Long-Term Real-World Outcomes in Patients with Hereditary Angioedema Receiving Lanadelumab for 3 or More Years

Abstract

Introduction

Hereditary angioedema (HAE) is a rare genetic disorder characterized by unpredictable, painful swelling attacks that significantly impair patients’ quality of life (QoL). Clinical trials of lanadelumab led to its approval for long-term prophylaxis in patients with HAE; however, real-world data on long-term lanadelumab use in patients with HAE are limited. This analysis describes real-world outcomes of patients with HAE who have received lanadelumab as long-term prophylaxis for ≥3 years.

Methods

From January 2023 to January 2024, investigators collected data from the Adelphi Wave II Disease Specific Programme™, a real-world, cross-sectional survey of physicians and their patients with HAE in the USA. Physicians retrospectively reported attack frequency, attack severity, and QoL before lanadelumab initiation, at 12, 24, and 36 months post initiation, and at the time of the survey.

Results

Physicians reported data on 51 patients who had received lanadelumab for ≥3 years. Before lanadelumab initiation, physicians reported attack severity as mild in 49.0% of patients and very severe in 8.2%; at 36 months post lanadelumab initiation, 62.5% of patients experienced mild attacks and none experienced very severe attacks in the preceding year. The proportion of patients experiencing ≥1 attack per month on average decreased from 54.0% before lanadelumab initiation to 9.8% at the time of the survey. The proportion of patients with good or excellent QoL increased from 68.6% before lanadelumab initiation to 88.2% at the time of the survey.

Conclusion

In this real-world HAE study, patients treated with lanadelumab for ≥3 years experienced improvements in attack frequency, disease severity, and QoL.

Introduction

Hereditary angioedema (HAE) is a rare genetic disorder characterized by recurrent, unpredictable attacks of bodily swelling [1]. The estimated prevalence of the disorder is 1:50,000, with both children and adults being affected [2]. The clinical manifestations of HAE result from a deficiency (HAE-C1INH-Type1) or dysfunction (HAE-C1INH-Type2) of the C1 esterase inhibitor, leading to dysregulation of the kallikrein-kinin cascade [3, 4]. This increases levels of bradykinin, which in turn increases vascular permeability, causing localized tissue swelling [3, 4].

HAE attacks manifest clinically as nonpitting, nonpruritic edema, primarily involving the subcutaneous tissue (face, limbs, and genitals), abdominal organs, and the upper airway [1]. HAE attacks are painful, functionally debilitating, and potentially fatal because an attack affecting the throat can cause asphyxiation. Patients may also experience fatigue, nausea, and vomiting during attacks [5]. These burdensome symptoms, along with the fear of future attacks, greatly impair patients’ physical, emotional, and social well-being, leading to reduced quality of life (QoL) [6–8].

Although on-demand treatments following an acute attack and short-term prophylactic treatment have roles in the management of HAE, these treatment options do not provide proactive prevention of unpredictable, highly burdensome attacks. Long-term prophylaxis (LTP) can reduce the frequency and severity of attacks and help improve patients’ health-related QoL [7]. Lanadelumab, a monoclonal antibody that inhibits plasma kallikrein, is approved for long-term prevention of HAE attacks in patients aged 2 years or older in the USA [9] and Europe [10] and aged 12 years or older in multiple other regions.

Although clinical trials have demonstrated the efficacy and safety of lanadelumab LTP [11–13], the inherent difficulties of clinical research on rare diseases make real-world data essential to better understand the long-term outcomes of lanadelumab treatment. Long-term data on LTP with lanadelumab are limited. There have been more than 5 years of real-world experience in the USA since approval in 2018, lending an opportunity to investigate long-term, real-world use. Understanding the maintenance of effectiveness and QoL over time is of high interest to patients and prescribers. Here, we describe physician-reported, real-world outcomes of patients with HAE who received lanadelumab LTP for at least 3 years, expanding on recently reported outcomes after 12 months of LTP therapies for HAE [14].

