Hereditary Angioedema Attack Rates Research Articles

Clinical Progress in Hepatic Targeting for Novel Prophylactic Therapies in Hereditary Angioedema

Hereditary angioedema (HAE) is typically caused by a deficiency of the protease inhibitor C1 inhibitor (C1INH). The absence of C1INH activity on plasma kallikrein and factor XIIa leads to overproduction of the vasoactive peptide bradykinin, with resulting angioedema. As the primary site of C1INH and prekallikrein production, the liver is recognized as an important therapeutic target in HAE, leading to the development of hepatic-focused treatment strategies such as GalNAc-conjugated antisense technology and gene modification. This report reviews currently available data on hepatic-focused interventions for HAE that have advanced into human trials. Donidalorsen is an investigational GalNAc3-conjugated antisense oligonucleotide that binds to prekallikrein mRNA in the liver and reduces the expression of prekallikrein. Phase 2 data with subcutaneous donidalorsen demonstrated a significant reduction in HAE attack rate compared with placebo. Phase 3 trials are underway. ADX-324 is a GalNAc3-conjugated short-interfering RNA being investigated in HAE. BMN 331 is an investigational AAV5-based gene therapy vector that expresses wild-type human C1INH and is targeted to hepatocytes. A single intravenous dose of BMN 331 is intended to replace the defective SERPING1 gene and enable patients to produce functional C1INH. A first-in-human phase 1/2 study is ongoing with BMN 331. NTLA-2002 is an investigational invivo clustered regularly interspaced short palindromic repeats/Cas9-based therapy designed to knock outthe prekallikrein-coding KLKB1 gene in hepatocytes; a phase 1/2 study is ongoing. Findings from these and other ongoing studies are highly anticipated with the expectation of expanding the array of treatment options in HAE.

Once-Daily Oral Berotralstat for Long-Term Prophylaxis of Hereditary Angioedema: The Open-Label Extension of the APeX-2 Randomized Trial

Berotralstat is a first-line, once-daily oral plasma kallikrein inhibitor approved for prophylaxis of hereditary angioedema (HAE) attacks in patients 12 years or older. This analysis examined the safety and effectiveness of long-term prophylaxis with berotralstat. APeX-2 was a phase 3, parallel-group, multicenter trial in patients with HAE caused by C1-inhibitor deficiency (NCT03485911). Part 1 was a randomized, double-blind, placebo-controlled evaluation of 150 and 110 mg of berotralstat over 24 weeks. In part 2, berotralstat-treated patients continued the same treatment, and placebo-treated patients were re-randomized to 150 or 110 mg of berotralstat for 24 weeks. In part 3, all patients were treated with open-label berotralstat at 150 mg, which could be continued for up to an additional 4 years. In part 3, the primary endpoint was long-term safety and tolerability. Secondary endpoints included HAE attack rates and quality of life (QoL). Eighty-one patients entered part 3. Treatment-emergent adverse events (TEAEs) occurred in 82.7% of patients, with most being mild or moderate in severity. The most common TEAEs were nasopharyngitis, urinary tract infection, abdominal pain, arthralgia, coronavirus infection, and diarrhea. Drug-related TEAEs occurred in 14.8% of patients, but none were serious. For patients who completed 96 weeks of berotralstat treatment (n= 70), the mean (standard error) change in attack rate from baseline was-2.21 (0.20) attacks/mo. Clinically meaningful improvements in QoL were also observed, with the largest improvements in the functioning domain. Berotralstat was generally well tolerated, provided rapid and sustained reductions in HAE attacks and improved QoL over 96 weeks.

Patient-level indirect treatment comparison of lanadelumab versus pdC1-INH i.v. in hereditary angioedema patients: PATCH study.

