- Email: [email protected]
The safety profile and sustained remission associated with response to multiple courses of intramuscular alefacept for treatment of chronic plaque psoriasis
The safety profile and sustained remission associated with response to multiple courses of intramuscular alefacept for treatment of chronic plaque psoriasis Janet L. Roberts, MD,a Jean-Paul Ortonne, MD,b Jerry K. L. Tan, MD,c Eileen Jaracz, PharmD,d and Ellen Frankel, MD,e on behalf of the Alefacept Clinical Study Group Portland, Oregon; Nice, France; Windsor, Ontario, Canada; Deerfield, Illinois; and Johnston, Rhode Island Background: Safety and efficacy of up to 3 courses of alefacept intramuscular (IM) in the treatment of chronic plaque psoriasis have been demonstrated in earlier trials. Objective: We sought to determine the safety and efficacy of up to 5 courses of alefacept IM in treating plaque psoriasis. Methods: A standard treatment course was defined as 15 mg of alefacept IM once weekly for 12 weeks, followed by 12 weeks of treatment-free observation. Patients with chronic plaque psoriasis, who had previously received alefacept IM, received up to 3 additional courses (A, B, and C). Efficacy was evaluated by Physician Global Assessment. Results: Safety profiles were similar to those for a single course of treatment. There were no cumulative adverse effects. At 2 weeks postdosing, 16%, 22%, and 19% of patients were rated clear or almost clear by Physician Global Assessment in courses A, B, and C, respectively, with 35%, 42%, and 42% achieving this response at any time during these courses. Patients who achieved clear or almost clear at 2 weeks postdosing remained so for a median duration of 214 and 126 days after courses A and B, respectively. Limitations: This was an extension study and therefore contained no control group. Conclusions: Up to 5 courses of alefacept IM may provide extended treatment-free, symptom-free periods in responders while maintaining the safety profile. ( J Am Acad Dermatol 2010;62:968-78.) Key words: alefacept; duration of response; open-label extension study; remission.
he chronic, protracted nature of plaque psoriasis (psoriasis vulgaris), along with its psychosocial consequences, represents a challenge in the management of extensive disease.
T
A long-term observational study of patients treated with psoralen plus ultraviolet (UV) A (PUVA) confirms that many patients with moderate to severe disease have some level of disease most of the time.1
From the Northwest Dermatology and Research Center, Portlanda; Service de Dermatologie, Hoˆpital L’Archet II, Niceb; Windsor Clinical Research Inc, Windsorc; Astellas Pharma US Inc, Deerfieldd; and Clinical Partners, LLC, Johnston.e Astellas Pharma US, Inc acquired ownership of Amevive from Biogen-Idec effective April 14, 2006, and has subsequently supported the publication of this study. Disclosure: Dr Roberts has participated in clinical trials for Biogen-Idec and is currently participating in a clinical trial for Abbott. Dr Ortonne is a speaker and consultant for Wyeth, Abbott, and Janssen-Cilag, and a speaker for Schering-Plough. Dr Tan has been a speaker and advisor for Biogen-Idec and Astellas and has conducted clinical trials for these companies. Dr Jaracz is a full-time employee of Astellas Pharma US, Inc. Dr Frankel, at Clinical Partners, LLC, is doing research for Abbott, Amgen, Astellas, Connectics, and Stiefel, and has received compensation from these companies for the trials. She is on
the speakers’ bureau for the above companies and for Collagenex and Triax. Portions of the information included in this article have been presented at the 64th Annual Meeting of the American Academy of Dermatology, San Francisco, CA, March 3e7, 2006, and at the 66th Annual Meeting of the American Academy of Dermatology, San Antonio, TX, February 1e5, 2008. Accepted for publication July 18, 2009. Reprints not available from the authors. Correspondence to: Janet L. Roberts, MD, Northwest Dermatology and Research Center, 2330 NW Flanders St, Suite 201, Portland, OR. E-mail: [email protected]. Published online April 15, 2010. 0190-9622/$36.00 ª 2009 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2009.07.032
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Despite treatment with topical agents, systemic theradditional courses of alefacept IM in patients with apies, and phototherapy, it is rare for patients to be plaque psoriasis who previously completed one or completely clear of disease. In the PUVA study two such treatment courses. Secondary objectives spanning 20 years, patients’ psoriasis did not require were to determine the efficacy of alefacept and treatment, on average, for only 1 year cumulatively.1 duration of remission, defined as continued reHowever, long-term treatment with conventional sponse without treatment, obtained with each addisystemic agents is recognized to be associated with tional treatment course. the risk of cumulative organ METHODS toxicity or morbidities that CAPSULE SUMMARY This study complied compound other diseases aswith the requirements for sociated with psoriasis, thus, Most standard treatments for chronic the conduct of clinical limiting the use of such plaque psoriasis require continuous 2,3 Biologic agents, trials as outlined by the agents. administration of medication to sustain developed to target specific International Conference response (ie, there is no potential for immunologic pathways, enon Harmonization, Good disease remission or treatment-free deavor to maximize effecClinical Practice, and other intervals). tiveness while reducing the applicable standards for the By contrast, alefacept may induce potential risk of side effects.4 protection of human subjects, Alefacept, the first biodisease remission that is sustained over confidentiality of personal logic agent approved for time. information, and integrity of treatment of psoriasis, is a clinical data. This study Alefacept is well tolerated over multiple fully human fusion protein (NCT00692172) was concourses. that is T lymphocyteedirducted from December 14, ected, with the ability to 2001, to November 30, 2004, both inhibit T-cell activation and predominantly and was prematurely terminated prior to some parinduce memory T-cell apoptosis, thereby reducing ticipating patients requiring a third treatment course pathogenic T cells in psoriatic skin.5 A distinctive for recurrence of their psoriasis. feature of treatment with alefacept is that short (12-week) periods of active treatment can produce Patients disease reduction that persists for weeks to Participants in this extension study had plaque months after treatment is discontinued.6 This psoriasis requiring systemic therapy or phototherapy characteristic offers patients with chronic, often (as determined by the investigator) before the bepersistent, disease the option to control psoriasis ginning of treatment in this study. Patients were without continuous treatment. In the pivotal phase drawn from two qualifying antecedent trials: the III clinical trial, 55 (33%) patients treated