Psoriasis and Psoriatic Arthritis: Targeted Immune Modulators

Number: 0658

Least Cost Medically Necessary Brands

There are several brands of targeted immune modulators on the market. There is a lack of reliable evidence that any one brand of targeted immune modulator is superior to other brands for medically necessary indications.  The following targeted immune modulators are least cost brands to Aetna: Enbrel (etanercept), Entyvio (vedolizumab), Inflectra (infliximab-dyyb), Otezla (apremilast), Remicade (infliximab), Renflexis (infliximab-abda), Simponi (golimumab), Simponi Aria (golimumab intravenous), Stelara (ustekinumab), Tremfya (guselkumab), Xeljanz and Xeljanz XR (tofacitinib). The least cost targeted immune modulator brands are at least as likely to produce equivalent therapeutic results compared with these more costly brands: Actemra (tocilizumab), Humira (adalimumab), Kineret (anakinra), Orencia (abatacept), Rituxan (rituximab), Skyrizi (risankizumab-rzaa) and Tysabri (natalizumab). Consequently, the more costly brands of targeted immune modulator will be considered medically necessary only if the member has a contraindication, intolerance or  ineffective response to the following numbers of trials of least cost brands of targeted immune modulators by indication:

• Ankylosing spondylitis – two least cost brands (i.e., Enbrel, Inflectra, Remicade, Renflexis, Simponi, Simponi Aria)
• Crohn’s disease – one least cost brand (not including Renflexis) (i.e., Entyvio, Inflectra, Remicade, Stelara)
• Juvenile idiopathic arthritis – trial of Enbrel (etanercept)
• Plaque psoriasis – three least cost brands (i.e., Enbrel, Inflectra, Otezla, Remicade, Renflexis, Stelara, Tremfya)
• Psoriatic arthritis – three least cost brands (i.e., Enbrel, Inflectra, Otezla, Remicade, Renflexis, Simponi, Simponi Aria, Stelara, Xeljanz, Xeljanz XR)
• Rheumatoid arthritis – three least cost brands (i.e., Enbrel, Inflectra, Remicade, Renflexis, Simponi, Simponi Aria, Xeljanz/Xeljanz XR)
• Ulcerative colitis – one least cost brand (not including Renflexis) (i.e., Entyvio, Inflectra, Remicade, Simponi, Xeljanz).

Note that Cimzia (certolizumab), Cosentyx (secukinumab), Ilaris (canakinumab), Ilumya (tildrakizumab-asmn), Kevzara (sarilumab), Olumiant (baricitinib), Siliq (brodalumab), and Taltz (ixekizumab) brands of targeted immune modulators do not require a trial of a least cost brand of targeted immune modulator; there may, however, be a higher copayment where these brands are covered under pharmacy plans with a tiered formulary. Please check benefit plan descriptions. If the least costly targeted immune modulators do not have the labeled indication (see Appendix), then Aetna considers medically necessary another brand of targeted immune modulator that has the required labeling indication. Also note that Renflexis is not a least cost brand for Crohn’s disease and ulcerative colitis indications.

Policy

Note: REQUIRES PRECERTIFICATION

Precertification of targeted immune modulators for psoriasis and psoriatic arthritis is required of all Aetna participating providers and members in applicable plan designs.  For precertification of these agents, call (866) 752-7021 (Commercial), (866) 503-0857 (Medicare), or fax (866) 267-3277.

1. Moderate to severe plaque psoriasis (PsO)

   Aetna considers targeted immune modulators adalimumab (Humira), apremilast (Otezla), brodalumab (Siliq), certolizumab (Cimzia), etanercept (Enbrel), guselkumab (Tremfya)  infliximab (Remicade, Inflectra, Renflexis), ixekizumab (Taltz), risankizumab-rzaa (Skyrizi), secukinumab (Cosentyx), tildrakizumab-asmn (Ilumya), and ustekinumab (Stelara) medically necessary for the treatment of moderate-to-severe plaque psoriasis who meet the following:
   
   
   1. For members who have previously received apremilast (Otezla) or a biologic disease-modifying antirheumatic drug (DMARD) indicated for the treatment of moderate-to-severe plaque psoriasis; or
   2. For treatment of moderate-to-severe plaque psoriasis when all of the following criteria are met:
      
      
      1. At least 3% of body surface area (BSA) is affected or crucial body areas (i.e., hands, feet, face, neck, scalp, genitals/groin, intertriginous areas) are affected; and
      2. Member meets any of the following criteria:
         
         
         1. Member has had an inadequate response or intolerance to either phototherapy (e.g., UVB, PUVA) or pharmacologic treatment with methotrexate, cyclosporine or acitretin; or
         2. Member has a clinical reason to avoid pharmacologic treatment with methotrexate, cyclosporine and acitretin (see Appendix A); or
         3. Member has severe psoriasis that warrants a biologic DMARD as first-line therapy. (i.e. at least 10% of the body surface area (BSA) or crucial body areas (e.g., hands, feet, face, neck, scalp, genitals/groin, intertriginous areas) are affected.

2. Active psoriatic arthritis (PsA)

   Aetna considers targeted immune modulators abatacept (Orencia), adalimumab (Humira), apremilast (Otezla), certolizumab (Cimzia), etanercept (Enbrel), infliximab (Remicade, Inflectra, Renflexis), ixekizumab (Taltz), golimumab (Simponi and Simponi Aria), secukinumab (Cosentyx), and ustekinumab (Stelara) medically necessary for the treatment of active psoriatic arthritis (PsA).
   
   Aetna considers targeted immune modulator tofacitinib (Xeljanz and Xeljanz XR) medically necessary when used in combination with a nonbiologic DMARD for the treatment of active PsA; see CPB 0839 - Tofacitinib (Xeljanz).
   

3. TB testing for all indications

   Except for apremilast (Otezla), member has a documented negative TB test (which can include a tuberculosis skin test (PPD), an interferon-release assay (IGRA), or a chest x-ray)Footnotes for TB test^*** within 6 months of initiating therapy for persons who are naive to biologics, and repeated yearly for members with risk factorsFootnotes for Risk Factors^**** for TB that are continuing therapy with biologics.

4. Continuation of therapy

   Aetna considers continuation of targeted immune modulators medically necessary for all members (including new members) who are using a targeted immune modulator for an indication outlined above and who achieve or maintain positive clinical response as evidenced by low disease activity or improvement in signs and symptoms of the condition. Note: for brodalumab (Siliq) only, further treatment is contraindicated and considered not medically necessary in persons who develop Crohn's disease during treatment.
   

5. Experimental and Investigational

   Aetna considers the use of targeted immune modulators in combination with other targeted immune modulators for psoriasis (e.g., adalimumab (Humira), certolizumab (Cimzia), etanercept (Enbrel), ustekinumab (Stelara), infliximab (Remicade), apremilast (Otezla), risankizumab-rzaa (Skyrizi) or tofacitinib (Xeljanz)) experimental and investigational because of insufficient evidence of effectiveness.
   
   Aetna considers combination use of two or more targeted immune modulators for psoriatic arthritis experimental and investigational because of insufficient evidence of effectiveness.

Notes:

As of June 8, 2009, efalizumab (Raptiva) is no longer available in the U.S. market (FDA, 2009).

As of November 16, 2011, alefacept (Amevive) is no longer available in the U.S. market.

Footnotes for TB Test^*** Targeted immune modulators (e.g. adalimumab (Humira), infliximab (Remicade) are contraindicated and considered not medically necessary for persons with active TB or untreated latent disease. If the screening test for TB is positive, there must be documentation of further testing to confirm there is no active disease. Do not administer these targeted immune modulators to persons with active TB infection. If there is latent disease, TB treatment must be started before initiation of targeted immune modulators.

Footnotes for risk factors^**** Risk factors for TB include: persons with close contact to people with infectious TB disease; persons who have recently emigrated from areas of the world with high rates of TB (e.g., Africa, Asia, Eastern Europe, Latin America, and Russia); children less than 5 years of age who have a positive TB test; groups with high rates of TB transmission (e.g., homeless persons, injection drug users, and persons with HIV infection); persons who work or reside with people who are at an increased risk for active TB (e.g., hospitals, long-term care facilities, correctional facilities, and homeless shelters) (CDC, 2016).

For ustekinumab for Crohn's disease, see CPB 0912 - Ustekinumab (Stelara) or CPB 0912m - Ustekinumab (Stelara) [Medicare].

Dosing Recommendations

Abatacept (Orencia) (BMS, 2019)

Available as:

• Intravenous infusion:
  
  
  • For Injection: 250 mg lyophilized powder in a single-use vial for reconstitution and dilution prior to intravenous infusion
    
    
• Subcutaneous injection:
  
  
  • Injection: 50 mg/0.4 mL, 87.5 mg/0.7 mL, 125 mg/mL solution in single-dose prefilled syringes for subcutaneous use
  • Injection: 125 mg/mL solution in a single-dose prefilled ClickJect™ autoinjector for subcutaneous use
    
    
• Psoriatic Arthritis: For adults with psoriatic arthritis, Orencia may be administered as an intravenous infusion (IV) or a subcutaneous (SC) injection. Orencia can be used with or without non-biologic DMARDs.
  
  
  • Intravenous regimen: weight-based dosing should be administered as a 30-minutes IV infusion. Following the initial IV administration, an IV infusion should be given at 2 and 4 weeks after the first infusion and every 4 weeks thereafter.
  • Subcutaneous regimen: 125 mg once weekly without the need for an IV loading dose. Persons switching from Orencia IV therapy to SC administration should administer the first SC dose instead of the next scheduled IV dose.

Adalimumab (Humira) (AbbVie, 2019)

• Available as a subcutaneous injection
  
  
  • Injection: 40 mg/0.8 mL in a single‐use prefilled pen (Humira Pen)
  • Injection: 40 mg/0.8 mL in a single‐use prefilled glass syringe
  • Injection: 40 mg/0.4 mL in a single‐use prefilled glass syringe
  • Injection: 20 mg/0.4 mL in a single‐use prefilled glass syringe
  • Injection: 10 mg/0.2 mL in a single‐use prefilled glass syringe
  • Injection: 40 mg/0.8 mL in a single‐use glass vial for institutional use only
    
    
• Psoriatic Arthritis (PsA): The recommended dose of Humira for adults with PsA is 40 mg administered every other week. Methotrexate (MTX), other non-biologic DMARDS, glucocorticoids, nonsteroidal anti-inflammatory drugs (NSAIDs), and/or analgesics may be continued during treatment with Humira.
• Plaque Psoriasis: The recommended dose of Humira for adults with plaque psoriasis is an initial dose of 80 mg, followed by 40 mg given every other week starting one week after the initial dose. The use of Humira in moderate to severe chronic plaque psoriasis beyond one year has not been evaluated in controlled clinical studies.

Apremilast (Otezla) (Celgene, 2019)

• Available as 10 mg, 20 mg, and 30 mg tablets
• Plaque Psoriasis and active psoriatic arthritis (PsA):
  
  The recommended dose for Otezla (apremilast) is 30 mg twice daily. To reduce risk of gastrointestinal symptoms, titrate to recommended dose according to the following schedule:
  
  
  • Day 1: 10 mg in morning
  • Day 2: 10 mg in morning and 10 mg in evening
  • Day 3: 10 mg in morning and 20 mg in evening
  • Day 4: 20 mg in morning and 20 mg in evening
  • Day 5: 20 mg in morning and 30 mg in evening
  • Day 6 and thereafter: 30 mg twice daily

Brodulumab (Siliq) (Valeant, 2017)

• Available as a subcutaneous injection:
  
  
  • 210 mg/1.5 mL solution in a single-dose prefilled syringe
    
    
• Plaque Psoriasis: The recommended Siliq dose is 210 mg administered by subcutaneous injection at Weeks 0, 1, and 2 followed by 210 mg every 2 weeks. If an adequate response has not been achieved after 12 to 16 weeks of treatment with Siliq, consider discontinuing therapy. Continued treatment beyond 16 weeks in persons who have not achieved an adequate response is not likely to result in greater success.

Certolizumab (Cimzia) (UCB, 2019)

• Available as 200 mg powder for reconstitution in a single‐use vial and 200 mg/mL in a single‐use prefilled glass syringe for subcutaneous administration.
• Plaque Psoriasis: The recommended dose of Cimzia for adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy is 400 mg (given as two subcutaneous injections of 200 mg each) every other week. For some persons (with body weight less than or equal to 90 kg), a dose of 400 mg (given as two subcutaneous injections of 200 mg each) initially and at Weeks 2 and 4, followed by 200 mg every other week may be considered.
• Psoriatic Arthritis: The recommended dose of Cimzia for adults with psoriatic arthritis is 400 mg (given as two subcutaneous injections of 200 mg) initially and at Weeks 2 and 4, followed by 200 mg every other week. For maintenance dosing, Cimzia 400 mg every 4 weeks can be considered.

Etanercept (Enbrel) (Amgen, 2019)

• Available as subcutaneous injection
  
  
  • Injection: 25 mg/0.5 mL and 50 mg/mL solution in a single-dose prefilled syringe
  • Injection: 50 mg/mL solution in single-dose prefilled SureClick Autoinjector
  • Injection: 25 mg lyophilized powder in a multiple-dose vial for reconstitution 
  • Injection: 50 mg/mL solution in Enbrel Mini® single-dose prefilled cartridge for use with the AutoTouch® reusable autoinjector only
    
    
• Plaque Psoriasis in persons 4 years or older:
  
  
  • Adults: 50 mg twice weekly for 3 months, followed by 50 mg once weekly
  • Pediatric: 0.8 mg/kg weekly, with a maximum of 50 mg per week
    
    
• Psoriatic Arthritis: 50 mg once weekly with or without methotrexate (MTX)

Golimumab (Simponi and Simponi Aria) (Janssen Biotech, 2018)

• Simponi is available as subcutaneous (SC) injection:
  
  
  • 50 mg/0.5 mL in a single-dose prefilled syringe or single-dose prefilled SmartJect autoinjector
  • 100 mg/mL in a single-dose prefilled syringe or single-dose prefilled SmartJect autoinjector
    
    
• Psoriatic Arthritis: The Simponi dose regimen is 50 mg administered by SC injection once a month. Simponi may be given with or without methotrexate or other nonbiologic Disease-Modifying Antirheumatic Drugs (DMARDs). Corticosteroids, non-biologic DMARDs, and/or NSAIDs may be continued during treatment with Simponi.
• Simponi Aria is available as intravenous (IV) infusion:
  
  
  • Injection: 50 mg/4 mL (12.5 mg/mL) solution in a single-dose vial
    
    
• Psoriatic Arthritis: The Simponi Aria dose regimen is 2 mg / kg given as an IV infusion over 30 minutes at weeks 0 and 4, then every 8 weeks thereafter. May be given with or without methotrexate or other non-biologic DMARDs. Corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), and/or analgesics may be continued during treatment with Simponi Aria.
• The efficacy and safety of switching between IV and SC formulations and routes of administration have not been established.

