Evaluating Biologic Therapies for Psoriasis Strategies to Reduce Cost and Improve Patient Access and Outcomes

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1 Evaluating Biologic Therapies for Psoriasis Strategies to Reduce Cost and Improve Patient Access and Outcomes Faculty William J. Cardarelli, PharmD Director of Pharmacy Revenue and Supply Atrius Health Harvard Vanguard Medical Associates Watertown, Massachusetts Alan Menter, MD Chair of Dermatology Baylor University Medical Center Dallas, Texas Supported by an educational grant from AbbVie. Disclosure Learning Objectives Dr. Cardarelli, PharmD: None Dr. Menter, MD: Advisory Board AbbVie, Allergan, Amgen, Boehringer Ingelheim, Eli Lilly, Janssen Biotech, Inc., LEO Pharma; Consultant AbbVie, Allergan, Amgen, Eli Lilly, Janssen Biotech, Inc., LEO Pharma, Novartis, Pfizer, Vitae, Xenoport; Investigator AbbVie, Allergan, Amgen, Anacor, Boehringer Ingelheim, Celgene, Dermira, Eli Lilly, Janssen Biotech, Inc., LEO Pharma, Merck & Co. Inc., Neothetics, Novartis, Pfizer, Regeneron, Symbio/Maruho, Xenoport; Speaker AbbVie, Amgen, Janssen Biotech, Inc., LEO Pharma; Grant Support AbbVie, Allergan, Amgen, Anacor, Boehringer Ingelheim, Celgene, Dermira, Janssen Biotech, Inc., LEO Pharma, Merck & Co. Inc., Neothetics, Novartis, Pfizer, Regeneron, Symbio/Maruho, Xenoport Quantify the clinical and economic consequences of suboptimal screening, delayed treatment, and patient nonadherence within the management of psoriasis and associated comorbidities Distinguish between the efficacy, safety, and pharmacoeconomic profiles of biologic therapies Translate consensus statements and recent clinical outcomes data of biologic therapies to informed formulary decisions Employ health plan strategies that assist providers in improving screening, monitoring, and patient adherence to treatment Overview of Psoriasis Approximately 7.5 million people in the United States have psoriasis Psoriasis occurs in all age groups but is primarily seen in adults Psoriasis usually occurs on the scalp, knees, elbows, hands, and feet Approximately 8% of those affected with psoriasis have mild to moderate disease, whereas % have moderate to severe psoriasis affecting >5% of the body surface area The most common form of psoriasis, affecting approximately 8% to 9% of patients with psoriasis, is plaque psoriasis Characterized by patches of raised, reddish skin covered with silvery-white scale In 13, the total direct cost of treatment associated with psoriasis was estimated to be between $51.7 and $63.2 billion The average age of mortality for patients with psoriasis is approximately years less than the general population American Academy of Dermatology. Accessed May 5, 16. International Federation of Psoriasis Associations. Psoriasis is a serious disease deserving global attention.pdf. Accessed May 18, 16. Comorbidities Associated with Psoriasis The incidence of Crohn s disease and ulcerative colitis, two types of inflammatory bowel disease, is 3.8 to 7.5 times greater in patients with psoriasis than in the general population Patients with psoriasis also have an increased incidence of lymphoma, heart disease, obesity, type 2 diabetes mellitus, and metabolic syndrome Depression and suicide, smoking, and alcohol consumption are also more common in patients with psoriasis The prevalence of depression in patients with psoriasis may be as high as 5% Studies have shown that patients with psoriasis experience physical and mental disability just like patients with other chronic illnesses such as cancer, arthritis, hypertension, heart disease, and diabetes mellitus American Academy of Dermatology. Accessed May 5, 16.

