Acute graft-versus-host disease (aGVHD) remains a serious complication of allogeneic hematopoietic stem cell transplantation (HSCT), and no nonimmunosuppressive pharmacologic therapies are currently available for prophylaxis. We conducted a Phase 1b, open-label, dose-escalation study to evaluate the safety, pharmacokinetics (PK), and preliminary activity of efmarodocokin alfa, an interleukin-22 agonist, administered with standard-of-care prophylaxis in patients undergoing matched unrelated and matched related donor allogeneic HSCT following myeloablative conditioning. Eighteen patients were enrolled across 3 dose cohorts receiving efmarodocokin alfa at 30 µg/kg every 4 weeks, 30 µg/kg every 2 weeks, or 60 µg/kg every 2 weeks. Efmarodocokin alfa was well-tolerated and demonstrated an acceptable safety and PK profile, characterized by predominantly Grades 1 to 2 adverse events and linear PK across all dose levels. All patients achieved neutrophil engraftment by Day 30. By Day 100 post-transplant, 5 patients (27.8%) developed Grade 2 aGVHD, 2 (11.1%) of which had Stage 1 lower GI aGVHD. No patients developed Grades 3 to 4 aGVHD. Exploratory analysis demonstrated a lower gastrointestinal aGVHD-free survival rate of 83.3% at Day 180 and overall survival of 77.8% at Day 365. Although conclusions regarding efficacy are limited by the small sample size and exploratory design, these results demonstrate favorable safety and PK characteristics and provide initial observations regarding the potential role of efmarodocokin alfa in the prevention of lower gastrointestinal aGVHD as a nonimmunosuppressive prophylactic strategy.

Chronic inflammation is an underlying feature of respiratory diseases such as chronic obstructive pulmonary disease (COPD). Novel therapies that target the inflammatory mechanisms driving acute exacerbations of COPD are required. The ST2 receptor, which binds the alarmin interleukin (IL)-33 to initiate an inflammatory response, is a potential target. Astegolimab, a fully human immunoglobulin G2 monoclonal antibody, which binds with high affinity to ST2 to prevent binding of IL-33, is a potential therapy for COPD. However, targeting inflammatory pathways that form part of the immune system may have unintended consequences, such as implications for the response to infection and cardiovascular function. Therefore, an understanding of astegolimab’s safety profile in clinical use is essential. This narrative review summarizes clinical safety data from published clinical trials of astegolimab with a focus on adverse events of interest, including infections and cardiac events. Astegolimab was shown to be well tolerated in > 580 patients with asthma, atopic dermatitis, COPD, and severe COVID-19 pneumonia who took part in Phase II trials. The frequency of adverse events (AEs) and serious AEs was similar between the astegolimab and placebo arms in each trial (AEs: 41–81

BACKGROUND & AIMS: Efmarodocokin alfa is an interleukin (IL)-22 agonist, with favorable pharmacokinetic properties and an acceptable safety profile. This study further explored the therapeutic potential of efmarodocokin alfa compared with vedolizumab in patients with ulcerative colitis (UC). METHODS: This randomized phase II trial evaluated the efficacy, safety, pharmacokinetics, and pharmacodynamics of 3 doses of efmarodocokin alfa administered intravenously every 4 weeks (30 mu g/kg [n = 43], 60 mu g/kg [n = 44], and 90 mu g/kg [n = 43]) compared with placebo (n = 22) and with vedolizumab (n = 43) in the treatment of moderate to severe UC. Key clinical outcomes were assessed through the modified Mayo Clinic Score, and endoscopic evaluations by a central reader. RESULTS: Efmarodocokin alfa was adequately tolerated with an acceptable safety profile. Although efmarodocokin alfa did not show statistically significant improvement in clinical remission, clinical response, endoscopic healing, or endoscopic remission at week 8 compared with placebo, vedolizumab demonstrated some efficacy. Clinical remission was achieved by 12%, 9%, and 12% of patients in the 30, 60, and 90 mu g/kg dose arms, respectively, compared with 9% and 26% of patients in the placebo and vedolizumab arms at week 8. Similarly, endoscopic healing at week 8 was achieved by 14%, 14%, and 12% of patients in the 30, 60, and 90 mu g/kg dose arms, respectively, compared with 14% and 33% of patients in the placebo and vedolizumab arms. A dose-dependent increase in pharmacodynamic biomarkers was observed (regenerating islet-derived protein 3-alpha and C-reactive protein levels). CONCLUSION: Efmarodocokin alfa did not demonstrate efficacy compared with placebo, and this phase II study was ended early for futility; however, there was evidence of target engagement (skin adverse events, regenerating islet-derived protein 3-alpha levels). ClinicalTrials.gov, Number: NCT03558152.

