Summary Basis of Decision for Taltz

Clinical Pharmacology

The medicinal ingredient of Taltz, ixekizumab, is a humanized immunoglobulin G subclass 4 (IgG4) monoclonal antibody that has a binding affinity of <3 pM to interleukin 17A (IL-17A), a naturally occurring proinflammatory cytokine. Elevated levels of IL 17A have been implicated in the pathogenesis of a variety of autoimmune diseases. Ixekizumab inhibits the release of proinflammatory cytokines and chemokines.

The clinical pharmacological data support the use of Taltz for the recommended indication.

Pooled pharmacokinetics data (with 6,059 ixekizumab serum concentrations from 1,399 psoriasis patients) from two early phase studies (studies RHAG and RHAJ) and one Phase III study (UNCOVER-1 [RHAZ]) were analyzed by the sponsor in a population pharmacokinetic modelling for exposure-response relationship exploration and pharmacokinetic characteristics following subcutaneous dose regimens. An additional exposure-response relationship analysis for efficacy and safety as well as an assessment of immunogenicity impact on pharmacokinetics was also performed by the sponsor using sparse pharmacokinetic samplings and efficacy and safety data from the three pivotal trials, UNCOVER-1 (RHAZ), UNCOVER-2 (RHBA), UNCOVER-3 (RHBC) (described in the Clinical Efficacy section).

Population pharmacokinetics analysis revealed that body weight and the status of immunogenicity have significant impact on the exposure of ixekizumab. There was an overall trend of decreasing exposure with increasing body weight. Anti-drug antibodies at higher titers ( = 160) and neutralizing antibodies were associated with decreasing drug concentration and clinical response. However, a definite relationship between immunogenicity and treatment-emergent adverse events, including hypersensitivity reactions, has not been established based on the currently available data.

Exposure-response simulation analysis based on efficacy and safety data across the three pivotal Phase III trials supported the authorised dose regimen. No apparent exposure-response relationships were observed for most treatment-emergent adverse events between the two ixekizumab dose levels and placebo across the three pivotal Phase III trials, except that the incidence of neutropenia Grade 2 (≥1,000 to <1,500 cells/mm³) showed a relationship with exposure but only during the induction treatment and did not require discontinuation of ixekizumab.

For further details, please refer to the Taltz Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Taltz in adult patients with moderate-to-severe plaque psoriasis has been evaluated in three pivotal multicentre, randomized, double-blind, placebo-controlled Phase III trials, UNCOVER-1 (RHAZ), UNCOVER-2 (RHBA) and UNCOVER-3 (RHBC). The trials enrolled a total of 3,866 patients 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 and Psoriasis Area and Severity Index (PASI) score ≥12, and who were candidates for phototherapy or systemic therapy. Patients with guttate, erythrodermic, or pustular psoriasis were excluded from the clinical trials.

Each pivotal study evaluated short-term efficacy (up to 12 weeks) of Taltz compared to placebo. In addition to placebo, the UNCOVER-2 and UNCOVER-3 trials included etanercept as an active comparator treatment.

In all three trials, subjects were randomized to either placebo or Taltz (80 mg every two weeks [Q2W] or 80 mg every four weeks [Q4W]) for 12 weeks, following a 160 mg starting dose. In the two active comparator trials (UNCOVER-2 and UNCOVER-3), subjects were also randomized to receive etanercept 50 mg twice weekly for 12 weeks. The co-primary endpoints were the proportion of patients who achieved at least a 75% reduction in PASI score (PASI 75) from baseline to Week 12 and the proportion of patients with an sPGA of 0 (clear) or 1 (minimal) with at least a 2-point improvement from baseline. In each of the pivotal trials, the treatment with Taltz demonstrated efficacy by achieving the co-primary endpoints of PASI 75 and sPGA of 0 or 1, as well as the secondary endpoint of PASI 90 (a reduction of at least 90% in PASI).

Specifically, among patients who received Taltz 80 mg Q2W during the induction dosing period of 12 weeks (the authorized induction regimen), the proportions of sPGA of 0 or 1 responders were:

• 81.8% versus (vs.) 3.2% in placebo-treated patients (difference 78.5%; 97.5% confidence interval [CI] [73.9%, 83.1%]) in the UNCOVER-1 trial;
• 83.2% vs. 2.4% in placebo-treated patients (difference 80.8%; 97.5% CI [75.6%, 86.0%]) and 36.0% in etanercept-treated patients (difference 47.2%; 97.5% CI [39.9%, 54.4%]) in the UNCOVER-2 trial; and
• 80.5% vs. 6.7% in placebo-treated patients (difference 73.8%; 97.5% CI [67.7%, 79.9%]) and 41.6% in etanercept-treated patients (difference 38.9%; 97.5% CI [31.7%, 46.1%]) in the UNCOVER-3 trial.