2 Barriers to Patient Care Barriers to Healthcare System Stigma Persistent symptoms Medication side effects Insurance coverage Poor flow of data between system and caregiver Delivery of system design Poor integration of behavioral health into primary care Reimbursement hurdles Comorbidities Nonadherence Eissing L, et al. J Eur Acad Dermatol Venereol. 16;3(4): Biologics Biologic Drug Classes Biologics include a range of products Vaccines Blood and blood components Gene therapy Recombinant therapeutic proteins Biologics are composed of sugars, proteins, or nucleic acids or complex combinations of these substances, or may be living entities such as cells and tissues Biologics are isolated from a variety of natural sources Human Animal Microorganisms What are Biologics Questions and Answers. medicalproductsandtobacco/cber/ucm13377.htm. Accessed May 6, 16. Tumor necrosis factor-alpha (TNF-α) blockers Certolizumab pegol Etanercept Adalimumab Infliximab Golimumab IL-12/23 Ustekinumab Secukinumab Ixekizumab IL = interleukin. National Psoriasis Foundation. Accessed May 14, 16. Evaluating Biologic Therapies for Psoriasis Strategies to Reduce Cost and Improve Patient Access and Outcomes Alan Menter, MD Apremilast Predicted mechanistic effects of (PDE4 inhibitor) in psoriasis Attenuation of T-cell activation Broad anti-inflammatory effects on immune accessory cells Possible direct effects on keratinocytes PDE4 = phosphodiesterase 4. Bjørgo E, et al. Handb Exp Pharmacol. 11;4: Gottlieb AB, et al. Curr Med Res Opin. 8;24(5): Schafer PH, et al. Br J Pharmacol. ;159(4): Otezla [product information]. Summit, NJ: Celgene Corp; 15.

3 Oral Apremilast (CC-4) Phase 3 Study: ESTEEM 2 Study Design A randomized, double-blind, placebo-controlled, phase 3, efficacy, and safety study (NCT ) Screening Randomization (2:1) Oral Apremilast 3 mg BID (n=275) Oral Placebo BID (n=138) Re-randomization (1:1) Week Patients had moderate to severe plaque psoriasis (PASI score 12, PGA 3, BSA %) Oral Apremilast 3 mg BID Oral Apremilast 3 mg BID Oral Placebo BID Loss of Response Oral Apremilast 3 mg BID Patients who achieved >PASI 5 response were re-randomized to apremilast or placebo. BID = twice daily; BSA = body surface area; PASI = Psoriasis Area and Severity Index; PGA = Physician Global Assessment. Paul C, et al. J Am Acad Dermatol. 14;7(suppl 1):AB184 (Abstract #P8412). Results Oral Apremilast (CC-4) Phase 3 Study: ESTEEM 2 At week 16, significantly more patients receiving APR3 achieved the following: PASI 75: 28.8% 3 mg vs 5.8% placebo PASI 5: 55.5% 3 mg vs 19.7% placebo In patients receiving apremilast, diarrhea and nausea were predominantly mild in severity, had the highest incidence during the first week of dosing, and generally resolved within 1 month SAEs (including serious infections, malignancies, and cardiovascular events) and laboratory value changes were consistent with prior apremilast studies; SAEs were low across treatment groups Conclusion Apremilast significantly reduced the severity of moderate to severe psoriasis, including nail, scalp, and palmoplantar involvement, and was generally well tolerated with no new safety or laboratory findings APR3 = apremilast 3 mg; SAE = serious adverse event. Rich P, et al. J Am Acad Dermatol. 16;74: Apremilast: Overall Safety Summary No new significant AEs were identified in these phase 2 trials AEs Increase in nausea, diarrhea, and headache: Up to % of patients Mostly mild and seen predominately in initial 3 to 4 weeks of treatment Weight loss (1-5 kg) Depression (occasional patient) No changes in laboratory parameters No cases of tuberculosis (new infection/reactivation) reported Approved for the treatment of psoriasis and psoriatic arthritis in 14 AE = adverse event. Papp K, et al. Poster presented at the 72nd Annual Meeting of the AAD, Denver, CO, 14 (Poster #8359); Paul C, et al. Poster presented at the 72nd Annual Meeting of the AAD, Denver, CO, 14 (Poster #8412); Reich K, et al. Poster presented at the 72nd Annual Meeting of the AAD, Denver, CO, 14 (Poster #8296). Apremilast (Otezla) National Drug Monograph. VA Pharmacy Benefits Management Services, Medical Advisory Panel, and VISN Pharmacist Executives; January 15. Current FDA-Approved Biologic Therapies for Psoriasis Type Agent Indication TNF-α antagonists IL-12/IL-23 antagonist antagonist FDA = US Food and Drug Administration. Etanercept Infliximab Adalimumab Ustekinumab Ixekizumab Secukinumab Psoriatic arthritis, Psoriasis Psoriatic arthritis, Psoriasis Psoriatic arthritis, Psoriasis Psoriatic arthritis, Psoriasis Psoriasis Psoriatic arthritis, Psoriasis Etanercept Etanercept in Psoriasis (Phase 3 US Study): PASI 75 Response Only soluble TNF receptor antagonist Fully human protein Does not bind complement in vitro (ie, not associated with complement-mediated cell lysis) Low immunogenicity Dosing schedule maintains stable serum concentrations Subcutaneous injection Extracellular domain of high-affinity human p75 TNF receptor Fc region of human IgG 1 Percentage of Patients (%) Weeks Weeks 59 Placebo/ Etanercept 25 mg BIW Etanercept 25 mg QW Etanercept 25 mg BIW Etanercept 5 mg BIW N=652 Clinical significance is unknown. TNF = tumor necrosis factor; IgG = immunoglobulin G. Enbrel [package insert]. Thousand Oaks, CA: Amgen; 15. P=.6; P<.1 vs placebo. BIW = twice weekly; QW = once weekly. Leonardi C, et al. N Engl J Med. 3;349:14-22.

