Berinert

The subjects were selected from the patient population (n = 172) receiving follow-up care at the Hungarian Angioedema Center. We included 26 patients (20 females, 6 males, mean age: 35.8 years) who presented at the Center for treatment for an acute edematous episode; 19 patients had type I, whereas 7 had type II C1-INH-HAE. The diagnosis of C1-INH-HAE was established by pedigree-analysis, as well as by the evaluation of the clinical manifestations and the complement parameters (C1-INH antigenic and functional levels, C1q, C4). Nine patients were on continuous danazol treatment, whereas the remaining 17 did not receive long-term prophylaxis. Human plasma-derived C1-INH concentrate (Berinert®, CSL Behring, Marburg, Germany) was reserved for the acute treatment of edematous attacks. The “symptom-free samples” were collected during the annual control visits. None of the patients had any clinical manifestation suggestive of an acute infection during the edematous attack and during annual control visits.

The treatment group received intravenous, pasteurized pdC1-INH concentrate (Berinert® (CSL Behring, Marburg, Germany)) which was either self-injected or administered by the patient’s general practitioner, at their local hospital or at our department. The usual dose comprised 500 U of pdC1-INH, which corresponds to a C1-INH plasma activity of about 500 mL of fresh plasma. For treatment of skin swellings, 500 U pdC1-INH was recommended. If the patient had a body weight over 80 kg or if the patient felt that the 500 U dose was not sufficiently effective, 1000 U pdC1-INH was administered. Patients were counseled that mild skin swellings should not be treated. Mild skin swellings were defined as swellings limited to the back of one hand or foot or swellings at one extremity or at the trunk with a diameter of < 20 cm. Treatment was recommended for all facial and genital swellings. In skin swellings of the extremities, treatment was only recommended when the swellings were > 20 cm in diameter or if the whole extremity was affected or when the swelling of one extremity was followed by a swelling of another extremity or parts of the trunk within 24 h. Doses higher than 1000 U were administered only if the clinical response was not sufficient. All patients received vaccination for hepatitis B virus.

To estimate the cost-effectiveness of on-demand treatment for HAE attacks, a decision-tree model from the U.S. commercial payer perspective was developed using TreeAge Pro 2018 R1 release (TreeAge Software, Williamstown, MA; Figure 1). The 4 comparators included were plasma-derived (pd)C1-INH (Berinert, CSL Behring GmbH)⁶ ; icatibant (Firazyr, Shire Orphan Therapies LLC)⁷ ; ecallantide (Kalbitor, Dyax Corp)⁸ ; and recombinant human (rh)C1-INH (Ruconest, Pharming Americas BV).⁹ The variables considered within the model can be seen in Table 1, along with the sources from which the values have been extracted. Beginning with variables that influence both cost and utility, we included proportion of redosing rates, self-administration, and risk of hospitalization. The latter variable was derived from an investigation in which HAE subjects were followed as they moved from health care provider (HCP) administration of rescue medication to self-administration; a rate of 22.8% for hospitalization when treatment was administered by an HCP compared with 3.6% when the subjects were able to self-administer.^{10 (link)}

Two ampules of Berinert (CSL Behring, King of Prussia, PA, USA) each containing 500 international units of C1-inh were dissolved in 20 mL PBS. The dissolved content was transferred to Spectra/Por Dialysis Membrane MWCO 6–8,000 (Spectrumlabs, Rancho Dominquez, CA, USA) and dialysed thrice against 5 L of PBS pH 7.4 for a total of 72 hours at 4°C. Protein concentration was measured by UV absorption at 280 nm (molar extinction coefficient: 0.382 mL mg⁻¹ cm⁻¹) to 6.4 mg/mL, and aliquots were stored at −80°C.

The rhC1INH expressed in the genetically engineered CHO cells was manufactured at JSC “GENERIUM” (Russian Federation) plasma-derived Berinert^® (CSL Behring GmbH, King of Prussia, PA, USA), human recombinant C1 inhibitor Ruconest^® purified from the milk of transgenic rabbits (conestat alfa, Pharming Group N.V., CR Leiden, The Netherlands).

The medical records of all patients affected by angioedema due to C1-INH who were diagnosed according to the criteria outlined by the Hereditary Angioedema International Working Group [1 (link)] and treated in the dentistry outpatient department of ASST Fatebenefratelli Sacco hospital (Milan, Italy) from 2009 to 2017 were considered for the analysis (see also S1 Data).
The following data were collected from patients’ records: demographic information, hurdles in access to dental care, oral health at first visit, follow-up, dental procedures, type of angioedema, attack frequency, attack therapy, long- and short-term prophylaxis, and onset of attacks in the 48 hours after the procedure. Data on attack frequency were collected from angioedema records one year before and one year after the procedure. Missing data in records were collected by phone calls with patients.
In almost all patients STP consisted of the administration of plasma-derived C1-INH (pd C1-INH, Berinert^®, CSL Behring, Pennsylvania, USA) one to three hours before the procedure. In one patient attenuated androgens (danazol 400mg/day) were administered every day starting five days before the procedure, and continued for two days after. In HAE and AAE patients, 1,000 IU and 1,500 IU were given, respectively.