Similarly, the other co-primary endpoint, PASI 75 was achieved by the following proportions of Taltz-treated patients:

• 89.1% compared to 3.9% in placebo-treated patients (difference 85.2%; 97.5% CI [81.2%, 89.2%]) in the UNCOVER-1 trial;
• 89.7% compared to 2.4% in placebo-treated patients (difference 87.4%; 97.5% CI [82.9%, 91.9%]) and 41.6% in etanercept-treated patients (difference 48.1%; 97.5% CI [41.2%, 55%]) in the UNCOVER-2 trial; and
• 87.3 % compared to 7.3% in placebo-treated patients (difference 80.0%; 97.5% CI [74.4%, 85.7%]) and 53.4% in etanercept-treated patients (difference 33.9%; 97.5% CI [27.0%, 40.7%]) in the UNCOVER-3 trial.

In each of the pivotal trials, Taltz-treated patients also met the key secondary endpoint of PASI 90. The proportions of PASI 90 responders were:

• 70.4% compared to 0.5% in placebo-treated patients (difference 70.4%; 97.5% CI [65.5%, 75.4%]) in the UNCOVER-1 trial;
• 70.7% compared to 0.6% in placebo-treated patients (difference 70.7%; 97.5% CI [64.4%, 75.7%]) and 18.7% in etanercept-treated patients (difference 51.9%; 97.5% CI [44.8%, 59.1%]) in the UNCOVER-2 trial; and
• 68.1% compared to 3.1% in placebo-treated patients (difference 64.9%; 97.5% CI [58.9%, 71.0%]) and 25.7% in etanercept-treated patients (difference 42.4%; 97.5% CI [35.1%, 49.1%]), in the UNCOVER-3 trial.

Two of the pivotal trials, UNCOVER-1 and UNCOVER-2, also evaluated the maintenance of Taltz efficacy for an additional 48 weeks after induction treatment, up to Week 60, using a randomized withdrawal design for Taltz-treated patients who met response criteria (defined as sPGA [0,1] at Week 12). In the maintenance dosing period, Taltz responders in the induction dosing period were re-randomised in a 1:1:1 ratio to receive either 80 mg Taltz Q4W, 80 mg Taltz every 12 weeks (Q12W), or placebo. In the UNCOVER-1 trial, the proportion of patients who maintained an sPGA (0,1) at week 60 was 74.8% for Taltz patients treated with the recommended induction and maintenance dose regimen compared to 7.7% in placebo-treated patients (difference 67.1%; 97.5% CI [55.4%, 78.8%]). However, the results of the maintenance phase of the UNCOVER-2 trial were not reported in the approved Taltz Product Monograph given that they were derived from an interim data analysis following a database lock that occurred after the last patient enrolled completed the Week 36 visit of the maintenance dosing period. Consequently, not all patients had completed the blinded maintenance dosing period, and the interim data analysis was based on a subset of patients who had either completed Week 60, discontinued treatment prior to Week 60, or relapsed prior to Week 60 at the time of the 36-week interim database lock. The sponsor has agreed to submit the final study report with the maintenance phase results of the UNCOVER-2 trial (see What follow-up measures will the company take? section).

Based on the efficacy data from the pivotal trials, the recommended dosing regimen for Taltz is 160 mg by subcutaneous injection (two 80 mg injections) at Week 0, followed by 80 mg (one injection) at Weeks 2, 4, 6, 8, 10, and 12, then 80 mg (one injection) every 4 weeks.

Overall, the efficacy data provided in this submission support the approval of Taltz for the treatment of adult patients with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

For more information, refer to the Taltz Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

Three pivotal randomized, double-blind, placebo-controlled Phase III trials, UNCOVER-1, UNCOVER-2, and UNCOVER-3 in plaque psoriasis patients (described in the Clinical Efficacy section) were integrated to evaluate the safety of Taltz in comparison to placebo for up to 12 weeks following the treatment initiation. In two of the trials (UNCOVER-2 and UNCOVER-3), the safety of Taltz was also compared with an active comparator, etanercept, up to 12 weeks of treatment duration. In total, 3,858 patients were evaluated (1,167 patients in Taltz 80 mg every two weeks [Q2W] group, 1,161 patients in Taltz 80 mg every four weeks [Q4W] group, 739 patients in etanercept 50 mg twice weekly group, and 791 patients in the placebo group).

