Safety and Efficacy of ABT-874, a Fully Human Interleukin 12/23 Monoclonal Antibody, in the Treatment of Moderate to Severe Chronic Plaque Psoriasis:  Results of a Randomized, Placebo-Controlled, Phase 2 Trial FREE

Psoriasis is a common T-cell–mediated systemic inflammatory disease affecting approximately 2% of adults, although the global and racial prevalence varies widely.^1- 3 Psoriasis has a major effect on quality of life^4- 6 and is associated with a number of psychological and psychosocial problems.^7- 8 Although traditional systemic therapies for the treatment of psoriasis are effective, their long-term use is frequently limited because of adverse effects.^9- 10 In addition, many patients with psoriasis are dissatisfied with traditional therapies,^1,11 and a substantial number of patients with moderate to severe disease are not receiving systemic therapy; thus, there is a clear need for therapies that are safer, easier to use, cost-effective, and able to be prescribed on a long-term basis.

Interleukin 12 (IL-12) and the related cytokine IL-23 are members of the IL-12 superfamily of cytokines that share a common p40 subunit.¹² These cytokines are central mediators of adaptive immune function.¹² Both cytokines contribute to the development of the type 1 T-helper cell (T_H1) immune response in psoriasis, but each has a unique role.^13- 15 Interleukin 12 primarily stimulates differentiation of T_H1 cells and subsequent secretion of interferon-γ, whereas IL-23 preferentially stimulates differentiation of naive T cells into effector T-helper cells (T_H17) that secrete IL-17, a proinflammatory mediator.^13,16- 17 Cytokines downstream of IL-23 and IL-17, specifically IL-22, may be a central determinant in not only the inflammation but also the cutaneous changes in psoriasis. The overexpression of IL-12 p40 and IL-23 p40 messenger RNA in psoriatic skin lesions and the recent identification of common variants in 2 genes (IL-12B [OMIM 161561] and IL-23R [OMIM 607562] that are associated with a greater risk for psoriasis in white individuals of European descent suggest that inhibition of IL-12 and IL-23 with a neutralizing antibody to the IL-12/23 p40 subunit protein may offer an effective therapeutic approach for the treatment of psoriasis.^15,18- 21

Recent phase 1 and 2 studies have suggested that targeting IL-12/23 p40 with monoclonal antibody therapy may be efficacious in psoriasis.^22- 23 The objective of the current trial was to demonstrate the efficacy and safety of a range of doses of a human IL-12/23 monoclonal antibody (ABT-874) compared with placebo in the treatment of patients with clinically stable moderate to severe chronic plaque psoriasis.²⁴

This was a 12-week, multicenter, randomized, double-blind, phase 2, placebo-controlled trial that was conducted at 24 North American centers, 16 in the United States and 8 in Canada. ABT-874 (Abbott Laboratories, Abbott Park, Illinois) is a recombinant, exclusively human-sequence, IgG1 monoclonal antibody with genetically engineered complementarity-determining regions that have high affinity for the IL-12/23 p40 subunit protein. Study medication or matching placebo was provided as a subcutaneous solution for injection. Patients were randomized in a 1:1:1:1:1:1 ratio in groups of 30 to receive 1 of 6 treatments with ABT-874: one 200-mg dose at week 0 (200 mg × 1); 100 mg every other week (EOW) for 12 weeks; 200 mg weekly for 4 weeks (200 mg × 4); 200 mg EOW for 12 weeks; 200 mg weekly for 12 weeks; or placebo. After week 12, all patients who achieved at least a 75% reduction in Psoriasis Area and Severity Index (PASI 75) response continued into a 36-week blinded observation/retreatment phase. The results of this latter portion of the study will be reported later, once data become available.

The study protocol was approved by an independent ethics committee or institutional review board at each of the study sites. The study was conducted in accordance with International Committee on Harmonisation, Good Clinical Practice, and Food and Drug Administration guidelines for clinical trials and the ethical principles that have their origin in the Declaration of Helsinki. Each investigator ensured that the study complied with local laws and customs. Each patient provided written informed consent (a statement about agents available for their condition by prescription outside the clinical trial was included) before any study-related procedures were initiated.

