A randomized, multicenter, double-blind, placebo-controlled phase 2 trial of ISA247 in patients with chronic plaque psoriasis

A randomized, multicenter, double-blind, placebo-controlled phase 2 trial of ISA247 in patients with chronic plaque psoriasis Robert Bissonnette, MD, FRCPC,a Kim Papp, MD, PhD, FRCPC,b Yves Poulin, MD, FRCPC,c Gilles Lauzon, MD, PhD, FRCPC,d Launa Aspeslet, PhD, RAC, COO,e Robert Huizinga, RN, NNC, MSc(Epi), CNeph(C),e Patrick Mayo, BSc, PhD,e Robert T. Foster, PhD, MPharm,e Randall W. Yatscoff, PhD, FCACB,e and Walter P. Maksymowych, BSc, MDChB, LMCC, MRCP, FRCPd on behalf of the ISA247 Psoriasis Study Group* Montreal, Waterloo, Que´bec City, and Edmonton, Canada Background: Use of current oral calcineurin inhibitors for the treatment of psoriasis is limited by toxicity. Objective: Evaluate the safety and efficacy of ISA247, a new oral calcineurin inhibitor, in plaque psoriasis patients. Methods: This 12-week, randomized, double-blind, placebo-controlled, parallel-group study included 201 plaque psoriasis patients with $ 10% body surface area involvement. Patients were randomized to placebo, ISA247 0.5 mg/kg/d, and ISA247 1.5 mg/kg/d groups. End points included a 2-point reduction in the Static Global Assessment score and a 75% reduction in the Psoriasis Area and Severity Index. Results: A 2-point SGA reduction was achieved in 0% (placebo), 15.6% (0.5 mg/kg/d), and 45.1% (1.5 mg/kg/d) (P \ .0001). A 75% reduction in the Psoriasis Area and Severity Index was achieved in 0% (placebo), 18.2% (0.5 mg/kg/d), and 66.7% (1.5 mg/kg/day) (P \ .0001). While serum creatinine increased in patients treated with ISA247 1.5 mg/kg/d, it remained within the normal range. Limitations: Longer-term studies are needed to evaluate the effect of ISA247 on renal function. Conclusion: ISA247 appears safe and effective for treating moderate to severe psoriasis. ( J Am Acad Dermatol 2006;54:472-8.)

P

soriasis is recognized as a complex, chronic skin condition that can have a significant impact on patients’ physical and mental health.1-4 The prevalence ranges from 0.5% to 4.6%, with an increasing prevalence in Caucasians and those living in northern latitudes.5 Though epidermal proliferation characterizes psoriasis, new treatments

From Innovaderm Research,a Montreal, Probity Medical Research,b Waterloo, Centre Dermatologique du Que´bec Me´tropolitain,c Que´bec City, University of Alberta,d Edmonton, and Isotechnika,e Edmonton. *Members of the ISA247 Psoriasis Study Group are listed in the Appendix. Funding sources: This research was funded entirely by the study sponsor, Isotechnika International Inc. Conflict of interest: Drs Yatscoff and Foster are employees of and hold shares in Isotechnika, and have applied for patents for ISA247. Dr Aspeslet is an employee of and holds shares in Isotechnika. Dr Maksymowych holds shares in Isotechnika, and has acted as a

472

Abbreviations used: ACE: BSA: CNi: ITT: PASI: SGA:

angiotensin-converting enzyme body surface area calcineurin inhibitor intention-to-treat Psoriasis Area and Severity Index Static Global Assessment

consultant for and received honoraria from Isotechnika. Dr Mayo and Mr Huizinga are employees of Isotechnika, while Dr Lauzon has acted as a consultant for Isotechnika. Drs Bissonnette, Papp, and Poulin declare no conflict of interest. Accepted for publication October 28, 2005. Reprint requests: Dr Robert Bissonnette, 1851 Sherbrooke St East, Ste 502, Montreal Qc H2K 4L5. E-mail: rbissonnette@ innovaderm.ca. Published online January 24, 2006. 0190-9622/$32.00 ª 2006 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2005.10.061

