Integrated Insights, Clinical Connections: Hereditary Angiodema (HAE)

Three New HAE Therapies May Increase Benefit Spend For Payers

Hereditary Angioedema, or HAE, is a genetic condition that is very rare and potentially life-threatening. Over the summer of 2025, the FDA approved three new HAE therapies: Andembry (garadacimab), Dawnzera (donidalorsen), and Ekterly (seberalstat). There are now 11 total drugs that have been FDA-approved for HAE since 2008. These therapies offer new ways to treat symptoms of HAE as well as prevent or reduce attacks. While they expand the current options for treatment, they also have the potential to create unforeseen costs for the payers covering them. Having more awareness of the impact HAE therapies could have on your member population can help you to prepare and better manage your pharmacy benefit strategy.

Clinical Pharmacist Highlight: HAE

HAE involves recurrent attacks of severe swelling (angioedema) in different places in the body including hands, feet, genitals, stomach, face, and throat. These attacks are often mistaken for allergic reactions or other conditions making it difficult to diagnose. They can be triggered by physical trauma or emotional stress, but many times the attacks happen without a known trigger. HAE usually begins in childhood or adolescence, can take years for formal diagnosis due to its rarity or misdiagnosis, and continues throughout an individual’s lifetime. HAE is genetic; if you have one member with HAE, chances are you may also have a family member or two in need of these high-cost drug therapies as well.

Affecting approximately 6,500 individuals in the US, this disease can result in emergency department visits and hospitalizations because of uncontrolled or poorly managed angioedema attacks. Attacks can involve incapacitating pain and discomfort, and those that involve the upper airway (laryngeal attacks) can be life-threatening requiring immediate medical attention. Although it is estimated that only 1-3% of attacks involve the upper airway, 50% of patients with HAE will experience at least one laryngeal attack in their lifetime. Fear of HAE attacks alone can lead to high rates of depression and anxiety in patients.

HAE treatment involves two broad strategies:

• Use of on-demand therapy to treat and reduce the impact of attacks
• Use of prophylactic therapy to reduce the frequency and severity of attacks

Therapeutic treatments have evolved, starting in 2008 with the FDA approval of Cinryze (intravenously (IV) administered every 3-4 days for prevention of HAE attacks) to more recently oral and self-administered subcutaneous (SC) options. Ease of use and less-frequent administration and effectiveness of therapy are key components of therapy selection, as some individuals experiencing less frequent attacks only require on-demand therapy while others benefit greatly from the use of prophylactic therapy.

Approved in July, Ekterly (sebetralstat) is the first oral on-demand medication for treatment of HAE. Like other on-demand medications, the first dose is taken at the onset of symptoms of an attack, and a second dose (known as redosing) can be taken at least 3 hours after if the response to the first dose is inadequate or if symptoms worsen or recur. In clinical trials, 38% of patients took a second dose within 12 hours. Other available on-demand therapies are injectable (IV or SC). An oral option enhances ease of use while remaining similar in cost. It may require redosing more often than other on-demand options which can result in a higher cost per attack

Why It Matters To Payers: Rare Condition with High Costs

The cost of HAE therapies can be substantial, with annual expenses exceeding $750,000 per person. Costs can further increase if attacks are more frequent or severe, which require more on-demand or acute medications as well as an increased likelihood of an emergency department visit or hospitalization.

Even if you do not have a current HAE patient, plan sponsors should be proactive in ensuring the right clinical management strategy is in place. Considerations should include drug benefit coverage with utilization management, the number of members with the diagnosis in the population, and how specialty pharmacies in the network are helping members to ensure the best clinical outcomes.

HAE Drug Benefit Considerations

Due to the high cost of HAE therapies and potential for overuse or misuse, we recommend UM strategies including prior authorization and quantity limits to ensure proper diagnosis, appropriate use, and optimal drug therapy benefit for patients. Step therapy could be considered to promote use of lower-cost treatments.

For example, when considering on-demand therapy, icatibant (generic Firazyr) is the lowest cost option and is a self-administered SC injection. In clinical trials, 9 out of 10 attacks were treated with a single dose, similar to other SC options. Approved for use in adults 18 years and older, it could be considered a first line therapy option in place of higher-cost branded on-demand options like Ekterly (sebetralstat), Berinert, or Ruconest. Treatment guidelines recommend patients have two standard doses on hand to effectively manage acute attacks. It’s not uncommon to find excessive quantities of drugs for on-demand treatment dispensed resulting in very high costs for payers. Excessive use of on-demand therapy can be an indication for intervention and assessment by the HAE care team.

The newest preventive or prophylactic treatment options include Andembry, which is a once monthly self-administered SC injection, and Dawnzera, a self-administered injection every 4-8 weeks. These new medications offer less frequent dosing which can be more favorable for patients and provide new ways to reduce or stop HAE attacks from occurring. This creates different options for patients who haven’t achieved optimal benefit from existing therapies.

Andembry is one of the costliest treatment options available at just under $700,000 per year, while Dawnzera is the costliest, when dosed every 4 weeks, at an estimated annual cost of $747,000. Product labeling for Dawnzera suggests less frequent dosing every 8 weeks may be considered. Cost of therapy, dosing frequency, clinical effectiveness, and first-line use of clinically appropriate lower-cost therapies should be considered for treatment and prevention of HAE.

UM strategies can be used to limit the number of HAE preventive medications available for coverage or require a trial of less costly, clinically effective treatment options such as Takhzyro (a self-administered injection dosed every 2-4 weeks at an annual cost of more than $500,000) or Orladeyo (an oral once-daily medication at a $310,000 annual cost). Differences in efficacy exist, and assessment of drug therapy benefit upon renewal of PA will be important to collect to ensure patients are achieving optimal drug therapy benefit.  

Integrated Data Highlight: HAE

Understanding the impact of HAE and how to manage it effectively is crucial. However, without data to inform these decisions, plans may be left uncertain and vulnerable to unexpected, and sometimes unnecessary, high costs.

Our consultants utilize PSG’s Artemetrx platform to gather in-depth data about HAE drug utilization and risks within your population. We analyze both pharmacy and medical data (integrated) related to HAE, regardless of the method of administration, whether IV , self-administered, or oral. This comprehensive approach provides insights into medication management options, drug and quantities dispensed, plan sponsor spend and trend, and details to the individual HAE member level. It also tracks emergency department visits, hospitalizations, and medication adherence at the individual drug level, helping to identify patterns in medication utilization.

By leveraging these insights, you can make informed coverage decisions and implement relevant UM criteria that ensure appropriate use and the best clinical outcomes for your members while also containing costs.

Inform Benefit Decisions, Enhance Member Outcomes

Like other rare diseases, members with HAE can benefit from the support and guidance of a thoughtful, team-based approach. Care navigators, pharmacists, and high-touch specialty pharmacy teams can optimize treatment regimens and assist in identification of HAE triggers. This coordinated care delivery can lead to less life-threatening attacks and a higher quality of life for individuals living with HAE.

As an employer or health plan, do your part in your important role of providing access to these life-changing medications. Create a sustainable strategy protected from unforeseen costs. Effective management begins with having the right insights.

At PSG, our clinical expertise converges with cutting-edge data intelligence through Artemetrx, empowering healthcare leaders with unparalleled strategic insights. If you would like to learn more about how integrated data can help support your pharmacy benefit strategy, connect with our experts!