Rare Disease, Rapid Progress: FDA's HAE Approvals in 2025 Signal Changing Course

A disease often associated with delayed diagnosis and treatment, hereditary angioedema (HAE) has drawn significant attention in 2025. The US Food & Drug Administration (FDA) approved 3 HAE treatments in just 3 months: garadacimab-gxii (Andembry) in June, sebetralstat (Ekterly) in July, and donidalorsen (Dawnzera) in August.1,2,3

“It's awesome. I love them all. It's like my children; you don't have a favorite,” Daniel Soteres, MD, PhD, from the University of Colorado Health Sciences Center, told HCPLive. “Every patient has an individual set of values, an individual health literacy. Their needs change over time. What works for a 5, 10, or 12-year-old may not work for a 16- or 18-year-old, [which] may not work for a 45-year-old. Having multiple options available for these patients is important.”

HAE, a rare genetic condition that causes recurrent, unpredictable, and potentially life-threatening swelling attacks in the face, throat, abdomen, hands, genitals, and feet, is estimated to occur in 1 in 50,000 people worldwide and 6,000 people in the United States.4

The disease can be difficult to diagnose since its symptoms often overlap with other forms of angiodema. A report published in May 2025 stated that up to 90% of HAE-related deaths occur in undiagnosed patients experiencing asphyxiation.5 

HAE has a large burden on patients’ lives. At the 2025 American College of Allergy, Asthma, & Immunology (ACAAI) Annual Scientific Meeting in Orlando, Florida, several speakers, including Soteres, highlighted new data showing that children with HAE often face delayed or inconsistent emergency care, shaping long-term negative views of their condition.6 Another study found the burden is greater than previously recognized, with missed school and activities in childhood and continued academic underachievement and absences into adolescence.7

Before June, there were 9 FDA-approved treatment options for HAE on the market, including 4 preventive and 4 attack-targeting therapies.8 Preventive therapies included berotralstat (Orladeyo; 2020), lanadelumab-flyo (Takhzyro; 2018), and C1 esterase inhibitor (human) products (Haegarda in 2017 and Cinryze in 2008), whereas treatments for acute attacks comprised conestat alfa (RUCONEST; 2014), icatibant (2011), C1 esterase inhibitor (human) (Berinert; 2009), and ecallantide (Kalbitor; 2009).8 These agents primarily work by replacing C1-INH, blocking bradykinin, or inhibiting kallikrein. Administration routes vary, with options of IV, subcutaneous, and oral. 

As of 2026, 12 FDA-approved products are available to prevent or treat HAE, enabling more personalized treatment plans. The newer therapies either act earlier in the HAE pathway, offer novel routes of administration, or leverage innovative molecular mechanisms.

“It makes me really proud,” said Raffi Tachdjian, MD, MPH, from UCLA Health. “I’ll speak on behalf of my colleagues, too, who are the specialists in HAE, that in the span of just 3 months, there were 3 new treatment modalities approved in HAE, which is mind-blowing, really, but it's really a testament to all the work that's gone into [the field] in the last two decades. If we think back 16 years ago, that’s when the launch of modern-era medicine came out for hereditary angioedema and and to think of how far we’ve come in the treatment landscape just makes my other colleagues and other specialties envious of the advances that we have made.”

Garadacimab-gxii

The FDA approved garadacimab-gxii, the only treatment targeting factor XIIa for prophylactic use to prevent HAE attacks in adults and children aged ≥ 12 years on June 16, 2025. This approval was awarded to CSL.

Garadacimab-gxii is the first HAE treatment to provide once-monthly dosing from day 1. Administered through a citrate-free, subcutaneous autoinjector in 15 seconds or less, it targets the top of the HAE cascade to prevent attacks. The therapy already holds approvals for treating HAE attacks in Australia, the United Kingdom, the European Union, Japan, Switzerland, and the United Arab Emirates.

The FDA’s decision relied on pivotal data from the placebo-controlled phase 3 VANGUARD trial, which evaluated garadacimab-gxii for prophylactic HAE treatment. In the study, participants received monthly subcutaneous injections of garadacimab-gxii or placebo for 6 months after an initial loading dose. Garadacimab-gxii led to 62% of treated patients remaining attack-free and produced ≥ 99% reductions in overall HAE attacks, attacks requiring on-demand therapy, and moderate or severe attacks compared with placebo. 

Sebetralstat

On July 7, 2025, KalVista Pharmaceuticals announced that the FDA approved sebetralstat, the first oral, on-demand therapy for the treatment of acute attacks of HAE in adult and pediatric patients aged ≥ 12 years.

Sebetralstat, a novel plasma kallikrein inhibitor, was studied in the phase 3 KONFIDENT and KONFIDENT-S open-label extension trials, where investigators reported a median time from attack onset to treatment of 4 minutes among 19 adolescents patients, with symptom relief beginning at a median of 1.79 hours, severity decreasing by 3.53 hours, and complete resolution occurring by 15.09 hours. These results build on the topline 2024 KONFIDENT data showing a median 1.3-hour time to symptom relief across 136 patients experiencing laryngeal, abdominal, or breakthrough attacks while on prophylaxis.

