Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.
Orladeyo® (berotralstat) is an oral therapy indicated for the prevention of hereditary angioedema (HAE) attacks in children who are at least 12 years of age.1 Orladeyo is a registered trademark of BioCryst Pharmaceuticals, Inc and was first approved by the US Food and Drug Administration (FDA) in December 2020.2 This therapy was the first oral treatment made available to HAE patients, broadening the landscape of preventive treatment, which had only been represented by medications administered via injections and infusions until then.2 The approval of Orladeyo was set to improve the quality of life of individuals living with HAE.
Approval of this therapy by the European Commission (EC) followed in April 2021, allowing Orladeyo to reach all European Union member states as well as Iceland, Norway, and Liechtenstein.3 In the United Kingdom, approval was granted by the Medicines and Healthcare Products Regulatory Agency (MHRA) the following month.4
Mechanism of Action and Use of Orladeyo
The active substance of Orladeyo is berotralstat, a plasma kallikrein inhibitor.5 In HAE, a characteristic C1-inhibitor deficiency causes a dysregulation of the amount of kallikrein, factor XIIa, and factor XIIf that is physiologically generated. These molecules have an important role in the regulation of bradykinin. The low C1-inhibitor levels in patients with HAE result in a higher amount of available bradykinin in the body via kallikrein activity, leading to the vasodilation and inflammation that precede HAE attacks, which are typically characterized by swelling and pain.1,5
The mechanism of action of berotralstat involves binding to kallikrein to inhibit its proteolytic activity. This binding event prevents the cleavage of high-molecular-weight kininogen (HMWK) and the release of bradykinin, which in turn decreases the amount of bradykinin available. This results in less vasodilation and inflammation, thereby preventing HAE episodes.1,5
Orladeyo is available as 110-mg and 150-mg capsules. The recommended dose is one 150 mg capsule taken orally with food once a day, although patients with moderate to severe hepatic impairment or gastrointestinal reactions or who are chronically using P-glycoprotein or breast cancer resistance protein (BCRP) inhibitors may require dose adjustment with the 110-mg formulation.1
Common adverse reactions following the use of Orladeyo include abdominal pain, vomiting, diarrhea, back pain, and gastroesophageal reflux disease. This therapy should not be used to treat acute HAE attacks. It can have an impact on heart rhythm, causing QT prolongation when taken at dosages higher than the recommended dose.1
Safety and Efficacy of Orladeyo
The safety, tolerability, pharmacodynamics, and pharmacokinetics of berotralstat were evaluated in a phase 2 clinical trial, APeX-1 (NCT02870972).6 This international, 3-part, dose-ranging, placebo-controlled trial enrolled 77 patients and studied 4 doses of the drug (62.5 mg, 125 mg, 250 mg, and 350 mg) administered once daily over a period of 28 days. The study reported that the 125-mg dose given once daily resulted in a 73.8% lower rate of HAE attacks compared to the placebo.7
FDA approval of Orladeyo was granted following the phase 3 trial, APeX-2 (NCT03485911).8 This was a multicenter, randomized, double-blind, placebo-controlled trial in which 121 patients aged 12 years and above were randomized to receive a daily dose of berotralstat at 110 mg or 150 mg or a placebo for 24 weeks. The primary efficacy endpoint of this trial was the rate of confirmed HAE attacks during the treatment period. The results showed that the 110-mg and 150-mg doses of berotralstat significantly reduced the attack rate in 29.8% and 44.3% of patients, respectively, when compared to the placebo.5 Both doses of the drug were well tolerated and safe, however, the daily dose of 150 mg had a more favorable benefit-to-risk profile. The most frequent adverse events reported were abdominal pain, vomiting, diarrhea, and back pain.9
Get full prescribing information for Orladeyo at MPR
In the second part of the APeX-2 trial, patients continued to receive berotralstat at the same initial dose or were rerandomized to receive 150 mg or 110 mg of berotralstat if they had initially been given the placebo. This study ran through weeks 24 to 48 with the aim of evaluating both the safety and tolerability of the drug, which were maintained over the full period of treatment.10
A similar phase 3 trial, APeX-J, was performed only in Japan (NCT03873116).11 In this study, 19 patients were randomized to receive 1 of the 2 available doses of berotralstat or a placebo, and the reported results support the reduced rate of HAE attacks following the use of the therapy at 150 mg.12
An additional open-label phase 2/3 trial is ongoing to determine the long-term safety and efficacy of berotralstat in HAE. In this APeX-S extension trial (NCT03472040), 227 enrolled patients are set to receive treatment with berotralstat at 110 mg or 150 mg once daily over 48 weeks of treatment.13,14A current analysis of data over more than 300 days of exposure to treatment showed that both doses were well tolerated, with the median HAE attack rates kept low over 12 months (0 attacks per month in both dosage groups). Evidence of tolerance was not observed, while improvements in quality of life were reported. Treatment‐emergent adverse events occurred in 91% of patients, and the most common events, which were mainly mild to moderate in severity, were upper respiratory tract infection, abdominal pain, headache, and diarrhea.14
The use of berotralstat for the treatment of HAE attacks is also under investigation in the ZENITH-1 trial (NCT03240133).15,16 This trial has confirmed a rapid onset of action for this drug (within 1 hour), as well as sustained activity for over 24 hours and robust dose response for the treatment of HAE attacks. Data derived from the study reported that a single oral dose of 750 mg was well tolerated and had superior efficacy compared to the placebo.16
