small molecules

2026-08-06 | A plain language summary of oral berotralstat for preventive treatment of hereditary angioedema attacks in children: early safety and efficacy results of the ongoing APeX-P study

What is this summary about? This plain language summary describes the interim results (early findings) of an ongoing study called APeX-P, which was published in the Annals of Allergy, Asthma & Immunology journal in 2025. The study looked at berotralstat, an oral (taken by mouth) medication, as a treatment option for hereditary angioedema (HAE) in children. HAE is a rare genetic disease that causes episodes of swelling (attacks) in different parts of the body, which can be serious. Attacks in the tongue and throat can be life-threatening. Berotralstat is taken once a day. Before the APeX-P study, the medication was approved in several countries to help prevent HAE attacks in people aged 12 and older. Berotralstat is now approved for use in people aged 2 and older in the United States. The APeX-P study researchers looked at which doses of berotralstat are appropriate for children aged 2 to under age 12, how children tolerated the medication, and how well berotralstat helps to prevent HAE attacks. The study also assessed children’s experiences and burdens with HAE. What were the results? Most of the children participating in the APeX-P study started having symptoms of HAE before they were 6 years old. Before beginning the study, children experienced burden because of HAE attacks, including missing school and needing emergency medical care because of their symptoms. After taking berotralstat for 12 weeks, children had fewer HAE attacks. The lower rate of attacks continued for up to 48-weeks (about 1 year—the study was still ongoing). This meant that children had fewer days with HAE symptoms. During the first 12 weeks of treatment with berotralstat, 3 HAE attacks (across all children in the study) needed medical care in a doctor’s office, clinic, or hospital. This need for medical care was 86% less than the 22 attacks needing medical care in the 12 weeks before the children started taking the medication. Most children in the study experienced at least 1 side effect after taking berotralstat; only 2 side effects (mild nausea or ‘feeling queasy’ and moderate headache) in 2 children were considered to be caused by the medication. Side effects were mild to moderate except in 1 patient who had an accident and a broken arm that was not caused by the medication. The most common side effects included a common cold, upper respiratory infection (in the nose, throat, or sinuses), or headache. What do the results mean? In the APeX-P study, children taking berotralstat tolerated the treatment well. The interim results show that berotralstat prevented attacks from HAE in young children. How to say (download PDF and double click sound icon to play sound)… APeX-P: AY-peks-pee Berotralstat: bear-oh-TRAL-stat Bradykinin: bray-DEE-ki-nin Hereditary angioedema: huh-REH-duh-tree AN-jee-oh-eh-DEE-muh Kallikrein: kal-uh-KREE-in Prophylaxis: pro-fuh-LACK-sis Angioedema: Swelling in the tissue under the skin. Genetic disease: Diseases caused by changes in a person’s DNA that can develop spontaneously or be passed on from parents to children. Tolerated: To handle a medication without having side effects that are serious or bothersome, or that are manageable enough for patients to continue taking the treatment. This is an abstract of the Plain Language Summary of Publication article. View the full Plain Language Summary PDF of this article to read the full-text Link to original article here

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2026-07-12 | Sebetralstat for breakthrough attacks in patients with hereditary angioedema receiving long-term prophylaxis in KONFIDENT-S.

Although long-term prophylaxis (LTP) reduces attack frequency in hereditary angioedema, patients may experience breakthrough attacks. Oral sebetralstat demonstrated favorable safety and efficacy compared with placebo in the randomized phase 3 KONFIDENT trial (NCT05259917), including in patients receiving LTP. The safety and effectiveness of sebetralstat in participants receiving LTP are being assessed in the KONFIDENT-S open-label extension study (NCT05505916). This interim analysis of the KONFIDENT-S study evaluated long-term safety and effectiveness of oral sebetralstat 600 mg for attacks of hereditary angioedema with C1-inhibitor deficiency in participants receiving LTP with lanadelumab, berotralstat, or C1 inhibitor. Efficacy end points included times to beginning of symptom relief, reduction in severity, and complete attack resolution. As of September 14, 2024, 35 participants receiving LTP experienced a mean ± standard deviation of 1.7 ± 1.5 attacks per month and treated 382 attacks with sebetralstat (1.3 ± 1.1 sebetralstat-treated attacks per month). Median (interquartile range) time from attack recognition to sebetralstat administration was 6 (1-40) minutes; time to beginning of symptom relief was 1.3 (0.8 to 3.8) hours, time to reduction in severity was 4.2 (1.3 to >12) hours, and time to complete attack resolution was 14.8 (4.6 to >24) hours. Effectiveness was similar for participants receiving berotralstat, lanadelumab, or C1 inhibitor. No serious or severe treatment-related treatment-emergent adverse events were reported. Sebetralstat was well tolerated and enabled early on-demand treatment of attacks in patients with hereditary angioedema with C1-inhibitor deficiency receiving LTP. Treatment of breakthrough attacks with sebetralstat resulted in rapid symptom relief, reduction in attack severity, and complete attack resolution, regardless of LTP mechanism of action.

