Taltz（ixekizumab）注射剂为全球第2款IL-17A抗炎药-获美国FDA批准治疗斑块型银屑病的上市新药
2016年3月24日，FDA已批准Taltz（ixekizumab，80mg/mL）注射液用于适合系统治疗（systemic therapy，即全身疗治）或光疗（phototherapy）的中度至重度斑块型银屑病（plaque psoriasis）成人患者的治疗。Taltz不能用于对活性药物成分ixekizumab或任何辅料有超敏反应（如过敏）的患者。ixekizumab是一种靶向促炎性细胞因子IL-17A的单克隆抗体，IL-17A被认为在多种自身免疫性疾病的炎性反应中发挥关键作用。
关于Taltz（ixekizumab）：
ixekizumab是一种单克隆抗体，针对具有促炎作用的细胞因子白介素-17A（IL-17A）具有较高的亲和力和特异性，可抑制IL-17A与IL-17受体的结合。对于银屑病患者而言，IL-17A在驱动角化细胞（皮肤细胞）过度增殖和活化方面发挥了重要作用。ixekizumab不会与细胞因子IL-17B、IL-17C、IL-17D、IL-17E或IL-17F相结合。Ixekizumab通过皮下注射给药。目前，礼来也正在推进ixekizumab治疗银屑病关节炎及其他炎症性疾病的相关临床研究
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use TALTZ safely and effectively. See full prescribing information for TALTZ.
TALTZ(ixekizumab) injection, for subcutaneous use
Initial U.S. Approval: 2016
INDICATIONS AND USAGE
TALTZ™ is a humanized interleukin-17A antagonist indicated for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. (1)
DOSAGE AND ADMINISTRATION
Administer by subcutaneous injection. (2.1)
Recommended dose is 160 mg (two 80 mg injections) at Week 0, followed by 80 mg at Weeks 2, 4, 6, 8, 10, and 12, then 80 mg every 4 weeks. (2.1)
DOSAGE FORMS AND STRENGTHS
Autoinjector
Injection: 80 mg/mL solution in a single-dose prefilled autoinjector. (3)
Prefilled Syringe
Injection: 80 mg/mL solution in a single-dose prefilled syringe. (3)
CONTRAINDICATIONS
Serious hypersensitivity reaction to ixekizumab or to any of the excipients. (4)
WARNINGS AND PRECAUTIONS
Infections: Serious infections have occurred. Instruct patients to seek medical advice if signs or symptoms of clinically important chronic or acute infection occur. If a serious infection develops, discontinue TALTZ until the infection resolves. (5.1)
Tuberculosis (TB): Evaluate for TB prior to initiating treatment. (5.2)
Hypersensitivity: If a serious allergic reaction occurs, discontinue TALTZ immediately and initiate appropriate therapy. (5.3)
Inflammatory Bowel Disease: Crohn's disease and ulcerative colitis, including exacerbations, occurred during clinical trials. Patients who are treated with TALTZ and have inflammatory bowel disease should be monitored closely. (5.4)
ADVERSE REACTIONS
Most common (≥1%) adverse reactions associated with TALTZ treatment are injection site reactions, upper respiratory tract infections, nausea, and tinea infections. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-545-5979 (1-800-LillyRx) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DRUG INTERACTIONS
Live Vaccines: Live vaccines should not be given with TALTZ. (7.1)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Revised: 3/2016
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
TALTZ™ is indicated for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.
2 DOSAGE AND ADMINISTRATION
2.1 Dosage
TALTZ is administered by subcutaneous injection. The recommended dose is 160 mg (two 80 mg injections) at Week 0, followed by 80 mg at Weeks 2, 4, 6, 8, 10, and 12, then 80 mg every 4 weeks.
2.2 Tuberculosis Assessment Prior to Initiation of TALTZ
Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with TALTZ [see Warnings and Precautions (5.2)].
2.3 Important Administration Instructions
There are two presentations for TALTZ (i.e., autoinjector and prefilled syringe). The TALTZ “Instructions for Use” for each presentation contains more detailed instructions on the preparation and administration of TALTZ [see Instructions for Use].
TALTZ is intended for use under the guidance and supervision of a physician. Patients may self-inject after training in subcutaneous injection technique using the autoinjector or prefilled syringe. Administer each injection at a different anatomic location (such as upper arms, thighs or any quadrant of abdomen) than the previous injection, and not into areas where the skin is tender, bruised, erythematous, indurated or affected by psoriasis. Administration of TALTZ in the upper, outer arm may be performed by a caregiver or healthcare provider.
If a dose is missed, administer the dose as soon as possible. Thereafter, resume dosing at the regular scheduled time.
