ICOTYDE Film-coated tablet Ref.[116431] Active ingredients: Icotrokinra

Icotrokinra reduced serum levels of proinflammatory cytokines, IL-17A, IL-17F, IL-19, IL-22 and β-defensin-2, relative to pretreatment levels in evaluated subjects with moderate-to-severe plaque psoriasis based on exploratory analysis of the pharmacodynamic markers. A decrease from baseline was observed in the expression of mRNA related to IL-23/Th17 pathway and psoriasis, including molecular targets IL17A, IL17F, IL19, IL22, IL23A, and DEFB4A, in lesional skin biopsies up to 24 weeks post treatment in an exploratory analysis of subjects with moderate-to-severe plaque psoriasis. The relationship between these pharmacodynamic markers and the mechanism(s) by which icotrokinra exerts its clinical effects is not fully understood.

Cardiac Electrophysiology

At 5 times the maximum recommended dose of ICOTYDE, clinically significant QTc interval prolongation was not observed.

Following the administration of icotrokinra 200 mg, the mean (standard deviation) maximum concentration (C_max) is 3.62 (1.48) ng/mL and total systemic exposure (AUC_inf) is 44.8 (11.4) ng*h/mL. Icotrokinra C_max and AUC increase in a dose-proportional manner between 0.05 to 5 times the recommended dosage in healthy subjects. Following multiple dose administration accumulation for C_maxwas up to 1.6-fold and for AUC was up to 1.5-fold. Icotrokinra steady state is reached in approximately 3 days.

No clinically relevant differences in icotrokinra pharmacokinetics were observed between healthy subjects and patients with moderate-to-severe plaque psoriasis.

Absorption

Icotrokinra median (min, max) time to maximum plasma concentration (T_max) is 2 (0.25, 8) hours.

Effect of Food

Icotrokinra AUC decreased by 43% and C_maxdecreased by 59% following administration with a high-fat meal (1000 calories, 50% fat) [see Dosage and Administration (2.2)].

No clinically significant differences in icotrokinra pharmacokinetics were observed following administration of caffeine.

Distribution

Icotrokinra is 52% bound to plasma protein. Blood to plasma partition ratio is 0.53. Icotrokinra steady state apparent (oral) volume of distribution is 92800 L.

Elimination

Icotrokinra median elimination half-life is 12 hours with an apparent (oral) clearance of 6550 L/h.

Metabolism

Icotrokinra is a peptide and it is metabolized by peptide catabolism into smaller peptides.

Excretion

Following oral administration of icotrokinra to healthy subjects, approximately 37% to 81% of the dose was recovered in feces within 24 hours as unchanged icotrokinra, and 0.001% of the dose was recovered in urine as unchanged icotrokinra.

Specific Populations

No clinically significant differences in the pharmacokinetics of icotrokinra were observed based on age (range: 12 to 87 years), body weight (range: 39 to 211 kg), sex, race (76% White, 20.1% Asian, 1.7% Black), ethnicity, immunogenicity, mild (eGFR ≥60 to <90 mL/min, [calculated according to Chronic Kidney Disease Epidemiology Collaboration]) renal impairment. The effect of mild (Child-Pugh Class A) to severe (Child-Pugh Class C) hepatic impairment on icotrokinra pharmacokinetics is unknown. Hepatic impairment is unlikely to affect icotrokinra elimination since the drug is not metabolized hepatically. However, patients with severe hepatic impairment were not studied in clinical trials.

Pediatric Patients

No clinically relevant differences in icotrokinra pharmacokinetics were observed in pediatric patients with moderate-to-severe plaque psoriasis 12 years of age and older who weigh at least 40 kg compared to adults.

Patients with Renal Impairment

Icotrokinra AUC increased by 2.47-fold in patients with moderate (eGFR ≥30 to <60 mL/min, [calculated according to Chronic Kidney Disease Epidemiology Collaboration]) and 2.78-fold in severe (eGFR ≥15 to <30 mL/min) renal impairment. No clinically significant differences in the pharmacokinetics of icotrokinra were observed in patients with mild renal impairment (eGFR ≥60 to <90 mL/min) based on population pharmacokinetic analysis.

Drug Interaction Studies

Clinical Studies

No formal drug-drug interaction studies have been conducted with icotrokinra. No clinically significant drug interactions have been identified.

In vitro Studies

CYP450 Enzymes: Icotrokinra does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. Icotrokinra does not induce CYP1A2, CYP2B6, and CYP3A4.

Transporter systems: Icotrokinra is not a substrate of P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1, and MATE2-K. Icotrokinra does not inhibit P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1, MATE2-K, and BSEP.

