Berotralstat (Orladeyo)

Berotralstat is a real, FDA-approved oral kallikrein inhibitor that completes this site's hereditary angioedema (HAE) cluster with its one genuinely different delivery format: a once-daily capsule, rather than the self-injected or infused drugs this site's icatibant, ecallantide, conestat alfa, Berinert & Cinryze, and lanadelumab & garadacimab pages all describe. Approved 3 December 2020 as the first oral HAE prophylactic of any kind, it rests on a real, placebo-controlled Phase 3 trial and now has more than five years of published long-term follow-up and a 2025 expansion down to children as young as 2.

The one oral option in this site's HAE cluster

Hereditary angioedema (HAE) attacks are driven by excess bradykinin generated through the same contact-activation cascade this site's icatibant, ecallantide, conestat alfa, Berinert & Cinryze, and lanadelumab & garadacimab pages already describe: Factor XIIa triggers plasma kallikrein, which cleaves a precursor into bradykinin, which then causes swelling through the B2 receptor. Every one of those drugs is a protein — an antibody, a replacement enzyme, or a recombinant peptide — delivered by injection or infusion. Berotralstat, developed by BioCryst Pharmaceuticals, is different in kind: a small-molecule, non-peptide organic compound that inhibits plasma kallikrein directly, the same target ecallantide blocks, but taken as an ordinary oral capsule once a day. The FDA approved it on 3 December 2020 as the first oral, once-daily therapy ever approved to prevent HAE attacks — every other prophylactic option on this site, before or since, requires a needle.

APeX-2: a real placebo-controlled trial, and a dose lowered along the way

Berotralstat's approval rested on APeX-2 (NCT03485911), a Phase 3, randomized, double-blind, placebo-controlled trial that assigned adult and adolescent HAE patients to one of two berotralstat doses (150mg or 110mg) or placebo, once daily, for 24 weeks. Mean monthly attack rates fell from 2.35 on placebo to 1.31 on the 150mg dose (p<0.001, the dose that went on to FDA approval) and to 1.65 on the lower 110mg dose (p=0.24, not statistically significant against placebo) (Wedner HJ, Aygören-Pürsün E, Bernstein J, Craig T, Gower R, Jacobs JS, Johnston DT, 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, PMID 33866032, DOI: 10.1016/j.jaip.2021.03.057).¹ The trial's two-dose design itself reflects a real dose-finding correction: an earlier development-stage look at higher doses found a dose-dependent, concentration-related increase in QTc interval (a measure of the heart's electrical recovery time), which is why the FDA-approved dose tops out at 150mg once daily and the label explicitly warns against exceeding it. An open-label extension of APeX-2 and a separate long-term safety study (APeX-S) have since published data out to several years of continuous use, and a 2025 interim analysis (APeX-P) extended the prophylactic indication down to children aged 2 to 11 using an oral-granule formulation.

A once-daily capsule with its own drug-interaction profile

Current status

Berotralstat has been commercially available in the US since shortly after its December 2020 approval, marketed by BioCryst Pharmaceuticals under the brand Orladeyo, and remains the only FDA-approved oral prophylactic for HAE as of this review — the other kallikrein-pathway and Factor-XIIa-pathway drugs this site covers (ecallantide, lanadelumab, garadacimab) are all still self-injected. Its list price has been reported in the range of roughly $300,000 per patient per year, broadly in line with the other rare-disease HAE prophylactics on this site rather than notably higher or lower. There is no wellness, off-label bodybuilding or grey-market interest in berotralstat of any kind we could find — a specialty-prescribed HAE prophylactic managed by a treating allergist or immunologist, not something available outside that channel.