Tildrakizumab for Moderate-to-Severe Plaque Psoriasis

Uyen Ngoc Mui, MD¹; Ravi R. Patel, MD¹; Ramya Vangipuram, MD²; Stephen K. Tyring, MD, PhD^1,2

¹Center for Clinical Studies, Houston, TX, USA
²Department of Dermatology, University of Texas Health Sciences Center, Houston, TX, USA

Conflict of interest:
Stephen Tyring has been an investigator on tildrakizumab studies for Merck & Co. (Sun Pharmaceutical Industries is the current maker of tildrakizumab). Uyen Ngoc Mui, Ravi Patel and Ramya Vangipuram have no conflicts to declare for this work.

Abstract:
Psoriasis is an immune-mediated inflammatory skin condition associated with many comorbidities and poor quality of life. The pathogenesis of psoriasis is complex and involves numerous proinflammatory cytokines. Many biologic therapies have been developed to block the action of these proinflammatory molecules, including inhibitors of tumor necrosis factor (TNF), interleukin (IL)-17, IL-12, and IL-23. IL-23 is composed of two subunits, p19 and p40. The p40 subunit is shared with IL-12, and inhibitors of the p40 subunit can block both IL-12 and IL-23 signaling. Recent advances in the understanding of psoriasis, however, have shown IL-23 to be more important than IL-12 in the pathogenesis of psoriasis. This has led to the development of IL-23p19 antagonists, the newest class of biologics for psoriasis. Here, we will discuss the safety and efficacy of tildrakizumab, a monoclonal antibody targeting IL-23p19.

Key Words:
biologics, interleukin-23 inhibitor, plaque psoriasis, tildrakizumab

Introduction

Psoriasis is a chronic, immune-mediated inflammatory skin condition characterized by well-defined erythematous plaques, scaling, itching, and burning. Plaque psoriasis is the most common type of psoriasis in older children and adults.¹ While two-thirds of patients develop psoriasis in adulthood, onset of childhood psoriasis is quite common.¹ Prevalence varies by country and is estimated to be 0.5-11% in adults and 1% in children.^2-4 Psoriasis is associated with many comorbidities and has a considerable impact on the quality of life, particularly in those with moderate-to-severe disease.^1,2,4 One-fifth of all patients who have psoriasis are diagnosed with moderate-to-severe disease, highlighting a need for safe, effective, and reliable treatments.²

Pathogenesis of Psoriasis

Psoriasis is a complex, multifactorial condition related to cellular immune dysregulation and abnormal keratinization.^1,5 Numerous growth and inflammatory signals, including an array of T-helper (Th) 1 and Th17 type cytokines, have been implicated in the pathogenesis of the disease.^5-7 The differentiation of Th cells into Th1 and Th17 is mediated by interleukin (IL)-12 and IL-23, respectively.⁷ Interferon (IFN)-γ is the defining cytokine of Th1 cells, and tumor necrosis factor (TNF)-α is also produced to a lesser extent.^7,8 Th17 cells produce various cytokines, including IL-17A, IL-17F, and IL-22.⁷ Th1 and Th17 pathways are responsible for keratinocyte proliferation, production of inflammatory cytokines, and migration of inflammatory cells into psoriatic lesions.^5,7 Recent advances have shown the IL-23/ Th17 signaling pathway to be more important in the pathogenesis of psoriasis.⁷

Current Treatments

Many options exist for the treatment of psoriasis. Mild psoriasis can be treated with topical therapy such as corticosteroids, coal tar preparations, vitamin D analogues, topical retinoids, calcineurin inhibitors, and salicylic acid.^5,6 Moderate-to-severe psoriasis may require treatment with phototherapy or systemic agents such as systemic corticosteroids, cyclosporine, methotrexate, retinoids, small molecule inhibitors, and biologics.⁵

