Tesidolumab

Complement inhibitors are the mainstay of paroxysmal nocturnal hemoglobinuria (PNH) treatment. The anti‐C5 monoclonal antibody eculizumab was the first treatment to improve hemolysis, thrombotic risk, and survival in PNH although at the price of a life‐long intravenous fortnightly drug. Additionally, suboptimal response may occur in up to 2/3 of patients with persistent anemia due to incomplete control of intravascular hemolysis, development of upstream C3‐mediated extravascular hemolysis (EVH), or concomitant bone marrow failure. Ravulizumab, a longer half‐life anti‐C5 developed from eculizumab, administered every 8 weeks, improved patient convenience, and reduced pharmacokinetic breakthrough hemolysis (BTH) by establishing more stable anti‐C5 concentrations. More recently, several other anti‐C5 compounds (crovalimab, pozelimab, tesidolumab, cemdisiran, zilucoplan, and coversin) are on study in clinical trials. Upstream inhibition of complement cascade was also explored with the anti‐C3 pegcetacoplan, and with the alternative pathway inhibitors iptacopan (anti‐factor B) and danicopan (anti‐factor D). These drugs efficiently target EVH and are able to improve anemia and transfusion need in suboptimal responders to anti‐C5. The route and schedule of administration (twice weekly subcutaneously for pegcetacoplan and twice or thrice oral daily dosing for iptacopan and danicopan, respectively) are very convenient but pose novel issues regarding adherence. Additionally, both anti‐C5 and upstream inhibitors do not resolve the unmet need of pharmacodynamic BTH events due to complement amplifying conditions such as infections, traumas, and surgery. In this review, we will recapitulate PNH physiopathology, clinical presentation, and diagnosis and describe available and developing drugs that will lead to a precision medicine approach for this rare though heterogenous disease.

Intravenous immunoglobulin (IVIG) (2000 mg/kg) increased the clearance of the mouse monoclonal antibody 7E3, directed against platelet integrin IIb/IIIa (alpha IIb beta 3, CD41/CD61) in rodents. We wanted to investigate the effect of IVIG on clearance of monoclonal antibodies in humans as there is extremely limited data regarding this interaction in the literature. Using the tyrosine protein kinase KIT anti‐cluster of differentiation 117 (c‐Kit) humanized monoclonal antibody (JSP191) as a case study, we used physiologically‐based pharmacokinetic (PBPK) modeling to evaluate the pharmacokinetic interaction between monoclonal antibodies and IVIG at doses (300–600 mg/kg) administered to patients with primary human immunodeficiency (PI). We first characterized the interaction between monoclonal antibodies and IVIG in PK‐Sim®/MoBi® using published literature data, including the following: IVIG plus 7E3 in mice and rats and IVIG plus the human anti‐C5 monoclonal antibody tesidolumab in adults with end‐stage renal disease. We next developed a PBPK model using digitized data for JSPI91 alone in older adults with myelodysplastic syndrome and acute myeloid leukemia and in pediatric patients with severe combined immunodeficiency (SCID). Finally, we simulated the impact of IVIG (300–2000 mg/kg) coadministration with JSP191 on the area under the curve of JSP191 in patients with SCID. Model predictions were within 1.5‐fold of observed values for 7E3 plus IVIG and tesidolumab plus IVIG as well as for JSP191 administered alone. Based on our simulations, IVIG doses ≥500 mg exceeded the 80%–125% no‐effect boundaries. IVIG treatment with monoclonal antibodies in patients with PI may result in a clinically significant interaction depending on the IVIG dose administered and the exposure–response relationship for the specific monoclonal antibody.