While the acute impact of the coronavirus disease 2019 (COVID-19) pandemic has waned, implications for clinical trials remain. In particular, guidance for evaluation of elevated liver tests due to COVID-19, its treatments, and COVID-19 vaccination is lacking. The IQ DILI Initiative, composed of experts from academia, regulatory agencies, and industry herein propose recommendations to address this gap. Extensive literature review was conducted and structured discussions were held between IQ DILI industry members, regulators, and academic experts in hepatology and DILI. Liver-related manifestations in nonhospitalized patients with COVID-19 are highly varied. Evidence of liver injury may occur after COVID-19 symptoms resolve and testing is negative. Treatments for COVID-19 may cause liver injury or alter pharmacokinetics. COVID-19 vaccination has been associated with rare but clear hepatotoxicity, typically consistent with drug-induced autoimmune-like hepatitis, although other presentations, severity, latency, and time to resolution have been reported. Liver injury occurred with mRNA and viral vector vaccines, and in individuals with and without underlying autoimmune or liver diseases. Drug developers and investigators should be aware of the potential liver-related manifestations related to COVID-19, its treatments, and COVID-19 vaccination, as this may impact study eligibility and causality assessment during a trial. COVID-19 testing should be considered part of DILI causality assessment, as a positive test may prevent premature termination of the investigational drug. Since clinical trial participants may not consider vaccinations in their medical history, specific inquiry about their receipt is important when liver tests are abnormal during screening and as part of DILI causality assessment.

Astegolimab, a fully human immunoglobulin G2 monoclonal antibody, binds with high affinity to ST2, the interleukin-33 receptor, thereby blocking ST2/interleukin-33 binding and subsequent inflammatory cascades involved in inflammatory diseases. Here, we present three randomized, double-blind, placebo-controlled, Phase I studies evaluating the safety, tolerability, pharmacokinetics, and immunogenicity of single-ascending doses of astegolimab in healthy participants and patients with mild atopic asthma (NCT01928368), multiple-ascending doses in healthy participants (NCT02170337), and single-ascending doses in healthy Japanese and White adults. Overall, 152 participants were enrolled, randomized, and treated with single- or multiple-ascending doses of astegolimab (n = 112) or placebo (n = 40) subcutaneously (2.1-560 mg) or intravenously (210 or 700 mg). No deaths, serious adverse events, or discontinuations due to adverse events occurred during the studies. No clinically meaningful differences in incidence of TEAEs were observed between treatment arms. Pharmacokinetic exposure increased more than dose proportionally over 2.1-420 mg for single-ascending doses but were approximately dose proportional for single- and multiple-ascending doses ≥ 70 mg following subcutaneous administration. No pharmacokinetic differences were observed based on ethnicity between Japanese and White participants following body weight adjustments. Incidence of antidrug antibodies to astegolimab in healthy participants in the single- and multiple-ascending dose studies was 14%-23% and 33%-50% for subcutaneous and intravenous administration, respectively. Astegolimab was well tolerated in these Phase I studies with no safety concerns identified. Thus, further assessment of astegolimab in targeted patient populations was justified; the Phase IIb ALIENTO and Phase III ARNASA trials in patients with chronic obstructive pulmonary disease are ongoing.

