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TAKHZYRO™
(lanadelumab-flyo) injection, for subcutaneous use
Lanadelumab-flyo is non-plasma derived, recombinant, fully human, monoclonal antibody (IgG1/κ-light chain) produced in Chinese Hamster Ovary (CHO) cells. Based on the amino acid sequence, the molecular weight of the non-glycosylated lanadelumab-flyo is 146 kDa. The calculated molecular mass of the fully reduced light chain is 23 kDa. The calculated molecular mass of the fully reduced and non-glycosylated heavy chain is 49 kDa.
TAKHZYRO (lanadelumab-flyo) injection is a sterile, preservative-free, clear to slightly opalescent, colorless to slightly yellow solution for subcutaneous use.
Each mL of ready-to-use TAKHZYRO solution contains lanadelumab-flyo 150 mg, citric acid monohydrate (4.1 mg), L-histidine (7.8 mg), polysorbate 80 (0.1 mg), sodium chloride (5.3 mg), sodium phosphate dibasic dihydrate (5.3 mg), and Water for Injection, USP. The solution has a pH of approximately 6.0 and an osmolality of approximately 300 mOsm/kg.
TAKHZYRO™ is indicated for prophylaxis to prevent attacks of hereditary angioedema (HAE) in patients 12 years and older.
The recommended starting dose is 300 mg every 2 weeks. A dosing interval of 300 mg every 4 weeks is also effective and may be considered if the patient is well-controlled (e.g., attack free) for more than 6 months.
TAKHZYRO is administered subcutaneously only.
TAKHZYRO is provided as a ready-to-use solution in a single-dose vial that does not require additional reconstitution or dilution for administration. TAKHZYRO is supplied as a clear to slightly opalescent, colorless to slightly yellow solution. Do not use the vial if it appears discolored or contains visible particles. Avoid vigorous agitation of the vial.
TAKHZYRO is intended for self-administration or administration by a caregiver. The patient or caregiver should be trained by a healthcare professional.
Take the TAKHZYRO vial out of the refrigerator 15 minutes before injecting to allow it to equilibrate to room temperature.
Using aseptic technique, withdraw the prescribed dose of TAKHZYRO from the vial using an 18-gauge needle. Change the needle on the syringe to a 27-gauge, ½-inch needle or other needle suitable for subcutaneous injection. Inject TAKHZYRO subcutaneously into the abdomen, thigh, or upper arm. Patients should inject the complete dose as prescribed by their physician. In clinical studies, the majority of patients self-administered TAKHZYRO over 10 to 60 seconds.
TAKHZYRO should be administered within 2 hours of preparing the dosing syringe. After the dosing syringe is prepared, it can be refrigerated at 36°F to 46°F (2°C to 8°C) and must be used within 8 hours.
Discard any unused portions of drug remaining in the vial and syringe.
For detailed instructions on the preparation and administration of TAKHZYRO see Instructions for Use.
TAKHZYRO is a sterile, preservative-free, clear to slightly opalescent, colorless to slightly yellow solution in a single-dose glass vial.
300 mg/2 mL (150 mg/mL) solution
Manufactured by: Dyax Corp. 300 Shire Way, Lexington, MA 02421. Revised: Nov 2018
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety of TAKHZYRO is primarily based on a 26-week, randomized, double-blind, parallel-group and placebo-controlled study (Trial 1) in 125 patients with Type I or II HAE. Eligible patients were also able to participate in an open-label extension study (Trial 2) up to 130 weeks. In Trial 1, a total of 84 patients with HAE aged 12 years and older received at least one dose of TAKHZYRO. Overall, 70% of patients were female and 90% of patients were Caucasian with a mean age of 41 years. The proportion of patients who discontinued study drug prematurely due to adverse events was 1.2% for TAKHZYRO-treated patients and 4.9% for placebo-treated patients. No deaths occurred in the trial.
The safety profile of TAKHZYRO was generally similar across all subgroups of patients, including analysis by age, sex, and geographic region.
Table 1 shows adverse reactions occurring in ≥10% of patients in any TAKHZYRO treatment group that also occurred at a higher rate than in the placebo treatment group in Trial 1.
