Summary Basis of Decision for Ilumya

 

Clinical Pharmacology

The pharmacokinetics of tildrakizumab, the medicinal ingredient in Ilumya, was characterized in three Phase I pharmacokinetic studies in healthy subjects and two Phase I studies in psoriasis patients. In addition, sparse pharmacokinetic data were collected from the two pivotal Phase III studies (described in the Clinical Efficacy section) and one Phase II study in psoriasis patients. Data collected from six of these studies constituted the database for a population pharmacokinetic modelling analysis of subcutaneously administered tildrakizumab.

The formulation used in the Phase I/II clinical trials was a lyophilized powder for solution for injection in a vial (herein referred to as lyophilized formulation), whereas a solution for injection housed in a prefilled syringe (herein referred to as PFS formulation) was used in the Phase III clinical trials. No dedicated clinical trials were conducted to compare the pharmacokinetics of tildrakizumab following administration of the lyophilized formulation and following administration of the commercial PFS formulation. The population pharmacokinetic model showed that the lyophilized formulation had 5% lower bioavailability than the PFS formulation. This difference is not considered clinically relevant, since the simulated difference in exposure of tildrakizumab, using formulation as a covariate, fell within the clinical comparability bounds for exposure of tildrakizumab, where the Psoriasis Area and Severity Index (PASI) response and safety findings are not expected to be different. Thus, the pharmacokinetic properties of tildrakizumab administered as a lyophilized formulation or as a PFS formulation are expected to be similar.

Following single-dose subcutaneous administration, the pharmacokinetics of tildrakizumab was dose proportional over a dose range of 50 mg to 400 mg.

Based on population pharmacokinetic modelling results, the pharmacokinetics of tildrakizumab in psoriatic patients was characterized by a mean (percent coefficient of variation [%CV]) clearance of 0.32 L/day (38%), volume of distribution of 10.8 L (24%), absorption half-life of 1.5 days (18%), and elimination half-life of 23.4 days (23%).

Following the proposed dose regimen of 100 mg of tildrakizumab administered subcutaneously at week 0, week 4, and every 12 weeks thereafter, steady state was achieved by 16 weeks, with no accumulation observed. At steady state, the mean values (%CV) of the area under the concentration-time curve (AUC) to the end of the dosing period (AUC_0-tau), maximum concentration (C_max), and time to reach maximum concentration (T_max) were 305 μg*day/mL (41%), 8.1 μg/mL (34%), and 6.2 days (46%), respectively. The median average concentration of tildrakizumab from week 1 to week 12 in psoriasis patients treated with the 100 mg dose was 6.4 μg/mL.

No pharmacokinetic studies were conducted in special populations (children, elderly, subjects with renal or hepatic impairment). The population pharmacokinetic analysis identified body weight as an important covariate on drug exposure. Lower average concentration and AUC were observed in subjects with higher body weights (over 90 kg). In clinical trials, in patients with a body weight over 90 kg, the 200 mg dose offered a minimal and inconsistent benefit over the 100 mg dose, and the risk-benefit profile was similar between the two doses. Thus, body weight-based dose adjustment is considered unnecessary.

Among patients treated with the 100 mg dose in the Phase III trials, the incidence of antibodies to tildrakizumab (anti-drug antibodies, ADAs) after up to week 64 of exposure was 7.6% (52 of 686 patients). Twenty-seven of the 52 patients (52%) who developed ADAs were positive for neutralizing antibodies. The pharmacokinetic profiles of tildrakizumab in ADA-positive patients were similar to those in the ADA-negative patients. However, lower mean tildrakizumab concentrations were found in patients with treatment-emergent neutralizing ADAs compared to patients who were negative for neutralizing ADAs.

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

Clinical Efficacy

Data derived from two pivotal Phase III trials (P010 [reSURFACE 1] and P011 [reSURFACE 2]) support the clinical efficacy of Ilumya for the treatment of adult patients with moderate-to-severe plaque psoriasis who are candidates for phototherapy or systemic therapy.

Based on results of a Phase IIb dose-range finding study, the pivotal studies used two doses of Ilumya (100 mg and 200 mg), administered subcutaneously at week 0, week 4, and every 12 weeks thereafter (for up to 64 weeks in the P010 trial and for up to 52 weeks in the P011 trial). Both trials included ongoing long-term (4-year) extension trials, the efficacy results of which were not available for Health Canada’s review.