Personalized dosing approaches play important roles in clinical practices to improve benefit: risk profiles. Whereas this is also important for drug development, especially in the context of drugs with narrow therapeutic windows, such approaches have not been fully evaluated during clinical development. Fazpilodemab (BFKB8488A) is an agonistic bispecific antibody which was being developed for the treatment of nonalcoholic steatohepatitis. The objective of this study was to characterize the exposure-response relationships of fazpilodemab with the purpose of guiding dose selection for a phase II study, as well as to evaluate various personalized dosing strategies to optimize the treatment benefit. Fazpilodemab exhibited clear exposure-response relationships for a pharmacodynamic (PD) biomarker and gastrointestinal adverse events (GIAEs), such as nausea and vomiting. Static exposure-response analysis, as well as longitudinal adverse event (AE) analysis using discrete-time Markov model, were performed to characterize the observations. Clinical trial simulations were performed based on the developed exposure-response models to evaluate probability of achieving target PD response and the frequency of GIAEs to inform phase II dose selection. Dynamic simulation of personalized dosing strategies demonstrated that the AE-based personalized dosing is the most effective approach for optimizing the benefit-risk profiles. The approach presented here can be a useful framework for quantifying the benefit of personalized dosing for drugs with narrow therapeutic windows.

BACKGROUND:Tryptase, a mast cell protease, has been identified as a potential therapeutic target in managing patients with refractory asthma. We assessed the efficacy, safety, pharmacokinetics, and pharmacodynamics of MTPS9579A, an anti-tryptase antibody, in a phase 2a randomized trial for patients with uncontrolled asthma and a phase 1c trial to understand activity within the lower respiratory tract. METHODS:Phase 2a patients (n = 134) received 1800 mg MTPS9579A or placebo intravenously every 4 weeks for 48 weeks. The primary endpoint was time to the first composite exacerbation event. Phase 1c patients (n = 27) received one intravenous dose of 300 or 1800 mg MTPS9579A or placebo. Both trials measured MTPS9579A concentrations and effects on tryptase in serum and nasal lining fluid; phase 1c also analyzed bronchial lining fluid. RESULTS:MTPS9579A did not meet the primary endpoint (hazard ratio = 0.90; 95% CI: 0.55-1.47; p = 0.6835); exacerbation rates in the placebo group were low. Serum and nasal MTPS9579A pharmacokinetics and tryptase levels were consistent with data from healthy volunteers. However, in phase 1c patients, compared to nasal levels, MTPS9579A bronchial concentrations were 6.8-fold lower, and bronchial active and total tryptase levels were higher (119-fold and 30-fold, respectively). Pharmacokinetic/pharmacodynamic modeling predicted intravenous doses of 3800 mg every 4 weeks would be necessary to achieve 95% active tryptase inhibition from baseline. CONCLUSIONS:The MTPS9579A dose tested in the phase 2a study was insufficient to inhibit tryptase in bronchial lining fluid, likely contributing to the observed lack of efficacy.

Background The interleukin-22 cytokine (IL-22) has demonstrated efficacy in preclinical colitis models with non-immunosuppressive mechanism of action. Efmarodocokin alfa (UTTR1147A) is a fusion protein agonist that links IL-22 to the crystallisable fragment (Fc) of human IgG4 for improved pharmacokinetic characteristics, but with a mutation to minimise Fc effector functions. Methods This randomised, phase 1b study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of repeat intravenous dosing of efmarodocokin alfa in healthy volunteers (HVs; n=32) and patients with ulcerative colitis (n=24) at 30–90 µg/kg doses given once every 2 weeks or monthly (every 4 weeks) for 12 weeks (6:2 active:placebo per cohort). Results The most common adverse events (AEs) were on-target, reversible, dermatological effects (dry skin, erythema and pruritus). Dose-limiting non-serious dermatological AEs (severe dry skin, erythema, exfoliation and discomfort) were seen at 90 μg/kg once every 2 weeks (HVs, n=2; patients, n=1). Pharmacokinetics were generally dose-proportional across the dose levels, but patients demonstrated lower drug exposures relative to HVs at the same dose. IL-22 serum biomarkers and IL-22-responsive genes in colon biopsies were induced with active treatment, and microbiota composition changed consistent with a reversal in baseline dysbiosis. As a phase 1b study, efficacy endpoints were exploratory only. Clinical response was observed in 7/18 active-treated and 1/6 placebo-treated patients; clinical remission was observed in 5/18 active-treated and 0/6 placebo-treated patients. Conclusion Efmarodocokin alfa had an adequate safety and pharmacokinetic profile in HVs and patients. Biomarker data confirmed IL-22R pathway activation in the colonic epithelium. Results support further investigation of this non-immunosuppressive potential inflammatory bowel disease therapeutic. Trial registration number NCT02749630.