Eligible patients were 18 years or older with a clinical diagnosis of psoriasis for at least 6 months (determined by patient interview and confirmation of diagnosis through physical examination by the investigator), stable plaque psoriasis for at least 2 months before screening and at baseline visits as determined by subject interview, moderate to severe plaque psoriasis defined by involvement of 10% or more body surface area at the baseline visit, a PASI score of 12 or higher at the baseline visit, and a physician's global assessment (PGA) of at least moderate disease at the baseline visit.

Patients were ineligible if they had previous exposure to systemic or biologic anti–IL-12 therapy; had nonplaque psoriasis; or were unable to discontinue topical psoriasis therapies at least 2 weeks before, UV-B light phototherapy at least 2 weeks before, psoralen–UV light phototherapy at least 4 weeks before, systemic therapies at least 4 weeks before, and biologic therapies at least 12 weeks before the baseline visit. Also excluded were patients who required intake of oral or injectable corticosteroids during the study (inhaled corticosteroids for stable medical conditions were allowed); had an exacerbation of asthma requiring hospitalization in the 10 years before screening; or had a poorly controlled medical condition, such as uncontrolled diabetes with documented history of recurrent infections, unstable ischemic heart disease, congestive heart failure, recent cerebrovascular accidents, and any other condition that in the opinion of the investigator would put the patient at risk by participation in the study. Patients who had an infection or risk factors for severe infection, had a history of malignant neoplasms other than successfully treated basal cell carcinoma (patients with a history of squamous cell carcinoma were excluded) or cervical carcinoma in situ, or had a history of major immunologic reaction (eg, serum sickness or anaphylactoid reaction) to an IgG-containing agent (eg, intravenous immune globulin, a fusion protein, or monoclonal antibody) were also excluded. The following baseline laboratory values were also exclusion criteria: hemoglobin less than 10 g/dL in women or less than 12 g/dL in men; white blood cell count less than 3000/μL; platelet count less than 100 000/μL; serum aspartate aminotransferase or alanine aminotransferase greater than or equal to 1.5 times the upper limit of normal; serum total bilirubin of 1.5 mg/dL or more; or serum creatinine of 1.6 mg/dL or more. (To convert hemoglobin to grams per liter, multiply by 10; to convert bilirubin to micromoles per liter, multiply by 17.104; and to convert creatinine to micromoles per liter, multiply by 88.4.)

Patients were allowed to continue treatment with medicated shampoos that did not contain corticosteroids, bland (without β- or α-hydroxy acids) emollients, or class VI or VII low-potency topical corticosteroids on their palms, soles, face, inframammary area, or groin area during the course of the study. Application of these topical psoriasis therapies was disallowed within 24 hours of a study visit. Vaccination with a live viral agent was not allowed within 1 month before dosing with study drug, during the study, or for 1 month after the last dose of study drug was administered.

Occurrence of any of the following clinically significant abnormal laboratory results led to immediate withdrawal of a patient from the study: aspartate aminotransferase or alanine aminotransferase level more than 5 times the upper limit of normal; serum total bilirubin level more than 3 times the upper limit of normal; serum creatinine level more than 3 times the upper limit of normal; creatine phosphokinase more than 5 times the upper limit of normal; hemoglobin level less than 8 g/dL; white blood cell count less than × 10⁹ 2000/μL; or platelet count less than 75 × 10³/μL. (To convert white blood cell count to × 10⁹ per liter, multiply by 0.001; to convert platelet count to × 10⁹ per liter, multiply by 1.)