Guselkumab (Tremfya) (Janssen Biotech, 2019)

• Available as subcutaneous injection: 100 mg/mL in a single-dose efilled syringe or single-dose One-Press person-controlled injector
• Plaque Psoriasis: The recommended dose is 100 mg at Week 0, Week 4, and every 8 weeks thereafter.

Infliximab (Remicade, Inflectra, Renflexis) (Janssen Biotech, 2018; Merck, 2019; Pfizer, 2019)

• Infliximab products (Remicade, Inflectra, and Renflexis) are available for injection using 100 mg of lyophilized infliximab, or its biosimilar, in a 20 mL vial for intravenous infusion.
• Plaque Psoriasis: Induction: 5 mg/kg at weeks 0, 2, and 6; and maintenance: 5 mg/kg IV every 8 weeks
• Psoriasis Arthritis: Induction: 5 mg/kg at weeks 0, 2, and 6; and maintenance: 5 mg/kg IV every 8 weeks

Ixekizumab (Taltz) (Eli Lilly, 2019)

• Available as subcutaneous injection: 80 mg/mL solution in a single-dose prefilled syringe, and 80 mg/mL solution in a single-dose prefilled autoinjector.
• Plaque Psoriasis: Recommended dose is 160 mg (two 80 mg injections) at Week 0, followed by 80 mg at Weeks 2, 4, 6, 8, 10, and 12, then 80 mg every 4 weeks.
• Psoriatic Arthritis:
  
  
  • Recommended dose is 160 mg by subcutaneous injection (two 80 mg injections) at Week 0, followed by 80 mg every 4 weeks
  • For persons with psoriatic arthritis who have coexistent moderate-to-severe plaque psoriasis, use the dosing regimen for plaque psoriasis
  • Talz may be administered alone or in combination with a conventional DMARD (e.g., methotrexate)

Risankizumab-rzaa (Skyrizi) (AbbVie, 2019b)

• Available as subcutaneous injection: 75 mg/0.83 mL in a single-dose prefilled syringe
• Plaque Psoriasis: The recommended dose is 150 mg (two 75 mg injections) administered by subcutaneous injection at Week 0, Week 4, and every 12 weeks thereafter

Secukinumab (Cosentyx) (Novartis, 2018)

• Available as subcutaneous injection:
  
  
  • Injection: 150 mg/mL solution in a single-use Sensoready pen
  • Injection: 150 mg/mL solution in a single-use prefilled syringe
  • For Injection: 150 mg, lyophilized powder in a single-use vial for reconstitution for healthcare professional use only
    
    
• Plaque Psoriasis: The recommended dose is 300 mg by subcutaneous injection at Weeks 0, 1, 2, 3, and 4 followed by 300 mg every 4 weeks. Each 300 mg dosage is given as 2 subcutaneous injections of 150 mg. For some individuals, a dosage of 150 mg may be acceptable.
• Psoriatic Arthritis:
  
  
  • For persons with PsA and coexistent moderate to severe plaque psoriasis (PsO), use the dosing and administration recommendations for PsO
  • For other individuals with PsA, administer Cosentyx with or without a loading dosage by subcutaneous injection. The recommended dosage:
    
    
    • With a loading dosage is 150 mg at weeks 0, 1, 2, 3, and 4 and every 4 weeks thereafter
    • Without a loading dosage is 150 mg every 4 weeks
    • If a person continues to have active psoriatic arthritis, consider a dosage of 300 mg.
      
      
• Cosentyx may be administered with or without methotrexate.

Tildrakizumab-asmn (Ilumya) (Merck, 2018)

• Available as subcutaneous injection: 100 mg/mL solution in a single-dose prefilled syringe.
• Plaque Psoriasis: The recommended dose is 100 mg at Weeks 0, 4, and every twelve weeks thereafter. Each syringe contains 1 mL of 100 mg/mL tildrakizumab-asmn.

Tofacitinib (Xeljanz and Xeljanz XR) (Pfizer, 2019)

• Xeljanz is available as 5 mg, 10 mg tablets
• Xeljanz XR is available as 11 mg tablets
• Psoriatic Arthritis (in combination with nonbiologic DMARDs): Xeljanz 5 mg twice-daily or Xeljanz XR 11 mg once-daily. Decrease dose to 5 mg once-daily in persons with moderate and severe renal impairment or moderate hepatic impairment.
• Discontinue dosing for persons with lymphocyte count less than 500 cells/mm3, confirmed by repeat testing, and persons with ANC less than 500 cells/mm3.

Ustekinumab (Stelara) (Janssen Biotech, 2018)

• Available as:
  
  
  • Subcutaneous Injection
    
    
    • Injection: 45 mg/0.5 mL or 90 mg/mL in a single-dose prefilled syringe
    • Injection: 45 mg/0.5 mL in a single-dose vial
      
      
  • Intravenous Infusion (For Crohn's disease)
    
    
    • Injection: 130 mg/26 mL (5 mg/mL) solution in a single-dose vial
      
      
• Plaque Psoriasis:
  
  
  • Adult dosing:
    
    
    • Weight less than or equal to 100 kg, the recommended dose is 45 mg administered subcutaneously (SC) initially and 4 weeks later, followed by 45 mg SC every 12 weeks
    • Weight greater than 100 kg, the recommended dose is 90 mg administered SC initially and 4 week later, followed by 90 mg SC every 12 weeks
      
      
  • Adolescent (12 years and older):
    
    
    • Weight based dosing is recommended at the initial dose administered SC, 4 weeks later, then every 12 weeks thereafter
      
      
• Psoriatic Arthritis: (adults) The recommended dosage is 45 mg administered SC initially and 4 weeks later, followed by 45 mg SC every 12 weeks. For persons with co-existent moderate-to-severe plaque psoriasis weighing greater than 100 kg, the recommended dosage is 90 mg administered SC initially and 4 weeks later, followed by 90 mg administered SC every 12 weeks.

Background

Psoriasis is a common chronic skin disease characterized by cutaneous inflammation and epidermal hyperproliferation.  Lesions appear on any part of the skin, but particularly the scalp, sacral area, and over the extensor aspect of the knees and elbows.

Ultraviolet light in conjunction with systemic psoralens (PUVA) is the phototherapy treatment of first choice for psoriasis other than localized psoriasis.  PUVA is a form of photochemotherapy that combines the use of a psoralens (e.g., methoxsalen) with ultraviolet A phototherapy in the range of 320 to 400 nm.  PUVA is highly effective in the treatment of psoriasis with resolution of skin lesions in over 85 % of patients after 20 to 30 treatments combining drug use and ultraviolet A irradiation.  UVB may be given alone or in combination with tar or dithranol.

Other systemic treatments for psoriasis include methotrexate or cyclosporine.  Both are contraindicated in pregnancy and require close monitoring.

Sbidian et al (2017) stated psoriasis is an immune-mediated disease for which some people have a genetic predisposition. The condition manifests in inflammatory effects on either the skin or joints, or both, and it has a major impact on quality of life. Although there is currently no cure for psoriasis, various treatment strategies allow sustained control of disease signs and symptoms. There have been several randomized controlled trials (RCTs) comparing the efficacy of different systemic treatments; however, due to lack of head-to-head comparison, the benefit of these treatments remains unclear. Sbidian and colleagues conducted a network meta-analysis to compare the efficacy and safety of conventional systemic agents (acitretin, ciclosporin, fumaric acid esters, methotrexate), small molecules (apremilast, tofacitinib, ponesimod), anti-TNF alpha (etanercept, infliximab, adalimumab, certolizumab), anti-IL12/23 (ustekinumab), anti-IL17 (secukinumab, ixekizumab, brodalumab), anti-IL23 (guselkumab, tildrakizumab), and other biologics (alefacept, itolizumab) for patients with moderate to severe psoriasis and ranked the treatments according to their efficacy and safety. The authors conducted a search of multiple databases which included CENTRAL, MEDLINE, Embase, and LILACS. An additional search of trial registers and the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) reports were used, to name a few. The selection criteria included RCTs of systemic and biological treatments in adults with moderate to severe plaque psoriasis or psoriatic arthritis at any stage of treatment, in comparison to placebo or another active agent. The data was ranked according to their effectiveness (as measured by the Psoriasis Area and Severity Index score (PASI) 90) and acceptability (the inverse of serious adverse effects). The authors included 109 studies, of which 39,882 participants were randomized. The authors found that most of the studies were placebo controlled (67%), 23% were head-to-head, and 10% were multi-armed with both an active comparator and placebo. In all, 86 trials were multicentric trials. All of the trials were limited to the induction phase (assessment at less than 24 weeks after randomization). All trials included in the network meta-analysis were measured between 12 and 16 weeks after randomization. The authors assessed the majority of studies (48/109) as being at high risk of bias; 38 were assessed as at an unclear risk, and 23, low risk. Network meta-analysis showed that all of the interventions (conventional systemic agents, small molecules, and biological treatments) were significantly more effective than placebo in terms of reaching PASI 90; however, the biologic treatments anti-IL17, anti-IL12/23, anti-IL23, and anti-TNF alpha were significantly more effective than the small molecules and the conventional systemic agents. Small molecules were associated with a higher chance of reaching PASI 90 compared to conventional systemic agents. At drug level, in terms of reaching PASI 90, all of the anti-IL17 agents and guselkumab (an anti-IL23 drug) were significantly more effective than the anti-TNF alpha agents infliximab, adalimumab, and etanercept, but not certolizumab. Ustekinumab was superior to etanercept. No clear difference was shown between infliximab, adalimumab, and etanercept. Only one trial assessed the efficacy of infliximab in this network; thus, these results have to be interpreted with caution. Tofacitinib was significantly superior to methotrexate, and no clear difference was shown between any of the other small molecules versus conventional treatments. Network meta-analysis also showed that ixekizumab, secukinumab, brodalumab, guselkumab, certolizumab, and ustekinumab outperformed other drugs when compared to placebo in terms of reaching PASI 90: the most effective drug was ixekizumab, followed by secukinumab, brodalumab, guselkumab, certolizumab, and ustekinumab. The authors found no significant difference between all of the interventions and the placebo regarding the risk of serious adverse effects (SAEs): the relative ranking strongly suggested that methotrexate was associated with the best safety profile regarding all of the SAEs, followed by ciclosporin, certolizumab, infliximab, alefacept, and fumaric acid esters. Considering both efficacy (PASI 90 outcome) and acceptability (SAEs outcome), highly effective treatments also had more SAEs compared to the other treatments, and ustekinumab, infliximab, and certolizumab appeared to have the better trade-off between efficacy and acceptability. Regarding the other efficacy outcomes, PASI 75 and Physician Global Assessment (PGA) 0/1, the results were very similar to the results for PASI 90. Information on quality of life was often poorly reported and was absent for a third of the interventions. The authors concluded that compared to placebo, the biologics ixekizumab, secukinumab, brodalumab, guselkumab, certolizumab, and ustekinumab are the best choices for achieving PASI 90 in people with moderate to severe psoriasis on the basis of moderate- to high-certainty evidence. At class level, the biologic treatments anti-IL17, anti-IL12/23, anti-IL23, and anti-TNF alpha were significantly more effective than the small molecules and the conventional systemic agents. Study limitations include induction therapy outcomes were measured between 12 to 16 weeks after randomization and is not sufficiently relevant for a chronic disease, low numbers of studies were found for some of the interventions, and younger ages and high level of disease severity (PASI 20 at baseline) may not be typical of patients seen in daily clinical practice. The authors note that short-term trials provide scanty and sometimes poorly reported safety data and thus do not provide useful evidence to create a reliable risk profile of treatments. For this study, the authors found no significant difference in the assessed interventions and placebo in terms of SAEs, with methotrexate appearing to have the best safety profile. The authors state that long-term information on the safety of the treatments should also be evaluated in non-randomized studies and post-marketing reports released from regulatory agencies. The authors suggest that future research include randomized trials comparing directly active agents once high-quality evidence of benefit against placebo is established, including head-to-head trials amongst and between conventional systemic and small molecules, and between biological agents. In addition, trials should include systematic subgroup analyses (e.g. assessing biological-naïve patients, baseline psoriasis severity, presence of psoriatic arthritis, etc.). Finally, in future psoriasis trials, researchers should look at the medium- and long-term benefit and safety of the interventions, as well as the comparative safety of different agents. 

The NICE guidance for the assessment and management of Psoriasis (2017) stated that topical therapy was first-line treatment, followed by second- or third-line treatment options (phototherapy or systemic therapy) which could be added on when topical therapy alone is unlikely to adequately control psoriasis, such as for extensive disease (e.g. more than 10% of body surface area affected), or at least 'moderate' on the static Physician's Global Assessment, or where topical therapy is ineffective, such as nail disease).

Psoriasis guidelines from the Academy of Dermatology (2011) stated that for mild disease, topical therapies are the mainstay as either monotherapy or in combination. For moderate to severe disease, topical therapies are commonly used in conjunction with phototherapy, traditional systemic agents, or biologic agents. Phototherapy, photochemotherapy, and traditional systemic agents are generally used for individuals with moderate or severe disease and in situations in which topical therapy is ineffective or otherwise contraindicated.

Guidelines on psoriasis from the British Association of Dermatologists (2017) state biologic therapy should be offered to people with psoriasis who require systemic therapy if:

1. methotrexate and ciclosporin have failed, are not tolerated or are contraindicated (see NICE guidelines CG153) and
2. the psoriasis has a large impact on physical, psychological or social functioning (e.g. Dermatology Life Quality Index [DLQI] or Children’s DLQI > 10 or clinically relevant depressive or anxiety symptoms) and

one or more of the following disease severity criteria apply:

1. the psoriasis is extensive (defined as body surface area [BSA] > 10% or Psoriasis Area and Severity Index [PASI] ≥ 10)
2. the psoriasis is severe at localized sites and associated with significant functional impairment and/or high levels of distress (e.g. nail disease or involvement of high-impact and difficult-to-treat sites such as the face, scalp, palms, soles, flexures and genitals).

Consider biologic therapy earlier in the treatment pathway in people with psoriasis who fulfill the disease severity criteria and who also have active psoriatic arthritis or who have psoriasis that is persistent, i.e. that relapses rapidly (defined as >50% baseline disease severity within 3 months of completion of any treatment) off a therapy that cannot be continued in the long-term (e.g. narrowband ultraviolet B).

Abatacept

Abatacept is a selective costimulation modulator which inhibits T cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. This interaction provides a costimulatory signal necessary for full activation of T lymphocytes. Activated T lymphocytes are implicated in the pathogenesis of psoriatic arthritis (PsA) and are found in the synovium of patients with PsA. In vitro, abatacept decreases T cell proliferation and inhibits the production of the cytokines TNF alpha (TNFα), interferon-γ, and interleukin-2. In a rat collagen-induced arthritis model, abatacept suppresses inflammation, decreases anti-collagen antibody production, and reduces antigen specific production of interferon-γ. The relationship of these biological response markers to the mechanisms by which Orencia exerts its clinical effects is unknown (BMS, 2017).

