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Verzenio

CLINICAL PHARMACOLOGY

Mechanism 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.

Pharmacodynamics

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.

Pharmacokinetics

The pharmacokinetics of
abemaciclib were characterized in patients with solid tumors, including
metastatic 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 Cmax 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 Cmax and AUC,
respectively.

Absorption

The absolute bioavailability of
abemaciclib after a single oral dose of 200 mg is 45% (19% CV). The median Tmax
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 Cmax 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 26.0 L/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
]. 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 AUC0-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
]. In subjects with severe hepatic impairment, the mean plasma
elimination half-life of abemaciclib increased to 55 hours compared to 24 hours
in subjects with normal hepatic function.

Drug Interaction Studies

Effects Of Other Drugs On Abemaciclib

Strong CYP3A Inhibitors

Ketoconazole (a strong CYP3A
inhibitor) is predicted to increase the AUC of abemaciclib by up to 16-fold.

Itraconazole (a strong CYP3A
inhibitor) is predicted to increase the relative potency adjusted unbound AUC
of abemaciclib plus its active metabolites (M2, M18 and M20) by 2.2-fold.
Coadministration of 500 mg twice daily doses of clarithromycin (a strong CYP3A
inhibitor) with a single 50 mg dose of VERZENIO (0.3 times the approved
recommended 150 mg dosage) increased the relative potency adjusted unbound AUC0-INF
of abemaciclib plus its active metabolites (M2, M18, and M20) by 1.7-fold
relative to abemaciclib alone in cancer patients.

Moderate CYP3A Inhibitors

Diltiazem and verapamil
(moderate CYP3A inhibitors) are predicted to increase the relative potency
adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and
M20) by 1.7-fold and 1.3-fold, respectively.

Strong CYP3A Inducers

Coadministration of 600 mg
daily doses of rifampin (a strong CYP3A inducer) with a single 200 mg dose of
VERZENIO decreased the relative potency adjusted unbound AUC0-INF of
abemaciclib plus its active metabolites (M2, M18, and M20) by 67% in healthy
subjects.

Moderate CYP3A Inducers

The effect of moderate CYP3A
inducers on the pharmacokinetics of abemaciclib is unknown.

Loperamide

Co-administration of a single 8
mg dose of loperamide with a single 400 mg dose of abemaciclib in healthy
subjects increased the relative potency adjusted unbound AUC0-INF of
abemaciclib plus its active metabolites (M2 and M20) by 12%, which is not
considered clinically relevant.

Endocrine Therapies

In clinical studies in patients
with breast cancer, there was no clinically relevant effect of fulvestrant,
anastrozole, letrozole, or exemestane on abemaciclib pharmacokinetics.

Effects Of Abemaciclib On Other
Drugs

Loperamide

In a clinical drug interaction
study in healthy subjects, coadministration of a single 8 mg dose of loperamide
with a single 400 mg abemaciclib (2.7 times the approved recommended 150 mg
dosage) increased loperamide AUC0-INF by 9% and Cmax by 35% relative to
loperamide alone. These increases in loperamide exposure are not considered
clinically relevant.

Metformin

In a clinical drug interaction
study in healthy subjects, coadministration of a single 1000 mg dose of
metformin, a clinically relevant substrate of renal OCT2, MATE1, and MATE2-K
transporters, with a single 400 mg dose of abemaciclib (2.7 times the approved
recommended 150 mg dosage) increased metformin AUC0-INF by 37% and Cmax by 22%
relative to metformin alone. Abemaciclib reduced the renal clearance and renal
secretion of metformin by 45% and 62%, respectively, relative to metformin
alone, without any effect on glomerular filtration rate (GFR) as measured by
iohexol clearance and serum cystatin C.

Endocrine Therapies

In clinical studies in patients
with breast cancer, there was no clinically relevant effect of abemaciclib on
the pharmacokinetics of fulvestrant, anastrozole, letrozole, or exemestane.

In Vitro Studies

Transporter Systems

Abemaciclib and its major
active metabolites inhibit the renal transporters OCT2, MATE1, and MATE2-K at
concentrations achievable at the approved recommended dosage. The observed
serum creatinine increase in clinical studies with abemaciclib is likely due to
inhibition of tubular secretion of creatinine via OCT2, MATE1, and MATE2-K [see
Adverse Effects]. Abemaciclib and its major metabolites at clinically
relevant concentrations do not inhibit the hepatic uptake transporters OCT1,
OATP1B1, and OATP1B3 or the renal uptake transporters OAT1 and OAT3.