In a 6-month transgenic rasH2 mouse study, no drug-related tumors were observed at oral doses of icotrokinra up to 500 mg/kg/day (76 times the MRHD based on AUC comparison). In a 2-year rat carcinogenicity study, no drug-related tumors were observed at oral doses of 20 mg/kg/day (16 times the MRHD based on AUC comparison).

Icotrokinra was not genotoxic in an in vitrobacterial reverse mutation assay (the Ames test), an in vitrohuman lymphocyte chromosomal aberration assay, or an in vivorat micronucleus and Comet assays.

In male rats, icotrokinra had no adverse effect on mating, fertility or early embryonic development of their offspring at oral doses up to 20 mg/kg/day (114 times the MRHD based on AUC comparison).

In female rats, icotrokinra had no adverse effect on estrous cyclicity, mating, fertility, or early embryonic parameters at oral doses up to 70 mg/kg/day (335 times the MRHD based on AUC comparison).

The efficacy of ICOTYDE was evaluated in four multi-center, randomized, double-blind, placebo and/or active comparator-controlled trials (Trial PSO-1 [NCT06143878], Trial PSO-2 [NCT06220604], Trial PSO-3 [NCT06095115], and Trial PSO-4 [NCT06095102]) that included 2500 subjects (2428 adults and 72 pediatric subjects 12 years and older who weigh at least 40 kg) with moderate-to-severe plaque psoriasis who were eligible for systemic therapy or phototherapy.

Adults with Moderate-to-Severe Plaque Psoriasis (Trials PSO-1 and PSO-2)

Trial Design

Trial PSO-1 and Trial PSO-2 enrolled 1505 adults with moderate-to-severe plaque psoriasis defined as Investigator's Global Assessment (IGA) score ≥3, a Psoriasis Area and Severity Index (PASI) score ≥12, and body surface area (BSA) involvement ≥10%.

Subjects were randomized to either ICOTYDE 200 mg orally once daily, deucravacitinib 6 mg orally once daily or placebo. At Week 16, subjects originally randomized to placebo received ICOTYDE 200 mg orally once daily thereafter. At Week 24, subjects originally randomized to deucravacitinib received ICOTYDE 200 mg orally once daily thereafter.

Baseline Characteristics

Baseline characteristics were consistent across both trials. In Trial PSO-1 and Trial PSO-2, 68% of subjects were male, 78% of subjects were White, 2% of subjects were Black, and 18% of subjects were Asian; for ethnicity, 16% identified as Hispanic or Latino. The mean age was 46 (range: 18 to 86) years, and the mean baseline weight was 88 kg. At baseline, subjects had a median affected BSA of 21%, a median PASI score of 18, and 14% had a history of psoriatic arthritis. The proportion of subjects with a baseline IGA score of 4 (severe) was 20%. At baseline, 72% had received prior systemic therapy, 33% of subjects had received prior phototherapy, and 26% had received prior biologic therapy.

Clinical Response

Trial PSO-1 and Trial PSO-2 assessed responses at Week 16 for ICOTYDE compared to placebo for two co-primary endpoints:

• the proportion of subjects who achieved IGA 0/1 response (defined as IGA score of 0 [cleared] or 1 [minimal] with a ≥2-grade improvement from baseline)
• the proportion of subjects who achieved at least a 90% improvement in PASI scores from baseline (PASI 90).

Other evaluated outcomes for ICOTYDE compared to placebo included IGA 0, PASI 75, PASI 100, Psoriasis Symptoms and Signs Diary (PSSD) Symptom Score of 0, and PSSD Itch Score improvement from baseline (≥4-point reduction).

Other comparisons between ICOTYDE and deucravacitinib that were secondary endpoints included:

• the proportion of subjects who achieved IGA 0/1 score with at least 2-grade improvement from baseline, IGA 0 score, PASI 75, PASI 90, and PASI 100 at Week 16 and Week 24
• the proportion of subjects who achieved PSSD Symptom Score of 0 at Week 16.

Tables 2 and 3 present the efficacy results in adults with moderate-to-severe plaque psoriasis for Trial PSO-1 and Trial PSO-2.

Table 2. Efficacy Results in Adults with Moderate-to-Severe Plaque Psoriasis (Trial PSO-1):

CI = Confidence interval; PASI = Psoriasis Area and Severity Index; IGA = Investigator's Global Assessment; PSSD = Psoriasis Symptoms and Signs Diary
^* Co-primary endpoints comparing ICOTYDE to placebo.
^† Includes subjects with baseline PSSD Symptom Score >0.
^‡ Includes subjects with baseline PSSD Itch Score ≥4.

