Verzenio abemaciclib 150 mg Tablet, 56-count — NDC 0002-5337-63 (Billing 00002-5337-63)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Abemaciclib is an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6). These kinases are activated upon binding to D-cyclins. In estrogen receptor-positive (ER+) breast cancer cell lines, cyclin D1 and CDK4/6 promote phosphorylation of the retinoblastoma protein (Rb), cell cycle progression, and cell proliferation.

In vitro, continuous exposure to abemaciclib inhibited Rb phosphorylation and blocked progression from G1 into S phase of the cell cycle, resulting in senescence and apoptosis. In breast cancer xenograft models, abemaciclib dosed daily without interruption as a single agent or in combination with antiestrogens resulted in reduction of tumor size.

12.2Pharmacodynamics Cardiac Electrophysiology Based on evaluation of the QTc interval in patients and in a healthy volunteer study, abemaciclib did not cause large mean increases (i.e., 20 ms) in the QTc interval.

12.3Pharmacokinetics The pharmacokinetics of abemaciclib were characterized in patients with solid tumors, including breast cancer, and in healthy subjects. Following single and repeated twice daily dosing of 50 mg (0.3 times the approved recommended 150 mg dosage) to 200 mg of abemaciclib, the increase in plasma exposure (AUC) and C max was approximately dose proportional. Steady state was achieved within 5 days following repeated twice daily dosing, and the estimated geometric mean accumulation ratio was 2.3 (50% CV) and 3.2 (59% CV) based on C max and AUC, respectively.

Absorption The absolute bioavailability of abemaciclib after a single oral dose of 200 mg is 45% (19% CV). The median T max of abemaciclib is 8.0 hours (range: 4.1-24.0 hours). Effect of Food A high-fat, high-calorie meal (approximately 800 to 1000 calories with 150 calories from protein, 250 calories from carbohydrate, and 500 to 600 calories from fat) administered to healthy subjects increased the AUC of abemaciclib plus its active metabolites by 9% and increased C max by 26%.

Distribution In vitro, abemaciclib was bound to human plasma proteins, serum albumin, and alpha-1-acid glycoprotein in a concentration independent manner from 152 ng/mL to 5066 ng/mL. In a clinical study, the mean (standard deviation, SD) bound fraction was 96.3% (1.1) for abemaciclib, 93.4% (1.3) for M2, 96.8% (0.8) for M18, and 97.8% (0.6) for M20. The geometric mean systemic volume of distribution is approximately 690.3 L (49% CV).

In patients with advanced cancer, including breast cancer, concentrations of abemaciclib and its active metabolites M2 and M20 in cerebrospinal fluid are comparable to unbound plasma concentrations. Elimination The geometric mean hepatic clearance (CL) of abemaciclib in patients was

26.0L/h (51% CV), and the mean plasma elimination half-life for abemaciclib in patients was 18.3 hours (72% CV). Metabolism Hepatic metabolism is the main route of clearance for abemaciclib. Abemaciclib is metabolized to several metabolites primarily by cytochrome P450 (CYP) 3A4, with formation of N-desethylabemaciclib (M2) representing the major metabolism pathway.

Additional metabolites include hydroxyabemaciclib (M20), hydroxy-N-desethylabemaciclib (M18), and an oxidative metabolite (M1). M2, M18, and M20 are equipotent to abemaciclib and their AUCs accounted for 25%, 13%, and 26% of the total circulating analytes in plasma, respectively. Excretion After a single 150 mg oral dose of radiolabeled abemaciclib, approximately 81% of the dose was recovered in feces and approximately 3% recovered in urine.

The majority of the dose eliminated in feces was metabolites. Specific Populations Age, Gender, and Body Weight Based on a population pharmacokinetic analysis in patients with cancer, age (range 24-91 years), gender (134 males and 856 females), and body weight (range 36-175 kg) had no effect on the exposure of abemaciclib. Patients with Renal Impairment In a population pharmacokinetic analysis of 990 individuals, in which 381 individuals had mild ren… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Abemaciclib is an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6). These kinases are activated upon binding to D-cyclins. In estrogen receptor-positive (ER+) breast cancer cell lines, cyclin D1 and CDK4/6 promote phosphorylation of the retinoblastoma protein (Rb), cell cycle progression, and cell proliferation.

In vitro, continuous exposure to abemaciclib inhibited Rb phosphorylation and blocked progression from G1 into S phase of the cell cycle, resulting in senescence and apoptosis. In breast cancer xenograft models, abemaciclib dosed daily without interruption as a single agent or in combination with antiestrogens resulted in reduction of tumor size.

12.3Pharmacokinetics The pharmacokinetics of abemaciclib were characterized in patients with solid tumors, including breast cancer, and in healthy subjects. Following single and repeated twice daily dosing of 50 mg (0.3 times the approved recommended 150 mg dosage) to 200 mg of abemaciclib, the increase in plasma exposure (AUC) and C max was approximately dose proportional. Steady state was achieved within 5 days following repeated twice daily dosing, and the estimated geometric mean accumulation ratio was 2.3 (50% CV) and 3.2 (59% CV) based on C max and AUC, respectively.

