Payers Should Keep Eye on Evolving HAE Space
by Angela Maas
Although hereditary angioedema is a relatively rare disease, pharma manufacturers continue to pursue therapies for HAE. The FDA approved a handful of novel new therapies last year, and more treatments are in the late-stage pipeline, some of which offer improved dosing over available options.
The genetic condition, which affects one in every 20,000 to 50,000 people, causes episodes of swelling in different body parts, such as the face, throat, hands or abdomen and can be fatal. It is mainly classified into three types. About 85% of patients are Type 1, which is characterized by low levels of the C1 esterase inhibitor protein. About 15% are Type 2 with normal or high levels of the protein, but it is dysfunctional. People with the very rare Type 3 have normal levels and function of the C1esterase inhibitor but have mutations in other genes.
Medications consist of therapies to treat acute HAE attacks and prophylactic agents to prevent attacks.
Last year, the FDA approved three new agents that offered advances in the field: Andembry (garadacimab-gxii) from CSL in June, KalVista Pharmaceuticals, Inc.’s Ekterly (sebetralstat) in July and Dawnzera (donidalorsen) from Ionis Pharmaceuticals, Inc. in August.
Andembry is the first and only factor XIIa inhibitor for HAE prophylaxis and is indicated for people at least 12 years old. Dosing via subcutaneous injection is once monthly.
Also approved for prophylaxis in people at least 12, Dawnzera, a plasma prekallikrein-directed oligonucleotide, is the first and only RNA-targeted medicine for HAE. The subcutaneous injectable is administered monthly although its label indicates that bimonthly dosing “may also be considered.”
The plasma kallikrein inhibitor Ekterly is indicated for the treatment of acute HAE attacks in people at least 12 years old. The medication is a tablet, making it the first oral route of administration approved for the indication.
With these approvals, there are 12 agents for HAE, evenly split between on-demand treatment and prophylaxis. Multiple generics of Takeda’s bradykinin B2 receptor antagonist Firazyr (icatibant), which treats acute HAE attacks, are available.
During a Feb. 2 Evercore ISI Immunology Expert Discussion hosted by analyst Gavin Clark-Gartner, Jonathan Field, M.D., a New York-based allergist-immunologist, explained that about two-thirds of his patients are on prophylactic therapy to prevent HAE attacks, and they always have an on-demand agent as well “just in case.” The remaining patients are on medication for acute attacks only.
Treatments Have Evolved in ‘Circular Way’
The evolution of treatments, he explained, has occurred “in a circular way,” starting from no treatments when he began practicing to the October 2008 approval of prophylactic drug Cinryze (C1 esterase inhibitor [human]) from Shire plc (which was later acquired by Takeda).
Firazyr’s August 2011 approval was a “real watershed,” claimed Field, as people could self-administer the drug during an attack rather than having to seek out treatment at a hospital or a physician’s office.
Over the years, several other therapies were approved, with one notable prophylactic agent, Takeda’s Takhzyro (lanadelumab-flyo), getting FDA approval in August 2018. People with HAE who had been resistant to prophylaxis now had a subcutaneous injectable option as opposed to an infusion, and they could dose it only once or twice a month as opposed to the more-frequent regimens of other agents.
Then, “the Holy Grail…that changed things,” he said, was the December 2020 approval of BioCryst Pharmaceuticals, Inc.’s Orladeyo (berotralstat) as the first oral, once-daily prophylactic medication. It was appealing to people unsure of whether they needed prophylaxis: “It’s simple. Everyone takes a pill. It’s straightforward; it works.”
Might Prophylactic Use Improve Again?
People’s willingness to take a preventive agent certainly depends on the severity and frequency of attacks, said Field. However, the availability of longer-acting agents, with time between doses stretching to every three or six months, may indeed boost uptake of these medications.
He said he has patients who are on Ekterly, mainly treatment-naïve people. The efficacy is good, he noted, but the drug is new, and his “biggest battle right now is getting coverage. The company is great, the reps are good,” as is the hub. But with “any new drug, no matter what the company says, it’s going to take a year for the insurances to recognize that.”
The appeal of having “to put a pill in their pocket and carry it is a good thing,” Field contended.
That said, injectable weight-loss and migraine drugs have helped counter the stigma of having to inject an HAE therapy, whether for prophylactic or on-demand use, he observed, so resistance to this route of administration may not be as high now as it was four or five years ago.”
Still, with HAE, “the quicker you use the acute treatment, the better outcome you have,” making an oral agent more desirable.
