Under-the-skin Formulation of C1-INH Prevents Swelling in HAE Patients, Trial Shows
Using under-the-skin delivery of a C1-inhibitor (C1-INH) formulation in patients with hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) decreased the number and severity of HAE attacks, was well-tolerated, and was associated with high patient satisfaction in a Phase 3 trial.
Deficiency or dysfunction of the C1-INH protein are the hallmarks of type 1 and type 2 hereditary angioedema (HAE), respectively. Delivering a healthy, donor-derived C1-INH is recommended as first-line therapy to prevent HAE attacks. Prior studies of intravenous-administered, plasma-derived C1-INH demonstrated significant increases in C1-INH inhibitor levels compared to placebo.
However, in the long term, IV administration may be problematic, particularly for patients with difficult access to their veins. Subcutaneous (under the skin) administration is more convenient and feasible for long-term prophylaxis, and Haegarda, a weight-based, human plasma-derived formulation of C1-INH, showed efficacy with this delivery method.
The multicenter, Shire-sponsored SAHARA Phase 3 trial (NCT02584959) assessed the efficacy and safety of under-the-skin delivery of a plasma-derived liquid formulation of C1-INH (pdC1-INH) for the prevention of HAE attacks in adolescents and adults.
Participants received either a fixed dose of pdC1-INH (2,000 IU) or a placebo over two 14-week periods, either crossing over from one group to the other at the end of the first 14 weeks, or continuously receiving pdC1-INH during 28 weeks to evaluate long-term safety. pdC1-INH was administered twice weekly into the abdomen.
Post-treatment visits occurred one week and one month after the last dose for follow-up safety analysis. Total study duration for each patient was approximately nine months.
The study’s main goal was to determine whether the treatment reduced the number of attacks during a treatment period. Secondary endpoints included the proportion of patients achieving a 50% or greater reduction in HAE attacks, the number of HAE attacks excluding the first two weeks of each treatment period to assess effect at steady state, severity of HAE attacks, and monthly number of attack-free days.
In parallel, the treatment’s safety, tolerability, immunogenicity (the ability to induce an immune response), and the occurrence of injection site reactions were also evaluated. Also, patients were asked to rate their overall experience at different times throughout the study.
A total of 75 patients, mean age 41 years, were included; 58 completed the study. Most had HAE type I (88.0%) and had received HAE therapy within the last year (90.7%). The mean number of attacks within the three months before screening was 11.9.
Treatment with pdC1-INH significantly reduced the number of monthly attacks, from 3.9 with placebo to 1.6. This represented a 79.5% reduction in attacks from day 1, and a 84.6% reduction from day 15, when levels of pdC1-INH in the blood were stable.
Compared to placebo, more patients had a clinical response to pdC1-INH — 77.4% vs. 23.6% — and more patients remained attack-free during the study period — 37.5% vs. 8.8%. The rate of severe attacks was also lower with pdC1-INH (26.8%) than with placebo (63.2%).
A similar proportion of patients experienced treatment-related adverse events, the most common of which were upper respiratory tract infection (12.5%) and headache (10.7%). No treatment-related serious adverse events or deaths occurred.
Injection site reactions were more frequent with pdC1-INH than with placebo, but were mostly mild. Also, no patients developed anti-C1-INH antibodies throughout the study.
Results of patient experience revealed that most patients were satisfied or very satisfied with self-administration (92%) and felt that under-the-skin delivery was better than IV in the long term (97%). Also, most patients who had received IV therapy preferred the subcutaneous route (88%), and 81% (48/59) regarded the syringe as easy to use. All 59 were able to self-administer.
“Our findings demonstrate that twice-weekly, fixed-dose, SC-administered liquid is an effective, well-tolerated option for prophylactic treatment against HAE attacks,” the scientists concluded.