Hereditary angioedema (HAE) is an autosomal dominant inherited disease in which patients suffer from local attacks primarily affecting skin and gastrointestinal tract, and sometimes even the upper respiratory tract leading to asphyxiation. Since head-to-head trials between authorized treatments are lacking, this study compares efficacy and safety of lanadelumab and intravenous plasma-derived C1-esterase inhibitor (pdC1-INH i.v.) in HAE patients on long-term prophylaxis by means of an indirect treatment comparison. Efficacy and safety of lanadelumab against pdC1-INH i.v. were analyzed in a fully prespecified indirect comparison based on individual patient data (n = 231) from the HELP and CHANGE clinical trials. Primary and secondary efficacy endpoints were compared using a generalized linear model for count data. Confounding variables were identified a priori via systematic literature research and validated by clinical experts. Adjustment of confounders was implemented using a conditional regression model. Lanadelumab showed a statistically significant improvement in reduction of HAE attack rates compared to pdC1-INH i.v. across multiple endpoints: Monthly attack rate of patients treated with lanadelumab was less than half compared to pdC1-INH i.v. (Rate ratio: 0.486; 95% CI: 0.253, 0.932). Monthly rate of laryngeal attacks was found to be five times lower for lanadelumab (Rate ratio: 0.2; 95% CI: 0.044, 0.915) and monthly rate of acute treated HAE attacks among lanadelumab patients was about one third of the attack rate of pdC1-INH i.v. patients (Rate ratio: 0.366; 95% CI: 0.185, 0.727). This study contributes to current knowledge in the treatment of HAE by indicating a statistically significant reduction of HAE attacks under lanadelumab compared to pdC1-INH i.v.

Efficacy and safety of lanadelumab in Japanese patients with hereditary angioedema: A phase 3 multicenter, open-label study.

The safety and efficacy of lanadelumab for the prevention of hereditary angioedema (HAE) attacks have not been studied in Japanese patients. We report outcomes from a phase 3, multicenter, open-label study (NCT04180163) of lanadelumab in Japanese patients with HAE. Japanese patients with HAE aged ≥12 years with ≥1 investigator-confirmed HAE attack during the 4-week run-in baseline period were enrolled into the study and received lanadelumab 300 mg every 2 weeks subcutaneously for 52 weeks. Dosing could be reduced to 300 mg every 4 weeks during the second 26-week treatment period if patients had well-controlled symptoms (e.g., attack-free) for 6 months. The primary efficacy endpoint was no investigator-confirmed HAE attacks (attack-free status) during days 0-182. Other outcomes included the rate of investigator-confirmed HAE attacks per month (28 days) and lanadelumab safety. Twelve patients (mean ± SD age 41.9 ± 12.4 years) were enrolled. During the first 26 weeks (days 0-182), five (41.7%) patients were attack-free. The mean ± SD HAE attack rate per month decreased by 74.0%, from 3.8 ± 2.4 during baseline to 1.2 ± 2.6 during the overall 52-week treatment period. There were no deaths or discontinuations due to treatment-emergent adverse events (TEAEs), no severe or serious TEAEs related to lanadelumab, and no positive anti-drug antibody results. The most frequent TEAEs were injection-site reactions (37 events in six patients). Most of the injection-site reaction adverse events were mild in severity. Results of this study support the findings from two global phase 3 studies for lanadelumab use as prophylactic therapy in Japanese patients with HAE.

Network meta-analysis for indirect comparison of lanadelumab and berotralstat for the treatment of hereditary angioedema.

Aim: With no head-to-head studies comparing the effectiveness of lanadelumab and berotralstat for prevention of hereditary angioedema (HAE) attacks, this network meta-analysis (NMA) aimed to indirectly compare the effectiveness of these treatments. Materials & methods: The NMA, using the published data from Phase IIItrials, was performed using a frequentist weighted regression-based approach following Rücker et al. Efficacy outcomes of interest were HAE attack rate per 28days and ≥90% reduction in monthly HAE attacks. Results & conclusion: In this NMA, lanadelumab 300mg administered every 2weeks or every 4weeks was associated with statistically significantly higher effectiveness versus berotralstat 150mg once daily (q.d.) or 110mg q.d. for both efficacy outcomes assessed.