The pivotal studies included 1,862 plaque psoriasis patients aged 18 years or older. At baseline, the patients had a body surface area involvement of ≥10%, a Physician Global Assessment (PGA) score of ≥3 in the overall assessment (plaque thickness, erythema, and scaling) of psoriasis on a severity scale of 0 to 5, a Psoriasis Area and Severity Index (PASI) score of ≥12, and were candidates for phototherapy or systemic therapy.

Trial P010 (reSURFACE 1) included three treatment arms (Ilumya 100 mg, Ilumya 200 mg, and placebo) for the primary efficacy assessments at week 12. At that point, the placebo-treated patients were rerandomized 1:1 to receive Ilumya100 mg or Ilumya 200 mg until week 28. At week 28, all non-responders (patients who did not achieve at least 50% improvement in PASI score from baseline) discontinued participation in the study, as per study design. Partial responders (patients who achieved improvement of 50% or greater but less than 75% improvement in PASI score from baseline) continued to receive treatment at the same dose (or at the higher, 200 mg dose, for half of the partial responders treated with Ilumya 100 mg). Responders (patients who achieved at least 75% improvement in PASI score from baseline [PASI 75]) were rerandomized to continue the same treatment or to receive placebo. Patients rerandomized to placebo were placed back on active treatment (at the same dose which they were originally receiving) if they experienced a relapse (i.e., a reduction of maximal PASI response by 50%).

Trial P011 (reSURFACE 2) included four treatment arms (Ilumya 100 mg, Ilumya 200 mg, etanercept, and placebo) for the primary efficacy assessments at week 12. After week 12 and until week 28, the placebo-treated patients were rerandomized 1:1 to receive 100 mg or 200 mg of Ilumya, whereas the etanercept-treated patients continued to receive etanercept. As per study design, at week 28, Ilumya non-responders discontinued participation in the study, while partial and full responders received either Ilumya 100 mg or Ilumya 200 mg according to a rerandomization scheme. Etanercept responders discontinued participation in the study, while partial or non-responders at week 28 were switched to Ilumya 200 mg.

In total, there were 616 patients randomized to Ilumya 100 mg, 622 to Ilumya 200 mg, 310 to placebo, and 313 to etanercept 50 mg (administered in trial P011 only). Of the Ilumya-treated patients, 8% to 9% discontinued treatment prior to week 28.

In both trials, the co-primary efficacy endpoints were the proportion of patients with a PASI 75 response at week 12 and the proportion of patients with a PGA score of “clear” or “minimal”, with at least a 2-grade reduction from baseline, at week 12. Key secondary endpoints were the proportion of patients who achieved improvement from baseline in PASI score of at least 90% (PASI 90) and 100% (PASI 100) at week 12.

After implementing non-responder imputation for missing data in the full analysis set, there were 62.5% of patients in the Ilumya100 mg arm, 64.0% in the Ilumya 200 mg arm, 48.2% in the etanercept 50 mg arm, and 5.8% in the placebo arm who achieved a PASI 75 response at week 12. Similarly, at week 12, 56.3%, 59.2%, 47.6%, and 5.8% of patients in the respective treatment arms achieved a PGA score of “clear” or “minimal”, with at least a 2-grade reduction from baseline. The differences in the two co-primary efficacy endpoints for each dose of Ilumya compared to placebo were statistically and clinically significant.

With regard to the key secondary endpoints, at week 12, a PASI 90 response was achieved by 36.7% of patients treated with Ilumya 100 mg, 36.0% of patients treated with Ilumya 200 mg, and 1.9% of placebo-treated patients, whereas a PASI 100 response was achieved by 13.2%, 12.9%, and 0.6% of patients in these groups, respectively. While patient-reported outcomes, measured by the Dermatology Life Quality Index (DLQI) questionnaire, were not incorporated as part of the key secondary endpoint testing strategy, it was noteworthy that, in both trials, 35% to 40% more patients in the Ilumya arms reported a DLQI score of 0 or 1 (minimal or no quality-of-life impairment) than in the placebo arms.

The following longer-term results relate to patients treated with the recommended dose of 100 mg of Ilumya.

In trial P010, 87.5% (98/112) of patients treated with Ilumya 100 mg who were PASI 75 responders at week 28 and who continued to receive the same dose of Ilumya maintained a PASI 75 response at week 64. Among the responders who at week 28 were rerandomized to receive placebo, about half maintained a PASI 75 response at week 64. Of the patients rerandomized to receive placebo who experienced a relapse and restarted the initial treatment of Ilumya 100 mg, 85.7% regained a PASI 75 response by week 64.

