Janus Kinase Inhibitor For Treatment Research Articles

An evaluation of fedratinib for adult patients with newly diagnosed and previously treated myelofibrosis

ABSTRACT Introduction Myelofibrosis (MF) is a life-shortening myeloproliferative neoplasm that has multiple features such as clonal proliferation, fibrosis and splenomegaly. Until recently, ruxolitinib, a Janus Kinase (JAK) 1/2 inhibitor was the only targeted therapy approved for transplant-ineligible patients with MF and who require treatment for symptoms and/or splenomegaly. However, the discontinuation rate with ruxolitinib at 3 to 5 years is high and mostly due to loss of response or toxicity, and these patients had no subsequent treatment. Areas covered Fedratinib, a selective JAK2 inhibitor, was approved by the Food and Drug Administration (FDA) in August 2019 for the treatment of intermediate-2 or high-risk primary or secondary MF, regardless of prior JAK inhibitor treatment for the management of symptoms and splenomegaly. We discuss herein the development of fedratinib and its pharmacology and pharmacokinetics as well as the clinical development and the future directions. We used PubMed for the search of articles related to fedratinib and myelofibrosis. Expert Opinion Fedratinib provided a second-line treatment for patients with MF who failed or discontinued ruxolitinib. New combinations of JAK inhibitors with other targeted therapies are a must in order to improve the management of MF.

Safety of Oral Janus Kinase Inhibitors in the Treatment of Moderate-to-Severe Atopic Dermatitis.

Multiple Janus Kinase (JAK) inhibitors were developed as potential treatments for moderate-to-severe atopic dermatitis (AD). There is a substantial amount of safety data from recent trials of oral JAK inhibitors in patients with AD. However, the vast majority of safety data for oral JAK inhibitors is derived from patients with rheumatoid arthritis and other immune-mediated disorders, and is primarily derived from tofacitinib, a pan-selective JAK inhibitor. This narrative review examines safety data for oral JAK inhibitors from studies in AD and other indications. The available data do demonstrate that rare but serious and life-threatening adverse events can occur with oral JAK inhibitor treatment and should be carefully considered in therapeutic shared decision making.

Preliminary Data from the Phase I/II Study of TP-3654, a Selective Oral PIM1 Kinase Inhibitor, in Patients with Myelofibrosis Previously Treated with or Ineligible for JAK Inhibitor Therapy

Introduction: Myelofibrosis (MF) is characterized by bone marrow (BM) fibrosis, ineffective hematopoiesis, splenomegaly, and debilitating symptoms. Expression of PIM-1 is significantly upregulated in MF hematopoietic cells, supporting exploration of PIM-1 as a potential therapeutic target in MF. TP-3654 is a highly selective oral investigational PIM-1 kinase inhibitor. When administered alone and in combination with ruxolitinib, TP-3654 reduced spleen size and BM fibrosis in JAK2V617F and MPLW515L murine MF models (Dutta, 2021). In addition, TP-3654 decreased cytokine response genes and serum TGF-b in progenitor cells and JAK2V617F mice, respectively. TP-3654 showed less hematopoietic inhibition than Janus kinase (JAK) inhibitors (ruxolitinib, pacritinib and momelotinib) in in vitro human megakaryocyte and erythrocyte cell colony formation. Methods: This Phase I/II study evaluates the safety and efficacy of TP-3654 monotherapy in patients with MF (NCT04176198). Key eligibility criteria include primary or secondary MF; intermediate or high-risk MF per DIPSS; previously treated with or ineligible for JAK inhibitor treatment; grade ≥2 BM fibrosis; platelet count ≥25x109/L; absolute neutrophil count ≥1x109/L; splenomegaly; and ≥2 measurable symptoms. The study aims to identify the maximum tolerated dose and/or recommended Phase II dose using a Bayesian logistic regression model (BLRM) with overdose control, and to assess clinical activity (spleen volume reduction [SVR], total symptom score [TSS] improvement, and BM fibrosis reduction), safety, pharmacokinetic, and pharmacodynamic markers in peripheral blood and BM biopsies. Results: As of 11 July 2022, 8 patients were enrolled across 5 dose levels in the dose escalation phase. At baseline, median age was 70 years (range, 61 to 77), median spleen volume was 2370 cm3 (range, 1189 to 4407), median total symptom score was 19 (range, 4 to 62), median platelet count was 120 x109/L (range 68 to 237), median hemoglobin was 10.1 g/dL (range, 5.9 to 13.7), and two patients were transfusion-dependent. All patients had received prior treatment with at least one JAK inhibitor. Median duration of prior JAK inhibitor treatment was 35 weeks (range, 13 to 269). Six patients had JAK2V16F mutation, 2 patients had CALR mutation. The median duration of TP-3654 treatment was 21 weeks (range, 1 to 45). No dose-limiting toxicities occurred. Treatment-related adverse events (TRAEs) occurring in >20% of patients included mild to moderate nausea, vomiting, and diarrhea. Grade ≥ 3 TRAEs included only 1 case of vomiting. No hematological TRAEs were reported. No discontinuation due to AE occurred. SVR was observed in 5 out of 6 evaluable patients (median best change -14%, range -3.2% to -35%) (Figure 1). Symptom improvement was observed in 5 out of 6 evaluable patients (median best change -70%, range -32 to -100%). A panel of cytokines were evaluated in plasma samples obtained at baseline and during TP-3654 treatment. Reductions in cytokines (TGF-b, IL-18, VEGF, RANTES, MMP-9, and TIMP-1) were observed after TP-3654 treatment (Figure 2). Patients with higher cytokine reductions correlated with higher reduction in total symptom score. Enrollment is ongoing, updated data will be presented. Conclusions: The preliminary clinical data in dose escalation show: 1) encouraging signs of clinical activity in spleen volume reduction, symptom improvement, and cytokine reduction with TP-3654 monotherapy in patients previously treated with JAK inhibitors, 2) TP-3654 is well tolerated with limited myelosuppressive adverse events. The non-clinical findings and preliminary clinical safety/efficacy data support accelerated development and assessment of TP-3654 as the optimal partner for combination with JAK inhibitors. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Three Adult Cases of STAT1 Gain-of-Function with Chronic Mucocutaneous Candidiasis Treated with JAK Inhibitors

