective interleukin 23 (IL-23) inhibitor approved for UC. Additional studies are required to determine how to position mirikizumab in both biologic-naïve and biologic-experienced patients with moderate to severe UC. CONCLUSION: Mirikizumab provides a novel mechanism of action for the treatment of moderate to severe UC and is another welcomed treatment advance in the treatment arsenal, providing a more selective mechanism of action while maintaining a comparable safety profile.

Emerging systemic drugs in the treatment of plaque psoriasis.

INTRODUCTION: Psoriasis is a common, chronic inflammatory skin condition that affects 2-3% of the US population and represents a large psychosocial burden for patients. Over the last decade, highly effective targeted therapies for psoriasis have been developed - namely, those targeting interleukin (IL)-17 and IL-23. The success of biologic agents targeting IL-17 and IL-23 underscores the importance of the IL-23/T helper (Th)17 cell axis in psoriasis pathogenesis. Oral small molecule drugs - such as Janus kinase (JAK) inhibitors, tyrosine kinase 2 (TYK2) inhibitors, and fumaric acid esters (FAEs) - are also being investigated for the treatment of psoriasis. AREAS COVERED: This article reviews systemic biologic and oral small molecule drugs currently undergoing clinical trials for the treatment of plaque psoriasis. EXPERT OPINION: Many patients with psoriasis have mild disease, and many with mild disease do not seek medical care for their condition. Many patients with mild disease could be adequately treated with topical treatments and phototherapy; however, adherence and feasibility have often been an issue with these treatment types. There seems to be limited room for development of novel biologics, as the existing ones are extraordinarily safe, effective, and convenient with few injections. Patients would prefer a safe, effective oral treatment; however, JAK inhibitors seem unlikely to fill this role completely.

Interleukin 23p19 inhibitors in chronic plaque psoriasis with focus on mirikizumab: A narrative review.

Psoriasis, a T-cell mediated chronic dermatosis, has a complex etiopathogenesis. There has been extensive research into the aberrant immune response, which leads to the formation of clinical lesions, and the need for developing better and safer drugs has been unrelenting. The past two decades of research has opened up new areas of the immune pathway that can be targeted in order to control the disease. Therefore, we have seen the emergence of biologics which either target T-cell receptors or inhibit Tumor Necrosis Factor-alpha (TNF-α) or inhibit interleukins (IL) like IL-12, IL-17, IL-17 receptor, and more recently IL-23. Drugs specifically targeting the p19 subunit of IL-23 have shown promising results in the management of chronic plaque psoriasis. This has given way to the development of a new class of biologics, that is, the IL-23p19 inhibitors that have a better safety profile as compared to its predecessors. In this review, we shall scrutinize the role of IL-23 and Th17 cell signaling in the evolution of the psoriatic lesions and summarize the clinical experience with IL-23p19 inhibitors especially mirikizumab in the treatment of chronic plaque psoriasis.

Safety and Pharmacokinetics of Single-Dose Mirikizumab in Chinese Healthy Participants: Results From a Phase 1 Study.

The objective of this phase 1 single-dose study was to evaluate the safety, tolerability, and pharmacokinetics of mirikizumab in Chinese healthy adults. Sixty participants were randomized within 5 planned dose cohorts: intravenous (IV) 300 mg, IV 600 mg, IV 1200 mg, subcutaneous (SC) 200 mg, and SC 400 mg to receive mirikizumab (10 participants in each cohort) or placebo (2 participants in each cohort). No death or serious adverse events occurred. Twenty-eight (56.0%) participants who received mirikizumab reported 49 treatment-emergent adverse events (TEAEs) and 8 (80.0%) participants who received placebo reported 18 TEAEs. The majority of TEAEs were mild in severity. Following IV 300-1200 mg mirikizumab, the arithmetic mean of both area under the concentration versus time curve from time 0 to infinity (AUC0-∞) and maximum observed drug concentration (Cmax) increased by approximately 3.5-fold, and the arithmetic mean half-life (t1/2) ranged from 9.64 to 12.0 days. Following SC 200 and 400 mg mirikizumab, the arithmetic mean of both AUC0-∞ and Cmax increased by approximately 1.6-fold, the median time to Cmax (tmax) was 2.98 days for both, and the arithmetic mean t1/2 was 10.6 and 10.5 days, respectively. Absolute bioavailability based on pooled SC and IV dose data was 38.2%. In this study, the safety and pharmacokinetic profile of mirikizumab were consistent with what has been reported in other studies.