Biologic therapies target specific pro-inflammatory molecules that are critical to the pathogenesis of psoriasis. Alefacept and efalizumab were the first biologics to receive approval from the US Food and Drug Administration (FDA) in 2003 for psoriasis, but were withdrawn from the market in 2011 and 2009, respectively, due to the availability of better tolerated and more effective biologic agents.^8,9 Other biologics that have been approved for psoriasis include TNF antagonists (etanercept, infliximab, and adalimumab), IL-12/IL-23p40 inhibitor (ustekinumab), IL-17A inhibitors (secukinumab, ixekizumab), IL-17A receptor antagonist (brodalumab), and IL-23p19 inhibitors (guselkumab, tildrakizumab).⁹

Phase 1 Studies

Tildrakizumab is a humanized monoclonal antibody that targets the p19 subunit of IL-23 and blocks the IL-23/Th17 signaling pathway. In 2015, Kopp et al. published results of the phase 1 study involving tildrakizumab in psoriasis patients.¹⁰ They conducted a three-part, multiple-dose, randomized, placebo-controlled, patient- and evaluator-blind, multi-center study of tildrakizumab in patients with moderate-to-severe psoriasis. Part 1 of the study examined the safety, tolerability and pharmacokinetics of rising doses of tildrakizumab at week 16 as the primary endpoints. Parts 2 and 3 examined the efficacy of tildrakizumab at week 16 as a secondary endpoint. Each study participant received a total of 3 doses of tildrakizumab or placebo intravenously and was followed for up to 1 year after the first dose.

Subjects who were treated with tildrakizumab in all parts of the study experienced clinically significant improvement in disease activity. Subjects on tildrakizumab 0.05-10 mg/kg had a mean reduction in the Psoriasis Area and Severity Index (PASI) score of 50-80% in all parts of the study.¹⁰ All 3 mg/kg and 10 mg/kg subjects achieved a reduction in PASI score of 75% (PASI 75) in part 1 by day 196 and a majority achieved PASI 75 in part 2 by day 112.¹⁰ A large proportion of 3 mg/kg and 10 mg/kg subjects also achieved PASI 90 by day 112.¹⁰

Phase 2 Studies

Efficacy and safety data from a randomized, placebo-controlled, parallel-group, dose-finding phase 2b trial in 355 adult patients with moderate-to-severe psoriasis were reported by Papp et al.¹¹ Study participants were randomly assigned to receive tildrakizumab (5 mg, 25 mg, 100 mg or 200 mg) or placebo via subcutaneous injection at weeks 0 and 4 and every 12 weeks thereafter until week 52. Re-randomization occurred at week 16. Subjects who achieved PASI 75 (responders) at week 16 while receiving 5 mg or 25 mg tildrakizumab continued on the respective dose every 12 weeks, while PASI 75 responders receiving 100 mg or 200 mg tildrakizumab were re-randomized to continue on the same or reduced dose (100 mg to 25 mg and 200 mg to 100 mg) every 12 weeks. Nonresponders at week 16 were re-randomized to receive 100 mg tildrakizumab (for placebo, and the 5 mg and 25 mg groups) or to 200 mg tildrakizumab (for the 100 mg group). Subjects who initially received 200 mg tildrakizumab continued to receive the same dose. The primary endpoint was the proportion of participants who achieved PASI 75 at week 16. Notable secondary endpoints included PASI 90 at week 16 and PASI 75 at week 52.

Approximately 74% of patients in the 200 mg tildrakizumab group achieved PASI 75, 66% in the 100 mg group, 64% in the 25 mg group, and 33% in the 5 mg group compared with 4% for placebo (P < 0.001 for each treatment group vs. placebo).¹¹ Significant improvement for PASI 90 at week 16 was also noted for the tildrakizumab groups vs. placebo (P < 0.001).¹¹ In addition, patients who received doses of 100 mg or 200 mg tildrakizumab after week 16 maintained efficacy at week 52, while those who continued to receive 5 mg and 25 mg tildrakizumab, or who had a reduction in dose from 100 mg to 25 mg experienced a loss in efficacy.¹¹ This study demonstrated the clinical efficacy of tildrakizumab in patients with moderate-to-severe chronic plaque psoriasis, with the higher doses (100 mg and 200 mg) showing the most optimal outcomes.