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2026-06-25 | Icatibant for acute hereditary angioedema attacks in pediatric patients: A systematized review

Background: Hereditary angioedema (HAE) is a rare, potentially life-threatening bradykinin-mediated disorder with limited pediatric treatment options and little comparative evidence. Icatibant, a bradykinin B2 receptor antagonist, has demonstrated efficacy in adults and has emerging evidence in children. Objective: To evaluate and synthesize clinical evidence on the efficacy and safety of icatibant for acute HAE attacks in pediatric patients. Methods: A literature search was performed by using medical literature data bases, clinical trial and research registries, and key journals through January 2026. The primary outcome was the time to onset of symptom relief. Secondary outcomes included the time to minimum symptoms, pain scores, adverse events, and feasibility of self- or caregiver administration. All included studies were nonrandomized, single-arm trials with heterogeneous designs and outcomes definitions; therefore, a meta-analysis was not performed, and all studies were descriptively evaluated. Results: This systematic review identified three clinical studies of icatibant for acute HAE attacks in children ages 0 to 17 years. Three open-label, phase III studies, which included 43 pediatric patients were reviewed. Icatibant demonstrated rapid symptom relief, with a median onset at ∼1 hour and minimum symptoms within 2 hours, although repeated dosing showed variability. Icatibant was well tolerated, with injection-site reactions as the most common adverse events and no serious treatment-related events. Self- or caregiver administration was feasible and effective in adolescents. Conclusion: Icatibant was safe and effective in the pediatric studies, providing rapid symptoms relief and a favorable tolerability profile. Despite limitations from small sample sizes and lack of comparator trials, current evidence supports icatibant as a targeted, practical option for treating acute HAE attacks in children.

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2026-05-15 | Probiotic supplementation to mitigate berotralstat gastrointestinal side effects: a multicenter case series from the ITACA network.

Berotralstat, the first oral plasma kallikrein inhibitor approved for hereditary angioedema (HAE) prophylaxis, may be associated with gastrointestinal (GI) side effects, particularly during the first three months of therapy. Probiotics have been shown to reduce GI disturbances in several conditions. This pilot study described GI tolerability in patients receiving initiation-phase probiotic co-administration alongside berotralstat and explored whether this supportive strategy merits further controlled evaluation. We analyzed 25 adolescents and adults with HAE treated with berotralstat across six Italian centers (December 2023-November 2025). All patients received probiotics during the early treatment phase. Demographic and clinical data, side effects, and monthly HAE attack rates were collected. Severity of complaints was graded using the Common Terminology Criteria for Adverse Events (CTCAE). Participants were 60% females, and the mean age for the cohort was 45 years (range 12-82). The most common probiotics were Lacteol® , Codex® , and Lactoflorene Plus® . GI complaints occurred in 5/25 patients (20%); only 3/25 (12%) experienced GI side effects while receiving probiotics. 2/25 GI complaints occurred after probiotic discontinuation. No serious side effects were reported. Mean monthly attack rate decreased from 2.6 to 0.8 attacks per month, ~3.3-fold reduction from baseline. Probiotic co-administration during early berotralstat therapy was accompanied by a low incidence of GI side effects, while clinical effectiveness was maintained. These preliminary findings support further controlled studies to validate probiotics as a supportive strategy for improving the tolerability of berotralstat.

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2026-04-27 | Berotralstat and Health-Related Quality of Life in Hereditary Angioedema: Pooled Analysis of the APeX-2 and APeX-J Trials.

In the phase 3 APeX-2 and APeX-J trials, improvements in health-related quality of life (HRQoL) were reported for berotralstat, the only oral, once-daily, long-term prophylaxis for hereditary angioedema (HAE). We conducted a post hoc trial analysis to evaluate the impact of berotralstat on HRQoL versus placebo through 24 weeks, and the long-term effects of treatment up to 96 weeks, using pooled APeX-2 and APeX-J patient data. Patients receiving berotralstat 150 mg or placebo using the Angioedema QoL (AE-QoL) questionnaire; total and domain scores were analysed. Changes from baseline through Week 24 were compared using mixed models for repeated measures (MMRM) to estimate least squares mean differences (LSMDs) with 95% confidence intervals (CI) and nominal p-values. After Week 24, in the absence of a placebo comparator, long-term changes from baseline were evaluated using within-subject effect sizes (Cohen's d) through Week 96 in patients receiving berotralstat. Clinical meaningful improvements in AE-QoL total and domain scores were assessed by minimal clinically important difference (6-point reduction in AE-QoL total score) and distributional criterion methods, respectively. The manufacturer of berotralstat (BioCryst Pharmaceuticals) funded this study. Overall, 47 and 45 patients received berotralstat and placebo, respectively. At Week 24, berotralstat showed significantly greater improvement in AE-QoL total (LSMD: -7.4; 95% CI: -14.3, -0.6; p < 0.05), functioning domain (LSMD: -10.9; 95% CI: -19.6, -2.3; p = 0.013) and fears/shame domain (LSMD: -8.7; 95% CI: -17.2, -0.2; p = 0.046) scores compared with placebo. Among patients receiving berotralstat, consistent sustained improvements were observed across all AE-QoL domains up to Week 96. Analyses of meaningful improvement in total score and domains showed an increase over time in the proportion of patients achieving meaningful change. Berotralstat significantly improved HRQoL versus placebo through 24 weeks and showed long-term beneficial effects through 96 weeks.

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proteins

2026-05-20 | Real-world treatment patterns and clinical burden of patients with hereditary angioedema treated with long-term prophylaxis.

