Determining biomarkers for evaluation and diagnosis of hereditary angioedema.

Rationale: Kallikrein-bradykinin-forming cascade is known to cause hereditary angioedema (HAE) acute angioedema (AE) attacks. Further research of HAE attacks is needed to explain disease heterogeneity, predict treatment response and identify biomarkers for monitoring HAE attacks. Differential expression of the microvascular endothelial cell-surface receptors for example, g-C1qR, cytokeratin-1, and plasminogen-activator-urokinase-receptor (PLAUR) were hypothesized as biomarkers of AE attacks. Method: To understand HAE attacks, the differentially expressed genes (DEGs) in RNAseq and mi-RNAseq data of total RNA extracted from skin biopsies of lesional versus non-lesional skin collected during and between attacks in Type-1 HAE patients (n = 11; F:M = 8:3) were compared. To understand the HAE variants, DEGs in skin biopsies from HAE with normal C1 inhibitor (n = 5, F:M = 5:0), and non-HAE (n = 7; F:M = 3:4) patients were compared. Gene-set enrichment analyses and regulator effects analysis of these DEGs identified biological pathways in HAE attacks and their regulators. Results: PLAUR gene, encoding urokinase-type plasminogen activator (u-PAR), was constitutively over-expressed in HAE-Type-1 versus non-HAE controls suggestive of overactive u-PAR-mediated signaling via binding to Factor-XII. Baseline PLAUR expression was associated with severe AE (p = 0.05). The 18 significant DEGs investigated between baseline and AE attack samples in Type1-HAE were enriched in beta1/beta3-integrin cell surface interactions and IL-6-mediated signaling. Regulator effects analysis suggests a role for IL-1b in HAE flares. AKT2, the mRNA regulated by the differentially-expressed miR-184A, was also associated with HAE attacks. Conclusion: Angiopoetin-activated ß1-integrin signaling pathways causing endothelial destabilization, and avid binding of factor XII to u-PAR are possible novel mechanisms for progression of the endothelial kinin-bradykinin-forming cascade in HAE attacks.

Long-term prevention of hereditary angioedema attacks with lanadelumab: The HELP OLE Study.

BACKGROUND: The aim was to evaluate long-term effectiveness and safety of lanadelumab in patients ≥12 y old with hereditary angioedema (HAE) 1/2 (NCT02741596). METHODS: Rollover patients completing the HELP Study and continuing into HELP OLE received one lanadelumab 300 mg dose until first attack (dose-and-wait period), then 300 mg q2wks (regular dosing stage). Nonrollovers (newly enrolled) received lanadelumab 300 mg q2wks from day 0. Baseline attack rate for rollovers: ≥1 attack/4 weeks (based on run-in period attack rate during HELP Study); for nonrollovers: historical attack rate ≥1 attack/12 weeks. The planned treatment period was 33 months. RESULTS: 212 patients participated (109 rollovers, 103 nonrollovers); 81.6% completed ≥30 months on study (mean [SD], 29.6 [8.2] months). Lanadelumab markedly reduced mean HAE attack rate (reduction vs baseline: 87.4% overall). Patients were attack free for a mean of 97.7% of days during treatment; 81.8% and 68.9% of patients were attack free for ≥6 and ≥12 months, respectively. Angioedema Quality-of-Life total and domain scores improved from day 0 to end of study. Treatment-emergent adverse events (TEAEs) (excluding HAE attacks) were reported by 97.2% of patients; most commonly injection site pain (47.2%) and viral upper respiratory tract infection (42.0%). Treatment-related TEAEs were reported by 54.7% of patients. Most injection site reactions resolved within 1 hour (70.2%) or 1 day (92.6%). Six (2.8%) patients discontinued due to TEAEs. No treatment-related serious TEAEs or deaths were reported. Eleven treatment-related TEAEs of special interest were reported by seven (3.3%) patients. CONCLUSION: Lanadelumab demonstrated sustained efficacy and acceptable tolerability with long-term use in HAE patients.

Conestat alfa for the treatment of angioedema attacks.

Recently, multiple C1 inhibitor (C1-INH) replacement products have been approved for the treatment of hereditary angioedema (HAE). This review summarizes HAE and its current treatment modalities and focuses on findings from bench to bedside trials of a new C1-INH replacement, conestat alfa. Conestat alfa is unique among the other C1-INH replacement products because it is produced from transgenic rabbits rather than derived from human plasma donors, which can potentially allow an unlimited source of drug without any concern of infectious transmission. The clinical trial data generated to date indicate that conestat alfa is safe and effective for the treatment of acute HAE attacks.