In a 32-week, open-label, multiple-dose, randomized, parallel-arm, pharmacokinetic bridging study

ABILIFY ASIMTUFII® (aripiprazole): TWO MONTHS of sustained therapeutic concentrations with ONE DOSE1

The aripiprazole concentrations of ABILIFY ASIMTUFII were explored in a pharmacokinetic bridging study, which was a 32-week, open-label, multiple-dose, randomized, parallel-arm, multicenter study (N=266) in patients living with schizophrenia or bipolar I disorder.1

Primary objectives included:1

  • To establish the similarity of aripiprazole plasma concentrations and exposure following ABILIFY ASIMTUFII and ABILIFY MAINTENA® (aripiprazole) administration
  • To establish the safety and tolerability of multiple-dose administrations of ABILIFY ASIMTUFII

Mean plasma concentrations of ABILIFY ASIMTUFII following the fourth administration were compared to concentrations following the seventh and eighth administrations of ABILIFY MAINTENA in adult patients living with schizophrenia or bipolar I disorder.1

Mean aripiprazole plasma concentrations assessed after the fourth dose of ABILIFY ASIMTUFII
vs the seventh and eighth doses of ABILIFY MAINTENA1

ABILIFY ASIMTUFII after the fourth dose (n=102)¹ABILIFY MAINTENA after the seventh and eighth doses (n=93)¹Aripiprazole plasma concentration (ng/mL)40030020010000Over this two-month dosing interval, the mean plasma concentration of ABILIFY ASIMTUFII remained between 200 ng/mL and 320 ng/mLOver this two-month dosing interval, the mean plasma concentration of ABILIFY ASIMTUFII remained between 200 ng/mL and 320 ng/mL²²2856Time (days)*
ABILIFY ASIMTUFII after the fourth dose (n=102) ¹ ABILIFY MAINTENA after the seventh and eighth doses (n=93) ¹ Aripiprazole plasma concentration (ng/mL) 400 300 200 100 0 0 Over this two-month dosing interval, the mean plasma concentration of ABILIFY ASIMTUFII remained between 200 ng/mL and 320 ng/mL Over this two-month dosing interval, the mean plasma concentration of ABILIFY ASIMTUFII remained between 200 ng/mL and 320 ng/mL ² ² 28 56 Time (days)*

*Day 0 corresponds to the 24th week of the 32-week study.1

ABILIFY ASIMTUFII 960 mg demonstrated comparable aripiprazole concentrations, and thus comparable efficacy, to ABILIFY MAINTENA 400 mg throughout the two-month dosing interval.1

ABILIFY MAINTENA Efficacy

IMPORTANT WARNING AND PRECAUTION REGARDING NEUROLEPTIC MALIGNANT SYNDROME (NMS)

NMS is a potentially fatal symptom complex reported in association with administration of antipsychotic drugs including aripiprazole. Clinical signs of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability. Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. Manage NMS with immediate discontinuation of aripiprazole, intensive symptomatic treatment, and monitoring.

Comparable efficacy over 32 weeks

Change from baseline in PANSS (schizophrenia) and YMRS (bipolar I disorder) total scores1

Schizophrenia1

Mean PANSS total scores were comparable 
for ABILIFY ASIMTUFII and ABILIFY MAINTENA groups for the duration of the 32-week trial.

ABILIFY ASIMTUFII:1

Baseline (n=92): 62.0

Week 32 (n=89): 59.4

ABILIFY MAINTENA:1

Baseline (n=93): 61.8

Week 32 (n=85): 60.1

Bipolar I Disorder1

Mean YMRS total scores were comparable 
for ABILIFY ASIMTUFII and ABILIFY MAINTENA groups for the duration of the 32-week trial.

ABILIFY ASIMTUFII:1

Baseline (n=40): 6.7

Week 32 (n=39): 4.8

ABILIFY MAINTENA:1

Baseline (n=41): 9.4

Week 32 (n=40): 4.7

PANSS=Positive and Negative Syndrome Scale; YMRS=Young Mania Rating Scale.

Patients treated with ABILIFY ASIMTUFII 960 mg remained clinically stable over the 32-week study period, comparable to those treated with ABILIFY MAINTENA 400 mg.1

IMPORTANT WARNING AND PRECAUTION REGARDING TARDIVE DYSKINESIA (TD)

Risk of TD, and the potential to become irreversible, are believed to increase with duration of treatment and total cumulative dose of antipsychotic drugs. TD can develop after a relatively brief treatment period, even at low doses, or after discontinuation of treatment. Prescribing should be consistent with the need to minimize TD. If antipsychotic treatment is withdrawn, TD may remit, partially or completely.

The safety profile of ABILIFY ASIMTUFII was comparable to that seen with ABILIFY MAINTENA.3

Safety Data

The efficacy of ABILIFY ASIMTUFII® (aripiprazole) is based on the adequate well-controlled studies of ABILIFY MAINTENA® (aripiprazole)1

Schizophrenia efficacy data

12-week study design

Primary endpoint: Mean change in PANSS total score from baseline to Week 10.2

A 12-week, randomized, double-blind, placebo-controlled study in which acutely relapsed adult patients* living with schizophrenia were randomized to either ABILIFY MAINTENA or intramuscular placebo. Safety was assessed throughout the duration of the study.2

*Baseline characteristics: PANSS total score ≥80 and PANSS score >4 on each of four specific psychotic symptoms (conceptual disorganization, hallucinatory behavior, suspiciousness/persecution, and unusual thought content).2

PANSS=Positive and Negative Syndrome Scale.

ABILIFY MAINTENA showed a statistically significant reduction in PANSS total score vs placebo at Week 102

ABILIFY MAINTENA (n=168) Placebo (n=172) Least squares mean reduction 
from baseline in PANSS total score 0 -5 -10 -15 -20 -25 -30 -35 0 Concomitant treatment with oral aripiprazole or placebo for 14 days after first injection -11.7 -26.8 Week 10 (<0.0001) P -8.9 Week 1 -27.2 Week 12 -5.0 -12.6 1 2 4 6 8 10 12 Weeks from randomization Number of patients at risk 162 162 144 134 126 108 99 99 167 167 157 140 117 96 81 68
ABILIFY MAINTENA (n=168) Placebo (n=172) Least squares mean reduction 
from baseline in PANSS total score 0 -5 -10 -15 -20 -25 -30 -35 0 Concomitant treatment with oral aripiprazole or placebo for 14 days after first injection -11.7 Week 10 (<0.0001) P -26.8 Week 1 -8.9 Week 12 -27.2 -5.0 -12.6 1 2 4 6 8 10 12 Weeks from randomization Number of patients at risk 162 162 144 134 126 108 99 99 167 167 157 140 117 96 81 68

*Baseline characteristics: PANSS total score ≥80 and PANSS score >4 on each of four specific psychotic symptoms (conceptual disorganization, hallucinatory behavior, suspiciousness/persecution, and unusual thought content).2

PANSS=Positive and Negative Syndrome Scale.

Study design

A 12-week, randomized, double-blind, placebo-controlled study in which acutely relapsed adult patients with schizophrenia were randomized to either ABILIFY MAINTENA (n=168) or intramuscular placebo (n=172). After initial injection, patients received 14 days of oral aripiprazole or oral placebo based on treatment arm.2

  • Primary endpoint was mean change in PANSS total score from baseline to Week 10.2
  • Safety was assessed throughout the duration of the study.2
Patients were receiving a range of medications prior to study enrollment3†
Risperidone21.5%
Quetiapine15.3%
Olanzapine8.2%
Aripiprazole6.5%
Another antipsychotic22.0%
No antipsychotic26.5%

†Percentages provided were patient-reported estimations. All patients underwent a seven-day washout period at trial entry.3

Screening phase

93.5% of patients were treated with an antipsychotic other than aripiprazole or no antipsychotic prior to study entry3

Patients without prior exposure received oral aripiprazole to establish tolerability.2

CGI-S=Clinical Global Impressions-Severity of Illness.

IMPORTANT WARNING AND PRECAUTION REGARDING CEREBROVASCULAR ADVERSE EVENTS, INCLUDING STROKE

Increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, have been reported in clinical trials of elderly patients with dementia-related psychosis treated with oral aripiprazole.

52-week maintenance study

Study design

In a 52-week, multiphase maintenance study of adult patients living with schizophrenia diagnosed ≥3 years with a history of symptom exacerbation or relapse when not receiving antipsychotic treatment.‡ Phases consisted of an open-label phase 1 (conversion to oral aripiprazole), an open-label phase 2 (stabilization on oral aripiprazole 10 mg to 30 mg once daily), a single-blind phase 3 (conversion and stabilization on ABILIFY MAINTENA 400 mg; patients continued on oral aripiprazole 10 mg to 20 mg for the first 14 days following the initial ABILIFY MAINTENA dose), and a double-blind, placebo-controlled, randomized phase 4 in which patients received either ABILIFY MAINTENA (n=269) or placebo IM depot (n=134).4

The hazard ratio was used to calculate the reduction in risk of relapse for patients on ABILIFY MAINTENA vs placebo.5

‡DSM-IV-TR criteria.4

§Relapse was defined as one or more of the following: clinical worsening, psychiatric hospitalization, risk of suicide, or violent behavior.4

This figure is based on a total of 80 relapse events.5

CI=confidence interval; DSM-IV-TR=Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision; HR=hazard ratio; IM=intramuscular.