N‐ and P‐co‐ion implantation enhances the electrical conductivity of nanocrystalline diamond films to 6.9 s cm−1 and improves the microplasma illumination (MI) characteristics of the films to a low breakdown voltage of 340 V, large plasma current density of 6.3 mA cm−2 (@510 V) with plasma life‐time stability of 10 h. N ions induce nanographitic phases in the films and P ions lower the resistance at the diamond‐to‐Si interface together promoting the conducting channels for effective electron transport, consequently attaining the improved MI properties of the films.

Background and Aims: BFKB8488A is a bispecific antibody targeting fibroblast growth factor receptor 1c and Klothoβ. This phase 1b study assessed safety, tolerability, pharmacokinetics, immunogenicity, and pharmacodynamics of BFKB8488A in patients with type 2 diabetes mellitus (T2DM) or NAFLD. Approach and Results: Patients were randomized to receive multiple doses of BFKB8488A at various dose levels and dosing intervals (weekly, every 2 weeks, or every 4 weeks) or placebo for 12 weeks. The primary outcome was the safety of BFKB8488A. Overall, 153 patients (T2DM: 91; NAFLD: 62) were enrolled and received at least one dose of treatment. Of these, 102 patients (62.7%) reported at least one adverse event (BFKB8488A: 83 [68.6%]; placebo: 19 [59.4%]). BFKB8488A exhibited nonlinear pharmacokinetics, with greater than dose‐proportional increases in exposure. The treatment‐emergent antidrug antibody incidence was 22.7%. Overall, trends in exposure‐dependent increases in high‐density lipoprotein (HDL) and decreases in triglyceride levels were observed. Decreases in alanine aminotransferase and aspartate aminotransferase were 0.7% and 9.2% for medium exposure and 7.3% and 11.2% for high‐exposure tertiles, compared with increases of 7.5% and 17% in the placebo group, respectively, at Day 85. In patients with NAFLD, the mean decrease from baseline liver fat was 13.0%, 34.5%, and 49.0% in the low‐, medium‐, and high‐exposure tertiles, respectively, compared with 0.1% with placebo at Day 85. Conclusions: BFKB8488A was adequately tolerated in patients with T2DM or NAFLD, leading to triglyceride reduction, HDL improvements, and trends in improvement in markers of liver health for both populations and marked liver fat reduction in patients with NAFLD. (ClinicalTrials.gov: NCT03060538).

BACKGROUND:The binding of IL-33 to its receptor ST2 (alias of IL1RL1) leads to the release of inflammatory mediators and may play a role in the pathogenesis of atopic dermatitis. Astegolimab is a fully human, IgG2 mAb that binds to ST2 and inhibits IL-33 signaling. OBJECTIVES:This study sought to assess the efficacy, safety, and pharmacokinetics of astegolimab in patients with atopic dermatitis. METHODS:This was a randomized, placebo-controlled, phase 2 study in which adults with chronic atopic dermatitis were randomized 1:1 to receive astegolimab 490 mg every 4 weeks or placebo, for 16 weeks. The primary outcome was the percentage of change from baseline to week 16 of the Eczema Area and Severity Index score. RESULTS:A total of 65 patients were enrolled in the study (placebo, n = 32; astegolimab, n = 33). The adjusted mean percentage of change from baseline to week 16 in the Eczema Area and Severity Index score was -51.47% for astegolimab compared with -58.24% for placebo, with a nonsignificant treatment difference of 6.77% (95% CI: -16.57-30.11; P = .5624). No differences were observed between treatment groups for secondary efficacy outcomes and in exploratory biomarkers (blood eosinophils, serum IL-5, serum CCL13). With the use of loading dose, pharmacokinetic exposure was sufficient from week 1. Astegolimab was well-tolerated, with a safety profile consistent with that observed in previous clinical trials. CONCLUSIONS:In patients with atopic dermatitis, astegolimab did not show a significant difference compared to placebo for the primary or secondary outcomes.

