Biologics: Changing the Treatment Scope for Psoriasis and Psoriatic Arthritis

Improvements in psoriasis therapies over the past decade have changed the way this disease is treated and managed, including increased use of biologic therapies, which are protein-based drugs made from living cells. Biologic agents have altered the treatment landscape in the management of moderate-to-severe psoriasis and psoriatic arthritis (PsA), leading to improved prognosis, control of symptoms, and better quality of life for the millions of individuals affected. Before the first biologic for psoriasis was FDA-approved, treatment options consisted of topical agents, phototherapy, and conventional systemic agents.

Biologic Agents for Psoriasis
Psoriasis, a disease of T-cell dysregulation, is an often debilitating inflammatory condition that significantly impacts a patient’s health-related quality of life, psychological well-being, and physical and social aspects of daily living.^1,2 A population-based study found that the incidence of psoriasis in the United States is rising, as it has doubled in the past several decades.^3,4

Currently, psoriasis affects 1% to 8% of the worldwide population, depending on the country.^3,5 Psoriasis is associated with PsA, inflammatory bowel disease, cardiovascular disease, and depressive illness. The causes of psoriasis are not fully understood, though a number of risk factors are recognized, including family history and environmental risk factors, such as smoking, stress, obesity, and alcohol consumption.^5,6 PsA is an inflammatory seronegative spondyloarthropathy.

The percentage of patients with psoriasis who develop PsA ranges from as low as 6% to as high as 42%. The prevalence of PsA throughout the United States has been estimated between 0.1% to 0.25%.⁷ Biologics used to treat psoriatic diseases block T-cell receptors or block proteins in the immune system, such as tumor necrosis factor-alpha (TNF-a) or interleukins (IL)-12 and 23.⁸

Currently, there are 6 FDA-approved biologics for psoriasis and PsA. These therapies belong to 1 of 2 categories: (1) TNF-a inhibitors, including adalimumab, certolizumab pegol, etanercept, golimumab, and infliximab; or (2) the IL-12/23 monoclonal antibody, ustekinumab. These biologics are typically effective and well-tolerated in long-term studies.^9-15 Each biologic has a unique mechanism of action, dosing schedule, and route of administration (Table 1).

“In the past year, more safety data has emerged on biologic therapies and it continues to be encouraging,” said Mark Lebwohl, MD, chair, department of dermatology, Icahn School of Medicine at Mount Sinai, New York, chairman emeritus, National Psoriasis Foundation Medical Board.

Before the emergence of biologics, systemic psoriasis therapies, such as methotrexate, cyclosporine, acitretin, and mycophenolate mofetil, were used when psoriasis was too extensive for topical therapy or was refractory to topical therapy and phototherapy. However, these medications suppress the entire immune function, requiring clinicians to do routine laboratory monitoring due to the increased liver and renal toxicity, hematologic conditions (eg, anemia, pancytopenia), and myelosuppresion. Systemic therapies are also contraindicated in various clinical settings, such as pregnancy and nursing mothers and individuals with liver or kidney disease.^6,16 

Efficacy and Tolerability
Biologics have changed the therapeutic management of psoriasis, providing clinicians with the opportunity to directly target the known key mediators in the pathogenesis of this disease.1 The increasing use of biologic medications may reflect the generally high efficacy rates, relatively good safety profiles, and demonstrated improvement in quality of life.¹⁷

“We know biologics are effective,” said Steven R. Feldman, MD, PhD, Center for Dermatology Research, departments of dermatology, pathology, and public health sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina.

Gary Goldenberg, MD, assistant professor, dermatology and pathology, departments of dermatology and pathology, Icahn School of Medicine at Mount Sinai, New York, agreed that biologics are efficacious for psoriasis. He also noted that more data on TNFs has shown systemic and cardioprotective benefits. “It is time to stop looking at psoriasis as just a skin disease. It is a systemic disease as much as anything else,” he said.

Here, we examine the 6 FDA-approved agents for the treatment of psoriasis and PsA.

Adalimumab
The REVEAL [The Randomized Controlled Evaluation of Adalimumab Every Other Week in Moderate to Severe Psoriasis Trial] study was a randomized, double-blind, placebo-controlled, phase 3 trial that evaluated the safety and efficacy of adalimumab in 1212 patients with moderate-to-severe chronic plaque psoriasis over the course of 52 weeks. Patients were randomized to receive adalimumab 40 mg subcutaneously every other week or placebo for 15 weeks.