The primary efficacy end point was the percentage of patients achieving at least PASI 75 response at week 12. The PASI is a measure of the severity of psoriatic lesions (in terms of erythema, induration, and desquamation) and the extent of body surface area involvement. The PASI score ranges from 0 (no psoriasis) to 72 (severe disease).²⁵ Other efficacy measures included the percentage of patients who achieved at least a PASI 75 response at weeks 1, 2, 4, and 8; the percentage of patients who achieved at least a PASI 50 or PASI 90 response at weeks 1, 2, 4, 8, and 12; and the percentage of patients who attained a PGA of “clear” or “minimal” at week 12 and at weeks 1, 2, 4, and 8. The PGA measures the severity of disease on a 6-point scale, which ranges from 0 (no disease, or clear) to 5 (very severe).²⁶

Adverse events (AEs), laboratory data, and vital signs were assessed throughout the study. Patients were closely monitored for signs of infection, malignancy, and immunologic reaction. Treatment-emergent AEs were defined as events that occurred between week 0 and the earlier of 45 days after the last nonmissing study drug dose or 1 day before the first retreatment dose (for patients continuing on to the 36-week trial).

With the assumption that 15% of the patients in the placebo group would achieve a PASI 75 response at week 12, the study designers determined that a sample size of 26 in each dosage group would be adequate to detect at least a 45% difference from a treated group by means of the Fisher exact test with 90% power at a 2-sided significance level of .05 (nQuery Advisor 4.0; Statistical Solutions, Saugus, Massachusetts). The study was designed to enroll approximately 180 patients, with 30 patients in each group.

The intention-to-treat population included all patients who were randomly assigned at week 0 and received at least 1 injection of study drug; this population was used for the efficacy analyses. All tests were performed at α = .05. Nonresponder imputation was used in the efficacy analyses; any patient with a missing PASI or PGA score at a visit was considered a nonresponder at that visit. To assess the effect of the missing data, a sensitivity analysis of week 12 data was completed by the last-observation-carried-forward method. The statistical comparisons of the treatment difference in PASI 75 response were conducted in the following sequential order to adjust for multiplicity: 200 mg weekly vs placebo, 200 mg EOW vs placebo, 100 mg EOW vs placebo, 200 mg × 4 vs placebo, and 200 mg × 1 vs placebo. The treatment difference between each ABT-874 treatment group and the placebo group for mean percentage change in PASI score was assessed by means of analysis of variance, with baseline PASI score and treatment group as factors. The safety analyses were conducted with the use of the safety population, which included all patients who received at least 1 injection of study drug.

A total of 180 patients were enrolled and randomly assigned to 1 of the 6 treatment groups (Figure 1). The first randomized visit occurred on November 21, 2005, and the last week 12 visit was on June 23, 2006. Most of the patients (77% of placebo-treated patients and 98% of all ABT-874 treatment group patients) completed the 12-week portion of the study.

Patients were well balanced across treatment groups with respect to demographic characteristics and disease activity (Table 1). Patients were predominantly male (74.4%) and white (92.2%). Mean body surface area involvement was 25% and mean PASI score was 18.8. Of the 180 patients, 52 (28.9%) had a history of psoriatic arthritis.

The percentage of patients achieving the primary end point of PASI 75 response at week 12 was statistically significantly greater (P < .001) in all of the ABT-874 treatment groups than in the placebo group (Table 2). The PASI 75 responses in all ABT-874 treatment groups were similar, with the exception of the 200 mg × 1 treatment group (Figure 2).

A subgroup analysis by demographics (sex, age, race, and weight), baseline disease characteristics (history of psoriatic arthritis, body surface area, and PASI score), and baseline therapy for psoriasis within 12 months of receiving study treatment (systemic biologic and nonbiologic, topical, and phototherapy) demonstrated consistent results for ABT-874–treated patients within the various subgroups at week 12 (data not shown).

Most of the patients in the ABT-874 dosage groups attained at least a PASI 50 response by week 12 (P < .001 for each difference compared with placebo). The percentage of patients achieving at least a PASI 90 response at week 12 was statistically significantly greater (P < .001) in all but 1 (200 mg × 1) of the ABT-874 treatment groups when compared with placebo. By week 12, significantly more (P < .001) patients in all ABT-874 treatment groups had attained a “clear” or “minimal” PGA rating than patients in the placebo group (Table 2).

