Dermatol Ther (Heidelb) (2021) 11:1319–1332 https://doi.org/10.1007/s13555-021-00554-4 ORIGINAL RESEARCH Efficacy and Safety of Netakimab, A Novel Anti-IL-17 Monoclonal Antibody, in Patients with Moderate to Severe Plaque Psoriasis. Results of A 54-Week Randomized Double-Blind Placebo-Controlled PLANETA Clinical Trial Luı́s Puig . Andrey L. Bakulev . Muza M. Kokhan . Alexey V. Samtsov . Vladislav R. Khairutdinov . Maria A. Morozova . Nikita A. Zolkin . Ivan V. Kuryshev . Alexey N. Petrov . Antonina V. Artemeva . Arina V. Zinkina-Orikhan Received: March 25, 2021 / Published online: May 31, 2021 Ó The Author(s) 2021 ABSTRACT randomly assigned to receive NTK 120 mg once every 2 weeks (NTK Q2W), NTK 120 mg once Introduction: Netakimab (NTK), an original every 4 weeks (NTK Q4W) or placebo. During humanized anti-interleukin-17 monoclonal the first 3 weeks, patients received subcuta- antibody, showed therapeutic efficacy in mod- neous injections of NTK or placebo (according erate-to-severe plaque psoriasis in a phase 2 to the allocation) once a week. Patients in the clinical study. Herein we report the results of NTK Q2W group then received NTK at weeks 4, 54 weeks of a phase 3 PLANETA trial aimed to 6, 8 and 10. Subjects in the NTK Q4W group evaluate the efficacy and safety of two NTK received NTK at weeks 6 and 10 and placebo at regimens vs. placebo. weeks 4 and 8. Patients in the placebo group Methods: Two hundred thirteen patients with received placebo injections at weeks 4, 6, 8 and moderate-to-severe plaque psoriasis were 10. Treatment was unblinded at week 12. Dur- ing the open-label phase, patients in both NTK Supplementary Information The online version groups continued to receive NTK Q4W. The contains supplementary material available at https:// primary efficacy endpoint was the proportion of doi.org/10.1007/s13555-021-00554-4. patients in each group who achieved a C 75% reduction from baseline in psoriasis area and L. Puig Department of Dermatology, Hospital de la Santa severity index (PASI 75) at week 12. Creu i Sant Pau, Barcelona, Spain Results: A total of 77.7%, 83.3% and 0% of patients had a PASI 75 response at week 12 in A. L. Bakulev the NTK Q2W, NTK Q4W and placebo groups, Saratov State Medical University, Saratov, Russia respectively (P \ 0.0001, Fisher’s exact test, M. M. Kokhan ITT). The effect was maintained throughout the Ural Research Institute of Dermatovenerology and 1-year treatment. NTK showed a good safety Immunopathology, Yekaterinburg, Russia profile and low immunogenicity. A. V. Samtsov  V. R. Khairutdinov Conclusion: Treatment with NTK results in S. M. Kirov Military Medical Academy, St- high rates of sustained clinical response in Petersburg, Russia patients with moderate-to-severe plaque psori- M. A. Morozova (&)  N. A. Zolkin  asis. The study is ongoing; thus, long-term use I. V. Kuryshev  A. N. Petrov  A. V. Artemeva  efficacy and safety data are forthcoming. A. V. Zinkina-Orikhan Clinical Trial Registration: The trial is regis- JSC BIOCAD, St-Petersburg, Russia e-mail: morozovama@biocad.ru tered at the US National Institutes of Health 1320 Dermatol Ther (Heidelb) (2021) 11:1319–1332 (ClinicalTrials.gov; NCT03390101). associated with a range of comorbidities. Symp- toms may vary from mild with a few local skin Keyword: Netakimab; Psoriasis; Interleukin-17 lesions to severe forms, affecting a significant pro- inhibitors portion of the body surface. Psoriasis can seriously affect patient social activity and quality of life. In 2012, the first published data established the pivotal role of interleukin-17 (IL-17) in the Key Summary Points immunopathogenesis of psoriasis and suggested that blockade of IL-17 signalling can be one of Netakimab is an original humanized anti- the therapeutic options [1]. interleukin-17 monoclonal antibody which Netakimab (NTK) is a novel recombinant showed therapeutic efficacy in plaque humanized IgG1 anti-IL-17 monoclonal anti- psoriasis and ankylosing spondylitis in phase body (mAb) with modified Fc-fragment (Fc- 2 clinical studies. The phase 3 PLANETA fragment crystallisable region) and CDR (com- clinical trial was conducted to evaluate the plementarity-determining regions). The superi- efficacy and safety of Q4W and Q2W ority of NTK at the dose of 120 mg over placebo netakimab dosing regimens vs. placebo in was shown in phase 2 trials