Phase 3 Studies

Two phase 3 trials, reSURFACE 1 and reSURFACE 2, were conducted to determine the efficacy and safety of tildrakizumab 200 mg and 100 mg vs. placebo and etanercept in adult patients with moderate-to-severe chronic plaque psoriasis.¹² In reSURFACE 1, 772 participants were randomized to treatment arms tildrakizumab 200 mg, tildrakizumab 100 mg, or placebo. In reSURFACE 2, 1,090 participants were randomly assigned to tildrakizumab 200 mg, tildrakizumab 100 mg, placebo, or etanercept 50 mg. Participants received either tildrakizumab, placebo or etanercept until week 64 in reSURFACE 1 or week 52 in reSURFACE 2. The co-primary endpoints were the proportion of participants achieving at least PASI 75 and the proportion of participants achieving a Physician’s Global Assessment (PGA) of “clear” or “minimal”, with at least a two-grade reduction from baseline, at week 12.

In reSURFACE 1, approximately 62% of patients in the tildrakizumab 200 mg group and 64% of patients in the 100 mg group achieved PASI 75 compared with 6% in the placebo group (P < 0.0001) (Figure 1).¹² Of those who achieved PGA responses of “clear” or “minimal”, 59% were in the 200 mg group and 58% in the 100 mg group, compared with 7% in the placebo group.¹² Similar results were noted in reSURFACE 2. At week 12, 66% in the 200 mg group and 61% in the 100 mg group achieved PASI 75, compared with 6% in the placebo group and 48% in the etanercept group (P < 0.0001 for comparison of tildrakizumab groups vs. placebo; P < 0.0001 for 200 mg vs. etanercept; P < 0.001 for 100 mg vs. etanercept) (Figure 1).¹² A PGA response was achieved in 59% of patients in the 200 mg group and 55% in the 100 mg group, compared with 4% in the placebo group and 48% in the etanercept group (P < 0.0001 for comparison of tildrakizumab groups vs. placebo; P = 0.0031 for 200 mg vs. etanercept; P = 0.0663 for 100 mg vs. etanercept).¹² In addition, a significantly higher proportion of patients in the tildrakizumab groups than in the placebo groups achieved PASI 90 and PASI 100 in both trials (P < 0.0001).¹²

Additional analyses were performed using pooled data from reSURFACE 1 and reSURFACE 2. Subgroup analysis of PASI 75 response rates at week 12 were similar to those in the overall population and were consistent across all subgroups including those who had received prior biologic treatment.¹³ Additionally, achievement of PASI 50 by week 8 was predictive of a PASI 50 and PASI 90 response at weeks 12 and 28, respectively.¹⁴ Moreover, recently published post hoc analysis of 2 phase 3 studies (reSURFACE 1 and reSURFACE 2) compared the efficacy and safety of tildrakizumab in patients with and without metabolic syndrome. Results suggested the efficacy and safety at week 52 for both tildrakizumab 100 mg and 200 mg are comparable regardless of metabolic syndrome status.¹⁵

Patient Reported Outcomes

Quality of life was measured by the Dermatology Life Quality Index (DLQI), where a score of 0 or 1 indicates little to no impact of skin disease on quality of life. In both the phase 2 and 3 trials, there were significant improvements in mean changes in DLQI for all tildrakizumab-treated groups.^11,12 A higher proportion of participants receiving tildrakizumab also achieved DLQI scores of 0 or 1 when compared with placebo at week 12 (reSURFACE 1: 42% and 44% vs. 5%, P < 0.001; reSURFACE 2: 40% and 47% vs. 8%, P < 0.001).¹² The proportion of participants achieving these scores increased at week 28 (100 mg: 52%; 200 mg: 57%; placebo to 100 mg: 52%; placebo to 200 mg: 56%).¹² Tildrakizumab 200 mg was also associated with higher rates of participants achieving these scores compared to etanercept 50 mg (47% vs. 36%, P = 0.0029).¹² participants receiving tildrakizumab also achieved DLQI scores of 0 or 1 when compared with placebo at week 12 (reSURFACE 1: 42% and 44% vs. 5%, P < 0.001; reSURFACE 2: 40% and 47% vs. 8%, P < 0.001).¹² The proportion of participants achieving these scores increased at week 28 (100 mg: 52%; 200 mg: 57%; placebo to 100 mg: 52%; placebo to 200 mg: 56%).¹² Tildrakizumab 200 mg was also associated with higher rates of participants achieving these scores compared to etanercept 50 mg (47% vs. 36%, P = 0.0029).¹²

