Table 4.
Summary of clinical trials of bradykinin B2 receptor antagonists and kallikrein inhibitors as on-demand or prophylactic treatment of HAE attacks.
| Therapy | Study and inclusion criteria | Treatments | Efficacy outcome(s) | Safety |
|---|---|---|---|---|
| On-Demand Treatment | ||||
| Bradykinin B2 Receptor Antagonist | ||||
| Icatibant (Firazyr) | Cicardi M, et al. (64) FAST-1 and FAST-2 DB, R, C, ph 3 Pts ≥18 y with type I or II HAE (abdominal or cutaneous attacks) |
FAST-1: Icatibant 30 mg SC (n = 27) PBO (n = 29) FAST-2: Icatibant 30 mg SC (n = 36) Oral tranexamic acid 3 g/d for 2 d (n = 38) |
FAST-1: icatibant vs. PBO FAST-2: icatibant vs. tranexamic acid Median (IQR) time to clinically significant relief of index symptom: FAST-1: 2.5 h (1.1–6.0) vs. 4.6 h (1.8–10.2; P = 0.1) FAST-2: 2.0 h (1.0–3.5) vs. 12.0 h (3.5–25.4; P < 0.001) Pts (95% CI) with clinically significant relief of index symptom 4 h after start of tx: FAST-1: 67% (46–84) vs. 46% (28–66; P = 0.2) FAST-2: 80% (63–92) vs. 31% (16–48; P < 0.001) Median (IQR) time to first symptom improvement (pt assessed) FAST-1: 0.8 h (0.5–2.0) vs. 16.9 h (3.2–NA; P < 0.001) FAST-2: 0.8 h (0.4–1.4) vs. 7.9 h (1.1–NA; P < 0.001) Median (IQR) time to first symptom improvement (investigator assessed) FAST-1: 1.0 h (0.8–2.0) vs. 5.7 h (2.0–11.2; P < 0.001) FAST-2: 1.5 h (0.7–3.0) vs. 6.9 h (4.0–13.8; P < 0.001) |
FAST-1: icatibant (n = 27) vs. PBO (n = 29) FAST-2: icatibant (n = 36) vs. tranexamic acid (n = 38) Any AEs: FAST-1: 44% (n = 12) vs. 66% (n = 19) FAST-2: 53% (n = 19) vs. 42% (n = 16) Tx-related AEs: FAST-1: 15% (n = 4) vs. 3% (n = 1) FAST-2: 14% (n = 5) vs. 11% (n = 4) SAEs: FAST-1: 0 vs. 0 FAST-2: 11% (n = 4) vs. 3% (n = 1) Injection-site reaction: FAST-1: 96% (n = 26) vs. 28% (n = 8) FAST-2: 97% (n = 35) vs. 26% (n = 10) |
| Lumry WR, et al. (65) FAST-3 MC, R, DB, PBO-C, ph 3 Pts ≥18 y with type I or II HAE (abdominal, cutaneous, or laryngeal attacks) |
Icatibant 30 mg SC (n = 46) vs. PBO (n = 47) 3/46 icatibant and 2/47 PBO pts had laryngeal attacks Tx administered ≤6 h of attack |
Median (95% CI) time to onset of symptom relief (icatibant vs. PBO): Nonlaryngeal attacksa: 2.0 h (1.5–3.0) vs. 19.8 h (6.1–26.3; P < 0.001) Laryngeal attacksb: 2.5 h (1.3–3.0) vs. 3.2 h (1.0–5.4) Median (95% CI) time to first symptom improvement (pt-assessed) Nonlaryngeal attacks: 0.8 h (0.5–1.0) vs. 3.5 h (1.9–5.4; P < 0.001) Laryngeal attacks: 1.0 h (0.6–2.5) vs. 2.1 h (0.5–3.9) Median (95% CI) time to first symptom improvement investigator-assessed) Nonlaryngeal attacks: 0.8 h (0.6–1.3) vs. 3.4 h (2.6–6.0; P < 0.001) Laryngeal attacks: 1.0 h (0.6–2.5) vs. 2.2 h (0.5–3.9) |
Icatibant 30 mg SC (n = 46) PBO (n = 46) ≥1 AE: 41.3% (n = 19) vs. 52.2% (n = 24) ≥1 drug-related AE: 10.9% (n = 5) vs. 6.5% (n = 3) ≥1 SAE: 0 vs. 6.5% (n = 3) ≥1 tx-related SAE: 0 vs. 0 AE-related deaths: 0 vs. 2.2%c (n = 1) |
|
| Kallikrein Inhibitor | ||||
| Ecallantide (Kalbitor) | Cicardi M, et al. (66) EDEMA3 trial 8 December 2005–10 February 2007 MC, R, DB, PBO-C, ph3 Pts ≥10 y with HAE (GI, laryngeal, peripheral attacks) |