At week 16, 71% of the adalimumab group versus 7% of the placebo group achieved a ≥75 improvement in the Psoriasis Area and Severity Index (PASI) score.^1,18 In the open-label extension of the REVEAL trial, patients received adalimumab for 3 years. Patients who initially sustained PASI 75 during REVEAL maintained their improvement after both 100 and 160 weeks of continuous therapy, and a PASI 75 was achieved by 83% and 76% of patients, respectively, with no difference in the safety profile from the original trial.^1,19

The efficacy of adalimumab was also shown in the treatment of PsA, according to 2-year data from the ADEPT [Adalimumab Effectiveness in Psoriatic Arthritis Trial] study. Patients with PsA who completed a 24-week, double-blind study of adalimumab versus placebo were eligible to enroll in an open-label, extension study and receive adalimumab 40 mg subcutaneously every other week for up to an additional 120 weeks.

After 24 weeks of double-blind treatment, the mean change in modified total Sharp Score (mTSS) was −0.2 for the 144 patients in the adalimumab group and 1 for the 152 patients in the placebo group. Compared with the 24-week responses, inhibition of radiographic progression and improvements in joint disease were maintained, with >20% of patients achieving the strict criterion of PASI 100.²⁰

Certolizumab Pegol
Certolizumab pegol is the most recent FDA-approved biologic treatment. Approval for certolizumab pegol for active PsA was based on data from the RAPID-PsA study, an ongoing, phase 3, multicenter, randomized, double-blind, placebo-controlled trial designed to evaluate the safety and efficacy of certolizumab pegol in 409 patients with active and progressive adult-onset PsA. Patients were randomized to receive placebo, or a loading dose of 400 mg certolizumab pegol at weeks 0, 2, and 4 followed by either certolizumab pegol 200 mg every other week or certolizumab pegol 400 mg every 4 weeks. Patients were evaluated for signs and symptoms of PsA using the American College of Rheumatology 20% (ACR20) response at week 12 and for structural damage using mTSS at week 24.²¹

ACR20 response at week 12 was significantly greater in patients treated with certolizumab pegol 200 mg every other week and certolizumab pegol 400 mg every 4 weeks than placebo (58% and 51.9% vs 24.3%, respectively). Patients treated with certolizumab pegol 200 mg every other week demonstrated greater reduction in radiographic progression compared with placebo-treated patients at week 24, as measured by change from baseline in mTSS. Patients treated with certolizumab pegol 400 mg every 4 weeks did not demonstrate greater inhibition of radiographic progression at week 24 compared with placebo-treated patients.²¹

Etanercept
The long-term efficacy and safety of etanercept has been evaluated in the treatment of psoriasis and PsA. The CRYSTEL [Clinical Randomized Year-Long Study Assessing the Safety and Efficacy of Etanercept in Psoriasis] study demonstrated that both continuous and intermittent etanercept treatment regimens improved PASI scores and quality of life.

In the 54-week, open-label study of patients with moderate-to-severe plaque psoriasis, the results found both treatment groups had significant improvement in PASI scores from baseline to week 54 (68% and 59%, respectively).^1,22-24

Etanercept efficacy in PsA was evaluated in an open-label, extension study in which 169 patients continued treatment with etanercept 25 mg twice weekly for up to 48 weeks. The results showed that ACR20 and PASI 50 were met by 64%, 84%, and 62%, respectively, of patients initially assigned to etanercept at the end of the 48-week, open-label period. Patients originally assigned to etanercept maintained an inhibition of radiologic progression for up to 2 years of treatment (mean adjusted change in mTSS, −0.38 from baseline to 2 years).^22,25

Golimumab
The 24-week efficacy and safety of golimumab in PsA was assessed in the GO-REVEAL [Golimumab—A Randomized Evaluation of Safety and Efficacy in Subjects with Psoriatic Arthritis Using a Human Anti-TNF Monoclonal Antibody] trial. The phase 3, multicenter, randomized, double-blind, placebo-controlled study randomized patients to receive placebo, golimumab 50 mg, or golimumab 100 mg every 4 weeks through week 20. Among the 74% of patients in whom at least 3% of the body surface area was affected by psoriasis at baseline, the results showed that 40% of those in the golimumab 50 mg group and 58% of those in the golimumab 100 mg group had at least 75% improvement in the PASI at week 14 compared with 3% of placebo-treated patients.²⁶