PurposeThe aim of this study was to characterize clinical effects and biomarkers in three patients with chronic mucocutaneous candidiasis (CMC) caused by gain-of-function (GOF) mutations in the STAT1 gene during treatment with Janus kinase (JAK) inhibitors.MethodsMass cytometry (CyTOF) was used to characterize mononuclear leukocyte populations and Olink assay to quantify 265 plasma proteins. Flow-cytometric Assay for Specific Cell-mediated Immune-response in Activated whole blood (FASCIA) was used to quantify the reactivity against Candida albicans.ResultsOverall, JAK inhibitors improved clinical symptoms of CMC, but caused side effects in two patients. Absolute numbers of neutrophils, T cells, B cells, and NK cells were sustained during baricitinib treatment. Detailed analysis of cellular subsets, using CyTOF, revealed increased expression of CD45, CD52, and CD99 in NK cells, reflecting a more functional phenotype. Conversely, monocytes and eosinophils downregulated CD16, consistent with reduced inflammation. Moreover, T and B cells showed increased expression of activation markers during treatment. In one patient with a remarkable clinical effect of baricitinib treatment, the immune response to C. albicans increased after 7 weeks of treatment. Alterations in plasma biomarkers involved downregulation of cellular markers CXCL10, annexin A1, granzyme B, granzyme H, and oncostatin M, whereas FGF21 was the only upregulated marker after 7 weeks. After 3 months, IFN-ɣ and CXCL10 were downregulated.ConclusionsThe clinical effect of JAK inhibitor treatment of CMC is promising. Several biological variables were altered during baricitinib treatment demonstrating that lymphocytes, NK cells, monocytes, and eosinophils were affected. In parallel, cellular reactivity against C. albicans was enhanced.

The effect of tofacitinib on residual pain in patients with rheumatoid arthritis and psoriatic arthritis

ObjectivePost hoc analysis of pooled data from nine randomised controlled trials to assess the effect of tofacitinib (oral Janus kinase inhibitor for treatment of rheumatoid arthritis (RA) and psoriatic arthritis...

Lineage plasticity in prostate cancer depends on JAK/STAT inflammatory signaling.

Drug resistance in cancer is often linked to changes in tumor cell state or lineage, but the molecular mechanisms driving this plasticity remain unclear. Using murine organoid and genetically engineered mouse models, we investigated the causes of lineage plasticity in prostate cancer and its relationship to antiandrogen resistance. We found that plasticity initiates in an epithelial population defined by mixed luminal-basal phenotype and that it depends on increased Janus kinase (JAK) and fibroblast growth factor receptor (FGFR) activity. Organoid cultures from patients with castration-resistant disease harboring mixed-lineage cells reproduce the dependency observed in mice by up-regulating luminal gene expression upon JAK and FGFR inhibitor treatment. Single-cell analysis confirms the presence of mixed-lineage cells with increased JAK/STAT (signal transducer and activator of transcription) and FGFR signaling in a subset of patients with metastatic disease, with implications for stratifying patients for clinical trials.

Janus kinase inhibitors for treatment of morphea and systemic sclerosis: A literature review.

Morphea and systemic sclerosis (SSc) are rare disorders of connective tissue characterized by increased skin thickness and fibrosis, with current treatment options having variable efficacies, many with limited therapeutic benefit. Janus kinase (JAK) inhibitors have been shown in preclinical studies to inhibit the fibrotic pathway in murine models of systemic sclerosis, by blocking TGF-beta mediated pathway of STAT protein activation. Additionally, case reports of the treatment of morphea and SSc with tofacitinib, a JAK 1/3 inhibitor, have shown improvement in skin sclerosis. Several JAK inhibitors have been developed and utilized in dermatologic and rheumatologic diseases. To date, tofacitinib has been by far the most commonly trialed JAK inhibitor in patients with SSc and morphea. Herein we review the preclinical studies reported in the literature supporting the use and efficacy of JAK inhibitors for the treatment of morphea and the cutaneous manifestations of SSc, as well as discuss the clinical cases published to date illustrating the benefits of JAK inhibitors in disease management. The pathogenesis and mechanism of action will be reviewed as it relates to the process of skin fibrosis in morphea and SSc, along with the murine models illustrating efficacy of JAK inhibitors in fibrotic disease. Based on available preclinical and clinical data as well as consideration of the mechanism of action of JAK inhibitors on the pathway for cutaneous fibrosis, there is promising evidence to support the use and further study of JAK inhibitors in the management of morphea and cutaneous fibrosis in SSc.

