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CC BY-NC-ND 4.0 · Thromb Haemost
DOI: 10.1055/a-2398-9344
New Technologies, Diagnostic Tools and Drugs

A Phase 1b PK/PD Study to Demonstrate Antigen Elimination with RLYB212, a Monoclonal Anti-HPA-1a Antibody for FNAIT Prevention

Christof Geisen
1   Institute of Transfusion Medicine and Immunohaematology, German Red Cross Blood Transfusion Service Baden-Württemberg-Hessen GmbH, Frankfurt am Main, Germany
,
Erika Fleck
1   Institute of Transfusion Medicine and Immunohaematology, German Red Cross Blood Transfusion Service Baden-Württemberg-Hessen GmbH, Frankfurt am Main, Germany
,
Stephan Martin Gastón Schäfer
2   Division Clinical Research, Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Frankfurt am Main, Germany
,
Carmen Walter
2   Division Clinical Research, Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Frankfurt am Main, Germany
,
Susanne Braeuninger
1   Institute of Transfusion Medicine and Immunohaematology, German Red Cross Blood Transfusion Service Baden-Württemberg-Hessen GmbH, Frankfurt am Main, Germany
,
Jens Søndergaard Jensen
3   Aixial Danmark A/S, Herlev, Denmark
,
Douglas Sheridan
4   Rallybio, New Haven, Connecticut, United States
,
Kiran Patki
4   Rallybio, New Haven, Connecticut, United States
,
Róisín Armstrong
4   Rallybio, New Haven, Connecticut, United States
,
Bjørn Skogen
5   Department of Laboratory Medicine, University Hospital of North Norway, Tromsø, Norway
,
Frank Behrens
2   Division Clinical Research, Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Frankfurt am Main, Germany
6   Division of Rheumatology, University Hospital Goethe-University Frankfurt am Main, Germany
7   Fraunhofer Cluster of Excellence Immune-Mediated Diseases CIMD, Frankfurt am Main, Germany
,
Erhard Seifried
1   Institute of Transfusion Medicine and Immunohaematology, German Red Cross Blood Transfusion Service Baden-Württemberg-Hessen GmbH, Frankfurt am Main, Germany
,
Jens Kjeldsen-Kragh 
5   Department of Laboratory Medicine, University Hospital of North Norway, Tromsø, Norway
8   Department of Clinical Immunology and Transfusion Medicine, Office for Medical Services, Region Skåne, Lund, Sweden
,
Mette Kjær   *
9   Faculty of Health Sciences, UiT—The Arctic University of Norway, Hammerfest, Norway
10   Finnmark Hospital Trust, Hammerfest, Norway
,
Michaela Köhm   *
2   Division Clinical Research, Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Frankfurt am Main, Germany
6   Division of Rheumatology, University Hospital Goethe-University Frankfurt am Main, Germany
7   Fraunhofer Cluster of Excellence Immune-Mediated Diseases CIMD, Frankfurt am Main, Germany
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Abstract

Background Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a rare bleeding disorder of the fetus/newborn caused by development of maternal alloantibodies against fetal human platelet antigens (HPAs), predominantly HPA-1a. Currently there are no treatments available to prevent maternal alloimmunization to HPAs or FNAIT.

Methods This proof-of-concept study (EudraCT Number: 2021-005380-49) was designed to assess the ability of subcutaneous (SC) RLYB212, a monoclonal anti-HPA-1a antibody, to eliminate HPA-1a-positive platelets in an antigen challenge model of a 30 mL fetal–maternal hemorrhage. Subjects were randomized to receive a single SC dose of RLYB212 or placebo on day 1 in a single-blinded manner, followed by transfusion of 10 × 109 HPA-1a-positive platelets on day 8.

Results Four subjects received 0.09 mg SC RLYB212, five received 0.29 mg SC RLYB212, and two received placebo. RLYB212 achieved rapid elimination of HPA-1a-positive platelets in a concentration-dependent manner, with concentrations as low as 3.57 ng/mL meeting the prespecified proof-of-concept criterion of ≥90% reduction in platelet elimination half-life versus placebo. Following HPA-1a-positive platelet transfusion, a rapid decline was observed in the concentration of RLYB212 over a period of 2 to 24 hours, corresponding to the time needed for RLYB212 to bind to ∼10% of HPA-1a on cell surfaces. RLYB212 was well tolerated with no reports of drug-related adverse events.

Conclusion The data from this study are consistent with preclinical efficacy data and support the potential use of RLYB212 as a prophylactic treatment for FNAIT that prevents maternal HPA-1a alloimmunization during at-risk pregnancies.

Keywords

alloimmunization - HPA-1a - fetal and neonatal alloimmune thrombocytopenia - prophylaxis - RLYB212

Data Availability Statement

Proposals for access to deidentified individual subject data should be sent to jkk@jkkmedical.com.


Authors' Contribution

D.S., K.P., and R.A. conceptualized the study and wrote the first draft of the study protocol. The protocol was finalized by Rallybio after being reviewed by C.G., S.M.G.S., C.W., J.S.J., F.B., J.K.-K., M.Kj., and M.Ko., and before submission to the Ethics Committee at Frankfurt University Hospital and the Paul-Ehrlich-Institut. C.G., E.F., J.K.-K., and M.Kj. validated the method for determining transfused platelets; E.F. performed the flow cytometry analyses; and C.G., E.F., J.K.-K., and M.Kj. approved all the flow cytometry plots before entry into the study database. M.Ko. was the principal investigator of the study. C.G. and E.F. performed the selection of platelet concentrates. C.G., E.F., S.M.G.S., C.W., S.B., F.B., and M.Ko. recruited and/or screened study participants. S.M.G.S., F.B., and M.Ko. performed administration of study drug, administration of platelets, and surveillance of study participants. Data were interpreted by C.G., S.M.G.S., C.W., J.S.J., D.S., K.P., R.A., B.S., F.B., E.S., J.K.-K., M.Kj., and M.Ko. Statistical analyses were performed by J.S.J. The manuscript was prepared by C.G., J.S.J., D.S., K.P., R.A., and J.K.-K., with medical writing support provided by Chameleon Communications International, Ltd (funded by Rallybio IPA, LLC). E.F., S.M.G.S., C.W., S.B., B.S., F.B., E.S., M.Kj., and M.Ko. reviewed and revised the manuscript. All authors approved the final manuscript.


Supplementary Material



Publication History

Received: 14 June 2024

Accepted: 17 August 2024

Accepted Manuscript online:
21 August 2024

Article published online:
12 September 2024

© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

Georg Thieme Verlag KG
Stuttgart · New York

 

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