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STA 2 R provides answers to important treatment defining questions! Is olanzapine likely to have enhanced efficacy? Do consensus data recommend avoiding risperidone due to altered metabolism? Are SSRIs likely to have decreased efficacy and increased risk of side effects?

WHAT IS SULT4A1? Sulfotransferase family 4A, member 1 is a brain sulfotransferase with many interesting properties. However, its exact activities and mechanisms remain unknown. Highly expressed in areas thought to be involved in etiology of psychosis Highly conserve through-out evolution – Minimal difference between mouse and man – No coding variants in man, just regulatory variation Binds numerous classes of molecules that might impact psychosis – Catecholamines – norepinephrine, epinephrine, isoprenoline (but not dopamine) – Neurosteroids – Thyroid hormones

Percentage of SUL4A1-1 positive and negative Caucasian patients that achieved clinically significant response in Phase I of the CATIE Study SULT4A1-1 status impacted response to olanzapine in the multiple studies, including CATIE

1 in 5 schizophrenia patients will be hospitalized in a given year. 1 in 2 hospitalized patients will return to the hospital within a year.

Percentage of SUL4A1-1 positive and negative Caucasian patients who returned to the hospital within one year after starting a new antipsychotic therapy in the CATIE Study Treating SULT4A1-1 positive Caucasian patients with olanzapine or quetiapine reduced the risk of hospitalization by over 80% in the CATIE Study

Based on the answer to the first two questions STA 2 R identifies three broad classes of patients based on likely response to antipsychotics Is olanzapine likely to have enhanced efficacy? YES Olanzapine treated patients are more likely to achieve clinically significant response and less likely to be hospitalized than patients treated with other drugs Do consensus data recommend avoiding risperidone due to altered metabolism? No Olanzapine unlikely to offer efficacy advantage over other drugs delivering less benefit Risperidone is likely to be metabolized normally and should be used as directed Risperidone should be avoided if possible or extreme care should be taken to manage the dose Olanzapine first line Risperidone first line First line????

Serotonin Transporter The STA 2 R panel tests for genetic variation in the serotonin transporter gene (SLC6A4) that impacts response to SSRIs. Promoter variants lead to altered transporter production Response to SSRIs is influenced by number of LA versions of SLC6A4 2 copies of LA version – Normal responders Expected response to SSRIs 1 copy of LA version – Intermediate responder Possible increased risk of poor response and adverse events 0 copies of LA version – Poor responder Increased risk of poor response and adverse events

What is the appropriate time to use STA 2 R? Initial medication selection: For patients currently not on medication Treatment switch: Poor efficacy, tolerability, or satisfaction Severe treatment failure: Exacerbations of psychosis SUREGENE DOES NOT RECOMMEND STA 2 R FOR PATIENTS EXHIBITING AN ACCEPTABLE CLINICAL RESPONSE TO CURRENT THERAPY

Is STA 2 R reimbursed? What is the clients responsibility? PlanCoverageClient responsibility MedicaidCoveredNo co-pay MedicareCoveredNo co-pay Private insuranceCoverage levels vary In-network for many national carriers Plan rules dictate co-pay Patient assistance program No collections Self-payNAPatient assistance program

Sample Test report Key treatment impacting questions Is Olanzapine likely to have enhanced efficacy? (YES) Client should be prescribed olanzapine (quetiapine if AEs unmanageable) Do consensus data recommend avoiding risperidone? (YES) Risperidone should be avoided Are SSRI’s likely to have decreased efficacy? (YES) Use non-SSRI antidepressants to manage co-morbid depression Do the detailed results below provide dosing recommendations? (YES) Check detailed results for dosing guidance

CYP2D6 Phenotype THERAPEUTIC IMPLICATIONS (adapted from published resources) AvoidAlternative ConsiderationAdjust DosageAdjustment Poor MetabolizerRisperidone † Quetiapine, olanzapine, clozapine Aripiprazole † 10 mg/day maximum Venlafaxine † Citalopram, sertralineClomipramine † Decrease 50% Amitriptyline † Citalopram, sertralineDoxepin † Decrease 60% Haloperidol † Decrease 50% Imipramine † Decrease 70% Nortriptyline † Decrease 60% Zuclopenthixol † Decrease 50%, or flupenthixol, quetiapine, olanzapine, clozapine SULT4A1-1 Phenotype THERAPEUTIC IMPLICATIONS (adapted from published resources) POSITIVE Consider olanzapine. SULT4A1-1 positive patients have been shown to demonstrate enhanced treatment efficacy and reduced hospitalization risk when treated with olanzapine compared to both SULT4A1-1 negative patients treated with olanzapine and SULT4A1-1 positive patients treated with risperidone.

CYP2C19 Phenotype THERAPEUTIC IMPLICATIONS (adapted from published resources) Poor Metabolizer Decreased metabolic clearance expected. Adjust Dosage Imipramine † Adjustment Decrease 30% Sertraline † Decrease 50% CYP1A2 Phenotype THERAPEUTIC IMPLICATIONS (adapted from published resources) HYPER- INDUCER Rapid metabolism expected, especially in smokers. Consider dose increases for medications inactivated by CYP1A2 particularly in smokers, or alternative medications. Common CYP1A2 medications next page. SLC6A4 Phenotype THERAPEUTIC IMPLICATIONS (adapted from published resources) Poor Responder Decreased serotonin transporter expression expected. Risk of decreased response to SSRI-based therapies and increased risk of adverse events. Consider non-SSRI antidepressant therapies, such as SNRIs or tricyclic antidepressant alternatives.

Competitive positioning Only reference competition when specifically asked! Key points of differentiation STA 2 R is the only test to offer: 1.Clinical efficacy data, including reduction in hospitalization rates 2.Inclusion criteria, e.g. recommending olanzapine 3.Dosing recommendations 4.Both Medicare and Medicaid billing 5.Proprietary markers 6.Research oriented company