Real-World Outcomes and Healthcare Utilization of Lanadelumab in Spain: Insights from First Cohort of Difficult-to-Treat Hereditary Angioedema Cases

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This is an interesting account of the real-life experience with lanadelumab from a single center in Spain. The article covers important topic of continuously growing interest and recognition among allergists involved in HAE management.

The introduction provides concise yet comprehensive insight into pathophysiological pathways leading to HAE symptoms. There is not much to add to this section.

Below please find my comments regarding the remaining part of the manuscript.

Major issues:

1.        Please briefly describe what are the criteria for the reimbursement or direct financing of the lanaldelumab LTP in HAE as per requirements of the Spanish healthcare providers and payers. This may differ form country to country in terms of number and severity of attacks and other parameters, therefore, it would be interesting to include a short Spanish perspective.

2.        Regarding materials and methods: Why were only HAE type 1 patients included? Later (line 129) the authors stated that they took care of HAE type 2 patients as well. Please clarify what was the reason of not analyzing them. Also, I could not find a clear reasin why only these 4 female sujects were enrolled. This requires clear statement in my opinion.

3.        Figure 1 looks cut in half – please provide the full version.

4.        It is not quite clear why the visits in hospital pharmacy were analyzed. Is it the usual way that HAE patients have their on-demand treatment distributed in the area where the authors practice? Please provide additional explanation, because the decrease in these visits’ frequency looks quite spectacular. In general, I think the authors should provide additional explanations regarding goals and procedures associated with each type of healthcare resource that the patients utilize, i.e., medical visits, nursing visits, hospital pharmacy visits – in particular. These features may be specific for the authors’ country healthcare system and require further explanation, in order to make the data on healthcare costs reduction more appealing.

5.        While discussing their findings, the authors may also consider referring to additional articles (apart from the ones they cite: Hahn etal 202 and Buttgereit et al 2024) containing recent real-life data from the Polish lanadelumab treatment base on electronic database records of 43 HAE subjects: Kucharczyk et al. Pediatr Med Rodz 2023; 19 (4): 334–342 DOI: 10.15557/PiMR.2023.0054 (https://pimr.pl/index.php/issues/2023-vol-19-no-4/lanadelumab-demonstrates-high-efficacy-in-reducing-the-frequency-of-angioedema-attacks-in-patients-with-severe-hae-in-real-life-settings#overlay), and from the real-life observations of 16 patients in the Russian Federation: Latysheva et al. Russian Journal of Allergy 2023; 20(2): 164-176. DOI: 10.36691/RJA5493, https://rusalljournal.ru/raj/article/view/5493. These are real-world studies on larger groups of patients also confirming efficacy of lanadelumab in terms of clinic and healthcare resources use, and I encourage the authors to refer to them to further strengthen their preliminary conclusions.

Minor issues

·        Please make sure, that abbreviations are explained first time when used, e.g. LTP (long term prophylaxis) on page 2

·        Line 116: „were conducted” instead of „were conducting”

·        Also, please consider modifying the title to make it visible that this is an account of 4 diffcult HAE cases.

Author Response

Reviewer 1

This is an interesting account of the real-life experience with lanadelumab from a single center in Spain. The article covers important topic of continuously growing interest and recognition among allergists involved in HAE management.

The introduction provides concise yet comprehensive insight into pathophysiological pathways leading to HAE symptoms. There is not much to add to this section.

Below please find my comments regarding the remaining part of the manuscript.

Major issues:

1. Please briefly describe what are the criteria for the reimbursement or direct financing of the lanaldelumab LTP in HAE as per requirements of the Spanish healthcare providers and payers. This may differ form country to country in terms of number and severity of attacks and other parameters, therefore, it would be interesting to include a short Spanish perspective.

Answer: Thank you for the accurate comment. The following text -including the corresponding references #8 and 9- has been added to the last version of the manuscript: “In Spain, lanadelumab is an additional therapeutic option for managing HAE attacks. It is funded for patients aged 12 and older with HAE types I and II and is specifically approved for the routine prevention of recurrent attacks [8]. It is particularly recommended for patients with high disease activity when ODT does not provide sufficient control. Evaluations consider the frequency and severity of attacks, quality of life impact, and overall disease burden [9]. The main goals of LTP with lanadelumab are to reduce attack frequency and severity and improve quality of life, though there is no specific attack frequency threshold for starting treatment. Due to its high cost, local healthcare providers use budgetary and hospital-specific protocols to manage access, ensuring efficient and safe use for patients with significant clinical needs.”