RAPID AND SUSTAINED REDUCTIONS IN HEREDITARY ANGIOEDEMA ATTACK RATES WITH LONG-TERM BEROTRALSTAT: REAL-WORLD OUTCOMES

<h3>Introduction</h3> Berotralstat, an oral once-daily prophylactic treatment for hereditary angioedema (HAE), has demonstrated sustained reduction in HAE attack rates and improvements in patient-reported quality of life in clinical trials. Here we present the preliminary efficacy data of patients in the United States receiving berotralstat in the real-world clinical setting. <h3>Methods</h3> This analysis is data collected through the sole-source pharmacy and included patients with confirmed HAE Type I/II based on laboratory tests and actively received berotralstat 110 or 150mg from 12/16/2020 to 5/20/22 for >270 days. Baseline attack rates were reported for the 90 days prior to berotralstat initiation. While on therapy, median attacks/month (25^th,75^th percentile) were calculated over each 90-day period by averaging each patient's monthly reported attack rate (1 month=∼28 days). Some patients did not report attack rates at each refill. <h3>Results</h3> In the patients who actively received berotralstat for >270 days (n=128) the median baseline attack rate was 1.7 attacks/month. A rapid reduction in median monthly attack rates was observed after starting berotralstat. During the first 90 days on therapy (days 1-90) the median monthly attack rate decreased to 0.3 (0,1.50) attacks/month; 0.5 (0,1.00) attacks/month from days 91-180; 0.3 (0,1.25) attacks/month from days 181-270; and 0.3 (0,1.25) attacks/month from days 271-360. The most common adverse events reported were consistent with clinical trials. <h3>Conclusions</h3> This data shows that berotralstat provided a rapid and sustained reduction in HAE attack rates within the first months of starting therapy making oral berotralstat an effective treatment option for patients with HAE.

IN VIVO CRISPR/CAS9 EDITING OF KLKB1 IN PATIENTS WITH HEREDITARY ANGIOEDEMA: A FIRST-IN-HUMAN STUDY

<h3>Introduction</h3> Hereditary angioedema (HAE) is a rare genetic disorder characterized by recurrent, debilitating and potentially fatal swelling attacks. Prophylactic treatments targeting kallikrein, a protease encoded by the <i>KLKB1</i> gene, significantly reduce the frequency of attacks. NTLA-2002 is an investigational CRISPR/Cas9-based therapy targeting <i>KLKB1</i> in hepatocytes, with the goal of achieving life-long control of HAE attacks after a single administration. <h3>Methods</h3> NCT05120830 is a first-in-human phase 1/2 study of NTLA-2002 in patients with HAE. The phase 1 is a single-ascending dose design with the primary objective of evaluating safety and identifying up to two doses to advance to the randomized phase 2 for further evaluation of efficacy and safety. <h3>Results</h3> Cohort 1 (25 mg; n = 3) completed the 16-week primary observation period. No DLTs or clinically significant laboratory abnormalities were observed. TEAEs were non-serious and spontaneously resolving, with the most common being infusion-related reactions (n = 2; CTCAE G1). All subjects demonstrated clinically significant, durable reduction in plasma kallikrein levels (mean 62 ± 27% at week 16) and HAE attack frequency from baseline, with 2 subjects remaining attack-free since infusion. Three subjects have been treated in Cohort 2 (75 mg). Follow-up is ongoing for all subjects in both cohorts. <h3>Conclusion</h3> A single 25 mg dose of NTLA-2002 has been well-tolerated to date, meeting pre-specified criteria for advancement to phase 2 with reduction in plasma kallikrein levels and HAE attack rate maintained throughout the 16-week period following infusion. Safety, pharmacodynamic and HAE attack rate data for both cohorts will be presented.

CONSISTENTLY LOW HEREDITARY ANGIOEDEMA ATTACK RATES OBSERVED WITH BEROTRALSTAT REGARDLESS OF PREVIOUS PROPHYLAXIS: REAL-WORLD OUTCOMES

<h3>Introduction</h3> Clinical trial data showed patients who switched to oral berotralstat monotherapy reported consistently low hereditary angioedema (HAE) attack rates. Here we present preliminary efficacy data of patients in the United States who initiated berotralstat treatment in the real-world clinical setting and were previously on another prophylactic therapy. <h3>Methods</h3> Data was collected through the sole-source pharmacy and included patients with confirmed HAE Type I/II who actively received berotralstat 110 or 150mg from 12/16/2020-5/20/22 and were stratified by previous prophylaxis. Baseline attack rates were reported for the 90 days prior to berotralstat initiation. While on therapy, median attacks/month(25^th,75^th percentile) were calculated over each 90-day period by averaging each patient's monthly reported attack rate (1 month=∼28 days). Some patients did not report attack rates at each refill. <h3>Results</h3> In patients treated with prior prophylaxis(n=129) the median baseline attack rate was 1.7 attacks/month which decreased to 0.3(0,1.31) from days 1-90; 0.6(0,1.00) from days 91-180; 0.5(0.25,1.00) from days 181-270; and 0.5(0,1.50) from days 271-360. Specifically, in the lanadelumab group(n=53), the baseline attack rate of 1.0 attack/month decreased to 0(0,0.50) from days 1-90; 0.3(0,0.75) from 91-180; 0.5(0,1.00) from 181-270; and 0.5(0,1.38) from 271-360. In the subcutaneous C1-inhibitor group(n=31), the baseline attack rate of 1.7 attacks/month decreased to 0.8(0,2.00) from days 1-90; 0.7(0,2.08) from 91-180; 1.0(0.54,1.50) from 181-270; and 1.0(0.29,2.17) from 271-360. Patients without prior prophylaxis(n=112) had similar attack rate reductions. The most common adverse events reported were consistent with clinical trials. <h3>Conclusions</h3> Patients previously treated with another prophylactic therapy reported consistently low HAE attack rates when treated with once daily berotralstat.

