scholarly journals Efficacy of JAK inhibitors in Crohn’s Disease

2019 ◽  
Vol 14 (Supplement_2) ◽  
pp. S746-S754 ◽  
Author(s):  
Gerhard Rogler
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Clinical Development ◽  
Phase Iii ◽  
Jak Inhibitor ◽  
Jak Inhibitors ◽  
Janus Kinases ◽  
Double Blinded

Abstract Inhibition of Janus kinases [JAKs] in Crohn’s disease [CD] patients has shown conflicting results in clinical trials. Tofacitinib, a pan-JAK inhibitor, showed efficacy in ulcerative colitis [UC] and has been approved for the treatment of patients with moderate to severe UC. In contrast, studies in CD patients were disappointing and the primary end point of clinical remission could not be met in the respective phase II induction and maintenance trials. Subsequently, the clinical development of tofacitinib was discontinued in CD. In contrast, efficacy of filgotinib, a selective JAK1 inhibitor, in CD patients was demonstrated in the randomized, double-blinded, placebo-controlled phase II FITZROY study. Upadacitinib also showed promising results in a phase II trial in moderate to severe CD. Subsequently, phase III programmes in CD have been initiated for both substances, which are still ongoing. Several newer molecules of this class of orally administrated immunosuppressants are being tested in clinical programmes. The concern of side effects of systemic JAK inhibition is addressed by either exclusively intestinal action or higher selectivity [Tyk2 inhibitors]. In general, JAK inhibitors constitute a new promising class of drugs for the treatment of CD.

scholarly journals AB0332 IMMUNOSUPPRESSIVE AND IMMONOMODULATING AGENTS IN RHEUMATOID ARTHRITIS: A SYSTEMATIC REVIEW OF CLINICAL TRIALS AND THEIR CURRENT DEVELOPMENT STAGE

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1464.1-1465
Author(s):  
J. Blaess ◽  
J. Walther ◽  
J. E. Gottenberg ◽  
J. Sibilia ◽  
L. Arnaud ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Systematic Review ◽  
B Cells ◽  
Phase I ◽  
Phase Ii ◽  
Clinical Development ◽  
Phase Iii ◽  
Jak Inhibitors ◽  
Exclusion Criteria ◽  
Immunomodulating Drugs

Background:Rheumatoid arthritis (RA) is the most frequent chronic inflammatory diseases with an incidence of 0.5% to 1%. Therapeutic arsenal of RA has continuously expanded in recent years with the recent therapeutic progress with the arrival of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), biological (bDMARDs) and targeted synthetic (tsDMARDs), JAK inhibitors. However, there are still some unmet needs for patients who do not achieve remission and who continue to worsen despite treatments. Of note, only approximately 40% of patients are ACR70 responders, in most randomized controlled trials. For these patients, finding new therapeutic avenues is challenging.Objectives:The objective of our study was to analyze the whole pipeline of immunosuppressive and immunomodulating drugs evaluated in RA and describe their mechanisms of action and stage of clinical development.Methods:We conducted a systematic review of all drug therapies in clinical development in RA in 17 databases of international clinical trials. Inclusion criterion: study from one of the databases using the keywords “Rheumatoid arthritis” (search date: June 1, 2019). Exclusion criteria: non-drug trials, trials not related to RA or duplicates. We also excluded dietary regimen or supplementations, cellular therapies, NSAIDs, glucorticoids or their derivatives and non-immunosuppressive or non-immunomodulating drugs. For each csDMARD, bDMARD and tsDMARD, we considered the study at the most advanced stage. For bDMARDs, we did not take into account biosimilars.Results:The research identified 4652 trials, of which 242 for 243 molecules met the inclusion and exclusion criteria. The developed molecules belong to csDMARDs (n=21), bDMARDs (n=117), tsDMARDs (n=105).Among the 21 csDMARDs molecules: 8 (38%) has been withdrawn, 4 (19%) are already labelled in RA (hydroxychloroquine, leflunomide, methotrexate and sulfasalazine) and 9 (43%) are in development: 1 (11%) is in phase I/II, 5 (56%) in phase II, 3 (33%) in phase IV.Among the 117 bDMARDs molecules: 69 (59%) has been withdrawn, 9 (8%) are labeled in RA (abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, rituximab, sarilumab, tocilizumab) and 39 (33%) are in development: 9 (23%) in phase I, 3 (8%) in phase I/II, 21 (54%) in phase II, 5 (12%) are in phase III, 1 (3%) in phase IV. bDMARDs currently under development target B cells (n=4), T cells (n=2), T/B cells costimulation (n=2),TNF alpha (n=2), Interleukine 1 or his receptor (n=3), Interleukine 6 or his receptor (n=7), Interleukine 17 (n=4), Interleukine 23 (n=1), GM-CSF (n=1), other cytokines or chemokines (n=5), integrins or adhesion proteins (n=3), interferon receptor (n=1) and various other targets (n=4).Among the 105 tsDMARDs molecules: 64 (61%) has been withdrawn, 6 (6%) JAK inhibitors, have just been or will probably soon be labelled (baricitinib, filgotinib, peficitinib, tofacitinib and upadacitinib), 35 (33%) are in development: 8 (24%) in phase I, 26 (74%) in phase II, 1 (3%) in phase III and. tsDMARDs currently under development target tyrosine kinase (n=12), janus kinase (JAK) (n=3), sphingosine phostate (n=3), PI3K pathway (n=1), phosphodiesterase-4 (n=3) B cells signaling pathways (n=3) and various other targets (n=10).Conclusion:A total of 242 therapeutic trials involving 243 molecules have been or are being evaluated in RA. This development does not always lead to new treatments since 141 (58%) have already been withdrawn. Hopefully, some of the currently evaluated drugs will contribute to improve the therapeutic management of RA patients, requiring a greater personalization of therapeutic strategies, both in the choice of molecules and their place in therapeutic sequences.Disclosure of Interests:Julien Blaess: None declared, Julia Walther: None declared, Jacques-Eric Gottenberg Grant/research support from: BMS, Pfizer, Consultant of: BMS, Sanofi-Genzyme, UCB, Speakers bureau: Abbvie, Eli Lilly and Co., Roche, Sanofi-Genzyme, UCB, Jean Sibilia: None declared, Laurent Arnaud: None declared, Renaud FELTEN: None declared

