Outcomes of pregnancies from the tildrakizumab phase I–III clinical development programme

2020 ◽  
Vol 183 (1) ◽  
pp. 184-186
Author(s):  
K. Haycraft ◽  
D. DiRuggiero ◽  
S.J. Rozzo ◽  
A.M. Mendelsohn ◽  
T. Bhutani
Keyword(s):  
Phase I ◽  
Development Programme ◽  
Clinical Development

scholarly journals Long-term safety of tofacitinib up to 9.5 years: a comprehensive integrated analysis of the rheumatoid arthritis clinical development programme

RMD Open ◽  
2020 ◽  
Vol 6 (3) ◽  
pp. e001395 ◽  
Author(s):  
Stanley B Cohen ◽  
Yoshiya Tanaka ◽  
Xavier Mariette ◽  
Jeffrey R Curtis ◽  
Eun Bong Lee ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Phase I ◽  
Safety Analysis ◽  
Development Programme ◽  
Clinical Development ◽  
Janus Kinase ◽  
Phase Iii ◽  
Jak Inhibitor ◽  
Link Type

ObjectiveTofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). We report the largest integrated safety analysis of tofacitinib, as of March 2017, using data from phase I, II, III, IIIb/IV and long-term extension studies in adult patients with RA.MethodsData were pooled for patients with RA who received ≥1 tofacitinib dose. Incidence rates (IRs; patients with events/100 patient-years [PY]; 95% CIs) of first-time occurrences were obtained for adverse events (AEs) of interest.Results7061 patients received tofacitinib (total exposure: 22 875 PY; median [range] exposure: 3.1 [0 to 9.6] years). IRs (95% CI) for serious AEs, serious infections, herpes zoster (all), opportunistic infections (excluding tuberculosis [TB]) and TB were 9.0 (8.6 to 9.4), 2.5 (2.3 to 2.7), 3.6 (3.4 to 3.9), 0.4 (0.3 to 0.5) and 0.2 (0.1 to 0.2), respectively. IRs (95% CI) for malignancies (excluding non-melanoma skin cancer [NMSC]), NMSC and lymphomas were 0.8 (0.7 to 0.9), 0.6 (0.5 to 0.7) and 0.1 (0.0 to 0.1), respectively. IRs (95% CI) for gastrointestinal perforations, deep vein thrombosis, pulmonary embolism, venous thromboembolism, arterial thromboembolism and major adverse cardiovascular events were 0.1 (0.1 to 0.2), 0.2 (0.1 to 0.2), 0.1 (0.1 to 0.2), 0.3 (0.2 to 0.3), 0.4 (0.3 to 0.5) and 0.4 (0.3 to 0.5), respectively. IR (95% CI) for mortality was 0.3 (0.2 to 0.3). IRs generally remained consistent across 6-month intervals to >78 months.ConclusionThis represents the largest clinical dataset for a JAK inhibitor in RA to date. IRs remained consistent with previous reports from the tofacitinib RA clinical development programme, and stable over time.Trial registration numbersNCT01262118; NCT01484561; NCT00147498; NCT00413660; NCT00550446; NCT00603512; NCT00687193; NCT01164579; NCT00976599; NCT01059864; NCT01359150; NCT02147587; NCT00960440; NCT00847613; NCT00814307; NCT00856544; NCT00853385; NCT01039688; NCT02187055; NCT00413699; NCT00661661.For summary of phase I, phase II, phase III, phase IIIb/IV and LTE studies included in the integrated safety analysis, see online supplemental table 1.