PHASE 2 OPEN-LABEL EXTENSION STUDY WITH DONIDALORSEN TREATMENT IN PATIENTS WITH HEREDITARY ANGIOEDEMA

<h3>Introduction</h3> Hereditary angioedema (HAE) is a potentially fatal disease characterized by recurrent, often disabling swelling. A phase 2 study (ISIS 721744-CS2, NCT04030598) in patients with HAE treated with donidalorsen reported a 90% reduction in HAE attacks and lower adverse event (AE) rates compared with placebo (71% vs 83%). Here we report the results of the open-label extension of the phase 2 study (ISIS 721744-CS3, NCT04307381). <h3>Methods</h3> Patients completing the phase 2 study were eligible for enrollment. The on-treatment study period consisted of fixed (Weeks 1–13, donidalorsen 80 mg subcutaneously every 4 weeks) and flexible treatment periods (Weeks 17–53). In the flexible dosing period, patients continued 80 mg every 4 weeks, or switched to 80 mg every 8 weeks or 100 mg every 4 weeks. <h3>Results</h3> Seventeen patients with HAE (mean age 38.9 years, 64.7% female) were enrolled. No serious AEs or patient discontinuation due to AEs were reported. Patients were HAE attack-free for 99.6% (95% CI, 99.3%–99.9%) of on-treatment study days. The overall mean HAE attack rate for the on-treatment period starting from Day 1 was 0.08/month, 94.6% lower than the phase 2 run-in rate (2.7/month). Patients receiving 80 mg every 8 weeks (n=8) had a 76% reduction in HAE attacks (mean 0.28/month) from baseline (n=5, HAE attack-free; n=3, reverted to 80 mg every 4 weeks). <h3>Conclusion</h3> Results of this study demonstrated sustained reduction in HAE attack rate and no new safety signals with donidalorsen treatment, confirming prior phase 2 study findings and supporting its continued development.

MATCHING-ADJUSTED INDIRECT TREATMENT COMPARISON BETWEEN LANADELUMAB AND BEROTRALSTAT FOR HEREDITARY ANGIOEDEMA PROPHYLAXIS

<h3>Introduction</h3> To date, no head-to-head studies compared the efficacy of lanadelumab and berotralstat for the prevention of hereditary angioedema (HAE) attacks. In this analysis, matching-adjusted indirect comparison (MAIC) was used to estimate comparative effectiveness of lanadelumab versus berotralstat over 48 weeks of treatment as there were no common comparators to link a network of evidence. <h3>Methods</h3> The MAIC used the data from the HELP open-label extension (HELP OLE; NCT02741596) and APeX-2 (NCT03485911) studies. To preserve randomization, patients from the HELP OLE Study were re-weighted to match the clinically relevant baseline characteristics from the APeX-2 study. The efficacy outcome of interest was the HAE attack rate per 28 days. <h3>Results</h3> In this analysis, lanadelumab 300 mg every 2 weeks (Q2W) was associated with a statistically significantly 73% lower HAE attack rate per 28 days compared with berotralstat 150 mg QD over 48 weeks of treatment (rate ratio [RR] 0.27; 95% CI 0.24, 0.31; p<0.00001). In a subgroup analysis that only considered patients from the HELP OLE Study who rolled over from lanadelumab 300 mg Q2W arm in the HELP Study, lanadelumab 300 mg Q2W was associated with a statistically significantly 81% lower HAE attack rate per 28 days compared with berotralstat 150 mg QD over 48 weeks of treatment (RR 0.19; 95% CI 0.12, 0.29; p<0.0001). <h3>Conclusion</h3> In this MAIC, lanadelumab 300 mg Q2W was associated with a statistically significantly lower rate of HAE attacks per 28 days versus berotralstat 150 mg QD at 48 weeks of treatment.

Treatment of hereditary angioedema-single or multiple pathways to the rescue.