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Fig 1. Comparison of the structure of ISA247 and cyclosporine A (CsA).

targeting specific components of the immune cascade have been developed as a result of recent advances in the understanding of the immune system’s role in this disease. For example, monoclonal antibodies and fusion proteins have been approved recently in various countries for the treatment of psoriasis.6,7 Cyclosporine, a calcineurin inhibitor (CNi), is considered to be one of the treatments that has the greatest efficacy8-12 and has been in use for more than a decade to treat psoriasis patients. However, the side effect profile of cyclosporine includes nephrotoxicity, hyperlipidemia, hypertension, headaches, hirsutism, tremor, and fatigue.12-15 Nephrotoxicity remains the major limitation to the long-term use of cyclosporine in patients with psoriasis, and evidence strongly suggests that the nephrotoxicity is dosedependent.16-19 Therefore, the Food and Drug Administration labelling recommends that cyclosporine be given only to patients who are refractory to other treatments and for a duration of no longer than 1 year of continuous treatment.20 ISA247 is a novel oral CNi that differs from cyclosporine A by the addition of a modified functional group on the amino acid 1 residue (Fig 1). ISA247 has a molecular weight of 1214.63 and binds to calcineurin in a fashion similar to that of cyclosporine (Isotechnika internal data). ISA247 has demonstrated an increased potency and a more favourable side effect profile in animal models,

compared with cyclosporine.21-23 In particular, studies of ISA247 in rats, dogs, and rabbits have revealed significantly less evidence of renal toxicity than with cyclosporine.22 The primary goal of this doseranging, placebo-controlled study was to demonstrate the efficacy and safety of ISA247, compared with placebo in stable plaque psoriasis patients.

METHODS Patients Men and women 18 to75 years of age with chronic plaque psoriasis of at least 6 months duration and a body surface area (BSA) involvement of 10% or more were enrolled; patients with erythrodermic, guttate, or pustular psoriasis were excluded. Patients also were excluded if they had (1) serious local infection or systemic infection in the prior 3 months; (2) significantly abnormal hematology, blood chemistry, or urinalysis; (3) positive human immunodeficiency virus, hepatitis C virus, or hepatitis B surface antigen; (4) a history of malignancy other than basal cell carcinoma; or (5) other skin disorders that might interfere with the assessment of psoriasis. Pregnant or nursing women also were excluded. Within 28 days of the first dose and throughout the study, the only treatments allowed for psoriasis were nonelanolin-based emollients for topical treatment (excepting the target sites) and 1.0% hydrocortisone cream on the groin, armpit, scalp, palms, and soles. Each site’s ethics committee or institutional review

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Table I. Static Global Assessment score Score

0 = Absent 1 = Slight

2 = Mild

3 = Moderate

4 = Marked

5 = Severe

Definition

Cleared, except for residual discoloration Majority of lesions have individual scores for elevation, erythema, and scaling that average 1 Majority of lesions have individual scores for elevation, erythema, and scaling that average 2 Majority of lesions have individual scores for elevation, erythema, and scaling that average 3 Majority of lesions have individual scores for elevation, erythema, and scaling that average 4 Majority of lesions have individual scores for elevation, erythema, and scaling that average 5