Across blinded and open-label clinical trials conducted a total of 4,204 plaque psoriasis patients were treated with Taltz. Of these, 2,190 psoriasis patients were exposed to Taltz for at least one year.

Main safety observations that are reflected in the Taltz Product Monograph include serious hypersensitivity, infections, inflammatory bowel diseases, neutropenia, and immunogenicity.

Taltz-treated patients in clinical trials have been reported to experience serious hypersensitivity reactions, including angioedema and urticaria. Therefore, Taltz is contraindicated in patients with known serious hypersensitivity to ixekizumab or to any of the excipients.

In the integrated data obtained from the three pivotal trials, the most commonly reported adverse reactions (>1% of patients) were injection site reactions, infections, nausea, and oropharyngeal pain.

The most frequent injection site reactions observed were erythema and pain. Injection site reactions were predominantly mild-to-moderate in severity and did not lead to discontinuation of Taltz.

Among infections, the most frequently reported were upper respiratory tract infections, including nasopharyngitis. Most were mild or moderate in severity and did not lead to early discontinuation. During the maintenance treatment period, the exposure-adjusted incidence rate of infections was 0.71 per patient year (56.0%) in patients treated with Taltz with the recommended dosing regimen (Q4W), compared with 0.78 per patient year (35.6%) in patients treated with placebo. The exposure-adjusted incidence rate of serious infections was 0.02 per patient year (1.4%) in patients treated with Taltz (Q4W) and 0.02 per patient year (0.7%) in patients treated with placebo.

Over the entire treatment period (across all psoriasis studies, a total of 4,204 plaque psoriasis patients were treated with Taltz for up to 60 weeks for the majority of patients), the exposure-adjusted incidence rate of infections was 0.47 per patient year (52.8%) in patients treated with Taltz. The exposure-adjusted incidence rate of serious infections was 0.02 per patient year (1.6%) in patients treated with Taltz. The increased risk of infection has been appropriately reflected in the Warnings and Precautions of the Taltz Product Monograph. Specifically, the section points out that Taltz should not be given to patients with active tuberculosis (TB), and that prior to initiating treatment with Taltz, patients should be evaluated for TB infection.

In the placebo-controlled and active-controlled period of the clinical trials (UNCOVER-2 and UNCOVER-3), neutropenia ≥Grade 3 (<1,000 cells/mm³) was observed in 0.3% of patients receiving Taltz Q2W, compared to 0.5% of patients treated with etanercept and 0.3% of patients treated with placebo. The remaining cases of neutropenia were low grade, either Grade 2 (2.6% for Taltz Q2W vs. 3.3% for etanercept; 0.3% for placebo; ≥1,000 to <1,500 cells/mm³) or Grade 1 (7.0% for Taltz Q2W vs. 9.9% for etanercept; 3.4% for placebo; ≥1,500 cells/mm³ up to normal). In general, neutropenia was transient and did not require discontinuation of Taltz and was not associated with an increased risk of infection.

Taltz also demonstrated a potential for immunogenicity, which is generally associated with all therapeutic proteins. Approximately 9% of patients treated with Taltz at the recommended dosing regimen developed anti-drug antibodies by Week 12. During the 60-week treatment period, anti-drug antibodies were detected in approximately 22% of Taltz-treated patients at the recommended dosing regimen. The clinical effects of antibodies to ixekizumab were dependent on the antibody titer. Higher antibody titers were associated with decreasing drug concentration and clinical response. Of the patients who developed anti-drug antibodies to ixekizumab during the 60-week treatment period, approximately 9% had antibodies that were classified as neutralizing; this is about 2% of subjects treated with Taltz at the recommended dosing regimen. Neutralizing antibodies were associated with low drug concentrations and reduced clinical response. An association between immunogenicity and treatment-emergent adverse events has not been established.

New cases or exacerbations of Crohn’s disease and ulcerative colitis were observed in Taltz-treated patients during clinical trials. This safety concern has been included in the Warnings and Precautions section of the Taltz Product Monograph.

Overall, the reported safety profile of Taltz is consistent with that of other biological products authorized for treatment of psoriasis. Appropriate warnings and precautions are in place in the approved Taltz Product Monograph to address the identified safety concerns. Additionally, in order to ensure that the benefit continues to outweigh any risks after authorization, Health Canada has required several post-approval activities to be carried out by the sponsor (described in What follow-up measures will the company take? section).

For more information, refer to the Taltz Product Monograph, approved by Health Canada and available through the Drug Product Database.