Primary immune thrombocytopenia (ITP) is a predominantly immunoglobulin G (IgG)-autoantibody-mediated disease characterized by isolated thrombocytopenia. Rozanolixizumab, a subcutaneously infused humanized monoclonal anti-neonatal Fc receptor (FcRn) antibody, reduced serum IgG in healthy volunteers. In this phase 2, multicenter, open-label study, patients with persistent/chronic primary ITP received 1 to 5 once-weekly subcutaneous infusions of rozanolixizumab (cumulative doses, 15-21 mg/kg). Primary objectives were safety and tolerability, and secondary objectives were clinical efficacy (change in platelet count) and pharmacodynamic effect (change in IgG). In all, 51 (77.3%) of 66 patients reported 1 or more adverse events (AEs), all mild-to-moderate, most commonly headaches (26 [39.4%] of 66), of which 15 were treatment related. Four patients had serious AEs, but none were treatment related. No AEs resulted in discontinuation of the study drug. No serious infections occurred. Platelet counts of ≥50 × 109/L were achieved at least once at any time after multiple infusions (5 × 4, 3 × 7, or 2 × 10 mg/kg: 35.7%, 35.7%, and 45.5% of patients, respectively) or single infusions (15 or 20 mg/kg: 66.7% and 54.5% patients, respectively). Minimum mean IgG levels and maximum mean platelet counts both occurred by day 8 in the higher (15 and 20 mg/kg) single-dose cohorts and maximum platelet count occurred by day 11 onward in the multiple-dose cohorts. No clinically meaningful changes occurred in IgA, IgM, IgE, or albumin levels. In patients with persistent/chronic primary ITP, rozanolixizumab demonstrated a favorable safety profile and rapid, substantial platelet increases concordant with substantial IgG reductions, especially with single doses. By day 8, in the 15 and 20 mg/kg single-dose cohorts, >50% patients achieved clinically relevant platelet responses (≥50 × 109/L), coinciding with the lowest mean IgG levels. These data support phase 3 development of rozanolixizumab in persistent/chronic primary ITP. This trial was registered at www.clinicaltrials.gov as #NCT02718716.
Macrophage polarization was analyzed using western blot, q-PCR, and flow cytometry. Phagocytic capacity of macrophages was measured by the engulfment of opsonized platelets. T-cell priming ability of macrophages was determined through co-culturing with CD4 + T cells and CD8 + T cells. We established a passive model of murine ITP. Platelet count was measured every other day. The retention of platelets in liver and spleen was assessed by the fluorescence intensity detected using the in vivo imaging system. Results: ITP patients manifested with an increased TNF-a expression which was inversely correlated with platelet count. Moreover, the numbers of TNF-a-expressing macrophages in spleen and CD16 + monocytes were more than that of healthy controls. TNF-a blockade inhibited M1 macrophage polarization by suppressing the NF-kB signaling pathway, and dampened the phagocytic capacity and T-cell priming ability of macrophages. Moreover, anti-TNF-a therapy reduced the number of non-classical monocytes and M1 macrophages, ameliorated the retention of platelets in spleen and liver, and significantly increased the platelet count of ITP mice. Summary/Conclusion:Our study demonstrated that TNF-a blockade could decrease the number and functions of pro-inflammatory subsets of monocytes/macrophages by inhibiting NF-kB signaling pathway, leading to remarkable attenuation of antibody-mediated platelet destruction both in vitro and in vivo, thus might be a promising therapeutic strategy for the management of ITP.
