University of Colorado Health Sciences Center

Daniel Soteres, MD, PhD

Quality of life (QoL) scores improved over 15 months in patients with 

 who treated breakthrough attacks with sebetralstat while on long-term prophylaxis (LTP), according to the recent KONFIDENT-S open-label extension analysis.

 Investigator Daniel F. Soteres, MD, MPH, a physician from Asthma & Allergy Associates, PC, discussed what those gains mean for patients already considered well-controlled.

“When you think about using a new medication, we want to know: Is it safe? Is it effective? And then our patients definitely want to know…what will it offer them in terms of improvement in their quality of life,” Soteres said.

Sebetralstat Shows QoL Gains on Top of HAE Prophylaxis in KONFIDENT-S

The analysis included 35 participants with type 1 HAE who experienced a total of 504 breakthrough attacks despite being on a long-term prophylaxis of either berotralstat (n = 16), lanadelumab (n = 13), or C1 inhibitor replacement (n = 6). With sebtralstat, the median time to the beginning of symptom relief was 1.3 hours for both berotralstat and lanadelumab and 1.8 hours for C1 inhibitor LTP.¹ Only 1.6% of the breakthrough attacks went untreated, and 22.3% of attacks required a second dose of sebtralstat within 12 hours.

The median time from attack recognition to sebetralstat administration was 6 minutes overall. This ranged from 1 minute in participants on C1 inhibitor LTP to 20 minutes in those on berotralstat. In this study, nearly 30% of attacks were treated while still mild.

Sebetralstat Improves Quality of Life in HAE

QoL scores were available for 34 participants. Among these patients, Angioedema Quality of Life Instrument scores improved by a squares mean of 10.3 points (−21.1 to 0.6) from baseline to month 15, exceeding the threshold considered clinically meaningful. The largest gains were in the fatigue/mood (-13.3), followed by gains in fears/shame (-11.2) and functioning (-9.6).¹ Treatment satisfaction was high, with 88.8% of sebetralstat-treated attacks rated satisfactory and 75.0% rated very or extremely satisfactory.¹

The Smaller C1 Inhibitor Subgroup in KONFIDENT-S

Effectiveness signals looked somewhat different among the 6 participants receiving C1 inhibitor (C1INH) LTP, whose median time to complete attack resolution was 16.6 hours versus 10.9 hours for berotralstat and 15.1 hours for lanadelumab.¹ Soteres cautioned against overinterpreting the small subgroup, noting patients on C1INH may be more accustomed to relief from injectable therapies, representing "a real paradigm shift" in understanding that a pill could offer comparable results. He added there could also be subtle differences in disease chemistry that respond more slowly, though efficacy still held for these patients.

Soteres said the findings reinforce existing guidance rather than change it: patients with HAE, including those stable on LTP, should keep 2 doses of on-demand therapy available at all times, a standard he has built into his own practice. He said sebetralstat's oral route remains a favorable on-demand option even for patients who continue to have it available alongside injectable choices.

Read part 1 of our interview with Soteres here: 

Sebetralstat Resolves Breakthrough HAE Attacks Despite Prior Prophylaxis.

Editor’s note: Reported disclosures for Soteres include KalVista Pharmaceuticals, BioCryst, CSL Behring, Intellia Therapeutics, Ionis Pharmaceuticals, Pharming, Pharvaris, and Takeda.

Kinaciyan T, Aygören-Pürsün E, Martinez-Saguer I, et al. Sebetralstat for breakthrough attacks in patients with hereditary angioedema receiving long-term prophylaxis in KONFIDENT-S. 

. 2026;5(5):100750. Published 2026 Jun 12. 