with 15 alefacept treatment arm of a randomized, doublemg of intramuscular (IM) alefacept compared with blind, placebo-controlled trial of alefacept IM,7 or its 22 (13%) patients treated with placebo achieved open-label extension trial of alefacept IM.6 Patients reduction of 75% of the baseline Psoriasis Area from the placebo arm of the double-blind, placeboand Severity Index (PASI) score during the study controlled trial were eligible to enter this trial only if (P \ .001).7 The majority of these patients they participated in the open-label extension trial. remained at a reduction of 50% of baseline PASI Thus, all patients had received at least one and (PASI 50) or greater throughout the 12-week possibly two courses of alefacept before this trial. postdosing observation period.7 For those patients Eligible patients in the two qualifying trials were who achieved reduction of 75% of baseline PASI aged 18 years or older with chronic plaque psoriasis score (PASI 75), clinical improvement of at least for longer than 12 months with involvement of 10% PASI 50 was maintained for a median duration of or more body surface area. 209 days, with a median duration of 216 days Exclusion criteria for patients included clinically without treatment.6 When symptoms of psoriasis significant abnormal hematology values; history of recurred, the lesions tended to reappear gradually, an immunosuppressive disorder; a CD41 T-cell and unlike with some other treatments, patients count at study entry of less than the lower limit of treated with alefacept typically did not experience normal (LLN) (ie, \404 cells/mm3); serious local rebound.5,7,8 infection or systemic infection within 3 months of The primary objective of this prospective, multistudy initiation; and a significant change in the national, open-label extension study was to deterpatient’s medical history since the previous study mine the safety (including antigenicity) of up to 3 with alefacept. d
d
d
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Abbreviations used: C/AC: CI: Emax: IM: LLN: MOB: PASI: PASI 50:
clear or almost clear confidence interval maximum reduction of lymphocytes intramuscular lower limit of normal mild or better Psoriasis Area and Severity Index reduction of 50% of baseline Psoriasis Area and Severity Index PASI 75: reduction of 75% of baseline Psoriasis Area and Severity Index PGA: Physician Global Assessment PUVA: psoralen plus ultraviolet A UV: ultraviolet
Treatment A standard treatment course was defined as 15 mg of alefacept IM once weekly for 12 weeks, followed by 12 weeks of treatment-free observation. Patients were eligible to receive up to 3 additional standard treatment courses (courses A, B, and C) if their disease was rated as anything except clear and CD41 T-cell counts were at or above the LLN (Fig 1). Throughout this study, treatment with the following was not permitted within 4 weeks (either before or after) of alefacept therapy: systemic retinoids, systemic steroids, systemic fumarates, methotrexate, cyclosporine, azathioprine, thioguanine, other systemic immunosuppressant agents, phototherapy (including UVB and PUVA), and other investigational treatments. Safety Safety assessments included physical examinations, complete blood cell counts, blood chemistry analyses, and anti-alefacept antibody screening. Adverse events were monitored throughout the study. Pharmacodynamics Pharmacodynamic responses were evaluated by monitoring circulating lymphocyte counts, including total, CD41, and CD81 T-cell counts. For each patient, the maximum reduction of lymphocytes (Emax) was determined from baseline to 2 weeks after the last injection for each course. The number of patients whose absolute count at the time of Emax was less than the LLN was determined. The LLN for total lymphocytes was defined in this study as 910 cells/mm3 for patients aged 58 years or younger and 800 cells/mm3 for patients aged 59 years or older, whereas those for CD41 and CD81 T lymphocytes were 404 cells/mm3 and 220 cells/mm3, respectively. Efficacy Disease status. Disease status was evaluated using a previously described 7-point Physician
Global Assessment (PGA) scale (Table I).7 Patients were monitored at study baseline, weekly during injections, monthly after courses A and B, until they were eligible for the next treatment course, and monthly until study termination after course C. Response was determined at 2 weeks after the final dose of alefacept in each course. In this study, a responder was defined as a patient who achieved a PGA rating of clear or almost clear (C/AC). Efficacy end points included the proportion of patients who achieved C/AC at 2 and 12 weeks postdosing, and the proportion of patients who achieved C/AC at any time during a treatment course. Duration of response. Duration of response, measured only for courses A and B, was the period in days for which patients remained at a PGA response level without additional treatment. Follow-up for course C was truncated as a result of study termination. Duration of response was evaluated as the time for which patients who achieved C/AC remained C/AC, and the duration for which they retained the PGA response of mild or better (MOB), without the use of phototherapy or other systemic therapy, which is a clinically meaningful end point. This duration was determined in courses A and B for two subgroups of patients who achieved the C/AC response: those who were rated C/AC at 2 weeks postdosing and those who were rated C/AC at any time during the treatment course. Time to retreatment, defined as the duration (in days) between the last dose of one treatment course and the first dose of the next treatment course, was measured for patients who achieved C/AC at 2 weeks postdosing.
Statistical methods Proportions of patients with adverse events were compared using Fisher exact test for 2 3 2 tables and x2 test with exact P values for 2 3 3 tables. Patients were included in the efficacy analysis if they had at least one dose of alefacept. Data were summarized using descriptive statistics. Time to response and duration of response were determined using Kaplan-Meier methods. Demographic data (based on the first study the patient was enrolled in) and baseline disease characteristics were summarized. Lymphocyte subsets were summarized with descriptive statistics. Patients were included in the lymphocyte analysis if they received at least one dose, and had at least one postdose measurement. Safety was summarized for patients who received at least one dose of alefacept. The incidence of coded adverse events was summarized. If a patient experienced the same adverse event more than once in an individual course, the event was counted only
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Fig 1. Study design. *Patients were drawn from two previous studies with up to two courses of intramuscular alefacept. LLN, Lower limit of normal (= 404 cells/mm3 for CD41 T-cell count); PGA, Physician Global Assessment.
once for that course. The incidence of patients with anti-alefacept antibodies was summarized.
