Hereditary Angioedema Autosomal-dominant disease Incidence: 1:10,000 to 1:50,000 worldwide, ~10,000 in U.S. Attacks –spontaneous, stress, trauma, injury, or surgery –swelling of the face, airway, extremities, and digestive tract –episodic, self-limited –occasionally life-threatening –duration-hours to days C1INH deficiency (Type I, 85%) or dysfunctional (Type II, 15%)
ConditionC1qC1s C1-INH antigenic C1-INH function C4C3 HAE-INN<30% LN HAE-IINNN/H<30%LN Estrogen-dependent inherited angioedema NNNNNN Acquired C1-INH deficiency type I <30% <50%L<30%N/L Acquired C1-INH deficiency type II L/(N)LN/LL<30%N/L HAE Classification H, High; L, low; N, normal
Management of HAE Avoidance of known triggers –Estrogens –ACE inhibitors Therapeutic Interventions –Anti-fibrinolytic agents (e.g., tranexamic acid) have been used in Europe –Attenuated androgens for increasing C1INH levels (prophylaxis) –FFP replacement (risk/benefit sometimes questioned) –C1INH concentrates in Europe –C1INH concentrates under IND in U.S.
C1 Esterase Inhibitor (Human) Product Information Trade name: Cinryze™ Sterile, stable, lyophilized preparation of highly purified C1 inhibitor derived from human plasma Manufactured under contract to Sanquin Blood Supply Foundation (The Netherlands)
US-licensed Source Plasma Two dedicated, independent and effective viral reduction steps –heat treatment at 60°C for 10 hours in an aqueous solution with stabilizers, and –nanofiltration through two sequential 15 nm Planova filters Additionally, PEG precipitation has been shown to remove viruses Cinryze™ Manufacturing
Questions to the Committee Question #1 Is the safety and efficacy evidence sufficient for approval of Cinryze TM for prophylactic treatment of HAE? Question #2 If the answer to Question #1 is yes, should post-marketing studies be performed to further evaluate the following: the optimal dose for prophylaxis in males and females immunogenicity long-term safety