Long-term prophylaxis (LTP) may reduce the hereditary angioedema (HAE) burden by reducing attack frequency, but real-world evidence is limited. To describe LTP treatment patterns and the frequency of HAE attacks leading to emergency department or inpatient visits (ED/IP) and healthcare resource use (HRU) before and after LTP initiation. Patients initiating LTP in the Komodo Research Database (1/1/2021-1/30/2024) were followed until discontinuation or data end. Treatment adherence overall and among patients with > 30 days of treatment was measured as the proportion of days covered ≥ 80%. Treatment persistence, defined as no interruption ≥ 90 days or switch, was evaluated overall and among patients with > 30 days of treatment using Kaplan-Meier (KM) analysis with KM rates and corresponding 95% confidence intervals (CI). Rates of HAE attacks leading to ED/IP and per-patient-per-year all-cause HRU before and after LTP initiation were reported among patients with > 30 days of treatment. All analyses were descriptive and no statistical testing was conducted. Overall, 499 patients were included (57 Haegarda [11%], 257 Orladeyo [52%], 185 Takhzyro [37%]; mean follow-up = 11.3 months; median age = 39 years; 69% female), among whom 449 had > 30 days of treatment (mean follow-up = 12.5 months). At 12 months after LTP initiation, 52.6% of patients in the overall study sample and 57.0% of patients with > 30 days of treatment were adherent. Based on KM analysis, persistence rates at 12 months after LTP initiation were 58.7% (95% CI = 53.8%; 63.4%) in the overall sample and 65.1% (59.9%; 69.9%) among patients with > 30 days of treatment. Among the patients with > 30 days of treatment, 38% had ≥ 1 HAE attack leading to ED/IP in the year before LTP initiation (mean = 0.82 attacks), decreasing to 23% after (mean = 0.51 attacks). In these 449 patients, annual HRU remained substantial before and after LTP initiation across settings (IP = 2.4 and 1.7 days [0.3 and 0.2 admissions]; ED = 1.5 and 1.2 visits; outpatient = 21.0 and 19.3 visits, respectively). Although recently available LTP can partly reduce the clinical burden of patients with HAE, novel therapies are needed to further alleviate this burden.

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2026-05-20 | Post Hoc Analysis of Recombinant C1 Inhibitor Clinical Data Using Contemporary Endpoints for Hereditary Angioedema.

Contemporary trials of medications to treat hereditary angioedema (HAE) attacks define efficacy endpoints using Patient Global Impression of Severity (PGI-S) and Patient Global Impression of Change (PGI-C) scales; these differ from the visual analog scale (VAS) and treatment effect questionnaire (TEQ) used in legacy recombinant human C1 esterase inhibitor (rhC1-INH) studies. This post hoc analysis aimed to evaluate pooled rhC1-INH trial data, mapped to contemporary HAE clinical trial endpoints and designs. Pooling data from three rhC1-INH trials for acute HAE attacks (NCT00225147, NCT01188564, NCT00262301), this analysis applied results from a bookmarking study to convert TEQ and VAS measurements to PGI-S and PGI-C scales. Kaplan-Meier estimates were calculated for time to complete resolution (TTCR; defined as "none" on PGI-S) and time to onset of symptom relief (TOSR; defined as "a little better" on PGI-C at ≥ 2 consecutive time points within 12 h). Log-rank tests were used to determine differences between treatment groups. Across trials, 48 and 60 patients received rhC1-INH 50 U/kg and placebo, respectively. The most common attack locations were peripheral (47.9% and 41.7%, respectively) and abdominal (35.4% and 35.0%, respectively). Baseline attack severity was either severe or very severe in all patients. Median [95% confidence interval (CI)] TOSR was 0.75 h (0.55-1.50) with rhC1-INH and 8.00 h (3.00-8.05) with placebo (P < 0.001). Median (95% CI) TTCR was 4.50 h (3.55-5.50) with rhC1-INH and 24.00 h (16.00- > 24.00) with placebo (P < 0.001). This post hoc analysis confirmed that rhC1-INH, compared with placebo, is associated with significantly shorter TOSR and TTCR of HAE attacks. ClinicalTrials.gov: NCT00225147, NCT01188564, NCT00262301.

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2025-05-30 | Substitution of reactive centre loop residues from C1 esterase inhibitor increases the inhibitory specificity of alpha-1 antitrypsin for plasma kallikrein.

C1 esterase inhibitor (C1INH) is a member of the serpin superfamily of proteins and controls plasma kallikrein (Pka). Purified C1INH concentrates are effective in controlling C1INH deficiency (hereditary angioedema, HAE). Because C1INH is a relatively slow inhibitor of Pka, we sought to develop a more effective inhibitor by exchanging reactive centre loop (RCL) residues in another serpin, alpha-1 antitrypsin (AAT) variant M358R, with the corresponding residues of C1INH. Novel, soluble, N-terminally hexahistidine-tagged variants were expressed in E. coli, purified by nickel chelate chromatography, and characterized kinetically. AAT/C1INH loop exchange mutants were designated by the RCL residues exchanged using the reactive centre P1-P1' convention. Maximal exchange mutant AC (10-4') inhibited Pka 78-fold and activated Factor XI (FXIa) 350-fold less rapidly than AAT M358R. Eleven additional variants were expressed, restoring AAT residues stepwise. The most selective variant was AC (10-3/4'), which restored AAT residues from P2-P3' compared to AC (10-4'), and inhibited Pka 1.9-fold more rapidly, and FXIa 1.6-fold less rapidly, for a gain in selectivity of 2.8-fold (p < 0.0001), without increasing the stoichiometry of inhibition (SI). The most active variant was AC (10-3), in which both the rate of Pka and FXIa inhibition were elevated relative to AAT M358R values, without SI elevation. Other variants exhibited slower reaction rates and/or elevated SI values. These results indicate that RCL exchanges can be productively employed to change serpin specificity and selectivity, but that the most effective exchanges may not be contiguous due to cooperativity between RCL residues.