4 Indications Infliximab Rheumatoid arthritis, Crohn s disease, psoriatic arthritis, ulcerative colitis, ankylosing spondylitis Contraindications Serious infection Thrombocytopenia Malignancies Administration Intravenous infusions 5 mg/kg at weeks, 2, and 6 weeks, then every 8 weeks Remicade [package insert]. Horsham, PA: Janssen Biotech, Inc; 15. Binding Binding Region Region NH Mouse 2 NH 2 Heavy Chain NH 2 NH 2 Hinge Region Human Heavy Chain S-S S-S COOH COOH Mouse Fab Region Human Fc Region Infliximab in Psoriasis: Maintenance of Response through Week 5 Key points of two EXPRESS studies PASI score at week was 75% but at week 5 was 6% Thus, approximately 25% of patients will lose PASI 75 response over 1 year of therapy Persistence of a PASI 75 response is associated with the maintenance of detectable serum levels of infliximab between infusions 5% of patients had significantly abnormal liver function test results (5X baseline) Question: Why were dermatologists not allowed (EMEA and FDA) to use concomitant MTX during these two pivotal studies? Always allowed in rheumatology studies! EMEA = European Medicines Agency; MTX = methotrexate. Reich K, et al. Dermatology. ;221(2): Menter A, et al. J Am Acad Dermatol. 7;56:31. e1-e15. Review of Infliximab Treatment for Psoriasis in Patients Receiving Therapy for at Least 1 Year Infliximab: Biologic Case Studies Study 1 patients with psoriasis were treated with infliximab at Baylor, Dallas, between 2 and 8 Results Mean follow-up: 2.2 years >9% clear at week 12 Concomitant MTX required by 52% of patients >1 standard dose of 5 mg/kg required by 87% of patients every 8 weeks to maintain clearance 16% of patients discontinued infliximab post 1 year of treatment, primarily due to loss of response Kamili QU, et al. J Drugs Dermatol. 11 May;(5): Pre-infliximab Dallas Case #1: SB Question: Based on this patient s morbid obesity, would other biologic agents produce such a dramatic response and maintain life-long clearance? Kamili QU, et al. J Drugs Dermatol. 11 May;(5): Post-infliximab after second infusion Adalimumab Adalimumab: REVEAL Phase 3 Study Summary Fully human IgG 1 mab Generated using phage display technology Administration Weekly or every other week subcutaneous injection (4 mg) C H2 C H3 S-S S-S Fab Fc PASI 75 response at week 16: 71% for adalimumab vs 7% for placebo At week 52, loss of adequate response was observed for significantly more patients re-randomized to placebo (28%) relative to patients re-randomized to adalimumab (5%) in period C mab = monoclonal antibody. Humira [product information]. North Chicago, IL: AbbVie Inc; 16. Study was divided into three treatment periods (A, B, and C). Menter A, et al. J Am Acad Dermatol. 8;58(1):6-115.