RESULTS Patient disposition, demographics, and baseline characteristics Of the total 183 patients enrolled in the study, 175 were dosed in course A, 121 in course B, and 88 in course C (Fig 2, A). There were 51 (29%) patients dosed in course A who achieved C/AC 12 weeks postdosing, of which 36 (71%) went on to receive course B (Fig 2, B). Similarly, there were 37 (31%) patients dosed in course B who achieved C/AC 12 weeks postdosing, of which 28 (76%) continued to course C. Of those who did not achieve C/AC 12 weeks postdosing, 85 (69%) from course A and 60 (71%) from course B continued to the subsequent course (Fig 2, B). Patient demographic and baseline characteristics were similar to those reported in prior studies of patients with moderate to severe psoriasis (Table II). Baseline disease severity was moderate or worse on the PGA scale for the majority of patients (76% in course A, 66% in course B, and 65% in course C). With additional courses, baseline severity shifted to more patients with milder disease and fewer patients with more severe disease. Safety Overall, 81% of patients in course A, 79% in course B, and 65% in course C reported adverse events. Serious adverse events were reported by 5% of
Table I. Physician Global Assessment scale Score
Category
1
Severe
2
Moderate to severe
3
Moderate
4
Mild to moderate
5
Mild
6
Almost clear
7
Clear
PGA
Very marked plaque elevation, scaling, and/or erythema Marked plaque elevation, scaling, and/or erythema Moderate plaque elevation, scaling, and/or erythema Intermediate between evaluation scores 3 (moderate) and 5 (mild) Slight plaque elevation, scaling, and/or erythema Intermediate between evaluation scores 5 (mild) and 7 (clear) No signs of psoriasis (postinflammatory hyperpigmentation may be present)
PGA, Physician Global Assessment.
patients in course A, 3% in course B, and none in course C. No event was reported by more than one patient in any course. Serious adverse events included those that were medically significant or required hospitalization, for example, atrial fibrillation, cholelithiasis, hemoptysis, Hodgkin disease, leukopenia, lymphadenopathy, lymphoma, mycoplasmal tracheobronchitis, myocardial infarction,
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Fig 2. A, Overall study patient disposition. Patients discontinued treatment for the following reasons: lost to follow-up (an = 1, bn = 0, cn = 1), adverse events (an = 2, bn = 2, cn = 0), voluntary withdrawal (an = 3, bn = 1, cn = 0), and administrative reasons (an = 3, bn = 1, cn = 2). B, Patient disposition based on achieving clear or almost clear (C/AC ) 12 weeks postdosing in courses A and B.
neutropenia, and pancreatitis. Adverse events led to discontinuation of alefacept therapy in 2% of patients in course A, and none in courses B and C. The most commonly reported adverse events ( $ 5%) during all 3 courses were nasopharyngitis, influenza, upper
respiratory tract infection, arthralgia, and headache (Table III). The rate at which these adverse events occurred, including infections, did not increase with multiple treatment courses (P $ .05). There was no indication of hepatotoxicity.
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Table II. Patient demographics and baseline characteristics Course A (n = 175)
Sex, No. (%) Male 116 Female 59 Race, No. (%) White 167 Other 8 Mean age, y (SD) 45.8 Mean duration of 22 psoriasis, y (range) Median BSA, % (range) 20 PGA rating, No. (%) Moderate to 74 severe/severe Moderate 59 Mild to moderate 29 Mild/almost 13 clear/clear
(66) (34)
Table III. Most common ( $ 5% incidence) adverse events
Course B (n = 121)
Course C (n = 88)
75 (62) 46 (38)
53 (60) 35 (40)
(95) 115 (5) 6 (12.6) 45.6 (6e64) 21
(95) 85 (5) 3 (12.7) 45.3 (6e53) 23
(97) (3) (11.9) (6e48)
(1e99) 14 (1e85) 10 (2e90) (42)
35 (29)
22 (25)
(34) (17) (7)
45 (37) 25 (21) 16 (13)
35 (40) 19 (22) 11 (13)
No. (%) of patients
Any adverse event Withdrawal because of adverse event Adverse event Nasopharyngitis Influenza Upper respiratory tract infection Arthralgia Headache Cough Injection site bruising Bronchitis Hypertension Herpes simplex
Course A (n = 175)
Course B (n = 121)
Course C (n = 88)
141 (81) 4 (2)
96 (79) 1 (\1)
57 (65) 0
21 (12) 15 (9) 14 (8)
15 (12) 9 (7) 11 (9)
8 (9) 3 (3) 5 (6)
12 11 10 9 5 5 4
4 14 4 5 6 7 6
4 (5) 5 (6) 1 (1) 2 (2) 0 1 (1) 4 (5)
(7) (6) (6) (5) (3) (3) (2)
(3) (12) (3) (4) (5) (6) (5)
Adverse events are presented by decreasing incidence in course A. BSA, Body surface area; PGA, Physician Global Assessment.
On average, the time of year when each alefacept treatment course was initiated did not appear to affect the incidence of infection observed. Infections were reported by 47%, 51%, and 33% of patients in courses A, B, and C, respectively. The proportion of patients with an infection did not increase with additional courses. All infections were uncomplicated and readily controlled by conventional therapy. One serious infection, mycoplasmal tracheobronchitis, developed in a 66-year-old man 31 weeks after his last dose of alefacept; he was hospitalized for 2 days and discharged on clarithromycin. This infection was considered to be unrelated to treatment by the investigator. No opportunistic infections were reported. Overall incidence rates of infections were similar in patients whose CD41 Tcell counts ever fell below 250 cells/mm3 compared with those whose CD41 T-cell counts were always above 250 cells/mm3: 7 (44%) vs 73 (46%) patients in course A, 3 (38%) vs 58 (51%) patients in course B, and 3 (50%) vs 25 (31%) patients in courses C, respectively (P $ .05). The proportion of patients testing positive for anti-alefacept antibodies remained low (\1%-1%) throughout all courses, suggesting that multiple courses of alefacept or treatment-free intervals between courses did not elicit an immune response. Anti-alefacept antibodies were detected in only two of 175 patients at any time during the study and were of low titer in both patients. One patient tested positive for anti-alefacept antibodies in course A, but was not dosed in courses B or C. This patient had
tested negative for anti-alefacept antibodies in the antecedent qualifying trials. The other patient tested positive for anti-alefacept antibodies in all 3 courses. The incidence of malignancies was 3% or less in each of the 3 treatment courses of alefacept. Malignancies were diagnosed in 7 patients during the study. Nine nonmelanoma skin cancers (3 squamous cell and 6 basal cell carcinomas) were reported in 5 patients with a long-standing history of psoriasis (18-50 years) and prior exposure to phototherapy (PUVA, UVB, or both) and systemic immunosuppressive therapy including methotrexate and cyclosporine. Two of these 5 patients also had a history of squamous cell carcinomas. Non-Hodgkin lymphoma was diagnosed in a 68-year-old woman who had psoriasis for 64 years and had previously been treated with methotrexate, retinoids, and PUVA; the diagnosis was 72 weeks after her first dose and 2 weeks after her last dose of alefacept. A 52-year-old man with a 44-year history of psoriasis was diagnosed with Hodgkin disease 93 weeks after his first dose and 1 week after his last dose of alefacept. He had been treated with immunosuppressive agents for an extended period of time, specifically methotrexate for 180 months and cyclosporine for 6 months. Pharmacodynamics Within each course, the mean counts of circulating lymphocytes, and CD41 and CD81 T lymphocytes (Fig 3), decreased during the active treatment phase, and gradually increased during the follow-up
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Fig 3. Mean total lymphocyte, CD41, and CD81 T-cell counts during each course.