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2025-04-10 | [A CASE OF HEREDITARY ANGIOEDEMA WITH NORMAL C1 INHIBITOR (HEREDITARY ANGIOEDEMA TYPE III) WITH A PATHOGENIC VARIANT IN THE PLG GENE].

Hereditary angioedema (HAE) is a rare genetic disease characterized by recurrent episodes of temporary organ swelling. Here, we report a case of HAE type III who experienced recurrent acute abdominal pain after starting low-dose estrogen therapy. Genetic analysis by Sanger sequencing led to the identification of a recurrent heterozygous missense variant c.988A>G (p.K330E) in the plasminogen (PLG) gene of the patient. This variant was previously found in her elder sister who also had the disease. She was treated with tranexamic acid as a long-term prophylactic. Her attacks did not increase during her pregnancy. We managed the patient with intravenous injection of C1-INH preparation before and after delivery. As the frequency of attacks increased after delivery and after the resumption of menstruation, the dose of tranexamic acid was increased, and a subcutaneous injection of lanadelumab was started.While the severity of attacks reduced, she experienced the attacks once or twice a month. After switching from lanadelumab to twice-weekly subcutaneous injections of C1-inhibitor (C1-INH), she had no attacks requiring additional treatment, although she had several minor attacks. To establish appropriate treatment for HAE type III, accumulation of cases, determination of the causative gene in each case, and elucidation of the pathology are warranted.

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2025-03-13 | Enhancement of plasma kallikrein specificity of antitrypsin variants identified by phage display and partial reversion.

The naturally occurring variant Alpha-1 Antitrypsin M358R (AAT M358R), modified at the P1 position of the reactive center loop (RCL), shifts its inhibitory protease target from neutrophil elastase to multiple coagulation and contact proteases, including activated plasma kallikrein (Pka; KLKB1). Our aim was to increase the specificity of AAT M358R for Pka as a potential novel therapeutic agent to treat pathological swelling arising from elevated Pka levels in patients with Hereditary Angioedema. Two AAT M358R T7Select phage display libraries randomized at RCL positions P7-P3 and P2-P3' were iteratively probed with Pka. The most abundant Pka-inhibitory motifs from phage display were P7-P3, QLIPS; and P2-P3', VRRAY (mutated residues in bold). AAT variants expressing these motifs, alone or in combination, as well as six less-mutated P7-P3 revertant proteins were expressed, purified, and characterized kinetically. Variants AAT M358R (QLIPS) (designated 7-QLIPS-3) and 7-FLEPS-3 exhibited significantly enhanced selectivity for Pka (over factor XIa) by factors of 6.9 and 9.2, respectively, without increasing the stoichiometry of inhibition (SI) or decreasing the inhibition rate relative to AAT M358R. No other variants matched this profile. Pro substitution at P4 was found to be important for enhanced inhibition of Pka by AAT M358R. Two novel variants with this substitution are more rapid and selective inhibitors of Pka than AAT M358R and may provide better control of Pka in vivo than existing HAE therapeutics.

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antibodies

2026-09-11 | c.1681-7 G>A Variant in the Factor XII Gene in a Family Diagnosed with HAE-FXII Does Not Affect Splice Site.

Introduction:Hereditary angioedema (HAE) is a rare, potentially life-threatening genetic condition characterized by recurrent episodes of localized tissue swelling, often affecting the skin, upper respiratory tract, and gastrointestinal system. HAE-FXII, also known as HAE with normal C1 inhibitor (C1INH), has been associated with mutations in only one of several genes, including FXII encoding coagulation factor XII (FXII). The aim of the study was to investigate the pathogenicity and functional consequences of the c.1681-7G>A intronic variant in the FXII gene according to ACMG guidelines in familial cases of HAE-FXII.Materials and Methods:Genetic analysis was performed using Sanger sequencing on affected individuals. To assess whether the variant affects splicing, in silico analysis and Messenger RNA (mRNA) studies were conducted on patient-derived samples.Results:The c.1681-7G>A variant was identified in multiple individuals from affected families. However, splicing analysis revealed that this intronic variant did not cause any alteration in mRNA processing. No aberrant transcripts were detected, and expression levels were comparable to controls, indicating that the variant does not have an effect on splicing or gene function.Discussion:The c.1681-7G>A variant in the FXII gene is unlikely to be a pathogenic alteration in HAE type III.Contribution to the Literature:These findings support its classification as a benign variant, emphasizing the importance of functional validation when interpreting intronic changes in genetic diagnostics.

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2026-07-11 | Garadacimab and the future of hereditary angioedema prophylaxis: a step upstream in the bradykinin pathway.

