Hereditary angioedema (HAE) is a rare, autosomal dominant disease commonly associated with a deficiency or dysfunction of C1-esterase-inhibitor (C1-INH) activity. It causes spontaneous, recurrent, and potentially life-threatening swelling attacks in various regions of the body.2
Even after the physical symptoms of an attack subside, this lifelong disease has an ongoing effect on patients’ quality of life.3,4 Fear of the next attack can limit the way patients live their lives. Patients may avoid2,3*:
The 2021 HAE WAO/EAACI Guideline recommends evaluating patients with HAE type I or II for preventive treatment at every visit.5
*Based on qualitative (n=30) and quantitative (n=186) survey responses in the 2011 Hereditary Burden of Illness Study in Europe.3,6
TAKHZYRO is indicated for routine prevention of recurrent attacks of hereditary angioedema in patients aged 12 years and older.1
The recommended starting dose is TAKHZYRO 300 mg every 2 weeks. In patients who are stably attack free on treatment, a dose reduction of TAKHZYRO 300 mg every 4 weeks may be considered, especially in patients with low weight.1
HELP=Hereditary angioEdema Long-term Prophylaxis.
HELP STUDY
Secondary endpoint: 83% relative reduction in the number of moderate or severe HAE attacks vs placebo at 6.5 months. LS mean monthly attack rate* (during treatment): 0.20 with TAKHZYRO (n=27); 1.22 with placebo (n=41). TAKHZYRO demonstrated statistical significance compared with placebo for all secondary efficacy endpoints in the HELP study (P<0.001).1,8
All results were with TAKHZYRO 300 mg every 2 weeks.
*LS mean monthly attack rate: investigator-confirmed attacks/4 weeks.1,8
HELP=Hereditary angioEdema Long-term Prophylaxis; LS=least squares.
HELP OLE
Secondary endpoint: 84% reduction in the number of moderate or severe HAE attacks vs baseline† at an average of 2.5 years. Change in mean monthly attack rate with TAKHZYRO (N=209) during the HELP OLE treatment period: 2.03 to 0.20.7
All results were with TAKHZYRO 300 mg every 2 weeks.
†For rollover patients, the baseline attack rate was calculated as the number of investigator-confirmed HAE attacks during the run-in period of the HELP study. For nonrollover patients, the baseline attack rate was calculated as the number of HAE attacks during the historical reporting period of the last 3 months, divided by the number of days they contributed to these periods, multiplied by 28 days.7
HELP=Hereditary angioEdema Long-term Prophylaxis; OLE=open-label extension.
IN THE HELP OLE
HELP STUDY
HELP OLE
All results were with TAKHZYRO 300 mg every 2 weeks.
‡These findings are exploratory or post hoc in nature and therefore require further investigation to corroborate.
HELP=Hereditary angioEdema Long-term Prophylaxis; OLE=open-label extension.
IN THE HELP OLE
Patients had zero attacks on average for nearly 15 months§ (415 days, mean [SD] of 14.8 [12.4] months) in the HELP OLE (N=209; prespecified exploratory endpoint).1,7¶
All results were with TAKHZYRO 300 mg every 2 weeks.
§One month was defined as 28 days.9
¶These findings are exploratory or post hoc in nature and therefore require further investigation to corroborate.
HELP=Hereditary angioEdema Long-term Prophylaxis; OLE=open-label extension.
HELP=Hereditary angioEdema Long-term Prophylaxis; OLE=open-label extension.
*TAKHZYRO is produced in Chinese hamster ovary (CHO) cells by recombinant DNA technology.1
cHMWK=cleaved high molecular weight kininogen.
HMWK=high molecular weight kininogen.
1 SUBCUTANEOUS SELF-INJECTION1
EVERY 2 WEEKS1
3 CHOICES FOR INJECTION SITE Abdomen, upper outer arms, or thighs1
TAKHZYRO may be self-administered or administered by a caregiver only after training on subcutaneous injection technique by a healthcare professional.1
This medicinal product should only be taken if prescribed. Treatment should be initiated under the supervision of a physician experienced in the management of patients with HAE.1
As shown on the Angioedema Quality of Life Questionnaire (AE-QoL), which measures the patient-reported impact of angioedema over a 4-week recall period across 4 domains, patients taking TAKHZYRO in the HELP study reported clinically meaningful improvement (reduction of ≥6) across all domains.1,12
Mean change in total AE-QoL score†: -21.3 with TAKHZYRO (n=26; P<0.05); -4.7 with placebo (n=38) (tertiary endpoint).11*
IN THE HELP STUDY
All patients, including those taking placebo, were permitted on-demand treatment for attacks.8
All results were with TAKHZYRO 300 mg every 2 weeks.