2. Regarding materials and methods: Why were only HAE type 1 patients included? Later (line 129) the authors stated that they took care of HAE type 2 patients as well. Please clarify what was the reason of not analyzing them. Also, I could not find a clear reasin why only these 4 female sujects were enrolled. This requires clear statement in my opinion.

Answer: Thank you for the precise remark. The following information has been added to clarify this issue in the materials and methods section of the manuscript:

• 14 (66.6%) did not require LTP
• 2 males (9.5%), with HAE type I and Type II, were on LTP with danazol

• 4 females (19%), with HAE type I, were receiving LTP with lanadelumab

The remaining patient, with AEA was on LTP with oral amchafibrin.

Among the patients receiving LTP with lanadelumab, three transitioned from plasma-derived C1-esterase inhibitor (PdC1-INH) treatment, while the fourth switched from danazol, which was administered intravenously twice a week due to lack of efficacy. The first patient had been on danazol since her twenties but switched to PdC1-INH because of high blood pressure. The second patient was referred from internal medicine after a biopsy confirmed androgenic alopecia; she had independently increased her danazol dosage to 600 mg daily and started PdC1-INH therapy in 2016, initially responding well. The third patient began PdC1-INH therapy during her first pregnancy, but her condition remained poorly controlled. The fourth patient developed hypertension after receiving low dose danazol (200 mg every 48 hours) since adolescence and refused parenteral administration due to a fear of needles, prompting the decision to try berotralstat. However, substituting danazol for berotralstat led to increased angioedema attacks, resulting in a clinical decision to continue berotralstat while gradually tapering danazol. This strategy failed to improve her condition, ultimately leading to a switch to lanadelumab. Currently, her husband administers the doses of lanadelumab after being trained by the nursing team, as she refused self-administration of all doses of PdC1-INH, which were given in the hospital.

The four investigated patients began LTP with lanadelumab between March 2021 and February 2024, with follow-up periods ranging from 5 to 40 months and a median duration of 23 months (IQR 16.25), resulting in a cumulative follow-up time of 91 months across all patients. All patients started treatment with a dosage of 300 mg administered subcutaneously every two weeks (SC q2W). After the first six months, the dosing interval was adjusted for two patients (50%) to 300 mg SC every four weeks (q4W). One patient initially required a more frequent adjustment, receiving lanadelumab 300 mg SC every ten days due to episodes occurring shortly before the two-week interval; however, this patient eventually returned to the standard two-week dosing. Throughout the study, all patients had icatibant available for ODT. Demographic and clinical characteristics are detailed in Table 1.

Also, please note that the following table (Table 2) has been added to include the pedigrees of families afflicted with angioedema at our Hospital as follows:

 

Pedigrees of families with various types of angioedema currently monitored at our Institution are presented in Table 2, illustrating the inheritance patterns and clinical features of affected individuals.

 

Table 2: Pedigrees of families with angioedema currently being followed at our Institution. In red: Patients on long-term prophylaxis (LTP) with lanadelumab.

 

Pedigrees of Families with Various Types of Angioedema
Family 1: One patient with HAE type II on Danazol for LTP.
Family 2: In this family, a baby is awaiting diagnosis.
Family 3: This family is from the United Kingdom and has minimal symptoms.
Family 4
Family 5
Family 6: One of the sisters overcame leukemia, during which she required C1-INH therapy; currently, she does not require LTP.
Family 7: This family includes patients number 1 and 2 from Table 1.
Family 8: In this family, the patient marked in red is number 3 from Table 1, and her brother is on LTP with danazol.
Family 9: This family includes patient number 4 from Table 1.
Family 10: Two members of this family live in Galicia, Spain; only one sister lives in our Autonomous Community (Canary Islands, Spain).
Family 11: The patient's two daughters have not been studied; they currently live in Germany.
Family 12: We have known this patient since 2000. She has never associated any medical process associated with C1q consumption. She is maintained on amchafibrin as LTP.

 

3. Figure 1 looks cut in half – please provide the full version.

Answer: Corrected. Thank you.

4. It is not quite clear why the visits in hospital pharmacy were analyzed. Is it the usual way that HAE patients have their on-demand treatment distributed in the area where the authors practice? Please provide additional explanation, because the decrease in these visits’ frequency looks quite spectacular. In general, I think the authors should provide additional explanations regarding goals and procedures associated with each type of healthcare resource that the patients utilize, i.e., medical visits, nursing visits, hospital pharmacy visits – in particular. These features may be specific for the authors’ country healthcare system and require further explanation, in order to make the data on healthcare costs reduction more appealing.

Answer: Thank you for the comment. The following information has been added to address this issue:

3.2. Roles of Medical, Nursing, and Hospital Pharmacy Teams in the Management and Control of HAE in Patients Receiving Biological Therapies

In our hospital, the management of biological therapies—often costly—requires close monitoring by medical professionals, nursing staff, and pharmacy teams. While this oversight may seem redundant, it is essential given the significant expenses and potential complexities associated with these therapies (Table 3).