Johnson V. Sebetralstat Shows Long Term Fast Relief of Breakthrough HAE Attacks. HCPLive. Published July 21, 2026. Accessed July 24, 2026. 

https://www.hcplive.com/view/sebetralstat-shows-long-term-fast-relief-breakthrough-hae-attacks

Soteres D. Sebetralstat Resolves Breakthrough HAE Attacks Despite Prior Prophylaxis. HCPLive. Published July 24, 2026. Accessed July 24, 2026. 

https://www.hcplive.com/view/sebetralstat-resolves-breakthrough-hae-attacks-prior-prophylaxis

Videos

Daniel Soteres, MD, discusses KONFIDENT-S data showing sebetralstat improved quality of life for HAE patients already stable on long-term prophylaxis.

show oral sebetralstat produced rapid, consistent symptom relief for breakthrough 

attacks in patients already on long-term prophylaxis (LTP) and left just 1.6% of attacks untreated.¹ Effectiveness was consistent regardless of which prophylactic agent patients were taking, with a median time to symptom relief of 1.3 hours.

Sebetralstat Resolves Breakthrough HAE Attacks Despite Prior Prophylaxis

The analysis evaluated 35 participants with HAE due to C1-inhibitor deficiency receiving LTP with berotralstat (n = 16), lanadelumab (n = 13), or C1 inhibitor replacement (n = 6).¹ Despite background prophylaxis, these participants experienced 504 breakthrough attacks and treated 382 of them (75.8%) with sebetralstat 600 mg, an oral plasma kallikrein inhibitor.¹

“Even people who are on those preventative therapies…can have breakthrough attacks of hereditary angioedema, and when that happens, the sebetralstat product worked well for them, even though it has an overlapping mechanism of action with some of those products," Investigator Daniel F. Soteres, MD, a physician from Asthma & Allergy Associates, PC, told 

He added that global guidelines call for every patient with HAE to keep 2 doses of on-demand medication available at all times in case an attack does not respond to the first.

KONFIDENT-S Data Show Consistent Relief Across LTP Regimens

Median time to beginning of symptom relief was 1.3 hours for participants on berotralstat, 1.3 hours for lanadelumab, and 1.8 hours for C1 inhibitor LTP.¹ Median time from attack recognition to sebetralstat administration was 6 minutes overall, ranging from 1 minute in participants on C1 inhibitor LTP to 20 minutes in those on berotralstat, and nearly 30% of attacks were treated while still mild.¹

Only 1.6% of the 504 breakthrough attacks went untreated, compared with roughly 50% of attacks in a prior real-world study of injectable on-demand therapy.¹ A second dose of sebetralstat was needed within 12 hours in 22.3% of attacks, and conventional injectable therapy was used in just 5.2% of sebetralstat-treated attacks.¹ Treatment-emergent adverse events occurred in 65.7% of participants, with 14.3% considered treatment-related, most commonly headache, nausea, and vomiting; no serious or severe treatment-related events were reported.¹

Counseling Patients Through Overlapping Mechanisms And Treatment Timing

Soteres said the overlapping mechanism of action between sebetralstat and kallikrein-inhibiting LTP agents was never a concern for him clinically.

"I'm an allergy and asthma doctor,” Soteres said. “We use overlapping mechanisms of action to treat disease in many regards.”

He also pointed to the oral, self-administered format as a likely driver of earlier treatment, since patients no longer need a private setting to self-inject and may feel more comfortable taking it. On setting expectations, Soteres cautioned that sebetralstat should not be framed to patients like an epinephrine autoinjector.

"It's not going to work in seconds," he said. “You do have to take the medicine and calm yourself. Let your loved one know what's going on and let the medicine do its job. You have to let the medicine do its work [for] over 20 minutes.”

Kinaciyan T, Aygören-Pürsün E, Martinez-Saguer I, et al. Sebetralstat for breakthrough attacks in patients with hereditary angioedema receiving long-term prophylaxis in KONFIDENT-S. 

. 2026;5(5):100750. Published 2026 Jun 12. 

Johnson V. Sebetralstat Shows Long Term Fast Relief of Breakthrough HAE Attacks. HCPLive. Published July 21, 2026. Accessed July 24, 2026. 

