Manufacturer: Celgene Corporation FDA Approval Date: 9/23/14 Otezla® - apremilast Manufacturer: Celgene Corporation FDA Approval Date: 9/23/14

Otezla®- apremilast Clinical Application Indications: Treatment of moderate to severe plaque psoriasis in patients who are candidates for phototherapy or systemic therapy Treatment of active psoriatic arthritis in adults Place in therapy: Oral alternative to Methotrexate and retinoids

Otezla®- apremilast Clinical Application Contraindications: Hypersensitivity to apremilast or any component of the formulation Warnings: Depression, suicidal ideation, and mood changes have been reported May cause weight loss Precautions: Systemic exposure increased in patients with CrCl <30 ml/min

Otezla®- apremilast Clinical Application Pregnancy: Category C Lactation: Excretion in breast milk is unknown, use caution

Otezla®- apremilast Drug Facts Pharmacology: Inhibits phosphodiesterase-4 (PDE4) preventing it from degrading cyclic adenosine monophosphate (cAMP) to AMP resulting in increased cAMP levels intracellularly. Cyclic AMP down regulates inflammatory response through several inflammatory mediators. Specific Mediators: nitric oxide synthase, TNF-alpha, IL-23, IL-10 Specific mechanisms by which this drug exerts therapeutic effects in psoriatic arthritis patients is not well defined PDE4 degrades cAMP to AMP, cAMP down-regulates inflammatory response

Otezla®- apremilast Drug Facts Pharmacokinetics: A Well absorbed; ~73% bioavailability D Vd 87 L; 68% protein bound M Hepatic: Major CYP3A4 Minor CYP1A2 and CYP2A6 E t1/2 6-9h; 58% in urine, 39% in feces

Otezla®- apremilast Drug Interactions Drug Interactions – Object Drugs: None

Otezla®- apremilast Drug Interactions Drug Interactions – Precipitant Drugs: Bosentan: ↓ concentration Strong CYP3A4 inducers: ↓concentration Dabrafenib: ↓ concentration Deferasirox: ↓ concentration Siltuximab: ↓ concentration St. John’s Wort: ↓ concentration Tocilizumab: ↓ concentration

Otezla®- apremilast Adverse Effects Common Adverse Effects: Serious Adverse Effects: Diarrhea (9%) [2%] Nausea (9%) [3%] Headache (6%) [2%] URI (4%) [2%] Nasopharyngitis (3%) [2%] Vomiting (3%) [0.4%] Abdominal pain (2%) [0.2%] Major SE difference depending on indication Weight loss is a 5-10% reduction in 16 weeks Weight Loss (10-12%) [3-5%] Depression (1%) [0.8-1.3%]

Otezla®- apremilast Monitoring Parameters Efficacy Monitoring: Signs and Symptoms of Psoriasis/psoriatic arthritis within 3 months of initiation Toxicity Monitoring: SCr: 3 months and annually Weight Loss: 3 months Depression: 3 months

Otezla®- apremilast Prescription Information Dosing: 30 mg BID Titration: Cost: UpToDate.com Accessed 11/03/2014 Starter Pack: $1012 30 mg Tablets #60: $2250 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 AM PM 10 mg 10 mg 20 mg 30 mg

Otezla®- apremilast Literature Review Phase 3 Psoriatic Arthritis Long-term Assessment of Clinical Efficacy (PALACE) Trial Randomized, placebo controlled study Included 504 patients from 13 countries Kavanaugh A, et al. Ann Rheum Dis 2014;73:1020-26

Otezla®- apremilast Literature Review Phase 1: 24 weeks 1:1:1 randomization to receive either apremilast 30 mg BID, apremilast 20 mg BID, or placebo Phase 2: 28 weeks Patients who received placebo in Phase 1 were randomized 1:1 to receive apremilast 20 mg BID or apremilast 30 mg BID Patients receiving apremilast in Phase 1 remained on that dose 52 weeks total This slide is for contextual purposes Kavanaugh A, et al. Ann Rheum Dis 2014;73:1020-26

Otezla®- apremilast Literature Review Primary Endpoint: Proportion of patients with 20% improvement in modified ACR response criteria at week 16 Secondary Endpoints: Change from baseline in Health Assessment Questionnaire- Disability Index (HAQ-DI) at week 16 Improvement in S/Sx of PsA, physical function, and psoriasis at 24 weeks Look up details on these scoring tools Kavanaugh A, et al. Ann Rheum Dis 2014;73:1020-26

Otezla®- apremilast Literature Review Baseline Characteristics Parameter Placebo Apremilast 20 mg BID Apremilast 30 mg BID Age (years) 51.1 48.7 51.4 BMI 31.1 30.9 30.6 Mean duration of PsA (years) 7.3 7.2 8.1 Mean HAQ-DI (0-3) 1.2 Psoriasis involvement of BSA 3% or more (n) 68 77 82 Mean PASI Score (0-72) 9.1 7.4 9.2 Kavanaugh A, et al. Ann Rheum Dis 2014;73:1020-26

Otezla®- apremilast Literature Review Intent to treat analysis Kavanaugh A, et al. Ann Rheum Dis 2014;73:1020-26

Otezla®- apremilast Literature Review Intent to treat analysis A reduction in this score is associated with improvement Kavanaugh A, et al. Ann Rheum Dis 2014;73:1020-26

Otezla®- apremilast Literature Review Psoriasis Area and Severity Index Kavanaugh A, et al. Ann Rheum Dis 2014;73:1020-26

Otezla®- apremilast Summary Apremilast is an effective oral agent for the treatment of psoriasis and psoriatic arthritis Maintenance Dose: 30 mg BID with dosing adjustment for CrCl <30 ml/min Weight and signs of depression must be monitored for as these are potentially serious adverse effects

Otezla®- apremilast References http://www.otezla.com Otezla (apremilast) package insert. Celgene Corporation. Sept. 2014. Apremilast. Lexicomp Drug Information. Accessed through UpToDate. Accessed on Nov 3, 2014. Kavanaugh A, et al. Ann Rheum Dis 2014;73:1020-1026 Papp KA, et al. JEADV 2013,27, e376-383