Methods

Study Design

Data for this analysis were obtained from the Adelphi Wave II Disease Specific Programme™, a real-world, cross-sectional survey conducted between January 2023 and January 2024 that utilized retrospective data collection from physicians and their patients with HAE in the USA [15–17]. The survey was conducted in line with European Pharmaceutical Marketing Research Association guidelines and as such did not require Ethics Committee approval. The Adelphi Disease Specific Programme™ questionnaires were submitted to the Pearl Institutional Review Board and following IRB review a waiver was granted, deeming the survey to be exempt from ethical approval (Pearl Institutional Review Board work order #23-ADRW-178/AG9371, dated January 9, 2023). In addition, the survey was conducted in full accordance with the relevant legislation at the time of data collection, including the US Health Insurance Portability and Accountability Act 1996 (US Department of Health and Human Services 2003) and Health Information Technology for Economic and Clinical Health Act legislation (Health Information Technology [HITECH] 2009). Physicians were recruited to participate in the Adelphi Disease Specific Programme™ by local fieldwork agents.

Eligibility criteria for physicians included a specialty in allergy, allergy-immunology, dermatology, otolaryngology, hematology, or pulmonology; and direct involvement in the treatment decisions and management of 2 or more patients with HAE in a typical month. Eligibility criteria for patients included confirmed diagnosis of HAE (patients would have been diagnosed with HAE-C1INH-Type1 if physicians reported decreased levels of C1INH and diagnosed with HAE-C1INH-Type2 if they had dysfunctional C1INH. Physicians were asked about which scans, tests, and assessments were conducted to aid diagnosis and what they used to monitor patients’ HAE); at least 1 HAE attack in the patient’s lifetime; and continuous treatment with lanadelumab as the only prophylactic medication for at least 3 years (this analysis only). Patients with a physician-reported diagnosis of HAE-nC1INH were excluded from this analysis owing to the considerable variation in clinical presentation, lack of consistency in how the diagnosis of HAE-nC1INH is determined and the expected small sample size. Patients were allowed to have received prior LTP with a different medication.

Assessments

Physicians used patients’ medical charts and their own expert clinical judgment to report on demographics, HAE attack frequency, HAE attack severity, hospitalization rate, and QoL. Additionally, details of current LTP, previous LTP, and reasons for switching treatments were also collected. Physicians retrospectively reported outcomes at the time of diagnosis, at the time of lanadelumab initiation, at 12, 24, and 36 months post lanadelumab initiation, and at the time of the survey. Physicians reported attack severity that was graded as grade I (mild), grade II (moderate), grade III (severe), or grade IV (very severe) at the time of the attack, based on the expert judgment of the treating physician. Physicians reported attack frequency, which was grouped into the following categories: 0 attacks, 1–3 attacks, 4–6 attacks, or 7–12 attacks.

Statistical Analysis

Descriptive statistics evaluating disease severity, frequency of attacks, hospitalization rate, and QoL among patients receiving lanadelumab LTP for at least 3 years were reported. Outcomes are reported before lanadelumab initiation, at months 12, 24, and 36 after starting lanadelumab, and at the time of the survey to understand changes over time. Variation in the sample sizes in the reporting of outcomes is not due to patient attrition, but to missing data and incomplete reporting.

Results

Patient Demographics and Clinical Characteristics

In total, 18 physicians provided data on 51 patients who had been receiving lanadelumab LTP for at least 3 years at the time of this analysis. All physicians were based in the USA as confirmed by local fieldwork agencies, and 16 (88.9%) were allergists or allergist-immunologists, and 2 (11.1%) were pulmonologists. Of the 51 included patients, 31 (60.8%) were male and 20 (39.2%) were female. All patients had either HAE-C1INH-Type1 (82.4%) or HAE-C1INH-Type2 (17.6%). Patients’ mean ± SD age was 35.8 ± 12.10 years. At the time of the survey, patients had been diagnosed with HAE for a mean ± SD of 10.8 ± 7.99 (n = 43) years and had received lanadelumab for a mean ± SD of 4.6 ± 1.07 (n = 51) years. While receiving lanadelumab, 72.5% (37 of 51) of patients were prescribed on-demand treatment in addition to lanadelumab, most commonly icatibant. Baseline demographic and clinical characteristics are provided in Table 1.