Hereditary angioedema (HAE) is a rare autosomal dominant disorder characterized by recurrent, potentially life-threatening episodes of bradykinin-mediated angioedema affecting the skin, gastrointestinal tract, and upper airway. Despite the availability of several prophylactic therapies, there is a need for effective and convenient treatment options. On 21 June 2024, the U.S. Food and Drug Administration approved Andembry™ (garadacimab-gxii), a first-in-class monoclonal antibody that inhibits activated Factor XII (FXIIa), for prophylaxis of HAE attacks in patients aged ≥12 years. By targeting FXIIa, garadacimab acts upstream in the kallikrein-kinin pathway, suppressing bradykinin generation and preventing vascular permeability associated with angioedema. Clinical trials demonstrated substantial reductions in attack frequency, with the phase 3 VANGUARD study reporting a 91.5% reduction in HAE attacks and that approximately 77% of patients remain attack-free during the study period. Garadacimab is administered as a 200-mg subcutaneous injection once monthly and has a favorable pharmacokinetic profile with an elimination half-life of approximately 18-20 days. Adverse events were generally mild, including headache, nasopharyngitis, and injection-site reactions. The approval of garadacimab represents an important advancement in HAE prophylaxis, offering a novel upstream mechanism, convenient dosing, and potential improvement in quality of life of the patients.

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2026-04-30 | Garadacimab for the long‐term prophylaxis of hereditary angioedema

Hereditary angioedema (HAE), a rare and debilitating disease characterized by recurrent and spontaneous attacks of tissue swelling, has a high unmet therapeutic need, with many patients experiencing insufficient disease control with current prophylactic treatments. The goal of HAE treatment as per guidelines is to achieve total disease control and to normalize patients' lives. Factor XII (FXII), the principal initiator of the contact system, ultimately regulates the kallikrein-kinin system. Activated FXII (FXIIa) converts plasma prekallikrein to plasma kallikrein, which cleaves high-molecular-weight kininogen to produce the vasoactive peptide bradykinin. In HAE pathophysiology, kallikrein-kinin system dysregulation results in excessive bradykinin production. The anti-FXIIa monoclonal antibody garadacimab is approved for long-term prophylaxis against HAE attacks. In the pivotal phase III (VANGUARD) and ongoing phase III open-label extension studies, garadacimab administered subcutaneously (2 × 200 mg loading dose followed by 200 mg once monthly) demonstrated durable efficacy with early onset of protection and a favorable long-term safety profile. Based on this and earlier clinical data, garadacimab has the potential to bring patients closer to achieving the guideline-recommended goals of disease control and normalization of life. Here, we provide an overview of the results from the garadacimab clinical development program.

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2026-04-14 | Factor XII in Thrombosis and Thromboinflammation: From Molecular Biology to Clinical Translation.

Factor XII (FXII) is a central mediator at the intersection of coagulation, fibrinolysis, inflammation, and immunity. It is activated upon contact with negatively charged surfaces, triggering the intrinsic coagulation pathway and driving thrombus formation and stabilization. Beyond clotting, FXII contributes to activation of the kallikrein-kinin system, generation of bradykinin, and modulation of inflammatory and immune responses. Congenital FXII deficiency does not increase bleeding risk, highlighting its unique role and making FXII inhibition an attractive strategy for anticoagulation and immune modulation with a potentially superior safety profile. Preclinical studies provide compelling evidence for this concept. In models of ischemic stroke and traumatic brain injury, FXII blockade significantly reduced infarct volume, improved neurological outcomes, and attenuated neuroinflammation without increasing hemorrhage. Similarly, in extracorporeal circulation and vascular stent implantation, FXII inhibition prevented thrombus formation and reduced fibrin deposition, achieving effects comparable to heparin but with markedly lower bleeding risk. Several classes of FXII inhibitors are currently in development, including antisense oligonucleotides, peptides, recombinant proteins, and monoclonal antibodies. Among them, Ixodes ricinus contact phase inhibitor (Ir-CPI) and recombinant human albumin-fused Infestin-4 (rHA-Infestin-4) have demonstrated strong antithrombotic efficacy in animal models. Most notably, garadacimab, a monoclonal anti-FXIIa antibody, has completed phase 3 trials and received regulatory approval for hereditary angioedema (HAE) prophylaxis, where it markedly reduces attack frequency with a favorable safety profile. This review summarizes current knowledge on FXII biology and evaluates its translational potential as a novel target for anticoagulant and anti-inflammatory therapies.

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2026-02-22 | Management of pregnancy, delivery and breast-feeding in hereditary angioedema: an analysis of 15 pregnancies with conventional treatment approaches and a case of Lanadelumab use.

