Oral PHA-022121 for the acute treatment and prophylaxis Of angioedema attacks in Patients with Acquired C1-Inhibitor Deficiency

• Provision of signed and dated informed consent form
• Male or female, aged > 35 at enrollment
• Diagnosis of AAE-C1-INH based upon all of the following:
1. Documented clinical history consistent with AAE-C1-INH (subcutaneous or mucosal, nonpruritic swelling withoutaccompanying urticarial and C1-INH activity < 0.63mE/L)
2. At least one of the following:
+ Age at reported onset of first angioedema symptoms ≥ 40 years AND family history negative for angioedema
+ C1q below lower limit of normal (88 kU/L) AND absence of SERPING1 mutation
+ Serological confirmation of antibodies against C1-INH
• Documented history of at least three angioedema attacks in the last 4 months, or at least two angioedemaattacks in the last 2 months.
• Reliable access and experience to use icatibant to effectively manage acute angioedema attacks
• Female patients of childbearing potential must agree to be abstinent or to use highly effective forms ofcontraception methods from enrollment through the end of the study. This includes progestin-only oralcontraceptive associated with inhibition of ovulation (oral, injectable, or implantable), intrauterine device (IUD, alltypes) or intrauterine hormone releasing systems (IUS). A female of childbearing potential whose male partner hashad a vasectomy must agree to use one additional form of medically acceptable contraception.
• Male patients, including males who are surgically sterile (post vasectomy), who have a female partner ofchildbearing potential must agree to be sexually abstinent or use a medically acceptable form of barriercontraception for 2 weeks after each administration of study drug. In addition, they must agree to not donatesperm during study participation.

Patients who meet any of the following criteria will be excluded from the study:
• Pregnancy or breast-feeding
• Clinically significant abnormal ECG, most notably a QTcF > 470 ms (for females) or > 450 ms (for males)
• Any clinically significant history of angina, myocardial infarction, syncope, stroke, left ventricular hypertrophy orcardiomyopathy, or any other cardiovascular abnormality within the previous year
• Any other systemic disease (e.g., gastrointestinal, renal, respiratory, neurological) or significant disease ordisorder that would interfere with the patient’s safety or ability to participate in the study
• Active infection with human immunodeficiency virus (HIV) or hepatitis B virus (HBV) or hepatitis C virus (HCV)
• History of abnormal hepatic function (AST > 2×ULN, ALT > 2×ULN, or total bilirubin > 1.5×ULN)
• History of abnormal renal function (eGFR CKD-EPI < 60 mL/min/1.73 m2)
• History of alcohol or drug abuse within the previous year, or current evidence of substance dependence or abuse(self-reported alcoholic intake > 3 drinks/day)
• History of documented severe hypersensitivity to any medicinal product
• Participation in any other investigational drug study currently, within the last 30 days or within 5 half-lives of studydrug at enrollment (whichever was longer)
• Regular use of corticosteroids, antihistamines, narcotics, and other pain relief medications for acute angioedemaattack treatment
• Use of concomitant medication that are moderate or potent inhibitors/inducers of CYP3A4 or are metabolized byCYP3A4 and have a narrow therapeutic range, such as clarithromycin, erythromycin, diltiazem, itraconazole,ketoconazole, ritonavir, verapamil, goldenseal and grapefruit as well as phenobarbital, phenytoin, rifampicin, St.John's Wort, and glucocorticoids (not for topical use or inhalation)