scholarly journals Ustekinumab Safety in Psoriasis, Psoriatic Arthritis, and Crohn’s Disease: An Integrated Analysis of Phase II/III Clinical Development Programs

Drug Safety ◽  
2019 ◽  
Vol 42 (6) ◽  
pp. 751-768 ◽  
Author(s):  
Subrata Ghosh ◽  
Lianne S. Gensler ◽  
Zijiang Yang ◽  
Chris Gasink ◽  
Soumya D. Chakravarty ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Psoriatic Arthritis ◽  
Crohn's Disease ◽  
Phase Ii ◽  
Clinical Development ◽  
Integrated Analysis ◽  
Development Programs

scholarly journals Correction to: Ustekinumab Safety in Psoriasis, Psoriatic Arthritis, and Crohn’s Disease: An Integrated Analysis of Phase II/III Clinical Development Programs

Drug Safety ◽  
2019 ◽  
Vol 42 (6) ◽  
pp. 809-809 ◽  
Author(s):  
Subrata Ghosh ◽  
Lianne S. Gensler ◽  
Zijiang Yang ◽  
Chris Gasink ◽  
Soumya D. Chakravarty ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Psoriatic Arthritis ◽  
Crohn's Disease ◽  
Phase Ii ◽  
Clinical Development ◽  
Integrated Analysis ◽  
Development Programs

scholarly journals A double-blinded randomised placebo-controlled phase II trial to evaluate high dose rifampicin for tuberculous meningitis: a dose finding study

2018 ◽  
Author(s):  
S Dian ◽  
V Yunivita ◽  
AR Ganiem ◽  
T Pramaesya ◽  
L Chaidir ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Tuberculous Meningitis ◽  
Phase Ii Trial ◽  
Standard Dose ◽  
Geometric Mean ◽  
Dose Finding ◽  
Phase Iii ◽  
High Dose ◽  
Double Blinded

ABSTRACTBackgroundHigh doses of rifampicin may help tuberculous meningitis (TBM) patients to survive. Pharmacokinetic-pharmacodynamic evaluations suggested that rifampicin doses higher than 13 mg/kg intravenously or 20 mg/kg orally (as previously studied) are warranted to maximize treatment response.MethodsIn a double-blinded, randomised, placebo-controlled phase II trial, we assigned 60 adult TBM patients in Bandung, Indonesia, to standard 450 mg, 900 mg or 1350 mg (10, 20 and 30 mg/kg) oral rifampicin combined with other TB drugs for 30 days. Endpoints included pharmacokinetic measures, adverse events and survival.ResultsA double and triple dose of oral rifampicin led to three and five-fold higher geometric mean total exposures in plasma in the critical early days (2±1) of treatment (AUC0-24h: 53·5 mg.h/L vs 170·6 mg.h/L vs. 293·5 mg.h/L, p<0·001), with proportional increases in CSF concentrations and without an increase in the incidence of grade 3/4 adverse events. Six-month mortality was 7/20 (35%, 9/20 (45%) and 3/20 (15%) in the 10, 20 and 30 mg/kg groups, respectively (p=0·12).ConclusionsTripling the standard dose caused a large increase in rifampicin exposure in plasma and CSF and was safe. Survival benefit with this dose should now be evaluated in a larger phase III clinical trial.

scholarly journals Myelofibrosis Drug Development through the Decade: Novel JAK Inhibitors

