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TAKHZYROTM(lanadelumab-flyo)injection
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
TAKHZYROTM safely and effectively. See full prescribing informationfor TAKHZYROTM.
TAKHZYROTM(lanadelumab-flyo)injection, for subcutaneous use.
Initial U.S. Approval: 2018.
--------------------INDICATIONS AND USAGE-----------------------------------
TAKHZYRO is a plasma kallikrein inhibitor (monoclonal antibody) indicatedfor prophylaxis to prevent attacks of hereditary angioedema (HAE) in patients12 years and older. (1)
--------------------DOSAGE AND ADMINISTRATION--------------------------
For subcutaneous use only
• Administer 300 mg every 2 weeks. Dosing every 4 weeks may beconsidered in some patients (2.1)
• Patients may self-administer. (2.2)
-------------------DOSAGE FORMS AND STRENGTHS ------------------------
Injection: 300 mg/2 mL (150 mg/mL) solution in a single-dose vial. (3)
-------------------------CONTRAINDICATIONS------------------------------------
None. (4)
-------------------------WARNINGS AND PRECAUTIONS ----------------------
Hypersensitivity reactions have been observed. In case of a severehypersensitivity reaction, discontinue TAKHZYRO administration andinstitute appropriate treatment. (5.1)
-------------------------------ADVERSE REACTIONS------------------------------
The most common adverse reactions are injection site reactions, upperrespiratory infections, headache, rash, myalgia, dizziness, and diarrhea. (6.1)
-------------------------------DRUG INTERACTIONS ------------------------------
No dedicated drug interaction studies have been conducted. (7)
To report SUSPECTED ADVERSE REACTIONS, contact Dyax Corp.(a wholly-owned, indirect subsidiary of Shire plc). 1-800-828-2088 orFDA at 1-800-FDA-1088 or www.fda.gov/medwatch.See 17 for PATIENT COUNSELING INFORMATION and
FDA-approved patient labeling.
Revised: 8/2018
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Dosage
2.2 Administration
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Hypersensitivity Reactions
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Immunogenicity
7 DRUG INTERACTIONS
7.1 Drug-Laboratory Test Interactions
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.4 Pediatric Use
8.5 Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not
listed.
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
TAKHZYROTM is indicated for prophylaxis to prevent attacks of hereditary angioedema (HAE) inpatients 12 years and older.
2 DOSAGE AND ADMINISTRATION
2.1 Dosage
The recommended starting dose is 300 mg every 2 weeks. A dosing interval of 300 mg every 4 weeks is alsoeffective and may be considered if the patient is well-controlled (e.g., attack free) for more than 6 months.
2.2 Administration
TAKHZYRO is administered subcutaneously only.
TAKHZYRO is provided as a ready-to-use solution in a single-dose vial that does not require additionalreconstitution or dilution for administration. TAKHZYRO is supplied as a clear to slightly opalescent, colorlessto slightly yellow solution. Do not use the vial if it appears discolored or contains visible particles. Avoidvigorous agitation of the vial.
TAKHZYRO is intended for self-administration or administration by a caregiver. The patient or caregivershould be trained by a healthcare professional.
Take the TAKHZYRO vial out of the refrigerator 15 minutes before injecting to allow it to equilibrate to roomtemperature.
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 subcutaneousinjection. Inject TAKHZYRO subcutaneously into the abdomen, thigh, or upper arm. Patients should inject thecomplete dose as prescribed by their physician. In clinical studies, the majority of patients self-administeredTAKHZYRO over 10 to 60 seconds.
TAKHZYRO should be administered within 2 hours of preparing the dosing syringe. After the dosing syringe isprepared, it can be refrigerated at 36ºF to 46ºF (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.3 DOSAGE FORMS AND STRENGTHS
TAKHZYRO is a sterile, preservative-free, clear to slightly opalescent, colorless to slightly yellow solution in asingle-dose glass vial.
Injection: 300 mg/2 mL (150 mg/mL) solution
4 CONTRAINDICATIONS None.
5 WARNINGS AND PRECAUTIONS
5.1 Hypersensitivity Reactions
Hypersensitivity reactions have been observed. In case of a severe hypersensitivity reaction, discontinueTAKHZYRO administration and institute appropriate treatment.
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in theclinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may notreflect the rates observed in practice.