A reduction in score shows improvement.1
In the HELP study, patient quality of life was also assessed using the EuroQol 5-Dimension 5-Level Measure (EQ-5D-5L) tool.11
*These findings are tertiary endpoint analyses and therefore require further investigation to corroborate.
†LS mean change from baseline at 6.5 months.1,8
HELP=Hereditary angioEdema Long-term Prophylaxis; LS=least squares; OLE=open-label extension.
Rollover patients from the HELP study experienced further quality-of-life improvement in the HELP OLE7
All results were with TAKHZYRO 300 mg every 2 weeks.
In the HELP OLE, patient quality of life was also assessed using the following tools: the EuroQol 5-Dimension 5-Level Measure (EQ-5D-5L), the Work Productivity and Activity Impairment Questionnaire: General Health (WPAI-GH), the Hospital Anxiety and Depression Scale (HADS), and the 12-Item Short-Form Survey (SF-12).13
‡These findings are tertiary endpoint analyses and therefore require further investigation to corroborate.
§LS mean change from baseline at 6.5 months in the HELP study. Mean change from Day 0 to the end of study in the HELP OLE.1,7
AE-QoL=Angioedema Quality of Life Questionnaire; HELP=Hereditary angioEdema Long-term Prophylaxis; LS=least squares; OLE=open-label extension; q2w=every 2 weeks.
Rollover patients from the HELP study experienced further quality-of-life improvement across all domains in the HELP OLE7,11,12
All results were with TAKHZYRO 300 mg every 2 weeks.
A reduction in score shows improvement.1
¶These findings are tertiary endpoint analyses and therefore require further investigation to corroborate.
#LS mean change from baseline at 6.5 months in the HELP study. Mean change from Day 0 to the end of study in the HELP OLE.1,7
AE-QoL=Angioedema Quality of Life Questionnaire; HELP=Hereditary angioEdema Long-term Prophylaxis; LS=least squares; OLE=open-label extension; q2w=every 2 weeks.
All results were with TAKHZYRO 300 mg every 2 weeks unless otherwise stated.
*The patient had a history of metabolic syndrome and fatty liver and used multiple concomitant suspect medications. The patient withdrew due to isolated, asymptomatic, and transient elevation of alanine transaminase (140 U/L) and aspartate transaminase (143 U/L) classified as related and severe on Day 139.14
HELP=Hereditary angioEdema Long-term Prophylaxis; OLE=open-label extension.
Please consult the TAKHZYRO Summary of Product Characteristics (SmPC) before prescribing.
TAKHZYRO treatment should be initiated under the supervision of a physician experienced in the management of patients with hereditary angioedema (HAE). TAKHZYRO may be self-administered or administered by a caregiver only after training on subcutaneous (SC) injection technique by a healthcare professional.
Hypersensitivity to the active substance or to any of the excipients.
Hypersensitivity reactions have been observed. In case of a severe hypersensitivity reaction, administration of TAKHZYRO must be stopped immediately and appropriate treatment must be initiated.
Traceability: In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
Hypersensitivity reactions have been observed. In case of a severe hypersensitivity reaction, administration of TAKHZYRO must be stopped immediately and appropriate treatment must be initiated.
General: TAKHZYRO is not intended for treatment of acute HAE attacks. In case of a breakthrough HAE attack, individualized treatment should be initiated with an approved rescue medication. There are no available clinical data on the use of lanadelumab in HAE patients with normal C1-INH activity.
Interference with coagulation test: Lanadelumab can increase activated partial thromboplastin time (aPTT) due to an interaction of lanadelumab with the aPTT assay. The reagents used in the aPTT laboratory test initiate intrinsic coagulation through the activation of plasma kallikrein in the contact system. Inhibition of plasma kallikrein by lanadelumab can increase aPTT in this assay. None of the increases in aPTT in patients treated with TAKHZYRO were associated with abnormal bleeding adverse events. There were no differences in international normalised ratio (INR) between treatment groups.
Sodium content: This medicinal product contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially 'sodium-free'.
No dedicated drug-drug interaction studies have been conducted. Based on the characteristics of lanadelumab, no pharmacokinetic interactions with co-administered medicinal products is expected.
As expected, concomitant use of the rescue medication C1 esterase inhibitor results in an additive effect on lanadelumab-cHMWK response based on the mechanism of action (MOA) of lanadelumab and C1 esterase inhibitor
Treatment with lanadelumab has been associated with development of treatment emergent anti-drug antibodies (ADA) in 11.9% (10/84) of subjects. All antibody titres were low. The ADA response was transient in 20% (2/10) of ADA positive subjects. 2.4% (2/84) of lanadelumab-treated subjects tested positive for neutralising antibodies.