Extended Induction and Prognostic Indicators of Response in Patients Treated with Mirikizumab with Moderately to Severely Active Ulcerative Colitis in the LUCENT Trials.

BACKGROUND: Efficacy and safety of mirikizumab, a p19-targeted anti-interleukin-23 monoclonal antibody, for moderately to severely active ulcerative colitis was demonstrated previously. We evaluated clinical response, baseline characteristics, and clinical status in patients not responding by 12 weeks (W) of induction who then received extended induction treatment. METHOD: Patients unresponsive to 300 mg of intravenous (IV) mirikizumab every 4 weeks by W12 received 3 additional 300 mg IV doses every 4 weeks. Week-4 responders received 200 mg mirikizumab every 4 weeks subcutaneously until W52. Patients responding by W12 but subsequently losing response received rescue therapy with 300 mg IV for 3 doses every 4 weeks. Logistic regression modelling was performed for patients not achieving W12 clinical response to assess baseline characteristics and W12 efficacy parameters and potential prognostic factors of clinical response at W24. RESULTS: Of patients not achieving clinical response during induction, 53.7% achieved response following extended induction. After 52W, 72.2%, 43.1%, and 36.1% of patients achieved clinical response, endoscopic, and clinical remission, respectively. Of induction responders who subsequently lost response, 63.2% and 36.8% achieved symptomatic response and remission, respectively, after receiving rescue therapy No prior biologic or tofacitinib treatment, no immunomodulators at baseline, age older than 40 years, and W12 modified Mayo Score improvement were positively associated with a response to extended induction. The safety profile was similar to initial induction, with 38.3% treatment emergent adverse events, mostly mild. CONCLUSION: With "extended induction," total of 80.3% mirikizumab-treated patients achieved clinical response by W24. Potential prognostic factors determining response include disease severity, disease phenotype, C-reactive protein, and previous biologic therapy.

Extended induction with mirikizumab led to clinical response in more than half of primary nonresponders. Intravenous reinduction therapy in patients losing response during treatment led to more than 60% achieving symptomatic response, confirming the clinical benefit of these treatment strategies for harder to treat patients.

Recent clinical evidence on nutrition, novel pharmacotherapy, and vaccination in inflammatory bowel diseases.

Inflammatory bowel diseases (IBD), which enclose Crohn's disease (CD) and ulcerative colitis (UC), are chronic, relapsing inflammatory ailments. Their specific pathogenesis is not completely clarified, the worldwide incidence and prevalence of IBD has been steadily growing, and there is still not a definitive cure. The management of IBD has become more and more targeted, with specific immune mediators identified to be involved in its pathogenesis. Vedolizumab, a humanised monoclonal antibody binding specifically to the α4ß7 integrin, is a gut-selective immunosuppressive biologic drug administered for both CD and UC. With the same indications as vedolizumab, ustekinumab is a fully human IgG1κ monoclonal antibody binding with specificity to the shared p40 protein subunit of human cytokines interleukin (IL)-12 and IL-23. Several selective IL-23p19 monoclonal antibodies (risankizumab, mirikizumab, and guselkumab) have also revealed admirable efficacy and safety in IBD patients. Nutrition is a very important environmental factor associated with the onset and progression of IBD, and the Western diet is considered to contribute to the development of IBD. In this narrative review, our aim is to present an overview of the main results from recent clinical studies on IBD regarding diet, new drug treatments, and also vaccination.

Determining the Treatment Strategy for Refractory Ulcerative Colitis Using Prostaglandin E-major Urinary Metabolite (PGE-MUM) Measurement.

Prostaglandin E-major urinary metabolite (PGE-MUM) is a valuable biomarker reflecting the cytokine profile. We encountered a case of a 14-year-old boy with pan-colitis-type ulcerative colitis who was unresponsive to steroids and infliximab. The patient's clinical symptoms gradually deteriorated and surgical treatment was strongly considered because anti-inflammatory therapy was unlikely to be effective. PGE-MUM levels were markedly elevated, indicating a T-helper 17 (Th17)-like cytokine profile. Because an antibody against interleukin 23 (IL-23) was presumed to be effective, the patient was treated with mirikizumab, after which he achieved remission. In the present case, measurement of PGE-MUM levels was useful in selecting anti-cytokine treatments for severe ulcerative colitis.