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 Ligelizumab treatment for severe asthma: learnings from the clinical development programme

2021 ◽  
Vol 10 (3) ◽  
Author(s):  
Jordis Trischler ◽  
Ivan Bottoli ◽  
Reinhold Janocha ◽  
Christoph Heusser ◽  
Xavier Jaumont ◽  
...  
Keyword(s):  
Severe Asthma ◽  
Development Programme ◽  
Clinical Development

Clinical Development Programme for Omeprazole

Digestion ◽  
1990 ◽  
Vol 47 (1) ◽  
pp. 54-58 ◽  
Author(s):  
A. Walan
Keyword(s):  
Development Programme ◽  
Clinical Development

The first recombinant FVIII produced in human cells - an update on its clinical development programme

Haemophilia ◽  
2013 ◽  
Vol 20 ◽  
pp. 1-9 ◽  
Author(s):  
L. A. Valentino ◽  
C. Negrier ◽  
G. Kohla ◽  
A. Tiede ◽  
R. Liesner ◽  
...  
Keyword(s):  
Development Programme ◽  
Clinical Development ◽  
Human Cells ◽  
Recombinant Fviii

scholarly journals Measuring outcomes in ultra-rare bone diseases: Methodology of the palovarotene fibrodysplasia ossificans progressiva clinical development programme

Bone Reports ◽  
2020 ◽  
Vol 13 ◽  
pp. 100609
Author(s):  
Robert J. Pignolo ◽  
Geneviève Baujat ◽  
Matthew A. Brown ◽  
Carmen De Cunto ◽  
Maja Di Rocco ◽  
...  
Keyword(s):  
Bone Diseases ◽  
Development Programme ◽  
Clinical Development ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Measuring Outcomes ◽  
Rare Bone Diseases

BIOEQUIVALENCE of a BIOSIMILAR FILGRASTIM and REFERENCE FILGRASTIM: IMPACT ON the MOBILIZATION of CD34+ PERIPHERAL BLOOD PROGENITOR CELLS in a RANDOMIZED, PHASE I STUDY.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4564-4564
Author(s):  
Miguel H Bronchud ◽  
Cornelius F Waller ◽  
Stuart J Mair ◽  
Rodeina Challand
Keyword(s):  
Phase I ◽  
Cell Count ◽  
Progenitor Cells ◽  
Clinical Development ◽  
Post Dose ◽  
Double Blind ◽  
Hematopoietic Stem ◽  
Cell Counts ◽  
Peripheral Blood Progenitor Cells ◽  
Biosimilar Filgrastim

