Acquired C1-inhibitor-deficiency (AAE-C1-INH) is a rare condition with a described prevalence of about 0.15:100,000 [1]. When studies are published, researchers are forced to report on small patient samples, leading to a lack of real-world data. Correspondingly, few studies have been performed investigating the efficacy of new medications towards treating these patients. Clinical trials testing efficacy of medications never include patients with AAE-C1-INH. As a result, no licensed therapy has been approved for AAE-C1-INH.

The disease is caused by an inappropriate consumption of the C1-INH associated with malignancy or through cleavage and inactivation of C1-INH by autoantibodies associated with autoimmune disorders. The pathophysiology of these disorders has not been fully defined, and patients with malignancy may also have autoantibodies to C1-INH [2, 3].

The resulting angioedema attacks cannot be clinically differentiated from those which occur in patients with hereditary angioedema (HAE), which has an estimated incidence of 1.5:100,000 [1]. Studies are regularly performed and treatment guidelines are available for C1-INH-HAE. However, no treatment guidelines are available and few studies are performed concerning AAE-C1-INH. Patients with AAE-C1-INH present with symptoms at an older age, typically older than 40 years, as compared to HAE patients [4]. Furthermore, AAE-C1-INH patients have a negative family history. A supporting diagnostic feature may be low levels of C1q which occur in about 70% of patients with AAE-C1-INH [2, 5].

Patients with HAE and AAE-C1-INH suffer from reoccurring angioedema attacks. These angioedema attacks may affect any cutaneous or mucocutaneous surfaces, including the extremities, face, genitalia, larynx, or gastrointestinal region. Attacks may be associated with hormonal fluctuations, physical trauma, infections, and stress, though they are often unpredictable. Swellings are painful and often lead to increased sick-leave. Additionally, laryngopharyngeal attacks may be deadly.

Berotralstat is currently the only licensed oral treatment for C1-INH-HAE patients aged 12 years or older approved by the FDA in December of 2020, and by the EMA in April of 2021. Berotralstat 150mg is taken once-a-day, and was shown to significantly reduce frequency of HAE attacks relative to placebo (respectively 1.65 vs. 2.35 attacks per month) over a 24-week period in the phase III APeX-2 trial [6]. The most common adverse effects include headaches as well as gastrointestinal complaints including abdominal pain and diarrhea. Published real-world evidence concerning Berotralstat is limited [7, 8]. A comparative meta-analysis juxtaposing prophylactic treatment using Lanadelumab given once every 2 or 4 weeks versus Berotralstat concluded that Lanadelumab has a superior effectiveness in reducing attacks within 28 days [9].

Treatment of the causative disease in patients with AAE-C1-INH is dependent on the underlying disease. In cases of low-grade hematological malignancy, the advantages of a therapy including potential side-effects of treatment are weighed against a watch-and-wait approach. Addressing the root cause of the disease is often – but not always - linked to symptom improvement [10,11,12]. In many cases, the underlying disease is an indolent lymphoma, which may not be deemed worthy of a chemotherapy. The adverse effects and toxicity caused by the chemotherapy are often worse than those symptoms caused by the indolent lymphoma itself. Additionally, a treatment-attempt via chemotherapy is also not a guarantee of success.

Frequently however, the underlying disorder cannot be effectively cured or even not found; in those cases, AAE-C1-INH may only be symptomatically treated. Currently, there are no licensed treatments by regulatory authorities for patients with AAE-C1-INH due to the small number of diagnosed patients and lack of clinical trials; therefore, treatment follows the therapy for HAE in an off-label fashion.

Approved therapies for patients with C1-INH-HAE may be stratified according to on-demand and prophylactic treatment. On-demand therapy includes the intravenously administered plasma derived C1-esterase inhibitor (Berinert) and (Cinryze), as well as the subcutaneously administered bradykinin B2 receptor antagonist (Icatibant) and the recombinant human-derived C1-esterase inhibitor (Conestat alfa). The subcutaneously administered kallikrein-inhibitor (Ecallantide) has been licensed from the FDA, though not from the EMA.

Prophylactic treatment options include intravenously administered plasma-derived C1-esterase inhibitor (Cinryze), subcutaneously administered plasma-derived C1-esterase inhibitor (Berinert), subcutaneously administered monoclonal antibody and kallikrein inhibitor (Lanadelumab), and orally administered kallikrein inhibitor (Berotralstat) [13].

The on-demand treatment with pdC1-INH has been shown to significantly reduce the duration of attacks in patients with AAE-C1-INH [14] and was shown to reduce frequency of attacks and improve quality of life in a case study [15]. When patients with AAE-C1-INH were treated for attacks on-demand with the bradykinin B2 receptor antagonist (Icatibant) or the kallikrein inhibitor (Ecallantide), an improved attack resolution was demonstrated [16, 17]. The kallikrein inhibitor Lanadelumab led to improved disease control and quality of life in patients with AAE-C1-INH [18].

Similar to patients with AAE-C1-INH, a lack of clinical trials and approved treatment options forces physicians to treat patients with HAE-nC1-INH according to their experience with patients with C1-INH-HAE. On-demand treatment with pdC1-INH substrate (Berinert) and bradykinin B2 receptor antagonist (Icatibant) has revealed reduced attack duration, time to symptom improvement, and attack intensity in smaller cohorts of 9–11 patients [19,20,21]. A smaller cohort of 3 patients described improved attack control after treatment with Lanadelumab [22]. In a case study, a reduction in attacks from 2 to 3 per month to zero was reported after 6 months of treatment with Berotralstat [23].

The primary goal of this study is to investigate the impact of treatment with Berotralstat 150mg on the frequency of angioedema attacks and quality of life as well as disease control. Patients with HAE-nC1-INH and AAE-C1-INH are rare subpopulations in which little or nothing is known about the effect of Berotralstat. Currently, no studies have described the use of Berotralstat in patients with AAE-C1-INH. This study documents the first described cases of treatment with Berotralstat in patients with acquired angioedema, and furthermore illustrates valuable real-world information. The secondary goal of this study is to report the impact of Berotralstat in patients with HAE-nC1-INH and AAE-C1-INH.