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Cibinqo

Cibinqo Mechanism of Action

Manufacturer:

Pfizer

Distributor:

Zuellig Pharma
Full Prescribing Info
Action
Pharmacology: Pharmacodynamics: Mechanism of action: CIBINQO is a Janus kinase (JAK)1 inhibitor. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of haematopoiesis and immune cell function. Within signalling pathways, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) which modulate intracellular activity including gene expression. CIBINQO modulates the signalling pathway at the point of JAK1, preventing the phosphorylation and activation of STATs.
CIBINQO reversibly and selectively inhibits JAK1 by blocking the adenosine triphosphate (ATP) binding site. In a cell-free isolated enzyme assay, CIBINQO has biochemical selectivity for JAK1 over the other 3 JAK isoforms JAK2 (28-fold), JAK3 (>340-fold) and tyrosine kinase (TYK) 2 (43-fold), and even higher selectivity over the broader kinome. In cellular settings, where JAK enzymes transmit signals in pairs (i.e., JAK1/JAK2, JAK1/JAK3, JAK1/TYK2, JAK2/JAK2, JAK2/TYK2), CIBINQO preferentially inhibits cytokine-induced STAT phosphorylation mediated by receptors utilising JAK1 relative to receptors utilising JAK2 only or JAK2/TYK2 pairs. The relevance of selective enzymatic inhibition of specific JAK enzymes to clinical effect is not currently known. Both the parent compound and the active metabolites inhibit cytokine signalling with similar levels of selectivity.
Pharmacodynamic effects: Clinical biomarkers: Treatment with CIBINQO was associated with dose-dependent reduction in serum markers of inflammation, including high sensitivity C-reactive protein (hsCRP), interleukin-31 (IL-31) and thymus and activation-regulated chemokine (TARC). These changes returned to near baseline within 4 weeks of drug discontinuation.
Cardiac electrophysiology: The effect of CIBINQO on the QTc interval was examined in subjects who received single doses of abrocitinib 600 mg in a placebo- and positive-controlled thorough QT study. In a concentration-QTc analysis, abrocitinib at therapeutic and supratherapeutic plasma concentrations did not lead to a prolongation of the QTc intervals.
Clinical efficacy and safety: The efficacy and safety of CIBINQO as monotherapy and in combination with background medicated topical therapies over 12 to 16 weeks were evaluated in 1,616 patients in 3 pivotal Phase 3 randomised, double-blind, placebo-controlled studies (MONO-1, MONO-2, and COMPARE). In addition, the efficacy and safety of CIBINQO in monotherapy over 52 weeks (with the option of rescue treatment in flaring subjects) was evaluated in 1,233 subjects in a Phase 3 induction, randomised withdrawal, double-blind, placebo-controlled study (REGIMEN). The patients in these 4 studies had moderate-to-severe atopic dermatitis as defined by Investigator's Global Assessment (IGA) score ≥3, Eczema Area and Severity Index (EASI) score ≥16, body surface area (BSA) involvement ≥10%, and Peak Pruritus Numerical Rating Scale (PP-NRS) ≥4 at baseline visit prior to randomisation. Patients who had a prior inadequate response or for whom topical treatments were medically unadvisable, or who had received systemic therapies were eligible for inclusion. All patients who completed the parent studies were eligible to enrol into the long-term extension study EXTEND.
Baseline characteristics: In the placebo-controlled studies (MONO-1, MONO-2, COMPARE) and the open label induction, randomised withdrawal study (REGIMEN) across all treatment groups 41.4% to 51.1% were female, 59.3% to 77.8% were Caucasian, 15.0% to 33.0% were Asian and 4.1% to 8.3% were Black, and the mean age was 32.1 to 37.7 years. In these studies, 32.2% to 40.8% had a baseline IGA of 4 (severe atopic dermatitis), and 41.4% to 59.5% of patients had received prior systemic treatment for atopic dermatitis. The baseline mean EASI score ranged from 28.5 to 30.9, the baseline PP-NRS ranged from 7.0 to 7.3 and the baseline Dermatology Life Quality Index (DLQI) ranged from 14.4 to 16.0.
Clinical response: 12-week monotherapy (MONO-1, MONO-2) and 16-week TCS combination (COMPARE) studies: A significantly larger proportion of patients achieved both primary endpoints IGA 0 or 1 and/or EASI-75 with 100 mg or 200 mg once daily CIBINQO compared with placebo at Week 12 or Week 16 (see Table 1).
A significantly greater proportion of patients achieved at least a PP-NRS 4-point improvement with 100 mg or 200 mg once daily CIBINQO compared with placebo. This improvement was observed as early as Week 2 and persisting through Week 12 (Figure 1).
In the COMPARE study, superiority of CIBINQO 200 mg compared with dupilumab at Week 2 was demonstrated for the proportion of patients achieving PP-NRS 4-point improvement with significantly higher itch responses seen as early as Day 4 after the first dose.
Treatment effects in subgroups (e.g., weight, age, sex, race and prior systemic immunosuppressant treatment) in MONO-1, MONO-2 and COMPARE were consistent with the results in the overall study population. (See Table 1 and 2.)