The mean percentage improvement in PASI scores from baseline increased over time for all ABT-874 treatment groups (Figure 3) and were statistically significantly greater for each ABT-874 treatment group compared with placebo at each time point (P < .001, except for the 100 mg EOW group at week 1, P = .02).

Therapy with ABT-874 was generally well tolerated (Table 3). Of the 150 patients treated with ABT-874, 1 (0.7%) discontinued the study owing to a localized skin discoloration; 2 (7%) of the 30 patients treated with placebo discontinued the study, 1 for psoriatic arthropathy and 1 for ovarian cancer. Two of 180 patients (1.1%) experienced serious AEs; 1 placebo-treated patient was diagnosed as having ovarian cancer on day 37, and 1 ABT-874–treated patient (200 mg × 1) was diagnosed as having costal chondritis on day 10. No patients experienced myocardial or cerebral infarctions, there were no opportunistic or other serious infections, and there were no deaths.

Patients receiving any dose of ABT-874 were significantly (P = .03) more likely than patients receiving placebo to experience an AE at least possibly related to study drug (ABT-874, 36.0% [54 of 150]; placebo, 10% [3 of 30]; Table 3); most of these AEs were related to the injection site (injection-site reaction, erythema, pruritus, or irritation).

Most AEs were mild: mild AEs occurred in 46.0% (69 of 150) of ABT-874–treated patients and 30% (9 of 30) of placebo-treated patients. The most common AE was injection-site reaction, occurring in 16.7% (25 of 150) of patients treated with any dose of ABT-874 (no reported injection-site reactions for placebo-treated patients; P = .03; Table 4). There were no statistically significant differences between the incidences of other AEs in the ABT-874–treated patients compared with placebo-treated patients. The next most frequently reported AEs were nasopharyngitis and upper respiratory tract infection.

Infectious AEs were reported by 32.8% (59 of 180) of all patients (placebo, 23.3% [7 of 30]; all ABT-874–treated patients, 34.7% [52 of 150]). The most common infectious AEs reported for any ABT-874 treatment group were nasopharyngitis (12.0% [18 of 150]), upper respiratory tract infection (10.7% [16 of 150]), and bronchitis and viral infection (both 2.7% [4 of 150]). On the basis of the Cochran-Armitage trend test, there was no statistically significant trend for more infectious AEs occurring in patients treated with the higher dosages of ABT-874 compared with placebo-treated patients (P = .08). No serious infectious AEs or opportunistic infections (including tuberculosis) were reported.

Two patients reported malignant neoplasms during the study. One placebo-treated patient was diagnosed as having ovarian cancer, which was ongoing as of day 129. One ABT-874–treated patient (200 mg × 4) was diagnosed as having a nonmelanoma skin cancer (squamous cell carcinoma) that was removed on day 133.

There were no clinically significant changes in hematologic measures, blood chemistry (including blood glucose concentrations), or vital signs compared with placebo.

This phase 2, multicenter, randomized, double-blind, placebo-controlled trial demonstrated statistically and clinically significant efficacy of ABT-874 in the treatment of moderate to severe chronic plaque psoriasis. Most of the patients (90%) in the ABT-874 multiple-dose groups achieved a PASI 75 or greater response by week 12, compared with 3% of placebo-treated patients. Even in the group that received a single 200-mg dose of ABT-874, 63% of patients had achieved at least a PASI 75 response by week 12. In addition, almost 100% of patients treated with ABT-874 reached a PASI 50 or greater response, an end point considered to be a clinically significant improvement,²⁷ by week 12. The results for other secondary end points, such as PASI 90 and a PGA of clear or minimal, were consistent with and supported the primary efficacy analysis.

Response to ABT-874 was rapid. Statistically significant separation between placebo- and ABT-874–treated patients occurred as early as week 1 for the mean percentage improvement in PASI scores. Improvement was sustained for the 12-week duration of the trial, even for patients in the ABT-874 200 mg × 1 and 200 mg × 4 dosage groups.