In July 2017, the U.S. Food and Drug Administration (FDA) approved Orencia (abatacept) for the treatment of adults with active psoriatic arthritis (PsA). PsA is a chronic, inflammatory disease that can affect the skin and musculoskeletal system, which can cause joint pain, stiffness and reduced range of motion.

FDA approval of Orencia for active PsA was based on the results from two randomized, double-blind, placebo-controlled studies (Studies PsA-I and PsA-II) in 594 adult patients with disease duration more than seven years. Patients had active PsA (≥ 3 swollen joints and ≥ 3 tender joints) despite prior treatment with DMARD therapy and had one qualifying psoriatic skin lesion of at least 2 cm in diameter. In PsA-I and PsA-II, 37% and 61% of patients, respectively, were treated with TNF inhibitors (TNFi) previously. A higher proportion of patients treated with Orencia 10 mg/kg IV or 125 mg SC achieved an ACR20 response at week 24 compared to placebo, 47.5% versus 19.0% and 39.4% versus 22.3% (p< 0.05), respectively. Responses were seen regardless of prior anti-TNFi treatment and regardless of concomitant non-biologic DMARD treatment. Improvements in enthesitis and dactylitis were seen with Orencia treatment at week 24 in both IV and SC (BMS, 2017).

For the adult patient, Orencia (abatacept) may be administered as an IV infusion or a subcutaneous (SC) injection, with or without non-biologic DMARDs.  The safety and efficacy of Orencia ClickJect autoinjector for subcutaneous injection have not been studied in patients under 18 years of age.

Concurrent therapy with Orencia and a TNF antagonist (such as adalimumab, etanercept, and infliximab) is not recommended because such combination therapy may increase risk for infections. In controlled clinical trials, adult RA patients receiving concomitant intravenous Orencia and TNF antagonist therapy experienced more infections (63%) and serious infections (4.4%) compared to patients treated with only TNF antagonists (43% and 0.8%, respectively), without an important enhancement of efficacy. Furthermore, it is not recommended that patients receive Orencia concomitantly with other biologic RA therapy, such as anakinra, because there is not enough informaton to assess the safety and efficacy of such comination therapy (BMS, 2017).

Maltose is present in Orencia for intravenous (IV) administration, which can result in falsely elevated blood glucose reading on the day of the infusion. When receiving Orencia through IV administration, patients that require blood glucose monitoring should be advised to consider methods that do not react with maltose, such as those based on glucose dehydrogenase nicotine adenine dinucleotide (GDH-NAD), glucose oxidase, or glucose hexokinase test methods.

Orencia for subcutaneous administration does not contain maltose; therefore, patients do not need to alter their glucose monitoring.

Common side effects of Orencia include: headache, upper respiratory infection, sore throat, and nausea (not an all-inclusive list).

Adalimumab

Adalimumab has been approved by the FDA for the treatment for adults with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy, and when other systemic therapies are medically less appropriate.  According to the FDA-approved labeling, adalimumab should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician.  Chronic plaque psoriasis is an autoimmune disease characterized by inflammed, scaly skin lesions known as plaques, which may crack and bleed.  While psoriasis can occur in people of all ages, it typically appears in patients between the ages of 15 and 35 years.  Approximately 25 % of persons with chronic plaque psoriasis exhibit moderate to severe disease.  Up to 30 % of psoriasis patients develop psoriatic arthritis.  Treatment may include topical agents, phototherapy or oral or injectable medications.

The FDA approval of adalimumab for chronic plaque psoriasis was based on 2 pivotal trials, REVEAL and CHAMPION, showing that approximately 3 out of 4 patients achieved 75 % clearance or better at week 16 of treatment versus placebo.  Both studies evaluated the efficacy and safety of Humira in clearing skin in moderate to severe adult plaque psoriasis patients versus placebo.  In addition, CHAMPION compared a biologic medication to methotrexate, a standard systemic treatment for psoriasis.   In each trial, reduction in disease activity was determined by the Psoriasis Area and Severity Index (PASI) and Physician's Global Assessment (PGA).  In REVEAL, a 52-week trial, the short-term and sustained clinical efficacy and safety of adalimumab were evaluated in 1,212 patients with moderate to severe chronic plaque psoriasis.  Patients experienced a significant reduction in the signs and symptoms of their disease at 16 weeks when treated with adalimumab.  Specifically, 71 % of patients receiving adalimumab achieved PASI 75 compared to 7 % of patients receiving placebo at week 16.  At week 16, 62 % of adalimumab-treated patients achieved a PGA score of clear or minimal compared to 4 % of placebo-treated patients.  In CHAMPION, a 16-week study evaluating 271 psoriasis patients, adalimumab-treated patients experienced a significant reduction in the signs and symptoms of their disease compared with methotrexate or placebo-treated patients.  Seventy-eight percent of patients treated with adalimumab (n = 99) achieved a PASI 75 response, compared to 19 % of patients treated with placebo (n = 48).  Seventy-one percent of patients treated with adalimumab achieved a PGA score of clear or minimal at 16 weeks of treatment, compared with 10 % of placebo-treated patients.  The safety profile of adalimumab in the plaque psoriasis clinical trials was reported to be similar to that seen in adalimumab clinical trials for rheumatoid arthritis.  The most commonly reported adverse events in adalimumab psoriasis trials were upper respiratory tract infection, nasopharyngitis (inflammation of the nose and pharynx), headache, sinusitis and arthralgia.  In clinical studies of plaque psoriasis, patients are treated with an initial 80 mg dose of adalimumab (2 40-mg injections) followed by 1 adalimumab injection (40 mg) 1 week later.  After that, a maintenance dose of 40 mg  was administered every other week.

Apremilast

Otezla (apremilast) is a phosphodiesterase‐4 inhibitor specific for cyclic adenosine monophosphate (cAMP). PDE4 inhibition results in increased intracellular cAMP levels. The specific mechanism(s) by which apremilast exerts its therapeutic action in psoriatic arthritis patients is not well defined.

Otezla (apremilast) is indicated for the treatment of adult patients with active psoriatic arthritis and patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. The FDA approved apremilast (Otezla) to treat adults with active psoriatic arthritis. The safety and effectiveness of apremilast, an inhibitor of phosphodieasterase-4 (PDE-4), were evaluated in three clinical trials involving 1,493 patients with active psoriatic arthritis. Patients treated with apremilast showed improvement in signs and symptoms of psoriatic arthritis, including tender and swollen joints and physical function, compared to placebo. In clinical trials, the most common side effects observed in patients treated with apremilast were diarrhea, nausea, and headache. The FDA is requiring a pregnancy exposure registry as a post-marketing requirement to assess the risks to pregnant women related to apremilast exposure.

The FDA approved apremilast (Otezla) for the treatment of patients with moderate to severe plaque psoriasis for whom phototherapy or systemic therapy is appropriate (Celgene, 2014). The approval of apremilast was based primarily on safety and efficacy results from two multi-center, randomized, double-blind, placebo-controlled studies - ESTEEM 1 and ESTEEM 2 - conducted in adult patients with moderate to severe plaque psoriasis: body surface area (BSA) involvement of ≥10%, static Physician Global Assessment (sPGA) of ≥3 (moderate or severe disease), Psoriasis Area and Severity Index (PASI) score ≥12, and candidates for phototherapy or systemic therapy (Celgene, 2014).

ESTEEM 1 and 2 are two large pivotal phase III randomized, placebo-controlled studies evaluating apremilast in patients with a diagnosis of moderate to severe plaque psoriasis for at least 12 months prior to screening, and who were also candidates for phototherapy and/or systemic therapy (Celgene, 2014). Approximately 1,250 patients were randomized 2:1 to receive either apremilast 30 mg twice daily or placebo after an initial five-day titration period, for the first 16 weeks, followed by a maintenance phase from weeks 16-32 in which placebo patients were switched to apremilast 30 mg twice daily through week 32, and a randomized withdrawal phase for responders from week 32 to week 52 based on their initial apremilast randomization and PASI-75 response. In the ESTEEM studies, apremilast treatment resulted in significant and clinically meaningful improvements in plaque psoriasis as measured by PASI scores at week 16. Clinical improvement as measured by sPGA scores of clear to almost clear were also demonstrated in both studies. The safety of apremilast was assessed in 1,426 patients from three clinical trials (Celgene, 2014). Side effects of apremilast were diarrhea, nausea, upper respiratory tract infection, tension headache, and headache.

According to the labeling, patients treated with apremilast should have their weight monitored regularly by a healthcare professional. If unexplained or clinically significant weight loss occurs, the weight loss should be evaluated and discontinuation of treatment should be considered. Treatment with apremilast was also associated with an increase in reports of depression compared to placebo.

Warnings and Precautions:

Depression ‐ Treatment with Otezla is associated with an increase in adverse reactions of depression. Prescribers should carefully evaluate the risks and benefits of initiation and continuation with Otezla.

Weight decrease ‐ Patients treated with Otezla should have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, discontinuation of Otezla should be considered.

Drug interactions:

Use with strong CYP450 enyme inducers (e.g. rifampin, phenobarbital, carbamazepine, phenytoin) is not recommended because loss of efficacy may occur.

Brodalumab

The FDA approved brodalumab (Siliq) injection, a monoclonal antibody that targets the IL-17 receptor for patients with moderate-to-severe plaque psoriasis.  Brodalumab is indicated for the treatment of moderate-to-severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy and have failed to respond or have lost response to other systemic therapies.

Brodalumab works by binding to IL-17RA with high affinity, therefore blocking the inflammatory downstream activity of IL-17A, IL-17F, IL-17A/F heterodimer and IL-17E. By targeting the IL-17 receptor, brodalumab prevents skin cells from accumulating. In three clinical studies that have been completed, more than 50% of patients who used brodalumab achieved total skin clearance within a year.

Brodalumab's safety and efficacy were established in three AMAGINE randomized, placebo-controlled clinical trials with a total of 4,373 adult participants with moderate-to-severe plaque psoriasis who were candidates for systemic therapy or phototherapy. More patients treated with brodalumab compared to placebo had skin that was clear or almost clear, as assessed by scoring of the extent, nature and severity of psoriatic changes of the skin. At the 210 mg dose, approximately twice as many patients on brodalumab achieved total skin clearance compared to ustekinumab at week 12 in two replicate comparator trials involving over 2,400 patients.

Brodalumab has a Black Box Warning for the risks in patients with a history of suicidal thoughts or behavior. Brodalumab was approved with a Risk Evaluation and Mitigation Strategy (REMS) involving a one-time enrollment for physicians and one-time informed consent for patients. Notable requirements of the Siliq REMS Program include the following:

• Prescribers must be certified with the program and counsel patients about this risk. Patients with new or worsening symptoms of depression or suicidality should be referred to a mental health professional, as appropriate.
• Patients must sign a Patient-Prescriber Agreement Form and be made aware of the need to seek medical attention should they experience new or worsening suicidal thoughts or behavior, feelings of depression, anxiety or other mood changes.
• Pharmacies must be certified with the program and must only dispense to patients who are authorized to receive Siliq.

Siliq is also approved with a Medication Guide to inform patients of the risk of suicidal ideation and behavior, and that because Siliq is a medication that affects the immune system, patients may have a greater risk of getting an infection, or an allergic or autoimmune condition. Patients with Crohn’s disease should not use Siliq. Health care providers should also evaluate patients for tuberculosis (TB) infection prior to initiating treatment with Siliq. Health care providers should not administer Siliq to patients with active TB infection, and should avoid immunizations with live vaccines in patients being treated with Siliq.

The most common adverse reactions were headache, arthralgia, fatigue, oropharyngeal pain, and diarrhea. Brodalumab is contraindicated in patients with Crohn's disease. Suicidal ideation and behavior have been reported. Serious infections have occurred therefore caution should be exercised when considering the use of brodalumab in patients with a chronic infection or a history of recurrent infection. Patients should be evaluated for tuberculosis infection prior to initiating treatment.

Certolizumab

On May 29, 2018, the U.S. Food and Drug Administration (FDA) approved the biologic Cimzia (certolizumab pegol) for the treatment of adults with psoriasis who are eligible for systemic therapy or phototherapy. Certolizumab is already approved in moderately to severely active Crohn’s disease, moderately to severely active rheumatoid arthritis, active psoriatic arthritis, and active ankylosing spondylitis. Certolizumab is a recombinant, humanized antibody Fab' fragment that binds to and blocks human TNFα, a key pro-inflammatory cytokine with a central role in inflammatory processes. A potential advantage of certolizumab pegol is minimal transfer across the placenta; unlike other anti-TNF biologics, certolizumab pegol does not bind the neonatal Fc receptor because it does not contain a fragment crystallizable (Fc) region, which is normally present in a complete antibody, and therefore does not fix complement or cause antibody-dependent cell-mediated cytotoxicity in vitro. It does not induce apoptosis in vitro in human peripheral blood-derived monocytes or lymphocytes, nor does certolizumab pegol induce neutrophil degranulation.

FDA approval of certolizumab in adult plaque psoriasis was based on three multicenter, randomized, double-blind studies (CIMPASI-1 [NCT02326298], CIMPASI-2 [NCT02326272], and CIMPACT [NCT02346240]) that enrolled subjects 18 years of age or older with moderate-to-severe plaque psoriasis who were eligible for systemic therapy or phototherapy. Subjects had a Physician Global Assessment (PGA) of 3 or greater (“moderate”) on a 5-category scale of overall disease severity, a Psoriasis Area and Severity Index (PASI) score 12 or greater, and body surface area (BSA) involvement of 10% or more.

Gottlieb et al (2018) stated certolizumab pegol, the only Fc-free, PEGylated anti-tumor necrosis factor biologic, demonstrated clinically meaningful improvements suggestive of a positive risk-benefit balance in phase 2 studies in adults with moderate-to-severe chronic plaque psoriasis. The authors assessed certolizumab (CZP) efficacy and safety versus placebo in two phase 3 studies (CIMPASI-1 (NCT02326298) and CIMPASI-2 (NCT02326272)). Of 587 participants screened for both studies, 234 were randomized in CIMPASI-1 and 227 were randomized in CIMPASI-2. At the baseline visit, patients were assigned to subcutaneous treatment with CZP 400 mg every 2 weeks, CZP 200 mg every 2 weeks (after loading dose of CZP 400 mg at weeks 0, 2, and 4), or placebo every 2 weeks until week 16 (initial treatment period) according to the randomization schedule produced by an independent biostatistician (2:2:1, stratified by site). Studies CIMPASI-1 and CIMPASI-2 assessed the co-primary endpoints of the proportion of patients who achieved a 75% reduction in Psoriasis Area and Severity Index (PASI 75) and Physician's Global Assessment of “clear” or “almost clear” (PGA of 0/1 ) with at least a 2-point improvement at Week 16. Secondary endpoints included week-16 PASI 90 responder rate, change in Dermatology Life Quality Index (DLQI) between baseline and week 16, and PASI 75 and PGA 0/1 responder rates at week 48. Other efficacy variables included PASI 90 responder rate at week 48 and PASI 100 (100% reduction in PASI from baseline PASI) and DLQI 0/1 (no/small impact of psoriasis on patient's quality of life) responder rates at week 16 and week 48. Safety was assessed via treatment-emergent adverse events (TEAEs). Eligible patients were 18 years of age or older with plaque psoriasis for at least 6 months with baseline PASI 12 or greater, body surface area affected 10% or more, and a Physician's Global Assessment (PGA) 3 or greater on a 5-point scale. All participants were candidates for systemic therapy, phototherapy, or photochemotherapy.