Donidalorsen

The third HAE approval of 2025, Ionis Pharmaceuticals’ donidalorsen, was announced on August 21, 2025. The FDA approved donidalorsen, an RNA-targeted medicine, to prevent HAE attacks in adults and children aged ≥ 12 years.

The decision followed a 2023 Orphan Drug Designation and drew on pivotal data from the phase 3 OASIS-HAE and OASISplus trials and the ongoing phase 2 OLE study, which together showed that donidalorsen, targeting prekallikrein, produced sustained reductions in HAE attacks, including a 96% mean reduction over 3 years in the OLE trial.

In OASIS-HAE, donidalorsen 80 mg every 4 or 8 weeks significantly lowered monthly attack rates by 81% and 55%, with 91% of patients on 4-week dosing achieving good disease control. OASISplus further demonstrated continued improvement after switching from other prophylactic therapies, with more than 90% attack-rate reductions and strong patient preference for donidalorsen.

What’s Next in HAE Research

HAE treatments in the pipeline include:

• ADARx Pharmaceuticals’ ADX-324: A short-interfering RNA therapy in development to reduce the production of prekallikrein
• Pharvaris’ deucrictibant: An oral bradykinin B2 receptor antagonist in development for both on-demand and prophylactic use
• Astria’s navenibart: A plasma kallikrein inhibitor delivered subcutaneously)
• Intellia’s lonvoguran ziclumeran: A single-dose gene-editing therapy using CRISPR/Cas9 technology, designed to inactivate the kallikrein B1 gene that controls kallikrein production

Beyond these drugs, several experts addressed the same critical need for HAE: treatments indicated for children under 12 years old.

“The burden of these attacks on children has previously been considered more of [an issue beginning at] the onset of puberty—you know, 11, 12, 14, 15 years old,” Soteres said. “It turns out [that] when you talk with healthcare providers, the caregivers, and the adolescents who are helping control and manage this disease and understand this disease, the attacks actually start a lot younger, as early as 5 years old, and some reports even as young as 2…As a pediatric-trained hereditary angioedema specialist, I see a lot of adults, but I do worry about the younger ones.”

In an interview with HCPLive, Michael Manning, MD, an allergy, asthma, & immunology specialist located in Arizona, also pointed to the limited treatment options for children under 12 with HAE as a key unmet need.

“HAE is really a disease of childhood,” Manning said. “Eighty-five percent of patients develop symptoms before the age of 20.”

Experts also highlighted additional research needs, including improving treatment portability and addressing gaps for rural patients, individuals who dislike or require frequent injections, and those who prefer not to take a daily pill.

But for now, the approvals of garadacimab-gxii, sebetralstat, and donidalorsen reflect a field gaining unprecedented momentum.

“We joke a little bit that there's going to be more HAE drugs than patients out there,” Manning said. “You know that's way off, but it's nice because the more we know, and the better we get at treating this, the better we get [at] finding a medication that is going to reach that goal of total control, and things like donidalorsen really get us really close with a potentially a 6 time a year injection to control this, versus something you’re doing every 2 to 3 or 4 days initially. So [we are] making great strides, and I’m happy about it. I like the research and development and finding ways to find something that everybody is going to potentially do well with.”

References:

1. Derman C. FDA Approves Factor XIIa-Targeting Garadacimab-gxii (ANDEMBRY) for HAE Attacks. Hcplive.com. Published June 17, 2025. Accessed November 26, 2025. https://www.hcplive.com/view/fda-approves-factor-xiia-targeting-garadacimab-gxii-andembry-for-hae-attacks

2. Johnson V. Sebetralstat FDA-Approved as First Oral, On-Demand for Hereditary Angioedema. Hcplive.com. Published July 7, 2025. Accessed November 26, 2025. https://www.hcplive.com/view/sebetralstat-fda-approved-as-first-oral-on-demand-for-hereditary-angioedema

3. Derman C. FDA Approves Donidalorsen to Prevent Hereditary Angioedema Attacks. HCPLive.com. Published August 21, 2025. Accessed November 26, 2025. https://www.hcplive.com/view/fda-approves-donidalorsen-to-prevent-hereditary-angioedema-attacks 

4. Learn About Hereditary Angioedema. DiscoverHAE. https://www.discoverhae.com/what-is-hereditary-angioedema

5. Grumach AS, Riedl MA, Cheng L, Jain S, Nova Estepan D, Zanichelli A. Hereditary angioedema diagnosis: Reflecting on the past, envisioning the future. World Allergy Organ J. 2025 May 14;18(6):101060. doi: 10.1016/j.waojou.2025.101060. PMID: 40487881; PMCID: PMC12142509.

6. Stewart P. Emergency Care Still Falling Short for Children With HAE, With Patricia Stewart, MD. Hcplive.com. Published November 18, 2025. https://www.hcplive.com/view/emergency-care-falling-short-children-hae-patricia-stewart-md

7. Tachdjian R. Importance of Addressing the Psychosocial Burden of HAE Among Children, With Raffi Tachdjian, MD. Hcplive.com. Published November 18, 2025. https://www.hcplive.com/view/importance-addressing-psychosocial-burden-hae-among-children-with-raffi-tachdjian-md

8. US Hereditary Angioedema Association. Haea.org. Published 2020. https://www.haea.org/pages/p/treatments