Table IV. Proportion of patients with total, CD41, and CD81 T-lymphocyte counts below the lower limit of normal Type of lymphocyte count below LLN Time point
Total
CD41
CD81
Patients, No. (%) Course A Course B Course C (n = 175) (n = 120) (n = 87)
At Emax 11 (6) 12 wk 3 (2) posttreatment At Emax 63 (36) 12 wk 19 (12) posttreatment At Emax 102 (58) 12 wk 44 (29) posttreatment
12 (10) 0
6 (7) 0
42 (35) 12 (11)
31 (36) 10 (12)
69 (58) 38 (34)
53 (61) 28 (34)
Fig 4. Proportion of patients who achieved clear or almost clear (C/AC ) across 3 treatment courses. PGA, Physician Global Assessment.
Emax, Maximum reduction of lymphocytes; LLN, lower limit of normal.
phase. The mean counts of total, CD41, and CD81 lymphocytes at Emax and at 12 weeks postdosing were not appreciably different across the treatment courses. There were no differences in total, CD41, and CD81 T-lymphocyte counts obtained by lymphocyte monitoring performed once weekly (course A) or once every 2 weeks (courses B and C). The percentage of patients with counts below the LLN at Emax and at 12 weeks after the last dose in each course was similar across courses for total lymphocytes, CD41 T lymphocytes, and CD81 T lymphocytes (Table IV). Efficacy Disease status. The proportion of patients achieving C/AC at 2 weeks postdosing was 16%,
22%, and 19% in courses A, B, and C, respectively (Fig 4). At 12 weeks postdosing (ie, end of treatment course), 29%, 31%, and 31% had a PGA of C/AC in courses A, B, and C, respectively. The proportion of patients achieving C/AC at any time during the treatment course was 35%, 42%, and 42% for courses A, B, and C, respectively. Patients across all levels of disease severity responded to alefacept. Among patients whose baseline disease severity for individual courses was rated moderate or worse, 29%, 35%, and 30% achieved C/AC during courses A, B, and C, respectively. Patients who attained C/AC in one course were eligible for the next course when they ceased to maintain this response. Of the patients who achieved C/AC in course A, 68% and 59%, respectively, achieved the same response in courses B and C. Similarly, 69% of patients who achieved C/AC in
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Fig 5. Duration of clear or almost clear (C/AC ) and mild or better (MOB) responses in patients who achieved C/AC. At 2 weeks postdosing for each course (A) and any time during treatment course (B). CI, Confidence interval; PGA, Physician Global Assessment.
course B also achieved it in course C, indicating that a majority of patients who achieved C/AC did so consistently and reproducibly over multiple courses of treatment. In addition, among patients who did not achieve C/AC in course A and received subsequent courses, 21 of 77 (27%) patients and 18 of 56 (32%) patients achieved this response in courses B and C, respectively. Similarly, 10 of 49 (20%) patients who did not achieve C/AC in course B achieved it in course C. Duration of response. Patients who achieved C/AC at 2 weeks postdosing in response to course A maintained this response for a median duration of 214 days, whereas those who achieved C/AC at 2 weeks postdosing in response to course B maintained this response for a median duration of 126 days (Fig 5, A). Furthermore, these patients remained at MOB for median durations of 340 days in response to course A and 283 days in response to course B. Patients who achieved C/AC at any time during a treatment course maintained this response for median durations of 146 days after treatment in course A
and 123 days after treatment in course B. The median duration of MOB response in these patients was 287 days after treatment in course A and 221 days after treatment in course B (Fig 5, B). Patients who achieved C/AC in response to course A were further evaluated for duration of response based on whether or not they received course B (Table V). All patients receiving course A and achieving C/AC had a longer median duration of treatment response than the subset that also received course B. Because of censoring caused by study termination prior to the patients’ requiring retreatment, the duration of response for patients who received only course A could be determined only for one of 4 response categories (Table V). Among responding patients who received only course A and achieved C/AC, the lower limits of the confidence intervals (CIs) ranged from 112 to 540 days, which was 2 to 5 times greater than the corresponding values for patients who received course B (range: 68-173 days). This may be explained by the finding that only 21 of the 28 patients who were rated C/AC at 2 weeks postdosing in course A were dosed in course B, and only 44 of the 61 patients who were rated C/AC at any time during course A were dosed in course B. Thus, patients with a positive outcome in course A may not have received course B possibly contributing to the observed shorter median duration of response in the latter course. Sustained duration of C/AC response was observed for both courses A and B in the subset of patients who achieved C/AC in both courses (Fig 6). For patients who achieved C/AC at 2 weeks postdosing in both courses (n = 11), the median duration of C/AC response was longer in course A (238 days; 95% CI: 105-488) than in course B (164 days; 95% CI: 123-225). Similar results were obtained for patients who achieved C/AC at any time during both courses (n = 30) with median duration of C/AC response being 169 days (95% CI: 105-222) for course A vs 133 days (95% CI: 119-200) for course B. The median durations at MOB for this subpopulation were similar in courses A (287 days; 95% CI: 173-399) and B (283 days; 95% CI: 221-332) for patients who responded at any time during both courses. A similar comparison could not be made for patients who responded at 2 weeks postdosing, because almost all of the patients were censored and the median duration for course B could not be estimated by Kaplan-Meier analysis. The duration of follow-up for these patients ranged from 121 to 545 days. Time to retreatment. The mean times to retreatment among patients who achieved C/AC at 2 weeks postdosing were 282 days (n = 21) after course A and 219 days (n = 17) after course B (Table VI).