The safety of TAKHZYRO is primarily based on a 26-week, randomized, double-blind, parallel-group andplacebo-controlled study (Trial 1) in 125 patients with Type I or II HAE. Eligible patients were also able toparticipate in an open-label extension study (Trial 2) up to 130 weeks. In Trial 1, a total of 84 patients withHAE aged 12 years and older received at least one dose of TAKHZYRO. Overall, 70% of patients were femaleand 90% of patients were Caucasian with a mean age of 41 years. The proportion of patients who discontinuedstudy drug prematurely due to adverse events was 1.2% for TAKHZYRO-treated patients and 4.9% forplacebo-treated patients. No deaths occurred in the trial.
The safety profile of TAKHZYRO was generally similar across all subgroups of patients, including analysis byage, sex, and geographic region.
Table 1 shows adverse reactions occurring in ≥10% of patients in any TAKHZYRO treatment group that alsooccurred 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
cIncludes headache, tension headache, sinus headache dIncludes rash, rash maculopapular, rash erythematous
Injection site reactions primarily consisted mainly of pain, erythema, and bruising at the injection site.
Therewas no meaningful difference in injection site reactions with self-administration.
Less Common Adverse Reactions
Other adverse reactions that occurred at a higher incidence in TAKHZYRO-treated patients compared toplacebo include hypersensitivity (1% vs 0%), increased aspartate transaminase (2% vs 0%), and increasedalanine transaminase (2% vs 0%).
Safety data from the ongoing open-label extension study, consisting of 109 rollover patients from Trial 1 and103 non-rollover HAE patients, is consistent with controlled safety data from Trial 1.
Laboratory Abnormalities
Transaminase elevations
During the placebo-controlled treatment period in Trial 1, the number of TAKHZYRO-treated patients withmaximum 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 transaminaseelevations 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 ULNAST). None of the patients were reported to have serious adverse reactions of elevated transaminases.
6.2 Immunogenicity
As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation ishighly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence ofantibody (including neutralizing antibody) positivity in an assay may be influenced by several factors includingassay methodology, sample handling, timing of sample collection, concomitant medications, and underlyingdisease. For these reasons, comparison of the incidence of antibodies to lanadelumab-flyo in the study describedbelow 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-drugantibody (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-treatedpatient 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 toadversely affect pharmacokinetics (PK), pharmacodynamics (PD), safety or clinical response.
7 DRUG INTERACTIONS
No dedicated drug interaction studies have been conducted [see Clinical Pharmacology (12.3)].
7.1 Drug-Laboratory Test Interactions
Coagulation tests
TAKHZYRO can increase activated partial thromboplastin time (aPTT) due to an interaction of TAKHZYROwith the aPTT assay. The reagents used in the aPTT laboratory test initiate intrinsic coagulation through theactivation of plasma kallikrein in the contact system. Inhibition of plasma kallikrein by TAKHZYRO canincrease aPTT in this assay. In Trial 1, prolongation of aPTT (>1x ULN) was observed at one or more timepoints 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 groupexperienced transient aPTT prolongation ≥1.5x ULN which was confounded by ongoing heparin therapy. Noneof the increases in aPTT in patients treated with TAKHZYRO were associated with abnormal bleeding adverseevents. There were no differences in INR values between treatment groups.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
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 trimesterof pregnancy; therefore, potential effects on a fetus are likely to be greater during the third trimester ofpregnancy. An enhanced pre-and postnatal development (ePPND) study conducted in pregnant monkeys atdoses resulting in exposures of up to 33 times the exposure achieved (on an AUC basis) at the maximumrecommended 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 clinicallyrecognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Data
Animal Data
In the ePPND study, pregnant cynomolgus monkeys were administered lanadelumab-flyo once weekly atsubcutaneous doses resulting in up to 33 times the exposure at the MRHD (on an AUC basis with maternalsubcutaneous doses up to 50 mg/kg/week) from gestation day 20, at the beginning of organogenesis, through toparturition. 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, orpostnatal development of offspring through 3 months of age. Lanadelumab-flyo crossed the placenta inmonkeys. Offspring were exposed to lanadelumab-flyo at approximately 50% of the maternal plasmaconcentration out to postnatal day 21 (PND 21). Lanadelumab-flyo concentrations were approximatelyequivalent in maternal and offspring plasma at PND 90.
8.2 Lactation
Risk Summary
There are no data on the presence of lanadelumab-flyo in human milk, its effects on the breastfed infant, or itseffects on milk production. Lanadelumab-flyo was detected in the milk of lactating cynomolgus monkeys atapproximately 0.2% of the maternal plasma concentration. The developmental and health benefits ofbreastfeeding should be considered along with the mother’s clinical need for TAKHZYRO and any potentialadverse effects on the breastfed infant from TAKHZYRO or from the underlying maternal condition.