Table 1.

Baseline demographic and clinical characteristics

Characteristics	Patients (N = 51)
Sex, n (%)
Male	31 (60.8)
Female	20 (39.2)
Age, mean±SD, years	35.8±12.1
Living setting, n (%)
Rural	1 (2.0)
Urban	12 (23.5)
Suburban	38 (74.5)
Ethnicity, n (%)
White	36 (70.6)
Black African American/African or Caribbean	9 (17.6)
Asian	1 (2.0)
Other	5 (9.8)
Employment, n (%)
Working full-time	41 (80.4)
Working part-time	5 (9.8)
Student	4 (7.8)
Homemaker	1 (2.0)
BMI, mean±SD	27.5±4.0
HAE type, n (%)
HAE-C1INH-Type1	42 (82.4)
HAE-C1INH-Type2	9 (17.6)
Years since diagnosis, mean±SD	10.8±8.0
Current treatment, n (%)
Lanadelumab only	14 (27.5)
Lanadelumab and on-demand	37 (72.5)
Prescribed on-demand treatment, n (%)
Icatibant	29 (78.4)
Conestat alfa	5 (13.5)
Ecallantide	2 (5.4)
C1INH	1 (2.7)
Patients with previous LTP treatments before lanadelumab, n (%)	17 (33.3)
Previous LTP treatment, n (%)	n = 17
C1INH (Cinryze)	10 (58.8)
C1INH (HAEGARDA)	3 (17.6)
Danazol	2 (11.8)
Tranexamic acid	1 (5.9)
Other	1 (5.9)
Attack severity before starting lanadelumab, n (%)	n = 49
Grade I (mild)	24 (49.0)
Grade II (moderate)	16 (32.7)
Grade III (severe)	5 (10.2)
Grade IV (very severe)	4 (8.2)
Typical monthly attack frequency before starting lanadelumab, n (%)	n = 50
0 attacks/month	23 (46.0)
1 attack/month	19 (38.0)
2–3 attacks/month	7 (14.0)
>3 attacks/month	1 (2.0)
QoL before starting lanadelumab, n (%)
Very poor	4 (7.8)
Poor	5 (9.8)
Fair	7 (13.7)
Good	21 (41.2)
Excellent	14 (27.5)
Comorbidities, n (%)
Anxiety	13 (25.5)
Depression	13 (25.5)

BMI, body mass index; C1INH, C1 inhibitor; HAE, hereditary angioedema; LTP, long-term prophylaxis; QoL, quality of life.

Prior LTP

Lanadelumab was the first LTP treatment for 66.7% (34 of 51) of patients; 27.5% (14 of 51) patients had received 1 prior LTP treatment and 5.9% (3 of 51) had received 2. Previous treatments among the 17 patients who had received a prior LTP, including C1INH, danazol, and tranexamic, are shown in Table 1. The most common (not mutually exclusive) reasons reported by physicians for patients discontinuing their previous LTP were that the dosing schedule was too frequent, the treatment was not effective (enough) at reducing the frequency of attacks, and the patient preferred a different route of administration (Fig. 1).

Fig. 1.

Reasons for discontinuation of previous LTP. ^an = 17.

Attack Frequency

Prior to starting any LTP, no patients typically experienced 0 attacks per month, while 32%, 58%, and 10% experienced 1 attack, 2–3 attacks, and more than 3 attacks per month, respectively. Prior to starting lanadelumab, 46% of patients typically experienced 0 attacks per month, 38% experienced 1 attack per month, 14% experienced 2–3 attacks per month, and 2% experienced more than 3 attacks per month. The proportion of patients experiencing 0 attacks per month at the time of the survey was 90.2%, 5.9% experienced 1 attack, and 3.9% experienced 2–3 attacks per month. The proportion of patients experiencing at least 1 attack per month on average decreased from 54.0% (27 of 50) prior to lanadelumab initiation to 9.8% (5 of 51) at the time of the survey. Additionally, the proportion of patients who had 0 attacks in the previous 12 months increased from 28.0% at month 12 to 40.0% and 55.1% at months 24 and 36, respectively, following lanadelumab initiation (Fig. 2).