board approved the study protocol. Each patient signed a written informed consent at the screening visit, and the study was conducted according to the Declaration of Helsinki and International Conference on Harmonization and Good Clinical Practice guidelines. Study design This was a randomized, double-blind, placebocontrolled, parallel-group study that was conducted in 12 Canadian centers. The study consisted of a single 12-week treatment course followed by a 6-week follow-up period. Patients took the study drug as oral capsules twice daily (12 hours apart). Forty-seven patients were randomized initially in a 1:2:2 ratio to receive placebo, ISA247 1.0 mg/kg/d, or ISA247 3.0 mg/kg/d. However, 3 patients experienced elevated creatinine levels early in the study, and, upon unblinding, it was found that all 3 patients were receiving ISA247 3.0mg/kg/d. Thus, the protocol was amended to reduce the dosages to 0.5 or 1.5 mg/kg/d for these patients and all new patients entering the study. Efficacy assessments The primary efficacy parameter was the percentage of patients who achieved at least a 2-point reduction in the Static Global Assessment (SGA) score calculated from baseline to the end of the 12-week treatment period. The SGA score definitions are presented in Table I. Secondary efficacy parameters included the Psoriasis Area and Severity Index (PASI),24,25 target site lesion assessment using a consistent representative plaque of psoriasis, and the percentage of BSA

involved with psoriasis. In addition to calculating mean percentage change from baseline, the percentage of patients achieving at least a 75% improvement in the PASI score at each visit after baseline was calculated. A representative plaque of psoriasis was identified at baseline and assessed for erythema, plaque elevation, scaling, and pruritus. The SGA, PASI, BSA, and target lesion scores were assessed at baseline, every 2 weeks to week 12, and 6 weeks posttreatment or at the time of withdrawal. Safety assessments All patients receiving at least 1 dose of study drug or placebo were included in the safety analysis. The incidence and severity of treatment-emergent adverse events was monitored throughout the study by measuring vital signs, and performing physical examinations, electrocardiograms, chest X-ray, and standard laboratory tests (complete blood count with differential and platelet count, complete serum chemistry panel, and urinalysis). A blood pregnancy test was administered to women at screening, baseline, and at 12 weeks. If patients were found to have a 30% or greater increase over baseline in serum creatinine, a second serum creatinine level was obtained. If the second creatinine level was increased by 30% or more over the baseline level, the patient was withdrawn. Statistical analysis The analysis of the primary efficacy end point was conducted on an intention-to-treat (ITT) basis, including those patients who completed at least 1 baseline and 1 postbaseline efficacy assessment, and had received at least 1 dose of study drug. Patients who were initially enrolled in the 1.0 and 3.0 mg/kg/d groups were analyzed in their respective end dose groups (0.5 and 1.5 mg/kg/d). A last observation carried forward analysis was used for patients who prematurely withdrew. The Cochrane-MantelHaenszel general association test stratified by pooled center was used to compare the proportion of patients achieving the primary efficacy variable, a 2-point reduction in the SGA, and for each of the following secondary efficacy variables: a 75% or greater improvement in the PASI score, compared with baseline, and a 70% or greater reduction in BSA involvement. A 2-way analysis of covariance with treatment, pooled center, and treatment-by-pooledcenter interaction was used to compare the means of the PASI score and the target lesion score between treatment groups. Chi-square tests were used to compare the differences in the number of patients reporting adverse events. A significance level of .05 was used for all analyses.

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Table II. Demographics* Parameter

Placebo (N = 41)

0.5 mg/kg ISA247 (N = 77)

1.5 mg/kg ISA247 (N = 83)

Age (y) Weight (kg) Gender (M:F) Previous phototherapy Previous systemic therapy Baseline PASI Baseline BSA

42.9 6 86.5 6 24:17 4.9% 4.9% 15.1 6 21.9 6

44.3 6 87.6 6 52:25 3.9% 9.8% 17.3 6 25.9 6

43.7 6 85.6 6 57:26 1.2% 15.6% 17.2 6 24.5 6

13.6 16.2

6.1 12.4

11.6 21.4

7.9 17.3

12.8 16.5

P value

NS NS NS NS NS NS NS

8.6 17.3

BSA, Body surface area; PASI, Psoriasis Area and Severity Index. *Mean 6 SD.