Table 3: Roles of Medical, Nursing, and Pharmacy Teams in Biological Therapy Management.

Roles of Medical, Nursing, and Hospital Pharmacy Teams in the Management and Control of HAE in Patients Receiving Biological Therapies

Medical Care
Monitoring of Effectiveness and Safety	Conduct regular assessments to measure treatment response, adjusting doses or changing therapies if necessary; monitor side effects or adverse reactions, and manage urgent episodes.
Coordination with Multidisciplinary Teams	Collaborate with pharmacy, nursing, and other healthcare professionals to implement administration, monitoring, and comprehensive patient management protocols.
Patient Education and Guidance	Inform patients of the benefits, risks, and possible side effects of biological therapy, ensuring they fully understand their treatment.
Management of Adverse Effects and Complications	Develop intervention strategies to address adverse events or complications related to therapy, including treatment adjustments and emergency care. Report adverse effects to pharmacovigilance.
Ongoing Research and Continuing Education	Participate in clinical studies, review scientific literature, and update knowledge on new therapies and advancements in biological treatments.
Cost-effectiveness Evaluation	Assess the cost-benefit relationship of biological therapies, especially in complex diseases, aiding in decision-making about treatment sustainability.
Clinical Documentation and Reporting	Maintain a detailed record of patient progress, treatment response, and any relevant incidents, ensuring a complete electronic medical record.
Nursing Care
Patient and Family Education	Explain the purpose of biological therapy, administration methods, and possible side effects, promoting self-care and addressing questions.
Safe Medication Administration	Prepare and administer biological therapies according to strict protocols, ensuring proper administration technique (subcutaneous, intravenous) and minimizing errors.
Monitoring of Adverse Effects	Observe and record signs of adverse reactions or undesirable events after administration, responding rapidly in emergencies and notifying the healthcare team.
Adherence Tracking and Support	Verify that patients follow the prescribed treatment, identifying barriers to adherence and providing support to ensure continuity of treatment.
Self-care and Self-administration Support	Train patients who must self-administer medication at home, teaching safe techniques and supervising their ability to perform the administration correctly.
Appointment Coordination and Scheduled Administration	Manage dosing schedules according to the treatment plan, ensuring patients receive therapies at the appropriate time.
Documentation and Reporting	Record all relevant information on administration, treatment response, and any incidents, maintaining open communication with the healthcare team. Nursing maintains its own electronic nursing record.
Emotional and Psychological Support	Provide emotional support, helping patients manage anxiety or concerns related to their treatment, promoting better adaptation to therapy.
Hospital Pharmacy Care
Personalized Dispensing and Patient Education	Provide detailed information on the use and handling of biological therapies, instructing patients on administration and potential side effects.
Pharmacotherapeutic Monitoring	Monitor treatment response, side effects, and make adjustments according to the patient's progress and clinical outcomes.
Pharmacovigilance	Identify and record adverse reactions and potential interactions, collaborating on adverse event reporting to pharmacovigilance systems.
Resource Optimization	Manage inventory and ensure availability of biological medications, considering their high cost and the need for special storage conditions.
Treatment Adherence Support	Supervise patient compliance with the therapeutic regimen, implementing strategies to improve adherence in long-term treatments.
Participation in Committees and Decision-making	Collaborate in multidisciplinary committees to evaluate the inclusion of new biological therapies and establish evidence-based usage protocols.
Cost and Efficiency Consulting	Analyze the cost-benefit relationship of biological therapies, supporting decisions on funding and prioritization of treatments for patients with specific clinical needs.

 

5. While discussing their findings, the authors may also consider referring to additional articles (apart from the ones they cite: Hahn etal 202 and Buttgereit et al 2024) containing recent real-life data from the Polish lanadelumab treatment base on electronic database records of 43 HAE subjects: Kucharczyk et al. Pediatr Med Rodz 2023; 19 (4): 334–342 DOI: 10.15557/PiMR.2023.0054 (https://pimr.pl/index.php/issues/2023-vol-19-no-4/lanadelumab-demonstrates-high-efficacy-in-reducing-the-frequency-of-angioedema-attacks-in-patients-with-severe-hae-in-real-life-settings#overlay), and from the real-life observations of 16 patients in the Russian Federation:Latysheva et al. Russian Journal of Allergy 2023; 20(2): 164-176. DOI: 10.36691/RJA5493, https://rusalljournal.ru/raj/article/view/5493. These are real-world studies on larger groups of patients also confirming efficacy of lanadelumab in terms of clinic and healthcare resources use, and I encourage the authors to refer to them to further strengthen their preliminary conclusions.