Abemaciclib is a substrate of
P-gp and BCRP. Abemaciclib and its major active metabolites, M2 and M20, are
not substrates of hepatic uptake transporters OCT1, organic anion transporting
polypeptide 1B1 (OATP1B1), or OATP1B3.

Abemaciclib Inhibits P-gp And
BCRP

The clinical consequences of
this finding on sensitive P-gp and BCRP substrates are unknown.

CYP Metabolic Pathways

Abemaciclib and its major
active metabolites, M2 and M20, do not induce CYP1A2, CYP2B6, or CYP3A at
clinically relevant concentrations. Abemaciclib and its major active
metabolites, M2 and M20, down regulate mRNA of CYPs, including CYP1A2, CYP2B6,
CYP2C8, CYP2C9, CYP2D6 and CYP3A4. The mechanism of this down regulation and
its clinical relevance are not understood. However, abemaciclib is a substrate
of CYP3A4, and time-dependent changes in pharmacokinetics of abemaciclib as a
result of autoinhibition of its metabolism was not observed.

P-gp And BCRP Inhibitors

In vitro, abemaciclib is a
substrate of P-gp and BCRP. The effect of P-gp or BCRP inhibitors on the
pharmacokinetics of abemaciclib has not been studied.

Clinical Studies

VERZENIO In Combination With An
Aromatase Inhibitor (Anastrozole Or Letrozole) (MONARCH 3)

Postmenopausal Women With HR-positive,
HER2-Negative Advanced Or Metastatic Breast Cancer With No Prior Systemic
Therapy In This Disease Setting

MONARCH 3 was a randomized
(2:1), double-blinded, placebo-controlled, multicenter study in postmenopausal
women with HR-positive, HER2-negative advanced or metastatic breast cancer in
combination with a nonsteroidal aromatase inhibitor as initial endocrine-based
therapy, including patients not previously treated with systemic therapy for
breast cancer.

Randomization was stratified by
disease site (visceral, bone only, or other) and by prior (neo)adjuvant
endocrine therapy (aromatase inhibitor versus other versus no prior endocrine
therapy). A total of 493 patients were randomized to receive 150 mg VERZENIO or
placebo orally twice daily, plus physician’s choice of letrozole (80% of
patients) or anastrozole (20% of patients). Patient median age was 63 years
(range, 32-88 years) and the majority were White (58%) or Asian (30%). A total
of 51% had received prior systemic therapy and 39% of patients had received
chemotherapy, 53% had visceral disease, and 22% had bone-only disease.

Efficacy results are summarized
in Table 12 and Figure 1. PFS was evaluated according to RECIST version 1.1 and
PFS assessment based on a blinded independent radiologic review was consistent
with the investigator assessment. Consistent results were observed across
patient stratification subgroups of disease site and prior (neo)adjuvant
endocrine therapy. At the time of the PFS analysis, 19% of patients had died,
and overall survival data were immature.

Table 12: Efficacy Results
in MONARCH 3 (Investigator Assessment, Intent-to-Treat Population)











  VERZENIO plus Anastrozole or Letrozole Placebo plus Anastrozole or Letrozole
Progression-Free Survival N=328 N=165
Number of patients with an event (n, %) 138 (42.1) 108 (65.5)
Median (months, 95% CI) 28.2 (23.5, NR) 14.8 (11.2, 19.2)
Hazard ratio (95% CI) 0.540 (0.418, 0.698)
p-value <0.0001
Objective Response for Patients with Measurable Disease N=267 N=132
Objective response ratea,b (n, %) 148 (55.4) 53 (40.2)
95% CI 49.5, 61.4 31.8, 48.5
Abbreviations: CI = confidence interval, NR = not
reached.
a Complete response + partial response.
b Based upon confirmed responses.

Figure 1: Kaplan-Meier Curves of Progression-Free
Survival: VERZENIO plus Anastrozole or Letrozole versus Placebo plus
Anastrozole or Letrozole (MONARCH 3)


VERZENIO In Combination With Fulvestrant
(MONARCH 2)

Patients With HR-positive,
HER2-Negative Advanced Or Metastatic Breast Cancer With Disease Progression On
Or After Prior Adjuvant Or Metastatic Endocrine Therapy