Data
Animal Data
Available pharmacokinetic data in cynomolgus monkeys have shown excretion of lanadelumab-flyo in milkatapproximately 0.2% of the maternal plasma level.
8.4 Pediatric Use
The safety and efficacy of TAKHZYRO were eva luated in a subgroup of patients (N=10) aged 12 to <18 yearsin Trial 1. Results of the subgroup analysis by age were consistent with overall study results [see AdverseReactions (6.1), Clinical Pharmacology (12.3) and Clinical Trials (14)]. An additional 13 adolescent patientsaged 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.
8.5 Geriatric Use
The safety and efficacy of TAKHZYRO were eva luated 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 AdverseReactions (6.1), Clinical Pharmacology (12.3) and Clinical Trials (14)].
10 OVERDOSAGE
There is no clinical experience with overdosage of TAKHZYRO.
11 DESCRIPTION
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 ofthe non-glycosylated lanadelumab-flyo is 146 kDa. The calculated molecular mass of the fully reduced lightchain is 23 kDa. The calculated molecular mass of the fully reduced and non-glycosylated heavy chain is49 kDa.
TAKHZYRO (lanadelumab-flyo) injection is a sterile, preservative-free, clear to slightly opalescent, colorlessto 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 dibasicdihydrate (5.3 mg), and Water for Injection, USP. The solution has a pH of approximately 6.0 and an osmolalityof approximately 300 mOsm/kg.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Lanadelumab-flyo is a fully human monoclonal antibody (IgG1/κ-light chain) that binds plasma kallikrein andinhibits 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 vascularpermeability 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 leadsto uncontrolled increases in plasma kallikrein activity and results in angioedema attacks. Lanadelumab-flyodecreases plasma kallikrein activity to control excess bradykinin generation in patients with HAE.
12.2 Pharmacodynamics
Concentration-dependent inhibition of plasma kallikrein, measured as reduction of cHMWK levels, wasdemonstrated after subcutaneous administration of TAKHZYRO 150 mg q4wks, 300 mg q4wks or 300 mgq2wks in patients with HAE.
TAKHZYRO did not prolong the QT/QTc interval.
12.3 Pharmacokinetics
Following subcutaneous administration, the pharmacokinetics of lanadelumab-flyo was approximatelydose-proportional in the therapeutic dose range in patients with HAE (Table 2). The pharmacokinetic propertiesand exposure (steady state) of lanadelumab-flyo in HAE patients, following subcutaneous administration of150 mg q4wks, 300 mg q4wks and 300 mg q2wks, are provided in Table 2. Following subcutaneousadministration of TAKHZYRO, peak plasma concentrations are reached within 5 days, and terminal eliminationhalf-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 150mg 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)
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)
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: maximumconcentration at steady-state; Cmin,ss: minimum concentration at steady state; Tmax: time to maximum concentration; t 1/2 terminal elimination half-life.
Specific Populations
Population pharmacokinetic analyses showed that age, gender and racedidnotmeaningfullyinfluencethepharmacokinetics of lanadelumab-flyo after correcting for body weight. Body weight was identified as animportant covariate describing the variability of clearance and volume of distribution, resulting in higherexposure (AUC and Cmax) in lighter patients. However, this difference is not considered to be clinically relevantand no dose adjustments are recommended for any of these demographics.
Pediatric Population
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 lessthan 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.
Renal Impairment
No dedicated studies have been conducted to eva luate 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 ofdistribution of lanadelumab-flyo.
Concomitant medications
The use of analgesic, antibacterial, antihistamine, anti-inflammatory and anti-rheumatic medications had noeffect 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.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Animal studies have not been conducted to eva luate the carcinogenic potential of lanadelumab-flyo. Published
literature supports bradykinin, which is elevated in HAE, as a pro-tumorigenic molecule. However, the8malignancy 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 thereproductive organs from sexually mature cynomolgus monkeys that received lanadelumab-flyo for 13 weeks atsubcutaneous doses up to 50 mg/kg/week (resulting in approximately 22 times the exposure at the MRHD on anAUC basis).
14 CLINICAL STUDIES
Trial 1 (NCT02586805)
The efficacy of TAKHZYRO for the prevention of angioedema attacks in patients 12 years of age and olderwith Type I or II HAE was demonstrated in a multicenter, randomized, double-blind, placebo-controlledparallel-group study (Trial 1).