Introduction Rozanolixizumab targets the human neonatal Fc receptor (FcRn). By blocking IgG recycling, this first-in-class subcutaneously (SC) infused monoclonal antibody aims to improve the course of immunoglobulin G (IgG)-mediated autoimmune diseases by reducing pathogenic autoantibody levels. We report the completed Phase II, open-label study of rozanolixizumab in patients (pts) with primary immune thrombocytopenia (ITP; NCT02718716). Methods Eligibility: ≥18 yrs old; primary ITP ≥3 months (persistent/chronic); platelet count <30x109/L (screening) and <35x109/L (baseline). Pts received single (15 or 20 mg/kg) or multiple (5 x 4 mg/kg, 3 x 7 mg/kg, 2 x 10 mg/kg weekly) doses of rozanolixizumab; total dose in each group ranged from 15-21 mg/kg. Treatment was infused SC (30-90 mins). An 8-week observation period followed the last study treatment. Primary objective: safety and tolerability of rozanolixizumab (occurrence of adverse events [AEs]); secondary objective: clinical efficacy (changes in platelet count) and pharmacodynamic effect (changes in IgG levels). Results Of the 66 pts enrolled, 65 (98.5%) completed the study (one discontinued due to lack of efficacy, 4 mg/kg multiple-dose cohort). All pts were included in the safety set (SS) and full analysis set (FAS) while 64 were included in the per protocol set (PPS) and pharmacodynamic set (PD)-PPS. Two pts were excluded due to protocol deviations: procedural non-compliance and/or prohibited medication use. Overall, 51/66 (77.3%) pts reported ≥1 AE, mostly mild-to-moderate headaches (26/66 [39.4%]; Table 1). None of 4 serious AEs was treatment-related: genital tract bleeding (4 mg/kg group), thrombocytopenia (10 mg/kg), thrombocytopenia and platelet count decrease (both 15 mg/kg). One pt in each multiple-dose group and 7/12 and 9/12 pts (15 and 20 mg/kg, respectively), reported AEs (mostly headaches) deemed treatment-related (Table 1). No serious infections were seen. Baseline disease characteristics suggested a difficult to treat population, with a median of 5.8 years ITP duration, 4 prior ITP therapies and approx. 30% of pts having previously received thrombopoetin receptor agonists (Table 2). More pts receiving a single (15 and 20 mg/kg) rozanolixizumab SC infusion achieved platelet count ≥50x109/L (8/12 [66.7%] and 6/11 [54.5%; one pt excluded] in the 15 and 20 mg/kg groups, respectively) compared with those receiving multiple SC infusions: 5/14 (35.7%), 5/14 (35.7%; one pt excluded) and 5/11 (45.5%) in the 4, 7 and 10 mg/kg groups, respectively. In particular, median time to platelet count ≥50x109/L was considerably shorter in pts receiving a single dose of rozanolixizumab (7 and 5 days in the 15 and 20 mg/kg groups, respectively) compared with multiple SC infusions (14, 14 and 8 days in the 4, 7 and 10 mg/kg groups, respectively). For early responses by Day 8, a platelet count of ≥50x109/L was achieved by 7/12 (58.3%) and 6/11 (54.5%) pts in the 15 and 20 mg/kg dose groups, respectively (13/23 pts receiving a single infusion), compared with 1/14 (7.1%), 2/14 (14.3%) and 3/11 (27.3%) pts in the 4, 7 and 10 mg/kg groups, respectively (6/39 pts receiving multiple infusions). Dose-dependent increases in platelet count were observed with peak median counts >100x109/L in the 15 and 20 mg/kg groups (Table 3). Dose-dependent decreases in mean serum IgG concentrations were observed by Day 8 (Table 3). The 20 mg/kg single-dose group achieved their nadir on Day 8 (mean IgG concentration: 3.9 g/L, reduction of 5.9 g/L (60.0%) from baseline), while the 5 x 4 mg/kg group achieved their nadir on Day 29 (mean IgG concentration: 5.6 g/L, reduction of 4.0 g/L (43.6%) from baseline). Exploratory analyses, using data at baseline and Day 8, suggested that the magnitude of serum IgG decrease was associated with the corresponding platelet increase. Conclusion Rozanolixizumab was well tolerated across all dose groups (4-20 mg/kg) with mild-to-moderate headaches seen at higher doses; no patient discontinued the study due to side effects. While improvements in platelet count and decreases in IgG levels were seen at all doses of rozanolixizumab, the single SC infusions (15 and 20 mg/kg) achieved these efficacy endpoints both sooner (by Day 8), more frequently and at numerically greater levels than multiple doses. These safety, tolerability, and efficacy data support Phase III development of rozanolixizumab in patients with primary ITP. Disclosures Robak: Takeda: Consultancy, Research Funding; UCB: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel grant, Research Funding; Amgen: Consultancy, Other: Travel