BACKGROUND: The course of hereditary angioedema (HAE) during pregnancy varies greatly. Limited treatment options complicate the management of HAE in this period. This study aimed to examine the clinical progression of HAE throughout the perinatal period in relation to management strategies. Additionally, we reported the first documented case of Lanadelumab (Takhzyro) therapy during pregnancy in a patient with HAE. RESULTS: We performed an observational study at the University Hospital Zurich (a tertiary treatment center), in which we included 7 HAE female HAE patients. We analyzed 15 pregnancies of these women. The average maternal age at delivery was 33 years (range: 21–41), and the average gestational age was 40 + 3/7 weeks. Fourteen deliveries were spontaneous, with one requiring vacuum extraction. There were no miscarriages during the study period. Maternal C1-INH levels averaged 0.09 g/l (range: 0.04–0.16), and functional activity averaged 28% (range: 17–42%). Of the 15 newborns, 8 were HAE-positive. Their mean birth weight was 3170 g (±546), compared to 3618 g (±225) in HAE-negative children. No significant complications or adverse outcomes were observed in either group. Attack frequency during pregnancy increased in 4 cases, decreased in 7, and remained unchanged in 4. Most women (60%) received plasma-derived C1-inhibitor (Berinert) for acute management; 27% used it prophylactically during pregnancy. One patient received combination therapy with Lanadelumab/Takhzyro® and Berinert®, showing good tolerability and effectiveness. The pregnancy proceeded without complications and the child was born healthy at term with normal birth weight. CONCLUSIONS: The variable evolution of HAE symptoms during pregnancy highlights the need for flexible and personalized treatment plans. Plasma-derived C1-inhibitor remains the recommended treatment during pregnancy due to its favorable therapeutic and safety profile. The first documented use of Lanadelumab during pregnancy was well tolerated and linked to positive outcomes for both mother and newborn. Although these findings are promising, further research is necessary to confirm the safety and effectiveness of Lanadelumab in this setting.

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oligonucleotides

2026-07-08 | Donidalorsen for the Treatment of Hereditary Angioedema: A Review of Clinical Studies.

Hereditary angioedema (HAE) is a rare disease characterized by recurrent attacks of severe tissue swelling caused by dysregulation of the kallikrein-kinin system. Donidalorsen is a triantennary N-acetyl galactosamine-conjugated antisense oligonucleotide designed to specifically and reversibly reduce plasma prekallikrein production by binding to plasma prekallikrein messenger RNA in the liver. This report reviews donidalorsen's mechanism of action and data on the pharmacodynamics, efficacy, patient-reported outcomes, and safety of donidalorsen from clinical trials in adolescent and adult participants. In a Phase 1 trial, subcutaneous (SC) administration of donidalorsen led to dose-dependent reductions in plasma prekallikrein concentrations. In a subsequent Phase 2, randomized, placebo-controlled study, donidalorsen 80 mg SC once every 4 weeks (Q4W) for 16 weeks resulted in a 90% mean reduction in monthly HAE attack rate vs placebo, which was sustained for up to 4 years in an open-label extension (OLE). In the Phase 3, randomized, placebo-controlled OASIS-HAE study, patients receiving donidalorsen 80 mg Q4W or once every 8 weeks (Q8W) experienced significant mean reductions in HAE attack rates vs placebo over Weeks 0 to 24 (Q4W: 81%; Q8W: 55%). Mean attack rates were reduced by 87% (Q4W) and 60% (Q8W) vs placebo over Weeks 4 to 24. Reductions in attack rate from OASIS-HAE baseline were sustained for up to 1 year in the OASISplus OLE (Q4W: 94%; Q8W: 95%). A notable study in the clinical program included a cohort of patients who switched from berotralstat, C1 inhibitor, or lanadelumab to donidalorsen for up to 1 year; mean attack rates were reduced by 68% vs baseline (on prior HAE prophylaxis). Donidalorsen treatment improved quality of life at all assessments. Across studies, donidalorsen had an acceptable safety and tolerability profile, with mostly mild to moderate adverse events reported. Overall, the clinical data are promising for donidalorsen as a long-term prophylactic medication for HAE.

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2026-04-23 | Hemophilia and hereditary angioedema: parallel therapeutic advances in genetic diseases of serine protease pathways.

Hemophilia and hereditary angioedema (HAE) are rare monogenic disorders characterized by the dysregulation of serine protease-based biological pathways, that is, blood coagulation and the kallikrein-kinin system. Although clinical manifestations differ profoundly (bleeding vs angioedema), both diseases have recently undergone parallel therapeutic revolutions, shaped by advances in molecular biology and biotechnology. Early management in the 1970s relied for both diseases on the episodic administration of plasma-derived products, subsequently replaced by recombinant products that improved safety and feasibility of prophylaxis regimens. In the last 20 years, the development of nonreplacement products, such as emicizumab and rebalancing agents in hemophilia and kallikrein/bradykinin pathway inhibitors in HAE, shifted clinical practice from the episodic management of clinical events to their prevention. More recently, gene and RNA-based therapies are further transforming both diseases toward curative attempts: in hemophilia, adeno-associated virus vector-mediated gene therapy and lentiviral stem-cell approaches; in HAE, antisense oligonucleotide-mediated kallikrein suppression. Emerging genome-editing approaches and biomarker- and genotype-driven strategies are poised to further improve and personalize treatment. The therapeutic trajectories of rare diseases such as hemophilia and HAE illustrate how mechanistic insights enable the transition from the episodic management of acute events to long-term disease control, offering prospects for curative interventions.

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2026-03-02 | Donidalorsen for Long-Term Prophylaxis of Hereditary Angioedema Attacks: Results from the OASISplus Open-Label Extension Cohort at Year 1.