5 Adalimumab: Results from an Open-Label Extension Study for Patients from REVEAL Results 75% / 9% / % improvement in PASI score response rates (last observation carried forward) was sustained in 83% / 59% / 33% of patients after weeks and 76% / 5% / 31% after 16 weeks of continuous therapy, respectively Some patients with less than PASI 75 responses in REVEAL also achieved long-term PASI 75 responses Adalimumab: Efficacy of Switching between TNF-α Inhibitors in Psoriasis Italian Psocare Registry study of 5423 patients receiving TNF-α therapy (September 5-September ) Study looked to assess the variables that predicted the efficacy of TNF-α switching 5 patients who switched to a second TNF-α inhibitor were assessed 75% improvement in PASI 75 score was reached by 29% after 16 weeks and by 45.6% after 24 weeks Patients who switched because of secondary loss of efficacy (loss of initial PASI 75 response) or AEs/intolerance were more likely to reach PASI 75 than those who switched as a result of primary inefficacy (PASI 75 never achieved) Gordon K, et al. J Am Acad Dermatol. 12 Feb; 66(2): Piaserico S, et al. J Am Acad Derm. 14;7(2): e3. Ustekinumab: Key Actions of IL-12 and IL-23 in Psoriasis Ustekinumab: Phase 3 PASI Response over 28 Weeks p4 p35 IL-12 p19 p4 IL-23 IFN- TH1 cell differentiation Ustekinumab TH17 cell differentiation IL-17 IL-22 keratinocyte hyperproliferation pro-inflammatory factors keratinocyte hyperproliferation Skin Plaques Increased inflammation Skin Plaques Ustekinumab is not known to bind to any other cytokines Torti DC, et al. J Am Acad Dermatol. 7;57: Fantuzzi F, et al. Expert Opin Ther Targets. 8;12(9): Percentage of Patients (%) PHOENIX 1: Week 28 ITT-NRI PASI 5 PASI 75 PASI 9 Ustekinumab 45 mg (n=25) Ustekinumab 9 mg (n=243) P<.1 vs placebo for all comparisons. ITT = intention to treat; NRI = nonresponder imputation. Leonardi CL, et al. Lancet. 8;371(9625): PHOENIX 2: Week 28 ITT-NRI PASI 5 PASI 75 PASI 9 Ustekinumab 45 mg (n=397) Ustekinumab 9 mg (n=4) Results of Ustekinumab Treatment after 1 Injection Baseline Week 12 Review of Ustekinumab Treatment for Psoriasis in Patients Maintained on Therapy for at Least 1 Year Study Medical records of 119 patients with psoriasis treated with ustekinumab at referral clinic in Dallas between 9 and 13 were reviewed for response rates, side effects, and concomitant therapies Results Median follow-up: 31 months 47% (56) of patients obtained near-complete clearance (ie, response of >9% of initial body surface area involvement) upon final follow-up visit or when ustekinumab treatment was discontinued 5% (59) of patients received concomitant systemic treatments, primarily MTX 42% (5) of patients required either an increase in the dose of ustekinumab to 9 mg and/or administration more frequently than every 12 weeks to achieve and maintain psoriasis clearance 19% (23) of patients discontinued treatment, primarily for suboptimal response or loss of response Wilder EG, et al. J Drugs Dermatol. 14;13(8):95-9.

6 The IL-17 Family Includes 6 Cytokines (IL17A IL-17F) Ixekizumab Family Member Main Function Receptor Neutrophil recruitment IL-17F /F heterodimer Extracellular pathogen defense Bone metabolism Regulation of intestinal inflammation Endothelial cell migration and angiogenesis Keratinocyte proliferation IL-17RA IL-17RC IL-25 (IL-17E) IL-17B IL-17C IL-17D Gu C, et al. Cytokine. 13 Nov;64(2): Promotes T H 2 responses Modulates allergic responses and asthma Provides protective immunity to extracellular pathogens (eg, parasitic infections) Under investigation IL-17RA IL-17RB IL-17RB IL-17RE Unknown Humanized IgG4 mab against Contains Ser to Pro mutation in the hinge region to prevent the formation of half antibodies Neutralizes homodimers and /F heterodimers Half-life:.5 days Positive proof-of-concept Psoriasis Rheumatoid arthritis Leonardi C, et al. N Engl J Med. 12;366(13): Genovese MC, et al. Arthritis Rheum. ;62(4): Ixekizumab Selectively Blocks Staphylococcus species Streptococcus species TLR2 Dendritic cell IL-23 Candida species dectin-1 dectin-2 IL-17 receptor Keratinocytes (and IL-22) Proinflammatory cytokine production (eg, ) Antimicrobial peptide production Anti-Interleukin-17 Monoclonal Antibody Ixekizumab in Chronic Plaque Psoriasis Th17 cell IL-22 (and ) Neutrophil accumulation IL-17 receptor Keratinocyte proliferation Back-to-back publication with brodalumab Leonardi C, et al. N Engl J Med. Mar 12;366(13): Ixekizumab: Anti-IL-17 