Efficacy and safety of mirikizumab as induction and maintenance therapy for Japanese patients with moderately to severely active ulcerative colitis: a subgroup analysis of the global phase 3 LUCENT-1 and LUCENT-2 studies.

BACKGROUND/AIMS: Mirikizumab is a p19-directed anti-interleukin-23 antibody with potential efficacy against ulcerative colitis (UC). We evaluated the efficacy and safety of mirikizumab in a Japanese subpopulation with moderately to severely active UC from the LUCENT-1 and LUCENT-2 studies. METHODS: LUCENT-1 and LUCENT-2 were phase 3, randomized, double-blind, placebo-controlled trials of mirikizumab therapy in adults with moderately to severely active UC. LUCENT-1 was a 12-week induction trial where patients were randomized 3:1 to receive intravenous mirikizumab 300 mg or placebo every 4 weeks (Q4W). Patients achieving a clinical response with mirikizumab following the induction study were re-randomized 2:1 to double-blind treatment with either mirikizumab 200 mg or placebo subcutaneously Q4W during the 40-week maintenance study. The primary outcomes were clinical remission at week 12 of LUCENT-1 and week 40 of LUCENT-2. RESULTS: A total of 137 patients enrolled in Japan were randomized to mirikizumab (n = 102) or placebo (n = 35). Compared with placebo, patients who received mirikizumab showed numerically higher clinical remission at week 12 of induction (32.4% [n = 33] vs. 2.9% [n = 1]) and at week 40 of maintenance (48.9% [n = 23] vs. 28.0% [n = 7]). A greater number of patients achieved key secondary endpoints in the mirikizumab group compared with placebo. The frequency of treatment-emergent adverse events was similar across mirikizumab and placebo groups. Efficacy and safety results observed in the Japanese subpopulation were generally consistent with those in the overall population. CONCLUSIONS: Mirikizumab induction and maintenance treatments were effective in Japanese patients with moderately to severely active UC. No new safety concerns were identified.

An evaluation of mirikizumab for the treatment of ulcerative colitis.

INTRODUCTION: Treatment of ulcerative colitis (UC) aims to reduce symptoms and complications by decreasing intestinal inflammation. A proportion of patients do not respond to, do not tolerate, or are inappropriate candidates for current therapies. Interleukin (IL)-23 is a novel therapeutic target and mirikizumab is the first anti-IL-23 antibody approved for the treatment of moderately to severely active UC. AREAS COVERED: This review summarizes the pro-inflammatory effects of IL-23 and outlines the pharmacokinetics of mirikizumab. It provides a synopsis of the available phase II and phaseIII evidence for the efficacy and safety of mirikizumab in UC. EXPERT OPINION: The mirikizumab clinical development program demonstrated its superiority over placebo and its favorable safety profile in the treatment of UC. Its positioning in therapeutic algorithms remains to be fully understood but mirikizumab has proven efficacy in both advanced therapy (AT)-naïve and AT-experienced patients. The inclusion in the license of extended induction for non-responders as well as rescue intravenous dosing allows for flexibility in patient with limited primary response and secondary loss of response.

Two-Year Efficacy and Safety of Mirikizumab Following 104 Weeks of Continuous Treatment for Ulcerative Colitis: Results From the LUCENT-3 Open-Label Extension Study.