in moderate-to- patients with moderate-to-severe plaque severe psoriasis (NCT02762994) and in anky- psoriasis losing spondylitis (NCT02763111) [2, 3]. Netakimab demonstrated high rates of The PLANETA study aimed to evaluate the sustained clinical response as early as the efficacy and safety of NTK Q2W (once every first few weeks of treatment, a favourable 2 weeks) vs. NTK Q4W (once every 4 weeks) vs. safety profile and good tolerability in placebo in patients with moderate-to-severe patients with moderate-to-severe plaque plaque psoriasis. In this article, we report the psoriasis and can be the treatment option for analysis of 1 year of the study. patients with moderate-to-severe plaque psoriasis METHODS In patients with moderate-to-severe plaque psoriasis NTK 120 mg should be PLANETA is the ongoing international, multi- administered once a week for the first centre, phase 3, double-blind, placebo-con- 3 weeks followed by NTK 120 mg Q4W trolled clinical study conducted in 24 injections investigational sites in the Russian Federation and the Republic of Belarus according to the Declaration of Helsinki following Good Clinical Practice guidelines. The study was approved by the Central Regulatory Authorities of the Rus- DIGITAL FEATURES sian Federation and the Republic of Belarus and Ethical Review Boards of each of the partici- This article is published with digital features, pating sites. The trial was registered at the US including a summary slide, to facilitate under- National Institutes of Health (ClinicalTrials.gov; standing of the article. To view digital features NCT03390101). for this article go to https://doi.org/10.6084/ Eligible patients were 18 years and older, had m9.figshare.14461808. an established diagnosis of moderate-to-severe plaque psoriasis for at least 6 months, were candidates for or had received at least one INTRODUCTION course of phototherapy or systemic therapy, had at least a 10% body surface area (BSA) Psoriasis is a chronic, systemic inflammatory dis- affected by psoriasis, a Psoriasis Area and ease with leading skin involvement that is Severity Index (PASI) score C 10, and a static Dermatol Ther (Heidelb) (2021) 11:1319–1332 1321 Physician’s Global Assessment (sPGA) score C 3 The treatment was unblinded at week 12. at screening. During the open-label phase, patients in both Patients were ineligible to participate in the NTK groups continued to receive the study drug study if they had other forms of psoriasis (e.g. Q4W (NTK Q2W/Q4W and NTK Q4W groups). guttate, erythrodermic or pustular) or any other Patients who received placebo were switched to skin diseases (e.g. eczema), previously used the active treatment and were administered mAbs targeting IL-17 or its receptor, or received NTK at weeks 12, 13 and 14 (induction) and more than one drug containing mAbs or their then Q4W through weeks 18–50 (placebo/NTK fragments. Any mAb had to be withdrawn for at Q4W group). Patients were followed up for least 12 weeks; systemic therapy and pho- 4 weeks after the last injection of the study totherapy within 4 weeks; and the range of drug. topical medications within 2 weeks before NTK was administered as two subcutaneous signing the informed consent (IC). All patients injections (1.0 ml containing NTK 60 mg); pla- were given adequate time to reflect on the cebo was administered as two indistinguishable information, had their questions answered, subcutaneous injections (1.0 ml each). gave free and voluntary consent to participate and signed an IC form. Study Outcomes All patients underwent chest x-ray and tuberculosis test (T-SPOT.TB test/QuantiFERON- The primary efficacy endpoint was the propor- TB Gold test/TB skin test) at screening. In case tion of patients who achieved a C 75% reduc- of ambiguous tuberculosis test results, patient tion from baseline in PASI (PASI 75) at week 12. underwent consultation with a specialized The secondary endpoints included the propor- physician. If active/latent infection was exclu- tion of patients attaining PASI 75 at weeks 8, 16, ded, the patient could be included in the study. 