mab in Chronic Plaque Psoriasis Ixekizumab: PASI Response over Time to Week Study Phase 2, double-blind, placebo-controlled trial 142 patients with moderate to severe plaque psoriasis Subcutaneous injections of, 25, 75, or 15 mg ixekizumab or placebo at weeks, 2, 4, 8, 12, and 16 Results PASI 75 at week 12: 82% vs 7.7% at the 15-mg dose Percentage of Patients (%) PASI 9 at week 12: 71% vs % for the 15-mg dose AEs occurred in 63% of patients in both groups No SAEs or MACEs were observed 2 4 Ixekizumab mg Ixekizumab 25 mg 6 8 Weeks Ixekizumab 75 mg Ixekizumab 15 mg 18 Placebo MACE = major adverse cardiovascular event. Leonardi C, et al. N Engl J Med. Mar 12;366(13): P<.5 compared to placebo. Leonardi C, et al. N Engl J Med. Mar 12;366(13):

7 Ixekizumab: Key Findings Ixekizumab had a rapid onset of action as evidenced by the following: Impressive PASI scores in the two highest-dose groups compared to placebo at week 1 Higher percentage of patients in the highest-dose group with PASI 75 or spga score of or 1 at week 2 Approximately 4% of patients in the two highest-dose groups (PASI and spga ) had clear skin at 12 weeks There were no SAEs TEAEs were similar across groups with no dose-related trend in any individual TEAE spga = Static Physician s Global Assessment; TEAE = treatment-emergent adverse event. Leonardi C, et al. N Engl J Med. Mar 12;366(13): Secukinumab: An mab That Selectively Targets IL-12 IL-23 T H 17 IL-23 receptor IL-22 receptor Yamauchi PS, et al. J Drugs Dermatol. 15;14(3): Nestle FO, et al. N Engl J Med. 9;361(5): Mease PJ. Curr Opin Rheumatol. 15;27(2): Lønnberg AS, et al. Clin Cosmet Investig Dermatol. 14;7: Cosentyx [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 15. Secukinumab: An mab That Selectively Targets receptor IL-12 T H 17 Secukinumab in Plaque Psoriasis Results of Two Phase 3 Trials IL-23 receptor Secukinumab IL-23 IL-22 The clinical significance of the secukinumab mechanism of action is unknown. Cosentyx [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 15. Langley RG, et al. N Engl J Med. 14;371(4): Secukinumab Induction and Maintenance Regimen: Finding Study Study Phase 2, randomized, double-blind, placebo-controlled 44 patients with moderate to severe psoriasis 15-mg induction subcutaneous injections Results PASI 75 and PASI 9 at weeks and 28 for fixed interval vs start of relapse Fixed interval: 85% PASI 75 and 58% PASI 9 Start of relapse: 67% PASI 75 and 21% PASI 9 Safety Nil increase in infection rates vs placebo Not Using a Biologic in a Patient with Moderate to Severe Psoriasis May Cause Deformed joints Decreased quality of life Heart attacks Strokes Early death Rich P, et al. Br J Dermatol. 13 Feb;168(2): Menter A, et al. J Am Acad Dermatol. 8;58(5):

8 Biosimilars Are Projected to Moderate Drug Expenditures and Expand Patient Access to Biologics Definitions Continuing growth in US prescription drugs Top drugs for first 9 months of 14 based on expenditures In clinics: infliximab, pegfilgrastim, epoetin alfa In hospitals: infliximab, rituximab, pegfilgrastim 7% to 9% projected increases in total drug expenditures for 15 across all settings Biosimilars are predicted to lead to a $44.2 billion reduction (range, $13-$66 billion) in direct spending on biologic drugs from According to the FDA, biosimilar or biosimilarity means: That the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components AND There are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product Schumock GT, et al. Am J Health Syst Pharm. 15;72(9): Mulcahy AW, et al. rand.org/content/dam/rand/pubs/perspectives/pe/pe127/rand_pe127.pdf. Accessed June 15. FDA. htm. Accessed June 15. Biosimilars Are Approved According to Specific, Highly Stringent Regulations The Many Faces of Psoriasis and Psoriatic Arthritis Quality standards for biosimilars are the same as for original biologics In highly regulated countries, biosimilars are evaluated according to rigorous guidelines and must have the following: Highly comparable structural and functional attributes No clinically relevant differences Products that do not meet these high standards are not approved and not put into circulation Biosimilars have been in use in Europe since 6 with safety profiles comparable to their respective reference product Strober BE, et al. J Am Acad Dermatol. 