Nuplazid™ - Pimavanserin Manufacturer: Acadia Pharmaceuticals FDA Approval Date: April 2016

Nuplazid™ - pimavanserin Objectives At the end of this presentation participants will be able to: Appropriately recommend Nuplazid™ - (pimavanserin) Effectively educate patients on the purpose, proper use and potential adverse effects of Nuplazid™ - (pimavanserin)

Nuplazid™ - pimavanserin Clinical Application Indications: Parkinson’s disease psychosis Place in therapy: Alternative to quetiapine Nuplazid™[package insert].

Nuplazid™ - pimavanserin Clinical Application Black Box Warning: Increased mortality in elderly patients with dementia-related psychosis Precautions: QT interval prolongation Orthostatic hypotension Hazardous tasks (CNS depression) Nuplazid™[package insert].

Nuplazid™ - pimavanserin Clinical Application Pregnancy: No human data available No teratogenic effect in animal studies Lactation: No data available Nuplazid™[package insert].

Nuplazid™ - pimavanserin Drug Facts Pharmacology: Atypical antipsychotic Antagonist/inverse agonist with high affinity for 5-HT­2A receptor & low affinity for 5-HT2C & sigma 1 receptors No affinity for 5-HT2B, dopaminergic, muscarinic, histaminergic, or adrenergic receptors, or to calcium channels Nuplazid™[package insert].

Nuplazid™ - pimavanserin Drug Facts Pharmacokinetics: A Not significantly affected by high-fat meals D Volume of distribution = 2,173 L M Primarily via CYP3A4 & CYP3A5, forming active N-desmethylated metabolite AC-279 E Half-life pimavanserin: 57 hrs; Active metabolite (AC-279): 200 hrs. Minimal excretion as unchanged drug < 2% Nuplazid™[package insert].

Nuplazid™ - pimavanserin Drug Interactions Drug Interactions – Object Drugs: None Drug Interactions – Precipitant Drugs: Strong CYP3A4 inhibitors: Cmax150%, AUC300% Strong CYP3A4 inducers: change in drug levels not tested Nuplazid™[package insert].

Nuplazid™ - pimavanserin Adverse Effects Common Adverse Effects: (pimavanserin%)[placebo%] Peripheral edema (7%) [2%] Confusional state (6%) [3%] Nausea (7%) [4%] Hallucination (5%) [3%] Constipation (4%) [3%] Gait disturbance (2%) [<1%] Nuplazid™[package insert].

Nuplazid™ - pimavanserin Monitoring Parameters Efficacy Monitoring: Symptom improvement Toxicity Monitoring: Mental status changes ECG for QT prolongation Nuplazid™[package insert].

Nuplazid™ - pimavanserin Prescription Information Dosing: 34 mg daily (two 17 mg capsules) If taking strong CYP3A4 inhibitors, 17 mg once daily is recommended Cost: – $2340/30 day supply ($1170 if taking only 17 mg daily) Source—UpToDate 08/07/2016 Nuplazid™[package insert].

Nuplazid™ - pimavanserin Literature Review Title: Pimavanserin for patients with Parkinson’s disease psychosis: a randomized, placebo-controlled phase 3 trial Objective: Is pimavanserin effective for treatment of hallucinations & delusions in Parkinson’s disease? Cummings J, et al. Lancet. 2014;383(9916):533-40.

Nuplazid™ - pimavanserin Literature Review Treatment Group Included: Parkinson’s disease psychosis w/ sx > 1 month, MMSE score ~26, mean age 72, ~35% female, ~95% white, 99% on dopaminergics, ~35% on cholinesterase inhibitors Excluded: Dementia diagnosis with or prior to Parkinson’s, stroke, MI w/in 6 months, CHF, QT prolongation, psychosis secondary to toxic or metabolic disorders Cummings J, et al. Lancet. 2014;383(9916):533-40.

Nuplazid™ - pimavanserin Literature Review Intervention: Pimavanserin PO 40mg vs. placebo once daily Double blind randomization n = 199 Improvement measured using SAPS-PD score Treatment period = 43 days Cummings J, et al. Lancet. 2014;383(9916):533-40.

Nuplazid™ - pimavanserin Literature Review Results: Endpoint Mean Baseline Score ∆ from Baseline in Placebo ∆ from Baseline in pimavanserin Difference (95% CI; p value) SAPS-PD 15.9 -2.73 -5.79 -3.06 (-4.91 to 1.20; p = 0.0014) SAPS-PD Hallucinations 11.1 -1.80 -3.81 -2.08 (-3.46 to -0.71; p = 0.0032) SAPS-PD Delusions 4.8 -1.01 -1.95 -1.16 (-2.22 to -0.10; p = 0.0325) Cummings J, et al. Lancet. 2014;383(9916):533-40.

Nuplazid™ - pimavanserin Literature Review Conclusions: Pimavanserin appears effective in treating Parkinson’s disease psychosis Minimal adverse reactions Further studies needed regarding long- term treatment, head-to-head comparisons, and using different symptom scales Cummings J, et al. Lancet. 2014;383(9916):533-40.

Nuplazid™ - pimavanserin Summary Nuplazid™, pimavanserin, is an atypical antipsychotic indicated for: hallucinations & delusions associated with Parkinson’s disease psychosis Avoid in dementia-related psychosis: Elderly patients with dementia-related psychosis are at an increased risk of death when treated with antipsychotic drugs Serious adverse reaction: QTc prolongation Common adverse reactions: peripheral edema, nausea, and confusion

Nuplazid™ - pimavanserin References http://www.acadia-pharm.com/wp- content/uploads/2016/04/NUPLAZID- pimavanserin-Package-Insert.pdf Nuplazid™[package insert]. San Diego, CA: ACADIA Pharmaceuticals Inc.; 2016. Cummings J, et al. Lancet. 2014;383(9916) :533-40.