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The proportion of patients who achieved PP-NRS4 over time in studies MONO-1, MONO-2 and COMPARE are shown in Figure 1. (See Figure 1.)

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Health-related outcomes: Both the 100 mg and 200 mg doses of CIBINQO, whether as monotherapy or combination therapy, led to a higher proportion of patients with reductions in DLQI than placebo at 12 weeks. Patients also had improved symptoms of atopic dermatitis, sleep disturbances, and anxiety and depression symptoms, from the patient's perspective, as measured by the POEM after 12 weeks, the sleep loss subscale of the SCORAD and the Hospital Anxiety and Depression Scale (HAD) scores.
Dose reduction: Open-label induction, randomised withdrawal study (REGIMEN): A total of 1,233 patients received open-label abrocitinib 200 mg once daily in the 12-week run-in phase. Among these patients, 798 patients (64.7%) met responder criteria (defined as achieving IGA [0 or 1] response and EASI-75) and were randomised to placebo (267 patients), abrocitinib 100 mg once daily (265 patients) or abrocitinib 200 mg once daily (266 patients).
Continuous treatment (200 mg continuous) and induction-maintenance treatment (200 mg for 12 weeks followed by 100 mg) prevented flare with 81.1% and 57.4% probability, respectively, versus 19.1% among patients who withdrew treatment (randomised to placebo) after 12 weeks of induction. Three hundred fifty-one (351) patients including 16.2% of 200 mg, 39.2% of 100 mg and 76.4% of placebo patients received rescue medication of 200 mg abrocitinib in combination with topical therapy. (See Figure 2.)

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Long-term efficacy: Eligible patients who completed the full treatment period of a qualifying parent study (e.g., MONO-1, MONO-2, COMPARE, REGIMEN) were considered for enrollment in the long-term extension study EXTEND. In EXTEND, patients received CIBINQO with or without background medicated topical therapy. Patients who were previously randomised to CIBINQO 100 mg or 200 mg once daily in parent studies continued the same dose in EXTEND as in the parent study, and the blind was maintained.
Among patients who achieved response after 12 weeks of treatment and entered EXTEND, the majority of patients maintained their response at Week 48 of cumulative treatment for both doses of CIBINQO [60% and 70% for IGA (0 or 1) response, 79% and 87% for EASI-75, and 62% and 83% for PP-NRS4 with 100 mg once daily and 200 mg once daily, respectively].
Among patients who did not achieve response after 12 weeks of treatment and entered EXTEND, a proportion of patients achieved late-onset response by Week 24 (from baseline) of continued treatment with CIBINQO [25% for IGA (0 or 1) response, and 50% and 59% for EASI-75 with 100 mg once daily and 200 mg once daily, respectively].
Patients who received dupilumab in the COMPARE study and subsequently entered EXTEND were randomised to either 100 mg or 200 mg of CIBINQO once daily upon entering EXTEND. Among non-responders to dupilumab, a substantial proportion of patients achieved response 12 weeks after switching to CIBINQO [34% and 47% for IGA (0 or 1) response, and 68% and 80% for EASI-75 with 100 mg once daily or 200 mg once daily, respectively].
Pharmacokinetics: Absorption: Abrocitinib is well-absorbed with over 91% extent of oral absorption and absolute oral bioavailability of approximately 60%. The oral absorption of abrocitinib is rapid and peak plasma concentrations are reached within 1 hour. Both Cmax and AUC of abrocitinib increased dose proportionally from 30 to 400 mg. Co-administration of CIBINQO with a high-fat meal had no clinically relevant effect on abrocitinib exposures (AUC and Cmax increased by approximately 26% and 29%, respectively, and Tmax was prolonged by 2 hours). In clinical studies, CIBINQO was administered without regard to food (see Dosage & Administration).
Distribution: After intravenous administration, the volume of distribution of CIBINQO is about 100 L. Approximately 64%, 37% and 29% of circulating abrocitinib and its active metabolites M1 and M2, respectively, are bound to plasma proteins. Abrocitinib and its active metabolites distribute equally between red blood cells and plasma.
Biotransformation: The in vitro metabolism of abrocitinib is mediated by multiple CYP enzymes, CYP2C19 (~53%), CYP2C9 (~30%), CYP3A4 (~11%) and CYP2B6 (~6%). In a human radiolabeled study, abrocitinib was the most prevalent circulating species, with 3 polar mono-hydroxylated metabolites identified as M1 (3-hydroxypropyl), M2 (2-hydroxypropyl), and M4 (pyrrolidinone pyrimidine). At steady state, M2 (11%) and M4 (24%) are major metabolites and M1 (9.6%) is a minor metabolite. Of the 3 metabolites in circulation, M1 and M2 have similar JAK inhibitory profiles as abrocitinib, while M4 was pharmacologically inactive. The pharmacologic activity of CIBINQO is attributable to the unbound exposures of parent molecule (~60%) as well as M1 (~10%) and M2 (~30%) in systemic circulation. The sum of unbound exposures of abrocitinib, M1 and M2, each expressed in molar units and adjusted for relative potencies, is referred to as the abrocitinib active moiety.
Elimination: The total body clearance of abrocitinib is 22 L/hr. The elimination half-life of abrocitinib is about 6 hours. Steady-state plasma concentrations of abrocitinib are achieved within 48 hours after once daily administration. CIBINQO is eliminated primarily by metabolic clearance mechanisms, with less than 1% of the dose excreted in urine as unchanged drug. The urinary excretion of the metabolites of abrocitinib is 16%, 14% and 15% of the administered abrocitinib dose for M1, M2 and M4, respectively, and the metabolites are substrates of OAT3 transporter. As a percent of total clearance, the renal elimination for M1 is 74% and >90% for M2 and M4, while the faecal elimination of M1, M2, and M4 are 8%, 4%, and 2% respectively.
Special populations: Body weight, gender, genotype, race, and age: Body weight, gender, CYP2C19/2C9 genotype, race, and age did not have a clinically meaningful effect on CIBINQO exposure (see Dosage & Administration).
Adolescents (≥12 to <18 years): Based on population pharmacokinetic analysis, the mean CIBINQO steady-state exposures in adolescent patients compared to adults at their typical body weights was not significantly different.
Paediatric (<12 years): The pharmacokinetics of CIBINQO in paediatric patients under 12 years of age have not yet been established (see Dosage & Administration).
Renal impairment: In a renal impairment study, patients with severe (eGFR <30 mL/min) and moderate (eGFR 30 to <60 mL/min) renal impairment had approximately 191% and 110% increase in active moiety AUCinf, respectively, compared to patients with normal renal function (eGFR ≥90 mL/min; see Dosage & Administration). Pharmacokinetics of abrocitinib have not been determined in patients with mild renal impairment, however, based on the results observed in other groups, an increase of up to 70% in active moiety exposure is expected in patients with mild renal impairment (eGFR 60 to <90 mL/min). The increase of up to 70% is not clinically meaningful as the efficacy and safety of abrocitinib in atopic dermatitis patients with mild renal impairment (n=756) was comparable to the overall population in Phase 2 and 3 clinical studies. The eGFR in individual patients was estimated using Modification of Diet in Renal Disease (MDRD) formula.
CIBINQO has not been studied in patients with ESRD on renal replacement therapy (see Dosage & Administration). In Phase 3 clinical studies, CIBINQO was not evaluated in patients with atopic dermatitis with baseline creatinine clearance values less than 40 mL/min.
Hepatic impairment: Patients with mild (Child Pugh A) and moderate (Child Pugh B) hepatic impairment had approximately 4% decrease and 15% increase in active moiety AUCinf, respectively, compared to patients with normal hepatic function. These changes are not clinically significant, and no dose adjustment is required in patients with mild or moderate hepatic impairment (see Dosage & Administration). In clinical studies, CIBINQO was not evaluated in patients with severe (Child Pugh C) hepatic impairment (see Contraindications), or in patients screened positive for active hepatitis B or hepatitis C (see Precautions).
Toxicology: Preclinical safety data: General toxicity: In toxicity studies of up to 1 month of CIBINQO dosing in rats initiated at 6-8 weeks and 9-weeks of age, a bone dystrophy finding was noted, at exposure of greater than or equal to 22 times the human AUC at the maximum recommended human dose (MRHD) of 200 mg. No bone findings were observed in rats at any dose in the 6-month toxicity study (up to 25 times the human AUC at the MRHD of 200 mg) or in any of the toxicity studies in cynomolgus monkeys (up to 30 times the human AUC at the MRHD of 200 mg).
Genotoxicity: CIBINQO is not mutagenic in the bacterial mutagenicity assay (Ames assay). Although CIBINQO is aneugenic in the in vitro TK6 micronucleus assay, CIBINQO is not aneugenic or clastogenic based on the results of the in vivo rat bone marrow micronucleus assay.
Carcinogenicity: No evidence of tumorigenicity was observed in Tg.rasH2 mice administered CIBINQO for 26 weeks at exposures equal to 0.6 and 0.2 times the human AUC at the MRHD of 200 mg in female and male mice, respectively. In the 104-week oral carcinogenicity study, CIBINQO resulted in statistically higher incidence of benign thymomas in female rats at exposures greater than or equal to 2.7 times the human AUC at the MRHD of 200 mg. No evidence of CIBINQO-related tumorigenicity was observed following oral CIBINQO administration in female rats at exposures equal to 0.6 times the human AUC at the MRHD of 200 mg or in male rats at exposures equal to 13 times the human AUC at the MRHD of 200 mg.
Reproductive and developmental toxicity: CIBINQO had no effects on male fertility or spermatogenesis at doses up to 70 mg/kg/day at exposures equal to 25 times the human AUC at the MRHD of 200 mg. CIBINQO resulted in effects on female fertility (lower fertility index, corpora lutea, and implantation sites) at exposures equal to 28 times the human AUC at the MRHD of 200 mg and higher postimplantation loss in rats at exposures greater than or equal to 10 times the human AUC at the MRHD of 200 mg. The effects on female fertility in rats reversed 1 month after cessation of CIBINQO administration. No effects on female fertility were noted at exposures equal to 1.9 times the human AUC at the MRHD of 200 mg.
No foetal malformations were observed in embryo-foetal development studies in rats or rabbits. In an embryo-foetal development study in pregnant rabbits, oral administration of CIBINQO during gestation days 7 to 19 had no effects on embryo-foetal survival or foetal morphological development at exposures equal to 7.6 times the human AUC at the MRHD of 200 mg. CIBINQO resulted in an increase incidences of unossified forelimb phalanges at exposures equal to 7.6 times the human AUC at the MRHD of 200 mg.
In an embryo-foetal development study in pregnant rats, oral administration of CIBINQO during gestation days 6 to 17 resulted in increased embryo-foetal lethality at exposures equal to 16 times the human AUC at the MRHD of 200 mg. No embryo-foetal lethality was observed in pregnant rats orally dosed with CIBINQO during organogenesis at exposures equal to 10 times the human AUC at the MRHD of 200 mg. CIBINQO resulted in increased incidences of skeletal variations of short 13th ribs at exposures greater than or equal to 10 times the human AUC at the MRHD of 200 mg and reduced ventral processes, thickened ribs, and unossified metatarsals were observed at exposures equal to 16 times the human AUC at the MRHD of 200 mg. No skeletal variations were noted in rats at exposures equal to 2.3 times the human AUC at the MRHD of 200 mg.
In a rat pre- and postnatal development study in pregnant rats, oral administration of CIBINQO during gestation day 6 through lactation day 21 resulted in dystocia with prolonged parturition and lower offspring body weights at exposures greater than or equal to 10 times the human AUC at the MRHD of 200 mg and lower postnatal survival at exposures equal to 16 times the human AUC at the MRHD of 200 mg. No maternal or developmental toxicity was observed in either dams or offspring at exposures equal to 2.3 times the human AUC at the MRHD of 200 mg.
Juvenile animal toxicity: In the juvenile rat study, oral administration of CIBINQO to rats initiated at postnatal Day 10 resulted in bone findings (malrotated and/or impaired use of the forelimbs, hindlimbs, or paws, fractures and/or abnormalities of the femoral head, and bony dystrophy), at exposures ≥0.8 times the human AUC at the MRHD of 200 mg. Irreversible low femur length and width were observed at exposures 26 times the human AUC at the MRHD of 200 mg.
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