Association between Hematological Indicesand Disease Activity in Patients with Rheumatoid Arthritis Treated with Janus Kinase Inhibitors for 24 Weeks.

Background and Objective: Hematological indices have been considered reliable markers for assessment of disease activity in rheumatoid arthritis (RA). This study assessed whether hematological indices reflect changes in disease activity in patients with RA treated with Janus kinase (JAK) inhibitors. Materials and Methods: This study recruited 123 patients with RA who completed a regimen of JAK inhibitors, including baricitinib or tofacitinib, for 24 weeks, and 80 age- and sex-matched healthy control subjects. Hematological indices were systemic immune-inflammation index (SII), neutrophil-to-hemoglobin and lymphocyte (NHL) score, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR). Disease Activity Score 28 joints using erythrocyte sedimentation rate (DAS28-ESR) was evaluated as a measure of RA disease activity. Results: At baseline, patients with RA had a significantly higher SII, NHL score, NLR, and PLR than controls (p < 0.001 for all). SII, NHL score, NLR, and PLR at baseline were associated with DAS28-ESR (p < 0.05 for all). Changes in SII, NHL score, NLR, and PLR were associated with those in DAS28-ESR during treatment with JAK inhibitors. Such treatment markedly decreased SII, NHL score, and NLR values compared to those at baseline (p < 0.001 for all) but did not decrease PLR (p = 0.056). There were no differences in changes in SII, NHL score, NLR, and PLR between baricitinib and tofacitinib treatments. No hematological index showed predictive potential with respect to non-response to JAK inhibitor treatment. Conclusions: This study showed that hematological indices might be useful in monitoring changes in disease activity in patients with RA treated with JAK inhibitors.

Safety of JAK inhibitor use in patients with rheumatoid arthritis who developed herpes zoster after receiving JAK inhibitors.

To determine the safety of Janus kinase inhibitor (JAKi) use following herpes zoster (HZ) reactivation in patients with rheumatoid arthritis (RA). Medical records of all patients who received JAKi at a tertiary referral center between August 2015 and June 2021 were retrospectively reviewed. Data from patients who developed HZ reactivation were collected, and the HZ-related safety of those who continued JAKis after reactivation was evaluated. Of the 416 patients who received JAKis, 33 (7.9%) developed HZ reactivation during treatment (tofacitinib, n = 22; baricitinib, n = 11). The mean age of the patients was 60.2 ± 11.8years. Fourteen patients (42.4%) received glucocorticoids with a median dose of 3.75mg of prednisone (IQR, 2.5-5.0). The median duration of JAKi administration before HZ reactivation was 11months (IQR, 4-29). JAKi was continued in 24 (72.7%) patients during the HZ episode, while it was temporarily discontinued and then resumed after the HZ episode in 5 (15.2%) patients. Three (9.1%) patients had acute complications, such as encephalitis with HZ ophthalmicus. Four (12.1%) patients, including the 3 with complications, permanently discontinued JAKis. Of the 29 patients who were observed for a median of 12months (IQR, 6-21) after the initial HZ reactivation episode, reactivation recurred in one (3.4%); this patient maintained JAKi treatment for a further 18months without additional HZ recurrence. JAKis were commonly continued or re-administered in patients with HZ reactivation, and the majority of these patients did not experience significant complications or recurrence of HZ reactivation. Thus, the use of JAKi after HZ reactivation episode seems to be tolerated.

Efficacy and Safety of Janus Kinase Inhibitors for the Treatment of Atopic Dermatitis: A Systematic Review and Meta-Analysis

Background: Current therapeutic options for atopic dermatitis (AD) are limited. Janus kinase (JAK) inhibitors may be viable alternatives. Objectives: To assess the efficacy and safety of JAK inhibitors for AD treatment. Methods: We searched PubMed, Embase, the Cochrane Controlled Register of Trials, Web of Science, Global Resource of Eczema Trials database, and ClinicalTrials.gov from inception to September 1, 2020. Randomized clinical trials (RCTs) comparing JAK inhibitors with placebo/vehicle treatment for AD patients were included. The primary study outcomes included (1) the change (%) from the Eczema Area and Severity Index (EASI) baseline expressed as weighted mean difference (WMD) and 95% confidence interval (95% CI), and (2) the Investigator’s Global Assessment (IGA) response and safety outcomes expressed as relative risk (RR) and 95% CI. Results: We included 14 RCTs published in 13 studies (3,822 patients). Treatment with JAK inhibitors significantly improved IGA response (RR 2.83, 95% CI 2.25–3.56, p < 0.001) and EASI score (WMD –28.82, 95% CI –34.48 to −23.16, p < 0.001). JAK inhibitor treatment achieved the largest improvement in both IGA response (RR 3.59, 95% CI 2.66–4.84, p < 0.001) and EASI score (WMD –42.00, 95% CI –48.64 to −35.36, p < 0.001) by week 4 of treatment. Topical JAK inhibitors were significantly more efficacious than oral inhibitors. Upadacitinib treatment for 4 weeks was most effective in reducing EASI score (WMD –53.92, 95% CI –69.26 to −38.58, p < 0.001), while abrocitinib for 4 weeks led to the most effective IGA response (RR 5.47, 95% CI 2.74–10.93, p < 0.001). There was no difference in the frequency of adverse events (AEs) leading to discontinuation; however, JAK inhibitors use, especially abrocitinib, led to a higher incidence of treatment-emergent AEs (RR 1.25, 95% CI 1.10–1.42, p = 0.001). Conclusion: Our results imply that JAK inhibitors are an effective and safe AD treatment. Nevertheless, further trials with longer duration and head-to-head comparisons of different JAK inhibitors are needed.