RESULTS Patients Between October 2001 and November 2002, 201 patients were randomized. Patient demographics are shown in Table II. A total of 41 patients were randomized to placebo, 77 patients to ISA247 0.5 mg/kg/d (of whom 16 initially received 1.0 mg/kg/d) and 83 patients to ISA247 1.5 mg/kg/d (of whom 19 initially received 3.0 mg/kg/d). Fifty-seven patients completed the study in the 0.5 mg/kg/d group, 53 in the 1.5 mg/kg/d group, and 26 in the placebo group. Reasons for patient withdrawal included clinical and laboratory adverse effects (23 patients, 11.4%); lack of efficacy (20 patients, 10.0%); and other reasons (8 patients, 3.9%). Four (1.9%) patients were lost to follow-up, and 3 (1.5%) patients each were withdrawn because of noncompliance or a need for prohibited treatment. Two (1.0%) patients each were withdrawn because of inappropriate enrollment or the sponsor’s request. Withdrawal in the placebo and ISA247 0.5 mg/kg/d groups were due mainly to lack of efficacy, while withdrawals in the ISA247 1.5 mg/kg/d group were due largely to laboratory abnormalities. Efficacy of treatment The proportion of patients meeting the primary efficacy outcome, a 2-point reduction in the SGA score, progressively increased from baseline for both ISA247 treatment groups, becoming statistically significant for the combined active treatment group by 4 weeks (P \ .001). This statistically significant difference continued to be seen at every visit up to week 12. By 12 weeks, 15.6% (12/77) in the 0.5 mg/kg/d group and 45.1% (37/82) of patients in the 1.5 mg/ kg/d group had achieved this efficacy end point, compared with none of the placebo-treated patients (P \.0001 for both active treatment groups). Treatment with the 1.5 mg/kg/d dose resulted in statistically significantly greater response rates than treatment with the 0.5 mg/kg/d from week 2 to week 12. The mean percentage change in the PASI

Table III. Percentage of patients with 75% PASI reduction Time point

Week Week Week Week Week

4 6 8 10 12

Placebo (N = 41)

0.5 mg/kg ISA247 (N = 77)

1.5 mg/kg ISA247 (N = 83)

P value*

0.0% 0.0% 0.0% 0.0% 0.0%

4.5% 3.2% 5.0% 11.1% 18.2%

26.5% 43.1% 56.9% 61.5% 66.7%

.013 .003 .001 \.001 \.001

*P value is based on the Cochran-Mantel-Haenszel test controlling for pooled center of success/failure response for the comparison of treatment vs placebo.

score showed dose-dependent decreases from baseline during the treatment period. At the primary end point (12 weeks), the proportion of patients achieving a 75% reduction in the PASI (PASI75) was 0% in the placebo group, 18% (10/55) in the 0.5 mg/kg/d group, and 67% (32/48) in the 1.5 mg/kg/d group (P \ .0001). Compared with placebo, a statistically significant difference was noted by 4 weeks in the 1.5 mg/kg/d group (P \ .05) and by 8 weeks in the 0.5 mg/kg/d group (P \ .05). At 6 weeks posttreatment, the mean PASI scores for both treatment groups continued to differ significantly from that of placebo patients. In both treatment groups, the percentage of patients who achieved a $ PASI75 score was seen to increase progressively to week 12 (Table III). Treatment with ISA247 (0.5 and 1.5 mg/kg/d combined) resulted in statistically significantly better scores than placebo for erythema (P # .007), plaque elevation (P # .001), scaling (P # .002), and pruritus (P # .022) beginning at week 4 and continuing at every visit to week 12. The dose-dependent nature of success with ISA247 was confirmed with 1.5 mg/ kg/d ISA247, demonstrating statistically significantly better scores (P = .000) than treatment with 0.5 mg/ kg/d ISA247 for erythema, plaque elevation, scaling, and pruritus beginning at week 4 and continuing to week 12.