Table 3. Efficacy Results in Adults with Moderate-to-Severe Plaque Psoriasis (Trial PSO-2):

CI = Confidence interval; PASI = Psoriasis Area and Severity Index; IGA = Investigator's Global Assessment; PSSD = Psoriasis Symptoms and Signs Diary
Trial PSO-2 enrolled 731 subjects, of which 723 subjects were evaluable for efficacy
^* Co-primary endpoints comparing ICOTYDE to placebo.
^† Includes subjects with baseline PSSD Symptom Score >0.
^‡ Includes subjects with baseline PSSD Itch Score ≥4.

Adults and Pediatric Subjects 12 Years of Age and Older with Moderate-to-Severe Plaque Psoriasis (Trial PSO-3)

Trial Design

Trial PSO-3 enrolled 684 subjects (618 adults and 66 pediatric subjects 12 years of age and older who weigh at least 40 kg) with moderate-to-severe plaque psoriasis defined as Investigator's Global Assessment (IGA) score ≥3, a Psoriasis Area and Severity Index (PASI) score ≥12, and BSA ≥10%.

Subjects were randomized to receive either ICOTYDE (200 mg orally once daily) or placebo for 16 weeks.

Baseline Characteristics

In Trial PSO-3, 65% of subjects were male, 72% of the subjects were White, 1% of the subjects were Black, and 24% of subjects were Asian; for ethnicity, 13% identified as Hispanic or Latino. The mean age was 43 (range: 12 to 85) years, the mean baseline weight was 86 kg, and 10% were 12 years to less than 18 years of age. At baseline, subjects had a median affected BSA of 20%, a median PASI score of 17, and 13% had a history of psoriatic arthritis. The proportion of subjects with a baseline IGA score of 4 (severe) was 25%. At baseline, 72% had prior systemic treatment, 30% of subjects had received prior phototherapy, and 34% had received prior biologic therapy.

Clinical Response

Trial PSO-3 assessed responses at Week 16 for ICOTYDE compared to placebo for two co-primary endpoints:

• the proportion of subjects who achieved IGA 0/1 response (defined as IGA score of 0 [cleared] or 1 [minimal] with a ≥2-grade improvement from baseline)
• the proportion of subjects who achieved PASI 90.

Other evaluated outcomes for ICOTYDE compared to placebo included IGA 0, PASI 75, PASI 100, PSSD Symptom Score of 0, and PSSD Itch Score improvement from baseline (≥4-point reduction).

Table 4 presents the efficacy results in adults and pediatric subjects 12 years of age and older for Trial PSO-3.

Table 4. Efficacy Results in Adults and Pediatric Subjects 12 Years of Age and Older with Moderate-to-Severe Plaque Psoriasis (Trial PSO-3):

CI = Confidence interval; PASI = Psoriasis Area and Severity Index; IGA = Investigator's Global Assessment; PSSD = Psoriasis Symptoms and Signs Diary
^* Co-primary endpoints comparing ICOTYDE to placebo.
^† Includes subjects with baseline PSSD Symptom Score >0.
^‡ Includes subjects with baseline PSSD Itch Score ≥4.

Maintenance and Durability of Clinical Response

In Trial PSO-3, adults who were randomized to ICOTYDE 200 mg orally once daily and were PASI 75 responders or IGA 0 or 1 responders at Week 24 were re-randomized to continue ICOTYDE 200 mg orally once daily or withdrawn from therapy (i.e., received placebo).

For adults who were re-randomized and had a PASI 90 response at Week 24, 84% (108/128) of subjects who continued on ICOTYDE maintained PASI 90 response at Week 52 compared to 21% (27/129) of subjects randomized to placebo. For PASI 90 responders at Week 24 who were re-randomized to placebo, the median time to loss of PASI 90 response was approximately 10 weeks.

For adults who were re-randomized and had an IGA 0/1 response at Week 24, 82% (123/150) of subjects who continued on ICOTYDE maintained IGA 0/1 response at Week 52 compared to 23% (35/150) of subjects randomized to placebo. For IGA 0/1 responders at Week 24 who were re-randomized to placebo, the median time to loss of IGA 0/1 response was approximately 10 weeks.

Pediatric Subjects 12 Years of Age and Older with Moderate-to-Severe Plaque Psoriasis

Trial PSO-3 included 66 pediatric subjects 12 years of age and older who weigh at least 40 kg.

Table 5 presents the efficacy results in pediatric subjects 12 years of age and older at Week 16 enrolled in Trial PSO-3.