Janus kinase inhibitors and major COVID-19 outcomes: time to forget the two faces of Janus! A meta-analysis of randomized controlled trials.

Coronavirus disease-2019 (COVID-19) represents a global public health nightmare. The “cytokine storm,” the most prominent underlying pathophysiologic mechanism of this disease, can theoretically be targeted at several stages. Janus kinase (JAK) inhibitors constitute a drug class that could ameliorate the inflammatory response and enhance antibody production. Herein, we aimed to evaluate the efficacy of JAK inhibitors in patients with COVID-19, performing the most updated relevant meta-analysis. We searched two major databases for randomized controlled trials (RCTs) enrolling adult patients with documented COVID-19 in the in-hospital setting, assigned either to JAK inhibitor treatment plus standard of care or standard of care alone. We set as primary efficacy outcome the endpoint of COVID-19 death on day 28 and as secondary efficacy composite outcome that of mechanical ventilation or initiation of extracorporeal membrane oxygenation (ECMO). We finally pooled data of interest from 4 RCTs in a total of 1338 subjects with documented COVID-19 infection, utilizing the following JAK inhibitors: baricitinib, ruxolitinib, tofacitinib, and nezulcitinib. Treatment with JAK inhibitor compared to control resulted in a significant reduction in the risk for COVID-19 death by 43%, while it also led to a significant decrease in the risk for mechanical ventilation or ECMO initiation by 36%. Herein, we demonstrate a clear benefit with JAK inhibitors added to standard of care in patients with COVID-19 in terms of risk reduction concerning major outcomes. Larger RCTs will elucidate their place in treatment armamentarium against COVID-19.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10067-021-05884-4.

Novel Therapies in Myeloproliferative Neoplasms: Beyond JAK Inhibitor Monotherapy.

Myeloproliferative neoplasms (MPNs) are clonal hematopoietic disorders that consist classically of polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). Janus kinase (JAK) inhibitors have become the standard of therapy in treating patients with intermediate- to higher-risk MF. However, JAK inhibitor (JAKi) treatment can be associated with development of resistance, suboptimal response, relapse, or treatment-related adverse effects. With no approved therapies beyond the JAKi class, the estimated median survival, post JAKi failure, is approximately two years or less; therefore, novel therapies are urgently needed in the MF field. In this review, we discuss ruxolitinib use in MPNs as well as causes of ruxolitinib failure or discontinuation. In addition, we review novel therapies being investigated alone or in combination with JAKi administration. We summarize concepts and mechanisms behind emerging novel therapies being studied for MPNs. This review of emerging novel therapies outlines several novel mechanisms of agents, including via promotion of apoptosis, alteration of the microenvironment, activation or inactivation of various pathways, targeting fibrosis, and telomerase inhibition.

Phase I/II Trial of Glasdegib in Heavily Pre-Treated Patients with Primary or Secondary Myelofibrosis

