Medication Policy Manual. Topic: Otezla, apremilast Date of Origin: May 9, 2014

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1 Medication Policy Manual Policy No: dru342 Topic: Otezla, apremilast Date of Origin: May 9, 2014 Committee Approval Date: January 19, 2015 Next Review Date: January 2016 Effective Date: April 1, 2015 IMPORTANT REMINDER This Medical Policy has been developed through consideration of medical necessity, generally accepted standards of medical practice, and review of medical literature and government approval status. Benefit determinations should be based in all cases on the applicable contract language. To the extent there are any conflicts between these guidelines and the contract language, the contract language will control. The purpose of medical policy is to provide a guide to coverage. Medical Policy is not intended to dictate to providers how to practice medicine. Providers are expected to exercise their medical judgment in providing the most appropriate care. Description Apremilast (Otezla) is an oral medication that inhibits phosphodiesterase-4 (PDE4), a protein present in immune cells that is associated with inflammation. It is used to treat chronic plaque psoriasis and psoriatic arthritis. dru342.1 Page 1 of 13

2 Policy/Criteria I. Most contracts require prior authorization approval of apremilast (Otezla) prior to coverage. Apremilast (Otezla) may be considered medically necessary when at least one of the criteria, A or B below, is met. A. A diagnosis of chronic plaque psoriasis (PsO) when established by or in consultation with a specialist in dermatology or rheumatology and all of criteria 1 through 4 below are met. OR 1. Clinical documentation supports involvement of at least 10% of the body surface area or there is significant functional disability. AND 2. Treatment with phototherapy (for example, UVB) or photochemotherapy was not effective, not tolerated, or is contraindicated (see Appendix 1). AND 3. Treatment with at least one oral DMARD (such as methotrexate) was not effective or not tolerated, unless all are contraindicated (see Appendix 2). AND 4. There is clinical documentation that treatment with three preferred biologic therapies were each not effective after at least a 12-week treatment course unless each were not tolerated or were contraindicated (see Appendix 3). B. A diagnosis of psoriatic arthritis (PsA) and both criteria 1 and 2 below are met. 1. Diagnosis is established by or in consultation with a specialist in dermatology or rheumatology. AND 2. There is clinical documentation that treatment with three preferred biologic therapies were each not effective after at least a 12-week treatment course unless each were not tolerated or were contraindicated (see Appendix 3). II. Administration, Quantity Limitations, and Authorization Period A. OmedaRx considers apremilast (Otezla) to be a self-administered medication. B. When prior authorization is approved, apremilast (Otezla) may be authorized in quantities of 60 tablets per 30 days. C. Authorization may be reviewed at least annually to confirm that current medical necessity criteria are met and that the medication is effective. dru342.1 Page 2 of 13

3 III. Apremilast (Otezla) is considered investigational when used for all other conditions, including but not limited to: A. Use in combination with a biologic response modifier (see Appendix 3), or tofacitinib (Xeljanz) B. Acne C. Ankylosing spondylitis (AS) D. Atopic dermatitis/contact dermatitis E. Behçet s disease F. Chronic pelvic pain syndrome G. Chronic prostatitis H. Cutaneous lupus I. Dermatomyositis J. Gouty arthritis K. Lichen planus L. Osteoarthritis M. Rheumatoid arthritis N. Rosacea O. Uveitis Position Statement - There are many treatments for chronic inflammatory conditions that are effective, have known long-term safety profiles, and are recommended by national treatment guidelines. - Non-medical therapies, such as prescribed exercise therapy, physical therapy, weight loss, and smoking cessation are important treatment plan components for patients suffering from many chronic inflammatory conditions. - When a systemic medication therapy is needed to manage a chronic inflammatory condition, generic oral therapies usually offer the best value. - When non-medical therapies and oral medications are inadequate, a biologic medication may be appropriate. - Preferred/formulary biologic medications for the treatment of chronic inflammatory conditions include: adalimumab (Humira), etanercept (Enbrel), infliximab (Remicade), golimumab IV (Simponi Aria) and ustekinumab (Stelara). - No studies have shown that any one biologic medication is more effective than another in the treatment of chronic inflammatory conditions; however, the data for some individual products is of sufficient quality that indirect comparison can be made. * Indirect comparison is made base on the calculated number needed to treat (NNT) which describes the average number of patients that need to be treated for one patient to benefit. * The lower the NNT, the more likely the medication will have a benefit. * Products with similar NNTs can be considered to have comparable efficacy. dru342.1 Page 3 of 13