12 Feb;66(2): Dactylitis Arthritis mutilans Enthesitis Evolution of Psoriasis Immunopathogenesis and Therapeutic Approaches over the Past 3 Decades A disease of keratinocyte dysfunction (pre-198s) Therapeutic approach: MTX, UVB, PUVA, retinoids An immunologic disease (198s) Therapeutic approach: Cyclosporine An IL-12/Th1-mediated disease (199-4) Therapeutic approach: Anti-CD2, anti-cd11a, TNF-α blockers An IL-23/Th17-mediated disease (5-present) Multiple therapeutic approaches: IL-12/IL-23, IL-23, IL-17, IL-17R blockers New Biologics: General Impressions PASI 9 is the new PASI 75! New biologics are more targeted to the skin immune system than to the systemic immune system, which makes efficacy very high and safety profiles very good It is too early to say whether biologics will improve systemic inflammation and decrease cardiovascular risks UVB = ultraviolet light B; PUVA = psoralen + ultraviolet light A; TNF = tumor necrosis factor. Blauvelt A. Expert Rev Dermatol. 7;2(1): Di Cesare A, et al. J Invest Dermatol. 9;129(6): Martin DA, et al. J Invest Dermatol. 13;133(1): Langley, RG, et al. N Engl J Med. 14 Jul 24;371(4):

9 Tildrakizumab: A Humanized IgG1κ mab that Targets the Unique p19 Subunit of IL-23 IL-23 Drugs in Development Clinical trials Results from a randomized, double-blind, phase 2b clinical trial showed that tildrakizumab was effective in treating moderate to severe plaque psoriasis At week 16, the proportion of subjects achieving PASI 75 was significantly higher at all doses when compared to placebo (4.4%) 33.3% on 5 mg 64.4% on 25 mg 66.3% on mg 74.4% on mg The final drug dose was given on week 4, and the participants were followed until week 72 Tildrakizumab demonstrated a low rate of relapse after cessation of therapy, with only 3.6% of the participants who achieved PASI 75 at week 52 on any dose of tildrakizumab relapsing before week 72 Phase 3 studies are in progress Tildrakizumab (MK-3222) [product information]. Whitehouse Station, NJ: Merck & Co; 16. Campa M, et al. Dermatol Ther (Heidelb). 16 Mar;6(1):1-12. Tildrakizumab: An Anti-IL-23 mab that Improves Psoriasis (Phase 2) BI PASI 75 Response Rate (%) Weeks 5 mg mg Placebo 25 mg mg Note: Tildrakizumab is not currently FDA approved for psoriasis. Presented at the 71st American Academy of Dermatology Annual Meeting. Miami, FL; 13. BI is a high-affinity mab targeting the p19 subunit of IL-23 and is currently in development for moderate to severe psoriasis and Crohn s disease Clinical trials A phase 1, proof-of-concept study of BI demonstrated a similar frequency of side effects with varying doses of BI compared to placebo The most common side effects were mild to moderate upper respiratory infections, mild nasopharyngitis, and mild to moderate headache After a single intravenous or subcutaneous dose, PASI 75 was achieved in 87% of subjects, PASI 9 in 58% of subjects, and PASI in 16% of subjects Additional trials are ongoing BI [product information]. Ingelheim, Germany: Boehringer Ingelheim; 15. Krueger JG, et al. J Allergy Clin Immunol. 15;136: e7. Guselkumab (CNTO 1959) Guselkumab (CNTO 1959) is a fully human IgG1λ monoclonal IL-23 antagonist targeting the unique p19 subunit of IL-23 Clinical trials In a phase 2, randomized, double-blind, placebo-controlled, dose-ranging, active-comparator study, patients randomized to guselkumab were significantly more likely to achieve a PGA score of (clear) or 1 (almost clear) at 16 weeks when compared to placebo: 34% in the 5-mg dose group, 61% in the 15-mg dose group, 79% in the 5-mg dose group, 86% in the -mg dose group, 83% in the -mg dose group, and 7% in the placebo group At 16 weeks, a score of or 1 on the PGA was seen in 58% of patients randomized to adalimumab, which was significantly lower than the 5-mg, -mg, and -mg doses of guselkumab Guselkumab (CNTO 1959) [product information]. Beerse, Belgium: Janssen Research and Development. Gordon KB, et al. N Engl J Med. 15;373: IL-23 and IL-17 as Treatment Targets in Psoriasis Conclusions Both IL-23 and IL-17 are promising targets in the treatment of moderate to severe plaque psoriasis Biologic drugs targeting these cytokines and their receptors have proved to be effective and safe in clinical trials and have offered greater efficacy than pre-existing biologics Evidenced by large proportions of patients achieving not only PASI 75 but also PASI 9 and PASI It is important to be vigilant in following the safety profile of these drugs both in clinical trials and in post-marketing registries to ensure their long-term safety Campa M, et al. Dermatol Ther (Heidelb). 16 Mar;6(1):1-12.