2.4 Preparation for Use of TALTZ Autoinjector and Prefilled Syringe
Before injection, remove TALTZ autoinjector or TALTZ prefilled syringe from the refrigerator and allow TALTZ to reach room temperature (30 minutes) without removing the needle cap.
Inspect TALTZ visually for particulate matter and discoloration prior to administration. TALTZ is a clear and colorless to slightly yellow solution. Do not use if the liquid contains visible particles, is discolored or cloudy (other than clear and colorless to slightly yellow). TALTZ does not contain preservatives, therefore discard any unused product remaining in the autoinjector or prefilled syringe.
Instruct patients using the autoinjector or prefilled syringe to inject the full amount (1 mL), which provides 80 mg of TALTZ, according to the directions provided in the Instructions for Use [see Instructions for Use]. 
3 DOSAGE FORMS AND STRENGTHS
TALTZ is a clear and colorless to slightly yellow solution available as:
Autoinjector
Injection: 80 mg/mL solution of TALTZ in a single-dose prefilled autoinjector
Prefilled Syringe
Injection: 80 mg/mL solution of TALTZ in a single-dose prefilled syringe
4 CONTRAINDICATIONS
TALTZ is contraindicated in patients with a previous serious hypersensitivity reaction, such as anaphylaxis, to ixekizumab or to any of the excipients [see Warnings and Precautions (5.3)].
5 WARNINGS AND PRECAUTIONS
5.1 Infections
TALTZ may increase the risk of infection. In clinical trials, the TALTZ group had a higher rate of infections than the placebo group (27% vs. 23%). Upper respiratory tract infections, oral candidiasis, conjunctivitis and tinea infections occurred more frequently in the TALTZ group than in the placebo group [see Adverse Reactions (6.1)].
Instruct patients treated with TALTZ to seek medical advice if signs or symptoms of clinically important chronic or acute infection occur. If a patient develops a serious infection or is not responding to standard therapy, monitor the patient closely and discontinue TALTZ until the infection resolves.
5.2 Pre-treatment Evaluation for Tuberculosis
Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with TALTZ. Do not administer to patients with active TB infection. Initiate treatment of latent TB prior to administering TALTZ. Consider anti-TB therapy prior to initiating TALTZ in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Patients receiving TALTZ should be monitored closely for signs and symptoms of active TB during and after treatment.
5.3 Hypersensitivity
Serious hypersensitivity reactions, including angioedema and urticaria (each ≤0.1%), occurred in the TALTZ group in clinical trials. If a serious hypersensitivity reaction occurs, discontinue TALTZ immediately and initiate appropriate therapy [see Adverse Reactions (6.1)].
5.4 Inflammatory Bowel Disease
Crohn's disease and ulcerative colitis, including exacerbations, occurred at a greater frequency in the TALTZ group (Crohn's disease 0.1%, ulcerative colitis 0.2%) than the placebo group (0%) during the 12-week, placebo-controlled period. During TALTZ treatment, monitor for onset or exacerbation of inflammatory bowel disease.
5.5 Immunizations
Prior to initiating therapy with TALTZ, consider completion of all age appropriate immunizations according to current immunization guidelines. Avoid use of live vaccines in patients treated with TALTZ. No data are available on the response to live or inactive vaccines.
6 ADVERSE REACTIONS
The following adverse drug reactions are discussed in greater detail in other sections of the label:
Infections [see Warnings and Precautions (5.1)]
Hypersensitivity Reactions [see Contraindications (4) and Warnings and Precautions (5.3)]
Inflammatory Bowel Disease [see Warnings and Precautions (5.4)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying and controlled 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.
Weeks 0 to 12:
Three placebo-controlled trials in subjects with plaque psoriasis were integrated to evaluate the safety of TALTZ compared to placebo for up to 12 weeks. A total of 1167 subjects (mean age 45 years; 66% men; 94% White) with plaque psoriasis received TALTZ (160 mg at Week 0, 80 mg every two weeks [Q2W] for 12 weeks) subcutaneously. In two of the trials, the safety of TALTZ (use up to 12 weeks) was also compared with an active comparator, U.S. approved etanercept [see Clinical Studies (14)].
In the 12-week, placebo-controlled period, adverse events occurred in 58% of the TALTZ Q2W group (2.5 per subject-year of follow-up) compared with 47% of the placebo group (2.1 per subject-year of follow-up). Serious adverse events occurred in 2% of the TALTZ group (0.07 per subject-year of follow-up), and in 2% of the placebo group (0.07 per subject-year of follow-up).
Table 1 summarizes the adverse reactions that occurred at a rate of at least 1% and at a higher rate in the TALTZ group than in the placebo group during the 12-week placebo-controlled period of the pooled clinical trials.