The study included 125 adult and adolescent patients with Type I or II HAE who experienced at least oneinvestigator-confirmed attack per 4 weeks during the run-in period. Patients were randomized into 1 of 4parallel treatment arms, stratified by baseline attack rate, in a 3:2:2:2 ratio (placebo, lanadelumab-flyo 150 mgq4wks, lanadelumab-flyo 300 mg q4wks, or lanadelumab-flyo 300 mg q2wks by subcutaneous injection) for the26-week treatment period. Patients ≥18 years of age were required to discontinue other prophylactic HAEmedications prior to entering the study; however, all patients were allowed to use rescue medications fortreatment of breakthrough HAE attacks.
Overall, 90% of patients had Type I HAE. A history of laryngeal angioedema attacks was reported in 65% ofpatients and 56% were on prior long-term prophylaxis. During the study run-in period, attack ratesof ≥3 attacks/month were observed in 52% of patients overall.
All TAKHZYRO treatment arms produced clinically meaningful and statistically significant reductions in themean HAE attack rate compared to placebo across all primary and secondary endpoints in the Intent-to-Treatpopulation (ITT) as shown in Table 3.
Table 3 Results of Primary and Secondary Efficacy Measures-ITT Population
Endpoint Statistics
Placebo
(N=41)
TAKHZYRO
150mg 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)
9
Table 3 Results of Primary and Secondary Efficacy Measures-ITT Population
Endpoint Statistics
Placebo
(N=41)
TAKHZYRO
150mg q4wks
(N=28)
300 mg q4wks
(N=29)
300 mg q2wks
(N=27)
% 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 attackrate (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 armscompared to placebo regardless of the baseline history of prior long-term prophylaxis, laryngeal attacks, orattack rate during the run-in period.
Additional pre-defined exploratory endpoints included the percentage of patients who were attack free for theentire 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 inHAE attack rate was observed in 100% of patients on 300 mg q2wks or q4wks and 89% on 150 mg q4wkscompared to 32% of placebo patients. A ≥70% reduction in HAE attack rates was observed in 89%, 76%, and79% of patients on 300 mg q2wks, 300 mg q4wks, and 150 mg q4wks, respectively, compared to 10% ofplacebo patients. A ≥90% reduction in HAE attack rates was observed 67%, 55%, and 64% of patients on 300mg 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 theTAKHZYRO 300 mg q2wks, 300 mg q4wks, and 150 mg q4wks groups respectively, compared to 2% ofplacebo patients.
Trial 2 (NCT02741596)
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 andwere 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 q2wkstreatment group (N=25) in Trial 1 remained attack-free. After the first HAE attack, all patients received openlabeltreatment with TAKHYZRO 300 mg q2wks.
16 HOW SUPPLIED/STORAGE AND HANDLING
How Supplied
• TAKHZYRO (lanadelumab-flyo) injection is a ready-to-use, clear to slightly opalescent, colorless toslightly yellow solution supplied in a carton containing one single-dose glass vial with chlorobutylrubber stopper, aluminum crimp seal and polypropylene flip-off cap.
• NDC 47783-644-01: 300 mg/2 mL (150 mg/mL) vial.
Storage and handling
• Store vials refrigerated at 36°F to 46°F (2°C to 8°C).
• Do not freeze. Do not shake.
• Keep the vial in the original carton in order to protect the vial from light.
17 PATIENT COUNSELING INFORMATION
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.Hypersensitivity
Advise patients to seek immediate medical attention if they experience any symptoms of serioushypersensitivity reactions [see Warnings and Precautions (5.1)].
Self-administration:
• Ensure that the patient/caregiver receives clear instructions and training on subcutaneous administrationand has demonstrated the ability to perform a subcutaneous injection.
• Instruct patients or caregivers in the technique of proper syringe and needle disposal, and advise themnot to reuse these items. Instruct patients to dispose needles and syringes in a puncture-resistant
container.
For more information, visit www.TAKHZYRO.com
Manufactured by:
Dyax Corp.
300 Shire Way
Lexington, MA 02421
U.S. License No. 1789
TAKHZYROTM is a trademark or registered trademark of Dyax Corp., a wholly-owned, indirect subsidiary of
Shire plc. SHIRE and the Shire Logo are trademarks or registered trademarks of Shire Pharmaceutical Holdings
Ireland Limited or its affiliates.
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