Abstract Number: PB0453
Meeting: ISTH 2021 Congress
Background: Prophylactic subcutaneous (SQ) administration of dalcinonacog alfa (DalcA), an engineered recombinant factor IX (FIX) variant with 22-fold enhanced potency compared with BeneFIX, provides stable and protective therapeutic FIX levels in individuals with Hemophilia B. Phase 1 and 2b studies demonstrated DalcA was well tolerated and efficacious, showing sustained FIX levels and no bleeding events from therapy start through washout. However, some subjects reported mild-to-moderate injection site reactions (ISR) consisting of pain and/or redness following initial SQ injections.
Aims: We investigated the underlying ISR mechanism after SQ DalcA administration.
Methods: We examined cutaneous microanatomic, cellular, and proteomic changes in the HypoSkin® injectable human skin biopsy platform (Genoskin, Salem, MA, USA) and Göttingen minipigs.
Results: Daily DalcA SQ injections for 14 days induced erythema and redness in minipigs comparable with observed human ISR. Ex vivo studies in HypoSkin showed that DalcA stimulated mast cell degranulation within 4 hours. In vitro studies further demonstrated that DalcA activates the Mas-related G protein-coupled receptor X2 (MRGPRX2) expressed by mast cells and associated with dermal ISR to a similar level as wild-type recombinant FIX. Since cationic drugs can stimulate MRGPRX2, we examined DalcA effect on MRGPRX2 activation when presented in alternative formulation buffers. Formulation buffers with higher pH and/or tween content reduced in vitro MRGPRX2-mediated cell activation, suggesting that modifying the DalcA formulation buffer may reduce in-vivo mast cell degranulation and downstream signaling of pain and dermal inflammation. A biomarker signature predictive of minipig ISR was generated from the cross comparison of cutaneous proteomes of minipig and ex vivo human skin models.
Conclusions: This approach of integrating ex vivo and in vitro studies with a defined biomarker signature coupled with a drug product stability profile facilitated identification of an improved formulation buffer expected to lower the risk of clinical ISR with SQ DalcA injection without impacting DalcA product quality.
To cite this abstract in AMA style:Le Moan N, Kelly L, Merle E, Descargues P, Gaudenzio N, Gagnon H, Chatterji A, Blouse GE. Mitigation of Injection Site Reactions after Subcutaneous Administration of Dalcinonacog Alfa (DalcA) in Hemophilia B Using Preclinical Models [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/mitigation-of-injection-site-reactions-after-subcutaneous-administration-of-dalcinonacog-alfa-dalca-in-hemophilia-b-using-preclinical-models/. Accessed October 19, 2021.
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