incb039110 and Graft-vs-Host-Disease

This article presents the population pharmacokinetic (PopPK) analysis and exposure-response analyses for the primary efficacy end point-acute graft-versus-host disease (aGVHD) day 28 response-and select safety measures (incidence of thrombocytopenia, hypertriglyceridemia, and cytomegalovirus infection) from a phase 3 randomized, double-blind study comparing itacitinib plus corticosteroids versus placebo plus corticosteroids for the treatment of aGVHD. The PopPK data set contained sparse data from patients with aGVHD and select enriched data from healthy volunteers. The structural model was a 2-compartment model with first-order elimination and dose-dependent nonlinear absorption with dual first-order absorption pathways with lag times. Strong cytochrome P450 (CYP) 3A inhibitor coadministration, moderate renal impairment, and participant population (healthy volunteers vs patients with aGVHD) were covariates on apparent clearance. Participant population was also a covariate on apparent intercompartmental clearance and lag time of the secondary absorption compartment. Apparent clearance decreased 42% with coadministration of strong CYP3A inhibitors. Simulations supported the following dose reductions with concomitant use of a strong CYP3A inhibitor: 300 mg once daily to 200 mg once daily, 400 mg once daily to 300 mg once daily, and 600 mg once daily to 400 mg once daily. No dose adjustment is recommended for any other covariate based on the magnitude of impact when they were retained in the model. The exposure-response relationship was characterized between itacitinib exposure and probability of aGVHD day 28 response using a linear logistic regression model. Both itacitinib exposure and aGVHD risk status were significant predictors of response. There was no relationship between itacitinib exposure and thrombocytopenia, hypertriglyceridemia, or cytomegalovirus infection.

Topics: Acetonitriles; Cytochrome P-450 CYP3A Inhibitors; Graft vs Host Disease; Humans; Hypertriglyceridemia; Thrombocytopenia

Acute graft-versus-host disease (GVHD) is a common and life-threatening complication of allogeneic haematopoietic stem cell transplantation (HSCT); there is an urgent unmet need for effective therapies. We aimed to evaluate the Janus kinase 1 inhibitor itacitinib versus placebo, both in combination with corticosteroids, for initial treatment of acute GVHD.. GRAVITAS-301 was an international, double-blind, adaptive (group sequential design) phase 3 study conducted at 129 hospitals and community practices in 19 countries. Eligible patients were aged 18 years or older, had previously received allogeneic HSCT for a haematological malignancy, developed grades II-IV acute GVHD, and received up to 2 days of systemic corticosteroids. Patients were stratified by clinical standard-risk or high-risk acute GVHD and randomly assigned (1:1), via a centralised interactive voice response system, to receive either oral itacitinib (200 mg) or placebo once daily, both in addition to corticosteroids. The primary endpoint was overall response rate (ORR) at day 28 (defined as the proportion of patients with complete response, very good partial response, or partial response 28 days after the start of treatment). For sample size determination, an absolute improvement in ORR at day 28 over standard therapy of 16% was considered clinically meaningful. Efficacy analyses were performed in the intention-to-treat population; safety analyses included patients who received at least one dose of study drug. GRAVITAS-301 is registered with ClinicalTrials.gov (NCT03139604) and is complete.. Between July 19, 2017, and Oct 3, 2019, 439 patients were randomly assigned to receive either itacitinib plus corticosteroids (n=219; itacitinib group) or placebo plus corticosteroids (n=220; placebo group). 173 (39%) patients were female and 390 (89%) were White. At baseline, 107 (24%) of 439 patients (itacitinib 51 [23%] of 219; placebo 56 [25%] of 220) had clinical high-risk acute GVHD. The ORR at day 28 was 74% (95% CI 67·6-79·7; 162 of 219; complete response 53% [116 of 219]) for itacitinib and 66% (59·7-72·6; 146 of 220; complete response, 40% [89 of 220]) for placebo (odds ratio for ORR 1·45, 95% CI 0·96-2·20; two-sided p=0·078). Grade 3 or worse adverse events occurred in 185 (86%) of 215 itacitinib recipients and 178 (82%) of 216 placebo recipients, and most commonly included thrombocytopenia or platelet count decreased (78 [36%] vs 68 [31%]), neutropenia or neutrophil count decreased (49 [23%] vs 45 [21%]), anaemia (42 [20%] vs 26 [12%]), and hyperglycaemia (26 [12%] vs 28 [13%]). Treatment-related deaths occurred in three of 215 patients (1%) in the itacitinib group and four of 216 (2%) in the placebo group.. The observed improvement in ORR at day 28 with the addition of itacitinib versus placebo to corticosteroids did not reach the prespecified significance level. Further studies might provide additional insight into the utility of selective JAK1 inhibition for the treatment of acute GVHD.. Incyte.