24, 42 and 52, PASI 90 and PASI 100 at weeks 8, Eligible patients were stratified by body 12, 16, 24, 42 and 52; the change from baseline weight (\ 100 kg/C 100 kg), previous treatment in PASI, the proportion of patients with sPGA 0 of psoriasis with mAb (previously treated/na- or 1 and sPGA 0 at weeks 8, 12, 16, 24, 42 and ive), PASI score (\ 20/C 20) and presence of 52; the proportion of patients with Dermatol- psoriatic arthritis (yes/no) and randomly ogy Life Quality Index (DLQI) 0 or 1 at weeks assigned in a 2:2:1 ratio to receive NTK 120 mg 24, 42 and 52; the change from baseline in itch Q2W (NTK Q2W group), NTK 120 mg Q4W severity (measured by visual analogue scale (NTK Q4W group) or placebo. The randomiza- [VAS], 0–100 mm) at weeks 1, 12, 24 and 52; tion was performed with random sequence Nail Psoriasis Severity Index (NAPSI) at weeks using an electronic centralized randomization 12, 24 and 52; and DLQI at weeks 8, 12, 24, 42 system. The study investigators, trial team and and 52. patients were blinded to the treatment alloca- The safety analysis included all data obtained tion during the first 12 weeks of the study. after the first injection of NTK/placebo. Adverse The main treatment period included the events (AEs) were reported according to Com- blinded phase (weeks 0–12) followed by an mon Terminology Criteria for Adverse Events open-label phase up to 54 weeks. The study was (CTCAE) v. 4.03 [4]. extended up to 3 years. During the first 3 weeks, Blood samples for the immunogenicity all patients received subcutaneous injections of analysis were obtained before the first dose of NTK or placebo (according to the allocation) NTK/placebo, at weeks 12, 24, and 54. The once a week (induction phase). Patients in the samples were analyzed using a validated NTK Q2W group then received the study drug at enzyme-linked immunosorbent assay (ELISA; weeks 4, 6, 8 and 10. Subjects in the NTK Q4W drug-tolerant method). In case of detection of group received NTK at weeks 6 and 10 and NTK-binding antibodies, we performed the placebo at weeks 4 and 8 to preserve blinding. analysis for the antibodies with neutralizing Patients in the placebo group received injec- activity. The immunogenicity endpoint was the tions containing placebo at weeks 4, 6, 8 and 10. 1322 Dermatol Ther (Heidelb) (2021) 11:1319–1332 proportion of patients with binding/neutraliz- processed using frequency tables, Fisher’s exact ing anti-drug antibodies at weeks 12, 24 and 54. test and Pearson’s chi-squared test. Statistical hypotheses were tested by two Sample Size steps: 1. Superiority hypotheses of NTK Q2W and This trial tested three hypotheses. The main NTK Q4W groups over placebo group; study hypothesis stated the non-inferiority of 2. Non-inferiority hypothesis of NTK Q4W NTK Q4W vs. Q2W at a significance level of and NTK Q2W. 0.05. The second and the third hypotheses sta- A statistical comparison of all secondary ted the superiority of NTK over placebo for each efficacy endpoints was performed between the of the dosing regimens, Q4W and Q2W, respectively, each at a significance level of 0.05. NTK Q2W/Q4W and NTK Q4W groups. Sec- ondary efficacy endpoints in the placebo/NTK To calculate the sample size, we used litera- Q4W group were assessed descriptively because ture data about the efficacy of ixekizumab in patients with moderate-to-severe plaque psori- comparison with the NTK Q2W/Q4W and NTK Q4W groups was not feasible because of the asis [5]. Assuming 89.1% and 82.6% PASI 75 difference in NTK treatment durations. response rate at week 12 in the Q2W and Q4W The efficacy and safety analyses were per- groups, respectively, a sample size of 154 formed according to the intention-to-treat (ITT) patients (77 in each NTK group) would provide principle and included all patients randomized approximately 80% power to demonstrate non- in the study (n = 213). For dichotomous inferiority with a 20.4% margin and 5% type I responder-type endpoints, missing responses at error rate. Non-inferiority margin was calcu- a post-baseline visit were imputed as a non-re- lated as 0.25 of the lower boundary 95% confi- sponder. For continuous endpoints, no missing dence interval (CI) (81.5%; 88.9%) for the data imputation rules were applied. difference between assumed PASI 75 response rate at week 12 in the Q2W and placebo groups, assuming the response rate of 3.9% in the pla- RESULTS cebo group. Also, a sample size of 193 patients (77 in each NTK group and 39 in the placebo From December 2017 (date of the first visit) to group) would provide [ 80% power to demon- June 2019 (date of completion of the analysed strate the