Safety

In the phase 1 trial, tildrakizumab was well tolerated up to the maximum dose of 10 mg/kg intravenously once monthly. The most common adverse events (AEs) were headache, nasopharyngitis, upper respiratory infections and cough, and there was no dose-related increase in AEs.¹⁰ Only one serious AE (convulsions) was deemed possibly related to study medication due to the timing of the dose, although several confounding factors exist including the subject’s lack of sleep, alcohol consumption, and use of benzodiazepines.¹⁰

Safety data from the phase 2 trial also demonstrated no significant difference in the overall incidence of AEs between those receiving tildrakizumab compared with placebo. The most frequently reported AEs were also nasopharyngitis and headache, but their incidences did not differ between treatment groups.¹¹ Twentythree participants reported serious AEs, but only 6 of those were assessed as possibly related to tildrakizumab. These serious AEs included bacterial arthritis, lymphoedema, melanoma, stroke, epiglottitis, and knee infection.¹¹

Similarly, in the phase 3 trials, the overall incidence of AEs was comparable in the tildrakizumab and placebo groups. The most common AEs in both reSURFACE trials were nasopharyngitis and upper respiratory tract infections.¹² Injection site reaction was more common in etanercept than tildrakizumab (9% vs. 1%).¹² The incidence of AEs of interest (severe infections, malignancies, skin cancers, major cardiovascular events, and drug-related hypersensitivity reactions) was low in both studies, and there was no significant difference between the treatment groups.

In all reported trials, there was no statistically significant difference in safety laboratories, vital signs, and electrocardiograms.^10-12

Long-term Efficacy and Safety

Long-term efficacy and safety data are available for the 1,237 participants from the two phase 3 trials who entered the long-term extension. Of the patients who received tildrakizumab 200 mg in the extension, PASI 50/75/90/100 was maintained by 97%/89%/83%/67% at the 1-year treatment period.¹⁶ Of the patients who received tildrakizumab 100 mg in the extension, PASI 50/75/90/100 was maintained by 99%/91%/79%/60% at the 1-year treatment period (Figure 2).¹⁶ At the 3-year treatment period, PASI 50/75/90/100 was maintained by 96%/84%/58%/25% of patients receiving tildrakizumab 100 mg.¹⁷ More than half of the patients maintained a PGA response of “clear” or “minimal” after 3 years of treatment.¹⁷ Results were similar in patients receiving tildrakizumab 200 mg.¹⁷ These findings show that tildrakizumab 100 mg/200 mg maintained efficacy in the treatment of moderate-to-severe chronic plaque psoriasis for at least 3 years.^16,17

Over a cumulative 3-year treatment period, the number of prespecified AEs of interest in the 100 mg/200 mg tildrakizumab groups in both studies were low. All prespecified AEs were reported at rates < 1.6 events per 100 patient-years. Three deaths were reported, but were deemed unrelated to study medication. These results showed that tildrakizumab 100 mg and 200 mg were well tolerated with a low rate of AEs of interest reported with long-term treatment.^17,18

Conclusion

Tildrakizumab is a promising therapeutic option for patients with moderate-to-severe chronic plaque psoriasis. The specificity of the drug in targeting the p19 subunit of IL-23 allows for the high efficacy and safety of long-term treatment as demonstrated in clinical trials. Moreover, maintenance of efficacy with tildrakizumab is high and has been shown to last for at least 3 years. In addition, tildrakizumab leads to improvement in the quality of life for psoriasis patients. Based on the efficacy and safety results from the two large phase 3 trials, the FDA approved tildrakizumab 100 mg subcutaneous injection for the treatment of moderate-to-severe chronic plaque psoriasis in adults over 18 years old. It is approved to be administered at weeks 0 and 4 and every 12 weeks thereafter.

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