Hereditary angioedema (HAE) is a rare disease caused by mutations in the SERPING1 gene. This results in deficient or dysfunctional C1 esterase inhibitor (C1-INH) and affects multiple proteases involved in the complement, contact-system, coagulation, and fibrinolytic pathways. Current options for the treatment and prevention of HAE attacks include treating all affected pathways via direct C1-INH replacement therapy; or specifically targeting components of the contact activation system, in particular by blocking the bradykinin B2 receptor (B2R) or inhibiting plasma kallikrein, to prevent bradykinin generation. Intravenously administered plasma-derived C1-INH (pdC1-INH) and recombinant human C1-INH have demonstrated efficacy and safety for treatment of HAE attacks, although time to onset of symptom relief varied among trials, specific agents, and dosing regimens. Data from retrospective and observational analyses support that short-term prophylaxis with intravenous C1-INH products can help prevent HAE attacks in patients undergoing medical or dental procedures. Long-term prophylaxis with intravenous or subcutaneous pdC1-INH significantly decreased the HAE attack rate vs. placebo, although breakthrough attacks were observed. Pathway-specific therapies for the management of HAE include the B2R antagonist icatibant and plasma kallikrein inhibitors ecallantide, lanadelumab, and berotralstat. Icatibant, administered for treatment of angioedema attacks, reduced B2R-mediated vascular permeability and, compared with placebo, reduced the time to initial symptom improvement. Plasma kallikrein inhibitors, such as ecallantide, block the binding site of kallikrein to prevent cleavage of high molecular weight kininogen and subsequent bradykinin generation. Ecallantide was shown to be efficacious for HAE attacks and is licensed for this indication in the United States, but the labeling recommends that only health care providers administer treatment because of the risk of anaphylaxis. In addition to C1-INH replacement therapy, the plasma kallikrein inhibitors lanadelumab and berotralstat are recommended as first-line options for long-term prophylaxis and have demonstrated marked reductions in HAE attack rates. Investigational therapies, including the activated factor XII inhibitor garadacimab and an antisense oligonucleotide targeting plasma prekallikrein messenger RNA (donidalorsen), have shown promise as long-term prophylaxis. Given the requirement of lifelong management for HAE, further research is needed to determine how best to individualize optimal treatments for each patient.

Hereditary angioedema due to C1 inhibitor deficiency: real-world experience from the Icatibant Outcome Survey in Spain

BackgroundThe Icatibant Outcome Survey (IOS) is an international registry monitoring the use of icatibant, a bradykinin B2 receptor antagonist indicated for the acute treatment of hereditary angioedema (HAE) attacks. Our goal was to assess disease characteristics and icatibant treatment outcomes in patients with HAE due to C1 inhibitor deficiency (HAE type 1 or 2 (HAE-1/2)) from Spain relative to other countries participating in IOS.MethodsDescriptive retrospective analyses of data are reported from 10 centers in Spain vs 51 centers in 12 other participating countries (July 2009 to January 2019).ResultsNo meaningful differences were identified between patients in Spain (n = 119) and patients across other countries (n = 907) regarding median age at symptom onset (15.0 vs 12.0 years) or diagnosis (22.3 vs 20.5 years). Overall HAE attack rates (total attacks/total years of follow-up) were 2.66 in Spain and 1.46 across other countries. Patients in Spain reported fewer severe/very severe HAE attacks before treatment (41.0% vs 45.9%; P < 0.0001) and, for icatibant-treated attacks, longer median time to treatment (2.9 vs 1.0 h), time to attack resolution (18.0 vs 5.5 h), and total attack duration (24.6 vs 8.0 h). Use of androgens for long-term prophylaxis was higher in Spain (51.2% vs 26.7%).ConclusionPatients with HAE-1/2 in Spain reported fewer severe/very severe attacks, administered icatibant later, and had longer-lasting attacks than did patients across other countries in IOS. These differences may indicate varying disease management practices (e.g., delayed icatibant treatment) and reporting. Efforts to raise awareness on the benefits of early on-demand treatment may be warranted.Trial registration: NCT01034969.

Long-term safety and effectiveness of berotralstat for hereditary angioedema: The open-label APeX-S study.

