Number of HAE Treatments Increasing

Manage High-Cost Therapies for Rare Disease

August 4, 2020
Senior Vice President, CVS Health and Chief Medical Officer, CVS Caremark
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For the past dozen years, patients with hereditary angioedema (HAE) have witnessed the expansion of treatment options. Since 2008, when Cinryze was approved, HAE treatments have grown to seven injectable therapies available for either prevention or treatment of acute attacks. The first preventive oral agent is expected in the fourth quarter of 2020.

What is HAE?

HAE is a debilitating rare genetic disease that causes swelling affecting different parts of the body but is not treatable using antihistamines, epinephrine, or corticosteroids. The severity and location of these unpredictable attacks vary and, depending on the location of the swelling, HAE can be fatal in up to 30 percent of patients.

It is believed that one in 10,000 to one in 50,000 people have HAE and it affects males and females equally, with symptoms starting in early childhood. More than 50 percent of patients visit an emergency room per year with half of those admitted into the hospital.ttps:// Attacks are self-limiting and typically resolve in two to five days without treatment.

Pictogram of a hospital building

of HAE patients visit the ER per year

Pictogram of a patient

of those are admitted to the hospital

Pharmacy Advisor addresses 10 chronic conditions, that affect 1 in 4 members

While the HAE population is relatively small, treatments are expensive and, without a cure, patients are required to continue medication for the rest of their lives. This makes it important to help ensure member access but also careful management to ensure appropriate utilization.

HAE treatments fall into two categories - some work to prevent attacks from occurring (preventive), while others are used when attacks happen (acute). Some of the therapies help to restore the balance of a blood protein, C1 esterase inhibitor (C1-INH). The C1-INH imbalance causes swelling. Of the three types of HAE, 85 percent of all patients are diagnosed with type I (low C1-INH) and 15 percent with type II (poorly functioning C1-INH). Few patients are diagnosed with HAE with normally functioning C1-INH (formerly known as type III), which was identified in 2000. Patients are often misdiagnosed with other conditions before they are identified as having HAE.

Preventive Treatments

Name Drug Class Route of Administration Patient Age
Cinryze (C1 esterase inhibitor [human]) C1-esterase inhibitor protein IV Children 6 years and over, adolescents, and adults
Haegarda (C1 esterase inhibitor [human]) C1-esterase inhibitor protein SC Adolescents 12 years and over and adults
Takhzyro (lanadelumab-flyo [recombinant]) Kallikrein inhibitor SC Adolescents 12 years and over and adults
Annual preventive treatments cost more than $500,000 on average.

Cinryze, from Takeda, was the first preventive treatment approved by the U.S. Food and Drug Administration (FDA) and is available for patients six years and older. It is administered through an intravenous (IV) infusion every three to four days. Cinryze utilizes human plasma to help increase the level of C1-esterase inhibitor protein to limit unpredictable swelling. Patients can train to self-administer it but that can be difficult due to the frequency of infusions required.

Nearly 10 years after Cinryze came to market, CSL Behring launched Haegarda as the first subcutaneous (SC) C1-INH preventive treatment. Similar to many of the earlier treatments, Haegarda works to replace the missing or dysfunctional C1-INH protein. Its subcutaneous delivery allows for a more gradual diffusion of the medication, as well as being generally preferred by patients compared with IV use, because they can learn to self-administer it. Recommended dosage is every three to four days.

Two years ago, Takeda’s Takhzyro came to market after a priority review by the FDA, with both an Orphan drug and Breakthrough Therapy designation. Clinical trials demonstrated that this kallikrein inhibitor resulted in a significant reduction in average HAE attack frequency compared to placebo over a 26-week treatment period. Administered every two weeks, Takhzyro works in C1-inhibitor deficient or dysfunction patients to reduce bradykinin activity that causes attacks. lanadelumab-in-reducing-hereditary-angioedema-attacks/. Approved in 2018 and self-administered, Takhzyro provides a more accessible preventive treatment for type I and type II patients who are 12 years or older.

Acute Treatments*

Name Drug Class Route of Administration Patient Age
Berinert (C1 inhibitor [human]) C1-esterase inhibitor protein IV Children 6 years and over, adolescents, and adults
Firazyr (icatibant acetate) Selective B2 bradykinin receptor antagonist SC Adults, 18 years and older
Kalbitor (ecallantide) Kallikrein inhibitor SC Adolescents 12 years and over and adults
Ruconest (C1 esterase inhibitor [recombinant]) C1-esterase inhibitor protein IV Adolescents 13 years and over and adults
Approximate treatment cost for each acute HAE attack can exceed $11,000.