As far as the prophylactic drugs, among Field’s patient population, a “handful” of people have been taking Cinryze “for 10, 12 years.…It still is an oldie but a goodie in a small group of patients.”
The next most-frequently used agent is Takhzyro “because of the simplicity.” Orladeyo also has some use, with about a quarter of his patients on that agent, and Field has two patients each on the newest agents.
Andembry, he said, “is a very clean drug. It’s got the best side-effect profile.” It’s also helpful for people with Type 3 HAE. While some insurers won’t cover the agent unless patients’ labs confirm HAE, other “insurers have recognized that factor XII inhibition seems to work for all types, so I think the coverage is good.” He has a Type 1 and a Type 3 patient on the agent.
Dawnzera appeals to people who mainly want less-frequent dosing, said Field, who has a Type 1 and a Type 2 patient on this medication.
Among the acute therapies, Pharming Healthcare, inc.’s Ruconest (C1esterase inhibitor [recombinant]) is not used often because it is not indicated for laryngeal use. However, the company is working on a prophylactic version of it, which “might change things.”
Will Long-Acting Drugs Pull Market Share?
With some HAE drugs in the late-stage pipeline, will those newer agents be able to pull share from existing treatments?
While it “depends on the patient,…many of them are open” to switching therapies, Field said. But if people are doing well on a therapy that is not burdensome, “I don’t think there’s a lot of desire to switch.” Another reason for hesitance is the potential that their health plan is not covering an agent, and “these are very expensive drugs,” with many exceeding half a million dollars annually for preventive care and anywhere from about $5,000 to more than $20,000 for on-demand use.
But there are “more sophisticated” patients who are “always looking for the next thing,” including potential gene therapies.
Among the agents to watch is Pharvaris NV’s deucrictibant, an oral bradykinin B2 receptor antagonist under investigation for both on-demand and prophylactic use. On Dec. 3, 2025, the company revealed positive RAPIDe-3 study data for on-demand treatment.
“We always try and find something that can be used both ways,” explained Field, who pointed out that one Orladeyo study explored a larger dose for prophylaxis and a regular dose for acute attacks. Having approval for both indications “may give [deucrictibant] an edge in efficacy” and appeal to payers, prescribers and patients alike.
When deucrictibant is compared with Ekterly, “it really comes down to two things,” he maintained: “onset of relief and completion of complete resolution.” Based on study data, the Pharvaris drug may have a very slight edge in the latter category, he said, but ultimately the medications are “about even.”
Prophylactic Phase 3 data for deucrictibant should be available later this year. So if it has an 80% to 85% overall attack reduction, how may the agent be viewed compared with Orladeyo? Those numbers, said Field, are “better than Orladeyo’s initial data, but now in the late years,” they are “on par.” But if a prescriber has a new patient who needs to improve symptoms quickly, deucrictibant may be the preferred option.
Another late-stage pipeline drug is BioCryst’s navenibart, which the company gained with its acquisition of Astria Therapeutics, Inc., which closed Jan. 23. The plasma kallikrein inhibitor is in Phase 3 studies for prophylactic use, with the potential for every-three-months and every-six-months dosing. Field said he is “extremely” excited for that dosing regimen.
“Other than gene therapy, with a cure, you have to think…this is something that is really revolutionary,” he stated. Twice-yearly treatment is “really a game changer.…Even every three months is impressive,” even though the latter regimen is similar to Dawnzera’s dosing.
As far as HAE gene therapies, NTLA-2002 (lonvoguran ziclumeran) from Intellia Therapeutics, Inc. is one agent in the late-stage pipeline. The CRISPR/Cas9 therapy is designed to inactivate the kallikrein B1 gene for long-term attack prevention.
On Sept. 18, 2025, the company said it had completed patient enrollment for its Phase 3 HAELO study and expected to report Phase 3 topline data in the first half of 2026. Intellia is “on track” to submit a biologics license application (BLA) “in the second half of 2026 for an anticipated U.S. launch in the first half of 2027,” said the company.
According to Field, certain people with HAE may be candidates for gene therapy. Someone whose disease is “severe and life-threatening, and they’re still going to fail therapies” may be interested in that option, as well as a person who “really wants to live a normal life, and they believe in the science; they’re comfortable with the potential side effects.”
It’s hard to have a clear picture of what uptake for such agents may look like, but from a clinical perspective, “if the safety works out, it’s the ‘C’ word — ‘cure’ — that we rarely use.”