Clinical Review

Novel Psoriasis Therapies and Patient Outcomes, Part 2: Biologic Treatments

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Biologic treatments have revolutionized the management of psoriasis and psoriatic arthritis (PsA). Anti–tumor necrosis factor (TNF) α monoclonal antibodies presently are approved by the US Food and Drug Administration (FDA) for treatment of these conditions. In this article, new therapies that target this pathway and other steps in the pathogenesis of psoriasis and PsA are discussed, including IL-12/IL-23, IL-17, T-cell activation in antigen-presenting cells, regulatory T cells, toll-like receptors, and granulocyte-macrophage colony-stimulating factor. This article is the second in a 3-part series on treatments presently in the pipeline for the management of psoriasis and PsA including topical agents, biologic treatments, and systemic therapies in phase 2 through phase 4 clinical trials as well as agents that are recently FDA approved. Pivotal clinical trials, mechanisms of action, patient outcomes, and pertinent safety information will be discussed for each new therapy. As our knowledge of the underlying pathogenesis of psoriasis and PsA deepens, it enables the development of more targeted therapies in the management of these conditions.

Practice Points

  • ­Novel biologic treatments promise exciting new therapeutic avenues for psoriasis and psoriatic arthritis (PsA).
  • ­Although biologics currently in use for treatment of psoriasis and PsA are in the form of tumor necrosis factor α inhibitors, other drugs in phase 2 through phase 4 clinical trials aim to target alternative pathways underlying the pathogenesis of these disorders, including IL-12/IL-23 inhibition, IL-17 inhibition, inhibition of T-cell activation in antigen-presenting cells, regulatory T-cell activation, toll-like receptor inhibition, and granulocyte-macrophage colony-stimulating factor inhibition.
  • ­New approaches to the management of psoriasis and PsA offer patients hope for more targeted treatment regimens.


 

References

Biologic agents that currently are in use for the management of moderate to severe psoriasis and psoriatic arthritis (PsA) include the anti–tumor necrosis factor (TNF) α monoclonal antibodies adalimumab, etanercept, and infliximab1; however, additional TNF-α inhibitors as well as drugs targeting other pathways presently are in the pipeline. Novel biologic treatments currently in phase 2 through phase 4 clinical trials, including those that have recently been approved by the US Food and Drug Administration (FDA), are discussed in this article, and a summary is provided in Table 1.

Tumor Necrosis Factor α Inhibitors

Certolizumab Pegol

Certolizumab pegol (CZP; UCB, Inc), a pegylated TNF-α inhibitor, is unique in that it does not possess a fragment crystallizable (Fc) region and consequently does not trigger complement activation. The drug is presently FDA approved for active PsA, rheumatoid arthritis, and ankylosing spondylitis. One phase 2 study reported psoriasis area severity index (PASI) scores of 75 in 83% (48/58) of participants who received CZP 400 mg at week 0 and every other week until week 10 (P<.001 vs placebo).3 In a 24-week phase 3 study (known as RAPID-PsA), 409 participants were randomized into 3 study arms: (1) CZP 400 mg every 4 weeks; (2) CZP 200 mg every 2 weeks; (3) placebo every 2 weeks.4 Of note, 20% of participants had previously received a TNF inhibitor. The study demonstrated improvements in participant-reported outcomes with use of CZP regardless of prior TNF inhibitor use.4

CHS-0214

CHS-0214 (Coherus BioSciences, Inc) is a TNF-α inhibitor and etanercept biosimilar that has entered into a 48-week multicenter phase 3 trial (known as RaPsOdy) for patients with chronic plaque psoriasis. The purpose of the study is to compare PASI scores for CHS-0214 and etanercept to evaluate immunogenicity, safety, and effectiveness over a 12-week period.5 Comparable pharmacokinetics were established in an earlier study.6

Inhibition of the IL-12/IL-23 Pathway

IL-12 and IL-23 are cytokines with prostaglan-din E2–mediated production by dendritic cells that share structural (eg, the p40 subunit) and functional similarities (eg, IFN-γ production). However, each has distinct characteristics. IL-12 aids in naive CD4+ T-cell differentiation, while IL-23 induces IL-17 production by CD4+ memory T cells. IL-17 triggers a proinflammatory chemokine cascade and produces IL-1, IL-6, nitric oxide synthase 2, and TNF-α.7

Briakinumab (ABT-874)

Briakinumab (formerly known as ABT-874)(Abbott Laboratories) is a human monoclonal antibody that inhibits the p40 subunit of IL-12 and IL-23. In a phase 3 trial of 350 participants with moderate to severe psoriasis, week 12 PASI 75 scores were achieved in 80.6% of participants who received briakinumab versus 39.6% of those who received etanercept and 6.9% of those who received placebo.8 In a 52-week phase 3 trial of 317 participants with moderate to severe psoriasis, PASI 75 scores were observed in 81.8% of participants who received briakinumab versus 39.9% of those who received methotrexate.9 In another 52-week phase 3 trial of 1465 participants with moderate to severe psoriasis, clinical benefit was reported at 12 weeks in 75.9% of participants for Dermatology Life Quality Index, and 64.8% and 54.1% for psoriasis- and PsA-related pain scores, respectively.10 However, ABT-874 was withdrawn by the manufacturer as of 2011 due to concerns regarding adverse cardiovascular events.9

BI 655066

BI 655066 (Boehringer Ingelheim GmbH) is a human monoclonal antibody that targets the p19 subunit of IL-23. A phase 1 study of the pharmacokinetics and pharmacodynamics of intravenous (IV) versus subcutaneous (SC) administration of BI 655066 as well as its safety and effectiveness versus placebo recently was completed (NCT01577550), but the results were not available at the time of publication. A phase 2 study comparing 3 dosing regimens of BI 655066 versus ustekinumab is ongoing but not actively recruiting patients at the time of publi-cation (NCT02054481).

Ustekinumab (CNTO 1275)

Ustekinumab (formerly known as CNTO 1275)(Janssen Biotech, Inc) is a human monoclonal antibody that inhibits the p40 subunit of IL-12 and IL-23. It was FDA approved for treatment of moderate to severe plaque psoriasis in September 200911 and PsA in September 201312 for adult patients 18 years or older. One phase 3 trial (known as ACCEPT) compared the effectiveness of ustekinumab versus etanercept in 903 participants with moderate to severe psoriasis at 67 centers worldwide.13 Participants were randomly assigned to receive SC injections of either 45 mg or 90 mg of ustekinumab (at weeks 0 and 4) or high-dose etanercept (50 mg twice weekly for 12 weeks). At week 12, PASI 75 was noted in 67.5% of participants who received 45 mg of ustekinumab and 73.8% of participants who received 90 mg compared to 56.8% of those who received etanercept (P=.01 and P<.001, respectively). In participants who showed no response to etanercept, PASI 75 was achieved in 48.9% within 12 weeks after crossover to ustekinumab. One or more adverse events (AEs) occurred through week 12 in 66.0% of the 45-mg ustekinumab group, 69.2% of the 90-mg group, and 70.0% of the etanercept group; serious AEs were noted in 1.9%, 1.2%, and 1.2%, respectively.13 A 5-year follow-up study of 3117 participants reported an incidence of AEs with ustekinumab that was comparable to other biologics, with malignancy and mortality rates comparable to age-matched controls.14

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