Table 1: Adverse Reactions Occurring in ≥1% of the TALTZ Group and More Frequently than in the Placebo Group in the Plaque Psoriasis Clinical Trials through Week 12 

Adverse Reactions	TALTZ 80 mg Q2W (N=1167) (n%)	Etanerceptb (N=287) (n%)	Placebo (N=791) (n%)
Injection site reactions	196 (17)	32 (11)	26 (3)
Upper respiratory tract infectionsa	163 (14)	23 (8)	101 (13)
Nausea	23 (2)	1 (<1)	5 (1)
Tinea infections	17 (2)	0	1 (<1)

a Upper respiratory tract infections cluster includes nasopharyngitis and rhinovirus infection.
b U.S. approved etanercept.
Adverse reactions that occurred at rates less than 1% in the TALTZ group and more frequently than in the placebo group during the 12-week induction period included rhinitis, oral candidiasis, urticaria, influenza, conjunctivitis, inflammatory bowel disease, and angioedema.
Weeks 13 to 60:
A total of 332 subjects received the recommended maintenance regimen of TALTZ 80 mg dosed every 4 weeks.
During the maintenance period (Weeks 13 to 60), adverse events occurred in 80% of subjects treated with TALTZ (1.0 per subject-year of follow-up) compared to 58% of subjects treated with placebo (1.1 per subject-year of follow-up). Serious adverse events were reported in 4% of subjects treated with TALTZ (0.05 per subject-year of follow-up) and none in the subjects treated with placebo.
Weeks 0 to 60:
Over the entire treatment period (Weeks 0 to 60), adverse events were reported in 67% of subjects treated with TALTZ (1.4 per subject-year of follow-up) compared to 48% of subjects treated with placebo (2.0 per subject-year of follow-up). Serious adverse events were reported in 3% of subjects treated with TALTZ (0.06 per subject-year of follow-up), and in 2% of subjects treated with placebo (0.06 per subject-year of follow-up).
Specific Adverse Drug Reactions:
Injection Site Reactions
The most frequent injection site reactions were erythema and pain. Most injection site reactions were mild-to-moderate in severity and did not lead to discontinuation of TALTZ.
Infections
In the 12-week, placebo-controlled period of the clinical trials in plaque psoriasis, infections occurred in 27% of subjects treated with TALTZ (1.2 per subject-year of follow-up) compared to 23% of subjects treated with placebo (1.0 per subject-year of follow-up). Serious infections occurred in 0.4% of subjects treated with TALTZ (0.02 per subject-year of follow-up) and in 0.4% of subjects treated with placebo (0.02 per subject-year of follow-up) [see Warnings and Precautions (5.1)].
During the maintenance treatment period (Weeks 13 to 60), infections occurred in 57% of subjects treated with TALTZ (0.70 per subject-year of follow-up) compared to 32% of subjects treated with placebo (0.61 per subject-year of follow-up). Serious infections occurred in 0.9% of subjects treated with TALTZ (0.01 per subject-year of follow-up) and none in the subjects treated with placebo.
Over the entire treatment period (Weeks 0 to 60), infections were reported in 38% of subjects treated with TALTZ (0.83 per subject-year of follow-up) compared to 23% of subjects treated with placebo (1.0 per subject-year of follow-up). Serious infections occurred in 0.7% of subjects treated with TALTZ (0.02 per subject-year of follow-up), and in 0.4% of subject treated with placebo (0.02 per subject-year of follow-up).
Laboratory Assessment of Cytopenia
Neutropenia
Over the entire treatment period (Weeks 0 to 60), neutropenia occurred in 11% of subjects treated with TALTZ (0.24 per subject-year of follow-up) compared to 3% of subjects treated with placebo (0.14 per subject-year of follow-up). In subjects treated with TALTZ, the incidence rate of neutropenia during Weeks 13 to 60 was lower than the incidence rate during Weeks 0 to 12.
In the 12-week, placebo-controlled period, neutropenia ≥ Grade 3 (<1,000 cells/mm3) occurred in 0.2% of the TALTZ group (0.007 per subject-year of follow-up) compared to 0.1% of the placebo group (0.006 per subject-year of follow-up). The majority of cases of neutropenia were either Grade 2 (2% for TALTZ 80 mg Q2W versus 0.3% for placebo; ≥1,000 to <1,500 cells/mm3) or Grade 1 (7% for TALTZ 80 mg Q2W versus 3% for placebo; ≥1,500 cells/mm3 to ˂2,000 cells/mm3). Neutropenia in the TALTZ group was not associated with an increased rate of infection compared to the placebo group.