BACKGROUND: Mirikizumab, a p19-directed interleukin-23 monoclonal antibody, is efficacious in inducing clinical remission at week 12 (W12) and maintaining clinical remission at W52 in patients with moderately to severely active ulcerative colitis. Results are presented from the open-label extension study through W104. METHODS: Clinical, symptomatic, quality-of-life, and adverse event outcomes are reported for mirikizumab induction responders and extended induction responders, including biologic-failed patients, who entered LUCENT-3, with data shown for W52 maintenance responders or remitters. Discontinuations or missing data were handled by nonresponder imputation (NRI), modified NRI (mNRI), and observed case (OC). RESULTS: Among W52 mirikizumab responders, clinical response at W104 was 74.5%, 87.2%, and 96.7% and clinical remission was 76.6%, 89.0%, and 98.3% for NRI, mNRI, and OC, respectively. Among W52 mirikizumab remitters, clinical response at W104 was 54.0%, 62.8%, and 70.1% and clinical remission was 65.6%, 76.1%, and 84.2%. Using mNRI, remission rates at W104 for W52 clinical remitters were 74.7% corticosteroid-free, 79.5% endoscopic, 63.9% histologic-endoscopic mucosal remission, 85.9% symptomatic, 59.8% bowel urgency, 80.5% Inflammatory Bowel Disease Questionnaire (using NRI), 71.2% histologic-endoscopic mucosal improvement, and 77.5% bowel urgency improvement. Previous biologic-failed vs not-biologic-failed patient data were generally similar. Extended induction mNRI clinical response was 81.9%. Serious adverse events were reported in 5.2% of patients; 2.8% discontinued treatment due to adverse events. CONCLUSIONS: Endoscopic, histologic, symptomatic, and quality-of-life outcomes support the long-term benefit of mirikizumab treatment up to 104 weeks in patients with ulcerative colitis, including biologic-failed patients, with no new safety concerns.

Long-term clinical response/remission, endoscopic, histologic, and symptomatic data from an open-label study in patients with moderately to severely active ulcerative colitis demonstrate that 2-year continuous mirikizumab treatment maintained clinical remission in a majority of induction clinical responders, regardless of previous biologic failure status.

Mirikizumab: A promising breakthrough in Crohn's disease treatment.

Introduction: Crohn's disease (CD) is a chronic, progressive inflammatory bowel disorder characterized by persistent inflammation and noncontiguous "skip lesions" throughout the gastrointestinal tract. With a prevalence of 100-300 cases per 100,000 individuals, CD is most common in Western Europe and North America. Symptoms include abdominal pain, diarrhea, fever, weight loss, and anemia, with severe cases leading to complications such as perianal abscesses and cutaneous fistulas. Treatment involves pharmaceutical interventions, bowel rest, and sometimes surgery, with biological therapies like ustekinumab and mirikizumab gaining prominence. Clinical Trials: The VIVID-1 trial assessed mirikizumab in patients with moderately to severely active CD. By Week 12, mirikizumab significantly outperformed placebo in clinical response (45.4% vs. 19.6%, p < 0.000001). By Week 52, it showed higher clinical remission rates (54.1% vs. 19.6%) and demonstrated non-inferiority to ustekinumab in clinical remission (p = 0.51). The SEQUENCE study compared risankizumab to ustekinumab, with risankizumab showing superior reductions in inflammatory markers and higher biologic remission rates at Weeks 8, 24, and 48. Both treatments had similar safety profiles, with common adverse events including COVID-19, anemia, and headache. Conclusion: Mirikizumab, based on the VIVID-1 trial outcomes, is a promising addition to CD therapy. It demonstrated significant clinical responses and remission rates, warranting further research on its long-term efficacy and safety. Updating professional guidelines and addressing affordability will ensure broader access and improved management of CD.

Mirikizumab Improves Quality of Life in Patients With Moderately-to-Severely Active Ulcerative Colitis: Results From the Phase 3 LUCENT-1 Induction and LUCENT-2 Maintenance Studies.