Table 5. Efficacy Results in Pediatric Subjects 12 Years of Age and Older with Moderate-to-Severe Plaque Psoriasis at Week 16 (Trial PSO-3):

CI = Confidence interval; PASI = Psoriasis Area and Severity Index; IGA = Investigator's Global Assessment

Adults and Pediatric Subjects 12 Years of Age and Older with Moderate-to-Severe Plaque Psoriasis of the Scalp or Genital Area (Trial PSO-4)

Trial Design

Trial PSO-4 enrolled 311 subjects (305 adults and 6 pediatric subjects 12 years of age and older who weigh at least 40 kg) with moderate-to-severe plaque psoriasis who had a minimum BSA involvement of ≥1%, an IGA score of ≥2 and had failed to respond to at least one topical therapy for the treatment of plaque psoriasis. Additionally, subjects in Trial PSO-4 had at least one of the following baseline conditions: ss-IGA score ≥3 (at least moderate plaque psoriasis of the scalp), static Physician's Global Assessment of Genitalia (sPGA-G) score ≥3 (at least moderate plaque psoriasis of the genital area), and/or Physician's Global Assessment of Hands and/or Feet (hf-PGA) score ≥3 (at least moderate plaque psoriasis of the hands and/or feet).

Subjects were randomized to receive either ICOTYDE 200 mg orally once daily or placebo for 16 weeks. At Week 16, subjects originally randomized to placebo switched to receive ICOTYDE 200 mg orally once daily, and subjects randomized to ICOTYDE at baseline remained on treatment through the end of study.

Baseline Characteristics

In Trial PSO-4, 64% of subjects were male, 78% of subjects were White, 1% of subjects were Black, and 20% of subjects were Asian; for ethnicity, 7% identified as Hispanic or Latino. The mean age was 45 (range: 12 to 87) years, the mean baseline weight was 86 kg, and 2% were 12 years to less than 18 years of age. The proportion of subjects with affected BSA less than 10% was 36% with a median affected BSA of 12%. Subjects had a median PASI score of 14, and 16% had a history of psoriatic arthritis. The proportion of subjects with a baseline IGA score of 3 (moderate), and 4 (severe) were 73% and 22%, respectively. The proportion of subjects with ss-IGA score of 3 or greater was 81%. The proportion of subjects with sPGA-G score of 3 or greater was 45%. The proportion of subjects with hf-PGA score of 3 or greater was 23%. Scalp, genital and hand/foot subpopulations were not mutually exclusive. At baseline, 73% had received prior systemic therapy, 39% of subjects had received prior phototherapy, and 33% had received prior biologic therapy.

Clinical Response

In Trial PSO-4, the primary endpoint was the proportion of subjects who achieved an IGA 0/1 response (defined as IGA score of 0 [cleared] or 1 [minimal] and a ≥2-grade improvement from baseline at Week 16).

Other secondary endpoints at Week 16 included proportion of subjects who achieved ss-IGA score of 0 (absence of disease) or 1 (very mild disease), Psoriasis Scalp Severity Index (PSSI) 90, improvement in scalp itch as measured by Scalp Itch Numerical Rating Scale (NRS) Score, sPGA-G score of 0 (clear) or 1 (minimal), improvement of genital itch severity as measured by a reduction of at least 4 points in the 11-point Genital Psoriasis Symptoms Scale (GPSS) Genital Itch NRS Score, and the patient-perceived impact of psoriasis of the genital area on limiting frequency of sexual activity (intercourse or other activities) as measured by the Genital Psoriasis Sexual Frequency Questionnaire (GenPs-SFQ) Item 2.

Table 6 presents the efficacy results in adults and pediatric subjects 12 years of age and older at Week 16 for Trial PSO-4.

Table 6. Efficacy Results in Adults and Pediatric Subjects 12 Years of Age and Older with Moderate-to-Severe Plaque Psoriasis of the Scalp or Genital Area at Week 16 (Trial PSO-4):

CI = Confidence interval; IGA = Investigator's Global Assessment; ss-IGA = Scalp-specific Investigator Global Assessment; PSSI = Psoriasis Scalp Severity Index; NRS = Numerical Rating Scale; sPGA-G = Static Physician's Global Assessment of Genitalia; GPSS = Genital Psoriasis Symptoms Scale; GenPs-SFQ = Genital Psoriasis Sexual Frequency Questionnaire
^* Primary endpoint comparing ICOTYDE to placebo.

Subgroup Analyses of Trials PSO-1, PSO-2, PSO-3 and PSO-4

An examination of age, gender, race, body weight, baseline disease severity, and previous treatment with systemic or biologic agents did not identify differences in response to ICOTYDE among these subgroups.