Thrombocytopenia
Ninety eight percent of cases of thrombocytopenia were Grade 1 (3% for TALTZ 80 mg Q2W versus 1% for placebo; ≥75,000 cells/mm3 to <150,000 cells/mm3). Thrombocytopenia in subjects treated with TALTZ was not associated with an increased rate of bleeding compared to subjects treated with placebo.
Active Comparator Trials
In the two clinical trials that included an active comparator, the rate of serious adverse events during weeks zero to twelve was 0.7% for U.S. approved etanercept and 2% for TALTZ 80 mg Q2W, and the rate of discontinuation from adverse events was 0.7% for U.S. approved etanercept and 2% for TALTZ 80 mg Q2W. The incidence of infections was 18% for U.S. approved etanercept and 26% for TALTZ 80 mg Q2W. The rate of serious infections was 0.3% for both TALTZ 80 mg Q2W and U.S. approved etanercept.
6.2 Immunogenicity
As with all therapeutic proteins there is the potential for immunogenicity with TALTZ. By Week 12, approximately 9% of subjects treated with TALTZ every 2 weeks developed antibodies to ixekizumab. Approximately 22% of subjects treated with TALTZ at the recommended dosing regimen developed antibodies to ixekizumab during the 60-week treatment period. The clinical effects of antibodies to ixekizumab are dependent on the antibody titer; higher antibody titers were associated with decreasing drug concentration and clinical response.
Of the subjects who developed antibodies to ixekizumab during the 60-week treatment period, approximately 10%, which equates to 2% of subjects treated with TALTZ at the recommended dosing regimen, had antibodies that were classified as neutralizing. Neutralizing antibodies were associated with reduced drug concentrations and loss of efficacy.
However, the assay to test for neutralizing antibodies has limitations detecting neutralizing antibodies in the presence of ixekizumab; therefore, the incidence of neutralizing antibodies development could be underestimated.
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 incidence of antibodies to TALTZ with the incidences of antibodies to other products may be misleading.
7 DRUG INTERACTIONS
7.1 Live Vaccinations
Avoid use of live vaccines in patients treated with TALTZ [see Warnings and Precautions (5.5)].
7.2 Cytochrome P450 Substrates
The formation of CYP450 enzymes can be altered by increased levels of certain cytokines (e.g., IL-1, IL-6, IL-10, TNFα, IFN) during chronic inflammation. Thus, TALTZ, an antagonist of IL-17A, could normalize the formation of CYP450 enzymes.
Therefore, upon initiation or discontinuation of TALTZ in patients who are receiving concomitant drugs which are CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for effect (e.g., for warfarin) or drug concentration (e.g., for cyclosporine) and consider dosage modification of the CYP450 substrate.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
There are no available data on TALTZ use in pregnant women to inform any drug associated risks. Human IgG is known to cross the placental barrier; therefore, TALTZ may be transmitted from the mother to the developing fetus. An embryofetal development study conducted in pregnant monkeys at doses up to 19 times the maximum recommended human dose (MRHD) revealed no evidence of harm to the developing fetus. When dosing was continued until parturition, neonatal deaths were observed at 1.9 times the MRHD [see Data]. The clinical significance of these nonclinical findings is unknown.
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.
Data
Animal Data
An embryofetal development study was conducted in cynomolgus monkeys administered ixekizumab. No malformations or embryofetal toxicity were observed in fetuses from pregnant monkeys administered ixekizumab weekly by subcutaneous injection during organogenesis to near parturition at doses up to 19 times the MRHD (on a mg/kg basis of 50 mg/kg/week). Ixekizumab crossed the placenta in monkeys.
In a pre- and post-natal development toxicity study, pregnant cynomolgus monkeys were administered weekly subcutaneous doses of ixekizumab up to 19 times the MRHD from the beginning of organogenesis to parturition. Neonatal deaths occurred in the offspring of two monkeys administered ixekizumab at 1.9 times the MRHD (on a mg/kg basis of 5 mg/kg/week) and two monkeys administered ixekizumab at 19 times the MRHD (on a mg/kg basis of 50 mg/kg/week). These neonatal deaths were attributed to early delivery, trauma, or congenital defect. The clinical significance of these findings is unknown. No ixekizumab-related effects on functional or immunological development were observed in the infants from birth through 6 months of age.
8.2 Lactation
Risk Summary
There are no data on the presence of ixekizumab in human milk, the effects on the breastfed infant, or the effects on milk production. Ixekizumab was detected in the milk of lactating cynomolgus monkeys. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for TALTZ and any potential adverse effects on the breastfed infant from TALTZ or from the underlying maternal condition.
8.4 Pediatric Use
The safety and effectiveness of TALTZ in pediatric patients (<18 years of age) have not been evaluated.