Background: Mirikizumab, an anti-IL-23p19 antibody, demonstrated efficacy in phase 3, randomized, double-blind, placebo-controlled LUCENT-1 (induction/NCT03518086) and LUCENT-2 (maintenance/NCT03524092) ulcerative colitis (UC) studies. We evaluated the effect of mirikizumab on quality-of-life (QoL) outcomes in these studies. Methods: In LUCENT-1, 1162 patients with moderately-to-severely active UC were randomized 3:1 to receive mirikizumab 300 mg intravenous or placebo every 4 weeks (Q4W) for 12 weeks. In LUCENT-2, mirikizumab induction responders (N = 544) were re-randomized 2:1 to receive mirikizumab 200 mg subcutaneous or placebo Q4W through week (W) 40 (W52 of treatment). QoL was assessed at W12 and W52 using patient-reported outcomes. Treatments were statistically compared using analysis of covariance model (continuous outcomes) and Cochran-Mantel-Haenszel test (binary outcomes). Results: At W12 and W52, mirikizumab showed significant improvement in Inflammatory Bowel Disease Questionnaire (IBDQ) total and domain scores (P < .001); 36-Item Short Form Health Survey (SF-36) Physical Component Summary (PCS), Mental Component Summary (MCS), and domain scores (P < .05); EQ-5D-5L scores (P < .001); Work Productivity and Activity Impairment Questionnaire (UC) scores (P < .05); Patient Global Rating of Severity (P < .001); and Patient Global Rating of Change (P < .01) scores. A significantly higher proportion of mirikizumab-treated patients achieved IBDQ response (W12: 72.7% vs 55.8%; W52: 79.2% vs 49.2%; P < .001), IBDQ remission (W12: 57.5% vs 39.8%; W52: 72.3% vs 43.0%; P < .001), and clinically important improvements in PCS (W12: 50.6% vs 41.5%; W52: 61.9% vs 36.9%; P < .01) and MCS (W12: 44.2% vs 37.8%; W52: 51.2% vs 34.6%; P < .05) scores. Conclusions: Mirikizumab improved QoL in patients with moderately-to-severely active UC in phase 3 LUCENT-1 and LUCENT-2 studies. Clinical trials registration number: LUCENT-1: NCT03518086; LUCENT-2: NCT03524092.

Resolving Histological Inflammation in Ulcerative Colitis With Mirikizumab in the LUCENT Induction and Maintenance Trial Programmes.

BACKGROUND AND AIMS: To evaluate the effect of mirikizumab, a p19-targeted anti-interleukin-23, on histological and/or endoscopic outcomes in moderately-to-severely active ulcerative colitis [UC]. METHODS: Endoscopic remission [ER], histological improvement [HI], histological remission [HR], histological-endoscopic mucosal improvement [HEMI], and histological-endoscopic mucosal remission [HEMR] were assessed at Week [W]12 [LUCENT-1: N = 1162, induction] and W40 [LUCENT-2: N = 544, maintenance] for patients randomised to mirikizumab or placebo. Analyses were performed to evaluate predictors of: HEMI at W12 with mirikizumab and HEMR at W40 in patients re-randomised to subcutaneous [SC] mirikizumab; associations between W12 histological/endoscopic endpoints and W40 outcomes in mirikizumab responders re-randomised to mirikizumab SC; and associations between W40 endoscopic normalisation [EN] with/without HR. RESULTS: Significantly more patients treated with mirikizumab achieved HI, HR, ER, HEMI, and HEMR vs placebo [p <0.001], irrespective of prior biologic/tofacitinib failure [p <0.05]. Lower clinical baseline disease activity, female sex, no baseline immunomodulator use, and no prior biologic/tofacitinib failure were predictors of HEMI at W12 [p <0.05]. Corticosteroid use and longer disease duration were negative predictors of achieving HEMR at W40 [p <0.05]. W12 HI, HR, or ER was associated with W40 HEMI or HEMR [p <0.05]; ER at W12 was associated with clinical remission [CR] [p <0.05] and corticosteroid-free remission [CSFR] at W40 [p = 0.052]. HR and HEMR at W12 were associated with CSFR, CR, and symptomatic remission at W40. Alternate HEMR [EN + HR] at W40 was associated with bowel urgency remission at W40 [p <0.05]. CONCLUSIONS: Early resolution of endoscopic and histological inflammation with mirikizumab is associated with better UC outcomes. Clinicaltrials.gov: LUCENT-1, NCT03518086; LUCENT-2, NCT03524092.

Clinical Effect of Mirikizumab Treatment on Bowel Urgency in Patients with Moderately to Severely Active Ulcerative Colitis and the Clinical Relevance of Bowel Urgency Improvement for Disease Remission.

