New Model Predicts Correlation Between Doses of Subcutaneous Medication and Risk for HAE Attacks

A new model estimates the association between doses of a subcutaneous medication and risk for an attack in hereditary angioedema (HAE) patients, a recent study shows.

The research, “Exposure-Response Model of Subcutaneous C1-Inhibitor Concentrate to Estimate the Risk of Attacks in Patients With Hereditary Angioedema,” was published in the journal CPT: Pharmacometrics & Systems Pharmacology.

HAE is a hereditary disease caused by missing or low levels of functional C1-esterase inhibitor (C1-INH), a protein that inhibits the activation of the complement system (a part of the immune system).

Mutations in the C1-INH gene result in two types of HAE: type 1 exhibits low levels of C1-INH in plasma, whereas type 2 is characterized by poorly functioning C1-INH.

Patients with HAE can experience attacks of swelling and pain in specific parts of the body, such as the stomach, hands, feet, arms, legs, genitals, throat, and face. Current therapy with administration of C1-INH effectively prevent attacks, and is able to restore and maintain C1-INH activity.

In 2017, the U.S. Food and Drug Administration approved a subcutaneous medication – Haegarda, a C1-INH by CSL Behring – for adults and adolescents, which enables more convenient treatment over the previously approved intravenous regimens.

Clinical studies showed that subcutaneous administration increased trough plasma levels – the lowest concentration of a medication before the next dose is administered – of C1-INH, and reduced the frequency of HAE attacks

However, “to date, no single exposure-response model has been established to quantify the decrease in HAE attacks observed with increasing C1-INH,” the researchers noted.

So, they set out to elucidate the association between functional C1-INH levels after subcutaneous treatment administration and the risk for an HAE attack. Furthermore, the research team also studied patient-related factors that may influence this correlation.

The research team used data from the COMPACT Phase 3 trial (NCT01912456), which evaluated the safety and clinical effectiveness of subcutaneous C1-INH in the prevention of HAE types 1 and 2. Patients received twice weekly doses of 40 IU/kg or 60 IU/kg C1-INH followed by placebo for up to 16 weeks, or vice versa.

Compared to no therapy, the model predicted that functional C1-INH levels of 33.1%, 40.3%, and 63.1% corresponded to 50%, 70%, and 90% reductions in the risk for HAE attacks, respectively.

Furthermore, based on trough functional C1-INH values for the 40 IU/kg and the 60 IU/kg doses of subcutaneous C1-INH, the model predicted that 50% and 67% of the population, respectively, would have a minimum of 70% reduction in the risk for an attack.

Of note, the preventative effect of subcutaneous C1-INH was independent of age, body weight, gender, baseline functional C1-INH levels, number of baseline HAE attacks, and HAE type.

“Based on this model, the maintenance of higher steady-state values of [functional C1-INH] would provide greater preventive effect, thus significantly decreasing the risk of experiencing an HAE attack compared to no treatment,” the researchers wrote.

The model may be explored further to establish individual dosing toward an almost complete prevention of HAE attacks, and to compare dosing regimens and routes of administration, they said.