Answer: Thank you for the valuable references that have been included as#19 and 20.

Minor issues

• Please make sure, that abbreviations are explained first time when used, e.g. LTP (long term prophylaxis) on page 2

Answer: Corrected, thank you.

• Line 116: „were conducted” instead of „were conducting”

Answer: Corrected, thank you.

• Also, please consider modifying the title to make it visible that this is an account of 4 diffcult HAE cases.

Answer: The title has been modified to make it more engaging, thank you.

From: Healthcare Utilization and Clinical Outcomes of Lanadelumab: Insights from Spain's First Cohort of Difficult-to-Treat Hereditary Angioedema Patients.

To: Real-World Outcomes and Healthcare Utilization of Lanadelumab in Spain: Insights from the First Cohort of Difficult-to-Treat Hereditary Angioedema Cases.

 

 

 

 

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

This is a very interesting articles about real-world utilization of lanadelumab in HAE patients.

I have some comments/suggestions:

1) In the bibliography of introduction it could be useful to cite the new classification of angioedema (DANCE)

2) line 43: is a potent vasodilator

3) line 49: to reduce is better of fro reduce?

4) Line 70: meeting is the correct word in this case?

5) Line 114: comparison

6) line 132: in my opinion it is very confounding to put together in this description patients with hae with c1 inhibitor deficinecy and acquired deficiency and Factor XII. Who didn't require ltp? in wich gropu? the 2 males in ltp wewre hereditary deficiency? it is not clear. I think his part could be improved.

7) Table 1: for patient 2 authors write that she was on pdc1in but she has alopecia secondary to danazol. it could be interesting to write somewhere how many years she was on danazol prior than pdC1inh. For patient 4 it could be interesting to clarify why she was taking danazol and berotralsts together. this is a off label therapy.in the part of the table escribing the number and location of acute attacks the authors write ...in previous year and months...it is not clear for me...how many months? i think this is very confodunding for readers. 

8) table 2: in the group before and after the authors included the same number of months for each patients? it is not clear for me

9) line 250: there appears? is it correct?

Author Response

Reviewer 2

This is a very interesting articles about real-world utilization of lanadelumab in HAE patients.

I have some comments/suggestions:

1) In the bibliography of introduction it could be useful to cite the new classification of angioedema (DANCE)

Answer: Thank you for the pertinent comment. The DANCE nomenclature has been adopted for the study (reference #3): Reshef, A., Buttgereit, T., Betschel, S. D., Caballero, T., Farkas, H., Grumach, A. S., ... & Maurer, M. (2024). Definition, acronyms, nomenclature, and classification of angioedema (DANCE): AAAAI, ACAAI, ACARE, and APAAACI DANCE consensus. Journal of Allergy and Clinical Immunology.  DOI: 10.1016/j.jaci.2024.03.024

2) line 43: is a potent vasodilator

Answer: Corrected, thank you.

3) line 49: to reduce is better of fro reduce?

Answer: To, thank you.

4) Line 70: meeting is the correct word in this case?

Answer: Corrected to fulfilling, thank you.

5) Line 114: comparison

Answer: Corrected, thank you.

6) line 132: in my opinion it is very confounding to put together in this description patients with hae with c1 inhibitor deficinecy and acquired deficiency and Factor XII. Who didn't require ltp? in wich gropu? the 2 males in ltp wewre hereditary deficiency? it is not clear. I think his part could be improved.

Answer: Thank you for the precise remark. The following information has been added to clarify this issue within the materials and methods section of the manuscript:

• 14 (66.6%) did not require LTP
• 2 males (9.5%), with HAE type I and Type II, were on LTP with danazol

• 4 females (19%), with HAE type I, were receiving LTP with lanadelumab

The remaining patient, with AEA was on LTP with oral amchafibrin.

Among the patients receiving LTP with lanadelumab, three transitioned from plasma-derived C1-esterase inhibitor (PdC1-INH) treatment, while the fourth switched from danazol, which was administered intravenously twice a week due to lack of efficacy. The first patient had been on danazol since her twenties but switched to PdC1-INH because of high blood pressure. The second patient was referred from internal medicine after a biopsy confirmed androgenic alopecia; she had independently increased her danazol dosage to 600 mg daily and started PdC1-INH therapy in 2016, initially responding well. The third patient began PdC1-INH therapy during her first pregnancy, but her condition remained poorly controlled. The fourth patient developed hypertension after receiving low dose danazol (200 mg every 48 hours) since adolescence and refused parenteral administration due to a fear of needles, prompting the decision to try berotralstat. However, substituting danazol for berotralstat led to increased angioedema attacks, resulting in a clinical decision to continue berotralstat while gradually tapering danazol. This strategy failed to improve her condition, ultimately leading to a switch to lanadelumab. Currently, her husband administers the doses of lanadelumab after being trained by the nursing team, as she refused self-administration of all doses of PdC1-INH, which were given in the hospital.