superiority of NTK over placebo for period by the last participant), a total of 213 each group with a 0% margin and 5% type I patients were randomized: NTK Q2W group error rate. With a potential withdrawal rate of (n = 85), NTK Q4W group (n = 84) and placebo 10%, the study should involve 213 patients. group (n = 44); 201 patients completed the 54 weeks of the trial, and 12 subjects discon- Statistical Analysis tinued treatment. The reasons for early with- drawal were AEs, pregnancy, IC withdrawal and The statistical analysis was performed using loss to follow-up (Fig. 1). two-sided hypothesis tests. The statistical sig- The baseline demographics and clinical nificance level was set as 0.05. characteristics were consistent across the three Quantitative data were tested for normality groups. The median patient age was 42, 41.5 using the Shapiro-Wilk test. Normally dis- and 39 years in the NTK Q2W/Q4W, NTK Q4W tributed quantitative data were analysed using and placebo/NTK Q4W groups, respectively. All the two-sample Student’s t-test and analysis of patients were Caucasian. The median disease variance. Non-normally distributed data were duration was 100–120 months. Previous ther- analysed using the Mann-Whitney, Wilcoxon, apy included phototherapy, systemic/topical Kruskal-Wallis and Friedman tests. Benjamini- corticosteroids and immunosuppressants. There Yekutieli adjustment was used for multiple were differences in the frequency of systemic comparisons. The categorical data were therapy (more frequent use of methotrexate in Dermatol Ther (Heidelb) (2021) 11:1319–1332 1323 Fig. 1 Patient disposition flow chart. IC informed consent, NTK netakimab, Q2W every 2 weeks, Q4W every 4 weeks, AEs adverse events the placebo/NTK Q4W group) that were con- of NTK in both dosing regimens were superior sidered insignificant because all eligible patients to that of placebo. did not use systemic therapy for at least 4 weeks The difference in PASI 75 rate at week 12 before signing the IC (Table 1). between the NTK Q4W and NTK Q2W groups was 5.6% with a 95% CI of - 7.4 to 18.8% Efficacy Analysis (P = 0.4603). The lower bound of the 95% CI (- 7.4%) did not exceed the pre-specified mar- A total of 77.7% of patients in the NTK Q2W gin of - 20.4%. Thus, the efficacy of NTK Q4W group and 83.3% of patients in the NTK Q4W was not inferior to that of NTK Q2W. group achieved PASI 75 at week 12 compared to During the first 12 weeks of treatment and 0% of patients in the placebo group; a 95% CI of afterward (when NTK was administered Q4W in 67.1–88.2% (P \ 0.0001) for the NTK Q2W vs. both groups), the proportion of patients placebo and 95% CI of 73.6–93% (P \ 0.0001) attaining PASI 75/90/100 and relative PASI for the NTK Q4W vs. placebo. The lower bound change vs. baseline did not differ between the of the 95% CI for the NTK Q4W and NTK Q2W NTK Q2W and NTK Q4W groups. Most patients groups (73.6% and 67.1%, respectively) exceeds achieved PASI 75 after as early as 8 weeks of the superiority margin (0%). Thus, the efficacies therapy (58.8% and 59.5% in the NTK Q2W and NTK Q4W groups, respectively). By week 52, 94.1% and 92.9% of patients achieved PASI 75, 1324 Dermatol Ther (Heidelb) (2021) 11:1319–1332 Table 1 Baseline demographics and clinical characteristics (n = 213) Variable NTK Q2W/Q4W NTK Q4W Placebo/NTK Q4W (n = 85) (n = 84) (n = 44) Age, years 42 [35–49] 41.5 [32–53] 39 [33–53] 2 BMI, kg/m 27.9 [24.5–31.9] 28.5 [25.5–32.5] 27.2 [24.2–30.0] Male sexa 63 (74.1) 58 (69.1) 35 (79.6) Disease duration, months 120 [36–204] 111 [36–183] 100 [34–193] BSA 20 [13.0–42.0] 22 [14.5–43.0] 22.5 [13.0–44.0] PASI score 18.4 [14.2–27.0] 17.9 [15.1–28.6] 19.7 [16.3– 29.4] NAPSI score 7 [0–29] 14 [2–28] 14 [0–37] sPGA score 3 [3–4] 4 [3–4] 4 [3–4] Itch (VAS, mm) 47 [27–67] 48 [27–71] 45.5 [23–70] DLQI score 13 [10–20] 13 [9–18] 15 [9–20] Medication history Monoclonal antibodies and JAK inhibitorsa 5 (5.9%) 6 (7.1%) 1 (2.3%) Systemic immunosuppressants 22 (25.9%) 29 (34.5%) 21 (47.7%) a Corticosteroids 23 (27.1%) 32 (38.1%) 16 (36.4%) Phototherapya 47 (55.3%) 50 (59.5%) 30 (68.2%) a Median and interquartile range are presented except variables marked with where no. (%) is presented NTK netakimab, Q2W once every 2 weeks, Q4W once every 4 weeks, BMI body mass index, BSA body surface area, DLQI Dermatology Life Quality Index, JAK Janus kinase, NAPSI