Infliximab
The phase 3 EXPRESS [European Infliximab for Psoriasis (Remicade) Efficacy and Safety Study] trial assessed the efficacy and safety of continuous treatment with infliximab in patients with moderate-to-severe plaque psoriasis. Patients were randomized to receive infusions of either infliximab 5 mg/kg or placebo at weeks 0, 2, and 6, then every 8 weeks to week 46. The results showed that 61% and 45% of infliximab-treated patients achieved PASI 75 and PASI 90, respectively, at 50 weeks.^1,27

The randomized, double-blind, placebo-controlled, multicenter, phase 3 IMPACT 2 [Induction and Maintenance Psoriatic Arthritis Clinical Trial 2] trial evaluated the efficacy of infliximab in 200 adult patients with active PsA for at least 6 months who had inadequate response to disease-modifying antirheumatic drugs (DMARDs) or nonsteroidal anti-inflammatory drugs (NSAIDs). During the 24-week, double-blind phase, patients received either infliximab 5 mg/kg or placebo at weeks 0, 2, 6, 14, and 22. At week 24, all placebo-treated patients crossed over to infliximab induction. Dosing continued for all patients through week 46. Treatment with infliximab resulted in improvement in signs and symptoms with 58% of infliximab-treated patients achieving ACR20 at week 14. At 6 months, the ACR20/50/70 responses were achieved by 54%, 41%, and 27%, respectively, of patients receiving infliximab.¹³

Ustekinumab
Recently published data from the PHOENIX 1 [Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Trial Evaluating the Efficacy and Safety of CNTO 1275 in the Treatment of Subjects with Moderate to Severe Plaque-type Psoriasis] study found that through 5 years of continuous treatment, ustekinumab demonstrated stable clinical response consistent with previous reports. Patients were randomly assigned to receive ustekinumab 45 mg or 90 mg at weeks 0 and 4, then every 12 weeks or placebo; placebo patients crossed over to ustekinumab at week 12. Clinical response through week 244 was evaluated using PASI scores in the overall population, initial responders, and partial responders.²⁸

Initial clinical response was generally maintained through week 244 for patients receiving 45 mg and 90 mg (PASI 75: 63.4% and 72%, respectively; PASI 90: 39.7% and 49%, respectively; PASI 100: 21.6% and 26.4%, respectively). Similarly, PASI 75 responses were generally maintained among initial responders receiving 45 mg and 90 mg (79.1% and 80.8%, respectively) and partial responders (57.6% and 55.1%, respectively).²⁸

Ustekinumab was also proven effective for PsA, according to 1-year data from the PSUMMIT 1 [Phase 3 Multicenter, Randomized, Double-blind, Placebo-controlled Trial of Ustekinumab, a Fully Human Anti-IL-12/23p40 Monoclonal Antibody, Administered Subcutaneously, in Subjects with Active Psoriatic Arthritis] trial. The study included 615 adult patients with active PsA for ≥6 months despite treatment with NSAID or DMARD therapy. Patients were randomized to receive ustekinumab 45 mg, ustekinumab 90 mg, or placebo at weeks 0 and 4 and then every 12 weeks thereafter. At week 24, all remaining patients in the placebo group received ustekinumab 45 mg, which they continued at week 28 and then every 12 weeks. The results showed that more patients taking ustekinumab 45 mg and 90 mg achieved ACR20 at week 24 compared with the placebo group (42.4% and 49.5% vs 22.8%, respectively); responses were maintained at week 52.²⁹

Overall, the most commonly reported adverse events were mild and did not result in discontinuation of therapy (Table 2).^9-14,30

Because there are adverse events associated with biologic therapy, clinicians should prescreen patients before initiation and continue monitoring patients during and after treatments.