BACKGROUND:The IL-33/ST2 pathway is linked with asthma susceptibility. Inhaled allergens, pollutants, and respiratory viruses, which trigger asthma exacerbations, induce release of IL-33, an epithelial-derived "alarmin." Astegolimab, a human IgG2 mAb, selectively inhibits the IL-33 receptor, ST2. Approved biologic therapies for severe asthma mainly benefit patients with elevated blood eosinophils (type 2-high), but limited options are available for patients with low blood eosinophils (type 2-low). Inhibiting IL-33 signaling may target pathogenic pathways in a wider spectrum of asthmatics.OBJECTIVES:This study evaluated astegolimab efficacy and safety in patients with severe asthma.METHODS:This double-blind, placebo-controlled, dose-ranging study (ZENYATTA [A Study to Assess the Efficacy and Safety of MSTT1041A in Participants With Uncontrolled Severe Asthma]) randomized 502 adults with severe asthma to subcutaneous placebo or 70-mg, 210-mg, or 490-mg doses of astegolimab every 4 weeks. The primary endpoint was the annualized asthma exacerbation rate (AER) at week 54. Enrollment caps ensured ∼30 patients who were eosinophil-high (≥300 cells/μL) and ∼95 patients who were eosinophil-low (<300 cells/μL) per arm.RESULTS:Overall, adjusted AER reductions relative to placebo were 43% (P = .005), 22% (P = .18), and 37% (P = .01) for 490-mg, 210-mg, and 70-mg doses of astegolimab, respectively. Adjusted AER reductions for patients who were eosinophil-low were comparable to reductions in the overall population: 54% (P = .002), 14% (P = .48), and 35% (P = .05) for 490-mg, 210-mg, and 70-mg doses of astegolimab. Adverse events were similar in astegolimab- and placebo-treated groups.CONCLUSIONS:Astegolimab reduced AER in a broad population of patients, including those who were eosinophil-low, with inadequately controlled, severe asthma. Astegolimab was safe and well tolerated.

Abstract Background Inflammatory bowel disease (IBD) is characterised by gut dysbiosis, weakened epithelial barrier, and a dysregulated immune system. Interleukin-22 (IL-22), an IL-10 family cytokine, has demonstrated efficacy in animal IBD models by promoting intestinal epithelial repair, increasing antimicrobial peptide production, and increasing mucin production via goblet cells1. UTTR1147A is a fusion protein in which IL-22 is linked with the Fc portion of IgG4 to improve the pharmacokinetic (PK) characteristics. Methods A phase I study (NCT02749630) was conducted to evaluate the safety, tolerability, PK, and pharmacodynamics (PD) of repeat IV dosing of UTTR1147A in healthy volunteers (HV) and UC patients with centrally read Mayo endoscopic score ≥ 2. 38 HVs and 24 UC patients were given UTTR1147A or placebo at doses ranging from 30 to 90 µg/kg either biweekly or monthly (6:2 UTTR1147A: placebo per cohort). PK and serum PD (REG3A and CRP) were studied across multiple time points and the Mayo Clinic Score was evaluated at baseline, day 30 and day 85. Results Overall, UTTR1147A was safe and adequately tolerated in HV and UC patients. The most common adverse events were on-target dermatological effects (dry skin, erythema, and pruritus) that were manageable, monitorable and reversible. Dose-limiting non-serious dermatological toxicities (severe dry skin, erythema, exfoliation, and discomfort) were seen in two HVs and 1 UC patient dosed with 90ug/kg Q2wk. There were 2 unrelated serious adverse events (ankle fracture and cytomegalovirus infection) that eventually resolved. PK analyses showed that UTTR1147A exposures were, in general, dose proportional within HVs and within UC patients, with a mean elimination half-life of ~16 days and ~12 days, respectively. At the same dose level, UC patients showed relatively lower drug exposures than HVs, possibly due to faster drug clearance. Consistent with the Phase Ia2, UTTR1147A directly induced production of serum PD biomarkers REG3A and CRP at all dose cohorts tested compared with placebo. Notably, UC patients appear to have attenuated serum PD responses compared with HV. Clinical response was observed in 7/18 patients, and clinical remission in 5/18 patients treated with UTTR1147A compared with 1/6 and 0/6 placebo patients, respectively. Conclusion UTTR1147A demonstrated adequate safety and PK profile in healthy volunteers and UC patients. PD biomarker data demonstrated pharmacological activity of UTTR1147A providing evidence of IL-22R pathway activation. Together with the preliminary signals of efficacy, these data support further investigation of this potential, novel non-immunosuppressive therapy in IBD.