Ecallantide 30 mg SC (n = 36) PBO (n = 36) Pts observed for ≥4 h after tx |
TOSd at 4 h post-tx (ecallantide vs. PBO): Mean (SD): 46.8 (59.3) vs. 21.3 (69.0) Median (range): 50.0 (−100.0 to 100.0) vs. 0 (−100.0 to 100.0; P = 0.004) Pts with significant improvement in overall response ≤4 h: 50% (n = 18) vs. 33% (n = 12) |
Ecallantide 30 mg SC (n = 36) PBO (n = 36) ≥1 AE: 56% (n = 20) vs. 33% (n = 12) ≥1 tx-related AE: 11% (n = 4) vs. 14% (n = 5) SAEs: 8% (n = 3) vs. 6% (n = 2) Most common AEs: Headache: 11% (n = 4) vs. 6% (n = 2) Diarrhea: 8% (n = 3) vs. 0 Pyrexia: 8% (n = 3) vs. 0 Nasopharyngitis: 6% (n = 2) vs. 3% (n = 1) Tachycardia, not otherwise specified: 6% (n = 2) vs. 3% (n = 1) Nasal congestion: 6% (n = 2) vs. 0 No AE-related mortality or study discontinuations |
| Levy RJ, et al. (67) EDEMA4 trial DB, R, PBO-C, ph 3 Pts ≥10 y with type I or II HAE (any attack location) |
Ecallantide 30 mg SC (n = 48) PBO (n = 48) Pts observed for ≥4 h after tx |
TOSd at 4 h post-tx (ecallantide vs. PBO): Mean (SD): 53.4 (49.7) vs. 8.1 (63.2) Median (range): 50.0 (−66.7 to 100) vs. 0 (−100.0 to 100.0; P = 0.003) Pts maintaining significant improvement in overall response through 24 h: 44% (n = 21) vs. 21% (n = 10; P = 0.02) |
Ecallantide 30 mg SC (n = 48) PBO (n = 48) ≥1 AE: 17% (n = 8) vs. 40% (n = 19) Most common AEs: Nausea: 6% (n = 3) vs. 2% (n = 1) Headache: 4% (n = 2) vs. 10% (n = 5) Dizziness: 4% (n = 2) vs. 2% (n = 1) Abdominal pain: 2% (n = 1) vs. 4% (n = 2) |
|
| Prophylactic Treatments | ||||
| Kallikrein Inhibitors | ||||
| Lanadelumab (Takhzyro) | Banerji A, et al. (68) HELP trial MC, R, DB, P, PBO-C, ph 3 Pts ≥12 y with type I or II HAE with ≥1 attack/q4 wk |
Lanadelumab (26 wk tx) 150 mg SC q4 wk (n = 28) 300 mg SC q4 wk (n = 29) 300 mg SC q2 wk (n = 27) PBO (n = 41) Run-in period attack rate (mean attacks/mo [SD]): Lanadelumab 150 mg q4 wk: 3.2 (1.8) 300 mg q4 wk: 3.7 (2.5) 300 mg q2 wk: 3.5 (2.3) PBO: 4.0 (3.3) |
Mean (95% CI) number of attacks/mo Lanadelumab 150 mg q4 wk: 0.5 (0.3–0.7) 300 mg q4 wk: 0.5 (0.4–0.8) 300 mg q2 wk: 0.3 (0.1–0.5) PBO: 2.0 (1.6–2.4) Mean difference (95% CI) in number of attacks/mo vs. PBO 150 mg q4 wk: −1.5 (−1.9 to −1.1; P < 0.001) 300 mg q4 wk: −1.4 (−1.8 to −1.0; P < 0.001) 300 mg q2 wk: −1.7 (−2.1 to −1.3; P < 0.001) |
Lanadelumab 150 mg q4 wk (n = 28) 300 mg q4 wk (n = 29) 300 mg q2 wk (n = 27) PBO (n = 41) Any AE: 150 mg q4 wk, 89.3% (n = 25); 300 mg q4 wk, 86.2% (n = 25); 300 mg q2 wk, 96.3% (n = 26), vs. PBO 75.6% (n = 31) Any tx-related AE: 60.7% (n = 17), 48.3% (n = 14), 70.4% (n = 19), vs. 34.1% (n = 14) Injection site pain: 42.9% (n = 12), 31.0% (n = 9), 51.9% (n = 14), vs. 26.8% (n = 11) Any SAE: 0, 10.3% (n = 3), 3.7% (n = 1), vs. 0 Any AE leading to discontinuation: 0, 3.4% (n = 1), 0, vs. 2.4% (n = 1) |
| Banerji A, et al. (69) OL extension trial Pts ≥12 y with type I or II HAE with ≥1 attack/q4 wk Planned treatment duration: 924 d |
