Raffi Tachdjian, MD, MPH

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

A disease often associated with delayed diagnosis and treatment, 

 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.

“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.

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.

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.

 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.

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).

 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.”

 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. 

On July 7, 2025, KalVista Pharmaceuticals announced that the 

, 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.

The third HAE approval of 2025, Ionis Pharmaceuticals’ donidalorsen, was announced on August 21, 2025. The 

, 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.

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.”

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

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

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

Learn About Hereditary Angioedema. DiscoverHAE. 

https://www.discoverhae.com/what-is-hereditary-angioedema

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.

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

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

US Hereditary Angioedema Association. Haea.org. Published 2020. 

Articles

Hereditary angioedema (HAE) has seen significant advancements in treatment options, with the FDA approving three new therapies in 2025: garadacimab-gxii, sebetralstat, and donidalorsen. These approvals expand the arsenal of HAE treatments, offering more personalized and effective management strategies. HAE, a rare genetic disorder causing unpredictable swelling, poses diagnostic challenges and significantly impacts patients' lives, especially children. The new treatments target different mechanisms and offer varied administration routes, enhancing patient care. Ongoing research aims to address unmet needs, particularly for children under 12 and rural patients.

Recent advancements in HAE treatments offer hope, but experts stress the need for more pediatric options and diverse therapies.

Importance of Addressing the Psychosocial Burden of HAE Among Children, With Raffi Tachdjian, MD

 is often approached through symptom control and attack prevention. However, emerging data highlight another equally important facet for pediatric patients: the psychosocial toll.

2025 American College of Allergy, Asthma, & Immunology (ACAAI) Annual Scientific Meeting

 in Orlando, Florida, Raffi Tachdjian, MD, MPH, from UCLA Health, presented on a recent study examining the psychosocial impact of HAE on young patients, caregivers, and clinicians.

“When we think of HAE, we've always been focused on the grown-ups,” Tachdjian told 

 during the meeting. “When we think of the pediatric age category, these kids often don't know how to express an attack because they don't have the experience or descriptions, and it could be a novel attack. We see a lot of negativity surrounding it.”

He observed drops in communication and attendance among children with HAE. Children with HAE often report missing both school and after-school activities. This absence raises concerns for many parents and healthcare professionals.

“That burden is higher than we thought it was,” Tachdjian continued. “This study is opening our eyes to that. It's an unmet need.”

These challenges evolve as patients age. Older adolescents begin to experience academic underachievement and ongoing school absences.

Tachdjian emphasized the importance of individualized, multi-pronged strategies. Effective interventions may include counseling, more frequent follow-up with healthcare providers, expanded parent-child communication, or increased peer and social support. He stressed that there is no single formula; instead, shared decision-making and exploration of each patient’s unique fears, such as anticipatory anxiety about future attacks, are critical for reducing distress.

Validated tools such as the Angioedema Control Test and the Angioedema Quality of Life instrument already help clinicians assess psychosocial burden, but new tools and parameters are in development. These could further guide care teams in identifying barriers early and tailoring support to improve long-term outcomes.

“I'd like to highlight that this is a big step,” Tachdjian said. “We're not by any means done, but it's a big step towards pushing this psychosocial aspect of a genetic condition that has other issues that come with it, such as fear, anxiety, depression, lack of communication, social skills, isolation, all things that we could fall into as a trap. As a healthcare team, we want to ensure that we're doing our best to prevent these negatives and really boost the positives.”

Relevant disclosures for Tachdjian include GENZYME CORPORATION, Regeneron Healthcare Solutions, Inc., BioCryst US Sales Co., LLC, Grifols USA, LLC, Takeda Pharmaceuticals U.S.A., Inc., CSL Behring, Pharming Healthcare, Inc., AstraZeneca Pharmaceuticals LP, GlaxoSmithKline, LLC., Dermavant Sciences, Inc., and X4 Pharmaceuticals, Inc.

Tachdjian, R. Psychosocial Impact of Hereditary Angioedema on Young Patients and Their Caregivers. Presented at ACAAI 2025 in Orlando, Florida, from November 6 – 10.

Videos

New qualitative findings reveal the underrecognized psychosocial burdens facing children with HAE and the unmet needs shaping their care.

Raffi Tachdjian, MD, MPH, FAAAAI, FACAAI:

 We could see we’re no longer driving cars—we’re flying airplanes when it comes to treating severe asthma. More intricate, and certainly requires more training and more experience, as we said earlier.

I wanted to thank each and every one of you for this rich and informative exchange and discussion. And I wanted to give you each a few more minutes to summarize your thoughts. I’ll start with you, Dr Chase. Do you have any last thoughts or last words?

: I think overall I’m really grateful to be practicing medicine at this time, the Halcyon era of therapies for asthma. I think that there’s never been a better time for us to really treat asthma. Although we’re not getting to a cure for these patients with asthma as of now. All these treatments, even if some of them may later on be shown to be disease-modifying, really are still chronic treatments. But I think that we’re getting to the point where the adverse effect profile, the tolerability of these medications, is just so good that for many patients, this has been a game changer for them. I’m very excited to be a part of medicine in this day and age. And I hope that patients can tell that we really are giving it our best. This is the reason it’s important to see a specialist for asthma because we’ve spent lots and lots of time learning all of this science. And now finally the pharmacologists are catching up to us in some sense. It’s a fun time to be in allergy and asthma management.