1. Orladeyo. Prescribing information. BioCryst Pharmaceuticals, Inc; 2022. Accessed June 8, 2022.
2. BioCryst announces FDA approval of Orladeyo™ (berotralstat), first oral, once-daily therapy to prevent attacks in hereditary angioedema patients. News release. BioCryst Pharmaceuticals, Inc; December 3, 2020.
3. BioCryst receives European Commission approval of Orladeyo™ (berotralstat), first oral, once-daily therapy to prevent attacks in hereditary angioedema patients. News release. BioCryst Pharmaceuticals, Inc; April 30, 2021.
4. BioCryst receives UK approval of Orladeyo™ (berotralstat), first oral, once-daily therapy to prevent attacks in hereditary angioedema patients. News release. BioCryst Pharmaceuticals, Inc; May 12, 2021.
5. Powell J, Piszczatoski C, Rubido E. Orladeyo (berotralstat): a novel oral therapy for the prevention of hereditary angioedema. Ann Pharmacother. 2022;56(4):488-493. doi:10.1177/10600280211032982
6. Efficacy and safety of BCX7353 to prevent angioedema attacks in subjects with hereditary angioedema (APeX-1). ClinicalTrials.gov. August 18, 2016. Updated March 23, 2021. Accessed June 8, 2022.
7. Aygören-Pürsün E, Bygum A, Grivcheva-Panovska V, et al. Oral plasma kallikrein inhibitor for prophylaxis in hereditary angioedema. N Engl J Med. 2018;379(4):352-362. doi:10.1056/NEJMoa1716995
8. Efficacy and safety study of BCX7353 as an oral treatment for the prevention of attacks in HAE (APeX-2). ClinicalTrials.gov. April 3, 2018. Updated March 3, 2022. Accessed June 8, 2022.
9. Zuraw B, Lumry WR, Johnston DT, et al. Oral once-daily berotralstat for the prevention of hereditary angioedema attacks: a randomized, double-blind, placebo-controlled phase 3 trial. J Allergy Clin Immunol. 2021;148(1):164-172.e9. doi:10.1016/j.jaci.2020.10.015
10. Wedner HJ, Aygören-Pürsün E, Bernstein J, et al. Randomized trial of the efficacy and safety of berotralstat (BCX7353) as an oral prophylactic therapy for hereditary angioedema: results of APeX-2 through 48 weeks (part 2). J Allergy Clin Immunol Pract. 2021;9(6):2305-2314.e4. doi:10.1016/j.jaip.2021.03.057
11. Study to evaluate the efficacy and safety of BCX7353 as an oral treatment for the prevention of HAE attacks in Japan (APeX-J). ClinicalTrials.gov. March 13, 2019. Updated March 4, 2021. Accessed June 8, 2022.
12. Ohsawa I, Honda D, Suzuki Y, et al. Oral berotralstat for the prophylaxis of hereditary angioedema attacks in patients in Japan: a phase 3 randomized trial. Allergy. 2021;76(6):1789-1799. doi:10.1111/all.14670
13. A long term safety study of BCX7353 in hereditary angioedema (APeX-S). ClinicalTrials.gov. March 21, 2018. Updated December 17, 2020. Accessed June 8, 2022.
14. Farkas H, Stobiecki M, Peter J, et al. Long-term safety and effectiveness of berotralstat for hereditary angioedema: the open-label APeX-S study. Clin Transl Allergy. 2021;11(4):e12035. doi:10.1002/clt2.12035
15. Study of BCX7353 as a treatment for attacks of hereditary angioedema. ClinicalTrials.gov. August 4, 2017. Updated April 1, 2021. Accessed June 8, 2022.
16. BioCryst reports ZENITH-1 results with oral BCX7353 which confirm rapid onset of action, sustained activity and robust dose response for treatment of acute HAE attacks. News release. BioCryst Pharmaceuticals, Inc; February 23, 2019.
Reviewed by Harshi Dhingra, MD, on 6/18/2022.