4 - When there is no demonstrated difference in safety or efficacy, the medication with the lowest cost often provides the best value for members. - Individual responses and tolerability of biologics are unpredictable and may vary between patients. If one biologic agent provides an inadequate response, another biologic may yet be effective. - Due to the potential for development of antibodies with anti-tnf therapies (see Table 1), which may result in loss of efficacy, clinical practice guidelines generally recommend a trial with no more than two anti-tnf therapies. [1] For those who have an inadequate response or intolerance to two anti-tnf therapies, it is reasonable to consider a biologic with an alternative mechanism of action and proven efficacy for the patient s diagnosis [e.g. abatacept (Orencia), tocilizumab (Actemra), rituximab (Rituxan), or ustekinumab (Stelara)]. - All biologics (both anti-tnfs and non-anti-tnfs) carry a risk of severe infections. There is no conclusive evidence that any one biologic option has a superior safety profile. - There is significant variation in recommended dosing across indications for individual medications; therefore, when multiple dosage forms of a biologic agent are available, coverage can be provided for those indications where the dosage form has been evaluated in randomized controlled trials, the dosage form has been proven safe and effective, and for which the dosage form has an established dose. For all other indications, the specific dosage form will be considered investigational. Clinical Efficacy Rheumatic Conditions Background - Treatments for rheumatic conditions may include non-medical therapies, medications for the management of symptoms, medications that modify the disease course such as oral or biologic disease modifying anti-rheumatic drugs (DMARD), including the first-in-class phosphodiesterase 4 (PDE4) inhibitor apremilast (Otezla) and the Janus kinase (JAK) inhibitor, tofacitinib (Xeljanz). - Medications to control inflammation such as nonsteroidal antiinflammatory medications (e.g. ibuprofen, indomethacin, and naproxen) and glucocorticoids (oral or injected into the joint) are effective for the management of symptoms, particularly during the early stages of disease. - Generic, orally administered DMARDs, including methotrexate (MTX), hydroxychloroquine, leflunomide, and sulfasalazine are effective for decreasing symptoms and slowing disease progression, have a proven track record, and have been the standard of care for many years. * MTX is considered effective in the treatment of rheumatoid arthritis (RA) and is the standard reference DMARD to which newer oral and biologic DMARDs are compared for efficacy. * Generic oral therapies have known potential risks. The management of these risks is well established. - The biologic agents can also decrease symptoms, help preserve joint functioning, and slow the progression of chronic inflammatory conditions; however, these medications also have significant risks. dru342.1 Page 4 of 13

5 - There is no comparative safety data within the biologics class that indicates one medication or mechanism of action is safer than alternatives, including anti-tnfs compared to non-anti- TNF medications. - In RA, the best response is seen when MTX is used concomitantly with any of the biologics. Infliximab (Remicade) and golimumab (Simponi, Simponi Aria) have been shown to be effective only when used with MTX. Treatment options other than infliximab (Remicade) or golimumab (Simponi, Simponi Aria) should be considered for patients who cannot take MTX. - Inhibiting PDE4 is a novel mechanism in the treatment of rheumatic conditions. PDE4 is a protein present in immune cells and is associated with inflammation. - JAK inhibition is a novel mechanism in the treatment of rheumatic conditions. JAKs are enzymes that stimulate hematopoiesis and promote immune cell function. Rheumatic Conditions Psoriatic Arthritis (PsA) - Several biologic agents have been shown to be effective in the treatment of PsA including the following: * Adalimumab (Humira) * Certolizumab pegol (Cimzia) * Etanercept (Enbrel) * Golimumab (Simponi) * Infliximab (Remicade) * Ustekinumab (Stelara) - All of these agents, with the exception of certolizumab pegol (Cimzia), have high quality data in the treatment of PsA (see Table 1) and, therefore, can be indirectly compared based on their calculated NNTs (see Table 2). - With the exception of certolizumab pegol (Cimzia), the efficacy of these agents in the treatment of PsA is similar. - Currently, the efficacy of apremilast (Otezla) relative to biologic DMARDs in the treatment of PsA is unknown. dru342.1 Page 5 of 13

