General Information

Orladeyo (berotralstat) is a plasma kallikrein inhibitor.

Orladeyo is specifically indicated for prophylaxis to prevent attacks of hereditary angioedema (HAE) in adults and pediatric patients 12 years of age and older.

Orladeyo is supplied as a capsule for oral administration. The recommended dose is one 150 mg capsule taken orally once daily with food.

Mechanism of Action

Orladeyo (berotralstat) is a plasma kallikrein inhibitor that binds to plasma kallikrein and inhibits its proteolytic activity. Plasma kallikrein is a protease that cleaves high-molecular-weight-kininogen (HMWK) to generate cleaved HMWK (cHMWK) and bradykinin, a potent vasodilator that increases vascular permeability resulting in swelling and pain associated with HAE. In patients with HAE due to C1- inhibitor (C1-INH) deficiency or dysfunction, normal regulation of plasma kallikrein activity is not present, which leads to uncontrolled increases in plasma kallikrein activity and results in angioedema attacks. Berotralstat decreases plasma kallikrein activity to control excess bradykinin generation in patients with HAE.

Side Effects

Adverse effects associated with the use of Orladeyo may include, but are not limited to, the following:

• abdominal pain
• vomiting
• diarrhea
• back pain
• gastroesophageal reflux disease

Clinical Trial Results

The FDA approval of Orladeyo was based on Part 1 of a multicenter, randomized, double-blind, placebo-controlled, parallel-group study (Trial 1). The study included 120 adult and adolescent patients who experienced at least two investigator confirmed attacks within the first 8 weeks of the run-in period and took at least one dose of study treatment. Patients were randomized into 1 of 3 parallel treatment arms, stratified by baseline attack rate, in a 1:1:1 ratio (berotralstat 110 mg, berotralstat 150 mg, or placebo by oral administration once daily, with food) for the 24-week treatment period.  Orladeyo significantly reduced attacks at 24 weeks, and this reduction was sustained through 48 weeks. HAE patients who completed 48 weeks of treatment (150 mg) saw reductions in their HAE attack rates, from a mean of 2.9 attacks per month at baseline to a mean of 1.0 attacks per month after 48 weeks of therapy. In the long-term open label APeX-S trial, patients completing 48 weeks of therapy (150 mg) had a mean attack rate of 0.8 attacks per month.