8.5 Geriatric Use
Of the 4204 psoriasis subjects exposed to TALTZ, a total of 301 were 65 years or older, and 36 subjects were 75 years or older. Although no differences in safety or efficacy were observed between older and younger subjects, the number of subjects aged 65 and over is not sufficient to determine whether they respond differently from younger subjects [see Clinical Pharmacology (12.3)]. 
10 OVERDOSAGE
In the event of overdosage, monitor the patient for any signs or symptoms of adverse reactions and institute appropriate symptomatic treatment immediately. 
11 DESCRIPTION
Ixekizumab is a humanized immunoglobulin G subclass 4 (IgG4) monoclonal antibody (mAb) with neutralizing activity against IL-17A. Ixekizumab is produced by recombinant DNA technology in a recombinant mammalian cell line and purified using standard technology for bioprocessing. Ixekizumab is comprised of two identical light chain polypeptides of 219 amino acids each and two identical heavy chain polypeptides of 445 amino acids each, and has a molecular weight of 146,158 Daltons for the protein backbone of the molecule.
TALTZ injection is a sterile, preservative free, clear and colorless to slightly yellow solution, for subcutaneous use available as 80 mg of ixekizumab in a 1 mL single-dose prefilled autoinjector or a single-dose prefilled syringe. The prefilled autoinjector and prefilled syringe each contain a 1 mL glass syringe with a fixed 27 gauge ½ inch needle. The TALTZ 80 mg prefilled autoinjector and prefilled syringe are manufactured to deliver 80 mg of ixekizumab.
Each mL is composed of ixekizumab (80 mg); Citric Acid Anhydrous, USP (0.51 mg); Polysorbate 80, USP (0.3 mg); Sodium Chloride, USP (11.69 mg); Sodium Citrate Dihydrate, USP (5.11 mg); and Water for Injection, USP. The TALTZ solution has a pH of 5.3 – 6.1.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Ixekizumab is a humanized IgG4 monoclonal antibody that selectively binds with the interleukin 17A (IL-17A) cytokine and inhibits its interaction with the IL-17 receptor. IL-17A is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Ixekizumab inhibits the release of proinflammatory cytokines and chemokines.
12.2 Pharmacodynamics
No formal pharmacodynamic studies have been conducted with TALTZ.
12.3 Pharmacokinetics
Absorption
Following a single subcutaneous dose of 160 mg in subjects with plaque psoriasis, ixekizumab reached peak mean (±SD) serum concentrations (Cmax) of 16.2 ±6.6 mcg/mL by approximately 4 days post dose.
Steady-state concentrations were achieved by Week 8 following the 160 mg starting dose and 80 mg every 2 weeks dosing regimen; the mean ±SD steady-state trough concentration was 9.3 ±5.3 mcg/mL. Steady-state concentrations were achieved approximately 10 weeks after switching from the 80 mg every 2 weeks dosing regimen to the 80 mg every 4 weeks dosing regimen at Week 12. The mean ±SD steady-state trough concentration was 3.5 ±2.5 mcg/mL.
In studies of subjects with plaque psoriasis, ixekizumab bioavailability ranged from 60% to 81% following subcutaneous injection. Administration of ixekizumab via injection in the thigh achieved a higher bioavailability relative to that achieved using other injection sites including the arm and abdomen.
Distribution
The mean (geometric CV%) volume of distribution at steady-state was 7.11 L (29%) in subjects with plaque psoriasis.
Elimination
The metabolic pathway of ixekizumab has not been characterized. As a humanized IgG4 monoclonal antibody ixekizumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.
The mean systemic clearance was 0.39 L/day (37%) and the mean (geometric CV%) half-life was 13 days (40%) in subjects with plaque psoriasis.
Weight
Ixekizumab clearance and volume of distribution increase as body weight increases.
Dose Linearity
Ixekizumab exhibited dose-proportional pharmacokinetics in subjects with plaque psoriasis over a dose range from 5 mg (not the recommended dose) to 160 mg following subcutaneous administration.
Specific Populations
Age: Geriatric Population
Population pharmacokinetic analysis indicated that age did not significantly influence the clearance of ixekizumab in adult subjects with plaque psoriasis. Subjects who are 65 years or older had a similar ixekizumab clearance as compared to subjects less than 65 years old.
Renal or Hepatic Impairment
No formal trial of the effect of hepatic or renal impairment on the pharmacokinetics of ixekizumab was conducted.