At week 16, significantly higher PASI 75 responder rates were observed for CZP 400 mg (CIMPASI-1, 75.8%; CIMPASI-2, 82.6%) and CZP 200 mg (CIMPASI-1, 66.5%; CIMPASI-2, 81.4%) than placebo (CIMPASI-1, 6.5%; CIMPASI-2, 11.6%; P < .0001 for all), and responses were maintained through week 48 for both CZP doses. At week 16, significantly higher PGA 0/1 responder rates were observed for CZP 400 mg (CIMPASI-1, 57.9%; CIMPASI-2, 71.6%) and CZP 200 mg (CIMPASI-1, 47.0%; CIMPASI-2, 66.8%) than placebo (CIMPASI-1, 4.2%; CIMPASI-2, 2.0%; P < .0001 for all); responses were maintained through week 48 for both CZP doses. No unexpected safety signals were identified. The safety profile was consistent with the therapeutic class. Adverse events were consistent with the anti-tumor necrosis factor class of drugs. The most common adverse reactions (incidence ≥7% and higher than placebo): upper respiratory tract infection, rash, and urinary tract infection. The limitations of this trial were that there was no active comparator arm and patients were excluded from the study for having a history of primary failure to biologic therapy. In addition, sample sizes are smaller than other phase 3 psoriasis trials, making it difficult to discern whether observed study variations are simply a consequence of patient numbers. The authors concluded that treatment with either certolizumab 400 mg or 200 mg every 2 weeks was associated with significant and clinically meaningful improvements in moderate-to-severe psoriasis. The 400-mg dose could provide additional clinical benefit.

Lebwohl et al (2018) assessed the safety and efficacy of certolizumab (CZP) in adults with moderate-to-severe chronic plaque psoriasis in a phase 3, multicenter, randomized, double-blind, parallel-group, placebo- and active-controlled study, followed by a placebo-controlled maintenance period and open-label follow-up period (CIMPACT; NCT02346240). During the initial period, 559 patients were randomized 3:3:1:3 (stratified by site) to CZP 400 mg every 2 weeks or CZP 200 mg every 2 weeks (after 400-mg loading doses at weeks 0, 2, and 4) for 16 weeks, placebo every 2 weeks for 16 weeks, or etanercept 50 mg twice weekly for 12 weeks. At week 16, patients in the CZP-treatment groups achieving a PASI 75 (≥75% reduction in the Psoriasis Area and Severity Index [PASI] from baseline) were re-randomized (2:2:1): from CZP 400 mg every 2 weeks to CZP 400 mg every 2 weeks, CZP 200 mg every 2 weeks, or placebo; and from CZP 200 mg every 2 weeks to CZP 400 mg every 4 weeks, CZP 200 mg every 2 weeks, or placebo for the 32-week maintenance period. Placebo-treated PASI 75 responders continued placebo for the maintenance period, and etanercept-treated PASI 75 responders, after a 4-week washout, were re-randomized (2:1) to CZP 200 mg every 2 weeks (after 400 mg loading doses at weeks 16, 18, and 20) or placebo. PASI 75 nonresponders at week 16 entered an escape arm and received treatment with CZP 400 mg every 2 weeks. Patients who were rerandomized and were PASI 50 nonresponders (had a <50% reduction in PASI from baseline PASI) at any visit during the maintenance period and patients who completed the double-blind maintenance period entered the open-label safety extension, which was ongoing at the time of publication, and received CZP 400 mg every 2 weeks. The primary efficacy endpoint was PASI 75 responder rate for both CZP doses versus placebo at week 12. Secondary efficacy endpoints were PASI 75 responder rate versus placebo at week 16; PGA 0/1 responder rate (clear/almost clear with ≥2-point improvement from baseline PGA score) versus placebo at weeks 12 and 16; PASI 90 responder rate versus placebo at weeks 12 and 16; PASI 75 responder rate versus etanercept at week 12; and PASI 75 responder rates at week 48 for patients achieving PASI 75 at week 16. Safety was assessed by treatment-emergent adverse events (TEAEs). Eligible patients were 18 years of age or older with plaque psoriasis for at least 6 months with baseline PASI 12 or greater, body surface area affected 10% or more, and a Physician's Global Assessment (PGA) 3 or greater on a 5-point scale. All participants were candidates for systemic therapy, phototherapy, or photochemotherapy.

By week 12, PASI 75 responder rate was significantly greater for CZP-treated patients versus placebo-treated patients (66.7% CZP 400 mg, p<00001; 61.3% CZP 200 mg, p<00001; 5.0% placebo). Differences were evident between the drug groups and the placebo group as early as week 4 and increased through week 16. At week 12, CZP 400 mg was superior and CZP 200 mg was non-inferior to etanercept for PASI 75 responder rate (66.7% CZP 400 mg, p=0.0152; 61.3% CZP 200 mg, p=0.1523; 53.5% Etanercept). Similar trends occurred for PGA 0/1 and PASI 90 responder rates for both doses of CZP versus placebo. All endpoints were significantly greater for certolizumab versus placebo with the greatest response seen with 400 mg. No new safety signals were observed. Adverse events were consistent with the anti-tumor necrosis factor class of drugs. The most common adverse reactions (incidence ≥7% and higher than placebo): upper respiratory tract infection, rash, and urinary tract infection. The limitation for this study was that etanercept was administered by un-blinded study staff or self-administered, but efficacy assessments were performed by a blinded assessor. The authors concluded that both certolizumab regimens improved psoriasis symptoms, with a greater response seen with the higher dose. 

Etanercept

Etanercept (Enbrel) (Immunex Corporation, Thousand Oaks, CA) gained FDA approval for the treatment of chronic moderate-to-severe chronic plaque psoriasis in April 2004.  The FDA approved a twice-weekly dose of 50 mg for the first 3 months of psoriasis treatment followed by a maintenance dose of 50 mg per week thereafter.  The FDA approval was based on the results of 2 phase III clinical studies involving adults with psoriasis who were treated for up to 12 months.  These studies reported nearly half (46 %) of those who received etanercept had a 75 % or greater improvement on the PASI after 3 months of treatment.  That response was sustained for an additional 3 months at the lower dose (25 mg once-weekly).

According to guidelines from the National Institute for Health and Clinical Excellence (NICE, 2006), etanercept, administered at a dose not exceeding 25 mg twice-weekly is recommended for the treatment of adults with plaque psoriasis only when their disease is severe and they have failed to respond to standard systemic therapies, as described above.

According to NICE guidelines, etanercept treatment should be discontinued in patients whose psoriasis has not responded adequately at 12 weeks.  Further treatment cycles are not recommended in these patients.

Guidelines from the British Association of Dermatologists (2005) stated that etanercept should be considered first choice for patients with significant, uncontrolled psoriatic arthritis, and for patients with stable psoriasis where a decision to treat with an tumor necrosis factor inhibitor has been made.

According to the FDA-approved labeling of Enbrel, the recommended dose of etancercept for psoriatic arthritis is 50 mg once weekly with or without methotrexate (MTX). The recommended dose of etanercept for adult plaque psoriasis is 50 mg twice weekly for 3 months, followed by 50 mg once weekly.

The FDA approved the supplemental Biologics License Application (sBLA) for the expanded use of etanercept) to treat pediatric patients (ages 4-17) with chronic moderate-to-severe plaque psoriasis (Amgen, 2016). The approval was based on results from a Phase 3 one-year study and its five-year open-label extension study to evaluate the safety and efficacy of etanercept in pediatric patients, ages 4 to 17, with chronic moderate-to-severe plaque psoriasis. In addition to demonstrating efficacy, the adverse events were similar to those seen in previous studies in adults with moderate-to-severe plaque psoriasis. 

Paller, et al. (2008) sought to assess the efficacy and safety of etanercept in children and adolescents with moderate-to-severe plaque psoriasis. In a 48-week study, 211 patients with psoriasis (4 to 17 years of age) were initially randomly assigned to a double-blind trial of 12 once-weekly subcutaneous injections of placebo or 0.8 mg of etanercept per kilogram of body weight (to a maximum of 50 mg), followed by 24 weeks of once-weekly open-label etanercept. At week 36, 138 patients underwent a second randomization to placebo or etanercept to investigate the effects of withdrawal and retreatment. The primary end point was 75% or greater improvement from baseline in the psoriasis area-and-severity index (PASI 75) at week 12. Secondary end points included PASI 50, PASI 90, physician's global assessment of clear or almost clear of disease, and safety assessments. At week 12, 57% of patients receiving etanercept achieved PASI 75, as compared with 11% of those receiving placebo (P<0.001). A significantly higher proportion of patients in the etanercept group than in the placebo group had PASI 50 (75% vs. 23%), PASI 90 (27% vs. 7%), and a physician's global assessment of clear or almost clear (53% vs. 13%) at week 12 (P<0.001). At week 36, after 24 weeks of open-label etanercept, rates of PASI 75 were 68% and 65% for patients initially assigned to etanercept and placebo, respectively. During the withdrawal period from week 36 to week 48, response was lost by 29 of 69 patients (42%) assigned to placebo at the second randomization. Four serious adverse events (including three infections) occurred in three patients during treatment with open-label etanercept; all resolved without sequelae. The investigators concluded that etanercept significantly reduced disease severity in children and adolescents with moderate-to-severe plaque psoriasis.

Paller, et al. (2016) reported on an extension study to evaluate long-term safety and efficacy of etanercept in children and adolescents with moderate to severe plaque psoriasis. The investigators reported on a 5-year, open-label extension study enrolled patients aged 4 to 17 years who had participated in a 48-week parent study. End points included occurrence of adverse events (AEs) and serious AEs including infections, and rates of 75% and 90% improvement in Psoriasis Area and Severity Index score and clear/almost clear on static physician global assessment. Of 182 patients enrolled, 181 received etanercept and 69 completed 264 weeks. Through week 264, 161 (89.0%) patients reported an AE, most commonly upper respiratory tract infection (37.6%), nasopharyngitis (26.0%), and headache (21.5%). Seven patients reported 8 serious AEs; only 1 (cellulitis) was considered treatment-related. No cases of opportunistic infections or malignancy were reported. Rates of 75% improvement in Psoriasis Area and Severity Index score (∼ 60%-70%) and 90% improvement in Psoriasis Area and Severity Index score  (∼ 30%-40%) and static physician global assessment status clear/almost clear (∼40%-50%) were maintained through week 264. The investigators noted that one limitation of this study was that the number of patients remaining on study at week 264 was small. The investigators concluded that etanercept in pediatric patients was generally well tolerated and efficacy was maintained in those who remained in the study for up to 264 weeks.

Golimumab

On October 20, 2017, Janssen Biotech, Inc. announced that the U.S. Food and Drug Administration (FDA) approved an intravenous (IV) formulation of Simponi Aria, golimumab, for the treatment of adults with active psoriatic arthritis (PsA). The approval was based on a pivotal Phase 3 study (GO-VIBRANT) which demonstrated significant efficacy of Simponi Aria over placebo, along with a consistent safety profile across all indications.

Go-VIBRANT was a Phase 3, multicenter, randomized, double-blind, placebo-controlled study which evaluated the efficacy and safety of Simponi Aria in biologic-naïve adults (18 years of age and older) with active PsA.  Criteria included a diagnosis of PsA for at least six months and had symptoms of active disease [≥5 swollen joints and ≥5 tender joints and a CRP level of ≥ 0.6 mg/dL]. Patients who were on stable doses of methotrexate (MTX) were allowed to enroll in the study and remained on MTX during the double-blind phase. Patients (n=480) were randomized one-to-one to receive Simponi Aria 2 mg/kg (N=241) or placebo (N=239) as a 30-minute IV infusion at Weeks 0, 4, 12 and 20. All patients on placebo received Simponi Aria at Week 24, Week 28 and every 8 weeks thereafter through Week 52. Patients in the Simponi Aria treatment group continued to receive Simponi Aria infusions at Week 28 and every 8 weeks through Week 52. The primary endpoint was ACR20 response at week 14. Multiplicity-controlled endpoints at week 14 or 24 included ACR50, ACR70, at least a 75 percent improvement in the Psoriasis Area Severity Index (PASI 75) and change from baseline in Health Assessment Questionnaire Disability Index (HAQ-DI), enthesitis, dactylitis, van der Heijde Sharps (vdH-S) and Short Form (SF)-36 Physical Component (PC)/Mental Component (MC) scores. The study continued through 60 weeks (Janssen, 2017).

Guselkumab

In July 2017, the U.S. Food and Drug Administration (FDA) approved Tremfya (guselkumab) for the treatment of moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. Guselkumab, an interleukin-23 (IL-23) blocker, is a human immunoglobulin G1 lambda (IgG1λ) monoclonal antibody that selectively binds to the p19 subunit of IL-23 and inhibits its interaction with the IL-23 receptor. IL-23 is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Guselkumab inhibits the release of proinflammatory cytokines and chemokines (FDA, 2017).

Tremfya received FDA approval based on results from Phase 3, multicenter, randomized, double-blind trials (VOYAGE 1, VOYAGE 2, and NAVIGATE studies). In VOYAGE 1 and VOYAGE 2, 1443 subjects, 18 years and older, were randomized to either Tremfya (100 mg at Weeks 0 and 4 and every 8 weeks thereafter), placebo or adalimumab (80 mg at Week 0 and 40 mg at Week 1, followed by 40 mg every other week thereafter). At 16 weeks, at least seven out of ten Tremfya-treated patients achieved at least 90 percent clearer skin, and more than 80 percent demonstrated cleared or almost cleared skin. Improvements were also demonstrated in psoriasis involving the scalp and in symptoms of plaque psoriasis including itch, pain, stinging, burning and skin tightness. Treatment resulted in clearer skin that lasted, as nearly nine out of ten patients who achieved PASI 90 at week 28 maintained that response at week 48. At week 24, more than seven out of ten patients treated with Tremfya reported at least 90 percent clearer skin compared with more than four out of ten patients treated with adalimumab (FDA, 2017; Johnson & Johnson, 2017).