Fig. 2.

HAE attack frequency at 12, 24, and 36 months following lanadelumab long-term initiation. ^an = 50; ^bn = 49.

Attack Severity

Before lanadelumab initiation, the severity of a typical attack was reported to be mild in 49.0% of patients, moderate in 32.7%, severe in 10.2%, and very severe in 8.2% (n = 49). After initiating lanadelumab LTP, the proportion of patients experiencing a typical attack graded as very severe decreased to 4.3% (2 of 47) after 12 months of lanadelumab LTP and 2.1% (1 of 47) after 24 months; after 36 months, no patients had experienced a very severe attack in the preceding year (Fig. 3). The proportion of patients with a typical attack severity graded as mild was 38.3% (18 of 47) at 12 months, increasing to 46.8% (22 of 47) at 24 months and 62.5% (30 of 48) at 36 months (Fig. 3).

Fig. 3.

HAE attack severity at 12, 24, and 36 months following lanadelumab LTP initiation. ^an = 49; ^bn = 47; ^cn = 48.

Hospitalizations

In the 12 months prior to survey completion, 7.3% (3 of 41) of patients were hospitalized due to a HAE attack. The rate of hospitalizations during the 12 months prior to data collection decreased in 63.3% (31 of 49) of patients compared with prior to lanadelumab initiation; the remaining 36.7% (18 of 49) of patients had never had a hospitalization before initiating lanadelumab (Fig. 4).

Fig. 4.

Change in hospitalization rate since lanadelumab initiation. HAE, hereditary angioedema. ^an = 49.

Health-Related QoL

At the time of the survey, 88.2% (45 of 51) of patients had good or excellent QoL per physicians’ reports; in comparison, physicians reported only 68.6% (35 of 51) of patients as having good or excellent QoL before initiation of lanadelumab (Fig. 5a). A higher proportion of patients who had received prior LTP before starting lanadelumab treatment were reported to have excellent QoL compared with patients who had not received prior LTP before lanadelumab treatment initiation (Fig. 5a). The proportion of patients reported as having excellent QoL increased from 19.6% (10 of 51) at 12 months to 35.3% (18 of 51) at 24 months and 56.9% (29 of 51) at 36 months (Fig. 5b). Physicians reported that 17.6% (9 of 51) of patients had poor or very poor QoL prior to lanadelumab initiation; at 12, 24, and 36 months following lanadelumab initiation, no patients had very poor or poor QoL per physicians’ reports. At the time of the survey, 7.8% (4 of 51) of patients had poor or very poor QoL.

Fig. 5.

QoL before starting lanadelumab treatment among patients receiving and not receiving prior long-term prophylaxis (LTP) (a) and during years 1, 2, and 3 after lanadelumab treatment initiation (b). ^an = 51; ^bn = 17; ^cn = 3.

Discussion

In this analysis of real-world findings from a physician-reported survey of patients with HAE who received lanadelumab LTP for at least 3 years, patients experienced a reduction in attack frequency, attack severity, and improvement in QoL. Severity of a typical attack was reduced from prior to lanadelumab initiation and continued to reduce over time from year 1 to year 3 after initiating lanadelumab. Progressive improvements in attack severity over the long-term follow-up was an interesting and important finding. Given the added disease burden and greater potential for fatality as the severity of attacks increases [1], the decrease in the number of very severe attacks in patients receiving lanadelumab is a key treatment goal.

Physician-reported patient QoL and rate of annual attacks were found to progressively improve over the 3-year follow-up, potentially highlighting the importance of comfort in experiencing satisfactory HAE management over time. Prior to starting LTP, no patients were attack free, highlighting the benefit of LTP in general. Prior to starting lanadelumab, patients who were on a previous LTP had better outcomes before starting lanadelumab treatment than those who were not. Regardless of prior LTP, patients saw incremental improvement in outcomes over time while receiving lanadelumab. However, the fact that 7.8% of patients were reported to have poor or very poor QoL post 36 months at the time of the survey, while none during years 1–3 is unexpected. The reasons for this are not clear and fluctuations in long-term QoL warrant further investigation; however, this might be partly attributable to recall or recency bias.