Drug Interaction Studies
Drug interaction studies have not been conducted with TALTZ.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Animal studies have not been conducted to evaluate the carcinogenic or mutagenic potential of TALTZ. Moreover published literature is mixed on potential effects on malignancy risk due to the inhibition of IL-17A activity, the pharmacological action of TALTZ. Some published literature suggests that IL-17A directly promotes cancer cell invasion, suggesting a potential beneficial effect by TALTZ, whereas other reports indicate IL-17A promotes T-cell mediated tumor rejection, suggesting a potential adverse effect by TALTZ. However, neutralization of IL-17A with TALTZ has not been studied in these models. Depletion of IL-17A with a neutralizing antibody inhibited tumor development in mice, suggesting a potential beneficial effect by TALTZ. The relevance of experimental findings in mouse models for malignancy risk in humans is unknown.
No effects on fertility parameters such as reproductive organs, menstrual cycle length, or sperm analysis were observed in sexually mature cynomolgus monkeys that were administered ixekizumab for 13 weeks at a subcutaneous dose of 50 mg/kg/week (19 times the MRHD on a mg/kg basis). The monkeys were not mated to evaluate fertility.
14 CLINICAL STUDIES
Three multicenter, randomized, double-blind, placebo-controlled trials (Trials 1, 2, and 3) enrolled a total of 3866 subjects 18 years of age and older with plaque psoriasis who had a minimum body surface area involvement of 10%, a static Physician Global Assessment (sPGA) score of ≥3 in the overall assessment (plaque thickness/induration, erythema, and scaling) of psoriasis on a severity scale of 0 to 5, a Psoriasis Area and Severity Index (PASI) score ≥12, and who were candidates for phototherapy or systemic therapy.
In all three trials, subjects were randomized to either placebo or TALTZ (80 mg every two weeks [Q2W]) for 12 weeks, following a 160 mg starting dose. In the two active comparator trials (Trials 2 and 3), subjects were also randomized to receive U.S. approved etanercept 50 mg twice weekly for 12 weeks.
All three trials assessed the changes from baseline to Week 12 in the two co-primary endpoints: 1) PASI 75, the proportion of subjects who achieved at least a 75% reduction in the PASI composite score that takes into consideration both the percentage of body surface area affected and the nature and severity of psoriatic changes (induration, erythema and scaling) within the affected regions, and 2) sPGA of “0” (clear) or “1” (minimal), the proportion of subjects with an sPGA 0 or 1 and at least a 2-point improvement.
Other evaluated outcomes included the proportion of subjects with an sPGA score of 0 (clear), a reduction of at least 90% in PASI (PASI 90), a reduction of 100% in PASI (PASI 100), and an improvement of itch severity as measured by a reduction of at least 4 points on an 11-point itch Numeric Rating Scale.
Subjects in all treatment groups had a median baseline PASI score ranging from approximately 17 to 18. Baseline sPGA score was severe or very severe in 51% of subjects in Trial 1, 50% in Trial 2, and 48% in Trial 3.
Of all subjects, 44% had received prior phototherapy, 49% had received prior conventional systemic therapy, and 26% had received prior biologic therapy for the treatment of psoriasis. Of the subjects who had received prior biologic therapy, 15% had received at least one anti-TNF alpha agent, and 9% had received an anti-IL 12/IL23. A total of 23% of study subjects had a history of psoriatic arthritis.
Clinical Response at Week 12
The results of Trials 1, 2, and 3 are presented in Table 2.
Table 2: Efficacy Results at Week 12 in Adults with Plaque Psoriasis in Trials 1, 2, and 3; NRIa 

Trial 1		Trial 2		Trial 3
TALTZ 80 mgc Q2W (N=433) n (%)	Placebo (N=431) n (%)	TALTZ 80 mgc Q2W (N=351) n (%)	Placebo (N=168) n (%)	TALTZ 80 mgc Q2W (N=385) n (%)	Placebo (N=193) n (%)
sPGA of “0” (clear) or “1” (minimal)b	354 (82)	14 (3)	292 (83)	4 (2)	310 (81)	13 (7)
sPGA of “0” (clear)	160 (37)	0	147 (42)	1 (1)	155 (40)	0
PASI 75b	386 (89)	17 (4)	315 (90)	4 (2)	336 (87)	14 (7)
PASI 90	307 (71)	2 (1)	248 (71)	1 (1)	262 (68)	6 (3)
PASI 100	153 (35)	0	142 (40)	1 (1)	145 (38)	0

a Abbreviations: N = number of patients in the intent-to-treat population; NRI = Non-Responder Imputation.
b Co-primary endpoints.
c At Week 0, subjects received 160 mg of TALTZ.
Examination of age, gender, race, body weight, and previous treatment with a biologic did not identify differences in response to TALTZ among these subgroups at Week 12.
Subjects treated with TALTZ 80 mg Q2W experienced improvement in itch severity when compared to placebo at Week 12.