The four investigated patients began LTP with lanadelumab between March 2021 and February 2024, with follow-up periods ranging from 5 to 40 months and a median duration of 23 months (IQR 16.25), resulting in a cumulative follow-up time of 91 months across all patients. All patients started treatment with a dosage of 300 mg administered subcutaneously every two weeks (SC q2W). After the first six months, the dosing interval was adjusted for two patients (50%) to 300 mg SC every four weeks (q4W). One patient initially required a more frequent adjustment, receiving lanadelumab 300 mg SC every ten days due to episodes occurring shortly before the two-week interval; however, this patient eventually returned to the standard two-week dosing. Throughout the study, all patients had icatibant available for ODT. Demographic and clinical characteristics are detailed in Table 1.

Also, please note that the following table (Table 2) has been added to include the pedigrees of families afflicted with angioedema at our hospital as follows:

 

Pedigrees of families with various types of angioedema currently monitored at our Institution are presented in Table 2, illustrating the inheritance patterns and clinical features of affected individuals.

 

Table 2: Pedigrees of families with angioedema currently being followed at our Institution. In red: Patients on long-term prophylaxis (LTP) with lanadelumab.

 

Pedigrees of Families with Various Types of Angioedema
Family 1: One patient with HAE type II on Danazol for LTP.
Family 2: In this family, a baby is awaiting diagnosis.
Family 3: This family is from the United Kingdom and has minimal symptoms.
Family 4
Family 5
Family 6: One of the sisters overcame leukemia, during which she required C1-INH therapy; currently, she does not require LTP.
Family 7: This family includes patients number 1 and 2 from Table 1.
Family 8: In this family, the patient marked in red is number 3 from Table 1, and her brother is on LTP with danazol.
Family 9: This family includes patient number 4 from Table 1.
Family 10: Two members of this family live in Galicia, Spain; only one sister lives in our Autonomous Community (Canary Islands, Spain).
Family 11: The patient's two daughters have not been studied; they currently live in Germany.
Family 12: We have known this patient since 2000. She has never associated any medical process associated with C1q consumption. She is maintained on amchafibrin as LTP.

 

7) Table 1: for patient 2 authors write that she was on pdc1in but she has alopecia secondary to danazol. it could be interesting to write somewhere how many years she was on danazol prior than pdC1inh. For patient 4 it could be interesting to clarify why she was taking danazol and berotralsts together. this is a off label therapy.in the part of the table escribing the number and location of acute attacks the authors write ...in previous year and months...it is not clear for me...how many months? i think this is very confodunding for readers. 

Answer: Thank you for the valuable comment. Corrected, please see former answer to question 6.

 

7) Table 1: for patient 2 authors write that she was on pdc1in but she has alopecia secondary to danazol. it could be interesting to write somewhere how many years she was on danazol prior than pdC1inh. For patient 4 it could be interesting to clarify why she was taking danazol and berotralsts together. this is a off label therapy.in the part of the table escribing the number andlocation of acute attacks the authors write ...in previous year and months...it is not clear for me...how many months? i think this is very confodunding for readers.

Answer: Thank you for the comment. In this patient, replacing danazol with berotralstat led to an increase in angioedema attacks, prompting the decision in a hospital clinical session to continue berotralstat while gradually tapering danazol. This approach also failed to improve her condition, leading to the decision to switch to lanadelumab.

Please note that Table 1 has been modified to clarify this point as follows:

Table 1: Demographic and clinical characteristics of each patient, before and after lanadelumab long term prophylaxis.

Patient 1

Patient 2

Patient 3

Patient 4

Gender/age (y)

♀/78

♀/53

♀/39

♀/48

HAE type

1

1

1

1

Comorbidities

Non-Hodgkin lymphoma HBP Nodular thyroid hyperplasia AMI Depression

Androgenic alopecia secondary to danazol Depression

Premature birth

HBP

Age at diagnosis of HAE

27 y

2 y

27 y

18 y

LTP prior to switching to lanadeluma

Pd1-inh i.v. 2x/week (Since 2017)

Pd1-inh i.v. 2x/week (Since 2019)

Pd1-inh i.v. 2x/week (Since 2022)

Danazol (Since 2002) + Berotralstat (since Oct 2023)