Similar to Cinryze, Berinert, CSL Behring’s HAE medication approved in 2009, is also a human plasma-derived C1-esterase inhibitor treatment administered by IV. However, Berinert is not a preventive treatment. It is approved to treat acute abdominal, laryngeal, or facial attacks in adults and children, and can be self-administered.

The FDA approved Kalbitor, the first subcutaneous treatment for acute HAE attacks, for patients 12 years and older. The treatment, from Takeda, inhibits the kallikrein protein, which reduces the effects of an attack and works to halt bradykinin protein creation. One limiting factor for those experiencing an HAE attack is that the patient must have a health care professional administer Kalbitor due to a risk of serious allergic reaction.

Another of the Takeda HAE treatments, Firazyr received FDA approval in 2011. As a selective B2 bradykinin receptor antagonist, Firazyr targets the bradykinin protein that can lead to attacks. Approved for those 18 years and older, the subcutaneous therapy is also portable and can be self-administered, which allows patients to receive treatment at home or at the office of a health care professional.

Ruconest, a manmade therapy from Pharming, received FDA approval in 2014. As the first recombinant IV-administered C1-esterase inhibitor, it can be manufactured without the need to rely on the availability (or safety) of human plasma. Patients aged 13 and older can learn how to self-administer Ruconest, which is sold as a powder to create a solution.

In the Pipeline

In December 2019, the FDA accepted a new drug application for berotralstat from BioCryst. If approved, berotralstat will be the first oral medication for prevention of HAE attacks. It is taken once daily and works to prevent the activity of the kallikrein. Evidence from clinical trials has shown that berotralstat will reduce the frequency of, and lower the need for medication for, acute attacks. It is expected to receive FDA approval in December 2020.

Pill bottle and drop bottle In the past 12 years, treatments have increased options for and started shifting standard of care for HAE patients.

Although there remains no cure for HAE, developments in the drug pipeline offer many patients hope while potentially altering client spend.

Trend and Pipeline Management

Overall spend on HAE treatments are likely to rise because of increased diagnosis, more treatments coming to market, and growth in the use of preventive treatments. In addition, we expect a shift in spending in this class from the medical to pharmacy benefit because of the approval of self-administered SC and oral agents in the pipeline, which make it more convenient for patients to administer the drug. While the expanding number of treatments offer options for patients, careful monitoring and management of the pipeline are key to helping ensure appropriate utilization and cost containment. We proactively develop and offer strategic cost management tools that help mitigate payor trend impact such as exclusive network placement, new-to-market review, prior authorization, and Specialty Guideline Management (SGM) criteria.

Checkmark Medical director review is required for all new and renewal requests for HAE medications prior to approval or denial.
Checkmark Advanced Utilization Oversight, a retrospective clinician review conducted for high cost claims, ensures HAE criteria are appropriately applied and include a comprehensive review of members’ overall therapy.
Checkmark We leverage competition within the class to help lower costs. For instance, we exclude certain products from our standard template formulary, while Takhzyro, Firazyr and Ruconest are preferred.
Checkmark Our SGM criteria is developed from clinical literature, nationally accepted practice guidelines and consensus statements. It is evaluated by the Clinical Program Oversight (CPO) Review Process, which includes criteria review by CVS Caremark Medical Directors and appropriate external clinical experts.

HAE is also part of the AccordantCare Rare nurse care management program. Specialized AccordantCare teams — comprised of registered nurses, social workers, and a medical director, all backed by a medical advisory board — offer whole-person support for plan members with rare conditions through targeted interventions designed to meet each person’s unique needs. This helps members better manage their condition, as well as comorbidities and side effects, for improved outcomes.

Want to learn more about treatments used to treat HAE? Ask Us
August 4, 2020
Senior Vice President, CVS Health and Chief Medical Officer, CVS Caremark

*Frequency and severity of attacks vary.

This document contains references to brand-name prescription drugs that are trademarks or registered trademarks of pharmaceutical manufacturers not affiliated with CVS Health.

Image source: Licensed from Getty Images, 2020.