BackgroundBerotralstat (BCX7353) is an oral, once‐daily inhibitor of plasma kallikrein recently approved for prevention of angioedema attacks in adults and adolescents with hereditary angioedema (HAE). The objective of this report is to summarize results from an interim analysis of an ongoing long‐term safety study of berotralstat in patients with HAE.MethodsAPeX‐S is an ongoing, phase 2, open‐label study conducted in 22 countries (ClinicalTrials.gov, NCT03472040). Eligible patients with a clinical diagnosis of HAE due to C1 inhibitor deficiency (HAE‐C1‐INH) were centrally allocated to receive berotralstat 150 or 110 mg once daily. The primary objective was to determine long‐term safety and the secondary objective was to evaluate effectiveness.ResultsEnrolled patients (N = 227) received berotralstat 150 mg (n = 127) or 110 mg (n = 100) once daily. The median (range) duration of exposure was 342 (11–540) and 307 (14–429) days for the 150‐mg and 110‐mg groups, respectively. Treatment‐emergent adverse events (TEAEs) occurred in 91% (n = 206) of patients. The most common TEAEs across treatment groups were upper respiratory tract infection (n = 91, 40%), abdominal pain (n = 57, 25%), headache (n = 40, 18%), and diarrhea (n = 31, 14%) and were mostly mild to moderate. Fifty percent (n = 113) of patients had at least one drug‐related adverse event (AE; 150 mg, n = 57 [45%]; 110 mg, n = 56 [56%]), and discontinuations due to AEs occurred in 19 (8%) patients (150 mg, n = 13 [10%]; 110 mg, n = 6 [6%]). Three (1.3%) patients experienced a drug‐related serious TEAE. Among patients who received berotralstat through 48 weeks (150 mg, n = 73; 110 mg, n = 30), median HAE attack rates were low in month 1 (150 mg, 1.0 attacks/month; 110 mg, 0.5 attacks/month) and remained low through 12 months (0 attacks/month in both dose groups). Mean HAE attack rates followed a similar trend, and no evidence for patient tolerance to berotralstat emerged. In both dose groups, angioedema quality of life scores showed clinically meaningful changes from baseline.ConclusionsIn this analysis, both berotralstat doses, 150 and 110 mg once daily, were generally well tolerated. Effectiveness results support the durability and robustness of berotralstat as prophylactic therapy in patients with HAE.Trial registrationThe study is registered with ClinicalTrials.gov (NCT03472040).

Randomized Trial of the Efficacy and Safety of Berotralstat (BCX7353) as an Oral Prophylactic Therapy for Hereditary Angioedema: Results of APeX-2 Through 48 Weeks (Part 2)

Berotralstat (BCX7353) is a recently approved, oral, once-daily kallikrein inhibitor for hereditary angioedema (HAE) prophylaxis. In the APeX-2 trial, berotralstat reduced HAE attack rates over 24 weeks, with a favorable safety and tolerability profile. Evaluate berotralstat safety, tolerability, and effectiveness over 48 weeks. APeX-2 is a phase 3, parallel-group, multicenter trial (NCT03485911) in patients with HAE due to C1 esterase inhibitor deficiency. Part 1 was double-blind and placebo-controlled, with patients randomized to 24 weeks of berotralstat 150 mg, 110 mg, or placebo. In part 2, patients continued berotralstat the same dose or, if initially randomized to placebo, were rerandomized to berotralstat 150 mg or 110 mg through weeks 24 to 48. The primary end point was safety and tolerability. One hundred eight patients received 1 or more doses of berotralstat in part 2. Treatment-emergent adverse events (TEAEs) occurred in 30 of 39 patients (77%) in the placebo group during part 1, and 25 of 34 patients (74%) re-randomized from placebo to berotralstat 110 mg or 150 mg in part 2, with drug-related TEAEs in 13 of 39 (33%), and 11 of 34 (32%) in the same groups. Most TEAEs were mild or moderate, with no serious drug-related TEAEs. The most common TEAEs were upper respiratory tract infections, abdominal pain, diarrhea, and vomiting. Mean (±standard error of the mean) monthly attack rates at baseline and week 48 were 3.06 (±0.25) and 1.06 (±0.25) in the berotralstat 150mg 48-week group and 2.97 (±0.21) and 1.35 (±0.33) in the berotralstat 110mg 48-week group. The safety, tolerability, and effectiveness of berotralstat were maintained over 48 weeks of treatment.