Nail Psoriasis Severity Index, PASI Psoriasis Area and Severity Index, sPGA static Physician Global Assessment, VAS visual analogue scale 78.8% and 77.4% of patients achieved PASI 90, As early as the first week of treatment, and 61.2% and 56% of patients achieved PASI patients in both NTK groups reported a reduc- 100 in the NTK Q2W/Q4W and NTK Q4W tion in itch severity; the effect was maintained groups, respectively. There were no statistically throughout the 1-year treatment period. The significant differences between the two groups use of NTK resulted in a significant improve- throughout the analysis period (P [ 0.05) ment in psoriatic nail damage assessed by NAPSI (Fig. 2). regardless of the dosing regimen. Patient-re- At the first assessment time point (week 8), ported outcomes as measured by the DLQI 56.5% and 60.7% of patients had ‘‘clean or showed that the impact of psoriasis on quality almost clean skin’’ (sPGA 0 or 1) and 48.2% and of life significantly decreased during therapy. By 45.2% (week 16) had ‘‘clean skin’’ (sPGA 0) in week 52, 69.4% of patients in the NTK Q2W/ the NTK Q2W and NTK Q4W groups, respec- Q4W group and 69.1% of patients in the NTK tively (P [ 0.05). At week 52, 84.7% and 85.7% Q4W group had a DLQI score of 0 or 1 (no of patients achieved the sPGA score of 0 or 1, impact on quality of life) (Table 2). and 61.2% and 58.3% of patients had the sPGA The patients in the placebo/NTK Q4W group score of 0 in the NTK Q2W/Q4W and NTK Q4W had a reduction of clinical signs of psoriasis groups, respectively (P [ 0.05). after as early as 4 weeks of therapy with NTK with the effect increasing through week 52: Dermatol Ther (Heidelb) (2021) 11:1319–1332 1325 1326 Dermatol Ther (Heidelb) (2021) 11:1319–1332 b Fig.2 Response to netakimab treatment (ITT analysis). baseline was - 10, - 37.5 and - 37 at weeks 12, ITT intention-to-treat principle, NTK netakimab, PASI 24 and 52, respectively, P \ 0.0001), nail dam- Psoriasis Area and Severity Index, Q2W every 2 weeks, age (median change from baseline in NAPSI was Q4W every 4 weeks. a PASI 75 responders; b PASI 90 0, - 11 and - 19 at weeks 12, 24 and 52, responders; c PASI 100 responders respectively, P \ 0.0001) and quality of life (50%, 50% and 68.2% of patients had DLQI 0 or 1 at weeks 24, 42 and 52, respectively). 38.6%, 77.3%, 86.4% and 95.5% of patients achieved PASI 75 at weeks 16, 24, 42 and 52, Safety respectively. By week 52, 81.8% and 65.9% of patients achieved PASI 90/100, respectively, and Throughout the placebo-controlled period, 70.5% of patients achieved a sPGA score of 0 treatment-emergent AEs (TEAEs) were reported (Fig. 2). The same significant improvement was in 20%, 16.7% and 20.5% of patients receiving observed in itch severity (median change from Table 2 Main efficacy endpoints Variable Week Group P value NTK Q2W/Q4W NTK Q4W (n = 85) (n = 84) n % n % PASI 75 8 50 58.8 50 59.5 1.00001 12 66 77.7 70 83.3 0.46031 52 80 94.1 78 92.9 0.7662 PASI 90 8 31 36.5 33 39.3 0.59291 12 47 55.3 47 56 1.00001 52 67 78.8 65 77.4 0.96751 PASI 100 8 16 18.8 16 19.1 1.00001 12 25 29.4 28 33.3 0.70131 52 52 61.2 47 56 0.59391 sPGA 0–1 8 48 56.5 51 60.7 0.68641 12 69 81.2 67 79.8 0.96981 52 72 84.7 72 85.7 1.00001 sPGA 0 16 41 48.2 38 45.2 0.81321 52 52 61.2 49 58.3 0.82591 DLQI 0 or 1 24 58 68.2 57 67.9 1.00001 52 59 69.4 58 69.1 1.00001 NTK netakimab, Q2W once every 2 weeks, Q4W once every 4 weeks, DLQI Dermatology Life Quality Index, PASI Psoriasis Area and Severity Index, sPGA static Physician Global Assessment, VAS visual analogue scale 1 Yates corrected chi-squared test; 2Fisher’s exact test Dermatol Ther (Heidelb) (2021) 11:1319–1332 1327 NTK Q2W, NTK Q4W and placebo, respectively (4.6%). Two patients had serious TEAEs not (P [ 0.05). Treatment-related AEs were regis- related to NTK. One patient with arterial tered in 9.4%, 10.7% and 6.8% of patients hypertension, type II diabetes and obesity had receiving NTK Q2W, NTK Q4W and placebo, worsening of the arterial hypertension, which respectively (P [ 0.05). led to hospitalization. The second patient dis- continued treatment because of the develop- Safety Results of NTK Q2W/Q4W and NTK ment of type II diabetes and collapse. Q4W Groups Treatment-related AEs were represented by neutropaenia, infections, hyperbilirubinaemia, During the 54 weeks, 40% and 40.5% of elevated aspartate