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Table IV. Summary of all adverse events occurring $ 5% per group MedDRA body system preferred term

Placebo (N = 41)

26 (63.4) All body systems: no. of patients (%) with AEs Gastrointestinal 9 (22.0) disorders Nausea 3 (7.3) Diarrhea 0 (0.0) Abdominal pain 1 (2.4) Vomiting 2 (4.9) Nervous system 7 (17.1) disorders Headache 6 (14.6) Dizziness 0 (0.0) Paresthesia 0 (0.0) Infections and 8 (19.5) infestations Nasopharyngitis 6 (14.6) Investigations 0 (0.0) 0 (0.0) Chemistry, abnormal 3 (7.3) General disorders/ administration site conditions Fatigue 2 (4.9) Musculoskeletal and 3 (7.3) connective tissue disorders Back pain 1 (2.4) Respiratory, thoracic, 5 (12.2) and mediastinal disorders Vascular disorders 1 (2.4) Worsening of 0 (0.0) hypertension Skin and 1 (2.4) subcutaneous tissue disorders Eye disorders 1 (2.4) Metabolism and 1 (2.4) nutrition disorders

0.5 mg/kg/d ISA247 (N = 77)

1.5 mg/kg/d ISA247 (N = 83)

50 (64.9)

68 (81.9)

19 (24.7)

32 (38.6)

4 2 1 0 16

(5.2) (2.6) (1.3) (0.0) (20.8)

9 6 5 5 23

(10.8) (7.2) (6.0) (6.0) (27.7)

12 1 1 10

(15.6) (1.3) (1.3) (13.0)

11 6 6 12

(13.3) (7.2) (7.2) (14.5)

8 (10.4) 9 (11.7) 5 (6.5)

9 (10.8) 19 (22.9) 12 (14.5)

5 (6.5)

14 (16.9)

2 (2.6) 8 (10.4)

8 (9.6) 11 (13.3)

5 (6.5) 7 (9.1)

1 (1.2) 11 (13.3)

8 (10.4) 6 (7.8)

10 (12.0) 5 (6.0)

6 (7.8)

8 (9.6)

5 (6.5) 2 (2.6)

3 (3.6) 5 (6.0)

AE, Adverse effect.

Safety and tolerability The overall incidence of adverse events occurring in 5% or more of patients is listed in Table IV. The most commonly reported adverse events classified as drug-related were nausea (placebo, 7.3%; 0.5 mg/ kg/d, 5.2%; and 1.5 mg/kg/d, 10.8%), headache (placebo, 14.6%; 0.5 mg/kg/d, 15.6%; and 1.5 mg/ kg/d, 13.3%), and abnormal chemistry changes (placebo, 0.0%; 0.5 mg/kg/d, 6.5%; and 1.5 mg/kg/d, 14.5%). No significant changes in mean blood

Fig 2. Serial serum creatinines.

pressure or electrocardiogram abnormalities were noted during the course of the study. New-onset hypertension was not observed during the study, although a slight increase in mean blood pressure was observed in 11 subjects (6 in the 0.5 mg/kg/d group and 5 in the 1.5 mg/kg/d group) with existing hypertension. Of these, 3 patients were originally assigned to the 1.0 mg/kg/d group and 2 to the 3.0 mg/kg/d group. However, no statistically significant changes in blood pressure were observed. Laboratory parameter changes in either ISA247 group that occurred at an incidence of at least 5% more than in placebo-treated patients included urea, creatinine, low-density lipoproteins, glucose, triglycerides, potassium, and magnesium. A maximal mean increase of 13.9 mol/L in serum creatinine was observed in the 1.5 mg/kg/d group at week 6 (Fig 2). Although this difference was statistically significant, the mean values remained within the normal range. A total of 9 patients (3 on 0.5 mg/kg/d and 6 on 1.5 mg/kg/d) demonstrated a $ 30% rise in serum creatinine. Of particular interest, all 9 were concomitantly taking potentially nephrotoxic agents, with 8 patients on angiotensin-converting enzyme (ACE) inhibitors. One patient at 0.5 mg/kg/d and 4 patients at 1.5 mg/kg/d had reduced magnesium levels. Magnesium level changes were all asymptomatic, and magnesium supplementation was not required. None of the changes reported in serum lipids was found to be statistically significant, and there were no significant changes in any other laboratory parameters during the course of treatment.