Topics: Acetonitriles; Adrenal Cortex Hormones; Double-Blind Method; Female; Graft vs Host Disease; Humans; Pyrazoles; Pyrimidines; Pyrroles; Treatment Outcome

A broad proteomic analysis was conducted to identify and evaluate candidate biomarkers potentially predictive of response to treatment with an oral selective Janus kinase 1 (JAK1) inhibitor, itacitinib, in acute graft-versus-host disease (GVHD). Plasma samples from 25 participants (identification cohort; NCT02614612) were used to identify novel biomarkers that were tested in a validation cohort from a placebo-controlled, randomised trial (n = 210; NCT03139604). The identification cohort received corticosteroids plus 200 or 300 mg itacitinib once daily. The validation cohort received corticosteroids plus 200 mg itacitinib once daily or placebo. A broad proteomic analysis was conducted using a proximity extension assay. Baseline and longitudinal comparisons were performed with unpaired t-test and one-way analysis of variance used to evaluate biomarker level changes. Seven candidate biomarkers were identified. Monocyte-chemotactic protein (MCP)3, pro-calcitonin/calcitonin (ProCALCA/CALCA), together with a previously identified prognostic acute GVHD biomarker, regenerating islet-derived protein (REG)3A, stratified complete responders from non-responders (participants with progressive disease) to itacitinib, but not placebo, potentially representing predictive biomarkers of itacitinib in acute GVHD. ProCALCA/CALCA, suppressor of tumorigenicity (ST)2, and tumour necrosis factor receptor (TNFR)1 were significantly reduced over time by itacitinib in responders, potentially representing response-to-treatment biomarkers. Novel biomarkers have the potential to identify patients with acute GVHD that may respond to itacitinib plus corticosteroid treatment (NCT02614612; NCT03139604).

Topics: Acetonitriles; Acute Disease; Adrenal Cortex Hormones; Biomarkers; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Proteomics; Pyrazoles; Pyrimidines; Pyrroles

The standard primary treatment for acute graft-versus-host disease (GVHD) requires prolonged, high-dose systemic corticosteroids (SCSs) that delay reconstitution of the immune system. We used validated clinical and biomarker staging criteria to identify a group of patients with low-risk (LR) GVHD that is very likely to respond to SCS. We hypothesized that itacitinib, a selective JAK1 inhibitor, would effectively treat LR GVHD without SCS. We treated 70 patients with LR GVHD in a multicenter, phase 2 trial (NCT03846479) with 28 days of itacitinib 200 mg/d (responders could receive a second 28-day cycle), and we compared their outcomes to those of 140 contemporaneous, matched control patients treated with SCSs. More patients responded to itacitinib within 7 days (81% vs 66%, P = .02), and response rates at day 28 were very high for both groups (89% vs 86%, P = .67), with few symptomatic flares (11% vs 12%, P = .88). Fewer itacitinib-treated patients developed a serious infection within 90 days (27% vs 42%, P = .04) due to fewer viral and fungal infections. Grade ≥3 cytopenias were similar between groups except for less severe leukopenia with itacitinib (16% vs 31%, P = .02). No other grade ≥3 adverse events occurred in >10% of itacitinib-treated patients. There were no significant differences between groups at 1 year for nonrelapse mortality (4% vs 11%, P = .21), relapse (18% vs 21%, P = .64), chronic GVHD (28% vs 33%, P = .33), or survival (88% vs 80%, P = .11). Itacitinib monotherapy seems to be a safe and effective alternative to SCS treatment for LR GVHD and deserves further investigation.

Topics: Acetonitriles; Adrenal Cortex Hormones; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Pyrazoles; Treatment Outcome

Topics: Acetonitriles; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Pyrazoles

Pharmacological modulation of the Janus kinase (JAK) family has achieved clinically meaningful therapeutic outcomes for the treatment of inflammatory and hematopoietic diseases. Several JAK1 selective compounds are being investigated clinically to determine their anti-inflammatory potential. We used recombinant enzymes and primary human lymphocytes to assess the JAK1 specificity of itacitinib (INCB039110) and study inhibition of signal transducers and activators of transcription (STAT) signaling. Rodent models of arthritis and inflammatory bowel disease were subsequently explored to elucidate the efficacy of orally administered itacitinib on inflammatory pathogenesis. Itacitinib is a potent and selective JAK1 inhibitor when profiled against the other JAK family members. Upon oral administration in rodents, itacitinib achieved dose-dependent pharmacokinetic exposures that highly correlated with STAT3 pharmacodynamic pathway inhibition. Itacitinib ameliorated symptoms and pathology of established experimentally-induced arthritis in a dose-dependent manner. Furthermore, itacitinib effectively delayed disease onset, reduced symptom severity, and accelerated recovery in three distinct mouse models of inflammatory bowel disease. Low dose itacitinib administered via cannula directly into the colon was highly efficacious in TNBS-induced colitis but with minimal systemic drug exposure, suggesting localized JAK1 inhibition is sufficient for disease amelioration. Itacitinib treatment in an acute graft-versus-host disease (GvHD) model rapidly reduced inflammatory markers within lymphocytes and target tissue, resulting in a marked improvement in disease symptoms. This is the first manuscript describing itacitinib as a potent and selective JAK1 inhibitor with anti-inflammatory activity across multiple preclinical disease models. These data support the scientific rationale for ongoing clinical trials studying itacitinib in select GvHD patient populations.

Topics: Animals; Arthritis, Experimental; Azetidines; Chemokine CCL2; Colitis; Dose-Response Relationship, Drug; Graft vs Host Disease; Humans; Inflammation; Inflammatory Bowel Diseases; Isonicotinic Acids; Janus Kinase 1; Lymphocytes; Mice; Mice, Inbred BALB C; Primary Cell Culture; Rats; Rats, Inbred Lew; Signal Transduction; STAT Transcription Factors; STAT3 Transcription Factor; T-Lymphocytes