The development of ADA including neutralising antibodies against TAKHZYRO did not appear to adversely affect the pharmacokinetic (PK) and pharmacodynamics (PD) profiles or clinical response.
The most commonly observed adverse reaction (52.4%) associated with TAKHZYRO was injection site reactions (ISR) including injection site pain, injection site erythema and injection site bruising. Of these ISRs, 97% were of mild intensity, 90% resolved within 1 day after onset with a median duration of 6 minutes.
Hypersensitivity reaction (mild and moderate pruritus, discomfort and tingling of tongue) was observed (1.2%)
| Very common (frequency ≥1/10): |
Injection site reactions* |
| Common (≥1/100 to <1/10): |
Hypersensitivity**, dizziness, rash maculo-papular, myalgia, alanine aminotransferase increased, aspartate aminotransferase increased. |
*Injection site reactions include: pain, erythema, bruising, discomfort, haematoma, haemorrhage, pruritus, swelling, induration, paraesthesia, reaction, warmth, oedema and rash.
**Hypersensitivity includes: pruritus, discomfort and tingling of tongue.
Suspected adverse reactions should be reported to Takeda at: GPSE@takeda.com.
Please see full EU Summary of Product Characteristics (SmPC).
References
1. Takhzyro. Summary of product characteristics. Takeda Pharmaceuticals International AG Ireland Branch; 2022. 2. Kaplan AP. Enzymatic pathways in the pathogenesis of hereditary angioedema: the role of C1 inhibitor therapy. J Allergy Clin Immunol. 2010;126(5):918-925. doi:10.1016/j.jaci.2010.08.012 3. Bygum A, Aygören-Pürsün E, Beusterien K, et al. Burden of illness in hereditary angioedema: a conceptual model. Acta Derm Venereol. 2015;95(6):706-710. doi:10.2340/00015555-2014 4. Bernstein JA. Severity of hereditary angioedema, prevalence, and diagnostic considerations. Am J Manag Care. 2018;24(suppl 14):S292-S298. 5. Maurer M, Magerl M, Betschel S, et al. The international WAO/EAACI guideline for the management of hereditary angioedema—the 2021 revision and update. World Allergy Organ J. 2022;15(3):100627. doi:10.1016/j.waojou.2022.100627 6. Caballero T, Aygören-Pürsün E, Bygum A, et al. The humanistic burden of hereditary angioedema: results from the Burden of Illness Study in Europe. Allergy Asthma Proc. 2014;35(1):47-53. doi:10.2500/aap.2013.34.3685 7. Banerji A, Bernstein JA, Johnston DT, et al; HELP OLE Investigators. Long-term prevention of hereditary angioedema attacks with lanadelumab: the HELP OLE study. Allergy. 2022;77(3):979-990. doi:10.1111/all.15011 8. Banerji A, Riedl MA, Bernstein JA, et al. Effect of lanadelumab compared with placebo on prevention of hereditary angioedema attacks: a randomized clinical trial. JAMA. 2018;320(20):2108-2121. doi:10.1001/jama.2018.16773 9. Cinryze. Summary of product characteristics. Shire Services BVBA; 2022. 10. Berinert 3000 IU. Summary of product characteristics. CSL Behring GmbH; 2021. 11. Lumry WR, Settipane RA. Hereditary angioedema: epidemiology and burden of disease. Allergy Asthma Proc. 2020;41(suppl 1):S8-S13. doi:10.2500/aap.2020.41.200050 12. Weller K, Groffik A, Magerl M, et al. Development and construct validation of the angioedema quality of life questionnaire. Allergy. 2012;67(10):1289-1298. doi:10.1111/all.12007 13. Riedl MA, Bernstein JA, Craig T, et al. An open-label study to evaluate the long-term safety and efficacy of lanadelumab for prevention of attacks in hereditary angioedema: design of the HELP study extension. Clin Transl Allergy. 2017;7:36. doi:10.1186/s13601-017-0172-9 14. Banerji A, Riedl MA, Bernstein JA, et al. Effect of lanadelumab compared with placebo on prevention of hereditary angioedema attacks: a randomized clinical trial. Supplement 2. Supplementary online content. JAMA. 2018;320(20):2108-2121. Accessed March 1, 2022. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583584/bin/jama-320-2108-s002.pdf 15. Banerji A, Bernstein JA, Johnston DT, et al; HELP OLE Investigators. Long-term prevention of hereditary angioedema attacks with lanadelumab: the HELP OLE study. Supporting information. Tables S1-S3. Allergy. 