Background: Characterized by the clonal proliferation of bone marrow stem cells and myeloid progenitors, patients with myelofibrosis (MF) have hepatosplenomegaly, abnormal blood counts, bleeding or thrombosis, and suffer debilitating disease-related symptoms. In preclinical models of MF, inhibitors of the Hedgehog (Hh) pathway were shown to inhibit growth and self-renewal of bone marrow stem/progenitor cells that differentiate into cells of the myeloid lineage and to reduce splenic fibrosis. Glasdegib is a potent and selective oral inhibitor of the Hh pathway, acting through the inhibition of Smoothened. Expression of Hh target genes has been shown to be upregulated in granulocytes isolated from MF patients. Here we present recent data from the lead-in cohort of a single arm, open-label phase 1b/2 trial of glasdegib in MF.Methods: Patients ≥18 years with primary/secondary MF previously-treated with ≥1 Janus Kinase inhibitor (JAKi) were enrolled and received glasdegib 100 mg orally once daily until there was no further clinical benefit. Primary endpoints include adverse events and laboratory abnormalities, as graded by National Cancer Institute Common Terminology Criteria for Adverse Events v 4.03. Secondary endpoints include the proportion of patients with spleen volume reduction ≥35% and the proportion of patients with hematologic improvement. All 21 subjects in the lead-in cohort provided plasma samples for pharmacokinetic (PK) analysis, with 19 subjects providing evaluable glasdegib samples (at steady state) for the purposes of glasdegib PK analysis.Results: Between October 2014 and October 2015, 21 patients were enrolled in this ongoing study. Mean age was 69 years (range 58-83) and the median duration of treatment with glasdegib was 85 days (range 22-512). Of the 21 subjects, 52% (n=11) were refractory patients who had shown an inadequate response to prior JAKi treatment. A total of five patients achieved a reduction in spleen volume, with a maximum reduction from baseline of 2.3% to 32.9% (Fig A). One patient on study had a positive anemia response, showing improvement from Grade (G) 3 to G2 and became transfusion independent while on treatment. One patient also had an improvement in absolute neutrophil counts (from G2 to G0). Dysgeusia (n=13, 62%), muscle spasms (n=12, 57%), alopecia (n=8, 38%), decreased appetite, fatigue (n=7 each, 33%), increased lipase, decreased weight (n=5 each, 24%), nausea, pyrexia, hyperuricemia, anemia (n=4 each, 19%), asthenia, constipation, cough, dehydration, prolonged electrocardiogram QT, decreased lymphocyte count, myalgia, pain in extremity, thrombocytopenia, and upper respiratory tract infection (n=3 each, 14%) occurred in ≥10% of patients. Despite the high frequency of muscle spasms, there were no significant changes in creatine kinase; only one patient showing a G1 increase compared with baseline. Following administration of 100 mg daily oral dose of glasdegib for 15 days, at steady state, the peak plasma concentrations (Cmax) generally occurred at 1 hour post dose (Fig B). The geometric mean (%CV of geometric means) values for AUCtau and Cmax were 13150 ng.hr/mL (50%) and 996.8 ng/mL (45%), respectively (Fig C). The pre-dose concentrations (Ctrough) following daily dosing were consistent over multiple cycles, with geometric mean Ctrough values of 204.1 ng/mL, 176.1 ng/mL and 189.5 ng/mL respectively, on Cycle 1 day 15, Cycle 2 day 1 and Cycle 3 day 1.Conclusions: Although some toxicities were observed, these data highlight the potential for glasdegib in patients with primary/secondary MF previously treated with JAKi. Following oral administration of 100 mg oral glasdegib once daily to steady state, peak plasma concentrations generally occurred at 1 hour post dose and glasdegib exposures were consistent over multiple cycles of dosing. Modest clinical activity was seen in some patients. [Display omitted] DisclosuresGerds:CTI BioPharma: Consultancy; Incyte: Consultancy. Tauchi:Pfizer Inc: Research Funding. Ritchie:Novartis: Consultancy, Research Funding; Incyte: Honoraria; Celgene: Speakers Bureau; Pfizer Inc: Honoraria. Deininger:Gilead: Research Funding; ARIAD: Consultancy; Ariad Pharmaceuticals, Bristol Myers Squibb, CTI BioPharma Corp, Gilead, Incyte, Novartis, Pfizer, Celgene, Blue Print, Galena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Pfizer: Consultancy; BMS: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy, Research Funding. Jamieson:Johnson and Johnson: Research Funding; GlaxoSmithKline: Research Funding; Celgene: Research Funding; Wintherix: Equity Ownership; Impact Biomedicines: Equity Ownership. Mesa:Novartis: Consultancy; Ariad: Consultancy; Galena: Consultancy; Incyte: Research Funding; Gilead: Research Funding; CTI: Research Funding; Promedior: Research Funding; Celgene: Research Funding. Heaney:Onconova Therapeutics: Research Funding; Novartis: Consultancy. Shaik:Pfizer Inc: Employment. Zhang:Pfizer Inc: Employment. DiRienzo:Pfizer Inc: Employment. Zeremski:Pfizer Inc: Employment. Chan:Pfizer Inc: Employment. Talpaz:Pfizer Inc: Consultancy, Other: Travel, Research Funding; ARIAD: Other: Travel, Research Funding.

Comparative effectiveness and safety of non-tumour necrosis factor biologics and Janus kinase inhibitors in patients with active rheumatoid arthritis showing insufficient response to tumour necrosis factor inhibitors: A Bayesian network meta-analysis of randomized controlled trials.

Both biologic and Janus kinase (JAK) inhibitor therapies have demonstrated substantial effectiveness in placebo-controlled studies in patients with active rheumatoid arthritis (RA) showing inadequate responses to tumour necrosis factor (TNF) inhibitors. The purpose of this study was to determine the relative effectiveness and safety of non-TNF biologics and JAK inhibitors in patients with RA showing insufficient response to TNF inhibitors. A Bayesian network meta-analysis incorporating direct and indirect data from randomized controlled trials (RCTs) was used to investigate the effectiveness and safety of non-TNF biologics (abatacept, rituximab, tocilizumab, salirumab and sirukumab) and JAK inhibitors (tofacitinib, baricitinib, upadacitinib and filgotinib) in patients with RA showing insufficient response to TNF inhibitors. Nine RCTs, evaluating 3577 patients for 12weeks fulfilled the inclusion requirements. JAK inhibitors and non-TNF biologics achieved a significant American College of Rheumatology 20% (ACR20) responserelative to the placebo. The ranking probability based on the surface under the cumulative ranking curve (SUCRA)showed that JAK inhibitor treatment was most likely to achieve the highest ACR20 response rate, followed by non-TNF biologics and placebo. The ACR50 rate displayed similar patterns as the ACR20 response rate, but non-TNF biologics have a higher value than JAK inhibitors based on the ACR70 response rate. Adverse events did not reach statistical significance nor did serious adverse events when looking at safety over 12weeks. The confidence intervals overlap, and there is no clinical significance to these safety data, even compared with placebo. Both non-TNF biologics and JAK inhibitors have similar effects in patients with active RA that are refractory to anti-TNF treatment, and there were no differences with regard to safety among the treatments.