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Table V. Duration of clear or almost clear and mild or better response in course A, summarized by dosing in course B Time of C/AC response
2 wk postdosing
Rating at which duration was measured
C/AC
MOB
Any time during treatment course
C/AC
MOB
No. and duration
Course A
Dosed in course B
No. (%) Censoring rate, No. (%) Median duration of response, d 95% CI, d
28 (100) 5 (18) 213.5
21 (100) 0 182.0
7 (100) 5 (71) NE
168.5e436.5
105.0e242.5
491.0eNE
28 (100) 11 (39) 340.0
21 (100) 5 (24) 330.5
7 (100) 6 (86) NE
185.5e540.0
172.5e371.0
540.0eNE
61 (100) 9 (15) 146.0
44 (100) 2 (5) 129.5
17 (100) 7 (41) 224.0
97.0e208.5
68.0e172.5
112.0e611.5
61 (100) 22 (36) 286.5
44 (100) 10 (23) 193.5
17 (100) 12 (71) NE
182.5e399.0
150.5e330.5
433.0eNE
No. (%) Censoring rate, No. (%) Median duration of response, d 95% CI, d No. (%) Censoring rate, No. (%) Median duration of response, d 95% CI, d No. (%) Censoring rate, No. (%) Median duration of response, d 95% CI, d
Not dosed in course B
C/AC, Clear or almost clear; CI, confidence interval; MOB, mild or better; NE, cannot be estimated from Kaplan-Meier curve. Duration of C/AC and MOB response was measured in patients who achieved C/AC in course A.
DISCUSSION Alefacept, a biological agent that inhibits activation of pathogenic T lymphocytes and induces their apoptosis,9,10 is exceptional in its ability to offer an extended treatment-free interval for those patients with psoriasis who experience a good response to a treatment course.4,11 When psoriasis reappears on termination of treatment, it does so without rebound flares. Furthermore, when psoriasis recurs, retreatment with alefacept appears to offer similar subsequent improvement in the majority of responders.6 The safety and efficacy of up to two courses of alefacept have previously been demonstrated in prospective, randomized, double-blind trials.6-8,12 An integrated analysis of 13 trials showed that up to 9 courses of alefacept can be safely administered to patients.13 This report presents, to our knowledge, the results of the first clinical trial designed to evaluate the safety and efficacy of up to 5 courses of alefacept for the treatment of psoriasis. Overall, up to 3 additional treatment courses of alefacept IM were safe and well tolerated in patients with plaque psoriasis. The incidence of adverse events (including infections), serious adverse events (including serious infections), discontinuations of alefacept, and study withdrawals were similar for all
courses in this study, supporting the lack of cumulative toxicity or nonspecific immunosuppressive effects. The incidence of anti-alefacept antibodies was low across all courses. In this study, the overall number of patients with malignancies was 4% (7 of 175), the majority of which were nonmelanoma skin cancers. Patients with psoriasis and a history of PUVA exposure are reported to have an increased risk of nonmelanoma skin cancers, with a relative risk of 17.6 for squamous cell carcinoma and 4.1 for basal cell carcinoma compared with the general population.14 Similarly, patients with psoriasis, especially those with a high exposure to methotrexate ( $ 36 months), are reported to have an increased risk for developing lymphoma, with an estimated 2- to 4-fold higher incidence compared with the rate in the general population.15,16 Based on these reports, the rate of malignancies observed in this study appears to be within the expected incidence rates for patients with psoriasis. Safety profiles of additional courses of alefacept were similar to those previously reported in patients receiving up to two courses of alefacept.6-8 It would be intuitive that only patients who experienced some improvement of their psoriasis without any adverse effects from a prior treatment with a therapeutic agent would participate or
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Fig 6. Duration of response in patients who achieved clear or almost clear (C/AC ) in both courses A and B at 2 weeks postdosing (A) and at any time during treatment course (B). CI, Confidence interval; MOB, mild or better; PGA, Physician Global Assessment.
Table VI. Time to retreatment among patients who achieved clear or almost clear at 2 weeks postdosing Time to retreatment, d
Mean SD Median Range
Course A (n = 21)
281.9 155.24 249.0 99e608
Course B (n = 17)
218.8 133.39 173.0 84e517
SD, Standard deviation.
continue to participate in a trial evaluating additional doses of that agent. However, interestingly, approximately 70% (69%-76% across all groups) of all patients in each of courses A and B continued to receive a subsequent course of alefacept irrespective of whether or not they derived clinical benefit from the prior course. These data suggest that selection bias of patients, if any, was minimal. Consistent with previous reports,5,9 the decrease in numbers of circulating T lymphocytes during the
active treatment phase of each course was followed by a recovery during the follow-up phase in the same course. Repeated courses of alefacept did not result in a progressive reduction in total lymphocytes, CD41 T lymphocytes, or CD81 T lymphocytes. As with previous studies, there was no increased incidence of adverse events (including infections or malignancies) in those patients whose CD41 Tlymphocyte counts ever decreased below 250 cells/mm3. These data are consistent with the selective reduction of pathogenic memory T cells by alefacept, which may help explain the absence of correlation between reduced peripheral T-lymphocyte counts and infection.9,10,17 The results of this study demonstrate that alefacept continues to be effective in up to 3 additional courses in patients who had previously received one or two treatment courses. The proportion of patients who achieved C/AC in this study was similar to that in previous studies of patients receiving up to two courses of alefacept IM,6,7 or intravenously.8 Similar proportions of patients achieved C/AC in each of the 3 courses (Fig 4). Patients who achieved C/AC in one course generally had a similar response to a subsequent course. Some patients who did not