 Well said. Dr Siri, do you have any parting words?

: I think as we focus on biological treatments, they really have the opportunity to revolutionize how we approach and treat moderate to severe asthma. Certainly, we can perhaps move the needle for the first time in decades. In terms of asthma management, we have to talk about the things that we reviewed, including phenotyping the patient and endotyping the patient. Thinking about the severity of asthma, thinking about risks of exacerbation, thinking about exposure to medications that may be harmful and specific to the biologics. We have to think about if these biologics are appropriate for that patient in terms of costs, economics, patient preference, and what their goals are. Are they trying to reduce the corticosteroid burden? Are they trying to improve lung function? Are they trying to reduce exacerbation? We have to communicate these goals very enticingly to the patient, but also clearly. Overall, I think that it’s an exciting time to be an allergist-immunologist dealing with asthma. Hopefully, moderate to severe asthma will improve over time.

 Very well said, as well. Dr White, any last words?

: I had 2 thoughts. The first is something that occurs to me probably once a month when I’m treating a patient. These biologics have really just revolutionized what we’re able to offer our patients. I sometimes think about what I used to do to treat these patients before we had this. And it’s crazy. They’re so essential now. But the other side of that is this other really interesting observation where I’ll see a patient, I’m like, “I have the exact biologic for you. I know that this is going to be amazing for you.” And then they come back in 2 or 3 months, and it was a dud. And the great thing is we have some options, and they may end up taking something that I didn’t necessarily predict that they would do great on, but we get them to a point where their quality of life is dramatically better. It’s sort of humbling to not totally understand this and to have these biomarkers that are still somewhat imprecise. But it’s super exciting. I’m so grateful that we have all of these amazing new options for our patients.

 Thank you for those words, Dr White, and I’ll throw my vote in there too. It sounds like we have high job satisfaction because we’re getting a lot of great responses from our patients, which makes it worthwhile for us to push the needle even further. And in a new era, such as this advent of biologics, it’s really exciting and I actually think it defines our field of allergy immunology. Again, I want to thank you all for this fantastic discussion. And if you enjoyed the content, please subscribe to our e-newsletters to receive upcoming episodes and some great content in your inbox. Thank you.

Raffi Tachdjian, MD, MPH, FAAAAI, FACAAI; Dareen D. Siri, MD, FAAAAI, FACAAI; Nicole Chase, MD, FAAP, FACAAI, FAAAAI; and Andrew White, MD, give final thoughts on asthma management, considering the current treatment landscape.

Final Thoughts on Treatment of Asthma

Raffi Tachdjian, MD, MPH, FAAAAI, FACAAI: 

We talked about biomarkers to start this conversation and segment, to qualify the level of severity of asthma. And we’re going to wind down now and come full circle. Dr Siri, what is the role of biomarkers as you progress prognostically and follow your patients who are on biologics?

: Thank you for asking me that because we’ve all been throwing out the word biomarkers without actually really defining them. The FDA defines biomarkers as something that we can objectively measure that really will give us a prediction in terms of health, disease, perhaps treatment response to a therapeutic, or even just an exposure. Specific to moderate and severe asthma, one of the big biomarkers we’re talking about is the eosinophil count, which is easily measured in a primary care office…. So thank you for doing a great job and getting a CBC [complete blood count] with differential before you refer them. We would love that. An eosinophil count greater than 150 [cells/µL] certainly can be indicative of type 2 inflammation. That is helpful, and that’s been borne out by some clinical studies that we talked about. And a count of 300 or greater has additional prognostic markers.

Fractional exhaled nitric oxide [FeNO] is also really important in terms of that correlation. FeNO may not be as available for a primary care audience, but certainly, for allergist immunologists, we measure it very frequently. And this could be indicative of airway inflammation and certainly interleukin-13 activity. Someone with a FeNO level of 20 or 25 ppb or greater is considered inflamed and could benefit from additional treatment.

You can think of that also in other pulmonary function testing such as spirometry. We can use FEV1 [forced expiratory volume in first second of expiration] as a measure. Also, impulse allometry, which is making a comeback, can be used as a measurement in terms of increased risk.

When we use biomarkers, we can also think about immunoglobulin…or some of the other blood work that we might check. Those don’t have as much of a predictive outcome as eosinophils and FeNO, but they certainly still would be helpful. Lastly, there may be something such as genetic biomarkers. This is becoming more and more advanced as time goes on. And I think at some point we will be able to direct treatment in terms of those genetic factors. That can be very helpful. In terms of the biomarkers, what do they do for us? Certainly, they can help us direct the right therapy. They can help us monitor the patient. They can help us predict the severity of the disease. I do think that we should follow this along because it’s going to be really helpful for us to discover more biomarkers that may be predictive for our patients.

Experts outline biomarkers to measure asthma, highlighting eosinophil count and fractional exhaled nitric oxide levels.