10 Biopharmaceuticals and Biosimilars in Psoriasis: What the Dermatologist Needs to Know Strober BE, et al. J Am Acad Dermatol. 12 Feb;66(2): Evaluating Biologic Therapies for Psoriasis Strategies to Reduce Cost and Improve Patient Access and Outcomes William Cardarelli, PharmD Opportunities for P&T Committee Increase committee s knowledge of psoriasis therapies Both current and emerging therapies Develop evidence-based guidelines for earlier treatment intervention Work closely with thought leaders to adapt recommendations as best practices change Understand the value of early diagnosis and treatment Explore opportunities for innovative strategies that maintain access while reducing costs Maximize adherence to lower overall costs and improve outcomes Consider formulary designs that reduce patient out-of-pocket spending Is this a place for the Medical Home? P&T = Pharmacy and Therapeutics. American Society of Health-System Pharmacists. ASHP guidelines on the pharmacy and therapeutics committee and the formulary system. Am J Health-Syst Pharm. 8; 65: American Academy of Dermatology Clinical Decision Tree Coverage Issues Anti-TNF +/- MTX Psoriasis +/- Psoriatic Arthritis YES Topicals/ Targeted phototherapy Lack of Effect Limited Disease UVB / PUVA Systemic Biologic Patients with nondeforming psoriatic arthritis without any radiographic changes, loss of range of motion, or interference with tasks of daily living should not automatically be treated with TNF inhibitors. It would be reasonable to treat these patients with nonsteroidal anti-inflammatory agent or to consult rheumatologist for therapeutic options. Patients with limited skin disease should not automatically be treated with systemic treatment if they do not improve, because treatment with systemic therapy may carry more risk than the disease itself. PUVA = psoralen plus ultraviolet (UV)-A. American Academy of Dermatology. Accessed May, Menter A, et al. J Am Acad Dermatol. 8;58(5): NO Extensive Disease What are the trends? Guideline revisions? Earlier, more aggressive therapy? Oral drugs are covered under pharmacy benefit, but access to drugs covered under medical benefit subject to P&T review Supportive medications: Coverage determined by route of administration Medicare Part B vs Part D determination further blurs the boundaries of coverage

11 Comparison of Annual Treatment Costs of Selected Agents Actual Total Cost Treatment Etanercept Adalimumab Ustekinumab Recommended Dosage Schedule Initial: 5 mg twice weekly for 3 months, then 5 mg once weekly Initial 8-mg single dose, then 4 mg every other week starting 1 week after initial dose Initial: Assuming kg: 45 mg at and 4 weeks, then every 12 weeks thereafter Average Initial Then Wholesale Price Maintenance Maintenance (14 USD) (USD) (USD) 15.47/mg 46,395 37, /mg 39,41 36, /mg 53,99 44,924 Dosing regimens for adalimumab and ustekinumab are based on FDA recommendations. Dosing regimen for etanercept is based on the PRESTA trial. Average wholesale price was determined from the Red Book Drug Topics, 14. USD = United States dollar. Cheng J, et al. Drugs in Context. 14;3: Accessed May 28, 16. Whether a product is being bought or sold, price is only a part of the actual total cost Costs of quality, including paying for outcomes, and costs of the transaction, including resources, effort, time, payment terms, and renegotiations, must be considered when assessing or comparing actual total costs of propositions, products, or services Price Unit cost Value The right product at the right time and place (quality and outcome) Transaction Cost of resources, effort, time, and doing business Christopher Barrat & Alan Chapman 4. Accessed May 19, 16. Comparative Effectiveness Research Direct comparison of existing healthcare interventions Assists patients and providers in making informed decisions to improve healthcare for individuals and the overall population Pragmatic trials: Clinical research trials Measure effectiveness: The benefit a treatment produces in routine clinical practice Different from regular clinical trials that measure efficacy: Whether the treatment works Two methods used by researchers to gather evidence Study the available evidence of each choice for different groups of patients from existing clinical trials, clinical studies, and other research Facilitate trials to find new evidence of effectiveness or comparative effectiveness of a test, treatment, procedure, or