2022;77(3):979-990. Accessed March 1, 2022. https://onlinelibrary.wiley.com/doi/10.1111/all.15011 16. Cinryze. Prescribing information. Takeda Pharmaceuticals; 2021. 17. Craig T, Zuraw B, Longhurst H, et al. Long-term outcomes with subcutaneous C1-inhibitor replacement therapy for prevention of hereditary angioedema attacks. J Allergy Clin Immunol Pract. 2019;7(6):1793-1802.e2. doi:10.1016/j.jaip.2019.01.054 18. A long term safety study of BCX7353 in hereditary angioedema (APeX-S). ClinicalTrials.gov identifier: NCT03472040. Updated December 17, 2020. Accessed March 1, 2022. https://clinicaltrials.gov/ct2/show/NCT03472040 19. Orladeyo. Prescribing information. BioCryst Pharmaceuticals, Inc; 2020. 20. Banerji A, Bernstein JA, Johnston DT, et al; HELP OLE Investigators. Long-term prevention of hereditary angioedema attacks with lanadelumab: the HELP OLE study. Supporting information. Figure S1. Allergy. 2022;77(3):979-990. Accessed March 1, 2022. https://onlinelibrary.wiley.com/doi/10.1111/all.15011 21. Banerji A, Riedl MA, Bernstein JA, et al. Effect of lanadelumab compared with placebo on prevention of hereditary angioedema attacks: a randomized clinical trial. Supplement 1. Protocol and statistical analysis plan. JAMA. 2018;320(20):2108-2121. Accessed March 1, 2022. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583584/bin/jama-320-2108-s001.pdf
*Including C1-INH alone, oral treatment (androgens or antifibrinolytics) alone, or both C1-INH and oral treatment.7,8
†Patients who had 1-<3 attacks during the run-in period is a calculation (n=60/125).8
‡In HELP OLE, nonrollover patients were required to have a historical attack rate of at least 1 attack within 12 weeks.7
C1-INH=C1 esterase inhibitor; HAE=hereditary angioedema; HELP=Hereditary angioEdema Long-term Prophylaxis; OLE=open-label extension.
The recommended starting dose is 300 mg every 2 weeks. In patients who are stably attack free on treatment, a dose reduction of 300 mg every 4 weeks may be considered, especially in patients with low weight.1
*LTP washout period was only for patients ≥18 years of age.14
†Run-in period could be shortened if patients experienced ≥3 attacks before completion of 4 weeks, and period could be extended to 8 weeks if patients did not experience any attacks within 4 weeks.21
‡Treatments were administered as 2 separate 1-mL injections in the upper arm every 2 weeks to maintain blinding.8
§The 4-week screening period did not include an LTP washout period.15
¶For rollover patients, Day 0 of the HELP OLE coincided with Day 182 (Week 26) of the HELP study. For nonrollover patients, the first dose was administered on Day 0.7
#Regardless of when the first HAE attack occurred, there was a minimum of 10 days between the first and second open-label doses.13
HAE=hereditary angioedema; HELP=Hereditary angioEdema Long-term Prophylaxis; LTP=long-term prophylaxis; OLE=open-label extension.
Primary endpoint: 73% relative reduction in attacks vs placebo (P<0.001; n=29 for TAKHZYRO, n=41 for placebo)1*
Secondary endpoint: significant reduction vs placebo in mean monthly rate of moderate or severe attacks from Day 0 to Day 182 (73%) (P<0.001; n=29 for TAKHZYRO, n=41 for placebo)1,8*
Prespecified exploratory endpoint: 31% of patients had zero attacks vs 2% with placebo (9/29 for TAKHZYRO; 1/41 for placebo) (Day 0-182) and in a post hoc sensitivity analysis, 45% had zero attacks vs 3% with placebo (13/29 for TAKHZYRO; 1/37 for placebo) (Day 70-182)1,8
*LS mean monthly attack rate: investigator-confirmed attacks/4 weeks.1,8
LS=least squares.
TAKHZYRO is indicated for routine prevention of recurrent attacks of hereditary angioedema (HAE) in patients aged 12 years and older.1
The recommended starting dose is TAKHZYRO 300 mg every 2 weeks. In patients who are stably attack free on treatment, a dose reduction of TAKHZYRO 300 mg every 4 weeks may be considered, especially in patients with low weight.1
▼ This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 of the Summary of Product Characteristics for how to report adverse reactions.
Please see full EU Product Information.
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