Lanadelumab started

March 2021

March 2022

January 2023

February 2024

Number and location of acute attacks in previous year and months after switch to lanadelumab

Before

After

Before

After

Before

After

Before

After

Extremities

7

0

3

0

27

4

0

Abdominal

5

2 attacks in first 6months after switch

8

4 attacks in first 12months after switch

17

5 attacks in first 3months after switch

3

Genital

0

0

0

0

5

3

0

Laryngeal

0

0

0

0

1

Others

0

0

0

0

1

1

0

Attack-free months since last HAE-attack, post lanadelumab therapy

33 months

16months

14 months

5 months

 

 

 

 

 

 

 

 

HAE: Hereditary Angioedema; AMI: Acute myocardial infarction; HBP: High blood pressure.

 

8) table 2: in the group before and after the authors included the same number of months for each patients? it is not clear for me

Answer: Thank you for the comment. Table 2 has been modified to table 4 to clarify this issue as follows:

Table 4: On-Demand Treatment (ODT) with icatibant: individual units before and after starting lanadelumab. The use of icatibant unitis as an ODT was analyzed across 96 total months prior to initiating lanadelumab therapy and 91 total months following the switch to lanadelumab.

Use of ODT	Before (n)	After (n)	Change (%)
Patient #1	17 units in 12 mo.	4 units in 40 mo.	-76
Patient #2	11 units in 12 mo.	6 units in 28 mo.	-45
Patient #3	34 units in 12 mo.	16 units in 18 mo.	-53
Patient #4	5 units in 12 mo.	0 units in 5 mo.	-100
TOTAL	67	26	-61

 

 

 

 

 

9) line 250: there appears? is it correct?

Answer: Corrected, thank you.

 

 

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The Authors have addressed my comments and remarks accordingly. Provided changes and amendments have considerably imporved the quality of the manuscript and have cleared up inconsistencies and ambiguities.

Just a small remark: please check the concordance of bibliographic data of references with the MDPI requirements.

Author Response

Reviewer 1

This is an interesting account of the real-life experience with lanadelumab from a single center in Spain. The article covers important topic of continuously growing interest and recognition among allergists involved in HAE management.

The introduction provides concise yet comprehensive insight into pathophysiological pathways leading to HAE symptoms. There is not much to add to this section.

Below please find my comments regarding the remaining part of the manuscript.

Major issues:

1. Please briefly describe what are the criteria for the reimbursement or direct financing of the lanaldelumab LTP in HAE as per requirements of the Spanish healthcare providers and payers. This may differ form country to country in terms of number and severity of attacks and other parameters, therefore, it would be interesting to include a short Spanish perspective.

Answer: Thank you for the accurate comment. The following text -including the corresponding references #8 and 9- has been added to the last version of the manuscript: “In Spain, lanadelumab is an additional therapeutic option for managing HAE attacks. It is funded for patients aged 12 and older with HAE types I and II and is specifically approved for the routine prevention of recurrent attacks [8]. It is particularly recommended for patients with high disease activity when ODT does not provide sufficient control. Evaluations consider the frequency and severity of attacks, quality of life impact, and overall disease burden [9]. The main goals of LTP with lanadelumab are to reduce attack frequency and severity and improve quality of life, though there is no specific attack frequency threshold for starting treatment. Due to its high cost, local healthcare providers use budgetary and hospital-specific protocols to manage access, ensuring efficient and safe use for patients with significant clinical needs.”

2. Regarding materials and methods: Why were only HAE type 1 patients included? Later (line 129) the authors stated that they took care of HAE type 2 patients as well. Please clarify what was the reason of not analyzing them. Also, I could not find a clear reasin why only these 4 female sujects were enrolled. This requires clear statement in my opinion.

Answer: Thank you for the precise remark. The following information has been added to clarify this issue in the materials and methods section of the manuscript:

• 14 (66.6%) did not require LTP
• 2 males (9.5%), with HAE type I and Type II, were on LTP with danazol

• 4 females (19%), with HAE type I, were receiving LTP with lanadelumab

The remaining patient, with AEA was on LTP with oral amchafibrin.

Among the patients receiving LTP with lanadelumab, three transitioned from plasma-derived C1-esterase inhibitor (PdC1-INH) treatment, while the fourth switched from danazol, which was administered intravenously twice a week due to lack of efficacy. The first patient had been on danazol since her twenties but switched to PdC1-INH because of high blood pressure. The second patient was referred from internal medicine after a biopsy confirmed androgenic alopecia; she had independently increased her danazol dosage to 600 mg daily and started PdC1-INH therapy in 2016, initially responding well. The third patient began PdC1-INH therapy during her first pregnancy, but her condition remained poorly controlled. The fourth patient developed hypertension after receiving low dose danazol (200 mg every 48 hours) since adolescence and refused parenteral administration due to a fear of needles, prompting the decision to try berotralstat. However, substituting danazol for berotralstat led to increased angioedema attacks, resulting in a clinical decision to continue berotralstat while gradually tapering danazol. This strategy failed to improve her condition, ultimately leading to a switch to lanadelumab. Currently, her husband administers the doses of lanadelumab after being trained by the nursing team, as she refused self-administration of all doses of PdC1-INH, which were given in the hospital.