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5477-5477
Author(s):  
Ali Younas Khan ◽  
Muhammad Junaid Tariq ◽  
Muhammad Usman ◽  
Awais Ijaz ◽  
Abdul Rafae ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Phase I Trial ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasm ◽  
Phase Iii ◽  
Jak Inhibitor ◽  
Jak Inhibitors ◽  
Phase Iii Trial ◽  
Grade 3

Abstract Introduction Myelofibrosis (MF), a BCR-ABL negative myeloproliferative neoplasm (MPN), has an annual incidence of 1 in 100000 for the primary MF and 0.3-0.7 in 100000 for secondary MF in the USA. MF patients have a median survival of 6.5 years. The primary mutation, JAK2V617F, occurs in 40-60% of MF cases. Ruxolotinib, a JAK inhibitor, has been the mainstay in treating high risk, debilitating MF but largely clinical needs are unmet. Methods A comprehensive literature research was performed using PubMed, Cochrane, EMBASE, Web of Science and Clinicaltrials.gov. We included all trials that were under development in phase I/II/III trials. Our search identified 1642 full-length manuscripts or abstracts with published results in the last decade ( Jan 2007 till Dec 2017) were screened for relevant studies. After screening by 2 independent reviewers, 212 articles were finalized for our final analyses. We have reviewed the mechanism of action, safety and efficacy of 2nd generation JAK inhibitors in this review. Results JAK1 inhibitor: Itacitinib reduced total symptom score (TSS) ≥ 50% in 15/42 (36%) patients. Mild gastrointestinal (GI) disturbances and some grade 3-4 myelosuppression (anemia: 33%, thrombocytopenia: 29%) were reported. JAK2 inhibitors: In PERSIST-1, pacritinib when compared to best available therapy (BAT) showed SVR ≥ 35% in 19.1% vs. 4.7% patients, with lower rates of myelosuppression (thrombocytopenia: 17%, anemia: 11%). In PERSIST-2, a phase III trial of pacritinb vs. BAT in patients with baseline cytopenias, similar efficacy was demonstrated (SVR ≥ 35%: 18% vs. 3%). Increasing rates of heart failure and intracranial hemorrhages led to a temporary hold which was lifted in August 2017. Lestaurtinib showed CI in 7 (44%) patients in a phase I trial (n=16) and 6 (27%) patients in a phase II trial (n=22). Most notable toxicities were G 1/2 GI disturbances, anemia occurred in 14% and thrombocytopenia in 23% of patients. In a phase III trial (n=193), fedratinib showed a SVR ≥ 35% and a TSS ≥ 50% in 40% and 36% patients, respectively. However, incidence of significant neurotoxicity and Wernicke's encephalopathy led to its suspension. Similarly, a trial of XL019 was terminated due to emergence of central and peripheral neurotoxicity. In a phase I trial (n=48), NS-018 exhibited a spleen length reduction (SLR) ≥ 50% in 20 (56%) patients along with prompt improvement in bone marrow fibrosis (37%). Anemia and thrombocytopenia were reported in 15% and 27% of patients, respectively. Dizziness (23%) and nausea (19%) were also reported. Gandotinib demonstrated SLR ≥50% in 62% patients, in a phase I trial (n=38). G1 diarrhea (55.3%) and nausea (42.1%) were the most common toxicities. JAK 1/2 inhibitors: SIMPLIFY-1 (S1), a phase III clinical trial (n=432) of momelotinib vs. ruxolotinib in JAK inhibitor-naïve patients, demonstrated non-inferiority for momelotinib, in spleen volume reduction (SVR) ≥ 35% (26.5% vs. 29%; p=0.01). However, SIMPLIFY-2 trial (S2), that compared these two drugs in JAK inhibitor exposed patients did not achieve similar responses with momelotinib (6.7% vs. 5.8%; p=0.90). Interestingly, momelotinib excelled at achieving transfusion independency in both trials (S1: 66.5% vs. 49.3%; p=0.001, S2: 43.3% vs 21.2%; p=0.001). Grade ≥ 3 infections and peripheral neuropathy were the major toxicities noted. These trials were suspended after 89% of patients failed to achieve the primary endpoint of SVR. AZD1480 demonstrated clinical improvement (CI) in four (11%) patients in a phase I trial (n=35). Most common adverse events included grade (G) 1-2 dizziness and anemia. Conclusion Novel JAK pathway inhibitors have shown promising efficacy in MF but safety concerns regarding the hematological (cytopenias) and non-hematological adverse effects needs to be addressed until their use in clinical practice is established. Momelotinib success in achieving anemia related endpoints is note-worthy and should be further explored in this regard. A phase II study [NCT03165734] evaluating pacritinib monotherapy as a second line treatment in patients with baseline thrombocytopenia is ongoing. Disclosures No relevant conflicts of interest to declare.

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