These data corroborate earlier studies of IL-12/23 as a potential target for the treatment of plaque psoriasis. In a phase 1 trial of 18 patients with moderate to severe psoriasis,²² a single dose of human monoclonal IL-12/23 p40 antibody (CNTO-1275) resulted in a dosage-dependent improvement in PASI score. These findings were confirmed in a double-blind, placebo-controlled, phase 2 trial that demonstrated dose-dependent improvements in PASI and PGA scores for patients with moderate to severe plaque psoriasis.²³ On the basis of a review of the medical literature and clinical trial registries, we believe that the current study is the only other phase 2 trial that has been reported for patients with moderate to severe psoriasis receiving the new class of human monoclonal IL-12/23 p40 antibodies. The demonstrated efficacy of ABT-874 and CNTO-1275 confirms that IL-12/23 p40 cytokines are likely to be important therapeutic targets for the treatment of psoriasis. Mechanistically, the 2 monoclonal antibodies are similar, but CNTO-1275 is a fully human IgG1, k antibody generated in human immunoglobulin transgenic mice and ABT-874 is a fully human IgG1, l antibody isolated from a human antibody phage display library and optimized in collaboration with Cambridge Antibody Technology Inc (Cambridge, England). Our findings are similar to the results of the CNTO-1275 trial. The efficacy of currently available targeted biologic therapies for the treatment of moderate to severe plaque psoriasis, including tumor necrosis factor antagonists (adalimumab, etanercept, and infliximab),^28- 30 alefacept (which selectively targets memory-effector T cells),³¹ and efalizumab (an anti-CD11a monoclonal antibody),³² show variable response (ie, PASI 75 response rates ranging from 21% to 80%) in clinical trials. Although the results for all ABT-874 dosage groups presented herein appear to compare favorably, the current study included small sample sizes for each dosage group and lacked an active comparator.

Treatment with ABT-874 was well tolerated, and most AEs were mild. Although ABT-874–treated patients were significantly more likely to experience an AE at least possibly related to study drug, most of these were injection-site–related AEs (injection-site reaction, erythema, pruritus, or irritation). There was no apparent association between an increased dose of ABT-874 and an increased incidence of AEs, although further study with larger sample sizes is warranted to further explore the possibility of a dose-related association.

Immunologic-related events are of particular interest for patients receiving anti–IL-12/23 antibodies. The most frequently reported infectious AEs were nasopharyngitis, upper respiratory tract infection, bronchitis, and viral infection. There were no serious infectious AEs reported for the duration of this trial. Of the 2 malignant neoplasms diagnosed during the study, ovarian cancer was diagnosed in a placebo-treated patient and nonmelanoma skin cancer was diagnosed in an ABT-874–treated patient. Future long-term studies and surveillance are required to evaluate the rates of rare but serious AEs.

This 12-week, placebo-controlled, multiple-dose clinical study demonstrates the statistically and clinically significant benefit of ABT-874 for the treatment of patients with moderate to severe chronic plaque psoriasis, with a good tolerability profile. Sample sizes in this phase 2 study are too small to permit reliable conclusions about efficacy and safety differences for the different dosages used. In addition, the trial was not of sufficient duration or statistically powered to detect differences in the occurrence of uncommon but serious AEs. These results underscore a pivotal role for IL-12/23 in a population of patients with psoriasis. Additional studies of ABT-874 are required to determine the optimal dosing regimen for sustained safety and efficacy in the treatment of patients with psoriasis.

Correspondence: Alexa B. Kimball, MD, MPH, Clinical Unit for Research Trials in Skin (CURTIS), Massachusetts General and Brigham and Women's Hospitals, Harvard Medical School, 50 Staniford St, No. 246, Boston, MA 02114 (harvardskinstudies@partners.org).

Accepted for Publication: July 11, 2007.