NAVIGATE findings demonstrated the effectiveness of Tremfya in patients who had an inadequate response to treatment with ustekinumab. NAVIGATE evaluated the efficacy of 24 weeks of treatment with Tremfya in subjects (N=268) who had not achieved an adequate response, defined as IGA ≥2 at Week 16 after initial treatment with ustekinumab (dosed 45 mg or 90 mg according to the subject’s baseline weight at Week 0 and Week 4). These subjects were randomized to either continue with ustekinumab treatment every 12 weeks or switch to Tremfya 100 mg at Weeks 16, 20, and every 8 weeks thereafter. In subjects with an inadequate response (IGA ≥2 at Week 16 to ustekinumab), greater proportions of subjects on Tremfya compared to ustekinumab achieved an IGA score of 0 or 1 with a ≥2 grade improvement at Week 28 (31% vs 14%, respectively; 12 weeks after randomization) (FDA, 2017).

The most common adverse reactions associated with Tremfya include upper respiratory infections, headache, injection site reactions, arthralgia, diarrhea, gastroenteritis, tinea infections, and herpes simplex infections (FDA, 2017).

A Phase 3 study evaluating Tremfya in the treatment of active psoriatic arthritis is ongoing, and a Phase 3 program evaluating the efficacy of Tremfya compared with Cosentyx^® (secukinumab) in the treatment of moderate to severe plaque psoriasis is underway (Johnson & Johnson, 2017).

Infliximab

The U.S. Pharmacopeial Convention (2003) has concluded that psoriatic arthritis and psoriasis are accepted indications for infliximab.  A controlled clinical study (Chaudhari et al, 2001) has demonstrated the short-term effectiveness of infliximab in plaque psoriasis.  In a controlled clinical trial in which patients and investigators were blinded for the first 10 weeks, participants were assigned to either of 2 doses of infliximab (5 mg/kg or 10 mg/kg at baseline, 2 weeks, and 6 weeks) or to placebo.  Nineteen of 22 patients assigned to infliximab achieved good or better physician's overall assessments, compared with 2 of 11 patients assigned to placebo.  In initial studies, remissions seemed to be durable, with many patients improving for 6 months or longer.  Subsequent randomized controlled clinical studies have confirmed the efficacy of infliximab for treatment of plaque psoriasis (Reich et al, 2005; Feldman et al, 2005; Gottlieb et al, 2004).

Guidelines from the British Association of Dermatologists (2005) stated that infliximab is useful in clinical circumstances requiring rapid control of psoriasis, e.g., in unstable erythrodermic or pustular psoriasis, due to its very rapid onset of action and high response rate.

Infliximab (Remicade/Inflectra/Renflexis) is FDA approved for treatment of reducing signs and symptoms of active arthritis, inhibiting the progression of structural damage, and improving physical function in persons with psoriatic arthritis. Furthermore, it has the FDA approval for treatment of adults with chronic severe (i.e., extensive and/or disabling) plaque psoriasis who are candidates for systemic therapy and when other systemic therapies are medically less appropriate (Janssen, 2018; Merck, 2019; Pfizer, 2019).

ixekizumab

Taltz (ixekizumab) is a humanized interleukin‐17A antagonist. Ixekizumab is a humanized IgG4 monoclonal antibody that selectively binds with the interleukin 17A (IL‐17A) cytokine and inhibits its interaction with the IL‐17 receptor. IL‐17A is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Ixekizumab inhibits the release of proinflammatory cytokines and chemokines.

Taltz (ixekizumab) has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of adults with moderate‐to‐severe plaque psoriasis who are candidates for systemic therapy or phototherapy. The FDA approval of Taltz was based on findings from a phase III study of 3,800 patients with moderate-to-severe plaque psoriasis (Lilly, 2016). This number includes patients who began the trial on Taltz or placebo, or active comparator (U.S.-approved etanercept). This clinical program included three double-blind, multicenter, Phase 3 studies—UNCOVER-1, UNCOVER-2 and UNCOVER-3—which demonstrated the safety and efficacy of Taltz in patients with moderate-to-severe plaque psoriasis. All three studies evaluated the safety and efficacy of Taltz (80 mg every two weeks, following a 160-mg starting dose) compared to placebo after 12 weeks. UNCOVER-2 and UNCOVER-3 included an additional comparator arm in which patients received etanercept (50 mg twice a week) for 12 weeks. UNCOVER-1 and UNCOVER-2 also evaluated response rates with Taltz during the maintenance period through 60 weeks.

In these studies, the co-primary efficacy endpoints at 12 weeks were a 75 percent improvement in the composite Psoriasis Area Severity Index (PASI) score and static Physician's Global Assessment (sPGA) 0 or 1 and at least a 2-point improvement from baseline (Lilly, 2016). In all three studies, at 12 weeks, 87 to 90 percent of patients treated with Taltz saw a significant improvement of their psoriasis plaques (PASI 75).  In addition, 81 to 83 percent of patients treated with Taltz achieved sPGA 0 or 1. The majority of patients treated with Taltz, 68 to 71 percent, achieved virtually clear skin (PASI 90) and 35 to 42 percent of patients saw complete resolution of their psoriasis plaques (PASI 100, sPGA 0). Among those patients treated with placebo, 7 percent or fewer achieved PASI 75, 7 percent or fewer achieved sPGA 0 or 1, 3 percent or fewer achieved PASI 90 and 1 percent or fewer achieved PASI 100 and sPGA 0. In UNCOVER-1 and UNCOVER-2, of patients who responded to Taltz (sPGA 0 or 1 and at least a 2-point improvement from baseline) at 12 weeks, 75 percent consistently maintained that response at the 60-week endpoint.

Taltz was also statistically superior to etanercept at all skin clearance levels, including PASI 75 and sPGA 0 or 1 at 12 weeks (Lilly, 2016). In an integrated analysis of the U.S. sites in the two active comparator studies—UNCOVER-2 and UNCOVER-3—the respective response rates for Taltz versus.  etanercept were 87 percent vs. 41 percent for PASI 75 and 73 percent vs. 27 percent for sPGA 0 or 1.  

Taltz may increase the risk of infection. Patients treated with Taltz had a higher rate of infections than patients treated with placebo (27 percent vs. 23 percent) (Lilly, 2016). Upper respiratory tract infections, oral candidiasis, conjunctivitis and tinea infections occurred more frequently in patients treated with Taltz compared to placebo. Serious infections have occurred. Instruct patients to seek medical advice if signs or symptoms of clinically important chronic or acute infection occur. If a serious infection develops, discontinue Taltz until the infection resolves.

Other warnings and precautions for Taltz include pre-treatment evaluation for tuberculosis, hypersensitivity reactions, inflammatory bowel disease and immunizations.

In UNCOVER-2 and UNCOVER-3, the rate of serious adverse events during the controlled induction period (weeks 0-12) was 0.7 percent for U.S.-approved etanercept and 2 percent for Taltz, and the rate of discontinuation from adverse events was 0.7 percent for etanercept and 2 percent for Taltz (Lilly, 2016). The incidence of infections was 18 percent for etanercept and 26 percent for Taltz. The rate of serious infections was 0.3 percent for both  etanercept and Taltz.

The most common adverse reactions (greater or equal to 1%) associated with Taltz treatment are injection site reactions, upper respiratory tract infections, nausea, and tinea infections (Lilly, 2016).

Warnings and precautions:

• Infections: serious infections have occured. Instruct patients to seek medical advice if signs or symptoms of clinically important chronic or acute infection occur. If a serious infection develops, discontinue Taltz until the infection resolves.
• Tuberculosis (TB): evaluate for TB prior to initiating treatment.
• Hypersensivity: if a serious allergic reaction occurs, discontinue Taltz immediately and initate appropriate therapy.
• Inflammatory bowel disease: Crohn's disease and ulcerative colitis, including exacerbations, occurred during clinical trials. Patients who are treated with Taltz and have inflammatory bowel disease should be monitored closely.

On December 1, 2017, Eli Lilly and Company announced the U.S. FDA approval of Taltz (ixekizumab) injection 80 mg/mL for the treatment of adults with active psoriatic arthritis (PsA) (Eli Lilly, 2017).

FDA approval was based on findings from two randomized, double-blind, placebo-controlled phase 3 studies (SPIRIT-P1 and SPIRIT- P2). Across both studies, patients were required to have a diagnosis of active PsA for at least six months and at least three tender and three swollen joints. The primary efficacy endpoint was the proportion of patients at 24 weeks achieving ACR20 response.

The SPIRIT-P1 study (NCT01695239) assessed the safety and efficacy of ixekizumab, a monoclonal antibody that inhibits interleukin-17A, in patients with active psoriatic arthritis (PsA). Patients were randomized to receive subcutaneous injections of placebo (n=106), adalimumab 40 mg once every 2 weeks (n=101), ixekizumab 80 mg once every 2 weeks (IXEQ2W) (n=103), or ixekizumab 80 mg once every 4 weeks (IXEQ4W) (n=107). Both ixekizumab regimens included a 160-mg starting dose. The primary objective was to assess the superiority of IXEQ2W or IXEQ4W versus placebo. Findings showed that significantly more patients treated with ixekizumab achieved an ACR20 response with IXEQ2W (62.1%) or IXEQ4W (57.9%) than placebo (30.2%). Disease activity and functional disability were significantly improved with both ixekizumab doses versus placebo at weeks 12 and 24, and found less progression of structural damage at week 24 (p≤0.01). At week 24, 58% of patients treated with ixekizumab achieved ACR20, than 30% for placebo. The authors concluded that ixekizumab improves disease activity, physical function, and inhibits structural damage progression in biologic-naïve patients with active PsA (Mease et al., 2017).

The SPIRIT-P2 study (NCT02349295) evaluated the safety and efficacy of ixekizumab compared to placebo in tumor necrosis factor inhibitor (TNFi)-experienced patients with active PsA who failed one or two TNF inhibitors. Patients (aged 18 years and older) who had psoriatic arthritis for at least 6 months, and who had previous inadequate response to tumour necrosis factor inhibitors (TNFi) were enrolled in the study. Patients (n=363) were randomized to receive a placebo (n=118) or subcutaneous injection of 80 mg ixekizumab every 4 weeks (n=122) or every 2 weeks (n=123) after a 160 mg starting dose. The investigators found at week 24, a higher proportion of patients attained ACR20 with ixekizumab (53% of patients) than placebo (20%). Serious adverse events were reported in three (3%) patients with ixekizumab every 4 weeks, eight (7%) with ixekizumab every 2 weeks, and four (3%) with placebo; no deaths were reported. Infections were reported in 47 (39%) patients with ixekizumab every 4 weeks, 47 (38%) with ixekizumab every 2 weeks, and 35 (30%) with placebo. The authors concluded that the safety profile was consistent with previous ixekizumab, and that both the 2-week and 4-week ixekizumab dosing regimens improved signs and symptoms of patients with active PsA who previously had inadequate response to TNFi (Nash et al., 2017).

Risankizumab-rzaa

On April 23, 2019, AbbVie Inc (Chicago, IL) announced the FDA approval of Skyrizi (risankizumab-rzaa), an interleukin-23 (IL-23) inhibitor, for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy.

FDA approval was based on four multicenter, randomized, double-blind, placebo and/or active-controlled pivotal studies: ULTIMMA-1, ULTIMMA-2, IMMHANCE and IMMVENT (NCT02684370, NCT02684357, NCT02672852, NCT02694523).

In the ULTIMMA-1 and ULTIMMA-2 trials, 997 subjects with moderate-to-severe chronic plaque psoriasis, ages 18 years or older, who had a body surface area (BSA) involvement of ≥10%, a static Physician’s Global Assessment (sPGA) score of ≥3 (“moderate”) in the overall assessment (plaque thickness/induration, erythema, and scaling) of psoriasis on a severity scale of 0 to 4, and a Psoriasis Area and Severity Index (PASI) score ≥12 were enrolled. Of the 997 subjects, 598 were randomized to the risankizumab-rzaa 150 mg group, 200 were randomized to the placebo group, and 199 to the biologic (ustekinumab) active control group. Risankizumab-rzaa was administered subcutaneously at Weeks 0, 4, and every 12 weeks thereafter. Both studies assessed the responses at Week 16 compared to placebo for two co-primary endpoints, the proportion of subjects achieving a 90% reduction from baseline in the Psoriasis Area Severity Index (PASI 90), and the proportion of subjects who achieved a sPGA score of 0 (“clear”) or 1 (“almost clear”). Secondary endpoints included the proportion of subjects who achieved PASI 100, sPGA 0, and Psoriasis Symptom Scale (PSS) 0 (“none”) at Week 16 versus placebo. Co-primary endpoints were met for both studies. At Week 16 both ULTIMMA-1 and ULTIMMA-2 found that PASI 90 was achieved in 75 percent of people treated with risankizumab-rzaa (Skyrizi), compared to 5 and 2 percent receiving placebo, respectively (p<0.001). PASI 100 was achieved in 36 and 51 percent of people treated with risankizumab-rzaa, compared to 0 and 2 percent receiving placebo, respectively (p<0.001). At one year (52 weeks), 82 and 81 percent of people treated with risankizumab-rzaa achieved PASI 90, and 56 and 60 percent achieved PASI 100, respectively (p<0.001); in addition, 58 and 60 percent achieved sPGA 0, respectively. An integrated analysis of ULTIMMA-1 and ULTIMMA-2 showed most people treated with risankizumab-rzaa who achieved PASI 90 and PASI 100 at Week 16 maintained this response at one year (88 and 80 percent, respectively) (AbbVie, 2019a; AbbVie, 2019b; Gordon et al., 2018).

In the IMMHANCE trial (NCT02672852), subjects who were originally on risankizumab-rzaa and had sPGA 0 or 1 at Week 28 were re-randomized to continue risankizumab-rzaa every 12 weeks or withdrawal of therapy. At Week 52, 87% (97/111) of the subjects re-randomized to continue treatment with risankizumab-rzaa had sPGA 0 or 1 compared to 61% (138/225) who were re-randomized to withdrawal of risankizumab-rzaa (AbbVie, 2019b).

Most common adverse reactions (≥ 1%) are upper respiratory infections, headache, fatigue, injection site reactions, and tinea infections.

Phase 3 trials of risankizumab-rzaa (Skyrizi) in psoriatic arthritis are ongoing (AbbVie, 2019a).

Secukinumab

The FDA has approved secukinumab (Cosentyx) injection for the treatment of moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy (Novartis, 2015). Secukinumab (previously known as AIN457) is a human monoclonal antibody (mAb) that selectively binds to interleukin-17A (IL-17A) and inhibits its interaction with the IL-17 receptor. 