Table 1: Adverse Reactions Observed in ≥10% of Patients Treated with TAKHZYRO in Trial 1
| Adverse Reaction | Placebo (N=41) |
TAKHZYRO | |||
| 150 mg q4wks (N=28) |
300 mg q4wks (N=29) |
300 mg q2wks (N=27) |
Total (N=84) |
||
| n (%) | n (%) | n (%) | n (%) | n (%) | |
| Injection site reactionsa | 14 (34) | 16 (57) | 13 (45) | 15 (56) | 44 (52) |
| Upper respiratory infectionb | 13 (32) | 3 (11) | 9 (31) | 12 (44) | 24 (29) |
| Headachec | 9 (22) | 3 (11) | 6 (21) | 9 (33) | 18 (21) |
| Rashd | 2(5) | 2 (7) | 3 (10) | 1 (4) | 6 (7) |
| Myalgia | 0 | 1 (4) | 0 | 3 (11) | 4 (5) |
| Dizziness | 0 | 1 (4) | 3 (10) | 1 (4) | 5 (6) |
| Diarrhea | 2 (5) | 3 (11) | 0 | 1 (4) | 4 (5) |
|
N= number of patients; n =number of patients experiencing the event; q2wks = every 2 weeks; q4wks = every 4 weeks a Injection site reactions include: pain, erythema, bruising, hematoma, hemorrhage, pruritus, swelling, induration, paraesthesia, reaction, warmth, edema and rash. b Includes upper respiratory infection, viral upper respiratory infection c Includes headache, tension headache, sinus headache d Includes rash, rash maculopapular, rash erythematous |
|||||
Injection site reactions primarily consisted mainly of pain, erythema, and bruising at the injection site. There was no meaningful difference in injection site reactions with self-administration.
Other adverse reactions that occurred at a higher incidence in TAKHZYRO-treated patients compared to placebo include hypersensitivity (1% vs 0%), increased aspartate transaminase (2% vs 0%), and increased alanine transaminase (2% vs 0%).
Safety data from the ongoing open-label extension study, consisting of 109 rollover patients from Trial 1 and 103 non-rollover HAE patients, is consistent with controlled safety data from Trial 1.
Transaminase elevations
During the placebo-controlled treatment period in Trial 1, the number of TAKHZYRO-treated patients with maximum transaminase (ALT or AST) levels >8, >5, or >3 times the upper limit of normal (ULN) was 1 (1.2%), 0 (0%), or 3 (3.6%) respectively, compared to 0 in the placebo-treated patients. These transaminase elevations were asymptomatic and transient. No patients had elevated total bilirubin >2x ULN. One TAKHZYRO-treated patient permanently discontinued treatment due to elevated transaminases (4.1x ULN AST). None of the patients were reported to have serious adverse reactions of elevated transaminases.
As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to lanadelumab-flyo in the study described below with the incidence of antibodies in other studies or to other products may be misleading.
In Trial 1, 10 (12%) lanadelumab-flyo-treated and 2 (5%) placebo-treated patients had at least 1 anti-drug antibody (ADA)-positive sample during the treatment period; antibody titers were low (range: 20 to 1280). The ADA response observed was transient in 2/10 lanadelumab-flyo and 1/2 placebo-treated patients. Pre-existing low titer antibodies were observed in 3 lanadelumab-flyo-treated patients and 1 placebo-treated patient with ADAs. Two patients receiving 150 mg q4wks had low titer antibodies classified as neutralizing.
The development of ADA including neutralizing antibodies against lanadelumab-flyo did not appear to adversely affect pharmacokinetics (PK), pharmacodynamics (PD), safety or clinical response.
No dedicated drug interaction studies have been conducted [see CLINICAL PHARMACOLOGY].
TAKHZYRO can increase activated partial thromboplastin time (aPTT) due to an interaction of TAKHZYRO 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 TAKHZYRO can increase aPTT in this assay. In Trial 1, prolongation of aPTT (>1x ULN) was observed at one or more time points in 3, 9, and 11 patients treated with TAKHZYRO 150 mg q4 wks, 300 mg q4 wks, and 300 mg q2 wks, respectively, compared to 5 placebo-treated patients. Only one patient in the 300 mg q2 wks treatment group experienced transient aPTT prolongation ≥1.5x ULN which was confounded by ongoing heparin therapy. None of the increases in aPTT in patients treated with TAKHZYRO were associated with abnormal bleeding adverse events. There were no differences in INR values between treatment groups.
Included as part of the "PRECAUTIONS" Section
Hypersensitivity reactions have been observed. In case of a severe hypersensitivity reaction, discontinue TAKHZYRO administration and institute appropriate treatment.
Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION and Instructions for Use). Inform patients of the risks and benefits of TAKHZYRO before prescribing or administering to the patient.
Advise patients to seek immediate medical attention if they experience any symptoms of serious hypersensitivity reactions [see WARNINGS AND PRECAUTIONS].