Toll of Biologic Therapy
A top concern of biologic therapy is the cost. The drug costs for treating psoriasis in the United States continue to increase, with a major contribution from biologics. Annual costs of biologics exceed those of other available therapies for psoriasis. The total cost for the first year of treatment ranged from $23,000 to $33,000. The comparison of annual costs for biologics for psoriasis was $26,862 for etanercept, $23,639 for infliximab, $23,538 for adalimumab, and $33,576 for ustekinumab.^1,31,32

A meta-analysis was completed that analyzed the incremental cost-effectiveness ratio per patient achieving PASI 75 for etanercept, adalimumab, infliximab, and ustekinumab 45 mg and 90 mg. The corresponding 6-month incremental cost-effectiveness ratio regarding PASI 75 was $32,643, $21,315, $27,782, $25,055, and $46,630, respectively. The researchers concluded that clinicians and policymakers should consider the efficacy and cost-effectiveness in addition to patients’ values and characteristics when deciding how to efficiently allocate resources for treating psoriasis.³²

The cost of biologics is also a consideration for patients. One study found that patients with lower income levels had increased cutbacks in personal expenses due to copayments. Furthermore, the mean annual out-of-pocket expense for current biologics was $557.12 per year, with a range of $0 to $7000.¹⁷

Education Is Vital
Education is an important component in biologic therapy for both clinicians and patients. Dr. Goldenberg recommended that physicians continue to be educated on the efficacy and safety of biologic therapy so they can educate patients. “Biologics are the gold standard, and it is important for physicians to know how to use all the drugs,” said Dr. Goldenberg.

“When deciding on an appropriate biologic therapy, I think it is helpful to inform patients of the advantages and disadvantages of the reasonable options, then let them choose,” said Dr. Feldman. “If they prefer that the [physician] chooses, the efficacy, safety, cost, and other practical issues should be considered.” Clinicians also need to factor in “patient comorbidities and determine if biologic therapy will improve or worsen these comorbidities,” added Dr. Lebwohl.

In a Web site-based survey that examined patient satisfaction with current treatment options for psoriasis, patients receiving biologic therapy were significantly more satisfied. Overall, patients rated treatment
effectiveness as most important, followed by treatment safety and doctor–patient communication.³⁴

In a separate study, researchers conducted a survey of 106 psoriasis patients at an academic medical center to discern patient attitudes toward biologics. The survey found that 62.6% of respondents were “very satisfied” with biologics, and 74.5% learned about biologics from their physician. When asked about concern that biologic medications will cause an adverse event, 57.5% of patients responded, “not worried at all.” The survey also found that compliance rates for biologic therapy was high, with 66.6% of respondents reporting “never” or “rarely” missing a dose.¹⁷

Biologics in the Pipeline
Many novel therapies are currently in the pipeline, ranging from developmental stages to clinical trials, that target various cytokines and regulatory molecules involved in the pathogenesis of psoriasis. Several new drugs that specifically target IL-23, such as guselkumab and tildrakizumab, are under development.³

One class of drugs coming close to approval is IL-17 receptor blockers, according to Bruce E. Strober, MD, PhD, during his presentation on psoriasis at the American Academy of Dermatology winter meeting. “There are 3 [IL-17 inhibitors] that will effectively shutdown psoriasis in the large percentage of patients with moderate-to-severe disease,” he said. These drugs include brodalumab, ixekizumab, and secukinumab.

Brodalumab is a human monoclonal antibody targeting the IL-17 receptor that inhibits binding of most of the IL-17 subtypes to the receptor. Phase 3 data from the AMAGINE-1 study of brodalumab in 661 patients with moderate-to-severe plaque psoria`sis appears promising. Results showed that 83.3% of patients in the 210 mg group and 60.3% of patients in the 140 mg group achieved PASI 75 responses compared with placebo (2.7%). Findings also showed that 70.3% of patients in the 210 mg group and 42.5% of patients in the 140 mg group achieved PASI 90 responses compared with placebo (0.9%). Furthermore, 41.9% of patients in the 210 mg group and 23.3% of patients in the 140 mg group achieved PASI 100 responses compared with placebo (0.5%).³⁵

Results of a phase 2 trial of ixekizumab (n=142), a humanized immunoglobulin (Ig) G4 monoclonal antibody against IL-17A, found that PASI scores were significantly improved versus placebo. At 12 weeks in the 150 mg group, patients achieving PASI 75, 90, and 100 were 82.1%, 71.4%, and 39.3%, respectively.^3,34

A third agent, secukinumab was developed as a human IgG1 monoclonal antibody to IL-17A. Phase 2 trials including 404 patients showed PASI 75 rates of >50% and >40% in the early and monthly dosing regimens, respectively, both significantly improved from placebo (P<.001).³

“The more options there are, the better we can take care of our patients,” said Dr. Goldenberg.—Eileen Koutnik Fotopoulos

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Adapted from an article in The Dermatologist’s 2014 Special Issue: Beyond Biologics.