DISCUSSION Cyclosporine is the most widely studied CNi in psoriasis patients.26 The main limitation for the

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long-term use of cyclosporine in the treatment of psoriasis is the risk of permanent structural renal damage,16,17,19,26 which presents a clear problem when treating a chronic disease like plaque-type psoriasis. Physicians therefore currently are using cyclosporine either to control only psoriasis flares or in a rotational approach with other treatment modalities. A small open-label study has shown that topical tacrolimus, another calcineurin inhibitor, has a very high efficacy for the treatment of facial and flexural psoriasis.27 However, improvement of trunk and limb plaques is often limited, possibly because of inadequate tacrolimus penetration. More recently oral pimecrolimus has also been shown to be efficacious for the treatment of psoriasis.28 These studies clearly show the high level of efficacy of calcineurin inhibitors in the treatment of psoriasis and suggest that there is a need for other less-toxic oral calcineurin inhibitors. The current study demonstrated the efficacy of ISA247 in the treatment of psoriasis as shown by a significant 2-point SGA reduction at 12 weeks in patients receiving 0.5 mg/kg/d, and 1.5 mg/kg/d; no patients given placebo achieved a 2-point SGA reduction at 12 weeks. Furthermore, a dose-dependent increase in the percentage of patients reaching a PASI-75 was found, with 67% in the 1.5 mg/kg/d group reaching this end point after 12 weeks of treatment. An interesting finding of the current study was the low placebo effect; no placebo-treated patient achieved a 2-point SGA reduction or reached PASI75 at week 12. This finding is in contradistinction to recently published studies with various biologic agents, in which from 4% to 14% of placebo-treated patients reached PASI75 by week 12.28-30 This difference may be explained by the fact that most patients in our study were recruited in the fall or winter, therefore minimizing the sun exposure effect on psoriasis improvement. The percentage of patients reaching a PASI75 in the current study compares very favorably with the data available from biologics that have recently been approved or that are in the process of being approved for the treatment of psoriasis. For example, the PASI75 for alefacept, efalizumab, and etancercept at week 12 was reported to be 33% (PASI75 at any time during the first course),28, 27%, and 49% respectively.29,30 In the current study, ISA247 was well tolerated by most patients. At 0.5 mg/kg/d the percentage of patients with any adverse event was similar to placebo-treated patients, and mean creatinine levels did not change. In the 1.5 mg/kg/d group, the adverse events that occurred at a higher rate than in placebo-treated patients included a significant increase in mean creatinine levels over baseline,