healthcare service Agency for Healthcare Research and Quality. What Is Comparative Effectiveness Research. Accessed November, 12. Roland M, et al. BMJ. 1998;316:285. MCO Initiatives to Improve Outcomes and Adherence Value-based benefit design Medication therapy management Formulary management Pay-for-performance Strengthen patient-provider relationships Patient empowerment Integrated communication channels Telephone counseling Medication reminders MCO = managed care organization. Tutty S, et al. Eff Clin Pract. ;3(4): Hoffman L. Am J Manag Care. 2;9:7-8. Provider Strategies to Increase Adherence Active patient participation Adequate communication Family support Positive reinforcement by provider Simplified drug regimen Strategies to Improve Medication Adherence: Integrated Communication Channels Multi provider-level communication with patients regarding the importance of medication adherence Physicians Pharmacists Nurses Case managers Provider responsibilities Communicate respect for the patient's perspective of his/her condition Provide rationale for any recommended treatment Negotiate a plan and anticipate and address problems Discuss adherence at every visit in a nonjudgmental way Establish a collaborative process of problem solving Roter D. J Pharmacoepidemiol. 1995;3:37-48.

12 Biosimilar vs Interchangeable Biosimilar vs Interchangeable (cont) Biosimilar Highly similar to the US-licensed reference biologic product notwithstanding minor differences in clinically inactive components No clinically meaningful differences from the reverence product in terms of safety, purity, and potency Interchangeable Biosimilar to the US-licensed reference product Expected to produce the same clinical result to the reference product in any given patient If a product is indicated for multiple administrations, then the product must be able to be alternated with the reference product without any loss of efficacy or change in risk of AEs Product may be substituted at the pharmacy level without the intervention of a healthcare provider FDA. valapplications/therapeuticbiologicapplications/biosimilars/default.htm. Accessed May 19, 16. FDA. valapplications/therapeuticbiologicapplications/biosimilars/default.htm. Accessed May 19, 16. Outstanding Questions Is the pathway to biosimilars still a work in progress? Is the cost to conduct studies and to achieve interchangeability prohibitive? How comfortable will physicians be prescribing biosimilar agents? How will MCOs manage these agents? FDA. valapplications/therapeuticbiologicapplications/biosimilars/default.htm. Accessed May 19, 16. Algorithm for Formulary Decision Making Drug review oral/written presentation by clinical pharmacist Experience/opinion oral comments by invited consultants and committee members Does drug offer substantial improvement in therapy over existing formulary drugs for like indications, or is it a completely new therapy not previously covered by medications? YES Add to formulary with guidelines for cost-effective and safe use if needed NO Does drug offer at least equal clinical benefit to existing formulary drugs for like indications? YES NO NO Can any safety concerns be managed? YES NO Does financial impact of drug support formulary addition? YES Add to formulary with guidelines for cost-effective use if needed Do not add to formulary Do not add to formulary The Future of Pharmacy Benefit Management The role of the pharmacy will become more prominent as healthcare reform unfolds The pharmacy will be forced out of its silo and into the care team Accountable care organization models will require more integration of medical and pharmacy data Physicians can no longer be agnostic to costs whether they occur in the medical arena or the pharmacy arena Aggressive management of the drug benefit and the pharmacy network will be critical to the ability of the MCOs to provide affordable access to drugs Narrow pharmacy networks Medication therapy management Trend management tools for specialty pharmacy drugs Conclusion MCOs can contribute to cost-effective, improved care in patients with psoriasis Understand the current treatment options better Evaluate the value of newer agents Design benefit language to address the needs of those patients with all stages of this disease Berger J, et al. Am J Pharm Benefits. 14;6(3): ajpb_mayjune14/drivers-of-change-in-pharmacy-benefit-management. Published online June, 14. Accessed May 15, 16.

13 Questions?