Rollovers from HELP trial (n = 109): Lanadelumab 300 mg (Day 0; last visit HELP trial); treatment paused until first HAE attack (dose-and-wait stage), at which point patients received second dose lanadelumab 300 mg and continued lanadelumab 300 mg q2 wk (regular dosing stage) Non-rollovers (n = 103): lanadelumab 300 mg q2 wk Mean (SD) lanadelumab exposure: 29.6 (8.2) months; 92.5% of patients completed ≥12 mo |
Reduction in attack rate Overall: 87.4% Rollovers (starting from regular dosing stage/second dose, not including first HAE attack): 92.4% Non-rollovers (starting from Day 0): 82.0% Attack-free (overall): Mean (SD), % days: 97.7% (6.0%) Mean, (SD), duration: 14.8 mo (415.0 d) ≥6 mo: 81.8% ≥12 mo: 68.9% |
Total (N = 212) Any AE: 97.2% (n = 206) Treatment-related AE: 54.7% (n = 116) Any SAE: 9.9% (n = 21) Any treatment-related SAE: 0 Any severe AE: 17.9% (n = 38) Any investigator-reported AESIs, including hypersensitivity reactions and disordered coagulation (hypercoagulability events and bleeding events): 6.1% (n = 13) Any hospitalizations due to AEs: 9.9% (n = 21) Any AE leading to discontinuation: 2.8% (n = 6) Most common AEs: Injection site pain: 47.2% (n = 100) Viral URTI: 42.0% (n = 89) Upper respiratory tract infection: 25.9% (n = 55) Headache: 24.5% (n = 52) Injection site erythema: 17.0% (n = 36) Arthralgia: 12.7% (n = 27) |
|
| Berotralstat (Orladeyo) | Zuraw B, et al. (63) APeX-2 trial, part 1 14 March 2018–10 April 2019 (first 24 weeks of treatment) MC, R, DB, P, PBO-C, ph 3 Pts aged ≥12 y (US and Canada) or ≥18 y (Europe) with type I or II HAE with ≥2 HAE attacks requiring treatment or causing functional impairment in first 56 d of run-in period |
Berotralstat orally once daily for 24 wk 110 mg (n = 41) 150 mg (n = 40) PBO (n = 40, 39 dosed) Mean (SD) baseline HAE attacks/28-d period over screening period of up to 70 d (investigator confirmed) Berotralstat 110 mg: 2.97 (1.36) 150 mg: 3.06 (1.56) PBO: 2.91 (1.12) |
Mean number of investigator-confirmed attacks/mo over 24 wk Berotralstat 110 mg: 1.65 150 mg: 1.31 PBO: 2.35 Attack rate ratio (95% CI) relative to PBO Berotralstat 110 mg: 0.70 (0.51–0.95), P = 0.024 150 mg: 0.56 (0.41–0.77), P < 0.001 |
Berotralstat 110 mg (n = 41) Berotralstat 150 mg (n = 40) PBO (n = 39) Any AE: 83% (n = 34)/85% (n = 34)/77% (n = 30) Any SAE: 2% (n = 1)/0/8% (n = 3) Tx-related AEs: 0 (all groups) AE leading to discontinuation: 7% (n = 3)/3% (n = 1)/3% (n = 1) Most common AEs (berotralstat 110 mg/berotralstat 150 mg/PBO): URTI: 32% (n = 13)/30% (n = 12)/28% (n = 11) Nausea: 15% (n = 6)/15% (n = 6)/18% (n = 7) Abdominal pain: 10% (n = 4)/23% (n = 9)/10% (n = 4) Vomiting: 10% (n = 4)/15% (n = 6)/3% (n = 1) Diarrhea: 10% (n = 4)/15% (n = 6)/0 Headache: 7% (n = 3)/10% (n = 4)/5% (n = 2) Back pain: 2% (n = 1)/10% (n = 4)/3% (n = 1) |
| Wedner HJ, et al. (70) APeX-2 trial, part 2 14 March 2018–25 September 2019 (first 48 wk of treatment) MC, R, DB, P, ph3 Pts aged ≥12 y (US and Canada) or ≥18 y (Europe) with type I or II HAE with ≥2 HAE attacks requiring treatment or causing functional impairment in first 56 d of run-in period |