MONARCH 2 (NCT02107703) was a
randomized, placebo-controlled, multicenter study in women with HR-positive,
HER2-negative metastatic breast cancer in combination with fulvestrant in
patients with disease progression following endocrine therapy who had not
received chemotherapy in the metastatic setting. Randomization was stratified
by disease site (visceral, bone only, or other) and by sensitivity to prior
endocrine therapy (primary or secondary resistance). Primary endocrine therapy
resistance was defined as relapse while on the first 2 years of adjuvant
endocrine therapy or progressive disease within the first 6 months of first
line endocrine therapy for metastatic breast cancer. A total of 669 patients
were randomized to receive VERZENIO or placebo orally twice daily plus
intramuscular injection of 500 mg fulvestrant on days 1 and 15 of cycle 1 and
then on day 1 of cycle 2 and beyond (28-day cycles). Pre/perimenopausal women
were enrolled in the study and received the gonadotropin-releasing hormone
agonist goserelin for at least 4 weeks prior to and for the duration of MONARCH
2. Patients remained on continuous treatment until development of progressive
disease or unmanageable toxicity.

Patient median age was 60 years
(range, 32-91 years), and 37% of patients were older than 65. The majority were
White (56%), and 99% of patients had an Eastern Cooperative Oncology Group
(ECOG) performance status of 0 or 1. Twenty percent (20%) of patients had de
novo metastatic disease, 27% had bone-only disease, and 56% had visceral
disease. Twenty-five percent (25%) of patients had primary endocrine therapy
resistance. Seventeen percent (17%) of patients were pre-or perimenopausal.

The efficacy results from the
MONARCH 2 study are summarized in Table 13 and Figure 2. Median PFS assessment
based on a blinded independent radiologic review was consistent with the
investigator assessment. Consistent results were observed across patient
stratification subgroups of disease site and endocrine therapy resistance. At
the time of primary analysis of PFS, overall survival data were not mature (20%
of patients had died).

Table 13: Efficacy Results
in MONARCH 2 (Investigator Assessment, Intent-to-Treat Population)











  VERZENIO plus Fulvestrant Placebo plus Fulvestrant
Progression-Free Survival N=446 N=223
Number of patients with an event (n, %) 222 (49.8) 157 (70.4)
Median (months, 95% CI) 16.4 (14.4, 19.3) 9.3 (7.4, 12.7)
Hazard ratio (95% CI) 0.553 (0.449, 0.681)
p-value p<.0001
Objective Response for Patients with Measurable Disease N=318 N=164
Objective response ratea (n, %) 153 (48.1) 35 (21.3)
95% CI 42.6, 53.6 15.1, 27.6
Abbreviation: CI = confidence interval.
a Complete response + partial response.

Figure 2: Kaplan-Meier Curves of Progression-Free Survival: VERZENIO plus Fulvestrant versus Placebo
plus Fulvestrant (MONARCH 2)


Kaplan-Meier Curves of Progression-Free Survival: VERZENIO plus Fulvestrant versus Placebo
plus Fulvestrant - Illustration

VERZENIO Administered As A Monotherapy
In Metastatic Breast Cancer (MONARCH 1)

Patients With HR-positive,
HER2-Negative Breast Cancer Who Received Prior Endocrine Therapy And 1-2
Chemotherapy Regimens In The Metastatic Setting

MONARCH 1 (NCT02102490) was a
single-arm, open-label, multicenter study in women with measurable HR-positive,
HER2-negative metastatic breast cancer whose disease progressed during or after
endocrine therapy, had received a taxane in any setting, and who received 1 or
2 prior chemotherapy regimens in the metastatic setting. A total of 132
patients received 200 mg VERZENIO orally twice daily on a continuous schedule
until development of progressive disease or unmanageable toxicity.

Patient median age was 58 years
(range, 36-89 years), and the majority of patients were White (85%). Patients
had an Eastern Cooperative Oncology Group performance status of 0 (55% of
patients) or 1 (45%). The median duration of metastatic disease was 27.6
months. Ninety percent (90%) of patients had visceral metastases, and 51% of
patients had 3 or more sites of metastatic disease. Fifty-one percent (51%) of
patients had had one line of chemotherapy in the metastatic setting. Sixty-nine
percent (69%) of patients had received a taxane-based regimen in the metastatic
setting and 55% had received capecitabine in the metastatic setting. Table 14
provides the efficacy results from MONARCH 1.

Table 14: Efficacy Results in MONARCH 1
(Intent-to-Treat Population)








  VERZENIO 200 mg

N=132
Investigator Assessed Independent Review
Objective Response Ratea,b n (%) 26 (19.7) 23 (17.4)
95% CI (%) 13.3, 27.5 11.4, 25.0
Median Duration of Response 8.6 months 7.2 months
95% CI (%) 5.8, 10.2 5.6, NR
Abbreviations: CI = confidence interval, NR = not
reached.
a All responses were partial responses.
b Based upon confirmed responses.

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