BACKGROUND: Ustekinumab (UST) is an effective therapy for moderate-severe ulcerative colitis (UC). 1,2 Histologic and endoscopic improvement of mucosa after induction are associated with clinical remission and steroid-free clinical remission at maintenance Wk44. 3 The association of histologic-endoscopic mucosal healing after UST induction or maintenance therapy with 2-yr outcomes in moderate-severe UC is not known.METHODS: In the UNIFI study of UST in moderate-severe UC, histologic-endoscopic mucosal healing was defined as achieving both endoscopic improvement (Mayo endoscopy subscore £1) and histologic improvement (ie, neutrophil infiltration in <5% of crypts, no crypt destruction, and no erosions, ulcerations, or granulation tissue; based on Geboes score).Associations of mucosal improvement after induction (irrespective of treatment) or UST maintenance with long-term efficacy of UST, disease severity, inflammation level, and dose adjustment were evaluated up to Wk92 in the long-term extension(LTE) of UNIFI.Analysis was conducted in pts who were randomized to receive UST maintenance therapy and continued UST in LTE.Tests with p<0.05 were considered statistically significant.RESULTS: Pts with histologic-endoscopic mucosal healing after induction had significantly lower disease activity (partial Mayo score and stool frequency) and a trend for lower inflammation measured by CRP and fecal calprotectin at maintenance Wk44 than those without induction mucosal healing(Table1).These improvements in disease activity were retained through LTE Wk92, with pts with induction histologic-endoscopic mucosal healing showing a continuous reduction of disease activity.Significantly lower disease activity, CRP, and fecal calprotectin were also observed through LTE among pts with histologic-endoscopic mucosal healing after UST maintenance compared to those without(Table1).Pts with histologic-endoscopic mucosal healing after induction remained on treatment longer than those without(p<0.05).Pts with histologicendoscopic mucosal healing after induction or maintenance were less likely to receive dose adjustment during LTE, but this association was not statistically significant.CONCLUSION: Early macroscopic and microscopic improvement of the mucosa is an indicator of positive long-term clinical outcomes and reductions in inflammatory burden. 1 BE Sands, et al.Safety and Efficacy of Ustekinumab Induction Therapy in Patients with Moderate to Severe Ulcerative Colitis: Results from the Ph 3 UNIFI Study.

With the widespread development of new drugs to treat chronic liver diseases (CLDs), including viral hepatitis and nonalcoholic steatohepatitis (NASH), more patients are entering trials with abnormal baseline liver tests and with advanced liver injury, including cirrhosis. The current regulatory guidelines addressing the monitoring, diagnosis, and management of suspected drug-induced liver injury (DILI) during clinical trials primarily address individuals entering with normal baseline liver tests. Using the same laboratory criteria cited as signals of potential DILI in studies involving patients with no underlying liver disease and normal baseline liver tests may result in premature and unnecessary cessation of a study drug in a clinical trial population whose abnormal and fluctuating liver tests are actually due to their underlying CLD. This position paper focuses on defining best practices for the detection, monitoring, diagnosis, and management of suspected acute DILI during clinical trials in patients with CLD, including hepatitis C virus (HCV) and hepatitis B virus (HBV), both with and without cirrhosis and NASH with cirrhosis. This is one of several position papers developed by the IQ DILI Initiative, comprising members from 16 pharmaceutical companies in collaboration with DILI experts from academia and regulatory agencies. It is based on an extensive literature review and discussions between industry members and experts from outside industry to achieve consensus regarding the recommendations. Key conclusions and recommendations include (1) the importance of establishing laboratory criteria that signal potential DILI events and that fit the disease indication being studied in the clinical trial based on knowledge of the natural history of test fluctuations in that disease; (2) establishing a pretreatment value that is based on more than one screening determination, and revising that baseline during the trial if a new nadir is achieved during treatment; (3) basing rules for increased monitoring and for stopping drug for potential DILI on multiples of baseline liver test values and/or a threshold value rather than multiples of the upper limit of normal (ULN) for that test; (4) making use of more sensitive tests of liver function, including direct bilirubin (DB) or combined parameters such as aspartate transaminase:alanine transaminase (AST:ALT) ratio or model for end-stage liver disease (MELD) to signal potential DILI, especially in studies of patients with cirrhosis; and (5) being aware of potential confounders related to complications of the disease being studied that may masquerade as DILI events.