An integrated analysis of the U.S. sites in the two active comparator studies using U.S. approved etanercept, TALTZ demonstrated superiority to U.S. approved etanercept (50 mg twice weekly) on sPGA and PASI scores during the 12 week treatment period. The respective response rates for TALTZ 80 mg Q2W and U.S. approved etanercept 50 mg twice weekly were: sPGA of 0 or 1 (73% and 27%); PASI 75 (87% and 41%); sPGA of 0 (34% and 5%); PASI 90 (64% and 18%), and PASI 100 (34% and 4%).
Maintenance and Durability of Response
To evaluate the maintenance and durability of response, subjects originally randomized to TALTZ and who were responders at Week 12 (i.e., sPGA of 0 or 1) in Trial 1 and Trial 2 were re-randomized to an additional 48 weeks of either a maintenance dose of TALTZ 80 mg Q4W (every four weeks) or placebo. Non-responders (sPGA >1) at Week 12 and subjects who relapsed (sPGA ≥3) during the maintenance period were placed on TALTZ 80 mg Q4W.
For responders at Week 12, the percentage of subjects who maintained this response (sPGA 0 or 1) at Week 60 (48 weeks following re-randomization) in the integrated trials (Trial 1 and Trial 2) was higher for subjects treated with TALTZ 80 mg Q4W (75%) compared to those treated with placebo (7%).
For responders at Week 12 who were re-randomized to treatment withdrawal (i.e., placebo), the median time to relapse (sPGA ≥3) was 164 days in the integrated trials. Among these subjects, 66% regained a response of at least 0 or 1 on the sPGA within 12 weeks of restarting treatment with TALTZ 80 mg Q4W. 
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
TALTZ injection is a sterile, preservative free, clear and colorless to slightly yellow solution available in a single-dose prefilled autoinjector or a single-dose prefilled syringe to deliver 80 mg ixekizumab.
TALTZ is supplied as:

Pack Size	NDC Code
Autoinjector
80 mg single-dose	Carton of 1	0002-1445-11
80 mg single-dose	Carton of 2	0002-1445-27
80 mg single-dose	Carton of 3	0002-1445-09
Prefilled syringe
80 mg single-dose	Carton of 1	0002-7724-11
80 mg single-dose	Carton of 2	0002-7724-27
80 mg single-dose	Carton of 3	0002-7724-09

16.2 Storage and Handling
TALTZ is sterile and preservative-free. Discard any unused portion.
TALTZ must be protected from light until use.
Store refrigerated at 2°C to 8°C (36°F to 46°F).
Do not freeze. Do not use TALTZ if it has been frozen.
Do not shake.
Discard the TALTZ single-dose autoinjector or syringe after use in a puncture-resistant container.
Not made with natural rubber latex.
17 PATIENT COUNSELING INFORMATION
Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions for Use) before the patient starts using TALTZ, and each time the prescription is renewed, as there may be new information they need to know.
Instructions on Self-Administration: Provide guidance to patients and caregivers on proper subcutaneous injection technique, including aseptic technique, and how to use the autoinjector or prefilled syringe correctly [see Instructions for Use].
Infection: Inform patients that TALTZ may lower the ability of their immune system to fight infections. Instruct patients of the importance of communicating any history of infections to the healthcare provider, and contacting their healthcare provider if they develop any symptoms of infection [see Warnings and Precautions (5.1)].
Allergic Reactions: Advise patients to seek immediate medical attention if they experience any symptoms of serious hypersensitivity reactions [see Warnings and Precautions (5.3)].