The Phase III clinical program included four placebo-controlled studies which examined secukinumab 300 mg and 150 mg in patients with moderate-to-severe plaque psoriasis (Novartis, 2015):

• ERASURE:

  (Efficacy of response and safety of two fixed secukinumab regimens in psoriasis) was a randomized, double-blind, placebo-controlled, multicenter, parallel-group Phase III study involving 738 patients with moderate-to-severe plaque psoriasis.

• FIXTURE:

  (the full year investigative examination of secukinumab vs. etanercept using 2 dosing regimens to determine efficacy in psoriasis) was a randomized, double-blind, placebo and active controlled, multicenter, parallel-group Phase III study involving 1306 patients with moderate-to-severe plaque psoriasis.

• FEATURE:

  (First study of secukinumab in prefilled syringes in subjects with chronic plaqUe-type psoriasis response) was a randomized double-blind, placebo-controlled, multicenter, Phase III study involving 177 subjects with moderate-to-severe plaque psoriasis. In this study, prefilled syringes (PFS) were introduced into the Cosentyx clinical program.

• JUNCTURE:

  (Judging the efficacy of secukinumab in patients with psoriasis using autoinjector: a clinical trial evaluating treatment results) was a double-blind, placebo-controlled, multicenter, Phase III study involving 182 subjects with moderate-to-severe plaque psoriasis. In this study, the autoinjector/pen (AI) was introduced into the Cosentyx clinical program.

In these studies, secukinumab met its primary endpoint and key secondary endpoints, including Psoriasis Area and Severity Index (PASI) 75 and 90 and Investigator's Global Assessment modified 2011 (IGA) 0/1 responses, showing significant skin clearance at Week 12 (Novartis, 2015). 

The recommended dose of secukinumab is 300 mg by subcutaneous injection at Weeks 0, 1, 2, 3, and 4 followed by 300 mg every 4 weeks (Novartis, 2015). For some patients, a dose of 150 mg may be acceptable. 

Cosentyx is contraindicated in patients with a previous serious hypersensitivity reaction to secukinumab or to any of the excipients (Novartis, 2015). Most common adverse reactions (> 1%) with sekukinumab are nasopharyngitis, diarrhea, and upper respiratory tract infections. 

In placebo-controlled clinical trials, higher rates of common infections such as nasopharyngitis (11.4% versus 8.6%), upper respiratory tract infection (2.5% versus 0.7%) and mucocutaneous infections with candida (1.2% versus 0.3%) were observed with secukinumab compared with placebo (Novartis, 2015).  The incidence of some types of infections appeared to be dose-dependent in clinical studies. The labeling of Consentyx recommends exercising caution when considering the use of secukinumab in patients with a chronic infection or a history of recurrent infection. If a patient develops a serious infection, the patient should be closely monitored and secukinumab should be discontinued until the infection resolves. 

The labeling recommends that patients be evaluated for tuberculosis (TB) infection prior to initiating treatment with secukinumab (Novartis, 2015).  Secukinumab should not be administered to patients with active TB infection. Treatment of latent TB should be initiated prior to administering secukinumab.  The labeling also states that anti-TB therapy should be considered prior to initiation of secukinumab in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed.  Patients receiving secukinumab should be monitored closely for signs and symptoms of active TB during and after treatment. 

The labeling recommends caution when prescribing secukinumab to patients with active Crohn's disease, as exacerbations of Crohn's disease, in some cases serious, were observed in secukinumab-treated patients during clinical trials (Novartis, 2015). The labeling recommends close monitoring of patients with active Crohn’s disease who are treated with secukinumab. 

Anaphylaxis and cases of urticaria occurred in secukinumab-treated patients in the clinical trials (Novartis, 2015).  The labeling recommends immediate discontinuation of secukinumab and initiation of appropriate therapy if an anaphylactic or other serious allergic reaction occurs. 

The labeling states that patients treated with secukinumab should not receive live vaccines (Novartis, 2015). Non-live vaccinations received during a course of secukinumab may not elicit an immune response sufficient to prevent disease. The labeling recommends completion of all age-appropriate immunizations prior to initiating therapy with secukinumab.

In a phase 3, double-blind, placebo-controlled study (McInnes, et al., 2015) undertaken at 76 centers in Asia, Australia, Canada, Europe, and the USA, adults (aged ≥18 years old) with active psoriatic arthritis were randomly allocated in a 1:1:1:1 ratio with computer-generated blocks to receive subcutaneous placebo or secukinumab 300 mg, 150 mg, or 75 mg once a week from baseline and then every 4 weeks from week 4. Patients and investigators were masked to treatment assignment. The primary endpoint was the proportion of patients achieving at least 20% improvement in the American College of Rheumatology response criteria (ACR20) at week 24. Analysis was by intention to treat. Between April 14, and Nov 25, 2013, 397 patients were randomly assigned to receive secukinumab 300 mg (n=100), 150 mg (n=100), 75 mg (n=99), or placebo (n=98). A significantly higher proportion of patients achieved an ACR20 at week 24 with secukinumab 300 mg (54 [54%] patients; odds ratio versus placebo 6·81, 95% CI 3·42-13·56; p<0·0001), 150 mg (51 [51%] patients; 6·52, 3·25-13·08; p<0·0001), and 75 mg (29 [29%] patients; 2·32, 1·14-4·73; p=0·0399) versus placebo (15 [15%] patients). Up to week 16, the most common adverse events were upper respiratory tract infections (four [4%], eight [8%], ten [10%], and seven [7%] with secukinumab 300 mg, 150 mg, 75 mg, and placebo, respectively) and nasopharyngitis (six [6%], four [4%], six [6%], and eight [8%], respectively). Serious adverse events were reported by five (5%), one (1%), and four (4%) patients in the secukinumab 300 mg, 150 mg, and 75 mg groups, respectively, compared with two (2%) in the placebo group. No deaths were reported. The investigators concluded that subcutaneous secukinumab 300 mg and 150 mg improved the signs and symptoms of psoriatic arthritis, suggesting that secukinumab is a potential future treatment option for patients with this disorder.

McInnes, et al. (2014) evaluated the efficacy and safety of secukinumab in patients with psoriatic arthritis (PsA). Investigators randomly assigned (2:1) 42 patients with active PsA fulfilling Classification for Psoriatic Arthritis (CASPAR) criteria to receive two intravenous secukinumab doses (10 mg/kg; n=28) or placebo (n=14) 3 weeks apart. The primary endpoint was the proportion of American College of Rheumatology (ACR) 20 responses at week 6 for secukinumab versus placebo (one-sided p<0.1). ACR20 responses at week 6, the primary endpoint, were 39% (9/23) for secukinumab versus 23% (3/13) for placebo (p=0.27). ACR20 responses were greater with secukinumab versus placebo at week 12 (39% (9/23) vs 15% (2/13), p=0.13) and week 24 (43% (10/23) vs 18% (2/11), p= 0.14). At week 6, 'good' European League Against Rheumatism response was seen in 21.7% (5/23) secukinumab versus 9.1% (1/11) placebo patients. Compared with placebo at week 6, significant reductions were observed among secukinumab recipients for C reactive protein (p=0.039), erythrocyte sedimentation rate (p=0.038), Health Assessment Questionnaire Disability Index (p=0.002) and Short Form Health Survey (SF-36; p=0.030) scores. The overall adverse event (AE) frequency was comparable between secukinumab (26 (93%)) and placebo (11 (79%)) recipients. Six serious AEs (SAEs) were reported in four secukinumab patients and one SAE in one placebo patient. The investigators concluded that, although the primary endpoint was not met, clinical responses, acute-phase reactant and quality of life improvements were greater with secukinumab versus placebo, suggesting some clinical benefit. The investigators stated that secukinumab exhibited satisfactory safety.

Tildrakizumab

Ilumya (tildrakizumab) is humanized IgG1/k monoclonal antibody that selectively binds to the p19 subunit of IL-23 and inhibits its interaction with the IL-23 receptor. In March 2018, the FDA approved tildrakizumab (Ilumya) for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

Reich et al (2017) conducted two three-part, parallel group, double-blind, randomised controlled studies, reSURFACE 1 (at 118 sites in Australia, Canada, Japan, the UK, and the USA) and reSURFACE 2 (at 132 sites in Europe, Israel, and the USA). Participants aged 18 years or older with moderate-to-severe chronic plaque psoriasis (body surface area involvement ≥10%, Physician's Global Assessment [PGA] score ≥3, and Psoriasis Area and Severity Index [PASI] score ≥12) were randomised (via interactive voice and web response system) to tildrakizumab 200 mg, tildrakizumab 100 mg, or placebo in reSURFACE 1 (2:2:1), or to tildrakizumab 200 mg, tildrakizumab 100 mg, placebo, or etanercept 50 mg (2:2:1:2). Randomisation was done by region and stratified for bodyweight (≤90 kg or >90 kg) and previous exposure to biologics therapy for psoriasis. Investigators, participants, and study personnel were blinded to group allocation and remained blinded until completion of the studies. Assigned medication was identical in appearance and packaging. Tildrakizumab was administered subcutaneously at weeks 0 and 4 during part 1 and at week 16 during part 2 (weeks 12 and 16 for participants re-randomised from placebo to tildrakizumab; etanercept was given twice weekly in part 1 of reSURFACE 2 and once weekly during part 2). The co-primary endpoints were the proportion of patients achieving PASI 75 and PGA response (score of 0 or 1 with ≥2 grade score reduction from baseline) at week 12. Safety was assessed in the all-participants-as-treated population, and efficacy in the full-analysis set. These trials are registered with ClinicalTrials.gov, numbers NCT01722331 (reSURFACE 1) and NCT01729754 (reSURFACE 2). These studies are completed, but extension studies are ongoing. The reSURFACE 1 trial ran from Dec 10, 2012, to Oct 28, 2015. The reSURFACE 2 trial ran from Feb 12, 2013, to Sept 28, 2015. In reSURFACE 1, 772 patients were randomly assigned, 308 to tildrakizumab 200 mg, 309 to tildrakizumab 100 mg, and 155 to placebo. At week 12, 192 patients (62%) in the 200 mg group and 197 patients (64%) in the 100 mg group achieved PASI 75, compared with 9 patients (6%) in the placebo group (p<0·0001 for comparisons of both tildrakizumab groups vs placebo). 182 patients (59%) in the 200 mg group and 179 patients (58%) in the 100 mg group achieved PGA responses, compared with 11 patients (7%) in the placebo group (p<0·0001 for comparisons of both tildrakizumab groups vs placebo). In reSURFACE 2, 1090 patients were randomly assigned, 314 to tildrakizumab 200 mg, 307 to tildrakizumab 100 mg, 156 to placebo, and 313 to etanercept. At week 12, 206 patients (66%) in the 200 mg group, and 188 patients (61%) in the 100 mg group achieved PASI 75, compared with 9 patients (6%) in the placebo group and 151 patients (48%) in the etanercept group (p<0·0001 for comparisons of both tildrakizumab groups vs placebo; p<0·0001 for 200 mg vs etanercept and p=0·0010 for 100 mg vs etanercept). 186 patients (59%) in the 200 mg group, and 168 patients (59%) [corrected] in the 100 mg group achieved a PGA response, compared with 7 patients (4%) in the placebo group and 149 patients (48%) in the etanercept group (p<0·0001 for comparisons of both tildrakizumab groups vs placebo; p=0·0031 for 200 mg vs etanercept and p=0·0663 for 100 mg vs etanercept). Serious adverse events were similar and low in all groups in both trials. One patient died in reSURFACE 2, in the tildrakizumab 100 mg group; the patient had alcoholic cardiomyopathy and steatohepatitis, and adjudication was unable to determine the cause of death. The authors concluded that in the two phase 3 trials, tildrakizumab 200 mg and 100 mg were efficacious compared with placebo and etanercept and were well tolerated in the treatment of patients with moderate-to-severe chronic plaque psoriasis.

Tofacitinib (Xeljanz, Xeljanz XR)

On December 14, 2017, Pfizer announced the U.S. Food and Drug Administration (FDA) approval of Xeljanz (tofacitinib) and Xeljanz XR for the treatment of adults with active psoriatic arthritis (PsA) who have had an inadequate response or intolerance to methotrexate or other disease-modifying antirheumatic drugs (DMARDs) (Pfizer, 2018).

The recommended dose of Xeljanz and Xeljanz XR is in combination with nonbiologic DMARDs. Tofacitinib (Xeljanz, Xeljanz XR) is not be used concomitantly with apremilast, biologic DMARDs (e.g., adalimumab, infliximab), or potent immunosuppressants (i.e., azathioprine, cyclosporine).

FDA approval and dosing recommendations for Xeljanz were based on the results from two pivotal studies, OPAL Broaden and OPAL Beyond, as well as data from an ongoing long-term extension trial, OPAL Balance (Pfizer, 2018).

Mease et al. (2017) conducted a 12-month, double-blind, active-controlled and placebo-controlled, randomized, phase 3 clinical trial (OPAL Broaden, NCT01877668) to evaluate tofacitinib in patients with active psoriatic arthritis (PsA) who previously had an inadequate response to non-biologic, conventional synthetic disease-modifying antirheumatic drugs (DMARDs), and who were tumor necrosis factor inhibitor (TNFi) naive. Patients were randomized to receive either: tofacitinib at a 5-mg dose taken orally twice daily (n=107), tofacitinib at a 10-mg dose taken orally twice daily (n=104), adalimumab at a 40-mg dose administered subcutaneously once every 2 weeks (n=106), placebo with a blinded switch to the 5-mg tofacitinib dose at 3 months (n=52), or placebo with a blinded switch to the 10-mg tofacitinib dose at 3 months (n=53). Primary end points were at 3 months were the proportion of patients who had an American College of Rheumatology 20 (ACR20) response (≥20% improvement from baseline in the number of tender and swollen joints and at least three of five other important domains) and the change from baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI). The authors found that ACR20 response rates at month 3 were 50% in the 5-mg tofacitinib group and 61% in the 10-mg tofacitinib group, as compared with 33% in the placebo group. The rate was 52% in the adalimumab group. The mean change in the HAQ-DI score was -0.35 in the 5-mg tofacitinib group and -0.40 in the 10-mg tofacitinib group, as compared with -0.18 in the placebo group. The score change was -0.38 in the adalimumab group. The rate of adverse events through month 12 was 66% in the 5-mg tofacitinib group, 71% in the 10-mg tofacitinib group, 72% in the adalimumab group, 69% in the placebo group that switched to the 5-mg tofacitinib dose, and 64% in the placebo group that switched to the 10-mg tofacitinib dose. There were four cases of cancer, three serious infections, and four cases of herpes zoster in patients who received tofacitinib during the trial. The authors concluded that at 3 months, tofacitinib was superior to that of placebo in patients with active PsA who had previously had an inadequate response to conventional synthetic DMARDs.