Background: Bowel urgency reduces ulcerative colitis patients' quality of life. Mirikizumab, a p19-directed anti-IL-23 antibody, demonstrates ulcerative colitis efficacy. Mirikizumab efficacy to reduce bowel urgency and bowel urgency association with other endpoints were analyzed in 2 Phase 3 trials. Methods: LUCENT-1 (Induction): 1162 patients randomized 3:1 to intravenous 300 mg mirikizumab or placebo every 4 weeks for 12 weeks. LUCENT-2 (Maintenance): 544 mirikizumab responders during induction were re-randomized 2:1 to subcutaneous mirikizumab 200 mg or placebo every 4 weeks for 40 weeks (52 weeks of continuous treatment). Bowel urgency was measured using the Urgency Numeric Rating Scale (0-10); for patients with LUCENT-1 baseline score ≥3, bowel urgency clinically meaningful improvement (≥3-point decrease) and remission (score ≤1) rates in mirikizumab versus placebo groups were compared at Weeks 12 and 52. Associations between bowel urgency and other efficacy endpoints were assessed at Weeks 12 and 52. Results: A significantly higher proportion of mirikizumab patients versus placebo achieved clinically meaningful improvement in bowel urgency and remission at Weeks 12 and 52. Significantly higher percentages of patients achieving bowel urgency clinically meaningful improvement or remission, compared with those who did not, also achieved endpoints for clinical, corticosteroid-free, endoscopic, and symptomatic remission; clinical response; normalized fecal calprotectin and C-reactive protein; and improved quality of life. Conclusions: In patients with ulcerative colitis, bowel urgency improvement was associated with better clinical outcomes than in patients without improvement during induction and maintenance. A greater proportion of mirikizumab patients achieved sustainable bowel urgency improvement and remission compared to placebo patients.

The Role of IL-23 Inhibitors in Crohn's Disease.

Promoting a Th17 pathogenic response, the interleukin (IL)-23 pathway is crucial in the pathophysiology of inflammatory bowel disease (IBD). With a favorable safety profile, ustekinumab, a monoclonal antibody targeting the shared p40 component of IL-12/23, is currently approved for the treatment of IBD in patients with disease refractory to corticosteroids and biologic drugs. Risankizumab, mirikizumab, and guselkumab are specific IL-23p19 antagonists tested for the treatment of Crohn's disease (CD). However, only risankizumab currently has been approved for its treatment. Trials with guselkumab and mirikizumab are currently ongoing, with promising preliminary efficacy and safety results. In this review, we provide a summary of the current knowledge about selective IL-23 inhibitors, focusing on their positioning in the therapeutic algorithm of patients with moderate to severe CD.

The Efficacy and Safety of Biologic Drugs in the Treatment of Moderate-Severe Crohn's Disease: A Systematic Review.

Conventional therapy is the most commonly used treatment for Crohn's disease (CD), but it does not always achieve disease control, which is why the use of biologic drugs is increasing. The aim of this study was to analyze the efficacy and safety of biologic drugs in adult patients diagnosed with moderate-severe CD. An intensive search was performed in PubMed, Web of Science and Medline to collect phase 2 or 3 clinical trials published between 2018 and 2023 that were randomized, placebo-controlled and double-blind trials analyzing the efficacy and safety of biologic drugs in adult patients diagnosed with CD. This systematic review was conducted according to the PRISMA statement. Thirteen clinical trials evaluating eight biologic drugs were included. Upadacitinib, vedolizumab, adalimumab, guselkumab, mirikizumab, ustekinumab and risankizumab showed statistically significant efficacy across different clinical, endoscopic, histological, genetic, biomarker or quality-of-life parameters. However, PF-00547659 only showed statistically significant results for the CDAI-70 at week 12. In terms of safety, the incidence and severity of adverse effects were analyzed, with all drugs being well tolerated and presenting a good safety profile since most adverse effects were mild. Biologic drugs can be considered an effective and safe option for the treatment of moderate-severe CD in adult patients with an inadequate response or intolerance to conventional therapy.

Drug Clearance in Patients with Inflammatory Bowel Disease Treated with Biologics.

Biological therapy is very effective for treating patients with moderate to severe inflammatory bowel disease (IBD). However, up to 40% can have primary non-response, and up to 50% of the patients can experience a loss of response to anti-tumor necrosis factor therapy. These undesirable outcomes can be attributed to either a mechanistic failure or pharmacokinetic (PK) issues characterized by an inadequate drug exposure and a high drug clearance. There are several factors associated with accelerated clearance of biologics including increased body weight, low serum albumin and immunogenicity. Drug clearance has gained a lot of attention recently as cumulative data suggest that there is an association between drug clearance and therapeutic outcomes in patients with IBD. Moreover, clearance is used by model informed precision dosing (MIDP) tools, or PK dashboards, to adjust the dosing for reaching a target drug concentration threshold towards a more personalized application of TDM. However, the role of drug clearance in clinical practice is yet to be determined. This comprehensive review aims to present data regarding the variables affecting the clearance of specific biologics, the association of clearance with therapeutic outcomes and the role of clearance monitoring and MIPD in patients with IBD.