achieve C/AC in one course achieved it in a subsequent course, a result consistent with a previous report showing that among patients who did not achieve PASI 50 with one treatment course, 53% achieved PASI 50 (vs 33% in the placebo group) and 19% achieved PASI 75 (vs 8% in the placebo group) with the second course of treatment.18 Thus, additional courses of alefacept may be valuable both for patients who achieve the desired response in a course and for those who do not. In addition, patients responded to alefacept regardless of baseline disease severity. Alefacept yielded extended response times among patients who achieved C/AC in course A (214 days) and those who achieved it in course B (126 days). There was a decrease in the median duration of response in course B compared with course A, possibly, in part, because of the differences in patient populations entering each course. The initial baseline severity of psoriasis, before the first alefacept treatment course in the antecedent trials, was similar between patients who received course A and those who received course B. Course A consisted of all study participants, whereas those in course B were patients who either did not achieve C/AC in course A, or did not maintain this PGA status during the study. Thus, some of the best responders received only course A. This may also explain the shorter time to retreatment in responders after course B, compared with course A. Comparison of duration
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of response in patients who achieved C/AC at 2 weeks postdosing in both courses A and B could not be made because of censoring. Overall, these data suggest that patients who are most likely to respond well to alefacept treatment may do so with fewer courses of treatment and have longer treatment-free intervals (ie, remissions). The similarity of efficacy, safety, and pharmacodynamic profiles reported in previous studies of up to two courses of alefacept IM,6,7 and the subpopulations assessed in this study suggests that repeated courses of alefacept IM may be an effective therapeutic option for these responding patients. In conclusion, up to 5 courses of alefacept IM were safe and effective in treating plaque psoriasis. For those patients who achieved significant improvement, additional courses of alefacept yielded sustained responses with remissions of up to 7 months. Among this subset of responders, multiple courses of alefacept IM can help achieve long-term control of plaque psoriasis without requiring continuous treatment, while maintaining the safety profile. Editorial assistance in the preparation of this manuscript was provided by Sudha Srinivasan, PhD, and Mukund Nori, PhD, MBA, Envision Pharma Inc, Southport, CT. Barabara Mathes, MD, and Rita Kristy, MS, of Astellas Pharma US, Inc provided assistance in writing this manuscript. REFERENCES 1. Nijsten T, Looman CW, Stern RS. Clinical severity of psoriasis in last 20 years of PUVA study. Arch Dermatol 2007;143:111321. 2. Kazlow Stern D, Tripp JM, Ho VC, Lebwohl M. The use of systemic immune moderators in dermatology: an update. Dermatol Clin 2005;23:259-300. 3. 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. 4. Langley RG, Gupta AK, Cherman AM, Inniss KA. Biologic therapeutics in the treatment of psoriasis, part 1: review. J Cutan Med Surg 2007;11:99-122.
5. Ellis CN, Krueger GG. Treatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes. N Engl J Med 2001;345:248-55. 6. Gordon KB, Langley RG. Remittive effects of intramuscular alefacept in psoriasis. J Drugs Dermatol 2003;2:624-8. 7. Lebwohl M, Christophers E, Langley R, Ortonne JP, Roberts J, Griffiths CE. An international, randomized, double-blind, placebocontrolled phase 3 trial of intramuscular alefacept in patients with chronic plaque psoriasis. Arch Dermatol 2003;139:719-27. 8. Krueger GG, Papp KA, Stough DB, Loven KH, Gulliver WP, Ellis CN. A randomized, double-blind, placebo-controlled phase III study evaluating efficacy and tolerability of 2 courses of alefacept in patients with chronic plaque psoriasis. J Am Acad Dermatol 2002;47:821-33. 9. Gordon KB, Vaishnaw AK, O’Gorman J, Haney J, Menter A. Treatment of psoriasis with alefacept: correlation of clinical improvement with reductions of memory T-cell counts. Arch Dermatol 2003;139:1563-70. 10. Gottlieb AB, Casale TB, Frankel E, Goffe B, Lowe N, Ochs HD, et al. Cd41 T-cell-directed antibody responses are maintained in patients with psoriasis receiving alefacept: results of a randomized study. J Am Acad Dermatol 2003;49:816-25. 11. Langley RG, Gordon KB. Duration of remission of biologic agents for chronic plaque psoriasis. J Drugs Dermatol 2007;6: 1205-12. 12. Krueger GG. Clinical response to alefacept: results of a phase 3 study of intravenous administration of alefacept in patients with chronic plaque psoriasis. J Eur Acad Dermatol Venereol 2003;17(Suppl):17-24. 13. Goffe B, Papp K, Gratton D, Krueger GG, Darif M, Lee S, et al. An integrated analysis of thirteen trials summarizing the long-term safety of alefacept in psoriasis patients who have received up to nine courses of therapy. Clin Ther 2005;27:1912-21. 14. Stern RS, Liebman EJ, Vakeva L. Oral psoralen and ultraviolet-A light (PUVA) treatment of psoriasis and persistent risk of nonmelanoma skin cancer. PUVA follow-up study. J Natl Cancer Inst 1998;90:1278-84. 15. Gelfand JM, Berlin J, Van Voorhees A, Margolis DJ. Lymphoma rates are low but increased in patients with psoriasis: results from a population-based cohort study in the United Kingdom. Arch Dermatol 2003;139:1425-9. 16. Stern RS. Lymphoma risk in psoriasis: results of the PUVA follow-up study. Arch Dermatol 2006;142:1132-5. 17. Scheinfeld N. Alefacept: a safety profile. Expert Opin Drug Saf 2005;4:975-85. 18. Menter A, Cather JC, Baker D, Farber HF, Lebwohl M, Darif M. The efficacy of multiple courses of alefacept in patients with moderate to severe chronic plaque psoriasis. J Am Acad Dermatol 2006;54:61-3.
he chronic, protracted nature of plaque psoriasis (psoriasis vulgaris), along with its psychosocial consequences, represents a challenge in the management of extensive disease.
