Berotralstat

Berotralstat is an inhibitor of the serine protease kallikrein, which cleaves high-molecular weight kininogen (HMWK) to release bradykinin, a potent vasodilator that increases vascular permeability. In patients with HAE, due to a deficiency or dysfunction of C1-INH, normal regulation of plasma kallikrein activity is impaired, resulting in uncontrolled increases in plasma kallikrein activity and bradykinin release, causing HAE attacks that manifest as angioedema. Patients treated with berotralstat 150mg for 96 weeks showed 90.8% fewer HAE attacks compared to baseline (Wender HJ et al. 2021).

Berotralstat (Orladeyo) is indicated for the routine prevention of recurrent attacks of hereditary angioedema (HAE) in adult and adolescent patients aged 12 years and older. Berotralstat is the only targeted oral long-term therapy for HAE to date and has been approved in the European Union since December 2022. The approval is based on the positive results of the multicenter three-part Phase III APeX-2 study (Zuraw B et al. 2021).

Pregnancy: The use of berotralstat during pregnancy is not recommended because there is no or very limited experience with the use of berotralstat in pregnant women and there are no adequate animal studies of reproductive toxicity.

Lactation: The available pharmacodynamic/toxicological data from animals showed that berotralstat passes into milk, therefore a risk to the breastfed infant cannot be excluded. A decision must therefore be made as to whether breastfeeding should be discontinued or whether treatment with berotralstat should be discontinued. Both the benefit of breastfeeding for the child and the benefit of the therapy for the woman must be taken into account

Berotralstat is approved for oral use in the form of hard capsules. The recommended dose for adults and adolescents aged 12 years and over and weighing ≥ 40 kg is 150 mg berotralstat once daily.

CYP3A4 substrates: Berotralstat is a moderate inhibitor of CYP3A4. Concomitant use may increase concentrations of other drugs that are CYP3A4 substrates. Dose adjustments may be necessary.

CYP2D6 substrates: Berotralstat is also a moderate inhibitor of CYP2D6. Concomitant use may increase exposure to other medicinal products that are CYP2D6 substrates. Dose adjustments may be necessary, particularly for drugs with a narrow therapeutic range (e.g. thioridazine, pimozide) or for drugs with a broad therapeutic range.

Oral contraceptives: As a moderate inhibitor of CYP3A4, berotralstat may increase the concentrations of oral contraceptives metabolized via CYP3A4.

As a mild inhibitor of CYP2C9, berotralstat may reduce the effectiveness of hormonal contraceptives such as desogestrel, which require CYP2C9 for the conversion of the prodrug into the active metabolite. Therefore, women using only desogestrel for contraception should switch to an alternative reliable contraceptive method.

Interactions may occur if the following compounds are used at the same time:

• P-gp and BCRP inhibitors: Berotralstat is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP), therefore close monitoring for adverse events is recommended with concomitant use of P-gp and BCRP inhibitors.
• P-gp and BCRP inducers (e.g. rifampicin, St. John's wort) can reduce the plasma concentration of berotralstat, which leads to a reduced efficacy of berotralstat. The use of P-gp inducers together with berotralstat is therefore not recommended.

Berotralstat must not be used in case of hypersensitivity to the active substance or any of the other ingredients of the medicinal product.

^ORLADEYO®

In addition to berotralstat, the antibody lanadelumab (^Takhzyro®) has also been available for this indication since 2019, although it cannot be administered orally but must be applied subcutaneously every two to four weeks.

Average half-life of berotralstat: approx. 93.0 H child substance(s): Berotralstat hydrochloride

1. Riedl MA et al. (2024) Oral Sebetralstat for On-Demand Treatment of Hereditary Angioedema Attacks. N Engl J Med 391:32-43.
2. Wedner HJ et al. (2021) 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 9:2305-2314.e4.
3. Zuraw B et al. (2021) Oral once-daily berotralstat for the prevention of hereditary angioedema attacks: A randomized, double-blind, placebo-controlled phase 3 trial. J Allergy Clin Immunol 148:164-172.