Safety, pharmacokinetics and pharmacodynamics of single rising doses of BI 655064, an antagonistic anti-CD40 antibody in healthy subjects: a potential novel treatment for autoimmune diseases

Albach, Fredrik N.; Wagner, Frank; Hüser, Andreas; Igel, Julia; Joseph, David; Hilbert, James; Schoelch, Corinna; Padula, Steven J.; Steffgen, Jürgen

doi:10.1007/s00228-017-2362-8

Cited by 33 publications

(38 citation statements)

References 31 publications

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“…26 These observations suggest that these events are independent of CD40 and are consistent with emerging clinical data (including this study), where to date, no such events have been attributable to iscalimab or other anti-CD40 antibodies. 27,28 Thus, specific targeting of CD40 receptor itself by iscalimab and the absence of thromboembolic events in clinical studies suggest clear differentiation between antibodies targeting CD40 or CD154.…”

Section: Discussionmentioning

confidence: 99%

“…This is in stark contrast to a recent FIH study with the anti-CD40 mAb BI655064 where ≈40% of subjects were found to be anti-drug antibody-positive after treatment. 27 The PK/PD data of single IV or SC doses of iscalimab in HS or RA patients indicated that iscalimab was subject to FcRn-mediated disposition (receptors responsible for IgG homeostasis by recycling/ salvage 29,30 ) as well as TMDD. TMDD is a process in which a substantial proportion of the drug (relative to dose) is bound to its target, affecting the disposition of the drug per se.…”

Section: Discussionmentioning

confidence: 99%

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First-in-human clinical trial to assess pharmacokinetics, pharmacodynamics, safety, and tolerability of iscalimab, an anti-CD40 monoclonal antibody

Espié

Koo

et al. 2020

American Journal of Transplantation

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Pascal Espié and YanLing He are co-first authors who have contributed equally to the work. James S. Rush and Peter Gergely have contributed equally to the work.Clinical Trial Registration Number: NCT02089087.Abbreviations: AEs, adverse events; AUC last , area under the plasma concentration-time curve from time zero to the last quantifiable concentration; BLQ, below limit of quantification;Iscalimab is a fully human, CD40 pathway blocking, nondepleting monoclonal antibody being developed as an immunosuppressive agent. We describe a first-in-human, randomized, double-blind, placebo-controlled study investigating the safety, tolerability, pharmacokinetics, and pharmacodynamics of iscalimab in healthy subjects and rheumatoid arthritis patients. Healthy subjects (n = 56) received single doses of intravenous iscalimab (0.03, 0.1, 0.3, 1, or 3 mg/kg), or subcutaneous iscalimab (3 mg/kg), or placebo. Rheumatoid arthritis patients (n = 20) received single doses of intravenous iscalimab (10 or 30 mg/kg) or placebo. Iscalimab exhibited target-mediated drug disposition resulting in dose-dependent and nonlinear pharmacokinetics. Complete (≥90%) CD40 receptor occupancy on whole blood B cells was observed at plasma concentrations >0.3-0.4 µg/mL. In subjects receiving 3 mg/kg iscalimab, antibody responses to keyhole limpet hemocyanin were transiently suppressed. CD40 occupancy by iscalimab prevented ex vivo human rCD154-induced expression of CD69 on B cells in whole blood. All doses were generally safe and well tolerated, with no clinically relevant changes in any safety parameters, including no evidence of thromboembolic events. Iscalimab appears to be a promising blocker of the CD40-CD154 costimulatory pathway with potential use in transplantation and other autoimmune diseases. K E Y W O R D S clinical research/practice, clinical trial, immunosuppressant -fusion proteins and monoclonal antibodies: B cell specific, immunosuppression/immune modulation, translational research/ science S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section. How to cite this article: Espié P, He Y, Koo P, et al. First-inhuman clinical trial to assess pharmacokinetics, pharmacodynamics, safety, and tolerability of iscalimab, an anti-CD40 monoclonal antibody. Am J Transplant. 2020;20: 463-473. https ://doi.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

First-in-human clinical trial to assess pharmacokinetics, pharmacodynamics, safety, and tolerability of iscalimab, an anti-CD40 monoclonal antibody

Espié

Koo

et al. 2020

American Journal of Transplantation

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“…The weekly subcutaneous 120 mg dose of BI 655064 was selected based on safety, pharmacokinetic and pharmacodynamic data from the single and multiple dose studies 14. All subcutaneous injections were given by staff at the study site.…”

Section: Methodsmentioning

confidence: 99%

“…BI 655064 is a humanised, antagonistic anti-CD40 monoclonal antibody that selectively binds CD40 and blocks the CD40–CD40L interaction;13 two mutations in the Fc region were introduced to prevent Fc-mediated antibody-dependent or complement-mediated cellular cytotoxicity and platelet activation 13. BI 655064 demonstrated potent and comparable binding properties in both human and cynomolgus monkey B-cells and did not cause platelet activation, aggregation or function 13–15…”

Section: Introductionmentioning

confidence: 99%

Effects of BI 655064, an antagonistic anti-CD40 antibody, on clinical and biomarker variables in patients with active rheumatoid arthritis: a randomised, double-blind, placebo-controlled, phase IIa study