aminotransferase (AST), ele- patients had TEAEs and 4.7% and 2.4% of vated alanine aminotransferase (ALT), hyperc- patients had grade 3/4 TEAEs in the NTK Q2W/ holesterolaemia and dermatitis. Severe therapy Q4W and NTK Q4W groups, respectively related AEs were represented by single cases of (P [ 0.05). Two patients (2.4%) in the NTK grade 3 neutropaenia and elevated ALT Q2W/Q4W group and one patient (1.2%) in the (Table 3). NTK Q4W group were withdrawn from the trial because of the AE ‘‘positive test for tuberculo- Immunogenicity sis’’, which was considered not related to the study treatment; subsequently, the diagnosis of The immunogenicity analysis included 210 active tuberculosis was not confirmed. patients. One patient (NTK Q2W/Q4W group) A total of 5% or more of patients had had binding anti-drug antibodies at week 12; at hypercholesterolaemia, neutropaenia, hyper- this time, he had 52.9% PASI improvement. He bilirubinaemia and upper respiratory tract achieved PASI 100 at week 24 and maintained infections. The most common treatment-re- 94.1% PASI improvement at week 52. The sec- lated AEs were represented by neutropaenia. ond patient (NTK Q4W group) had binding The AEs were mostly mild to moderate (grade anti-drug antibodies at week 24; at this time, he 1/2). Severe treatment-related AEs were (one achieved PASI 100 and maintained the response case each): grade 3 neutropaenia, grade 4 neu- throughout the analysis period. Neutralizing tropaenia and grade 3 lymphopaenia. The only antibodies were not detected. treatment-related serious AE (SAE) was one case of grade 3 pneumonia in the NTK Q4W group, which led to hospitalization. The patient pre- DISCUSSION sented with low-grade fever and mild cough 2 days after the third NTK injection and was The aim of this phase 3 clinical trial was to admitted to the hospital. Based on the results of evaluate and compare the efficacy and safety of physical examination and chest x-ray, lower NTK Q2W and Q4W dosing regimens versus lobe pneumonia was diagnosed. After 1 week of placebo during the first 12 weeks of treatment treatment with ceftriaxone, the patient com- with further assessment of the efficacy and pletely recovered and continued the participa- safety of 1-year treatment with NTK in patients tion in the trial. with moderate-to-severe plaque psoriasis. PASI 75 is considered to be a reliable and objective tool to assess the efficacy of biologics Safety Results of the Placebo/NTK Q4W and is commonly used in the clinical trials of IL- Group 17 inhibitors in patients with psoriasis [6, 7]. In the PLANETA study, the blinding was main- From week 13 to week 54, TEAEs were recorded tained throughout the double-blind period; well in 50% of patients; 15.9% of patients had grade trained and experienced dermatologists assessed 3/4 TEAEs. The most frequent TEAEs were the treatment efficacy. Thus, the risk of bias in hypercholesterolaemia (4.6%), neutropaenia the measurement of the outcomes is low. (6.8%) and upper respiratory tract infections Table 3 Summary of safety data 1328 Variable NTK Q2W/Q4W NTK Q4W Placebo/Q4W NTK Q2W/Q4W NTK Q4W Placebo/Q4W (n = 85) (n = 84) (n = 44) (n = 85) (n = 84) (n = 44) N % Incidence n % Incidence n % Incidence n % Incidence n % Incidence n % Incidence rate/100 rate/100 rate/100 rate/100 rate/100 rate/100 patient—year patient—year patient—year patient—year patient—year patient—year Weeks 0–12 Weeks 0–54 Weeks 13–54 Any TEAEs 17.0 20 86.6 15 16.7 66.9 9 20.5 89.5 34 40 38.9 34 40.5 40.2 22 50 64 Severe TEAEs 1.0 1.2 5.1 1 1.2 4.5 1 2.3 9.9 4 4.7 4.6 2 2.4 2.4 7 15.9 20.4 Serious TEAEs 1 1.2 4.5 1 1.2 1.2 2 4.6 5.8 Early withdrawal due to 2 2.4 2.3 1 1.2 1.2 1 2.3 2.9 TEAEs Summary of severe TEAEs (grades 3–4) Neutropaenia 2 2.4 2.3 3 6.8 8.7 Lymphopaenia 1 1.2 1.1 1 2.3 2.9 Hypercholesterolaemia 1 1.2 1.2 Creatinine increased AST increased 1 1.2 1.1 ALT increased 1 2.3 2.9 Hyperbilirubinaemia 1 2.3 2.9 Hepatitis toxic 1 2.3 2.9 Pneumonia 1 1.2 1.2 Diabetes mellitus 1 2.3 2.9 Collapse 1 2.3 2.9 Alcohol addiction 1 2.3 2.9 syndrome Hypertensive disease 1 2.3 2.9 Summary of treatment-related AEs Neutropaenia (grades 4 4.7 4.6 4 4.8 4.7 3 6.8 8.7 2–4) Leukopaenia (grades 2 2.4 2.3 2 2.4 2.4 1–2) Lymphopaenia (grades 2 2.4 2.3 2–3) Lymphocytosis (grade 2) 1 1.2 1.1 Infections (grades 2–3) 4 4.7 4.6 3 3.6 3.5 3 6.8 8.7 Dermatol Ther (Heidelb) (2021) 