although these levels remained within the normal range. It should be noted that this group included patients who were enrolled initially at 3.0 mg/kg/d and whose dose was decreased. Overall, only 3 patients (3.9%) in the 0.5 mg/kg/d group and 6 patients (7.2%) in the 1.5 mg/kg/d group showed a 30% increase in creatinine over baseline, compared with a reported rate of 12% for patients treated with cyclosporine at a mean dose of 3.3 mg/kg/day for a period of 3 months.9,10 Most patients who presented a 30% increase in creatinine over baseline were on ACE inhibitors. ACE inhibitors are usually considered an option for the treatment of post-transplant hypertension; however, cases of enhanced cyclosporine nephrotoxicity also have been reported after administration of ACE inhibitors.31 The infection rate did not increase in patients treated with ISA247 during this 12-week study. De novo hypertension was not observed, and no statistically significant changes in mean blood pressure and lipid parameters were observed, compared with placebo in either ISA247 treatment group. In conclusion, treatment with ISA247 induced a statistically and clinically significant dose-dependent improvement in psoriasis severity, and it was well tolerated. Thus, future studies that would include dosage-level testing of ISA247 for efficacy and glomerular filtration rate measures for safety are warranted. The authors would like to thank Dr Luba Wolchuk and Dr Anthony Shardt for their editorial assistance throughout the preparation of this paper. REFERENCES 1. Feldman SR, Fleischer AB Jr, Reboussin DM, Rapp SR, Bradham DD, Exum ML, et al. The economic impact of psoriasis increases with psoriasis severity. J Am Acad Dermatol 1997; 37:564-9. 2. Rapp SR, Feldman SR, Exum ML, Fleischer AB Jr, Reboussin DM. Psoriasis causes as much disability as other major medical diseases. Journal of the American Academy of Dermatology 1999;41:401-7. 3. Krueger GG, Feldman SR, Camisa C, Duvic M, Elder JT, Gottlieb AB, et al. Two considerations for patients with psoriasis and their clinicians: what defines mild, moderate, and severe psoriasis? What constitutes a clinically significant improvement when treating psoriasis? J Am Acad Dermatol 2000;43:281-5. 4. Krueger G, Koo J, Lebwohl M, Menter A, Stern RS, Rolstad T. The impact of psoriasis on quality of life: results of a 1998 National Psoriasis Foundation patient-membership survey. Arch Dermatol 2001;137:280-4. 5. Lebwohl M. Psoriasis. Lancet 2003;361:1197-204. 6. Gottlieb AB, Lebwohl M, Totoritis MC, Abdulghani AA, Shuey SR, Romano P, et al. Clinical and histologic response to single-dose treatment of moderate to severe psoriasis with an anti-CD80 monoclonal antibody. J Am Acad Dermatol 2002;47:692-700. 7. Weinberg JM, Saini R, Tutrone WD. Biologic therapy for psoriasisethe first wave: infliximab, etanercept, efalizumab, and alefacept. J Drugs Dermatol 2002;1:303-10.

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8. Ellis CN, Fradin MS, Messana JM, Brown MD, Siegel MT, Hartley AH, et al. Cyclosporine for plaque-type psoriasis. Results of a multidose, double-blind trial. N Engl J Med 1991;324:277-84. 9. Ho VC, Griffiths CE, Albrecht G, Vanaclocha F, Leon-Dorantes G, Atakan N, et al. Intermittent short courses of cyclosporin (Neoral(R)) for psoriasis unresponsive to topical therapy: a 1year multicentre, randomized study. The PISCES Study Group. Br J Dermatol 1999;141:283-91. 10. Ho VC, Griffiths CE, Berth-Jones J, Papp KA, Vanaclocha F, Dauden E, et al. Intermittent short courses of cyclosporine microemulsion for the long-term management of psoriasis: a 2-year cohort study. J Am Acad Dermatol 2001;44:643-51. 11. Lebwohl M, Ellis C, Gottlieb A, Koo J, Krueger G, Linden K, et al. Cyclosporine consensus conference: with emphasis on the treatment of psoriasis. J Am Acad Dermatol 1998;39:464-75. 12. Shupack J, Abel E, Bauer E, Brown M, Drake L, Freinkel R, et al. Cyclosporine as maintenance therapy in patients with severe psoriasis. J Am Acad Dermatol 1997;36:423-32. 13. Koo J, Lee J. Cyclosporine: what clinicians need to know. Dermatol Clin 1995;13:897-907. 14. Markham T, Watson A, Rogers S. Adverse effects with longterm cyclosporin for severe psoriasis. Clin Exp Dermatol 2002; 27:111-4. 15. Paul CF, Ho VC, McGeown C, Christophers E, Schmidtmann B, Guillaume JC, et al. Risk of malignancies in psoriasis patients treated with cyclosporine: a 5 y cohort study. J Invest Dermatol 2003;120:211-6. 16. Margolis DJ, Guzzo C, Johnson J, Lazarus GS. Alterations in renal function in psoriasis patients treated with cyclosporine, 5 mg/kg/day. J Am Acad Dermatol 1992;26:195-7. 17. Powles AV, Cook T, Hulme B, Baker BS, Lewis HM, Thomas E, et al. Renal function and biopsy findings after 5 years’ treatment with low-dose cyclosporin for psoriasis. Br J Dermatol 1993;128:159-65. 18. Powles AV, Baker BS, Fry L. Reversibility of impaired renal function after long-term cyclosporin for psoriasis. Br J Dermatol 1994;131:141-2. 19. Powles AV, Hardman CM, Porter WM, Cook T, Hulme B, Fry L. Renal function after 10 years’ treatment with cyclosporin for psoriasis. Br J Dermatol 1998;138:443-9. 20. Novartis. Neoral Soft Gelatin Capsules (cyclosporine capsules, USP) MODIFIED. 2002. 21. Abel MD, Aspeslet LJ, Freitag DG, Naicker S, Trepanier DJ, Kneteman NM, et al. ISATX247: a novel calcineurin inhibitor. J Heart Lung Transplant 2001;20:161. 22. Aspeslet L, Freitag D, Trepanier D, Abel M, Naicker S, Kneteman N, et al. ISA(TX)247: a novel calcineurin inhibitor. Transplant Proc 2001;33:1048-51.