T
A long-term observational study of patients treated with psoralen plus ultraviolet (UV) A (PUVA) confirms that many patients with moderate to severe disease have some level of disease most of the time.1
From the Northwest Dermatology and Research Center, Portlanda; Service de Dermatologie, Hoˆpital L’Archet II, Niceb; Windsor Clinical Research Inc, Windsorc; Astellas Pharma US Inc, Deerfieldd; and Clinical Partners, LLC, Johnston.e Astellas Pharma US, Inc acquired ownership of Amevive from Biogen-Idec effective April 14, 2006, and has subsequently supported the publication of this study. Disclosure: Dr Roberts has participated in clinical trials for Biogen-Idec and is currently participating in a clinical trial for Abbott. Dr Ortonne is a speaker and consultant for Wyeth, Abbott, and Janssen-Cilag, and a speaker for Schering-Plough. Dr Tan has been a speaker and advisor for Biogen-Idec and Astellas and has conducted clinical trials for these companies. Dr Jaracz is a full-time employee of Astellas Pharma US, Inc. Dr Frankel, at Clinical Partners, LLC, is doing research for Abbott, Amgen, Astellas, Connectics, and Stiefel, and has received compensation from these companies for the trials. She is on
the speakers’ bureau for the above companies and for Collagenex and Triax. Portions of the information included in this article have been presented at the 64th Annual Meeting of the American Academy of Dermatology, San Francisco, CA, March 3e7, 2006, and at the 66th Annual Meeting of the American Academy of Dermatology, San Antonio, TX, February 1e5, 2008. Accepted for publication July 18, 2009. Reprints not available from the authors. Correspondence to: Janet L. Roberts, MD, Northwest Dermatology and Research Center, 2330 NW Flanders St, Suite 201, Portland, OR. E-mail: [email protected]. Published online April 15, 2010. 0190-9622/$36.00 ª 2009 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2009.07.032
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Despite treatment with topical agents, systemic theradditional courses of alefacept IM in patients with apies, and phototherapy, it is rare for patients to be plaque psoriasis who previously completed one or completely clear of disease. In the PUVA study two such treatment courses. Secondary objectives spanning 20 years, patients’ psoriasis did not require were to determine the efficacy of alefacept and treatment, on average, for only 1 year cumulatively.1 duration of remission, defined as continued reHowever, long-term treatment with conventional sponse without treatment, obtained with each addisystemic agents is recognized to be associated with tional treatment course. the risk of cumulative organ METHODS toxicity or morbidities that CAPSULE SUMMARY This study complied compound other diseases aswith the requirements for sociated with psoriasis, thus, Most standard treatments for chronic the conduct of clinical limiting the use of such plaque psoriasis require continuous 2,3 Biologic agents, trials as outlined by the agents. administration of medication to sustain developed to target specific International Conference response (ie, there is no potential for immunologic pathways, enon Harmonization, Good disease remission or treatment-free deavor to maximize effecClinical Practice, and other intervals). tiveness while reducing the applicable standards for the By contrast, alefacept may induce potential risk of side effects.4 protection of human subjects, Alefacept, the first biodisease remission that is sustained over confidentiality of personal logic agent approved for time. information, and integrity of treatment of psoriasis, is a clinical data. This study Alefacept is well tolerated over multiple fully human fusion protein (NCT00692172) was concourses. that is T lymphocyteedirducted from December 14, ected, with the ability to 2001, to November 30, 2004, both inhibit T-cell activation and predominantly and was prematurely terminated prior to some parinduce memory T-cell apoptosis, thereby reducing ticipating patients requiring a third treatment course pathogenic T cells in psoriatic skin.5 A distinctive for recurrence of their psoriasis. feature of treatment with alefacept is that short (12-week) periods of active treatment can produce Patients disease reduction that persists for weeks to Participants in this extension study had plaque months after treatment is discontinued.6 This psoriasis requiring systemic therapy or phototherapy characteristic offers patients with chronic, often (as determined by the investigator) before the bepersistent, disease the option to control psoriasis ginning of treatment in this study. Patients were without continuous treatment. In the pivotal phase drawn from two qualifying antecedent trials: the III clinical trial, 55 (33%) patients treated with 15 alefacept treatment arm of a randomized, doublemg of intramuscular (IM) alefacept compared with blind, placebo-controlled trial of alefacept IM,7 or its 22 (13%) patients treated with placebo achieved open-label extension trial of alefacept IM.6 Patients reduction of 75% of the baseline Psoriasis Area from the placebo arm of the double-blind, placeboand Severity Index (PASI) score during the study controlled trial were eligible to enter this trial only if (P \ .001).7 The majority of these patients they participated in the open-label extension trial. remained at a reduction of 50% of baseline PASI Thus, all patients had received at least one and (PASI 50) or greater throughout the 12-week possibly two courses of alefacept before this trial. postdosing observation period.7 For those patients Eligible patients in the two qualifying trials were who achieved reduction of 75% of baseline PASI aged 18 years or older with chronic plaque psoriasis score (PASI 75), clinical improvement of at least for longer than 12 months with involvement of 10% PASI 50 was maintained for a median duration of or more body surface area. 209 days, with a median duration of 216 days Exclusion criteria for patients included clinically without treatment.6 When symptoms of psoriasis significant abnormal hematology values; history of recurred, the lesions tended to reappear gradually, an immunosuppressive disorder; a CD41 T-cell and unlike with some other treatments, patients count at study entry of less than the lower limit of treated with alefacept typically did not experience normal (LLN) (ie, \404 cells/mm3); serious local rebound.5,7,8 infection or systemic infection within 3 months of The primary objective of this prospective, multistudy initiation; and a significant change in the national, open-label extension study was to deterpatient’s medical history since the previous study mine the safety (including antigenicity) of up to 3 with alefacept. d
d
d
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Abbreviations used: C/AC: CI: Emax: IM: LLN: MOB: PASI: PASI 50:
clear or almost clear confidence interval maximum reduction of lymphocytes intramuscular lower limit of normal mild or better Psoriasis Area and Severity Index reduction of 50% of baseline Psoriasis Area and Severity Index PASI 75: reduction of 75% of baseline Psoriasis Area and Severity Index PGA: Physician Global Assessment PUVA: psoralen plus ultraviolet A UV: ultraviolet
Treatment A standard treatment course was defined as 15 mg of alefacept IM once weekly for 12 weeks, followed by 12 weeks of treatment-free observation. Patients were eligible to receive up to 3 additional standard treatment courses (courses A, B, and C) if their disease was rated as anything except clear and CD41 T-cell counts were at or above the LLN (Fig 1). Throughout this study, treatment with the following was not permitted within 4 weeks (either before or after) of alefacept therapy: systemic retinoids, systemic steroids, systemic fumarates, methotrexate, cyclosporine, azathioprine, thioguanine, other systemic immunosuppressant agents, phototherapy (including UVB and PUVA), and other investigational treatments. Safety Safety assessments included physical examinations, complete blood cell counts, blood chemistry analyses, and anti-alefacept antibody screening. Adverse events were monitored throughout the study. Pharmacodynamics Pharmacodynamic responses were evaluated by monitoring circulating lymphocyte counts, including total, CD41, and CD81 T-cell counts. For each patient, the maximum reduction of lymphocytes (Emax) was determined from baseline to 2 weeks after the last injection for each course. The number of patients whose absolute count at the time of Emax was less than the LLN was determined. The LLN for total lymphocytes was defined in this study as 910 cells/mm3 for patients aged 58 years or younger and 800 cells/mm3 for patients aged 59 years or older, whereas those for CD41 and CD81 T lymphocytes were 404 cells/mm3 and 220 cells/mm3, respectively. Efficacy Disease status. Disease status was evaluated using a previously described 7-point Physician
Global Assessment (PGA) scale (Table I).7 Patients were monitored at study baseline, weekly during injections, monthly after courses A and B, until they were eligible for the next treatment course, and monthly until study termination after course C. Response was determined at 2 weeks after the final dose of alefacept in each course. In this study, a responder was defined as a patient who achieved a PGA rating of clear or almost clear (C/AC). Efficacy end points included the proportion of patients who achieved C/AC at 2 and 12 weeks postdosing, and the proportion of patients who achieved C/AC at any time during a treatment course. Duration of response. Duration of response, measured only for courses A and B, was the period in days for which patients remained at a PGA response level without additional treatment. Follow-up for course C was truncated as a result of study termination. Duration of response was evaluated as the time for which patients who achieved C/AC remained C/AC, and the duration for which they retained the PGA response of mild or better (MOB), without the use of phototherapy or other systemic therapy, which is a clinically meaningful end point. This duration was determined in courses A and B for two subgroups of patients who achieved the C/AC response: those who were rated C/AC at 2 weeks postdosing and those who were rated C/AC at any time during the treatment course. Time to retreatment, defined as the duration (in days) between the last dose of one treatment course and the first dose of the next treatment course, was measured for patients who achieved C/AC at 2 weeks postdosing.
