Recombinant Replacement Therapy for Hereditary Angioedema Due to C1 Inhibitor Deficiency

Abstract

Hereditary angioedema is a rare genetic condition transmitted as an autosomal dominant trait and characterized most commonly by the production of either inadequate or nonfunctioning C1 esterase inhibitor (C1-INH), a blood protein that regulates proteases in the complement, fibrinolytic and contact systems. Patients with hereditary angioedema suffer from episodic, unpredictable manifestations of edema affecting multiple anatomical locations, including the GI tract, facial tissue, the upper airway, oropharynx, urogenital region and/or the arms and legs. A rational approach to treatment is replacement of C1-INH protein, to normalize the levels of C1-INH activity and halt the progression of the biochemical activation processes underlying the edema formation. Ruconest is a highly purified recombinant human C1-INH. This article will focus on the results of ten clinical studies demonstrating the efficacy and safety of Ruconest(®) (Pharming Group NV, Leiden, the Netherlands), which is now approved for use in Europe, Israel and the USA.

The international WAO/EAACI guideline for the management of hereditary angioedema—The 2017 revision and update

“…Safety data from controlled and uncontrolled studies with rhC1‐INH support a favorable safety profile. Transmission of human viruses is not a concern …”

Assessment of inhibitory antibodies in patients with hereditary angioedema treated with plasma-derived C1 inhibitor

“…In contrast, patients with C1-INH-HAE have at least some intrinsic C1-INH, and the protein is familiar to the immune system. 25 Furthermore, differences in immunogenicity to C1-INH compared with FVIII may be related to the fact that inhibitory Abs react with the reactive center loop of the C1-INH, which is a very conservative region, whereas the C1 and C2 domains in FVIII evolutionally appeared later. 26,27 It is reported that hemophilia patients with missense mutations in the C1 and C2 domains of FVIII have a 3-fold higher risk of developing FVIII inhibitors than patients with missense mutations in other domains.…”

Recombinant human C1 esterase inhibitor (Conestat alfa) for prophylaxis to prevent attacks in adult and adolescent patients with hereditary angioedema

“…Subsequent 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 Immunology 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 [52]. Conestat alfa in doses of 50 U/Kg significantly reduces cHK [53].…”

“…The outcomes reported by the authors were that the mean number of attacks of hereditary angioedema over 4 weeks was significantly reduced with conestat alfa twice weekly, and once weekly, versus placebo, with mean differences of -44 attacks (p<00001) and -28 attacks (p=00004), respectively[33].In addition, prophylaxis with conestat alfa for HAE has been reported in sporadic case report series, both used in long-term prophylaxis, and as a successful choice in short-term prophylaxis before deemed invasive procedures[35]. (Table 2)e) Post marketing surveillanceThe database following safety and tolerability of conestat alfa includes clinical and laboratory data arising from almost 1600 administrations of rhC1-INH in twelve completed clinical development program studies [53].…”