Furthermore, patients who had experienced a HAE-related hospitalization before initiation of LTP with lanadelumab experienced numerically lower rates of hospitalization after beginning treatment. In addition to reduced costs associated with healthcare resource utilization, these improvements in hospitalization rates, attack frequency, and attack severity likely contributed to the improved QoL that patients receiving lanadelumab experienced over the course of their treatment. These improvements may have also reduced the anxiety about future attacks that many patients feel [6, 18], further enhancing QoL. As anxiety and depression are common comorbidities in patients with HAE [6, 8, 19], further research and analysis of changes in these conditions and their relationship to QoL in patients receiving lanadelumab is warranted.

While the trend of a sustained increase in QoL over 3 years of lanadelumab treatment are informative initial long-term findings, they are based solely on physician report which might not accurately reflect the true patient experience if there has been insufficient dialog between patient and physician [20, 21]. As such, future research into the long-term impact of LTP treatment on QoL should consider utilizing validated patient-reported outcome measures, such as the Angioedema Quality of Life Questionnaire.

The reduction in the number of HAE attacks after lanadelumab initiation reported in this analysis is in line with findings from clinical studies such as the phase 3 HELP open-label extension study, which demonstrated an overall 87.4% decrease in attack rate (mean ± SD lanadelumab exposure 29.6 ± 8.2 months) [11]. Additionally, in the phase 4 observational EMPOWER study, a 79% reduction in attacks as well as improvements in QoL were observed after lanadelumab LTP treatment (in patients who had received <4 doses of lanadelumab prior to the study) [13].

The results presented here expand on these findings and previously reported outcomes at 12 months among patients in the Adelphi DSP [14] by reporting a sustained reduction in attack rates and severity and improved QoL at 3 years post lanadelumab LTP initiation. They are also consistent with real-world studies that have reported notable reductions in attack rates and severity and improvements in QoL after 6 months of lanadelumab treatment [22], and sustained well-controlled disease in patients who had been receiving lanadelumab LTP for 4 years [23]. Taken with the findings presented here, the results suggest that the clinical benefit of lanadelumab LTP can occur soon after treatment initiation and be maintained long-term in real-world settings.

Although LTP is the primary focus of this analysis, it is notable that 27.5% of patients were prescribed lanadelumab only, given that US guidelines recommend that management plans include on-demand medication for every patient [24]. This might reflect that on-demand medications are under-prescribed in real-world clinical practice, which is of potential concern given the unpredictable and serious nature of attacks. Interestingly, a real-world study among patients receiving lanadelumab LTP who reported well-controlled disease found that no HAE attacks were experienced after 146 of 147 potentially attack-inducing medical procedures despite no use of short-term prophylaxis [23].

The main strength of this study is the long-term follow-up period, adding to the limited real-world data on long-term treatment outcomes. However, limitations of this study should be considered, including those related to its retrospective, real-world, cross-sectional design, such as the potential for unmeasured confounding variables between groups, selection bias, and recall bias. Specifically, the use of physician-patient consultations as a method of data capture introduced the potential for selection bias as those patients who chose to more frequently consult with their physicians were more likely to be included in the study. Additionally, with retrospective data collection, information important to the measured outcomes may not have been gathered at the time, thus limiting the analyses. Data were also missing for some patients, an inherent limitation of studies in real-world clinical practice. Furthermore, physicians used their clinical judgment and medical records to retrospectively determine outcomes, introducing an element of subjectivity to the results, for example, attack severity was subjectively based on expert clinical judgment, and variability in treating physicians’ definitions of severity may have introduced inconsistencies. As data were drawn from real-world clinical practice, no data using validated patient-reported outcome measures such as the Angioedema Quality of Life Questionnaire were available as they were not routinely completed during patient-physician consultations. Retrospective data collection may also have introduced recall bias as physicians were asked to recall information from before the initiation of lanadelumab. However, the vast majority of patients (47 of 51) were managed by the same physician throughout their treatment.

