Berotralstat (BCX7353) is a novel oral prophylactic treatment for hereditary angioedema: Review of phase II and III studies

Abstract

Background: Hereditary angioedema (HAE) is a rare genetic disorder characterized by unpredictable and potentially life-threatening episodes of swelling in various parts of the body. These attacks can be painful and debilitating, and affect apatient’s quality of life. Every patient who experiences an attack should be treated with on-demand medication to mitigateattack severity and duration. Many patients with HAE also receive long-term prophylaxis to reduce the frequency and severity of edema episodes. Although long-term prophylaxis reduces the disease burden for patients with HAE, available intravenous and subcutaneous treatments are accompanied by a significant treatment burden because of the logistical, emotional, and physical challenges posed by their long-term parenteral nature. Androgens are an effective oral prophylactic treatment; however, they are associated with significant adverse events and are not suitable for all patients. Thus, the HAE community has expressed interest in the development of alternative oral prophylactic therapies for preventing HAE attacks.Objective: Here, we review the phase II and III clinical data of berotralstat (BCX7353), which was approved by the U.S. Food and Drug Administration in December 2020.Results: Berotralstat is an oral, second-generation, synthetic, small-molecule plasma kallikrein inhibitor taken once dailyfor the prevention of HAE attacks in patients ages greater than or equal to 12 years. Results from the APeX studies (APeX-1 NCT02870972, APeX-2 NCT03485911, APeX-S NCT03472040, APex-J NCT03873116) demonstrated the efficacy of berotralstat as longterm prophylaxis for patients with HAE, which showed a reduction in the attack rate and on-demand medication usage.Berotralstat was well tolerated, and gastrointestinal treatment-emergent adverse events were generally mild and selflimited.Conclusion: Oral berotralstat is an effective and safe long-term prophylactic treatment for patients with HAE that will provide patients unable to tolerate parenteral therapies with the option of disease control. Berotralstat may be associated with reduced treatment burden compared with injectable therapies, highlighting the importance of patient preference with regard tothe administration route of their HAE prophylactic treatment.

Synthesis and Structural Characterization of Macrocyclic Plasmin Inhibitors

“…Otherwise, in metabolism studies with the benzylamine containing fXa inhibitor DPC‐423 in rodents, numerous metabolites and conjugates at the benzylamine group were identified, which might raise some concern for its use in drug development [31–33] . However, a structurally very similar inhibitor of plasma kallikrein was recently approved for the oral treatment of hereditary angioedema [34] . Notably, berotralstat contains an identical benzylamine group attached to a similar substituted pyrazole ring as previously used in DPC‐423.…”

Small molecule drugs for atopic dermatitis, rheumatoid arthritis, and hereditary angioedema

“…54,55 Oral treatments may also be associated with increased convenience and ease of administration; reduced treatment-related stress and anxiety; and reduced impact on work and everyday activities, which would all contribute to improved QoL for patients. 42,55 Finally, as the cost of production is lower for SMDs than for biologics, there may be a reduced economic burden on patients receiving oral vs injectable therapies. 1,48 Despite the potential benefits associated with the oral route of SMD administration, concerns have been raised regarding adherence, primarily because of the risk of forgetting to take daily oral medications.…”

“…40 Berotralstat is an oral SMD that selectively inhibits plasma kallikrein and is administered once daily; it is also the first targeted oral prophylaxis available for patients with HAE. 41,42 Plasma kallikrein inhibitors have greatly improved patients' symptoms and QoL; however, there are no head-to-head trials directly comparing the efficacy of these treatments to each other or other biological prophylactic medications. 43 All the approved medications for HAE prophylaxis are generally well tolerated, although the biologics are typically associated with a risk of injection site reactions, and berotralstat, an SMD, is associated with an increased risk of developing gastrointestinal events.…”

Angioedema and Fatty Acids

“…Lanadelumab is a human-specific monoclonal antibody targeting plasma kallikrein that acts as an inhibitor and reduces downstream bradykinin generation; several studies showed that lanadelumab potentiates the therapeutic preventive effect for angioedema development [29][30][31][32]. Berotralstat suppresses the development of angioedema by the inhibitory action of plasma kallikrein, subsequently decreases bradykinin production, and shows strong regulatory action for angioedema; this efficacy was confirmed by several clinical studies [33][34][35][36]. These agents are expected to broaden the range of treatment options for angioedema and improve clinical outcomes.…”