Donidalorsen, a prekallikrein-directed antisense oligonucleotide indicated for prophylaxis of hereditary angioedema (HAE) attacks in patients aged ≥12 years, demonstrated efficacy and acceptable safety in the phase 3, placebo-controlled OASIS-HAE trial (NCT05139810). Here, we report 1-year results from the corresponding open-label extension (OLE) cohort of the OASISplus study (NCT05392114). OASISplus included patients who rolled over from OASIS-HAE. Patients who received donidalorsen 80 mg or placebo subcutaneously every 4 weeks (Q4W) in OASIS-HAE received donidalorsen Q4W in OASISplus. Patients who received donidalorsen 80 mg or placebo every 8 weeks (Q8W) in OASIS-HAE received donidalorsen Q8W or Q4W, if not attack-free in the final 8 weeks of OASIS-HAE. The primary endpoint was safety (ie, incidence of treatment-emergent adverse events [TEAEs]). Secondary endpoints included the monthly rate of HAE attacks and Angioedema Quality of Life (AE-QoL). The OLE cohort included 83 patients (Q4W, n=69 [83%]; Q8W, n=14 [17%]). Of these, 75 (90.4%) completed Year 1, and 6 patients receiving donidalorsen Q8W in OASIS-HAE switched to the Q4W dosing group in the OLE. Median donidalorsen exposure was 392.3 days. From Weeks 0 to 52, reductions in mean HAE attack rate from OASIS-HAE baseline were 94% (Q4W) and 95% (Q8W), and patients reported clinically meaningful improvements in mean AE-QoL total score at Week 52 (Q4W, 28.1 points; Q8W, 26.7 points). Twenty-two (27%) patients reported treatment-related TEAEs; none were serious, and injection-site reactions were the most frequently reported. Donidalorsen demonstrated sustained reductions in HAE attack rate, improvements in QoL, and an acceptable safety profile after 1 year of treatment.

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2026-02-02 | Population Pharmacokinetic/Pharmacodynamic Modeling of Donidalorsen, an Antisense Oligonucleotide in Development for Prophylaxis of Hereditary Angioedema.

Hereditary angioedema (HAE) is a rare disorder linked to kallikrein-kinin system dysregulation, which leads to uncontrolled activation of plasma prekallikrein. Donidalorsen is an antisense oligonucleotide designed to selectively degrade prekallikrein messenger RNA and thereby reduce prekallikrein production. We aimed to develop population pharmacokinetic and pharmacokinetic/pharmacodynamic models of donidalorsen and evaluate the impact of potential intrinsic/extrinsic covariates on exposure and prekallikrein response. Plasma donidalorsen and prekallikrein data were obtained from phase 1 to 3 studies in healthy volunteers (NCT03263507, 721744-CS9) and adult and adolescent patients with HAE (NCT04030598, NCT05139810). The evaluated doses were 20, 40, 60, and 80 mg every 4 weeks (Q4W) and 80 mg every 8 weeks (Q8W), administered subcutaneously over 13-21 weeks. Donidalorsen pharmacokinetics were well described by a linear 2-compartment model with first-order absorption. The population terminal elimination half-life was 31.4 days. Prekallikrein was well described by an indirect response model with inhibition of prekallikrein production by donidalorsen. Covariate analysis identified body weight as the main factor affecting pharmacokinetic exposure; however, this effect was not considered clinically significant. The developed population pharmacokinetic/pharmacodynamic model well characterized the donidalorsen exposure-prekallikrein response relationship. Modeling analyses support that no dose adjustment is needed with respect to intrinsic/extrinsic factors in adults and adolescents with HAE. The nearly identical simulated pharmacokinetic or prekallikrein time courses for Q4W versus monthly dosing and for Q8W versus every-2-month dosing regimens support switching to more convenient regimens for patients.

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2025-11-10 | Exposure-Response Analysis of Donidalorsen for the Treatment of Hereditary Angioedema.

Hereditary angioedema (HAE) is characterized by recurrent attacks of severe tissue swelling. In the OASIS-HAE phase 3 study (NCT05139810), donidalorsen, an RNA-targeted antisense oligonucleotide that reduces prekallikrein production in the liver, significantly reduced HAE attack rates. To characterize the relationship between prekallikrein concentrations and HAE attack rates following donidalorsen and predict the efficacy of potential dosing regimens, an exposure-response model was developed using data from OASIS-HAE. Simulations were conducted to evaluate the following regimens: 80 mg once every 4 weeks (Q4W), 8 weeks (Q8W), 1 month (Q1M), and 2 months (Q2M), and a switch to Q2M dosing for patients who were attack-free for 3 months on the Q1M regimen. The relationship between prekallikrein concentrations and HAE attack rates was well characterized by a sigmoidal Emax (maximum effect) model with baseline attack rate and baseline prekallikrein concentration included as covariates. The average prekallikrein concentration estimated to result in a 90% reduction in attack rate (EC10) was 47.1 mg/L. Predicted percent reductions in attack rates at steady state were similar for Q4W (84.1%) vs. Q1M (82.9%) and Q8W (72.6%) vs. Q2M (70.2%) dosing. Predicted reductions in attack rate remained similar and clinically meaningful in patients who switched from Q1M to Q2M dosing (94.0% in month 1 and 91.3% in month 2 of the 2-month dosing interval at steady state). Overall, exposure-response analyses supported the efficacy of Q1M and Q2M dosing and indicated that switching to Q2M dosing could be a viable approach for patients who are attack-free on the Q1M regimen.