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ac96658a-d7dc-4c7c-8928-2adcdf4318b2

美国FDA批准礼来Taltz(Ixekizumab)治疗中重度斑块状银屑病
——几项关键临床研究结果显示：大部分患者接受Taltz(Ixekizumab)治疗后的12周已取得皮损显著消退（PASI 75，sPGA 0或1），且众多患者取得皮损实质性消退 (PASI 90) 或皮损完全消退 (PASI 100，sPGA 0)
2016年3月25日，礼来制药于近日宣布美国食品和药品管理监督局 (FDA) 批准Taltz® (Ixekizumab) 80mg/mL注射剂用于那些适用于全身性治疗或光疗治疗的中重度斑块状银屑病成年患者。Taltz不应当用于既往对 Ixekizumab 过敏或对其中任何赋形剂过敏的患者（如速发过敏反应）。Taltz作用于特异性靶点IL-17A--一种可引发银屑病基础性炎症的蛋白。
银屑病是一种影响皮肤的慢性、免疫性疾病。在美国，银屑病累及约750万人口，其中约20%为中重度斑块状银屑病患者。斑块状银屑病是最常见的银屑病形式，表现为身体表面抬高的红色斑块，上面堆积覆盖银白色的皮肤死细胞，患者常有疼痛或瘙痒。银屑病的确切病因不明，但已了解到遗传和环境因素对于该疾病的发生起到一定作用。
“很多银屑病患者仍在寻求如何才能成功控制这种疾病的治疗方法。”礼来美国总裁Alex Azar表示：“随着Taltz的获批，我们非常自豪能为患者提供一种新的治疗方案，帮助患者取得皮损实质性消退甚至是皮损完全消退。”
FDA 对于Taltz的批准是基于迄今为止获准进行的最大规模 III期临床试验结果，该试验共入组21个国家逾3800例中重度斑块状银屑病患者。该入组患者数量包括临床试验中开始接受Taltz或安慰剂、或活性对比药物（美国批准的依那西普）的患者。该临床试验包括了三项双盲、多中心、3期研究-UNCOVER-1、UNCOVER-2和UNCOVER-3-这些研究证实了Taltz用于中重度斑块状银屑病患者的安全性和有效性。全部三项研究均评价了12周后Taltz（在160-mg起始剂量后，每2周或4周80 mg）相较于安慰剂的安全性和有效性。此外，UNCOVER-2和UNCOVER-3研究还包括了一个对比药物组，该组患者接受在美批准的依那西普（50mg，每周两次）治疗，为期12周。UNCOVER-1和UNCOVER-2还评价了60周维持期内Taltz的应答率。
这些研究在治疗12周时复合主要有效性终点是银屑病面积严重性指数 (PASI) 评分取得75%改善，以及静态医生整体评分(sPGA)为0或1（自基线至少改善2分）。PASI通过评估受损皮肤的平均发红程度、厚度和鳞屑（分别根据0到4分量表分级），测量以受累皮肤所占体表面积加权的银屑病程度和严重性，而sPGA是医生在特定时间点上对银屑病患者病损严重性的评估，而且是FDA评估有效性的一个必需的测量指标。
在全部三项研究中，87%-90%的患者使用Taltz治疗12周后出现了银屑病斑块的显著改善 (PASI75)。此外，Taltz治疗的患者中有81%-83%取得了sPGA 0或1。大部分接受Taltz治疗的患者 (68%-71%) 取得了皮损实质性消退 (PASI 90)，并有35%-42%的患者出现了银屑病完全消退(PASI 100, sPGA 0)。接受安慰剂的患者仅有7%或更少取得PASI 75、仅有7%或更少取得sPGA 0或1、仅有3%或更少取得PASI 90以及仅有1%或更少取得PASI 100和sPGA 0。
在研究 UNCOVER-1和UNCOVER-2中，12周时对 Taltz应答的患者（sPGA 0或1，至少自基线至少改善2分）中有75%直至60周终点始终维持治疗应答。
Taltz的皮损消退（包括12周时的 PASI 75和sPGA 0或1）均优于在美批准的依那西普，且差别有统计学显著性。在对两项活性药物对比研究（UNCOVER-2 和 UNCOVER-3）的美国研究中心结果进行的整合分析中，Taltz与美批准的依那西普治疗应答率比较，PASI 75分别为87%和27%，而sPGA 0或1分别为73%和27%。
有关Taltz安全性的数据源于4204例自愿参加对照和非对照临床试验的中重度斑块状银屑病患者构成的数据库。
Taltz可能增加感染风险。相较于安慰剂组患者，接受Taltz治疗的患者有较高的感染率 (27% vs 23%)。与安慰剂组相比，上呼吸道感染、口腔念珠菌病、结膜炎和癣感染更常见于接受Taltz治疗的患者。曾出现严重感染病例。如果出现有临床重要性的慢性或急性感染的症状或体征，应指导患者就医诊治。如果出现严重感染，应停用Taltz直至感染消失。
Taltz治疗的其他警告和注意事项包括治疗前对结核、超敏反应、炎性肠病和免疫状况进行评估。
在 UNCOVER-2和UNCOVER-3中，在美批准的依那西普在研究的诱导期（0-12周）内的严重不良事件发生率为0.7%，Taltz为2%。依那西普因不良事件停药的发生率为0.7%，Taltz 为2%。依那西普的感染发生率为18%，Taltz 为26%。依那西普和Taltz的严重感染发生率均为0.3%。
“皮肤斑块皮损完全消退是银屑病治疗的一个重要目标。”主要研究作者、圣路易斯大学医学院医学临床皮肤学教授Craig Leonardi博士表示：“Taltz的获批，使医生有了一个新的选择来帮助患者取得皮损实质性消退或完全消退；事实上，10例患者中有4例可取得皮损完全消退。基于这些研究结果，医生可以让患者治疗安心，因为Taltz可提供持续稳定的治疗效果