11:1319–1332 Table 3 continued Variable NTK Q2W/ NTK Q4W(n = 84) Placebo/Q4W(n = 44) NTK Q2W/ NTK Q4W(n = 84) Placebo/Q4W(n = 44) Q4W(n = 85) Q4W(n = 85) N % Incidence n % Incidence n % Incidence n % Incidence n % Incidence n % Incidence rate/100 rate/100 rate/100 rate/100 rate/100 rate/100 patient—year patient—year patient—year patient—year patient—year patient—year Weeks 0–12 Weeks 0–54 Weeks 13–54 Hyperbilirubinaemia 3 3.5 3.4 1 1.2 1.2 1 2.3 2.9 (grade 2) AST increased (grade 2) 1 1.2 1.1 1 1.2 1.2 1 2.3 2.9 ALT increased (grade 1 1.2 1.1 1 2.3 2.9 2–3) Hyperglycaemia (grade 2) 1 1.2 1.1 2 2.4 2.4 Dermatol Ther (Heidelb) (2021) 11:1319–1332 Hypercholesterolaemia 2 4.6 5.8 (grade 2) Dizziness (grade 1) 1 1.2 1.1 1 1.2 1.2 Eczema (grade 2) 1 1.2 1.1 Dermatitis (grade 2) 1 2.3 2.9 Abdominal pain (grade 1 1.2 1.2 2) Blood pressure increased 1 1.2 1.2 (grade 2) Liver transaminases 1 1.2 1.1 increased (grade 2) Tonsillitis (grade 2) 1 1.2 1.1 Viral conjunctivitis (grade 1 1.2 1.2 2) NTK netakimab, Q2W once every 2 weeks, Q4W once every 4 weeks, TEAE treatment-emergent adverse event, AST aspartate aminotransferase, ALT alanine aminotransferase 1329 1330 Dermatol Ther (Heidelb) (2021) 11:1319–1332 The assessment of the primary endpoint treatment period. All treatment-related AEs demonstrated that both NTK dosing regimens were expected and common for all IL-17 inhi- were significantly more effective than placebo bitors: neutropaenia, lymphopaenia and upper and that the Q4W dosing regimen was as respiratory tract infections. None of them led to effective as Q2W during the 12 weeks of treat- treatment discontinuation. ment. The analysis of all secondary efficacy The following limitations of the trial could endpoints showed no significant differences be considered: patients included in this trial had between the NTK Q2W/Q4W and NTK Q4W rather short duration of the disease (approxi- treatment groups throughout the 1-year treat- mately 10 years) and \ 10% of patients in each ment period. group were exposed to biologics prior to the We observed very low efficacy in the placebo inclusion in the study. group—the PASI 75 response rate was 0% at Thus, in patients with moderate-to-severe week 12. In phase 3 clinical trials of ixekizumab plaque psoriasis NTK 120 mg should be admin- the PASI 75 response rate in the placebo group istered once a week for the first 3 weeks fol- varied from 2.4 to 7.3% [6]. In core clinical trials lowed by NTK 120 mg Q4W injections. of secukinumab the placebo effect according to PASI 75 at week 12 varied from 0 to 4.5% [7]. We found the systematic review of 27 studies CONCLUSION aimed to determine the outcome in the placebo groups in randomized controlled trials of sys- NTK demonstrated high rates of sustained temic drugs for chronic plaque-type psoriasis. clinical response as early as the first few weeks of Included trials used different outcome measures treatment, a favourable safety profile and good (BSA, mean percentage of PASI score reduction, tolerability in patients with moderate-to-severe decrease in the average global score, investiga- plaque psoriasis. However, as the study is tor’s overall assessment and investigator’s final ongoing, more efficacy and safety data of long- judgment). The efficacy outcomes in placebo term NTK use will be obtained over the coming groups were low in most studies. The authors years. conclude that the effect of treatment in placebo groups varied widely across studies in an unpredictable way [8]. Thus, the efficacy results ACKNOWLEDGEMENTS obtained in the PLANETA study are consistent with the literature data. We acknowledge the collaboration and com- The patients who received placebo during mitment of all investigators and staff. the first 12 weeks of the study and then were switched to NTK showed the improvement in Funding. Sponsorship for this study and the clinical signs of psoriasis after as early as 4 weeks Rapid Service Fee were funded by JSC BIOCAD, of therapy with the active drug, with the effect Ul. Italianskaya 17, St Petersburg, Russia, increasing through week 52; 95.5%, 81.8% and 191186. 