Preventive Medicines for HAE Type 1/2 Have Limited Cost-effectiveness, Review Finds

The three prophylactic medicines currently on the market for hereditary angioedema (HAE) — the C1 esterase inhibitors Cinryze and Haegarda, and Takzyhro (lanadelumab) — all reduce the number and severity of swelling attacks in patients with type 1/2 disease, without significant adverse events, a study found. But researchers report that these medicines have a limited cost-effectiveness, and suggest that prices should be aligned with the demonstrated benefit for sustainable access.

The review study, “The Effectiveness and Value of Lanadelumab and C1 Esterase Inhibitors for Prophylaxis of Hereditary Angioedema Attacks,” was published in the Journal of Managed Care & Specialty Pharmacy.

HAE is a rare genetic disorder characterized by sudden and recurrent episodes of swelling in the deeper layers of the skin, the upper airway, and the gastrointestinal tract.

The disease is caused by genetic mutations in the SERPING1 gene, leading to lower levels of C1-inhibitor (C1-INH), in the case of HAE type 1, or to a dysfunctional C1-INH whose levels remain normal or elevated in the case of HAE type 2.

In both cases, the lack of a functional C1-IHN leads to the continuous production of the enzyme kallikrein, which in turn increases bradykinin levels. Bradykinin is a peptide that regulates blood pressure and inflammation by dilating blood vessels; its overproduction is the main cause of HAE attacks.

“HAE attacks are typically treated with on-demand administration of C1-INH replacement products, kallikrein inhibitors, or bradykinin receptor antagonists. Some patients with frequent attacks receive [long-term preventive treatment] to prevent or reduce the frequency and severity of attacks,” the scientists said.

So far, two C1-INH replacement products — Shire‘s Cinryze and CSL Behring‘s Haegarda — and Shire’s Takzyhro (lanadelumab), an inhibitor of kallikrein, have been approved by the U.S. Food and Drug Administration (FDA) as long-term prophylactic agents for HAE.

In this review study, researchers summarized the findings of a systematic review carried out by the Institute for Clinical and Economic Review (ICER) regarding the safety, efficacy, and cost-effectiveness of long-term prophylaxis with all three drugs compared to on-demand treatment for HAE type 1 and 2.

In the case of Cinryze, a multi-center, randomized, controlled Phase 3 trial (NCT01005888) involving 22 HAE patients, and an open-label Phase 3 extension study (NCT00462709) involving 146 HAE patients over the course of 2.6 years showed that Cinryze successfully reduced the frequency, duration, and severity of HAE attacks compared to a placebo.

These findings were supported by another Phase 3 randomized crossover study (NCT02052141) showing that long-term prophylaxis with Cinryze reduced the frequency of HAE attacks 71%-85% compared to a placebo in a group of 12 children with HAE.

In the case of Haegarda, only one randomized controlled Phase 3 trial (NCT01912456) involving 90 HAE patients age 12 and up met the authors’ inclusion criteria. Data showed that long-term prophylactic treatment with Haegarda at two different doses reduced the frequency (up to 84% on average at the highest dose), duration, and severity of HAE swelling attacks and minimized the need for rescue medications compared to a placebo.

Finally, in the case of Takzyhro, a randomized, double-blind, placebo-controlled, multi-center Phase 3 trial (NCT02586805) involving 125 HAE patients age 12 and up showed that prophylactic treatment with Takzyhro at three different doses significantly reduced the frequency of HAE attacks (73%-87%) compared to a placebo.

Moreover, a higher percentage of patients treated with Takzyhro remained attack-free over the course of the study compared to those treated with placebo (39%-44% vs. 2%).

All three medicines were considered safe and highly tolerable. The most common adverse events were mild and included infections, headaches, hypersensitivity, dizziness, and injection site reactions. Serious adverse events leading to treatment interruption were rare and not directly associated with prophylactic treatment.

Regarding cost-effectiveness, all three drugs had low or intermediate scores. However, investigators were less confident about Takzyhro’s overall net health benefit due to the lack of long-term safety data.

“For patients with HAE 1/2, prophylaxis with Cinryze, Haegarda, and Takhzyro showed significant clinical benefits by reducing the number and severity of HAE attacks, without significant adverse events when compared with no long-term prophylaxis. However, the data were not sufficient to distinguish any drug as clinically superior to the other,” investigators stated.

“Further efforts are needed to help align the price of these treatments with their demonstrated benefit in order to ensure sustainable access to high-value care for all patients,” they concluded.