6 Efficacy of apremilast (Otezla) in psoriatic arthritis (PsA) - The efficacy of apremilast (Otezla) in the treatment of PsA was evaluated in three randomized, placebo-controlled trials in a total of 1,493 patients with active PsA despite treatment with an oral DMARD. Previous treatment with up to one biologic medication was also permitted. Patients were allowed to remain on stable doses of oral DMARDs, low dose corticosteroids, or nonsteroidal antiinflammatory medications for the duration of the trials. [2] - The primary endpoint assessed was the proportion of patients who achieved a 20% improvement in the American College of Rheumatology criteria (ACR20) at 16 weeks. - In all three studies, the proportion of patients who achieved ACR20 was statistically significantly greater with apremilast (Otezla) than with placebo (32% to 41% vs 18% to 19%, respectively). [2] Skin Conditions Chronic Plaque Psoriasis (PsO) - Several biologic agents have been shown to be effective in the treatment of PsO including the following: * Adalimumab (Humira) * Etanercept (Enbrel) * Infliximab (Remicade) * Ustekinumab (Stelara) - All of these agents have high quality data in the treatment of PsO (see Table 1) and, therefore, can be indirectly compared based on their calculated NNTs (see Table 2). - The efficacy of these agents in the treatment of PsO is similar. - Currently, the efficacy of apremilast (Otezla) relative to biologic DMARDs in the treatment of PsO is unknown. Efficacy of apremilast (Otezla) in chronic plaque psoriasis (PsO) - The efficacy of apremilast (Otezla) in the treatment of PsO was evaluated in two, unpublished, randomized, placebo-controlled trials in a total of 1,257 subjects with moderate to severe plaque psoriasis [body surface area (BSA) involvement of 10%, static Physician Global Assessment (spga) of 3, Psoriasis Area and Severity Index (PASI) score 12, candidates for phototherapy or systemic therapy]. Patients were allowed to use low-potency topical corticosteroids on the face, axilla and groin. Patients with scalp psoriasis were allowed to use coal tar shampoo and/or salicylic acid scalp preparations on scalp lesions. [2] - The primary endpoint assessed was the proportion of patients who achieved a 75% improvement in the Psoriasis Area and Severity Index (PASI-75) at 16 weeks. [2] - In each study, the proportion of patients who achieved PASI-75 was statistically significantly greater with apremilast (Otezla) than with placebo (29% to 33% vs 5% to 6%, respectively). [2] dru342.1 Page 6 of 13

7 Other Conditions Apremilast (Otezla) has been studied in a variety of other conditions. Due to lack of published data, lack of high quality data, or lack of positive data these conditions are considered investigational. Details of select investigational uses are reported below. Ankylosing spondylitis (AS) - One double-blind, placebo-controlled, single-center, pilot study evaluated the efficacy of apremilast (Otezla) in patients with AS. The primary endpoint in this study, change in Bath Ankylosing Spondylitis Disease Activity Index at week 12, was not met. [3] Behçet s disease - Apremilast (Otezla) is currently approved for Behçet s disease in Europe; however, there is no published data evaluating the efficacy of apremilast (Otezla) in patients in the U.S. [4] Safety Summary - All biologic and non-biologic DMARDs have an adequate track record of clinical experience ( 3 years) with the exception of tofacitinib (Xeljanz), vedolizumab (Entyvio) and golimumab (Simponi Aria); however, the compound golimumab has been available as Simponi since All biologics (both anti-tnfs and non-anti-tnfs) carry a risk of severe infections. There is no conclusive evidence that any one biologic option has a superior safety profile. - Apremilast (Otezla) has a short track record of clinical experience (< 1 year) in the U.S. for the treatment of PsA. It has been approved in Europe for the treatment of Behçet s disease since August Immune suppression and subsequent increased risk of infection or malignancy is a potential risk with all biologic and non-biologic DMARDs. Serious infections such as tuberculosis and fungal infections should be considered prior to starting any of these therapies. - Branded DMARDs are not recommended to be given concomitantly, should be used with caution when given concomitantly with other immunosuppressive therapies, and may interfere with live vaccines. Safety of apremilast (Otezla) - The most common ( 5%) adverse events reported in clinical trials with apremilast (Otezla) were diarrhea, nausea, and headache. - Significant warnings include worsening of depression or suicidal thoughts, excessive weight loss, and drug interactions which may result in loss of efficacy. - Other medications used in the treatment of PsA have varying safety profiles; however, all suppress the immune system and are, therefore, associated with an increased risk of infection and malignancy. Apremilast (Otezla) is not associated with this risk. dru342.1 Page 7 of 13