Reduction in Attacks in Hereditary Angioedema (HAE) With Berotralstat is Consistent Regardless of Prior Prophylactic Treatment: A Subgroup Analysis of the Phase 3 APeX-2 Trial

Prophylactic treatment in the management of HAE is common. Berotralstat is an oral once-daily selective plasma kallikrein inhibitor that was shown to reduce HAE attack rates in a Phase 3 study (NCT03485911). This post hoc analysis evaluated the efficacy of berotralstat in patients previously treated with prophylactic medications. A total of 121 patients were randomized to berotralstat 110 mg:150 mg:placebo daily for 24 weeks. Investigator-confirmed attacks were analyzed for patients grouped by type of prior prophylaxis: prior C1 esterase inhibitor (C1-INH), prior androgen, and no prior prophylaxis. Prior C1-INH and prior androgen categories were not mutually exclusive. Overall, 75% of patients in the berotralstat 150 mg dose group and 73% in the placebo group had prior prophylactic treatment. Among patients with prior C1-INH prophylaxis or prior androgen use, berotralstat 150 mg significantly reduced attacks compared to placebo during the treatment period (C1-INH, 1.58 attacks/month vs placebo 2.84 attacks/month, p = 0.012; androgens, 1.35 attacks/month vs placebo 2.60 attacks/month, p <0.001). Lastly, patients without prior prophylaxis had a reduction in attacks (0.86 attacks/month compared with 1.78 attacks/month in placebo; p = 0.056). In this subgroup analysis, patients with prior C1-INH prophylaxis or prior androgen use treated with berotralstat demonstrated a significant reduction in attacks vs. placebo, making oral berotralstat a valuable potential preventive treatment option for patients with HAE.

Pharmacological and clinical study results of Berotralstat Hydrochloride for long-term prophylactic treatment of hereditary angioedema

Hereditary angioedema (HAE) is a rare disease that causes serious health problem and affects on quality of life for patient due to recurrent episodes of angioedema in various body such as the skin, larynx, digestive tract, and limbs. Many HAE patients have deficiency or dysfunction of C1 inhibitor, impaired regulation of plasma kallikrein activity and overproduction of bradykinin, resulting in leading to episodes of increased capillary hyper permeability and angioedema. Therapy of HAE consists of on-demand treatment for acute attack and prophylactic treatment by suppressing the onset of acute attack in the short and long term. However, no drug has been approved for long-term prophylaxis in Japan. Berotralstat hydrochloride (ORLADEYO Capsules 150 mg) is an oral, selective plasma kallikrein inhibitor approved for the suppression of the onset of acute attacks in HAE in Japan in January 2021. Preclinical studies demonstrated that Berotralstat is a potent and highly specific inhibitor of human plasma kallikrein activity. Berotralstat suppressed bradykinin production in the HUVEC system. Clinical studies demonstrated that oral administration of Berotralstat to HAE type I or type II patients at a dose of 150 mg once daily showed a reduction of HAE attack rate and clinically significant change in angioedema quality of life score. The most common side effect was gastrointestinal symptoms. In conclusion, preclinical and clinical data indicated that Berotralstat is an effective treatment for long-term prophylactic treatment by suppressing the onset of acute attack in HAE patient and is considered to be a useful treatment option for patients.

Oral once-daily berotralstat for the prevention of hereditary angioedema attacks: A randomized, double-blind, placebo-controlled phase 3 trial

Berotralstat (BCX7353) is an oral, once-daily inhibitor of plasma kallikrein in development for the prophylaxis of hereditary angioedema (HAE) attacks. Our aim was to determine the efficacy, safety, and tolerability of berotralstat in patients with HAE over a 24-week treatment period (the phase 3 APeX-2 trial). APeX-2 was a double-blind, parallel-group study that randomized patients at 40 sites in 11 countries 1:1:1 to receive once-daily berotralstat in a dose of 110 mg or 150 mg or placebo (Clinicaltrials.gov identifier NCT03485911). Patients aged 12 years or older with HAE due to C1 inhibitor deficiency and at least 2 investigator-confirmed HAE attacks in the first 56 days of a prospective run-in period were eligible. The primary efficacy end point was the rate of investigator-confirmed HAE attacks during the 24-week treatment period. A total of 121 patients were randomized; 120 of them received at least 1 dose of the study drug (n= 41, 40, and 39 in the 110-mg dose of berotralstat, 150-mg of dose berotralstat, and placebo groups, respectively). Berotralstat demonstrated a significant reduction in attack rate at both 110 mg (1.65 attacks per month; P= .024) and 150 mg (1.31 attacks per month; P< .001) relative to placebo (2.35 attacks per month). The most frequent treatment-emergent adverse events that occurred more with berotralstat than with placebo were abdominal pain, vomiting, diarrhea, and back pain. No drug-related serious treatment-emergent adverse events occurred. Both the 110-mg and 150-mg doses of berotralstat reduced HAE attack rates compared with placebo and were safe and generally well tolerated. The most favorable benefit-to-risk profile was observed at a dose of 150 mg per day.