Author Contributions: Dr Kimball had full access to all of the data and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors served on the steering committee for the ABT-874 psoriasis study and were involved in the design of the study, enrollment of patients, interpretation of data, review of the manuscript, and the decision to submit the manuscript for publication. Study concept and design: Kimball, Gordon, Langley, Chartash, and Valdes. Acquisition of data: Kimball, Gordon, Langley, Menter, and Chartash. Analysis and interpretation of data: Kimball, Langley, Chartash, and Valdes. Drafting of the manuscript: Chartash. Critical revision of the manuscript for important intellectual content: Kimball, Gordon, Langley, Menter, Chartash, and Valdes. Statistical analysis: Kimball. Obtained funding: Chartash. Administrative, technical, and material support: Gordon, Langley, and Chartash. Study supervision: Menter, Chartash, and Valdes.

ABT-874 Psoriasis Study Investigators: Diane R. Baker, MD, Lake Oswego, Oregon; Chantal Bolduc, MD, Montreal, Quebec, Canada; Ellen H. Frankel, MD, Johnston, Rhode Island; Scott A. Fretzin, MD, Indianapolis, Indiana; Bernard S. Goffe, MD, Seattle, Washington; Kenneth B. Gordon, MD, Evanston, Illinois; Aditya K. Gupta, MD, London, Ontario, Canada; Tiffani K. Hamilton, MD, Alpharetta, Georgia; Michael P. Heffernan, MD, St Louis, Missouri; Alexa B. Kimball, MD, Boston, Massachusetts; James M. Krell, MD, Birmingham, Alabama; Gerald G. Krueger, MD, Salt Lake City, Utah; Richard G. Langley, MD, Halifax, Nova Scotia, Canada; Craig L. Leonardi, MD, St Louis; Catherine Maari, MD, Laval, Quebec, Canada; Robert T. Matheson, MD, Portland, Oregon; Alan Menter, MD, Dallas, Texas; Kim A. Papp, MD, Waterloo, Ontario, Canada; David M. Pariser, MD, Norfolk, Virginia; Yves P. Poulin, MD, Sainte-Foy, Quebec, Canada; Les A. Rosoph, MD, North Bay, Ontario, Canada; Pranav B. Sheth, MD, Cincinnati, Ohio; Stacy R. Smith, MD, San Diego, California; Darryl P. Toth, MD, Windsor, Ontario, Canada; Stephen K. Tyring, MD, Houston, Texas.

Financial Disclosure: Dr Kimball is or has been an investigator, speaker, and consultant for Amgen, Centocor, Abbott Laboratories, Biogen Idec, and Genentech. Dr Gordon has received honoraria and research support and has served as a consultant for Abbott Laboratories, Amgen, and Centocor. Dr Langley has served on the Scientific Advisory Board and been an investigator for Abbott Laboratories, Amgen, Astellas Pharma Inc, Boehringer Ingelheim, Centocor, and Genentech, and has received lecture fees from Abbott Laboratories, Amgen/Wyeth, Astellas Pharma Inc, Genentech, and Novartis. Dr Menter has received research support and lecture honoraria from Abbott Laboratories, Amgen, Biogen Idec, Centocor, Genentech, and Wyeth. Drs Chartash and Valdes are employees of Abbott Laboratories and hold stock and stock options in Abbott Laboratories.

Funding/Support: Abbott Laboratories funded this study and participated in the study design, data collection, data management, data analysis, data interpretation, and manuscript preparation.

Previous Presentations: This study was presented in part as oral and poster presentations at the 68th Annual Meeting of the Society for Investigative Dermatology; May 11, 2007; Los Angeles, California; as an oral presentation at the 21st World Congress of Dermatology; October 5, 2007; Buenos Aires, Argentina; and as an e-poster presentation at Academy 2007, the Summer Meeting of the American Academy of Dermatology; August 2-4, 2007; New York, New York.

Additional Contributions: Jianhau Zhong, PhD, of Abbott Laboratories, performed the statistical analysis. Jennifer Alexander, MS, MBA, of JK Associates Inc assisted in the drafting of the manuscript.