Phase 2 multiple-dose study of an FcRn inhibitor, rozanolixizumab, in patients with primary immune thrombocytopenia

Abstract

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.

Conflict of interest statement

Conflict-of-interest disclosure: T.R. has received consultancy fees and/or research funding from AbbVie, Acerta, Amgen, BeiGene, Gilead, Janssen, Morphosys AG, Roche, and Takeda and honoraria, research funding, or for other activities from AbbVie, Janssen, and UCB Pharma. I.J. has received consultancy fees and/or has supported speaker’s bureaus for AbbVie, Alexion, Amgen, Bristol-Myers Squibb, Celgene, CellTrion, Grifols, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Servier, Shionogi, Shire, and Takeda. V.M. is an employee of the Institute of Oncology and Arensia Exploratory Medicine. N.C. has received consultancy fees, advisory board funding, and/or honoraria from Amgen, Novartis, Principia, and Rigel. G.L. has received consultancy fees from AstraZeneca, Conatus, Creablis, Medicines for Malaria Venture, Mylan, Pfizer, Sigmoid Pharma, UCB Pharma, and Ziarco. J.B.B. has received consultancy fees from Amgen, Argenx, UCB Pharma, Dova, Kezar, Momenta, Novartis, Regeneron, and Rigel and has supported speaker’s bureaus for Novartis and 3SBio. S.J. has received support for studies and consultancy and speaker’s bureau fees and has undertaken clinical trials and provided conference support for Binding Site, Biocryst, Biotest, CSL Behring, LFB, Grifols, Octapharma, Pharming, Shire/Takeda, SOBI, UCB Pharma, Weatherden, and Zarodex. P.K., U.M., F.W., R.S., and J.K. are employees of UCB Pharma and may hold stock or stock options. The remaining authors declare no competing financial interests.

© 2020 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

TP0001 study design. Star denotes occurrence of Data Monitoring Committee meeting: safety data review of at least 6 patients in each dose cohort occurred before opening subsequent dose cohorts. In total, 127 patients were screened, 61 patients did not qualify according to the screening results (1 because of an AE, 48 because of ineligibility, 3 because consent was withdrawn, and 9 for other reasons). Overall, 66 patients were enrolled of whom 65 (98.5%) completed the study; 1 patient discontinued because of lack of efficacy. SC, subcutaneous.

Figure 2.

Percentage of patients who had a platelet count ≥50 × 109/L over all visits (per protocol set).

Figure 3.

Rozanolixizumab clinical efficacy. (A) Mean platelet count over time after rozanolixizumab subcutaneous infusion (per protocol set). Arrows indicate time of rozanolixizumab subcutaneous infusion. *Baseline platelet counts were derived from central laboratory data. (B) Time to first clinically relevant response (platelet count ≥50 × 109/L) in the patients classified as responders (per protocol set).

Figure 4.

Serum IgG levels after treatment with rozanolixizumab. (A) Mean serum IgG levels (pharmacodynamic per protocol set); arrows indicate time of rozanolixizumab subcutaneous infusion. *Minimum post-baseline mean. †Day when minimum post-baseline mean was achieved. (B) Percent change from baseline in serum IgG levels (pharmacodynamic per protocol set). Arrows indicate time of rozanolixizumab subcutaneous infusion.

Figure 5.

Percentage change from baseline in immunoglobulin levels after rozanolixizumab infusion (full analysis set). (A) IgA. (B) IgM. (C) IgE.