Abstract Abstract 4564 Background Granulocyte colony-stimulating factor (G-CSF) stimulates the proliferation and differentiation of hematopoietic stem and progenitor cells. Recombinant human G-CSF (filgrastim) was developed by Amgen to enhance mobilization of peripheral blood progenitor cells (PBPCs) prior to autologous or allogeneic hematopoietic stem/progenitor cell transplantation. After the patent expiry of Amgen filgrastim (Neupogen®), Hospira developed a biosimilar filgrastim. Preclinical and phase I studies supported the bioequivalence of Hospira filgrastim and Amgen filgrastim in terms of their physicochemical, pharmacokinetic and pharmacodynamic characteristics (Skrlin A, et al. EHA 2009, Abstract 0568; Waller CF, et al. EHA 2009, Abstract 0562). Here we compare the impact of Hospira filgrastim and Amgen filgrastim on CD34+ PBPC mobilization in a randomized, double-blind phase I study. Aim To demonstrate the bioequivalence of Hospira filgrastim and Amgen filgrastim with respect to the mobilization of CD34+ PBPCs. Methods Healthy, male or female volunteers aged 18–50 years were enrolled at Charles River Clinical Services, Edinburgh, UK, between 2 November 2006 and 24 January 2007. Using a computer-generated randomization list, volunteers were first randomized to 5μg/kg or 10μg/kg dose groups, before further randomization to order of agent administration. Subcutaneous injections of Hospira filgrastim or Amgen filgrastim were administered under double-blind conditions on five consecutive days (days 1–5), with crossover to the alternative agent after a washout period of ≥13 days. Blood samples were taken at day 1 (pre dose), day 3 (6 hours [h] post dose), day 5 (6 h post dose), day 7 (48 h post dose) and day 10 (120 h post dose). Mean CD34+ cell counts were evaluated by flow cytometry and bioequivalence was assessed using a mixed effects analysis of variance model. Bioequivalence was concluded if the 90% confidence intervals (CI) for the ratio of ‘test’ (Hospira filgrastim) to ‘reference’ (Amgen filgrastim) mean CD34+ cell counts at day 5 were completely within the conventional bioequivalence limits of 0.80–1.25. Results Twenty-four volunteers were randomized to the 5μg/kg group and 26 to the 10μg/kg group. At both doses, CD34+ cell counts were similar with Hospira filgrastim and Amgen filgrastim across all time points. Regardless of agent or dose, mean CD34+ cell count at day 1 was 2.2–2.8 cells/μl, increasing to a maximum count at day 5. In the 5μg/kg group, mean CD34+ cell count at day 5 (n=24) was 47.2 cells/μl (95% CI: 36.1, 61.7) with Hospira filgrastim and 46.0 cells/μl (95% CI: 33.6, 63.0) with Amgen filgrastim. In the 10μg/kg group, mean CD34+ cell count at day 5 (n=23) was 81.9 cells/μl (95% CI: 64.5, 104.0) with Hospira filgrastim and 77.5 cells/μl (95% CI: 59.4, 101.3) with Amgen filgrastim (Figure 1). At both doses, 90% CIs for the ratios of test to reference mean CD34+ cell counts at day 5 were within the predefined range required to demonstrate bioequivalence. The incidence of adverse events (AEs) was slightly lower with Hospira filgrastim than with Amgen filgrastim at both doses (5μg/kg, 79 vs 83%; 10μg/kg, 77 vs 92%). The most frequently reported AEs of any severity (mild/moderate/severe) with each agent at each dose were back pain (38–62%) and headache (44–58%), which could be treated with standard analgesics. Conclusions Hospira filgrastim and Amgen filgrastim are similar in their ability to stimulate mobilization of CD34+ PBPCs. These data add to a growing body of evidence in support of the bioequivalence of these agents. Hospira filgrastim may provide a useful alternative to Amgen filgrastim as a growth factor to support PBPC mobilization and transplantation. The bioequivalence of these agents may enable Hospira filgrastim to be used without the need to adapt PBPC harvesting protocols. The continued clinical development of Hospira filgrastim is warranted. Acknowledgments Medical writing support provided by Hannah FitzGibbon (GeoMed) with financial support from Hospira. Disclosures: Bronchud: Hospira UK Ltd: Consultancy. Waller:Hospira UK Ltd: Consultancy. Off Label Use: Hospira filgrastim is a biosimilar filgrastim that is in clinical development for the treatment of neutropenia associated with cytotoxic chemotherapy.. Mair:Charles River Clinical Services: Employment. Challand:Hospira UK Ltd: Employment.

Role of pharmacogenetic studies in early clinical development: Phase I studies with lapatinib

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3029-3029 ◽  
Author(s):  
T. Z. Zaks ◽  
A. Akkari ◽  
L. Briley ◽  
M. Mosteler ◽  
A. G. Stead ◽  
...  
Keyword(s):  
Phase I ◽  
Healthy Volunteers ◽  
Kinase Inhibitor ◽  
Clinical Development ◽  
Pharmacokinetic Data ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Phase I Studies ◽  
Clinical Drug Development

