Raffi Tachdjian, MD, MPH

In the second part of his conversation with HCPLive, Raffi Tachdjian, MD, MPH, from the department of pediatrics at the University of California Los Angeles, further contextualized new real-world data demonstrating sustained reductions in 

 attack rates at 18 months following initiation of berotralstat (ORLADEYO).

Tachdjian emphasized that one of the most clinically meaningful aspects of the analysis is its scale and inclusion of patients with normal C1 inhibitor HAE (HAE-nC1INH), a subgroup historically underrepresented in clinical trials. The study cohort represents one of the largest real-world populations receiving long-term oral prophylaxis, offering insight into treatment performance beyond controlled trial settings.

The analysis included patients with HAE from Optimal Care (Dec 2020–Jan 2024) with ≥ 2 dispensings and documented attack assessments before and after treatment. Among the sample, 390 had a C1 esterase inhibitor (C1INH) deficiency, and 311 had normal C1INH (HAE-nC1INH).

Over 12 months, mean monthly attack rates decreased from 2.50 to 0.79 among patients with HAE-C1INH and from 4.59 to 1.68 among those with HAE-nC1INH (both P <.001). Reductions continued through 18 months of follow-up and were observed regardless of baseline attack frequency or HAE subtype.

In this Q&A, Tachdjian explains how to interpret the sustained attack reductions at 12 and 18 months, explores differences in response between HAE-C1INH and HAE-nC1INH that may influence treatment decisions, and discusses how these real-world data complement or differ from findings in clinical trials.

 What is the most clinically meaningful takeaway from these real-world attack rate reductions following berotralstat initiation?

The exciting thing about this study is that it represents one of the largest real-world patient population cohorts that are receiving long-term prophylaxis for hereditary angioedema, and this [includes] patients with normal C1 inhibitor HAE. This is a population in which clinical data are limited.

 How should clinicians interpret the sustained reductions at 12 and 18 months when counseling patients about long-term prophylaxis expectations?

The significant attack reductions observed at 12 months and sustained at 18 months in this study suggest that the clinical benefit of treatment with ORLADEYO can be maintained over time, including in patients with higher baseline disease activity and different HAE types. This provides additional context for treatment discussions, reinforcing that long-term prophylaxis with ORLADEYO can offer durable disease control for many patients—an essential objective in the management of hereditary angioedema.

 Were there differences in response between HAE-C1INH and HAE-nC1INH that should influence treatment strategy?

In this real-world study, we observed clinically and statistically meaningful differences in response for patients with HAE-C1INH and those with HAE-nC1INH, which is notable given the more limited evidence base in the latter group. These findings suggest that ORLADEYO could be considered as part of a long-term prophylactic strategy for people with HAE regardless of type.

 How does real-world specialty pharmacy data complement—or differ from—what we learned in clinical trials?

While clinical trials establish efficacy and safety in a controlled environment, real-world specialty pharmacy data show us how ORLADEYO performs across a diverse HAE population in routine clinical practice, including patients with varying disease severity and types. Seeing significant and sustained attack reductions outside the trial setting through a protocol-driven real-world study reinforces confidence in the role of ORLADEYO as a long-term prophylactic option across HAE types and disease severity.

Tachdjian R. HCPLive. Sustained HAE Attack Reductions at 18 Months with Berotralstat, With Raffi Tachdjian, MD. HCPLive. Published on February 16, 2026. Accessed on February 18, 2026. 

https://www.hcplive.com/view/sustained-hae-attack-reductions-18-months-berotralstat-raffi-tachdjian-md

Davis-Lorton M, Tachdjian R, Lopez-Gonzalez L, et al. Attack rate reductions following berotralstat initiation among US patients with hereditary angioedema in the real-world. 

Articles

A large specialty pharmacy cohort supports sustained reductions in attack rates across HAE subtypes, including normal C1 inhibitor disease.

Real-World HAE Control with Berotralstat at 18 Months, With Raffi Tachdjian, MD

Sustained HAE Attack Reductions at 18 Months with Berotralstat, With Raffi Tachdjian, MD

In a large real-world cohort, berotralstat initiation was associated with significant reductions in monthly 

 attack rates at 12 months, with sustained benefit through 18 months across HAE subtypes and baseline severities.

“The exciting thing about this study is that it basically represents one of the largest real-world patient population cohorts that are receiving long-term prophylaxis for hereditary angioedema, and this included patients with normal C1 inhibitor HAE,” Raffi Tachdjian, MD, MPH, from the department of pediatrics at the University of California Los Angeles, told 

 “This is a population in which the clinical data are limited.”

The retrospective analysis leveraged specialty pharmacy data from Optime Care, between December 2020 and January 2024. Investigators evaluated 390 patients with HAE with C1 esterase inhibitor (C1INH) and 311 with normal C1INH (HAE-nC1INH) who had at ≥ 2 dispensing and documented attack assessments before and after treatment initiation. Patients were stratified by baseline attack frequency (≥ 5, 2–4, 1, or 0 attacks per month).

Over 12 months, mean monthly attack rates fell from 2.50 to 0.79 among patients with HAE-C1INH and from 4.59 to 1.68 among those with HAE-nC1INH (both 

 < .001), with reductions maintained through 18 months of follow-up. Reductions were observed regardless of baseline attack frequency or HAE subtype.

Among patients with ≥1 attack per month at baseline, initiation of berotralstat resulted in statistically significant declines in attack rates. Most patients with 0 baseline attacks per month-maintained attack-free status during follow-up (70–85% in HAE-C1INH; 61–81% in HAE-nC1INH), reinforcing the durability of response.

Tachdjian underscored the importance of re-discussing prophylactic options with clinicians. He characterized berotralstat as a viable first-line option or alternative for patients dissatisfied with injectable prophylaxis, particularly those with needle aversion or treatment fatigue. With recent label expansion down to age 2 years, he said that the oral agent now spans a broader pediatric-to-adult population.

“I don't think there remain too many unanswered questions as far as durability or tolerability,”

“Obviously, we continue to have vigilance in any drug that's out there, but whether it's the specialty pharmacy data, obviously, the clinical trials, the pivotal phase 3 data that is read out, really point to the fact that this has efficacy and safety, both things we look for. In my mind…there's compliance with the regimen and reporting back on any kind of attacks or safety signals to make sure that they are being taken care of in this prophylactic environment.”

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.

Davis-Lorton M, Tachdjian R, Lopez-Gonzalez L, et al. Attack rate reductions following berotralstat initiation among US patients with hereditary angioedema in the real-world. 

Videos

Real world study shows significant 12- and 18-month attack rate reductions across HAE subtypes and baseline severities following berotralstat initiation.

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. 

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.”

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

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