23. Maksymowych WP, Jhangri GS, Aspeslet L, Abel MD, Trepanier DJ, Naicker S, et al. Amelioration of accelerated collagen induced arthritis by a novel calcineurin inhibitor, ISA(TX)247. J Rheumatol 2002;29:1646-52. 24. Feldman SR, Fleischer AB Jr, Reboussin DM, Rapp SR, Exum ML, Clark AR, et al. The self-administered psoriasis area and severity index is valid and reliable. J Invest Dermatol 1996;106:183-6. 25. Fleischer AB Jr, Feldman SR, Rapp SR, Reboussin DM, Exum ML, Clark AR, et al. Disease severity measures in a population of psoriasis patients: the symptoms of psoriasis correlate with self-administered psoriasis area severity index scores. J Invest Dermatol 1996;107:26-9. 26. Heydendael VM, Spuls PI, Opmeer BC, de Borgie CA, Reitsma JB, Goldschmidt WF, et al. Methotrexate versus cyclosporine in moderate-to-severe chronic plaque psoriasis. N Engl J Med 2003;349:658-65. 27. Freeman AK, Linowski GJ, Brady C, Lind L, Vanveldhuisen P, Singer G, et al. Tacrolimus ointment for the treatment of psoriasis on the face and intertriginous areas. J Am Acad Dermatol 2003;48:564-8. 28. Gottlieb AB, Griffiths CE, Ho VC, Lahfa M, Mrowietz U, Murrell DF, et al. Oral pimecrolimus in the treatment of moderate to severe chronic plaque-type psoriasis: a double-blind, multicentre, randomized, dose-finding trial. Br J Dermatol 2005; 152:1219-27. 29. Gordon KB, Papp KA, Hamilton TK, Walicke PA, Dummer W, Li N, et al. Efalizumab for patients with moderate to severe plaque psoriasis: a randomized controlled trial. Jama 2003; 290:3073-80. 30. Leonardi CL, Powers JL, Matheson RT, Goffe BS, Zitnik R, Wang A, et al. Etanercept as monotherapy in patients with psoriasis. N Engl J Med 2003;349:2014-22. 31. Garcia TM, da Costa JA, Costa RS, Ferraz AS. Acute tubular necrosis in kidney transplant patients treated with enalapril. Ren Fail 1994;16:419-23.

APPENDIX Members of the ISA247 Psoriasis Study Group K. Barber, Calgary, Alberta; R. Bissonnette, Montreal, Quebec; D. Gratton, Montreal, Quebec; W. Gulliver, St. John’s, Newfoundland; A. Gupta, London, Ontario; P. Hull, Saskatoon, Saskatchewan; G. Lauzon, Edmonton, Alberta; C. Lynde, Markham, Ontario; K. Papp, Waterloo, Ontario; Y. Poulin, Sainte-Foy, Quebec; D. Toth, Windsor, Ontario.