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2026-07-28 | Status of Current Clinical Trials on Therapy for Hereditary Angioedema 2309515

Abstract Introduction Hereditary angioedema (HAE) is a rare autosomal dominant deficiency or dysfunction of C1 esterase inhibitor, resulting in dysregulated kallikrein—bradykinin signaling and potentially life-threatening angioedema. While existing C1-INH products and kallikrein inhibitors have improved disease control, new clinical trials aim to further reduce treatment burden and achieve durable prophylaxis through novel therapeutic strategies. Methods Active and recruiting HAE clinical trials were identified through the trial registry on clinicaltrials.gov. Results A total of twenty-two trials were identified, eleven of which are recruiting as of December 2025, and eleven others that are active but no longer recruiting. The sole drug in phase 4 is CSL312 (Garadacimab), a fully human IgG4 monoclonal antibody targeting activated factor XIIa. Drugs in phase 3 include: NTLA-2002, a single-dose intravenous gene therapy targeting inactivation of the KLKB1 gene; Navenibart, an IgG1 monoclonal antibody inhibiting activated kallikrein; OCTA-C1-INH, a virus-inactivated, nanofiltrated, highly purified concentrate of C1-INH derived from pooled human plasma; ADX-324, an siRNA therapy to reduce hepatic production of prekallikrein (PKK); Donidalorsen, an antisense oligonucleotide targeted against hepatic PKK mRNA; Sebetralstat and berotralstat, both plasma kallikrein inhibitors that reduce production of bradykinin; and deucrictibant, a competitive bradykinin B2 receptor antagonist. Drugs in phase 2 are: BW-20805, another siRNA therapy targeting human hepatic PKK mRNA; and BMN 331, an AAV5-based gene therapy that introduces the SERPING1 gene which encodes wild-type human C1INH protein. Conclusion Advances in gene therapy, biologics, RNA interference therapeutics, and improved replacement strategies hold promise for transforming both rescue and prophylactic management for HAE. Ongoing evaluation of safety, durability of response, and real-world applicability will be critical in defining the future standard of care for HAE. Funding Source n/a Topic Categories Translational and Interventional Immunology (TI)

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2026-07-27 | Lonvoguran ziclumeran: a CRISPR-CAS9-based gene therapy for the treatment of hereditary angioedema.

Hereditary angioedema (HAE) is a rare genetic disorder characterized by recurrent swelling caused by dysregulation of the kallikrein-kinin pathway. Although current therapies effectively reduce attack frequency, treatment remains lifelong. Lonvoguran ziclumeran (Lonvo-z; NTLA-2002) is the first systemically administered in vivo CRISPR/Cas9 gene-editing therapy designed to provide durable suppression of plasma kallikrein through permanent disruption of the KLKB1 gene. This review summarizes the pathophysiology and current management of HAE, the development of Lonvo-z, its lipid nanoparticle delivery platform, and the technical advances enabling in vivo genome editing. Preclinical studies and clinical evidence, including early-phase trials and the Phase 3 HAELO study, are reviewed with emphasis on efficacy, safety and clinical implications. Lonvo-z represents a major milestone in precision medicine and the clinical application of systemic genome editing. A single administration has produced sustained reductions in plasma kallikrein levels and HAE attack frequency. Although long-term follow-up is ongoing, current evidence supports its potential as the first one-time disease-modifying treatment for HAE and a landmark advance in CRISPR-based therapeutics.

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2025-11-01 | SAFETY/TOLERABILITY OF A ONE-TIME INFUSION OF LONVOGURAN ZICLUMERAN (LONVO-Z, NTLA-2002) FOR HEREDITARY ANGIOEDEMA

Introduction Lonvoguran ziclumeran (lonvo-z, NTLA-2002) is an investigational, CRISPR-based, one-time infusion intended to treat hereditary angioedema (HAE). To date, lonvo-z has been well-tolerated and demonstrated clinical efficacy. We report updated safety/tolerability in patients receiving lonvo-z 50mg, focusing on adverse events reported within the first 24 hours after the start of infusion. Methods Twenty-one patients received one infusion of lonvo-z 50mg (initial lonvo-z 50mg, n=15; placebo-lonvo-z crossover, n=6) in the ongoing Phase 1/2 study (NCT05120830). Pretreatment (corticosteroids day before and day of infusion; H1/H2 blockers day of infusion) was administered. Results As of 12Feb25, treatment-emergent adverse events (TEAEs) occurred in 20/21 (95.2%) patients treated with lonvo-z 50mg; Day 1 TEAEs occurred in 13/20 (65%) patients. Infusion-related reactions (IRRs) occurred in 10/21 patients (47.6%), with rapid onset after infusion start (median [range] time to onset: 0.3 [0-8.2] hours). IRR symptoms occurring in >1 patient: headache (n=3), nausea (n=2), and fever (n=2). Symptom duration varied (median [range]: 8.4 hours [12 min to 21.3 days]). All IRRs resolved; in 8/10 patients, symptoms resolved in <24 hours; 2 patients had IRR symptoms lasting >24 hours (headache, 22 days; increased thirst, 7 days). Four patients received treatment for IRRs: dexamethasone (n=3), acetaminophen (n=2), and ibuprofen (n=2). Two patients required infusion rate change/interruption; none discontinued the infusion. Conclusion A one-time infusion of lonvo-z 50mg was well-tolerated, resulting in high rates of attack-free and LTP-free status in patients. Most IRRs occurred shortly after infusion and resolved same day. All patients received the full dose of lonvo-z.

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