Visvanathan

Daniluk²,

Ptaszynski³

et al. 2019

Ann Rheum Dis

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ObjectiveTo evaluate the safety, efficacy and therapeutic mechanism of BI 655064, an antagonistic anti-CD40 monoclonal antibody, in patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX-IR).MethodsIn total, 67 patients were randomised to receive weekly subcutaneous doses of 120 mg BI 655064 (n=44) or placebo (n=23) for 12 weeks. The primary endpoint was the proportion of patients who achieved 20% improvement in American College of Rheumatology criteria (ACR20) at week 12. Safety was assessed in patients who received at least one dose of study drug.ResultsAt week 12, the primary endpoint was not met, with 68.2% of patients treated with BI 655064 achieving an ACR20 vs 45.5% with placebo (p=0.064); using Bayesian analysis, the posterior probability of seeing a difference greater than 35% was 42.9%. BI 655064 was associated with greater changes in CD40–CD40L pathway-related markers, including reductions in inflammatory and bone resorption markers (interleukin-6, matrix metalloproteinase-3, receptor activator of nuclear factor-κB ligand), concentration of autoantibodies (immunoglobulin [Ig]G rheumatoid factor [RF], IgM RF, IgA RF) and CD95+ activated B-cell subsets. No serious adverse events (AEs) related to BI 655064 treatment or thromboembolic events occurred; reported AEs were mainly of mild intensity.ConclusionAlthough blockade of the CD40–CD40L pathway with BI 655064 in MTX-IR patients with RA resulted in marked changes in clinical and biological parameters, including reductions in activated B-cells, autoantibody production and inflammatory and bone resorption markers, with a favourable safety profile, clinical efficacy was not demonstrated in this small phase IIa study.Trial registration numberNCT01751776

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“…Additionally, as in the healthy volunteer study (Goldwater et al, ), bleselumab exhibited nonlinear PK in psoriasis patients in the dose range of 0.1–3.0 mg/kg, which was evidenced by disproportionate increases in systemic exposure with dose. Indeed, nonlinear PK has also been reported with other anti‐CD40 antibodies (Albach et al, ; Bensinger et al, ). Bleselumab is a monoclonal antibody, designed with a high affinity for a specific target.…”

Section: Discussionmentioning

confidence: 68%

Randomized, controlled study of bleselumab (ASKP1240) pharmacokinetics and safety in patients with moderate‐to‐severe plaque psoriasis

Kumar

Papp

Tainaka

et al. 2018

Biopharm & Drug Disp

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This study evaluated the pharmacokinetics (PK), efficacy, safety, and tolerability of bleselumab – a fully‐human anti‐CD40 monoclonal recombinant IgG4. Patients with moderate‐to‐severe psoriasis were randomized on day 1 to receive bleselumab or placebo on days 1, 15 and 29 in a dose‐escalation of bleselumab at 0.1, 0.3, 1.0 or 3.0 mg/kg. The safety‐analysis set (SAF) and full‐analysis set (FAS) included all patients who received bleselumab or placebo, and the PK‐analysis set (PKAS) included patients in the SAF with ≥1 quantifiable serum bleselumab concentration. Serial blood samples were collected after each dose, and the bleselumab serum concentration was measured. After each dose, the area‐under‐the‐concentration–time curve over 336 hours (AUC336) and the maximum serum concentration (Cmax), and dose proportionality of AUC336 and Cmax were determined. The psoriasis area and severity index (PASI) score, the physician static global assessment (PSGA) score, the percentage body surface area (%BSA) affected with psoriasis, adverse events and laboratory parameters were assessed. Sixty patients were randomized and included in the SAF/FAS (bleselumab, n = 49; placebo, n = 11); 48 formed the PKAS. Bleselumab Cmax and AUC336 were more than dose proportional in the range 0.1–3.0 mg/kg, suggesting nonlinear PK after single/multiple doses. No clinically significant infusion reactions, cytokine‐release syndrome, or thromboembolic events were reported. Bleselumab did not improve the PASI scores, PSGA scores, or %BSA versus placebo. Transient elevation of alanine aminotransferase and aspartate aminotransferase levels by >3 × upper limit of normal were observed in four (8.2%) and two (4.1%) patients, respectively, in the 1.0 or 3.0 mg/kg groups. Patients with liver function test increases had no concurrent changes in bilirubin. Bleselumab demonstrated nonlinear PK after single and multiple doses, with few adverse reactions.

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Safety, pharmacokinetics and pharmacodynamics of single rising doses of BI 655064, an antagonistic anti-CD40 antibody in healthy subjects: a potential novel treatment for autoimmune diseases

Cited by 33 publications

References 31 publications

First-in-human clinical trial to assess pharmacokinetics, pharmacodynamics, safety, and tolerability of iscalimab, an anti-CD40 monoclonal antibody

First-in-human clinical trial to assess pharmacokinetics, pharmacodynamics, safety, and tolerability of iscalimab, an anti-CD40 monoclonal antibody

Effects of BI 655064, an antagonistic anti-CD40 antibody, on clinical and biomarker variables in patients with active rheumatoid arthritis: a randomised, double-blind, placebo-controlled, phase IIa study

Randomized, controlled study of bleselumab (ASKP1240) pharmacokinetics and safety in patients with moderate‐to‐severe plaque psoriasis

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