Lanadelumab demonstrates rapid and sustained prevention of hereditary angioedema attacks.

BackgroundLanadelumab demonstrated efficacy in preventing hereditary angioedema (HAE) attacks in the phase 3 HELP Study.ObjectiveTo assess time to onset of effect and long‐term efficacy of lanadelumab, based on exploratory findings from the HELP Study.MethodsEligible patients with HAE type I/II received lanadelumab 150 mg every 4 weeks (q4wks), 300 mg q4wks, 300 mg q2wks, or placebo. Ad hoc analyses evaluated day 0‐69 findings using a Poisson regression model accounting for overdispersion. Least‐squares mean monthly HAE attack rate for lanadelumab was compared with placebo. Intrapatient comparisons for days 0‐69 versus steady state (days 70‐182) used a paired t test for continuous endpoints or Kappa statistics for categorical endpoints.ResultsOne hundred twenty‐five patients were randomized and treated. During days 0‐69, mean monthly attack rate was significantly lower with lanadelumab (0.41‐0.76) vs placebo (2.04), including attacks requiring acute treatment (0.33‐0.61 vs 1.66) and moderate/severe attacks (0.31‐0.48 vs 1.33, all P ≤ .001). More patients receiving lanadelumab vs placebo were attack free (37.9%‐48.1% vs 7.3%) and responders (85.7%‐100% vs 26.8%). During steady state, the efficacy of lanadelumab vs placebo was similar or improved vs days 0‐69. Intrapatient differences were significant with lanadelumab 300 mg q4wks for select outcomes. Lanadelumab efficacy was durable—HAE attack rate was consistently lower vs placebo, from the first 2 weeks of treatment through study end. Treatment emergent adverse events were comparable during days 0‐69 and 70‐182.ConclusionProtection with lanadelumab started from the first dose and continued throughout the entire study period.

Pharmacokinetics, Pharmacodynamics, and Exposure-Response of Lanadelumab for Hereditary Angioedema.

Hereditary angioedema (HAE) with C1 inhibitor deficiency is a rare disorder characterized by unpredictable, potentially life‐threatening recurrent angioedema attacks. Lanadelumab is a fully human monoclonal antibody with selective binding to active plasma kallikrein, and prevents the formation of cleaved high molecular weight kininogen (cHMWK) and bradykinin, thereby preventing HAE attacks. The clinical pharmacology of lanadelumab was characterized following subcutaneous administration in 257 subjects (24 healthy subjects and 233 patients with HAE). The pharmacokinetics of lanadelumab were described using a one‐compartment model with first‐order rate of absorption and linear clearance, showing slow absorption and a long half‐life (14.8 days). A covariate analysis retained body weight and health status on apparent clearance (CL/F) and body weight on volume of distribution (V/F). Population estimates of CL/F and V/F were 0.0249 L/hour (0.586 L/day) and 12.8 L, respectively. An indirect‐response Imax model showed 53.7% maximum suppression in cHMWK formation with a low potential for interactions with concomitant medications (analgesic, anti‐inflammatory, and antirheumatic medications). A 300 mg dose administered Q2W was associated with a mean steady‐state minimum concentration (Cmin,ss; 25.4 μg/mL) that was ~ 4.5‐fold higher than the half‐maximal inhibitory concentration for cHMWK reduction (5.71 μg/mL). Exposure‐response analyses suggest that 300 mg Q2W dosing was associated with a significantly reduced HAE attack rate, prolonged time to first attack after treatment initiation, and lower need for concomitant medications. The response was comparable across patient body weight groups. Findings from this analysis support the dosing rationale for lanadelumab to prevent attacks in patients with HAE.

Advances in Hereditary Angioedema: The Prevention of Angioedema Attacks With Subcutaneous C1-Inhibitor Replacement Therapy.

Hereditary angioedema (HAE) is a debilitating condition caused by a functional C1-inhibitor (C1-INH) deficiency and characterized clinically by episodes of subcutaneous or submucosal swelling. C1-INH replacement is highly effective for preventing HAE attacks and can improve health-related quality of life. Once available only for intravenous use, C1-INH is now available as a subcutaneous formulation for self-administration, shown to provide sustained plasma levels of C1-INH and reducing the monthly median HAE attack rate by 95% versus placebo in the phase 3 COMPACT study. Subcutaneously administered C1-INH satisfies multiple unmet needs in the management of patients with HAE.