New international guideline for HAE management - HAE International (HAEi). HAE International (HAEi). Published May 3, 2022. Accessed July 24, 2026. 

https://haei.org/new-international-guideline-for-hae-management/

Articles

Interim KONFIDENT-S results indicate oral sebetralstat 600 mg enabled rapid, consistent control of breakthrough hereditary angioedema attacks among patients with C1-inhibitor deficiency receiving long-term prophylaxis (berotralstat, lanadelumab, or C1 inhibitor). Across 504 attacks, median time to initial symptom relief was ~1.3 hours (1.8 hours with C1 inhibitor prophylaxis), and only 1.6% of attacks were untreated. Early, self-administered dosing likely supported prompt use, with acceptable tolerability and no serious treatment-related events.

Daniel Soteres, MD, discusses KONFIDENT-S data showing sebetralstat quickly resolves breakthrough HAE attacks in patients on long-term prophylaxis

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.

HAE Attacks May Begin as Early as 2 Years Old, With Daniel Soteres, MD, PhD

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

, Daniel Soteres, MD, PhD, from the University of Colorado Health Sciences Center, presented new data on the attack burden affecting children aged 2 – 11 years with 

“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 told HCPLive during the meeting. “It turns out when you talk with healthcare providers, the caregivers, and the adolescents who are helping control and manage this disease and understand this disease, that the attacks actually start a lot younger, as early as 5 years old, and some reports even as young as 2.”

The analysis incorporated 3 stakeholder perspectives: caregivers of children aged 2–11 years, adolescents aged 12–17 years who completed the questionnaire themselves, and clinicians across allergy/immunology, pediatrics, and primary care who were interviewed about their experiences treating pediatric HAE. Together, these viewpoints helped characterize daily life disruptions that have not been well quantified in the literature.

Soteres emphasized that HAE attacks in children are often misunderstood. Rather than brief episodes, attacks can escalate over several hours and peak for 2 to 5 days, interfering with school, social activities, sleep, athletics, and family routines.

Participants identified several aspects of attacks that are particularly disruptive: prolonged pain, functional limitations, swelling in visible areas, and embarrassment or fear associated with attacks in sensitive locations such as the mouth or genital region. Soteres noted that clinicians should be aware that these physical and emotional burdens arise earlier than previously recognized, reinforcing the need for timely diagnosis and individualized care planning.

Soteres highlighted the importance of both on-demand and preventive therapy. He noted that all pediatric patients should have rapid access to ≥ 2 doses of on-demand treatment. Preventive strategies, whether daily oral therapies or intermittent injections, can help reduce the frequency and severity of attacks and create greater day-to-day stability for families.

“[We’re still working to understand] uncontrolled hereditary angioedema in the pediatric population,” Soteres said. “The poster we're presenting today gives an important explanation and insight into the disease state in that group.”

Relevant disclosures for Soteres include GENZYME CORPORATION, BioCryst US Sales Co., LLC, Takeda Pharmaceuticals U.S.A., Inc., CSL Behring, Pharming Healthcare, Inc., and AstraZeneca Pharmaceuticals LP.

At ACAAI 2025, HCPLive also spoke with Patricia Stewart, MD, from the Mississippi Asthma & Allergy Clinic, and Raffi Tachdjian, MD, MPH, from UCLA Health, on the burden of HAE attacks among children.

Soteres D. Burden of Attack for Young Patients with Hereditary Angioedema and Their Caregivers. Presented at ACAAI 2025 in Orlando, Florida, from November 6 – 10.

Stewart P. Emergency Care Still Falling Short for Children With HAE, With Patricia Stewart, MD. Hcplive.com. Published November 18, 2025. Accessed November 20, 2025. 

Tachdjian R. Importance of Addressing the Psychosocial Burden of HAE Among Children, With Raffi Tachdjian, MD. Hcplive.com. Published November 18, 2025. Accessed November 20, 2025. 

A study presented at ACAAI 2025 reveals HAE attacks may start in toddlers, highlighting significant daily burdens and the importance of timely diagnosis and treatment.