Animal studies have not been conducted to evaluate the carcinogenic potential of lanadelumab-flyo. Published literature supports bradykinin, which is elevated in HAE, as a pro-tumorigenic molecule. However, the malignancy risk in humans from an antibody that inhibits plasma kallikrein activity, such as lanadelumab-flyo, which lowers bradykinin levels, is currently unknown.
Male and female fertility were unaffected based upon no observed adverse histopathological findings in the reproductive organs from sexually mature cynomolgus monkeys that received lanadelumab-flyo for 13 weeks at subcutaneous doses up to 50 mg/kg/week (resulting in approximately 22 times the exposure at the MRHD on an AUC basis).
There are no available data on TAKHZYRO use in pregnant women to inform any drug associated risks. Monoclonal antibodies such as lanadelumab-flyo are transported across the placenta during the third trimester of pregnancy; therefore, potential effects on a fetus are likely to be greater during the third trimester of pregnancy. An enhanced pre-and postnatal development (ePPND) study conducted in pregnant monkeys at doses resulting in exposures of up to 33 times the exposure achieved (on an AUC basis) at the maximum recommended human dose (MRHD) revealed no evidence of harm to the developing fetus.
The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Animal Data
In the ePPND study, pregnant cynomolgus monkeys were administered lanadelumab-flyo once weekly at subcutaneous doses resulting in up to 33 times the exposure at the MRHD (on an AUC basis with maternal subcutaneous doses up to 50 mg/kg/week) from gestation day 20, at the beginning of organogenesis, through to parturition. There were no lanadelumab-flyo-related effects on maintenance of pregnancy or parturition. Maternal lanadelumab-flyo treatment had no effects on embryo-fetal development, survival, growth, or postnatal development of offspring through 3 months of age. Lanadelumab-flyo crossed the placenta in monkeys. Offspring were exposed to lanadelumab-flyo at approximately 50% of the maternal plasma concentration out to postnatal day 21 (PND 21). Lanadelumab-flyo concentrations were approximately equivalent in maternal and offspring plasma at PND 90.
There are no data on the presence of lanadelumab-flyo in human milk, its effects on the breastfed infant, or its effects on milk production. Lanadelumab-flyo was detected in the milk of lactating cynomolgus monkeys at approximately 0.2% of the maternal plasma concentration. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for TAKHZYRO and any potential adverse effects on the breastfed infant from TAKHZYRO or from the underlying maternal condition.
Animal Data
Available pharmacokinetic data in cynomolgus monkeys have shown excretion of lanadelumab-flyo in milk at approximately 0.2% of the maternal plasma level.
The safety and efficacy of TAKHZYRO were evaluated in a subgroup of patients (N=10) aged 12 to <18 years in Trial 1. Results of the subgroup analysis by age were consistent with overall study results [see ADVERSE REACTIONS, CLINICAL PHARMACOLOGY and Clinical Studies]. An additional 13 adolescent patients aged 12 to <18 years were enrolled in the open-label extension study.
The safety and efficacy of TAKHZYRO in pediatric patients < 12 years of age have not been established.
The safety and efficacy of TAKHZYRO were evaluated in a subgroup of patients (N=5) aged ≥65 years in Trial 1. Results of the subgroup analysis by age were consistent with overall study results [see ADVERSE REACTIONS, CLINICAL PHARMACOLOGY and Clinical Studies].
There is no clinical experience with overdosage of TAKHZYRO.
None.
Lanadelumab-flyo is a fully human monoclonal antibody (IgG1/κ-light chain) that binds plasma kallikrein and inhibits its proteolytic activity. Plasma kallikrein is a protease that cleaves high-molecular-weight-kininogen (HMWK) to generate cleaved HMWK (cHMWK) and bradykinin, a potent vasodilator that increases vascular permeability resulting in swelling and pain associated with HAE. In patients with HAE due to C1-inhibitor (C1-INH) deficiency or dysfunction, normal regulation of plasma kallikrein activity is not present, which leads to uncontrolled increases in plasma kallikrein activity and results in angioedema attacks. Lanadelumab-flyo decreases plasma kallikrein activity to control excess bradykinin generation in patients with HAE.
Concentration-dependent inhibition of plasma kallikrein, measured as reduction of cHMWK levels, was demonstrated after subcutaneous administration of TAKHZYRO 150 mg q4wks, 300 mg q4wks or 300 mg q2wks in patients with HAE.
TAKHZYRO did not prolong the QT/QTc interval.