8 Tables and Appendices Table 1. Summary of Evidence Quality by Indication for Select Disease Modifying Anti- Rheumatic Drugs (DMARD) Generic (brand) [Original FDA-approval Date] Route/Site of Administration Mechanism of action Rheumatoid Arthritis Psoriatic Arthritis Ankylosing Spondylitis Juvenile Idiopathic Arthritis Systemic Juvenile Idiopathic Arthritis Chronic Plaque Psoriasis Crohn s Disease Ulcerative Colitis infliximab (Remicade) [8/1998] etanercept (Enbrel) [11/1998] adalimumab (Humira) [12/2002] certolizumab pegol (Cimzia) [4/2008] golimumab (Simponi) [4/2009] golimumab (Simponi Aria) [7/2013] rituximab (Rituxan) [11/1997] anakinra (Kineret) [11/2001] canakinumab (Ilaris) [6/2009] tocilizumab (Actemra) [1/2010] tocilizumab (Actemra) [10/2013] ustekinumab (Stelara) [9/2009] natalizumab (Tysabri) [11/2004] vedolizumab (Entyvio) [5/2014] IV/HCP IV/HCP IV/HCP IV/HCP, HCP TNF antagonist (anti- TNF) TNF antagonist (anti- TNF) TNF antagonist (anti- TNF) TNF antagonist (anti- TNF) TNF antagonist (anti- TNF) B-lymphocyte depleter IL-1 receptor antagonist IL-1β receptor antagonist IL-6 receptor antagonist IL-12, -23 receptor antagonist a x x x a a x x x x x x x IV/HCP Integrin inhibitor x IV/HCP Integrin inhibitor x x x abatacept (Orencia) [12/2005] abatacept (Orencia) [12/2011] IV/HCP T-lymphocyte inhibitor x tofacitinib (Xeljanz) [11/2012] PO/Pat JAK inhibitor x apremilast (Otezla) [3/2014] PO/Pat PDE-4 inhibitor b HCP = healthcare provider administered; IL = interleukin; IV = intravenous; JAK = Janus kinases; Pat = patient (self) administered; PDE = phosphodiesterase; PO = oral; SC = subcutaneous; TNF = tumor necrosis factor; = FDAapproved indication and high confidence data; x = FDA-approved indication and less than high confidence data; = not FDA-approved, but specifically recommended by clinical practice guidelines a Refers to data for induction therapy only. Data for maintenance therapy is less than high confidence. b =FDA approved, but evidence has not undergone complete appraisal dru342.1 Page 8 of 13

9 Table 2. Summary of Likelihood of Symptom Improvement with Select Disease Modifying Anti-Rheumatic Drugs (DMARDs) a Condition Description of symptom improvement Medication abatacept (Orencia) adalimumab (Humira) anakinra (Kineret) apremilast (Otezla) certolizumab pegol (Cimzia) etanercept (Enbrel) golimumab (Simponi) infliximab (Remicade) natalizumab (Tysabri) rituximab (Rituxan) tocilizumab (Actemra) tofacitinib (Xeljanz) ustekinumab (Stelara) vedolizumab (Entyvio) Ankylosing Spondylitis At least a 20% improveme nt in ASAS (Range 3-4) Psoriatic Arthritis At least a 20% improveme nt in ACR criteria Rheumatoid Arthritis At least a 20% improveme nt in ACR criteria (Range 3-4) Chronic Plaque Psoriasis At least a 75% improveme nt in PASI Crohn s Disease Remission based on the CDAI Ulcerative Colitis Remission based on the Mayo score Initial NNT = 7 (Range 5-8) Ongoing Initial NNT = 11 Ongoing NNT = 7 (Range 3-4) NNT = 6 (Range 4-8) (Range 3-4) (Range 3-5) at this time at this time Initial Ongoing Initial Ongoing (Range 3-5) (Range 4-5) Initial Ongoing Initial Ongoing ACR = American College of Rheumatology; ASAS = Assessment in Ankylosing Spondylitis International Working Group Criteria; PASI = Psoriasis Area Severity Index a In select conditions. Likelihood of symptom improvement relative to placebo after three to six months of treatment based on number needed to treat (NNT). An NNT represents the average number of patients that need to be treated for one patient to benefit and can be calculated only where there is high confidence data. dru342.1 Page 9 of 13