Absorption The absolute bioavailability of abemaciclib after a single oral dose of 200 mg is 45% (19% CV). The median T max of abemaciclib is 8.0 hours (range: 4.1-24.0 hours). Effect of Food A high-fat, high-calorie meal (approximately 800 to 1000 calories with 150 calories from protein, 250 calories from carbohydrate, and 500 to 600 calories from fat) administered to healthy subjects increased the AUC of abemaciclib plus its active metabolites by 9% and increased C max by 26%.

Distribution In vitro, abemaciclib was bound to human plasma proteins, serum albumin, and alpha-1-acid glycoprotein in a concentration independent manner from 152 ng/mL to 5066 ng/mL. In a clinical study, the mean (standard deviation, SD) bound fraction was 96.3% (1.1) for abemaciclib, 93.4% (1.3) for M2, 96.8% (0.8) for M18, and 97.8% (0.6) for M20. The geometric mean systemic volume of distribution is approximately 690.3 L (49% CV).

In patients with advanced cancer, including breast cancer, concentrations of abemaciclib and its active metabolites M2 and M20 in cerebrospinal fluid are comparable to unbound plasma concentrations. Elimination The geometric mean hepatic clearance (CL) of abemaciclib in patients was

26.0L/h (51% CV), and the mean plasma elimination half-life for abemaciclib in patients was 18.3 hours (72% CV). Metabolism Hepatic metabolism is the main route of clearance for abemaciclib. Abemaciclib is metabolized to several metabolites primarily by cytochrome P450 (CYP) 3A4, with formation of N-desethylabemaciclib (M2) representing the major metabolism pathway.

Additional metabolites include hydroxyabemaciclib (M20), hydroxy-N-desethylabemaciclib (M18), and an oxidative metabolite (M1). M2, M18, and M20 are equipotent to abemaciclib and their AUCs accounted for 25%, 13%, and 26% of the total circulating analytes in plasma, respectively. Excretion After a single 150 mg oral dose of radiolabeled abemaciclib, approximately 81% of the dose was recovered in feces and approximately 3% recovered in urine.

The majority of the dose eliminated in feces was metabolites. Specific Populations Age, Gender, and Body Weight Based on a population pharmacokinetic analysis in patients with cancer, age (range 24-91 years), gender (134 males and 856 females), and body weight (range 36-175 kg) had no effect on the exposure of abemaciclib. Patients with Renal Impairment In a population pharmacokinetic analysis of 990 individuals, in which 381 individuals had mild renal impairment (60 mL/min ≤ CLcr <90 mL/min) and 126 individuals had moderate renal impairment (30 mL/min ≤ CLcr <60 mL/min), mild and moderate renal impairment had no effect on the exposure of abemaciclib [see Use in Specific Populations ( 8.6 )] .

The effect of severe renal impairment (CLcr <30 mL/min) on pharmacokinetics of abemaciclib is unknown. Patients with Hepatic Impairment Following a single 200 mg oral dose of abemaciclib, the relative potency adjusted unbound AUC 0-INF of abemaciclib plus its active metabolites (M2, M18, M20) in plasma increased 1.2-fold in subjects with mild hepatic impairment (Child-Pugh A, n=9), 1.1-fold in subjects with moderate hepatic impairment (Child-Pugh B, n=10), and 2.4-fold in subjects with severe hepatic impairment (Child-Pugh C, n=6) relative to subjects with normal hepatic function (n=10) [see Use in Specific Populations ( 8.7 )] .

In subjects with severe hepatic impairment, the mean pl… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Cardiac Electrophysiology Based on evaluation of the QTc interval in patients and in a healthy volunteer study, abemaciclib did not cause large mean increases (i.e., 20 ms) in the QTc interval.

14 CLINICAL STUDIES

14.1Early Breast Cancer VERZENIO in Combination with Standard Endocrine Therapy (monarchE) Patients with HR-positive, HER2-negative, node-positive early breast cancer at high risk of recurrence monarchE (NCT03155997) was a randomized (1:1), open-label, two cohort, multicenter study in adult women and men with HR-positive, HER2-negative, node-positive, resected, early breast cancer with clinical and pathological features consistent with a high risk of disease recurrence. To be enrolled, patients had to have HR-positive HER2-negative early breast cancer with tumor involvement in at least 1 axillary lymph node (pALN) and to be enrolled in cohort 1 had to have either: ≥4 pALN or 1-3 pALN and at least one of: tumor grade 3 or tumor size ≥50 mm Patients enrolled in cohort 2 could not have met the eligibility criteria for cohort 1.

To be enrolled in cohort 2, patients had to have 1-3 pALN and Ki-67 score ≥20%. Breast tumor samples were tested at central sites using the Ki-67 IHC MIB-1 pharmDx (Dako Omnis) assay to establish if the Ki-67 score was ≥20%. Patients were randomized to receive 2 years of VERZENIO plus physician's choice of standard endocrine therapy or standard endocrine therapy alone.

Randomization to treatment was stratified by prior treatment (neoadjuvant chemotherapy versus adjuvant chemotherapy versus no chemotherapy); menopausal status (premenopausal versus postmenopausal); and region (North America/Europe versus Asia versus other). Men were stratified as postmenopausal. After the end of the study treatment period, standard adjuvant endocrine therapy was continued for a duration of at least 5 years if deemed medically appropriate.

The major efficacy outcome measure was invasive disease–free survival (IDFS). IDFS was defined as the time from randomization to the first occurrence of: ipsilateral invasive breast tumor recurrence, regional invasive breast cancer recurrence, distant recurrence, contralateral invasive breast cancer, second primary non-breast invasive cancer, or death attributable to any cause. Overall survival (OS) was an additional outcome measure.

A statistically significant difference in IDFS was observed in the intent-to-treat (ITT) population which was primarily attributed to the patients treated in cohort 1. Of 5637 patients randomized, 5120 (91%) were randomized in cohort 1. Patient median age was 51 years (range, 22-89 years), 99% were women, 70% were White, 24% were Asian, 1.7% were Black or African American, 2.1% were American Indian or Alaska Native, and 0.1% were Native Hawaiian or Other Pacific Islander.

Forty-three percent of patients were premenopausal. Most patients received prior chemotherapy (37% neoadjuvant, 59% adjuvant) and prior radiotherapy (96%). Sixty-five percent of the patients had 4 or more positive lymph nodes with 22% having ≥10 positive lymph nodes, 41% had Grade 3 tumor, and 24% had pathological tumor size ≥50 mm.

The majority of patients (99%) had estrogen receptor positive disease and 87% had progesterone receptor positive disease. Initial endocrine therapy received by patients included letrozole (39%), tamoxifen (31%), anastrozole (22%), or exemestane (8%). Efficacy results for cohort 1 are summarized in Table 16 and Figure 1 .

Table 16: Efficacy Results in monarchE in Cohort 1 Abbreviations: CI = confidence interval. VERZENIO Plus Tamoxifen or an Aromatase Inhibitor N=2555 Tamoxifen or an Aromatase Inhibitor N=2565 Invasive Disease–Free Survival (IDFS) Number of patients with an event, n (%) 317 (12) 474 (18) Hazard ratio (95% CI) 0.65 (0.57, 0.75) IDFS at 48 months, % (95% CI) 85.5 (83.8, 87.0) 78.6 (76.7, 80.4) Figure 1: Kaplan-Meier Curves of Invasive Disease–Free Survival VERZENIO plus Tamoxifen or an Aromatase Inhibitor versus Tamoxifen or an Aromatase Inhibitor in Cohort 1 (monarchE) A final OS analysis was conducted after 630 death events were observed in cohort 1.

Exploratory OS results showed a HR of 0.84 (95% CI: 0.71, 0.98) for patients tr… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Abemaciclib was assessed for carcinogenicity in a 2-year rat study. Abemaciclib was not carcinogenic in male and female rats at oral doses up to 3 mg/kg/day (approximately 1 time the exposure at the maximum recommended human dose based on AUC). Abemaciclib and its active human metabolites M2 and M20 were not mutagenic in a bacterial reverse mutation (Ames) assay or clastogenic in an in vitro chromosomal aberration assay in Chinese hamster ovary cells or human peripheral blood lymphocytes.

Abemaciclib, M2, and M20 were not clastogenic in an in vivo rat bone marrow micronucleus assay. Abemaciclib may impair fertility in males of reproductive potential. In repeat-dose toxicity studies up to 3-months duration, abemaciclib-related findings in the testis, epididymis, prostate, and seminal vesicle at doses ≥10 mg/kg/day in rats and ≥0.3 mg/kg/day in dogs included decreased organ weights, intratubular cellular debris, hypospermia, tubular dilatation, atrophy, and degeneration/necrosis.

These doses in rats and dogs resulted in approximately 2 and 0.02 times, respectively, the exposure (AUC) in humans at the maximum recommended human dose. In a rat male fertility study, abemaciclib had no effects on mating and fertility at oral doses up to 10 mg/kg/day (approximately 2 times the exposure at the maximum recommended human dose based on AUC). In a rat female fertility and early embryonic development study, abemaciclib did not affect mating and fertility at doses up to 20 mg/kg/day (approximately 3 times the exposure at the maximum recommended human dose based on AUC).

13.2Animal Toxicology and/or Pharmacology In repeat-dose toxicity studies up to 6-months duration, oral administration of abemaciclib resulted in retinal atrophy of the eyes in mice at a dose of 150 mg/kg/day (approximately 10 times the exposure at the maximum recommended human dose based on AUC) and in rats at a dose of 30 mg/kg/day (approximately 5 times the exposure at the maximum recommended human dose based on AUC). In a 2-year rat carcinogenicity study, oral administration of abemaciclib resulted in retinal atrophy in the eyes at doses ≥0.3 mg/kg/day (approximately 0.05 times the exposure at the maximum recommended human dose based on AUC).