Gladman et al. (2017) conducted a 6 month randomized, placebo-controlled, double-blind, phase 3 trial (OPAL Beyond, NCT01882439) to evaluate tofacitinib in patients with active psoriatic arthritis (PsA) who had previously had an inadequate response to TNFi.  Patients (n=395) were randomized to receive either 5 mg of tofacitinib administered orally twice daily (n=132); 10 mg twice daily (n=132), placebo, with a switch to 5 mg of tofacitinib twice daily at 3 months (n=66), or placebo, with a switch to 10 mg of tofacitinib twice daily at 3 months (n=65). At 3 months, the rates of ACR20 response were 50% with the 5-mg dose of tofacitinib and 47% with the 10-mg dose, as compared with 24% with placebo. The corresponding mean changes from baseline in HAQ-DI score were -0.39 and -0.35, as compared with -0.14 (P<0.001 for both comparisons). Serious adverse events occurred in 4% of the patients who received the 5-mg dose of tofacitinib continuously and in 6% who received the 10-mg dose continuously. The authors concluded that over 3 months, tofacitinib was more effective than placebo for reducing disease activity in patients with active PsA who had an inadequate response to TNF inhibitors.

In both the OPAL Broaden and OPAL Beyond, all patients were required to receive a stable background dose of a single nonbiologic DMARD.

Ustekinumab

Stelara (ustekinumab) is a human IgG1κ monoclonal antibody that binds with high affinity and specificity to the p40 protein subunit used by both the interleukin (IL)‐12 and IL‐23 cytokines. IL‐12 and IL‐23 are naturally occurring cytokines that are involved in inflammatory and immune responses, such as natural killer cell activation and CD4+ T‐cell differentiation and activation. In in vitro models, ustekinumab was shown to disrupt IL‐12 and IL‐23 mediated signaling and cytokine cascades by disrupting the interaction of these cytokines with a shared cell‐surface receptor chain, IL‐12 β1. Stelara is produced in a well characterized recombinant cell line and is purified using standard bio‐processing technology. The manufacturing process contains steps for the clearance of viruses.

Stelara (ustekinumab) is indicated for the treatment of adolescents (12 years or older) and adult patients (18 years or older) with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy and for the treatment of adult patients with active psoriatic arthritis, either alone or with methotrexate. Stelara is also indicated for persons with moderate to severe Crohn's disease.

In September 2009, the FDA approved ustekinumab (Stelara) for the treatment of  adults with moderate-to-severe psoriasis.  Ustekinumab is a fully human monoclonal antibody that binds with high specificity and affinity to the cytokines interleukin (IL)-12 and IL-23, thereby suppressing IL-12- and IL-23-mediated inflammation associated with psoriasis.  In a review on the use of biological agents in the treatment of psoriasis, Tzu et al (2008) noted that IL-12/IL-23 inhibitors are new agents.  Furthermore, Rozenblit and Lebwohl (2009) stated that new biologic therapies for psoriasis and psoriatic arthritis include antibodies to IL-12 and IL-23.

Weber and Keam (2009) noted that in 2 large, phase III trials in patients with moderate-to-severe plaque psoriasis, significantly more subcutaneous ustekinumab 45 or 90 mg recipients (administered as 2 injections 4 weeks apart) than placebo recipients achieved a 75 % improvement on the PASI 75 score at 12 weeks.  Other efficacy measures, including the physician's global assessment (PGA) of clinical response at week 12, also favored ustekinumab over placebo.  Psoriatic symptom control was maintained during ustekinumab maintenance therapy (administered once every 12 weeks) for up to 76 weeks.  In a phase II trial in patients with active plaque psoriasis and psoriatic arthritis, signs and symptoms of arthritis and psoriatic symptom control were improved to a greater extent with ustekinumab than with placebo at 12 weeks, based on the proportion of patients achieving a 20 % improvement in ACR response criteria (arthritis) or PASI 75 (skin symptoms).  Health-related quality of life, assessed using the Dermatology Life Quality Index and the Health Assessment Questionnaire disability index, was improved to a significantly greater extent with ustekinumab than with placebo at week 12.  Subcutaneous ustekinumab was generally well-tolerated in clinical trials, with most treatment-emergent adverse events being of mild severity.

In a phase III, parallel, randomized, double-blind, placebo-controlled trial (PHOENIX 1), Leonardi et al (2008) examined the safety and effectiveness of ustekinumab for the treatment of psoriasis.  A total of 766 patients with moderate-to-severe psoriasis were randomly assigned to receive ustekinumab 45 mg (n = 255) or 90 mg (n = 256) at weeks 0 and 4 and then every 12 weeks; or placebo (n = 255) at weeks 0 and 4, with subsequent cross-over to ustekinumab at week 12.  Patients who were initially randomized to receive ustekinumab at week 0 who achieved long-term response (at least 75 % improvement in psoriasis area and severity index [PASI 75] at weeks 28 and 40) were re-randomized at week 40 to maintenance ustekinumab or withdrawal from treatment until loss of response.  Both randomizations were done with a minimization method via a centralized interactive voice response system.  The primary endpoint was the proportion of patients achieving PASI 75 at week 12.  Analyses were by intention-to-treat.  All randomized patients were included in the efficacy analysis.  Overall, 171 (67.1 %) patients receiving ustekinumab 45 mg, 170 (66.4 %) receiving ustekinumab 90 mg, and 8 (3.1 %) receiving placebo achieved PASI 75 at week 12 (difference in response rate versus placebo 63.9 %, 95 % confidence interval [CI]: 57.8 to 70.1, p < 0.0001 for 45 mg and 63.3 %, 57.1 to 69.4, p < 0.0001 for 90 mg).  At week 40, long-term response had been achieved by 150 patients in the 45-mg group and 172 patients in the 90-mg group.  Of these, 162 patients were randomly assigned to maintenance ustekinumab and 160 to withdrawal.  PASI 75 response was better maintained to at least 1 year in those receiving maintenance ustekinumab than in those withdrawn from treatment at week 40 (p < 0.0001 by log-rank test).  During the placebo-controlled phase, adverse events occurred in 278 (54.5 %) of the 510 patients receiving ustekinumab and 123 (48.2 %) of the 255 receiving placebo.  Serious adverse events occurred in 6 (1.2 %) of 510 patients receiving ustekinumab and in 2 (0.8 %) of 255 receiving placebo in this phase.  The pattern of adverse events was much the same in the placebo cross-over and randomized withdrawal phases as it was in the placebo-controlled phase.  The authors concluded that ustekinumab seems to be effective for the treatment of moderate-to-severe psoriasis; dosing every 12 weeks maintains efficacy for at least 1 year in most patients.

In a multi-center, phase III, double-blind, placebo-controlled trial (PHOENIX 2), Papp et al (2008) assessed the safety and effectiveness of ustekinumab in psoriasis patients and assessed dosing intensification in partial responders.  A total of 1,230 patients with moderate-to-severe psoriasis (defined by a PASI score greater than or equal to 12, and at least 10 % total body surface area involvement) were randomly assigned to receive ustekinumab 45 mg (n = 409) or 90 mg (n = 411) at weeks 0 and 4, then every 12 weeks, or placebo (n = 410).  Partial responders (i.e., patients achieving greater than or equal to 50 % but less than 75 % improvement from baseline in PASI) were re-randomized at week 28 to continue dosing every 12 weeks or escalate to dosing every 8 weeks.  Both randomizations were done with a minimization method via a centralized interactive voice response.  The primary endpoint was the proportion of patients achieving at least PASI 75 at week 12.  Analyses were by intention-to-treat.  All randomized patients were included in the efficacy analysis.  Overall, 273 (66.7 %) patients receiving ustekinumab 45 mg, 311 (75.7 %) receiving ustekinumab 90 mg, and 15 (3.7 %) receiving placebo achieved the primary endpoint (difference in response rate 63.1 %, 95 % CI: 58.2 to 68.0, p < 0.0001 for the 45-mg group versus placebo and 72.0 %, 67.5 to 76.5, p < 0.0001 for the 90-mg group versus placebo).  More partial responders at week 28 who received ustekinumab 90 mg every 8 weeks achieved PASI 75 at week 52 than did those who continued to receive the same dose every 12 weeks (22 [68.8 %] versus 11 [33.3 %]; difference in response rate 35.4 %, 95 % CI: 12.7 to 58.1, p = 0.004).  There was no such response to changes in dosing intensity in partial responders treated with ustekinumab 45 mg.  During the placebo-controlled phase, 217 (53.1 %) patients in the 45-mg group, 197 (47.9 %) in the 90-mg group, and 204 (49.8 %) in the placebo group experienced adverse events; serious adverse events were seen in 8 (2.0 %) patients in the 45-mg group, 5 (1.2 %) in the 90-mg group, and 8 (2.0 %) in the placebo group.  The authors concluded that although treatment with ustekinumab every 12 weeks is effective for most patients with moderate-to-severe psoriasis, intensification of dosing to once every 8 weeks with ustekinumab 90 mg might be necessary to elicit a full response in patients who only partially respond to the initial regimen.

Landells et al (2015) stated safe and effective therapies are needed for pediatric patients with psoriasis. On October 13, 2017, Janssen Biotech, Inc., announced that the FDA approved an expanded indication for Stelara (ustekinumab) for the treatment of adolescents (12 years of age or older) with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. The FDA-approval of ustekinumab in adolescents (12 years or older) was based on data from a multicenter, randomized, double blind, placebo-controlled study that evaluated ustekinumab in patients age 12 to 17 years who had moderate-to-severe psoriasis. Patients (n = 110) were randomly assigned to ustekinumab standard dosing (SD; 0.75 mg/kg [≤60 kg], 45 mg [>60-≤100 kg], and 90 mg [>100 kg]) or half-standard dosing (HSD; 0.375 mg/kg [≤60 kg], 22.5 mg [>60-≤100 kg], and 45 mg [>100 kg]) at weeks 0 and 4 and every 12 weeks or placebo at weeks 0 and 4 with crossover to ustekinumab SD or HSD at week 12. Clinical assessments included the proportion of patients achieving a Physician's Global Assessment of cleared/minimal (PGA 0/1), at least 75% improvement in Psoriasis Area and Severity Index (PASI 75), and at least 90% in PASI (PASI 90). Adverse events (AEs) were monitored through week 60. At week 12, 67.6% and 69.4% of patients receiving ustekinumab HSD and SD, respectively, achieved PGA 0/1 versus 5.4% for placebo (P < .001). Significantly greater proportions receiving ustekinumab achieved PASI 75 (HSD, 78.4%; SD, 80.6%; placebo, 10.8%) or PASI 90 (HSD, 54.1%; SD, 61.1%; placebo, 5.4%) at week 12 (P < .001). Through week 12, 56.8% of placebo patients, 51.4% of HSD patients, and 44.4% of SD patients reported at least one AE; through week 60, 81.8% reported AEs. The study was small relative to adult trials. The authors concluded that in this patient population (12-17 years), the standard ustekinumab dose provided response comparable to that in adults with no unexpected AEs through 1 year.

In a phase II, randomized, double-blind, placebo-controlled, cross-over study, Gottlieb et al (2009) evaluated the safety and effectiveness of ustekinumab for psoriatic arthritis.  Patients with active psoriatic arthritis were randomly allocated via interactive voice response system to either ustekinumab (90 mg or 63 mg) every week for 4 weeks (weeks 0 to 3) followed by placebo at weeks 12 and 16 (n = 76; Group 1) or placebo (weeks 0 to 3) and ustekinumab (63 mg) at weeks 12 and 16 (n = 70; Group 2).  The first 12 weeks of the study were placebo-controlled.  Masking was maintained to week 16, and patients were followed-up to week 36 [corrected].  The primary endpoint was American College of Rheumatology 20 % improvement (ACR20) response at week 12.  Analysis was by intention-to-treat.  At week 12, 32 (42 %) patients in Group 1 and 10 (14 %) in Group 2 achieved the primary endpoint (difference 28 % [95 % CI: 14.0 to 41.6]; p = 0.0002).  Of 124 (85 %) participants with psoriasis affecting 3 % or more body surface area, 33 of 63 (52 %) in Group 1 and 3 of 55 (5 %) in Group 2 had a 75 % or greater improvement in psoriasis area and severity index score at week 12 (47 % [33.2 to 60.6]; p < 0.0001).  During the placebo-controlled period (weeks 0 to 12), adverse events arose in 46 (61 %) patients in Group 1 and 44 (63 %) in Group 2; serious adverse events were recorded in 3 (4 %) Group 2 patients (none in Group 1).  The authors concluded that ustekinumab significantly reduced signs and symptoms of psoriatic arthritis and diminished skin lesions compared with placebo, and the drug was well-tolerated.  They stated that larger and longer term studies are needed to further characterise ustekinumab safety and effectiveness for the treatment of psoriatic arthritis.

Ryan et al (2010) examined the safety and efectiveness of ustekinumab in all clinical studies to date, using PubMed listed publications and official product websites.  Ustekinumab has shown significant effectiveness in the treatment of chronic plaque psoriasis in phase III studies, and promising results in phase II studies in psoriatic arthritis.  Effectiveness has been shown in Crohn's disease only in non-responders to infliximab.  Furthermore, ustekinumab did not show benefit in the treatment of multiple sclerosis.

The effectiveness of ustekinumab in treating psoriasis were reproduced in the phase III, multi-center, randomized ACCEPT trial (2008).  This head-to-head study comparing ustekinumab and etanercept for the treatment of moderate-to-severe psoriasis showed ustekinumab superior to etanercept according to primary and major secondary efficacy endpoints.  The primary endpoint of the trial was the percentage of participants achieving at least a 75 % reduction in psoriasis at week 12 as measured by PASI 75.  At week 12, after 2 subcutaneous injections at weeks 0 and 4, 68 % and 74 % of patients receiving ustekinumab 45 mg or ustekinumab 90 mg, respectively, achieved a PASI 75 compared with 57 % of patients receiving etanercept 50 mg subcutaneous injections twice-weekly for 12 weeks (p = 0.012 for ustekinumab 45 mg; p < 0.001 for ustekinumab 90 mg, each compared with etanercept).