3029 Background: Rash and diarrhea are a class effect of ERBB1 inhibitors. These events are relatively mild with Lapatinib (a dual ERBB1/ERBB2 kinase inhibitor). Finding a genetic basis for patients who may be predisposed to these adverse events, from the outset of clinical development, may improve the understanding of the mechanisms of these side effects and may have implications for use and dosing. Methods: DNA was isolated from peripheral blood of 107 Caucasian subjects from eight monotherapy phase I studies including 73 healthy volunteers and 34 cancer patients, 100 of whom had associated pharmacokinetic data. 284 single nucleotide polymorphisms (SNPs) from five candidate genes of transporters (ABCB1, ABCG2) and enzymes (CYP 3A4 and 3A5, and 2C19) for which lapatinib is a substrate were genotyped and examined for associations with pharmacokinetic variables (dose-normalized AUC, Cmax, and Tmax) as well as rash (15 cases) and diarrhea (18 cases). Results: Skin rash and diarrhea in this phase I cohort were only mild, (i.e. grade I or II). Statistically significant associations were observed between 34 SNPs in CYP2C19, rash (22 SNPs) and diarrhea (6 SNPs), and between 15 SNPs in ABCB1 and Tmax. Notably, 3/3 subjects (2 healthy volunteers, one patient) homozygous for the CYP2C19*2 allele experienced both mild rash and diarrhea. Extensive linkage disequilibrium was observed among these associated SNPs. Conclusions: Our results suggest that it is possible to determine pharmacogenetic associations with side effect phenotypes during the earliest phase of clinical drug development. These results are currently being validated on a larger cohort of patients from phase II lapatinib clinical trials. [Table: see text]

Phase I study of BPM31510 and vitamin K in patients with high grade glioma recurrent after a bevacizumab-containing regimen.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 2543-2543
Author(s):  
Seema Nagpal ◽  
Reena Parada Thomas ◽  
Sophie Bertrand ◽  
Hari Priya Yerraballa ◽  
Michael Iv ◽  
...  
Keyword(s):  
Phase I ◽  
Vitamin K ◽  
Phase I Study ◽  
High Grade Glioma ◽  
Clinical Development ◽  
High Grade ◽  
Open Label ◽  
Tumor Bed ◽  
Mitochondrial Superoxide ◽  
Open Label Phase

2543 Background: BPM31510 is an ubidecarenone-lipid conjugate nanodispersion in clinical development for advanced malignancies, including high grade glioma (HGG). BPM31510’s anti-cancer effect is mediated by induction of mitochondrial superoxide and activation of cell death in glioblastoma models. Herein, we present preliminary pharmaco-kinetic and dynamic data, and survival from a phase I study of BPM31510 + Vitamin K in HGG with progression after bevacizumab (BEV). Methods: This was an open-label phase I study of BPM31510 continuous infusion with Vitamin K (10mg IM qweek) using a mTPI design, starting at 110mg/kg 2X/week, allowing 2 dose escalations & 1 de-escalation. Patients had received ChemoRT and were in recurrence after BEV. Results: Of 12 patients treated with BPM31510, 9 completed the 28-day DLT period. 2 patients came off study for progressive disease; 1 patient after asymptomatic hemorrhage into tumor bed (G1). 10 patients had primary GB, 2 had AA. Median age was 54.5yo (27-67) and KPS 70 (60-90). On Day 1 of BPM31510, a dose dependent increase in Cmax was observed; Tmax values were similar for all doses. AUC was linear with dose escalation. For all doses, Day 4 Cmax values were higher compared to Day 1. In contrast there was variable decrease in Tmax (table). Of evaluable patients, 4 patients received the highest dose 171mg/kg, where a single patient experienced DLT: G3 AST & ALT. The most common grade 1/2 AEs were elevated AST, rash, and fatigue, each occurring in 4 patients. The mOS for 9 eligible/evaluable patients was 128 days (95% CI: 48-209) while PFS was 34 days (95% CI of mean 8.9). Two patients are currently alive >12 months. Conclusions: BPM31510 + vitamin K demonstrated a safe profile to maximum dose of 171mg/kg twice/week with potential therapeutic utility in treatment-refractory HGG patients. Multi-omic molecular profiles characterizing AE and response to be reported from the study will be investigated for next phase of clinical development. Clinical trial information: NCT03020602 . [Table: see text]

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