10 Appendix 1: Absolute and Relative Contraindications for Phototherapy/Photochemotherapy - Type 1 or type 2 skin - History of photosensitivity - Increased risk of photosensitivity due to concomitant disease state (e.g. porphyria, systemic lupus erythematosus) or chronic medication use (e.g. tetracycline or sulfonamide antibiotics) - Treatment of facial or scalp lesions - Treatment of lesions in the groin area - Treatment of lesions on the palms of the hands or soles of the feet, or on nail beds - Presence of premalignant lesions (e.g. actinic keratosis) - History of melanoma or squamous-cell carcinoma - Physical inability to stand for the required exposure time Appendix 2: Select List of Oral Disease Modifying Anti-rheumatic Drugs (DMARD) Oral DMARDS for Rheumatic and Skin Conditions azathioprine (Imuran) methotrexate (oral, injectable) cyclosporine (Gengraf, Neoral, Sandimmune) mycophenolate (CellCept, Myfortic) hydroxychloroquine (Plaquenil) sulfasalazine (Azulfidine) leflunomide (Arava) dru342.1 Page 10 of 13

11 Appendix 3: Select Biologic Response Modifiers - Actemra, tocilizumab - Cimzia, certolizumab pegol - Enbrel, etanercept* - Entyvio, vedolizumab - Humira, adalimumab* - Kineret, anakinra - Orencia, abatacept - Remicade, infliximab* - Rituxan, rituximab - Simponi, golimumab - Stelara, ustekinumab* - Tysabri, natalizumab * Preferred/formulary medications for dermatology-related conditions Cross References Actemra, tocilizumab dru209 Cimzia, certolizumab dru160 Enbrel, etanercept dru035 Entyvio, vedolizumab dru356 Humira, adalimumab dru081 Kineret, anakinra dru049 Orencia, abatacept dru129 Rituxan, rituximab dru214 Simponi, golimumab dru183 Tysabri, natalizumab dru111 Xeljanz, tofacitinib dru289 dru342.1 Page 11 of 13

12 Codes Number Description CPT Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); initial, up to 1 hour Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); each additional hour (List separately in addition to code for primary procedure) (Use in conjunction with 96365, 96367) Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); additional sequential infusion, up to 1 hour (List separately in addition to code for primary procedure) (Use in conjunction with 96365, 96374, 96409, if provided as a secondary or subsequent service after a different initial service is administered through the same IV access. Report only once per sequential infusion of same infusate mix) Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); concurrent infusion (List separately in addition to code for primary procedure) (Use in conjunction with 96365, 96366, 96413, 96415, Report only once per encounter) HCPCS J0129 Injection, abatacept, 10 mg, for intravenous use J0135 J0717 J1438 J1602 J1745 J2323 J3262 J3357 J9310 Injection, adalimumab, 20 mg (to be used only when drug is given under direct supervision of a physician) Injection, certolizumab pegol, 1 mg (to be used only when drug is given under direct supervision of a physician) Injection, etanercept, 25 mg and 50 mg (to be used only when drug is given under direct supervision of a physician) Injection, golimumab, 1 mg, for intravenous use Injection, infliximab, 10 mg Injection, natalizumab, 1 mg Injection, tocilizumab, 1 mg, for intravenous use Injection, ustekinumab, 1 mg Injection, rituximab, 100 mg dru342.1 Page 12 of 13

13 References 1. European League Against Rheumatism recommendations for the management of psoriatic arthritis with pharmacological therapies. [cited 09/13/2013]; Available from: 2. Otezla [package insert]. Summit, NJ: Celgene Corporation; 03/ Pathan, E, Abraham, S, Van Rossen, E, et al. Efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in ankylosing spondylitis. England, p European Medicines Agency (EMA) [internet database]. London, United Kingdom: European Union; Updated daily dru342.1 Page 13 of 13