Following subcutaneous administration, the pharmacokinetics of lanadelumab-flyo was approximately dose-proportional in the therapeutic dose range in patients with HAE (Table 2). The pharmacokinetic properties and exposure (steady state) of lanadelumab-flyo in HAE patients, following subcutaneous administration of 150 mg q4wks, 300 mg q4wks and 300 mg q2wks, are provided in Table 2. Following subcutaneous administration of TAKHZYRO, peak plasma concentrations are reached within 5 days, and terminal elimination half-life is ~2 weeks. The anticipated time to reach steady state concentration was approximately 70 days. At steady-state, the mean accumulation ratio is approximately 1.44, 1.42, and 2.43 for dosing regimen of 150 mg q4wks, 300 mg q4wks and 300 mg q2wks, respectively.
Table 2 Mean (SD) Pharmacokinetic Parameters of Lanadelumab-flyo Following Subcutaneous Administration (Trial 1)
| Pharmacokinetic Parameters | Lanadelumab-flyo | ||
| 150 mg q4wks (N=28) |
300 mg q4wks (N=29) |
300 mg q2wks (N=27) |
|
| CL/F (L/day) |
0.667 (0.162) | 0.742 (0.239) | 0.809 (0.370) |
| Vc/F (L) |
14.1 (2.93) | 14.9 (4.45) | 16.6 (4.79) |
| AUCtau,ss (μg*day/mL) |
233 (56.6) | 441(137) | 408 (138) |
| Cmax,ss (μg/mL) |
12.0 (3.01) | 23.3 (7.94) | 34.4 (11.2) |
| Cmin,ss (μg/mL) |
4.81 (1.40) | 8.77 (2.80) | 25.4 (9.18) |
| tmax (day) |
5.17 (1.09) | 5.17 (1.12) | 4.11 (0.377) |
| t1/2 (day) |
14.9 (2.00) | 14.2 (1.89) | 15.0 (2.48) |
| CL/F: apparent clearance; Vc/F: apparent volume of distribution; AUCtau,ss: area under the curve over the dosing interval at steady-state; Cmax,ss: maximum concentration at steady-state; Cmin,ss: minimum concentration at steady state; Tmax: time to maximum concentration; t1/2 terminal elimination half-life. | |||
Population pharmacokinetic analyses showed that age, gender and race did not meaningfully influence the pharmacokinetics of lanadelumab-flyo after correcting for body weight. Body weight was identified as an important covariate describing the variability of clearance and volume of distribution, resulting in higher exposure (AUC and Cmax) in lighter patients. However, this difference is not considered to be clinically relevant and no dose adjustments are recommended for any of these demographics.
Based on population pharmacokinetics (PK) analyses, the mean lanadelumab-flyo (±SD) AUCss was 629 (204) μg*day/mL following SC administration of TAKHZYRO 300 mg every 2 weeks in pediatric patients 12 to less than 18 years of age. This is approximately 37% higher than the mean AUCss in adult patients (460 μg*day/mL) under the same dosing regimen, due to lower body weight in pediatric patients.
No dedicated studies have been conducted to evaluate the PK of lanadelumab-flyo in renal impairment patients. Based on population pharmacokinetic analysis, renal impairment (estimated GFR: 60 to 89 mL/min/1.73m2, [mild, N=98] and 30 to 59 mL/min/1.73m2, [moderate, N=9]) had no effect on the clearance or volume of distribution of lanadelumab-flyo.
The use of analgesic, antibacterial, antihistamine, anti-inflammatory and anti-rheumatic medications had no effect on clearance and volume of distribution of lanadelumab-flyo.
For breakthrough HAE attacks, use of rescue medications such as plasma-derived and recombinant C1-INH, icatibant or ecallantide had no effects on clearance and volume of distribution of lanadelumab-flyo.
The efficacy of TAKHZYRO for the prevention of angioedema attacks in patients 12 years of age and older with Type I or II HAE was demonstrated in a multicenter, randomized, double-blind, placebo-controlled parallel-group study (Trial 1).
The study included 125 adult and adolescent patients with Type I or II HAE who experienced at least one investigator-confirmed attack per 4 weeks during the run-in period. Patients were randomized into 1 of 4 parallel treatment arms, stratified by baseline attack rate, in a 3:2:2:2 ratio (placebo, lanadelumab-flyo 150 mg q4wks, lanadelumab-flyo 300 mg q4wks, or lanadelumab-flyo 300 mg q2wks by subcutaneous injection) for the 26-week treatment period. Patients ≥18 years of age were required to discontinue other prophylactic HAE medications prior to entering the study; however, all patients were allowed to use rescue medications for treatment of breakthrough HAE attacks.
Overall, 90% of patients had Type I HAE. A history of laryngeal angioedema attacks was reported in 65% of patients and 56% were on prior long-term prophylaxis. During the study run-in period, attack rates of ≥3 attacks/month were observed in 52% of patients overall.
