Biosimilars in rare diseases: a focus on paroxysmal nocturnal hemoglobinuria

Abstract

Biologics, a class of medicines grown in and purified from genetically engineered cell cultures, have transformed the management of many cancers and rare diseases, such as paroxysmal nocturnal hemoglobinuria. As prescription drug spending has increased and exclusivity periods have expired, manufacturers have developed biosimilars—biologics that may be more affordable and highly similar to a licensed biological therapeutic, with no clinically meaningful differences in safety or efficacy. With biosimilars gaining regulatory approval around the globe and broadening patient access to biologics, this review aims to help rare disease healthcare providers familiarize themselves with biosimilars, understand their development and regulatory approval process, and address practical considerations that may facilitate their use.

Paroxysmal Nocturnal Hemoglobinuria: Current Management, Unmet Needs, and Recommendations

“…There are currently three eculizumab biosimilars, 66 and their reduced cost should allow for expanded availability of complement inhibition in jurisdictions currently still without these life-saving therapies. Two of the molecules, ABP-959 67 , 68 and SB12 49 , 69 are either recently available in some countries or are in the process of being assessed by national health authorities.…”

Understanding pharmacological complement inhibition in paroxysmal nocturnal hemoglobinuria

“…1 The authors demonstrate that this small C5 inhibitor given subcutaneously as monotherapy efficiently controls intravascular hemolysis, as shown by lactate dehydrogenase (LDH) levels, in both eculizumab-naïve and eculizumab-treated patients with paroxysmal nocturnal hemoglobinuria (PNH), possibly leading to transfusion avoidance and hemoglobin stabilization. 2 However, this clinical benefit remained quite heterogeneous, with profound inter-patient variability and limited efficacy especially in patients switching from eculizumab to zilucoplan. 2 In recent years, a plethora of novel anti-complement agents have entered into preclinical and clinical development, especially for PNH,3 the prototypic example of a purely complement-mediated hemolytic anemia.…”

“…2 However, this clinical benefit remained quite heterogeneous, with profound inter-patient variability and limited efficacy especially in patients switching from eculizumab to zilucoplan. 2 In recent years, a plethora of novel anti-complement agents have entered into preclinical and clinical development, especially for PNH,3 the prototypic example of a purely complement-mediated hemolytic anemia. Even if, clinically speaking, the most promising results are coming from the so-called proximal inhibitors,4 the development of novel terminal complement inhibitors is shedding light on our understanding of pharmacological complement inhibition.…”

“…As a possible mechanism of reduced efficacy in patients switched from eculizumab, the authors propose the accumulation of high-density C3b on PNH erythrocytes, enabling non-enzymatic cleavage of C5 (i.e., conformational change5), claiming that this residual efficacy is a kind of iatrogenic effect due to a transiently combined effect of the two C5 inhibitors at the time of the switch. 2 The authors built their hypothesis on some in vitro data, which showed that combined exposure to eculizumab and zilucoplan results in a larger proportion of C3b-opsonized PNH erythrocytes. 2 However, their theory is not convincing for a number of reasons.…”

“…2 The authors built their hypothesis on some in vitro data, which showed that combined exposure to eculizumab and zilucoplan results in a larger proportion of C3b-opsonized PNH erythrocytes. 2 However, their theory is not convincing for a number of reasons. In 2009, we originally described C3 opsonization as an ineluctable phenomenon in PNH patients treated with eculizumab.6 This phenomenon has been reproduced in the inhibition seen with anti-C5 mAb is only partial, and C3 deposition is observed in all non-lysed PNH erythrocytes.…”