65.9% of patients achieved PASI 75, 90 and 100, respectively; 70.5% of patients achieved sPGA Authorship. All named authors meet the score 0 after 40 weeks of treatment with NTK. International Committee of Medical Journal Significant improvement was observed in itch Editors (ICMJE) criteria for authorship for this severity, nail damage and quality of life. Thus, article, take responsibility for the integrity of the observed dynamics confirm the validity of the work as a whole, and have given their the results obtained in the NTK Q2W/Q4W and approval for this version to be published. NTK Q4W treatment groups. NTK was well tolerated. The safety profile Authors’ Contributions. Conceptualization, was comparable in both NTK dosing regimens methology and design: Antonina V. Artemeva, and placebo during the placebo-controlled per- Arina V. Zinkina-Orikhan, Nikita A. Zolkin, Ivan iod and throughout the open-label NTK V. Kuryshev; Data acquisition, data analysis and Dermatol Ther (Heidelb) (2021) 11:1319–1332 1331 interpretation: Andrey L. Bakulev, Muza M. (Authorization by the Ministry of Healthcare of Kokhan, Alexey V. Samtsov, Vladislav R. the Republic of Belarus No. 01-11-14/1368 of Khairutdinov; Nikita A. Zolkin, Ivan V. Kury- February 05, 2018) and Ethical Review Boards of shev, Alexey N. Petrov, Antonina V. Artemeva, each of the participating sites. A list of the Arina V. Zinkina-Orikhan, Maria A. Morozova; Ethics Committee is provided as a Supplement. Writing—original draft preparation: Maria A. The study was performed in accordance with Morozova, Antonina V. Artemeva, Arina V. the Helsinki Declaration of 1964 and its later Zinkina-Orikhan; Writing—review and editing: amendments. All subjects provided informed Luı́s Puig, Andrey L. Bakulev, Muza M. Kokhan, consent to participate in the study. There was Alexey V. Samtsov, Vladislav R. Khairutdinov, no identifiable information in our paper. Nikita A. Zolkin, Ivan V. Kuryshev. Data availability. The datasets generated Disclosures. Luı́s. Puig has received consul- during and/or analysed during the current tancy/speaker’s honoraria from and/or partici- study are available from the corresponding pated in clinical trials sponsored by Abbvie, author on reasonable request. Almirall, Amgen, Baxalta, Biogen, Boehringer Ingelheim, Celgene, Gebro, Janssen, JSC BIO- Open Access. This article is licensed under a CAD, Leo-Pharma, Lilly, Merck-Serono, MSD, Creative Commons Attribution-NonCommer- Mylan, Novartis, Pfizer, Regeneron, Roche, cial 4.0 International License, which permits Sandoz, Samsung-Bioepis, Sanofi and UCB. any non-commercial use, sharing, adaptation, Andrey L. Bakulev has received consultancy/ distribution and reproduction in any medium speaker’s honoraria from and/or participated in or format, as long as you give appropriate credit clinical trials sponsored by Abbvie, Amgen, to the original author(s) and the source, provide Boehringer Ingelheim, Celgene, Janssen, JSC a link to the Creative Commons licence, and BIOCAD, Leo-Pharma, Lilly, MSD, Novartis, indicate if changes were made. The images or Pfizer, Sanofi, UCB and Zeldis Pfarma. Muza M. other third party material in this article are Kokhan has received consultancy/speaker’s included in the article’s Creative Commons honoraria from and/or participated in clinical licence, unless indicated otherwise in a credit trials sponsored by Celgene, Janssen, JSC BIO- line to the material. If material is not included CAD, Leo-Pharma, Lilly, Novartis, Pfizer and in the article’s Creative Commons licence and Sanofi. Alexey V. Samtsov has received consul- your intended use is not permitted by statutory tancy/speaker’s honoraria from and/or partici- regulation or exceeds the permitted use, you pated in clinical trials sponsored by Celgene, will need to obtain permission directly from the Glenmark, Jadran and JSC BIOCAD. Vladislav R. copyright holder. To view a copy of this licence, Khairutdinov has received consultancy/speak- visit http://creativecommons.org/licenses/by- er’s honoraria from and/or participated in clin- nc/4.0/. ical trials sponsored by Abbvie, Belupo, Bosnalec, Celgene, Glenmark, Jadran, Janssen, JSC BIOCAD, Leo-Pharma, Lilly, MSD, Novartis, Pfizer, Sanofi and Sun Pharma. Maria A. Moro- REFERENCES zova, Antonina V. Artemeva, Arina V. Zinkina- Orikhan, Nikita A. Zolkin, Ivan V. Kuryshev and 1. Zhu S, Qian Y. IL-17/IL-17 receptor system in autoim- mune disease: mechanisms and therapeutic potential. Alexey N. Petrov are JSC BIOCAD employees. Clin Sci (Lond). 2012;122(11):487–511. 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