In a phase II clinical trial, Kavanaugh et al (2010) evaluated the effect of ustekinumab on physical disability and health-related quality of life (HRQoL) in patients with psoriatic arthritis (PsA).  Patients with active PsA were randomized (1:1 ratio) to receive either ustekinumab at weeks 0, 1, 2, and 3 and placebo at weeks 12 and 16 (n = 76) or placebo at weeks 0, 1, 2, and 3 and ustekinumab at weeks 12 and 16 (n = 70).  Physical function was assessed using the disability index from the Health Assessment Questionnaire-Disability Index (HAQ-DI) in all randomized patients.  HRQoL was evaluated using the DLQI in a subset of patients (84.9 %) with at least 3 % body surface area (BSA) psoriasis involvement at baseline.  At baseline, overall mean HAQ-DI and DLQI scores were 0.9 and 11.5, respectively, indicating impaired physical function and moderate effect on HRQoL.  At week 12, ustekinumab patients had significantly more improvement (decrease) in the mean HAQ-DI (-0.31) and DLQI (-8.6) scores versus placebo (-0.04 and -0.8, respectively; p < 0.001 for both comparisons).  At week 12, 58.7 % (37/63) of ustekinumab-treated patients had a DLQI score of 0 or 1 (no negative effect of disease or treatment on HRQoL) versus 5.5 % (3/55) for placebo (p < 0.001).  The results also indicated a positive but weak correlation between improvement in physical function and HRQoL, pain, and skin response as well as between improvement in joint and skin responses in patients receiving ustekinumab or placebo.  The authors concluded that ustekinumab significantly improved physical function and HRQoL in patients with PsA and psoriasis involving at least 3 % BSA.  Limitations of the study included the short duration of the placebo-controlled period and the relatively small patient population.

Kurzeja et al (2011) stated that interleukin (IL)-23 is an important regulator of T helper-17 lymphocytes, which influence the cutaneous immune system by production of IL-17 and several other pro-inflammatory cytokines.  This pathway has been recently linked to the pathogenesis of psoriasis and numerous other skin diseases.  A newly developed biologic drug, ustekinumab, which targets the p40 subunit of IL-12 and IL-23, was approved by the U.S. FDA and the European Medicines Agency in 2009 for the treatment of moderate to severe psoriasis.  Administered as subcutaneous injections of 45 mg at weeks 0 and 4, and then every 12 weeks, ustekinumab produces a 75 % improvement in the PASI in 66.4 to 75.7 % of patients and a DLQI score of 0 or 1 in 55 to 56 % of patients after 12 weeks of therapy.  A recent clinical trial also indicates the possible efficacy of ustekinumab in psoriatic arthritis.  The proportion of patients who had at least 1 adverse event through 12 weeks in clinical studies was 51.6 to 57.6 % in the ustekinumab group and 50.4 % in the placebo group.  Serious adverse events were observed in 1.4 to 1.6 % of patients treated with ustekinumab and in 1.4 % of patients receiving placebo.  Injection-site reactions occurred in 1 to 2 % of patients and 5 % of patients developed anti-ustekinumab antibodies.  The authors concluded that further studies are needed to evaluate the long-term safety and effectiveness of ustekinumab.

U.S. Food and Drug Administration (FDA) has approved ustekinumab (Stelara), a fully human anti–IL-12/23p40 monoclonal antibody, alone or in combination with methotrexate for the treatment of adult patients (18 years or older) with active psoriatic arthritis. The approval was supported by findings from two pivotal phase 3 multicenter, randomized, double-blind, placebo-controlled trials of ustekinumab administered subcutaneously in subjects with active psoriatic arthritis (PSUMMIT I and PSUMMIT II), which evaluated the efficacy and safety of subcutaneously administered ustekinumab 45 mg or 90 mg at weeks 0, 4 and then every 12 weeks. The trials included 927 patients diagnosed with active psoriatic arthritis who had at least five tender and five swollen joints and C-reactive protein (CRP) levels of at least 0.3 mg/dL in spite of previous treatment with conventional therapy. PSUMMIT II also included 180 patients with previous exposure to 1-5 tumor necrosis factor (TNF) inhibitors. Results from PSUMMIT 1 showed that at week 24, 42 percent and 50 percent of patients receiving ustekinumab 45 mg and 90 mg, respectively, achieved at least 20 percent improvement in signs and symptoms according to the American College of Rheumatology criteria (ACR 20), the primary endpoint for both studies. In PSUMMIT II, 44 percent of patients receiving ustekinumab 45 mg and 44 percent of patients receiving ustekinumab 90 mg achieved ACR 20 at week 24. Additionally, ustekinumab improved soft tissue components of the disease, including dactylitis (inflammation of the finger or toe), enthesitis (inflammation of the entheses, the sites where tendons or ligaments attach to bone) and skin component as measured by Psoriasis Area and Severity Index score (PASI) 75.

The product labeling for Stelara has the following warnings and precautions:

• Infections: Serious infections have occurred. Do not start Stelara during any clinically important active infection. If a serious infection develops, stop Stelara until the infection resolves.
• Theoretical Risk for Particular Infections: Serious infections from mycobacteria, salmonella and Bacillus Calmette‐Guerin (BCG) vaccinations have been reported in patients genetically deficient in IL‐12/IL‐23. Diagnostic tests for these infections should be considered as dictated by clinical circumstances.
• Tuberculosis (TB): Evaluate patients for TB prior to initiating treatment with Stelara.
• Initiate treatment of latent TB before administering Stelara.
• Malignancies: Stelara may increase risk of malignancy. The safety of Stelara in patients with a history of or a known malignancy has not been evaluated.
• Anaphylaxis or other clinically significant hypersensitivity reactions may occur.
• Reversible Posterior Leukoencephalopathy Syndrome (RPLS): One case was reported. If suspected, treat promptly and discontinue Stelara.

Appendix

Appendix A: Examples of Clinical Reasons to Avoid Pharmacologic Treatment with Methotrexate, Cyclosporine or Acitretin

1. Alcoholism, alcoholic liver disease, or other chronic liver disease
2. Breastfeeding
3. Drug interaction
4. Cannot be used due to risk of treatment-related toxicity
5. Pregnancy or planning pregnancy
6. Significant comorbidity prohibits use of systemic agents (examples include liver or kidney disease, blood dyscrasias, uncontrolled hypertension)
   
   

Table: Brands of Targeted Immune Modulators and FDA-approved Indications:

Brand Name	Generic Name	FDA Labeled Indications
Actemra	tocilizumab	Giant cell arteritis Juvenile idiopathic arthritis Rheumatoid arthritis Systemic juvenile idiopathic arthritis Cytokine release syndrome (CRS)
Cimzia	certolizumab	Ankylosing spondylitis or axial spondyloarthritis Crohn's disease Plaque psoriasis Psoriatic arthritis Rheumatoid arthritis
Cosentyx	secukinumab	Ankylosing spondylitis Plaque psoriasis Psoriatic arthritis
Enbrel	etanercept	Ankylosing spondylitis Juvenile idiopathic arthritis Plaque psoriasis Psoriatic arthritis Rheumatoid arthritis
Entyvio	vedolizumab	Crohn's disease Ulcerative colitis
Humira	adalimumab	Ankylosing spondylitis Crohn's disease Hidradenitis suppurativa Juvenile idiopathic arthritis Plaque psoriasis Psoriatic arthritis Rheumatoid arthritis Ulcerative colitis Uveitis
Ilaris	canakinumab	Periodic fever syndromes   Systemic juvenile idiopathic arthritis
Ilumya	tildrakizumab-asmn	Plaque psoriasis
Inflectra	infliximab	Ankylosing spondylitis Crohn's disease Psoriatic arthritis Plaque psoriasis Rheumatoid arthritis Ulcerative colitis
Kevzara	sarilumab	Rheumatoid arthritis
Kineret	anakinra	Cryopyrin-associated periodic syndromes Rheumatoid arthritis
Olumiant	baricitinib	Rheumatoid arthritis
Orencia	abatacept	Juvenile idiopathic arthritis Psoriatic arthritis Rheumatoid arthritis
Otezla	apremilast	Oral ulcers associated with Behçet’s Disease Plaque psoriasis Psoriatic arthritis
Remicade	infliximab	Ankylosing spondylitis Crohn's disease Psoriatic arthritis Plaque psoriasis Rheumatoid arthritis Ulcerative colitis
Rinvoq	upadacitinib	Rheumatoid arthritis
Rituxan	rituximab	Granulomatosis with polyangiitis Microscopic polyangiitis Pemphigus vulgaris Rheumatoid arthritis
Siliq	brodalumab	Plaque psoriasis
Simponi	golimumab	Ankylosing spondylitis Psoriatic arthritis Rheumatoid arthritis Ulcerative colitis
Simponi Aria	golimumab intravenous	Ankylosing spondylitis Psoriatic arthritis Rheumatoid arthritis
Skyrizi	risankizumab-rzaa	Plaque psoriasis
Stelara	ustekinumab	Crohn's disease Plaque psoriasis Psoriatic arthritis
Taltz	ixekinumab	Ankylosing spondylitis Plaque psoriasis Psoriatic arthritis
Tremfya	guselkumab	Plaque psoriasis
Tysabri	natalizumab	Crohn's disease Multiple sclerosis
Xeljanz	tofacitinib	Rheumatoid arthritis Psoriatic arthritis Ulcerative Colitis
Xeljanz XR	tofacitinib, extended release	Rheumatoid arthritis Psoriatic arthritis Ulcerative colitis

Table: CPT Codes / ICD-10 Codes / HCPCS Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
Other CPT codes related to the CPB:
71045 - 71048	Radiologic examination, chest
86359 - 86361	T cells: total count; absolute CD4 and CD8 count, including ratio; or absolute CD4 count
86480 - 86481	Tuberculosis test, cell mediated immunity antigen response measurement; [interferon-release assay (IGRA)]
86580	Skin test; tuberculosis, intradermal
96365 - 96368	Intravenous infusion, for therapy, prophylaxis, or diagnosis
96369 - 96371	Subcutaneous infusion for therapy or prophylaxis (specify substance or drug)
96372	Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
96379	Unlisted therapeutic, prophylactic, or diagnostic intravenous or intra-arterial injection or infusion
96401	Chemotherapy administration, subcutaneous or intramuscular; non-hormonal anti-neoplastic
96409 - 96411	intravenous, push technique, single or initial, or each additional
96413 - 96417	Chemotherapy administration; intravenous infusion technique
96900	Actinotherapy (ultraviolet light)
96910 - 96922	Photochemotherapy; tar and ultraviolet B (Goeckerman treatment) or petrolatum and ultraviolet B, psoralens and ultraviolet A (PUVA), photochemotherapy (Goeckerman and/or PUVA), for severe photo-responsive dermatoses requiring at least four to eight hours of care under direct supervision of the physician (includes application of medication and dressings), laser treatment for inflammatory skin disease (psoriasis); total area less than 250 sq cm, 25
Abatacept (Orencia):
HCPCS codes covered if selection criteria are met:
J0129	Injection, abatacept, 10 mg
ICD-10 codes covered for indications listed in the CPB (not all inclusive):
L40.0 - L40.9	Psoriasis
Siliq, Guselkumab (Tremfya) :
Guselkumab (Tremfya):
HCPCS codes covered if selection criteria are met:
J1628	Injection, guselkumab, 1 mg
ICD-10 codes covered if selection criteria are met:
L40.0 - L40.9	Psoriasis [for adults with moderate-to-severe chronic plaque psoriasis]
ICD-10 codes not covered for indications listed in the CPB:
K50.00 - K50.919	Crohn's disease
Infliximab:
HCPCS codes covered if selection criteria are met:
J1745	Injection, infliximab, 10 mg excludes biosimilar, 10 mg [ Remicade ]
Q5103	Injection, infliximab-dyyb, biosimilar, (Inflectra), 10 mg
Q5104	Injection, infliximab-abda, biosimilar, (Renflexis), 10 mg
Q5105 - ZA	Injection, filgrastim (G-CSF), biosimilar, 1 microgram [Zarxio]
Q5105 - ZB	Injection, filgrastim (G-CSF), biosimilar, 1 microgram [Inflicta]
Q5105 - ZC	Injection, filgrastim (G-CSF), biosimilar, 1 microgram [Renflexis]
Q5109	Injection, infliximab-qbtx, biosimilar, (Ixifi), 10 mg
ICD-10 codes covered if selection criteria are met:
L40.0 - L40.9	Psoriasis [for adults with moderate-to-severe chronic plaque psoriasis]
Tildrakizumab:
HCPCS codes covered if selection criteria are met:
J3245	Injection, tildrakizumab, 1 mg
Secukinumab (Cosentyx):
No specific code
ICD-10 codes covered if selection criteria are met:
L40.0 - L40.9	Psoriasis
Golimumab (Simponi):
HCPCS codes covered if selection criteria are met:
J1602	Injection, golimumab, 1mg for intravenous use
ICD-10 codes covered if selection criteria are met:
L40.0 - L40.9	Psoriasis
Etanercept (Enbrel):
HCPCS codes covered if selection criteria are met:
J1438	Injection, etanercept, 25 mg
ICD-10 codes covered if selection criteria are met:
L40.0 - L40.9	Psoriasis [for ages 4 and older with moderate-to-severe chronic plaque psoriasis]
Adalimumab (Humira):
HCPCS codes covered if selection criteria are met:
J0135	Injection, adalimumab, 20 mg
ICD-10 codes covered if selection criteria are met:
L40.0 - L40.9	Psoriasis [for adults with moderate-to-severe chronic plaque psoriasis]
Apremilast (Otezla):
No specific code
ICD-10 codes covered if selection criteria are met:
L40.0 - L40.9	Psoriasis
Ustekinumab (Stelara):
HCPCS codes covered if selection criteria are met:
J3357	Ustekinumab, for subcutaneous injection, 1 mg
J3358	Ustekinumab, for intravenous injection, 1 mg
Other HCPCS codes related to the CPB:
A4633	Replacement bulb/lamp for ultraviolet light therapy system, each
E0691 - E0694	Ultraviolet light therapy systems
J7500	Azathioprine, oral, 50 mg
J7501	Azathioprine, parenteral, 100 mg
J7502	Cyclosporine, oral, 100 mg
J7515	Cyclosporine, oral, 25 mg
J7516	Cyclosporine, parenteral, 250 mg
J8610	Methotrexate, oral, 2.5 mg
J9250	Methotrexate sodium, 5 mg
J9260	Methotrexate sodium, 50 mg
ICD-10 codes covered if selection criteria are met:
K50.00 - K50.919	Crohn's disease
L40.0 - L40.9	Psoriasis [for ages 12 and older with moderate-to-severe chronic plaque psoriasis] [not covered for erythrodermic psoriasis]
Certolisumab (Cimzia):
HCPCS codes covered if selection criteria are met:
J0717	Injection, certolizumab pegol 1 mg
ICD-10 codes covered if selection criteria are met:
L40.0 - L40.9	Psoriasis
Tofacitinib (Xeljanz, Xeljanz XR):
No specific code
ICD-10 codes covered if selection criteria are met:
L40.50 - L40.59	Arthropathic psoriasis
Ixekizumab (Taltz):
No specific code
ICD-10 codes covered if selection criteria are met:
L40.50 - L40.59	Arthropathic psoriasis
Risankizumab-rzaa (Skyrizi):
HCPCS codes covered if selection criteria are met:
Risankizumab-rzaa (Skyrizi) - no specific code:
ICD-10 codes covered if selection criteria are met:
L40.0 - L40.9	Psoriasis [for adults with moderate-to-severe chronic plaque psoriasis]

The above policy is based on the following references: