Cathy Southammakosane, MDMedical Officer, Division of Psychiatry

Center for Drug Evaluation and ResearchOffice of New Drugs

U.S. Food and Drug Administration

ALKS 3831 for Schizophrenia: Clinical Overview of Efficacy and Safety

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• Overview of antipsychotic metabolic considerations• Overview of olanzapine/samidorphan

– Regulatory history• Efficacy

– Study ALK3831-302– Study ALK3831-A303– Study ALK3831-A305

• Safety– Adverse events and investigations– Concurrent opioid use

• Conclusion www.fda.gov

Outline

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ALKS 3831Drug: olanzapine and samidorphanProposed proprietary name: LybalviTherapeutic class: atypical antipsychotic and mu opioid receptor antagonist new molecular entity (NME)

Proposed indications:1. Schizophrenia2. Bipolar I disorder: acute treatment of manic and mixed episodes, maintenance treatment, adjunct to valproate or lithium in the treatment of manic or mixed episodes

Dosage Strengths and Formulation: 5/10mg, 10/10mg, 15/10mg, and 20/10mg tablets

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End-of-Phase 2 Meeting

Minimum of two studies of different types necessary for approval:

1. Three-arm, 4- to 8-week study of acute treatment of schizophrenia – Treatment arms: ALKS 3831, placebo, and olanzapine

2. Active-controlled study monitoring weight change for at least 6 months with an open-label extension of 6 months– Treatment arms: ALKS 3831 and olanzapine

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Study A303 Protocol Assessment

Approval contingent upon antipsychotic efficacy with significantly less weight gain:

• Antipsychotic efficacy compared to placebo • Mean differences in percent weight change from baseline • Categorical differences in weight change • Effects on laboratory based metabolic parameters

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ALK3831-302

• Subjects (N=309)• Adults with schizophrenia

• Description• Phase 2, proof-of-concept, randomized, controlled trial (RCT)• Part A 12-week double-blind treatment• Part B 12-week active-controlled treatment

• Endpoints • Primary: Change in PANSS from randomization to end of Part A• Exploratory: Percent change in body weight from randomization to

end of Part A

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Study 302: Subjects• Select inclusion / exclusion criteria:

– Ages 18-50 years – Stable weight and body mass index (BMI) 17-30 kg/m²– Not antipsychotic naive– No diabetes

• Olanzapine lead-in weight change stratification– ≤ 0 kg, > 0 to < 1 kg, or ≥ 1 kg

• Analysis populations:– Full Analysis Set (FAS) 1: randomized, received ≥ 1 dose of study drug, ≥ 1 post-baseline PANSS– FAS 2: FAS 1 + olanzapine lead-in weight gain

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Study 302: Antipsychotic EfficacyExploratory Analysis

[Source: Applicant’s Clinical Study Report for Study ALK3831-302, Figure 5, page 81]

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ALK3831-A303

• Subjects (N=561)• Adults with schizophrenia

• Description• Phase 3 RCT• Treatment arms: ALKS 3831 or olanzapine• 24 week outpatient study

• Co-Primary Endpoints • Percent change in body weight from baseline to Week 24• Proportion of subjects with >10% weight gain from baseline to Week

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Study A303: Design

[Source: Applicant’s Clinical Study Report for ALK3831-A303, Figure 1, page 20]

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Study A303: Baseline Characteristics

• 73% male• Mean age 40 years (minimum (min) 18, maximum (max) 55)• 71% black, 23% white, 14% Hispanic/Latino• Mean weight 77 kg (min 40, max 116)• Mean BMI 25 kg/m² (min 18, max 30)

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Study A303: Coprimary Endpoints

• Percent change in body weight

• Proportion of subjects with >10% weight gain

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Study A303: Categorical Weight Gain (Completers)

[Source: FDA generated]

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Study A303: Glycemic Parameters

[Source: Applicant’s Clinical Study Report for Study ALK3831-A303, Figure 19, 20, and 21, pages 88 and 89]

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ALK3831-A305

• Subjects (N=403)• Adults with acute exacerbation schizophrenia

• Description• Phase 3 RCT• Treatment arms: ALKS 3831, olanzapine, or placebo• 4 week study (2 to 4 week inpatient)

• Endpoint • PANSS change from baseline to Week 4

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Study A305: Design

[Source: Applicant’s Clinical Study Report for ALK3831-A305, Figure 1, page 19]

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Study A305: Baseline Characteristics

• 91% male• Mean age 41 years (min 18, max 67)• 69% white, 28% black, 3% Hispanic/Latino• Mean PANSS scores 101.7 (ALKS 3831 101.8, olanzapine 100.6, and

placebo 102.7)

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Long-term Studies A304 and A306

• Subjects (A304 N=265, A306 N=277)• Adults with schizophrenia

• Description• Phase 3 open-label extension• Treatment arm: ALKS 3831• 52 week study

• Endpoint • Safety and tolerability

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Study A306: Weight Over Time

[Source: Applicant’s Integrated Summary of Efficacy, Figure 38, page 141]

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Study A304: Weight Over Time

[Source: Applicant’s ISE, Figure 38, page 141]

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Limitations• Self-selecting subjects• No comparator arm• Missing data• Ongoing open-label study • Cross-study comparisons• No subject characteristics or other factors

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Safety: Investigations

Class effects• Weight gain and metabolic changes• Liver enzyme increase• Hyperprolactinemia• Leukopenia, neutropenia, and agranulocytosis• Orthostatic hypotension• Extrapyramidal symptoms

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Safety: Concurrent Opioid Use• Precipitated opioid withdrawal

– One subject• Inadequate analgesia

– Eighteen subjects discussed opioid concomitant use – no report inadequate analgesia

• Concurrent opioid abuse– Three subjects

• Opioid overdose– One subject

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Clinical Summary• Antipsychotic effectiveness

• No new safety signals

• Precipitated opioid withdrawal, inadequate analgesia, and opioid overdose

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Clinical Summary: Weight MitigationStudy A303

• Primary and secondary weight endpoints statistically significant• Percent change from baseline: ALKS 3831 4.21%, olanzapine 6.59%

• Mean weight difference: -2.4% (95% CI: -3.9, -0.9)

• Proportion with >10% weight gain: ALKS 18% vs. OLZ 30%• Proportion with >7% weight gain: ALKS 28% vs. OLZ 43%

• Missing data and lack of long-term control arm• Favorable waist circumference and blood pressure changes• Mixed metabolic laboratory results- unfavorable glycemic trends

Study 302• Olanzapine-subtracted weight change not dose-related: -1.2% to -1.9%• No notable changes in waist circumference, metabolic laboratory results, and blood pressure

Celeste Mallama, PhD, MPHEpidemiologist

Office of Surveillance and EpidemiologyOffice of Pharmacovigilance and Epidemiology

Center for Drug Evaluation and ResearchFood and Drug Administration

Consideration of Potential Risks Associated with ALKS 3831 in Real World Settings of

Opioid Use

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Provide a brief overview of epidemiologic, surveillance, and drug utilization data to inform discussion of the potential risks associated with this product, which contains a new opioid antagonist, in the setting of acute or chronic opioid use (either medical or nonmedical), and discuss proposed mitigation of these risks

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Objective

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1) Opioid withdrawal

2) Inadequately controlled pain

3) Opioid overdose

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Potential Risks

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• Chronic opioid use was 3x more common in patients with bipolar disorder compared to patients with no mental health disorder (10% vs. 3%) in a 2015-2016 health system sample1

• Individuals with bipolar disorder have a higher risk of opioid nonmedical use (NMU)* and opioid use disorder (OUD)2,3

– Based on limited national survey data: • Potentially >5% of patients with bipolar disorder use opioids

nonmedically• Potentially 1-3% have an OUD

Opioid Use, Nonmedical Use, and Opioid Use Disorder in Proposed Patient Population (I)

1. Owen-Smith et al., BMC Psychiatry, 2020; 2. Martins et al., Psychol Med, 2012; 3. Saha et al., Journal of Clinical Psychiatry, 2016;

*Use in any way not directed by a doctor, including use without a prescription of one’s own; use in greater amounts, more often, or longer than told to take a drug, or use in any other way not directed by a doctor.

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• Evidence is mixed on whether chronic pain and opioid use are more common with schizophrenia1,2

• Data are sparse on NMU and OUD in patients with schizophrenia

– Older survey data (1980-20023,4) suggest opioid NMU is higher in patients with schizophrenia

Opioid Use, Nonmedical Use, and Opioid Use Disorder in Proposed Patient Population (II)

1. Owen-Smith et al., BMC Psychiatry, 2020; 2. Birgenheir et al., General Hospital Psychiatry, 2013; 3. Regier et al., JAMA, 1990; 4. Martins et al., Drug and Alcohol Dependence, 2011

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• Bupropion/naltrexone (contains an opioid antagonist)– Indicated for chronic weight management, contraindicated with chronic opioid use – In 2019, approximately 341,000 prescriptions for bupropion/naltrexone were

dispensed from U.S. outpatient retail pharmacies1

• From December 2016-August 2020, 13 cases reported to the FDA Adverse Event Reporting System (FAERS) of suspected opioid withdrawal in patients taking concurrent bupropion/naltrexone and at least one opioid product2

• Majority of these cases reported hospitalization• Limitations:

– Limited to cases reported to FAERS– As this is a labeled adverse event, likely not totality of events

Spontaneous Reporting of Opioid Withdrawal in Population using Bupropion/Naltrexone

FAERS: FDA Adverse Event Reporting System1 IQVIA, National Prescription AuditTM database. 2019. Extracted September 2020.2 Lopez A. Pharmacovigilance Memorandum: Concomitant use of bupropion/naltrexone with an opioid product and relevance to olanzapine/samidorphan. Draft in progress.

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• From September 2014-August 2016, 11% of patients on bupropion/naltrexone had concurrent claims for select* opioid products, despite their contraindication in product labeling1

• From December 2016-August 2020, 1 case reported to FAERS describing reduced analgesic effect in a patient taking concurrent bupropion/naltrexone and an opioid product2

Drug Utilization and Spontaneous Reporting Data Related to Risk Scenario #2: Inadequately Controlled Pain

*Select opioid products include acetaminophen/codeine, acetaminophen/hydrocodone, acetaminophen/oxycodone, acetaminophen/tramadol, codeine, fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, and tramadol 1. Source: Symphony Health database. 2014-2016. Extracted 2017.; 2. Lopez A. Pharmacovigilance Memorandum: Concomitant use of bupropion/naltrexone with an opioid

product and relevance to olanzapine/samidorphan. Draft in progress.

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• In studies of patients with OUD treated with oral naltrexone, overdose risk was higher immediately following cessation of oral naltrexone1,2

– Note: Overdose risk likely lower in ALKS 3831 patient population

Epidemiologic Evidence: Opioid Overdose

1. Morgan et al., Drug and Alcohol Dependence, 2019; 2. Gibson et al., Drug and Alcohol Review, 2007

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Applicant's Proposed Risk Management Strategies

1) Opioid withdrawal– Contraindication, Warnings and Precautions, Medication Guide

• Patient should be opioid-free prior to treatment

2) Inadequately controlled pain– Warnings and Precautions, Medication Guide

• If opioid therapy is needed, ALKS 3831 should be stopped• Consider olanzapine or another antipsychotic

3) Opioid overdose– Warnings and Precautions, Medication Guide

• Alert patients with prior opioid use they may be more sensitive to opioids after treatment discontinuation

• Counsel patients on the serious consequences of trying to overcome the opioid blockade

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• Potential safety concerns related to samidorphan’s opioid antagonist effect in real-world settings of opioid use warrant consideration

• Epidemiologic data suggest that a non-trivial proportion of the indicated population may be exposed to opioids and be vulnerable to these potential risks

• If approved, it is possible that these risks could be mitigated through labeling alone, however we welcome the committee’s input

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Conclusion