grant; Roche: Consultancy, Other: Travel grant, Research Funding; Abbvie: Consultancy, Honoraria, Other: Travel grant, Research Funding; Gilead: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Acerta: Research Funding; Morphosys AG: Research Funding. Jarque:Abbie: Consultancy, Speakers Bureau; Alexion: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; CellTrion: Consultancy; Gilead: Consultancy, Speakers Bureau; Grifols: Consultancy; Janssen: Consultancy, Speakers Bureau; MSD: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Servier: Speakers Bureau; Shionogi: Consultancy, Speakers Bureau; Shire: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau. Musteata:Arensia EM: Other: Principal Investigator; Institute of Oncology: Employment. Cooper:Principia: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kiessling:UCB Biosciences: Employment, Equity Ownership. Massow:UCB Biosciences GmbH: Employment. Woltering:UCB: Employment. Snipes:UCB Biosciences Inc: Employment. Ke:UCB Pharma: Employment, Equity Ownership. Langdon:AstraZeneca: Consultancy; Conatus: Consultancy; Pfizer: Consultancy; UCB Pharma: Consultancy; Ziarco: Consultancy; MMV: Consultancy; Sigmoid Pharma: Consultancy; Mylan: Consultancy; Creablis: Consultancy. Haier:UCB Pharma Sprl: Employment, Equity Ownership. Bussel:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Momenta Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Dova Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; 3S Bio: Speakers Bureau; UCB: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Tranquil: Honoraria, Membership on an entity's Board of Directors or advisory committees; Physician Education Resource: Speakers Bureau; Kezar Life Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; RallyBio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; argenx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Jolles:UCB Pharma: Consultancy, Other: Drug Safety Committee; CSL Behring: Consultancy, Honoraria, Research Funding, Speakers Bureau; Shire/Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Octapharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; LFB: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharming: Consultancy, Honoraria, Research Funding, Speakers Bureau.
TPS8074 Background: Engineered toxin bodies (ETBs) are comprised of a proprietarily engineered form of Shiga-like Toxin A subunit (SLT-A) genetically fused to antibody-like binding domains. ETBs work through novel mechanisms of action and are capable of forcing internalization, self-routing through intracellular compartments to the cytosol, and inducing potent cell-kill via the enzymatic and permanent inactivation of ribosomes. MT-3724 represents a novel ETB modality comprised of an anti-CD20 single-chain variable fragment genetically fused to SLT-A. It is capable of efficient internalization once bound to CD20 and can induce potent direct cell-kill via enzymatic ribosome inactivation. MT-3724 is currently being studied in three ongoing Phase 2 studies for relapsed or refractory diffuse large B-cell lymphoma (r/rDLBCL). Methods: The primary objective of this single-arm, Phase 2 study (NCT02361346) is to determine the efficacy of MT-3724 monotherapy in r/rDLBCL based on overall response rate (ORR), defined as the proportion of subjects with a complete/partial response according to the Lugano criteria, as assessed by independent, central review. Key secondary objectives include safety, progression-free survival, investigator‐assessed ORR, duration of response, overall survival, and pharmacodynamics. Adverse events will be assessed and documented according to Common Terminology Criteria for Adverse Events version 5.0. Key eligibility criteria include adult subjects with histologically confirmed, r/rDLBCL, with ≥2 prior standard of care systemic NHL treatment regimens, and ≥1 measurable lesion. As rituximab and other CD20-targeting antibodies compete with MT-3724 for the same CD20 domain, minimum washout periods from these agents must be observed. Subjects remain eligible post stem cell transplant or chimeric antigen receptor T-cell therapy. Subjects will receive 50 µg/kg MT-3724 IV over 1 hour on Days 1, 3, 5, 8, 10 and 12 of a 21-day treatment cycle. The anticipated sample size is N = 100. Interim analyses will be performed to confirm minimum efficacy thresholds based on the encouraging data observed in the completed phase 1 portion of the study [Hamlin et al. Blood 2019;134(Suppl 1):4098]. Multiple global sites are enrolling subjects. Clinical trial information: NCT02361346 .
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.