Potential Disease-Modifying Activity of Imetelstat Demonstrated By Reduction in Cytogenetically Abnormal Clones and Mutation Burden Leads to Clinical Benefits in Relapsed/Refractory Myelofibrosis Patients

Potential Disease-Modifying Activity of Imetelstat Demonstrated By Reduction in Cytogenetically Abnormal Clones and Mutation Burden Leads to Clinical Benefits in Relapsed/Refractory Myelofibrosis Patients

Correlation Analyses of Imetelstat Exposure with Pharmacodynamic Effect, Efficacy and Safety in a Phase 2 Study in Patients with Higher-Risk Myelofibrosis Refractory to Janus Kinase Inhibitor Identified an Optimal Dosing Regimen for Phase 3 Study

Correlation Analyses of Imetelstat Exposure with Pharmacodynamic Effect, Efficacy and Safety in a Phase 2 Study in Patients with Higher-Risk Myelofibrosis Refractory to Janus Kinase Inhibitor Identified an Optimal Dosing Regimen for Phase 3 Study

A budget impact analysis for making treatment decisions based on anti-cyclic citrullinated peptide (anti-CCP) testing in rheumatoid arthritis

Aim: Given that rheumatoid arthritis (RA) patients with high anti-citrullinated protein antibodies (ACPA) titer values respond well to abatacept, the aim of this study was to estimate the annual budget impact of anti-cyclic citrullinated peptide (anti-CCP) testing and treatment selection based on anti-CCP test results.Materials and methods: Budget impact analysis was conducted for patients with moderate-to-severe RA on biologic or Janus kinase inhibitor (JAKi) treatment from a hypothetical US commercial payer perspective. The following market scenarios were compared: (1) 90% of target patients receive anti-CCP testing and the results of anti-CCP testing do not impact the treatment selection; (2) 100% of target patients receive anti-CCP testing and the results of anti-CCP testing have an impact on treatment selection such that an increased proportion of patients with high titer of ACPA receive abatacept. A hypothetical assumption was made that the use of abatacept would be increased by 2% in Scenario 2 versus 1. Scenario analyses were conducted by varying the target population and rebate rates.Results: In a hypothetical health plan with one million insured adults, 2,181 patients would be on a biologic or JAKi treatment for moderate-to-severe RA. In Scenario 1, the anti-CCP test cost was $186,155 and annual treatment cost was $101,854,295, totaling to $102,040,450. In Scenario 2, the anti-CCP test cost increased by $20,684 and treatment cost increased by $160,467, totaling an overall budget increase of $181,151. This was equivalent to a per member per month (PMPM) increase of $0.015. The budget impact results were consistently negligible across the scenario analyses.Limitations: The analysis only considered testing and medication costs. Some parameters used in the analysis, such as the rebate rates, are not generalizable and health plan-specific.Conclusions: Testing RA patients to learn their ACPA status and increasing use of abatacept among high-titer ACPA patients result in a small increase in the total budget (<2 cents PMPM).

Efficacy and Safety of Oral Janus Kinase Inhibitors for Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis

Background: Janus kinase (JAK) inhibitors are novel agents for treatment of inflammatory bowel disease. We aimed to determine the efficacy and safety of Janus kinase (JAK) inhibitors for the treatment of Crohn's disease (CD) and ulcerative colitis (UC). Methods: A systematic review and meta-analysis were conducted. PubMed, Embase, and CENTRAL were searched to November 1, 2018 for randomized placebo-controlled trials (RCTs) of JAK inhibitors in adult patients with CD or UC. Clinical, endoscopic, and safety outcomes were extracted and rates relative to placebo were pooled using a random-effects model. Findings: A total of 12 RCTs (5 CD, 7 UC) were included. Patients were randomized to placebo (n=844), tofacitinib (n=1,882), filgotinib (n=130), peficitinib (n=176), upadacitinib (n=387), or TD-1473 (n=31). JAK inhibitor treatment was associated with induction of clinical remission in CD (relative risk RR 1∙38 [95% confidence interval CI 1∙04-1∙83], p=0 ∙025, I2=14%) and UC (RR 3∙07 [95% CI: 2∙03-4∙63], p<0∙001, I2=0%). In UC, JAK inhibitor treatment was associated with induction of endoscopic remission (endoscopic Mayo subscore MCSe=0/1) (RR 2∙43 [95% CI: 1∙64- 3∙59], p<0∙001, I2=27%) and mucosal healing (MCSe=0) (RR 5∙50 [95% CI: 2∙46-12∙32], p<0∙001, I2=0%). JAK inhibitor treatment increased the risk of infection compared to placebo (RR 1∙40 [95% CI: 1∙18-1∙67], p<0∙001, I2=0%), particularly for herpes zoster. All studies were rated as low or unclear risk of bias. Interpretation: JAK inhibitors are effective for induction of clinical and endoscopic remission in CD and UC, although are associated with an increased risk of infectious complications. Funding Statement: There was no funding source for this study. Christopher Ma is supported by a Clinician Fellowship from the Canadian Institutes of Health Research and the Canadian Association of Gastroenterology. Niels Vande Casteele is supported by a Research Scholar Award from the American Gastroenterological Association. Declaration of Interests: Christopher Ma, Jeffrey Lee, Anish Mitra, Anouar Teriaky, and Daksh Choudhary have no conflicts of interest to disclose. Tran Nguyen is an employee of Robarts Clinical Trials, Inc. Niels Vande Casteele has received research support from R-Biopharm and Takeda and consulting fees from Janssen, Pfizer, Progenity, Prometheus, Takeda, and UCB. Reena Khanna has received consulting/speaker fees from AbbVie, Encycle, Janssen, Merck, Pendopharm, Pfizer, Roche, Robarts Clinical Trials, Shire, and Takeda Canada. Remo Panaccione has received scientific advisory board fees from Abbott/AbbVie, Amgen, Janssen, Merck, Pfizer, Prometheus Laboratories, Salix Pharma, Shire, Takeda, and Warner Chilcott, consulting fees from Abbott/AbbVie, Amgen, Aptalis, Astra Zeneca, Baxter, BMS, Centocor, Elan/Biogen, Eisai, Ferring, GSK, Janssen, Merck, Millennium, Pfizer, Proctor & Gamble, Prometheus Therapeutics and Diagnostics, Schering-Plough, Shire, Takeda, UCB Pharma, and Warner Chilcott, research grants from Abbott/AbbVie, Amgen, Aptalis, Astra Zeneca, Baxter, BMS, Centocor, Eisai, Elan/Biogen, Ferring, GSK, Janssen, Merck, Millennium, Pfizer, Proctor & Gamble, Prometheus, Shire, Schering-Plough, Takeda, UCB Pharma, and Warner Chilcott, and speaker’s bureau fees from Abbott/AbbVie, Amgen, Aptalis, Astra Zeneca, Baxter, BMS, Centocor, Eisai, Elan/Biogen, Ferring, GSK, Janssen, Merck, Millennium, Pfizer, Proctor & Gamble, Prometheus, Schering-Plough, Shire, Takeda, UCB Pharma, and Warner Chilcott. Brian Feagan has received grant/research support from Millennium Pharmaceuticals, Merck, Tillotts Pharma AG, AbbVie, Novartis Pharmaceuticals, Centocor Inc., Elan/Biogen, UCB Pharma, Bristol-Myers Squibb, Genentech, ActoGenix, and Wyeth Pharmaceuticals Inc.; consulting fees from Millennium Pharmaceuticals, Merck, Centocor Inc., Elan/Biogen, Janssen440 Ortho, Teva Pharmaceuticals, Bristol-Myers Squibb, Celgene, UCB Pharma, AbbVie, Astra Zeneca, Serono, Genentech, Tillotts Pharma AG, Unity Pharmaceuticals, Albireo Pharma, Given Imaging Inc., Salix Pharmaceuticals, Novonordisk, GSK, Actogenix, Prometheus Therapeutics and Diagnostics, Athersys, Axcan, Gilead, Pfizer, Shire, Wyeth, Zealand Pharma, Zyngenia, GiCare Pharma Inc., and Sigmoid Pharma; and speaker’s fees from UCB, AbbVie, and J&J/Janssen. Vipul Jairath has received consulting fees from AbbVie, Eli Lilly, GlaxoSmithKline, Arena pharmaceuticals, Genetech, Pendopharm, Sandoz, Merck, Takeda, Janssen, Robarts Clinical Trials, Topivert, Celltrion; speaker’s fees from Takeda, Janssen, Shire, Ferring, Abbvie, Pfizer Ethics Approval Statement: PRISMA guidelines referenced.

STAT1 Gain-of-Function Mutations Cause High Total STAT1 Levels With Normal Dephosphorylation.