ABILIFY MAINTENA (n=269) significantly delayed time to relapse§ vs placebo (n=134) in a 52-week study (HR=0.199 [95% CI, 0.1-0.3], P<0.0001)4,5¶

Primary endpoint:      
Time from randomization to relapse4

ABILIFY MAINTENA (n=269) Placebo (n=134) Proportion of patients with relapse 0.8 0.6 0.4 0.2 0.0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Weeks from randomization ⁴ reduced risk of relapse vs placebo 80% Number of patients at risk 269 244 201 186 153 130 104 76 63 54 44 36 30 23 134 118 85 68 53 45 37 27 22 14 12 9 5 3
ABILIFY MAINTENA (n=269) Placebo (n=134) Proportion of patients with relapse 0.8 0.6 0.4 0.2 0.0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Weeks from randomization ⁴ reduced risk of relapse vs placebo 80% Number of patients at risk 269 244 201 186 153 130 104 76 63 54 44 36 30 23 134 118 85 68 53 45 37 27 22 14 12 9 5 3

‡DSM-IV-TR criteria.

§Relapse was defined as one or more of the following: clinical worsening, psychiatric hospitalization, risk of suicide, or violent behavior.

This figure is based on a total of 80 relapse events.

CI=confidence interval; DSM-IV-TR=Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision; HR=hazard ratio; IM=intramuscular.

The placebo-controlled, 52-week maintenance study evaluated the time to relapse for adult patients with schizophrenia4

Study design

A multiphase study that included open-label stabilization on oral aripiprazole, single-blind stabilization on ABILIFY MAINTENA (along with oral aripiprazole for the first 14 days), and a 52-week, randomized, double-blind, placebo-controlled study in which adult patients with schizophrenia were randomized to either ABILIFY MAINTENA (n=269) or intramuscular placebo (n=134).4

The study enrolled patients with schizophrenia diagnosed ≥3 years and a history of symptom exacerbation or relapse when not receiving antipsychotic treatment.4#

OPEN-LABEL
PHASE 1

4-6 weeks

CONVERSION TO
ORAL ARIPIPRAZOLE
n=633
OPEN-LABEL
PHASE 2

4-12 weeks

STABILIZATION ON
ORAL ARIPIPRAZOLE 
15 mg to 30 mg
once daily
n=710
SINGLE-BLIND
PHASE 3

12-36 weeks

CONVERSION AND STABILIZATION ON
ABILIFY MAINTENA® (aripiprazole)
400 mg
n=576

Patients continued on oral aripiprazole 10 mg to 20 mg for the first 14 days following the initial ABILIFY MAINTENA dose.

DOUBLE-BLIND,
PLACEBO-CONTROLLED, RANDOMIZED
PHASE 4

Up to 52 weeks

ABILIFY MAINTENA
n=269
OR
Placebo IM Depot
n=134

Patients were randomized at baseline to receive either ABILIFY MAINTENA or placebo.

Primary endpoint: Time from randomization to relapse4

Relapse was defined as one or more of the following:4

  • Clinical worsening
    • CGI-Improvement score ≥5 and an increase on any of the 4 specific PANSS** items to a score >4: with an absolute increase of ≥2 on that specific item since randomization or with an absolute increase of ≥4 on the combined score of these items since randomization
  • Psychiatric hospitalization
    • Due to worsening of psychotic symptoms
  • Risk of suicide
    • CGI-SS score of 4 (severely suicidal) or 5 (attempted suicide) on part 1 or CGI-SS score of 6 (much worse) or 7 (very much worse) on part 2
  • Violent behavior
    • Clinically significant self-injury, injury to another person, or property damage

#DSM-IV-TR criteria.4

**PANSS items were conceptual disorganization, hallucinatory behavior, suspiciousness, or unusual thought content.4     
CGI=Clinical Global Impression; CGI-SS=Clinical Global Impression of Severity of Suicidality.

IMPORTANT WARNING AND PRECAUTION REGARDING NEUROLEPTIC MALIGNANT SYNDROME (NMS)

NMS is a potentially fatal symptom complex reported in association with administration of antipsychotic drugs including aripiprazole. Clinical signs of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability. Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. Manage NMS with immediate discontinuation of aripiprazole, intensive symptomatic treatment, and monitoring.

Bipolar I disorder efficacy data

52-week study design

In a 52-week multiphase maintenance study of adult patients living with bipolar I disorder with a history of ≥1 manic or mixed episode with manic symptoms that required hospitalization and/or treatment with either a mood stabilizer and/or antipsychotic (N=266).6

The placebo-controlled, 52-week maintenance study evaluated the time to recurrence for adult patients living with bipolar I disorder.6

Maintenance study of adult patients living with bipolar I disorder consisted of four phases.6

OPEN-LABEL
PHASE 1

4-6 weeks

CONVERSION TO
ORAL ARIPIPRAZOLE
n=466
OPEN-LABEL
PHASE 2

2-8 weeks

STABILIZATION ON 
ORAL ARIPIPRAZOLE 15 mg to 30 mg 
once daily
n=632††
SINGLE-BLIND
PHASE 3

12-28 weeks

CONVERSION AND
STABILIZATION ON
ABILIFY MAINTENA® (aripiprazole)
400 mg
n=425

Patients continued on oral aripiprazole 10 mg to 20 mg
for the first 14 days following
the initial
ABILIFY MAINTENA dose.

DOUBLE-BLIND,
PLACEBO-CONTROLLED, RANDOMIZED
PHASE 4

Up to 52 weeks

ABILIFY MAINTENA
n=133
OR
Placebo IM Depot
n=133

Patients were randomized at baseline to receive either ABILIFY MAINTENA or placebo.

††Including those patients entering the trial on oral aripiprazole.6
IM=intramuscular.

Recurrence was defined as one or more of the following:6

Clinical worsening

  • YMRS total score ≥15
    OR
  • MÅDRS total score ≥15
    OR
  • CGI-BP-S overall score >4
    OR
  • Serious AE of worsening BP-I
    OR
  • Discontinuation due to lack of efficacy or due to an AE of worsening BP-I
    OR
  • Clinical worsening with the need for addition of a mood stabilizer, antidepressant treatment, antipsychotic medication, and/or increase greater than the allowed benzodiazepine doses for treatment of symptoms of an underlying mood disorder

Psychiatric hospitalization

  • For any mood episode

Increased risk of suicide

  • Score ≥4 on the MÅDRS item 10
    OR
  • Answer of YES on question 4 or 5 on the C-SSRS

AE=adverse event; BP-I=bipolar I disorder; CGI-BP-S=Clinical Global Impression-Bipolar Version-Severity; C-SSRS=Columbia-Suicide Severity Rating Scale; MÅDRS=Montgomery-Åsberg Depression Rating Scale; YMRS=Young Mania Rating Scale.

ABILIFY MAINTENA significantly delayed time to recurrence‡‡ of any mood episode vs placebo over one year (HR=0.45 [95% CI, 0.30-0.68], P<0.0001)6§§

‡‡Recurrence was defined as clinical worsening, psychiatric hospitalization, or increased risk of suicide.6

§§This figure is based on a total of 103 recurrences.1  
CI=confidence interval; HR=hazard ratio.

ABILIFY MAINTENA significantly delayed time to recurrence‡‡ of any mood episode vs placebo over one year (HR=0.45 [95% CI, 0.30-0.68], P<0.0001)6§§

Primary endpoint: Time from randomization to recurrence‡‡     
of any mood episode1,6

ABILIFY MAINTENA (n=132) Placebo (n=133) Proportion of patients with recurrence 0.6 0.4 0.2 0.0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Weeks from randomization Number of patients at risk 132 125 111 101 93 85 84 80 76 72 70 69 67 62 133 121 104 91 84 75 67 59 55 53 50 48 43 37
ABILIFY MAINTENA (n=132) Placebo (n=133) Proportion of patients with recurrence 0.6 0.4 0.2 0.0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Weeks from randomization Number of patients at risk 132 125 111 101 93 85 84 80 76 72 70 69 67 62 133 121 104 91 84 75 67 59 55 53 50 48 43 37

IMPORTANT WARNING AND PRECAUTION REGARDING TARDIVE DYSKINESIA (TD)

Risk of TD, and the potential to become irreversible, are believed to increase with duration of treatment and total cumulative dose of antipsychotic drugs. TD can develop after a relatively brief treatment period, even at low doses, or after discontinuation of treatment. Prescribing should be consistent with the need to minimize TD. If antipsychotic treatment is withdrawn, TD may remit, partially or completely.

Exploratory analyses from the pivotal 52-week maintenance study of ABILIFY MAINTENA in adults living with bipolar l disorder7

75 75 % % (HR=0.249; 95% CI 0.137-0.451) (HR=0.249; 95% CI 0.137-0.451) reduced risk of recurrence of mixed/manic mood episodes vs placebo reduced risk of recurrence of mixed/manic mood episodes vs placebo ⁷ ⁷ Delayed time to recurrence for a manic episode
ormixed episode
Delayed time to recurrence for a manic episode
ormixed episode
(HR=0.259; 95% CI 0.136-0.495) (HR=0.202; 95% CI 0.044-0.939) (HR=0.259; 95% CI 0.136-0.495) (HR=0.202; 95% CI 0.044-0.939) ⁷ ⁷ (HR=0.932; 95% CI 0.497-1.747) (HR=0.932; 95% CI 0.497-1.747) ⁷ ⁷ No substantial difference in the time to a depressive episode No substantial difference in the time to a depressive episode
75 75 % % (HR=0.249; 95% CI 0.137-0.451) (HR=0.249; 95% CI 0.137-0.451) reduced risk of recurrence of mixed/manic mood episodes vs placebo reduced risk of recurrence of mixed/manic mood episodes vs placebo ⁷ ⁷ Delayed time to recurrence for a manic episode
ormixed episode
Delayed time to recurrence for a manic episode
ormixed episode
(HR=0.259; 95% CI 0.136-0.495) (HR=0.202; 95% CI 0.044-0.939) (HR=0.259; 95% CI 0.136-0.495) (HR=0.202; 95% CI 0.044-0.939) ⁷ ⁷ (HR=0.932; 95% CI 0.497-1.747) (HR=0.932; 95% CI 0.497-1.747) ⁷ ⁷ No substantial difference in the time to a depressive episode No substantial difference in the time to a depressive episode

Data limitation: The pivotal maintenance trial was not designed to assess, nor statistically powered to examine, the combined risk of mixed/manic episodes, excluding depressive episodes. These results require cautious interpretation and may represent change findings.

The HR was used to calculate the reduction in risk of recurrence for patients on ABILIFY MAINTENA vs placebo.6

IMPORTANT WARNING AND PRECAUTION REGARDING METABOLIC CHANGES

Atypical antipsychotic drugs have caused metabolic changes including:

  • Hyperglycemia/Diabetes Mellitus: Hyperglycemia, in some cases extreme and associated with ketoacidosis, hyperosmolar coma, or death, has been reported in patients treated with atypical antipsychotics including aripiprazole. Patients with diabetes mellitus should be regularly monitored for worsening of glucose control; those with risk factors for diabetes (e.g., obesity, family history of diabetes), should undergo baseline and periodic fasting blood glucose testing. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia should also undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.
  • Dyslipidemia: Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.
  • Weight Gain: Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

The safety profile of ABILIFY ASIMTUFII was comparable to that seen with ABILIFY MAINTENA.1

Safety Data

Non-pivotal analyses

32-week pharmacokinetic simulation

From initiation, ABILIFY ASIMTUFII showed similar aripiprazole concentrations to ABILIFY MAINTENA1

Median simulated aripiprazole plasma concentrations were similar 
to ABILIFY MAINTENA from initiation through 32 weeks1*

ABILIFY ASIMTUFII ABILIFY MAINTENA Aripiprazole plasma
concentration (ng/mL) 400 300 200 100 0 14 days of oral aripiprazole overlap 4 8 12 16 20 24 28 32 Time (weeks)
ABILIFY ASIMTUFII ABILIFY MAINTENA Aripiprazole plasma concentration (ng/mL) 400 300 200 100 0 14 days of oral aripiprazole overlap 4 8 12 16 20 24 28 32 Time (weeks)

IMPORTANT WARNING AND PRECAUTION REGARDING METABOLIC CHANGES 
Atypical antipsychotic drugs have caused metabolic changes including:

  • Hyperglycemia/Diabetes Mellitus: Hyperglycemia, in some cases extreme and associated with ketoacidosis, hyperosmolar coma, or death, has been reported in patients treated with atypical antipsychotics including aripiprazole. Patients with diabetes mellitus should be regularly monitored for worsening of glucose control; those with risk factors for diabetes (e.g., obesity, family history of diabetes), should undergo baseline and periodic fasting blood glucose testing. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia should also undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug.
  • Dyslipidemia: Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.
  • Weight Gain: Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

*Based on a simulation population of N=1000.1

The safety profile of ABILIFY ASIMTUFII was comparable to that seen with ABILIFY MAINTENA.2

Safety Data