In trial P011, 93.6% (191/204) of patients treated with Ilumya 100 mg who were PASI 75 responders at week 28 maintained PASI 75 response at week 52. Among the patients who were partial responders at week 28, 68.4% achieved a PASI 75 response after continued treatment with Ilumya100 mg from week 28 to week 52.

The results of both trials were similar following various sensitivity (subgroup) analyses.

Approximately 7.6% of patients treated with Ilumya 100 mg for up to 64 weeks developed antibodies to tildrakizumab (anti-drug antibodies, ADAs). Among these patients, 52% had antibodies that were classified as neutralizing. Of note, decreased efficacy was detected among Ilumya-treated patients who were positive for ADAs, particularly if they also had neutralizing ADAs. There was a 20% to 30% decrease in the proportion of Ilumya-treated patients achieving a PASI 75 response at week 12 when comparing ADA-positive to ADA-negative patients. However, these findings were based on a small sample size of approximately 5% of patients with treatment-emergent ADAs at that time.

While the P011 pivotal trial included one active comparator (etanercept, a tumour necrosis factor inhibitor), neither pivotal trial assessed Ilumya against other anti-IL-23 drugs, given that at the time of the clinical development of Ilumya, no other anti-IL-23 drugs were commercially available.

In summary, the recommended regimen of 100 mg of Ilumya administered at week 0, week 4, and every 12 weeks thereafter, offers significant benefit in terms of improvement of the common indicators of psoriatic disease severity and status (PASI and PGA scores). Patients who responded to treatment in the clinical trials were very likely to continue to exhibit improvement for up to 64 weeks. Data beyond 64 weeks were not available for assessment.

Indication

The New Drug Submission for Ilumya was filed by the sponsor with the following indication, which Health Canada subsequently approved:

• Ilumya (tildrakizumab injection) is indicated 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 Ilumya Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The safety profile of Ilumya in patients with moderate-to-severe plaque psoriasis is based primarily on pooled data from two pivotal Phase III clinical trials (P010 [reSURFACE 1] and P011 [reSURFACE 2], described in the Clinical Efficacy section).

In total, the pooled safety dataset included 1,861 patients (616 patients treated with Ilumya 100 mg, 622 patients treated with Ilumya 200 mg, 310 patients treated with placebo, and 313 patients treated with etanercept 50 mg). Among the 1,238 patients who were exposed to Ilumya, 642 received Ilumya 100 mg for at least 52 weeks, 587 for at least 78 weeks, and 469 for at least 104 weeks.

Through the 12-week placebo-controlled periods of the pivotal trials, the most frequently reported (in at least 10% of patients) adverse events were upper respiratory tract infections, which occurred in 15.1% of patients in the Ilumya 100 mg group as compared to 12.3% of patients in the placebo group. The overall rate of infections and infestations was similar between the Ilumya 100 mg group and the placebo group: 20.9% versus 21.0%.

No events of anaphylaxis were reported in patients treated with Ilumya for up to 64 weeks in the clinical trials. However, several cases of urticaria occurred during this period. Apart from drug-related hypersensitivity, adverse events of special interest included infections (those classified as serious adverse events or requiring intravenous antibiotics), malignancies (non-melanoma skin cancers and melanoma skin cancers), and major adverse cardiovascular events. Based on the available evidence, exposure to Ilumya over a period of 64 weeks is not associated with an increased incidence of the aforementioned serious adverse events. In addition, no serious adverse events of suicidal ideation and behaviour were reported in the clinical trials.

Treatment with any therapeutic protein is accompanied by the risk of immunogenicity (the development of anti-drug antibodies, which have the potential to neutralize the biological activity of the drug). Approximately 7.6% of patients treated with Ilumya 100 mg for up to 64 weeks developed antibodies to tildrakizumab. Among these patients, 52% had antibodies that were classified as neutralizing.

The safety profile of Ilumya in the select subset of patients with moderate-to-severe plaque psoriasis who entered the open-label, uncontrolled, safety extension studies was consistent to that observed in the placebo-controlled studies.

Appropriate warnings and precautions are in place in the approved Ilumya Product Monograph to address the identified safety concerns.

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