Signal transducer and activator of transcription (STAT1)1 gain of function (GOF) pathogenic variants have been associated with increased levels of phosphorylated STAT1 and STAT1-dependent cellular responses. Delayed dephosphorylation was proposed as the underlying mechanism leading to the characteristically raised pSTAT1 levels. We examined the levels of STAT1 protein and message as well as rates of STAT1 phosphorylation, dephosphorylation, and degradation associated with STAT1 GOF pathogenic variants. Fresh peripheral blood mononuclear cells (PBMC) from 14 STAT1 GOF patients carrying 10 different pathogenic variants in the coiled-coil, DNA binding, and SH2 domains and healthy donors were used to study STAT1 levels and phosphorylation (pSTAT1) following IFNγ and IFNα stimulation. STAT1 protein levels were measured by flow cytometry and immunoblot. STAT1 mRNA levels were measured using quantitative reverse transcription PCR. STAT1 protein degradation was studied using cycloheximide. Patient IFNγ and IFNα induced peak pSTAT1 was higher than in healthy controls. The velocity of pSTAT1 dephosphorylation after treatment of IFNγ stimulated CD14+ monocytes with the Janus Kinase (JAK)-inhibitor ruxolitinib was significantly faster in patient cells. STAT1 protein levels in patient CD14+ monocytes and CD3+ T cells were higher than in healthy donors. There was a strong and positive correlation between CD14+ STAT1 protein levels and peak pSTAT1 levels. Patient fresh PBMC STAT1 mRNA levels were increased at rest and after 16 h of incubation. STAT1 protein degradation was similar in patient and healthy volunteer cells. Patient IFNγ receptors 1 and 2 and JAK2 levels were normal. One patient in our cohort was treated with the oral JAK inhibitor ruxolitinib. Treatment was associated with normalization of both STAT1 protein and peak pSTAT1 levels. After JAK inhibitor treatment was stopped the patient's CD14+ monocyte STAT1 protein and peak phosphorylation levels increased proportionally. These findings suggest that patients with STAT1 GOF mutations have higher levels of total STAT1 protein, leading to high levels of pSTAT1 after stimulation, despite rapid STAT1 dephosphorylation and normal degradation.

PS1456 FAVORABLE OVERALL SURVIVAL OF IMETELSTAT‐TREATED RELAPSED/REFRACTORY MYELOFIBROSIS PATIENTS COMPARED WITH CLOSELY MATCHED REAL WORLD DATA

Background:Myelofibrosis (MF), particularly Intermediate‐2 (Int‐2) or High‐Risk disease, is a life‐threatening disease for which the Janus Kinase inhibitor (JAKi), ruxolitinib, is currently the only approved therapy. Currently, there is no approved or effective therapy for patients (pts) who lack or lose response to ruxolitinib, and these pts have a notably poor prognosis (median overall survival [OS] 12–14 mo) (Kuykendall et al Ann Hematol 2018; Newberry et al Blood 2017). Imetelstat, a 13‐mer oligonucleotide that specifically targets the RNA template of human telomerase, is a potent competitive inhibitor of telomerase enzymatic activity. In a Phase 2 study of imetelstat (2 doses) in JAKi‐relapsed/refractory (R/R) Int‐2 or High‐Risk MF (MYF2001; NCT02426086), spleen volume reduction and total symptom score improvements and median OS of 29.9 mo (95% CI 22.8, NE) were observed in the 9.4 mg/kg arm (Mascarenhas et al ASH 2018 #685).Aims:To further assess the potential OS benefit of imetelstat, pts treated with 9.4 mg/kg in MYF2001 were compared to a closely matched patient population from real‐world data (RWD), treated contemporaneously.Methods:MYF2001 pts had MF that was R/R to JAKi, defined as documented progressive disease (PD) during or after JAKi treatment. For the historical control, external RWD were collected from a single‐center study which included 114 pts who had discontinued ruxolitinib. A closely matched cohort was identified using the guidelines for inclusion and exclusion criteria as defined in MYF2001 protocol and consisted of pts with MF who had discontinued JAKi due to lack or loss of response and were subsequently treated with best available therapy (BAT) at the Moffitt Cancer Center.OS was measured from the time of JAKi discontinuation to death or censored at last follow‐up. To improve comparability, propensity score weighting approaches using average treatment effect for overlap population (ATO) and stabilized inverse probability treatment weighting (sIPTW) methods were used for critical baseline covariates (age, platelet count, time from diagnosis to JAKi discontinuation, JAKi duration, spleen size, sex, DIPSS score, ECOG, MF type, transfusion status, JAK2 mutation). Sensitivity analyses (to address early deaths post JAKi discontinuation observed in the RWD and the impact of subsequent transplant on OS) were explored to enhance the robustness of the results.Results:57 pts (treated with imetelstat 9.4 mg/kg) from MYF2001 and 38 pts treated with BAT from RWD (median follow‐up, 23 and 43 mo, respectively) were analyzed with improved balanced baseline covariates after propensity score adjustment. Overlap weighting results (ATO) are summarized in the Figure, showing a 65% lower risk of death with imetelstat vs BAT (hazard ratio [HR], 0.35; 95% CI 0.18, 0.68; P = 0.0019). Sensitivity analysis results were consistent with the primary findings. With sIPTW, median OS was 30.69 mo (95% CI 25.2, not estimable) with imetelstat vs 12.04 mo (95% CI 9.5, 16.6) with BAT (HR, 0.33; 95% CI 0.18, 0.61; P = 0.0003), with 12‐mo OS rates of 85% and 52%, respectively and 24‐mo OS rates of 66% and 24%, respectively.Summary/Conclusion:These analyses showed that treatment with imetelstat was associated with a lower risk of death compared to BAT in closely matched pts with Int‐2 or High‐Risk MF after JAKi failure. Despite the limitations of such comparative analyses, this bridging of RWD with clinical trial data suggests favorable OS of imetelstat treatment in this very poor‐prognosis population and warrants further evaluation.image