The four investigated patients began LTP with lanadelumab between March 2021 and February 2024, with follow-up periods ranging from 5 to 40 months and a median duration of 23 months (IQR 16.25), resulting in a cumulative follow-up time of 91 months across all patients. All patients started treatment with a dosage of 300 mg administered subcutaneously every two weeks (SC q2W). After the first six months, the dosing interval was adjusted for two patients (50%) to 300 mg SC every four weeks (q4W). One patient initially required a more frequent adjustment, receiving lanadelumab 300 mg SC every ten days due to episodes occurring shortly before the two-week interval; however, this patient eventually returned to the standard two-week dosing. Throughout the study, all patients had icatibant available for ODT. Demographic and clinical characteristics are detailed in Table 1.

Also, please note that the following table (Table 2) has been added to include the pedigrees of families afflicted with angioedema at our Hospital as follows:

 

Pedigrees of families with various types of angioedema currently monitored at our Institution are presented in Table 2, illustrating the inheritance patterns and clinical features of affected individuals.

 

Table 2: Pedigrees of families with angioedema currently being followed at our Institution. In red: Patients on long-term prophylaxis (LTP) with lanadelumab.

 

Pedigrees of Families with Various Types of Angioedema
Family 1: One patient with HAE type II on Danazol for LTP.
Family 2: In this family, a baby is awaiting diagnosis.
Family 3: This family is from the United Kingdom and has minimal symptoms.
Family 4
Family 5
Family 6: One of the sisters overcame leukemia, during which she required C1-INH therapy; currently, she does not require LTP.
Family 7: This family includes patients number 1 and 2 from Table 1.
Family 8: In this family, the patient marked in red is number 3 from Table 1, and her brother is on LTP with danazol.
Family 9: This family includes patient number 4 from Table 1.
Family 10: Two members of this family live in Galicia, Spain; only one sister lives in our Autonomous Community (Canary Islands, Spain).
Family 11: The patient's two daughters have not been studied; they currently live in Germany.
Family 12: We have known this patient since 2000. She has never associated any medical process associated with C1q consumption. She is maintained on amchafibrin as LTP.

 

3. Figure 1 looks cut in half – please provide the full version.

Answer: Corrected. Thank you.

4. It is not quite clear why the visits in hospital pharmacy were analyzed. Is it the usual way that HAE patients have their on-demand treatment distributed in the area where the authors practice? Please provide additional explanation, because the decrease in these visits’ frequency looks quite spectacular. In general, I think the authors should provide additional explanations regarding goals and procedures associated with each type of healthcare resource that the patients utilize, i.e., medical visits, nursing visits, hospital pharmacy visits – in particular. These features may be specific for the authors’ country healthcare system and require further explanation, in order to make the data on healthcare costs reduction more appealing.

Answer: Thank you for the comment. The following information has been added to address this issue:

3.2. Roles of Medical, Nursing, and Hospital Pharmacy Teams in the Management and Control of HAE in Patients Receiving Biological Therapies

In our hospital, the management of biological therapies—often costly—requires close monitoring by medical professionals, nursing staff, and pharmacy teams. While this oversight may seem redundant, it is essential given the significant expenses and potential complexities associated with these therapies (Table 3).

Table 3: Roles of Medical, Nursing, and Pharmacy Teams in Biological Therapy Management.

Roles of Medical, Nursing, and Hospital Pharmacy Teams in the Management and Control of HAE in Patients Receiving Biological Therapies