In conclusion, treatment with lanadelumab LTP for at least 3 years reduced the severity and frequency of attacks and improved QoL in patients with HAE. Relevant HAE outcomes were maintained or progressively improved over time while receiving lanadelumab. Long-term real-world research on patients with HAE receiving lanadelumab, along with comparison of the results with those for other LTP treatments, will further aid treatment decisions and improve outcomes in patients.

Acknowledgments

Under the direction of authors, Ashley Oney, MD, and Jon Waldron, PhD, employees of Envision Catalyst, an Envision Medical Communications agency, a part of Envision Pharma Group, provided writing assistance for this manuscript. Editorial assistance in formatting, proofreading, copyediting, and fact-checking was also provided by Envision Catalyst, an Envision Medical Communications agency, a part of Envision Pharma Group. Takeda Pharmaceuticals USA, Inc. provided funding to Envision Catalyst, an Envision Medical Communications agency, a part of Envision Pharma Group, for support in writing and editing this manuscript. The interpretation of the data was made by the authors independently.

Statement of Ethics

The Adelphi Disease Specific Programme™ questionnaires were submitted to the Pearl Institutional Review Board and following IRB review a waiver was granted, deeming the survey to be exempt from ethical approval (Pearl Institutional Review Board work order #23-ADRW-178/AG9371, dated January 9, 2023). Therefore, written informed consent to participate was not required as determined by the IRB and inferred by completion of the questionnaire.

Conflict of Interest Statement

W.R.L. has served as a member of advisory boards for Astria Therapeutics, BioCryst, BioMarin, CSL Behring, Intellia Therapeutics, KalVista Pharmaceuticals, Novartis, Pharvaris, and Takeda; has received research grants from AstraZeneca, Astria Therapeutics, BioCryst, BioMarin, CSL Behring, Intellia Therapeutics, Ionis, KalVista Pharmaceuticals, Takeda, and Teva; has received consulting fees from Astria Therapeutics, BioCryst, CSL Behring, Fresenius Kabi, Pharming, and Takeda; has received payments for lectures from AstraZeneca, BioCryst, CSL Behring, GSK, Pharming, and Takeda; and is an advisory board member of the US Hereditary Angioedema Association. M.D.-L. has served as a member of advisory boards and speaker’s bureaus for BioCryst, CSL Behring, Pharming, Pharvaris, and Shire (a Takeda Co.); has received a research grant as an investigator/clinical trial investigator from Shire (a Takeda Co.); and is an advisory board member of the US Hereditary Angioedema Association. D.S. has served as an adviser for CSL Behring, Cycle Pharmaceuticals, KalVista Pharmaceuticals, and Shire/Takeda; served as a consultant for BioCryst, KalVista Pharmaceuticals, and Pharming; conducted research for BioCryst, BioMarin, Ionis, KalVista Pharmaceuticals, Pharvaris, and Shire/Takeda; and served as a speaker for BioCryst, CSL Behring, Pharming, and Shire/Takeda. L.E. is a former employee of Adelphi Real World. K.W.-C. is an employee of Adelphi Real World. D.F., K.S., S.J., and B.G.S. are employees of Takeda Pharmaceuticals USA, Inc., and hold stock/stock options in Takeda Pharmaceutical Company Limited.

Funding Sources

The study was sponsored by Takeda Pharmaceuticals, Inc., Cambridge, MA, USA.

Author Contributions

B.G.S., D.F., K.S., and S.J. contributed to the conceptualization of the study. L.E. and K.W.-C. contributed to data curation and analysis. W.R.L., M.D.L., D.S., L.E., K.W.-C., D.F., K.S., S.J., and B.G.S. contributed to the interpretation of data, drafted and critically reviewed the manuscript, and have approved the final version of the manuscript.

Funding Statement

The study was sponsored by Takeda Pharmaceuticals, Inc., Cambridge, MA, USA.

Data Availability Statement

All data that support the findings of this study are the intellectual property of Adelphi Real World. All requests for access should be addressed directly to Kieran Wynne-Cattanach at kieran.wynne-cattanach@adelphigroup.com.