All TAKHZYRO treatment arms produced clinically meaningful and statistically significant reductions in the mean HAE attack rate compared to placebo across all primary and secondary endpoints in the Intent-to-Treat population (ITT) as shown in Table 3.
Table 3 Results of Primary and Secondary Efficacy Measures-ITT Population
| Endpoint Statistics | Placebo (N=41) |
TAKHZYRO | ||
| 150 mg q4wks (N=28) |
300 mg q4wks (N=29) |
300 mg q2wks (N=27) |
||
| Number of HAE Attacks from Day 0 to 182a | ||||
| LS Mean (95% CI) monthly attack rateb | 1.97 (1.64, 2.36) |
0.48 (0.31, 0.73) |
0.53 (0.36, 0.77) |
0.26 (0.14, 0.46) |
| % Reduction relative to placebo (95% CI)c | 76 (61, 85) |
73 (59, 82) |
87 (76, 93) |
|
| Adjusted p-valuesd | <0.001 | <0.001 | <0.001 | |
| Number of HAE Attacks Requiring Acute Treatment from Day 0 to 182 | ||||
| LS Mean (95% CI) monthly attack rateb | 1.64 (1.34, 2.00) |
0.31 (0.18, 0.53) |
0.42 (0.28, 0.65) |
0.21 (0.11, 0.40) |
| % Reduction relative to placebo (95% CI)c | 81 (66, 89) |
74 (59, 84) |
87 (75, 93) |
|
| Adjusted p-valuesd | <0.001 | <0.001 | <0.001 | |
| Number of Moderate or Severe HAE Attacks from Day 0 to 182 | ||||
| LS Mean (95% CI) monthly attack rateb | 1.22 (0.97, 1.52) |
0.36 (0.22, 0.58) |
0.32 (0.20, 0.53) |
0.20 (0.11, 0.39) |
| % Reduction relative to placebo (95% CI)c | 70 (50, 83) |
73 (54, 84) |
83 (67, 92) |
|
| Adjusted p-valuesd | <0.001 | <0.001 | <0.001 | |
|
CI=confidence interval; SD=standard deviation; LS=least squares. Note: Results are from a Poisson regression model accounting for over dispersion with fixed effects for treatment group (categorical) and normalized baseline attack rate (continuous), and the logarithm of time in days each patient was observed during the treatment period as an offset variable in the model. a Primary efficacy endpoint. b Model-based treatment period HAE attack rate (attacks/4 weeks). c Calculated as the ratio of the model-based treatment period HAE attack rates (lanadelumab/placebo) minus 1 multiplied by 100. d Adjusted p-values for multiple testing. |
||||
The mean reduction in HAE attack rate was consistently higher across the TAKHZYRO treatment arms compared to placebo regardless of the baseline history of prior long-term prophylaxis, laryngeal attacks, or attack rate during the run-in period.
Additional pre-defined exploratory endpoints included the percentage of patients who were attack free for the entire 26-week treatment period and the percentage of patients achieving threshold (≥50%, ≥70%, ≥90%) reductions in HAE attack rates compared to run-in during the 26-week treatment period. A ≥50% reduction in HAE attack rate was observed in 100% of patients on 300 mg q2wks or q4wks and 89% on 150 mg q4wks compared to 32% of placebo patients. A ≥70% reduction in HAE attack rates was observed in 89%, 76%, and 79% of patients on 300 mg q2wks, 300 mg q4wks, and 150 mg q4wks, respectively, compared to 10% of placebo patients. A ≥90% reduction in HAE attack rates was observed 67%, 55%, and 64% of patients on 300 mg q2wks, 300 mg q4wks, and 150 mg q4wks, respectively, compared to 5% of placebo patients.
The percentage of attack-free patients for the entire 26-week treatment period was 44%, 31%, and 39% in the TAKHZYRO 300 mg q2wks, 300 mg q4wks, and 150 mg q4wks groups respectively, compared to 2% of placebo patients.
Patients who completed Trial 1 were eligible to rollover into an open-label extension study. Rollover patients, regardless of randomization group in Trial 1, received a single dose of TAKHZYRO 300 mg at study entry and were followed until the first HAE attack occurred. All efficacy endpoints were exploratory in this uncontrolled, unblinded study. At week 4 post-dose, approximately 80% of patients who had been in the 300 mg q2wks treatment group (N=25) in Trial 1 remained attack-free. After the first HAE attack, all patients received open-label treatment with TAKHYZRO 300 mg q2wks.
No information provided. Please refer to the WARNINGS AND PRECAUTIONS sections.