Pts taking berotralstat in part 1 continued same dose; pts taking PBO re-randomized to berotralstat 110 or 150 mg once daily (all blinded) Berotralstat once daily for 48 wk 110 mg (n = 37) 150 mg (n = 37) PBO for 24 weeks, then berotralstat for 24 wk 110 mg (n = 17) 150 mg (n = 17) Mean (SE) baseline attack rate (attacks/mo): Berotralstat 110 mg: 2.97 (0.21) Berotralstat 150 mg: 3.06 (0.25) Mean (SE) attack rate at week 24 (before berotralstat) PBO → berotralstat 110 mg: 2.39 (0.41) PBO → berotralstat 150 mg: 2.56 (0.61) |
Mean (SEM) number of investigator-confirmed attacks/month at 48 wk: Berotralstat 110 mg: 1.35 (0.33) Berotralstat 150 mg: 1.06 (0.25) PBO → berotralstat 110 mg: 1.25 (0.32) PBO → berotralstat 150 mg: 0.57 (0.23) |
Berotralstat 110 mg (n = 41) Berotralstat 150 mg (n = 40) Results up to wk 48: Any AE: 92.7% (n = 38)/95.0% (n = 38) Any SAE: 2.4% (n = 1)/2.5% (n = 1) Tx-related SAE: 0 (both groups) AE-related discontinuation: 9.8% (n = 4)/7.5% (n = 3) Investigator-identified rash 0/5.0% (n = 2) Most common AEs (berotralstat 110 mg/berotralstat 150 mg): URTI: 36.6% (n = 15)/52.5% (n = 21) Nausea: 19.5% (n = 8)/20.0% (n = 8) Abdominal pain: 9.8% (n = 4)/30.0% (n = 12) Dyspepsia: 9.8% (n = 4)/12.5% (n = 5) Diarrhea: 12.2% (n = 5)/17.5% (n = 7) Vomiting: 9.8% (n = 4)/15.0% (n = 6) Headache: 9.8% (n = 4)/12.5% (n = 5) Flatulence: 7.3% (n = 3)/7.5% (n = 3) Back pain: 4.9% (n = 2)/12.5% (n = 5) Gastroesophageal reflux disease: 9.8% (n = 4)/5.0% (n = 2) |
|
AE, adverse event; AESI, adverse event of special interest; APeX-2, Angioedema Prophylaxis 2; C, controlled; DB, double-blind; EDEMA, Evaluation of DX88’s Effects in Mitigating Angioedema; FAST, For Angioedema Subcutaneous Treatment; GI, gastrointestinal; HAE, hereditary angioedema; HELP, Hereditary Angioedema Long-term Prophylaxis; IQR, interquartile range; MC, multicenter; NA, not available; P, parallel group; PBO, placebo; PBO-C, placebo-controlled; ph, phase; pts, patients; R, randomized; SAE, serious adverse event; SC, subcutaneous; TOS, treatment outcome score; tx, treatment; URTI, upper respiratory tract infection; VAS, visual analog scale.
a
Symptom relief defined as 50% decrease from pretreatment in VAS-3 score; VAS-3 is a 3-symptom composite visual analog scale score for cutaneous and/or abdominal attacks that includes scores for skin swelling, skin pain, and abdominal pain.
b
Symptom relief defined as 50% decrease from pretreatment in VAS-5 score; VAS-5 is a 5-symptom composite visual analog scale score for laryngeal attacks that includes scores for skin swelling, skin pain, abdominal pain, difficulty swallowing, and voice change.
c
Myocardial infarction.
d
Score is a composite of patient-reported outcomes related to site(s) of symptoms, baseline symptom severity, and treatment response. Scores range from +100 (significant improvement in symptoms) to -100 (significant worsening of symptoms).