Impact of Bowel Urgency on Quality of Life and Clinical Outcomes in Patients With Ulcerative Colitis.

Background: Bowel urgency is commonly experienced by patients with ulcerative colitis (UC) and is associated with reduced health-related quality of life (QoL). Mirikizumab, a humanized monoclonal antibody directed against the p19 subunit of IL-23, significantly reduced bowel urgency in a double-blind, randomized, placebo-controlled Phase 2 clinical trial in patients with moderate-to-severe UC (NCT02589665). Methods: All patients (N = 249) reported symptoms including absence or presence of bowel urgency. Absence of urgency was defined as no urgency for the 3 consecutive days prior to each scheduled visit. Missing urgency data were imputed as present. After 12 weeks of induction treatment, patients who achieved clinical response continued maintenance mirikizumab treatment through Week 52. We assessed the relationship of urgency with QoL, clinical outcomes, and inflammatory biomarkers at Weeks 12 and 52. Results: Patients with absence of urgency demonstrated significantly greater improvement in Inflammatory Bowel Disease Questionnaire (IBDQ) scores even after adjusting for rectal bleeding (RB) and stool frequency (SF), significantly higher rates of all clinical outcomes at Weeks 12 and 52, and a greater decrease in inflammatory biomarkers C-reactive protein and fecal calprotectin compared to those with presence of urgency. Absence of urgency at Week 12 was associated with improved IBDQ scores at Week 52, while Week 12 RB or SF status was not. Conclusions: Absence of urgency is strongly associated with improvement in QoL as well as clinical measures of UC disease activity. These findings suggest urgency may be a useful surrogate marker of disease activity and an important treatment target for UC.

The Role of Master Protocols in Pediatric Drug Development.

Master protocols are innovative clinical trial designs that enable new approaches to analytics and operations, creating value for patients and drug developers. To date, the use of master protocols in pediatric drug development has been limited, focused primarily on pediatric oncology with limited experience in rare and ultra-rare pediatric diseases. This article explores the application of master protocols to pediatric programs required by FDA and EMA based on adult developmental programs. These required programs involve multiple assets developed in limited pediatric populations for registrational purposes. However, these required programs include the possibility for extrapolation of efficacy and safety from the adult population. The use of master protocols is a potential solution to the challenge of conducting clinical trials in small pediatric populations provided that such use would improve enrollment or reduce the required sample size. Toward that end, Janssen and Lilly have been working on a collaborative cross-company pediatric platform trial in pediatric Crohn's disease using an innovative Bayesian analysis. We describe how two competing companies can work together to design and execute the proposed platform, focusing on selected aspects-the usefulness of a single infrastructure, the regulatory submission process, the choice of control group, and the use of pediatric extrapolation. Master protocols offer the potential for great benefit in pediatrics by streamlining clinical development, with the goal of reducing the delay in pediatric marketing approvals when compared to adults so that children have timelier access to safe and effective medications.

Emerging therapies for ulcerative colitis.

INTRODUCTION: Despite advances in the medical management of ulcerative colitis (UC), a subgroup of patients does not respond to currently available therapies. A number of novel drugs are in late stages of clinical development or have recently received regulatory approval for UC. AREAS COVERED: This review focuses on three drug classes that have recently been approved or are awaiting approval for UC: antibodies against interleukin (IL)-23, sphingosine-1-phosphate receptor (S1PR) modulators, and selective inhibitors of Janus kinases (JAK). We provide an overview of their mechanism of action and summarize available evidence for their efficacy and safety. Finally, we discuss expected future challenges in UC management. EXPERT OPINION: The evaluated drugs have demonstrated efficacy with an acceptable safety profile. IL-23 antagonists appear to be safest with very few (serious) adverse events, while the use of S1PR modulators or JAK inhibitors has been associated with infectious and cardiovascular/thromboembolic events, albeit in low numbers. Although advances in drug development are promising, there is an urgent need for (validated) biomarkers to guide rational treatment selection. The scarcity of head-to-head trials also complicates comparisons between available drugs. Breaking the therapeutic ceiling of efficacy in UC will require marked advances in management extending well beyond drug development.