Medical Care
Monitoring of Effectiveness and Safety	Conduct regular assessments to measure treatment response, adjusting doses or changing therapies if necessary; monitor side effects or adverse reactions, and manage urgent episodes.
Coordination with Multidisciplinary Teams	Collaborate with pharmacy, nursing, and other healthcare professionals to implement administration, monitoring, and comprehensive patient management protocols.
Patient Education and Guidance	Inform patients of the benefits, risks, and possible side effects of biological therapy, ensuring they fully understand their treatment.
Management of Adverse Effects and Complications	Develop intervention strategies to address adverse events or complications related to therapy, including treatment adjustments and emergency care. Report adverse effects to pharmacovigilance.
Ongoing Research and Continuing Education	Participate in clinical studies, review scientific literature, and update knowledge on new therapies and advancements in biological treatments.
Cost-effectiveness Evaluation	Assess the cost-benefit relationship of biological therapies, especially in complex diseases, aiding in decision-making about treatment sustainability.
Clinical Documentation and Reporting	Maintain a detailed record of patient progress, treatment response, and any relevant incidents, ensuring a complete electronic medical record.
Nursing Care
Patient and Family Education	Explain the purpose of biological therapy, administration methods, and possible side effects, promoting self-care and addressing questions.
Safe Medication Administration	Prepare and administer biological therapies according to strict protocols, ensuring proper administration technique (subcutaneous, intravenous) and minimizing errors.
Monitoring of Adverse Effects	Observe and record signs of adverse reactions or undesirable events after administration, responding rapidly in emergencies and notifying the healthcare team.
Adherence Tracking and Support	Verify that patients follow the prescribed treatment, identifying barriers to adherence and providing support to ensure continuity of treatment.
Self-care and Self-administration Support	Train patients who must self-administer medication at home, teaching safe techniques and supervising their ability to perform the administration correctly.
Appointment Coordination and Scheduled Administration	Manage dosing schedules according to the treatment plan, ensuring patients receive therapies at the appropriate time.
Documentation and Reporting	Record all relevant information on administration, treatment response, and any incidents, maintaining open communication with the healthcare team. Nursing maintains its own electronic nursing record.
Emotional and Psychological Support	Provide emotional support, helping patients manage anxiety or concerns related to their treatment, promoting better adaptation to therapy.
Hospital Pharmacy Care
Personalized Dispensing and Patient Education	Provide detailed information on the use and handling of biological therapies, instructing patients on administration and potential side effects.
Pharmacotherapeutic Monitoring	Monitor treatment response, side effects, and make adjustments according to the patient's progress and clinical outcomes.
Pharmacovigilance	Identify and record adverse reactions and potential interactions, collaborating on adverse event reporting to pharmacovigilance systems.
Resource Optimization	Manage inventory and ensure availability of biological medications, considering their high cost and the need for special storage conditions.
Treatment Adherence Support	Supervise patient compliance with the therapeutic regimen, implementing strategies to improve adherence in long-term treatments.
Participation in Committees and Decision-making	Collaborate in multidisciplinary committees to evaluate the inclusion of new biological therapies and establish evidence-based usage protocols.
Cost and Efficiency Consulting	Analyze the cost-benefit relationship of biological therapies, supporting decisions on funding and prioritization of treatments for patients with specific clinical needs.

 

5. While discussing their findings, the authors may also consider referring to additional articles (apart from the ones they cite: Hahn etal 202 and Buttgereit et al 2024) containing recent real-life data from the Polish lanadelumab treatment base on electronic database records of 43 HAE subjects: Kucharczyk et al. Pediatr Med Rodz 2023; 19 (4): 334–342 DOI: 10.15557/PiMR.2023.0054 (https://pimr.pl/index.php/issues/2023-vol-19-no-4/lanadelumab-demonstrates-high-efficacy-in-reducing-the-frequency-of-angioedema-attacks-in-patients-with-severe-hae-in-real-life-settings#overlay), and from the real-life observations of 16 patients in the Russian Federation:Latysheva et al. Russian Journal of Allergy 2023; 20(2): 164-176. DOI: 10.36691/RJA5493, https://rusalljournal.ru/raj/article/view/5493. These are real-world studies on larger groups of patients also confirming efficacy of lanadelumab in terms of clinic and healthcare resources use, and I encourage the authors to refer to them to further strengthen their preliminary conclusions.

Answer: Thank you for the valuable references that have been included as#19 and 20.

Minor issues

• Please make sure, that abbreviations are explained first time when used, e.g. LTP (long term prophylaxis) on page 2

Answer: Corrected, thank you.

• Line 116: „were conducted” instead of „were conducting”

Answer: Corrected, thank you.

• Also, please consider modifying the title to make it visible that this is an account of 4 diffcult HAE cases.

Answer: The title has been modified to make it more engaging, thank you.

From: Healthcare Utilization and Clinical Outcomes of Lanadelumab: Insights from Spain's First Cohort of Difficult-to-Treat Hereditary Angioedema Patients.

To: Real-World Outcomes and Healthcare Utilization of Lanadelumab in Spain: Insights from the First Cohort of Difficult-to-Treat Hereditary Angioedema Cases.

 

PLEASE CHECK THE PDF-VERSION FOR SUBMITTED FIGURES 2 and 3. THANK YOU.

 

 

Author Response File: Author Response.pdf