Statistical methods Proportions of patients with adverse events were compared using Fisher exact test for 2 3 2 tables and x2 test with exact P values for 2 3 3 tables. Patients were included in the efficacy analysis if they had at least one dose of alefacept. Data were summarized using descriptive statistics. Time to response and duration of response were determined using Kaplan-Meier methods. Demographic data (based on the first study the patient was enrolled in) and baseline disease characteristics were summarized. Lymphocyte subsets were summarized with descriptive statistics. Patients were included in the lymphocyte analysis if they received at least one dose, and had at least one postdose measurement. Safety was summarized for patients who received at least one dose of alefacept. The incidence of coded adverse events was summarized. If a patient experienced the same adverse event more than once in an individual course, the event was counted only
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Fig 1. Study design. *Patients were drawn from two previous studies with up to two courses of intramuscular alefacept. LLN, Lower limit of normal (= 404 cells/mm3 for CD41 T-cell count); PGA, Physician Global Assessment.
once for that course. The incidence of patients with anti-alefacept antibodies was summarized.
RESULTS Patient disposition, demographics, and baseline characteristics Of the total 183 patients enrolled in the study, 175 were dosed in course A, 121 in course B, and 88 in course C (Fig 2, A). There were 51 (29%) patients dosed in course A who achieved C/AC 12 weeks postdosing, of which 36 (71%) went on to receive course B (Fig 2, B). Similarly, there were 37 (31%) patients dosed in course B who achieved C/AC 12 weeks postdosing, of which 28 (76%) continued to course C. Of those who did not achieve C/AC 12 weeks postdosing, 85 (69%) from course A and 60 (71%) from course B continued to the subsequent course (Fig 2, B). Patient demographic and baseline characteristics were similar to those reported in prior studies of patients with moderate to severe psoriasis (Table II). Baseline disease severity was moderate or worse on the PGA scale for the majority of patients (76% in course A, 66% in course B, and 65% in course C). With additional courses, baseline severity shifted to more patients with milder disease and fewer patients with more severe disease. Safety Overall, 81% of patients in course A, 79% in course B, and 65% in course C reported adverse events. Serious adverse events were reported by 5% of
Table I. Physician Global Assessment scale Score
Category
1
Severe
2
Moderate to severe
3
Moderate
4
Mild to moderate
5
Mild
6
Almost clear
7
Clear
PGA
Very marked plaque elevation, scaling, and/or erythema Marked plaque elevation, scaling, and/or erythema Moderate plaque elevation, scaling, and/or erythema Intermediate between evaluation scores 3 (moderate) and 5 (mild) Slight plaque elevation, scaling, and/or erythema Intermediate between evaluation scores 5 (mild) and 7 (clear) No signs of psoriasis (postinflammatory hyperpigmentation may be present)
PGA, Physician Global Assessment.
patients in course A, 3% in course B, and none in course C. No event was reported by more than one patient in any course. Serious adverse events included those that were medically significant or required hospitalization, for example, atrial fibrillation, cholelithiasis, hemoptysis, Hodgkin disease, leukopenia, lymphadenopathy, lymphoma, mycoplasmal tracheobronchitis, myocardial infarction,
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Fig 2. A, Overall study patient disposition. Patients discontinued treatment for the following reasons: lost to follow-up (an = 1, bn = 0, cn = 1), adverse events (an = 2, bn = 2, cn = 0), voluntary withdrawal (an = 3, bn = 1, cn = 0), and administrative reasons (an = 3, bn = 1, cn = 2). B, Patient disposition based on achieving clear or almost clear (C/AC ) 12 weeks postdosing in courses A and B.
neutropenia, and pancreatitis. Adverse events led to discontinuation of alefacept therapy in 2% of patients in course A, and none in courses B and C. The most commonly reported adverse events ( $ 5%) during all 3 courses were nasopharyngitis, influenza, upper
respiratory tract infection, arthralgia, and headache (Table III). The rate at which these adverse events occurred, including infections, did not increase with multiple treatment courses (P $ .05). There was no indication of hepatotoxicity.
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Table II. Patient demographics and baseline characteristics Course A (n = 175)
Sex, No. (%) Male 116 Female 59 Race, No. (%) White 167 Other 8 Mean age, y (SD) 45.8 Mean duration of 22 psoriasis, y (range) Median BSA, % (range) 20 PGA rating, No. (%) Moderate to 74 severe/severe Moderate 59 Mild to moderate 29 Mild/almost 13 clear/clear
(66) (34)
Table III. Most common ( $ 5% incidence) adverse events
Course B (n = 121)
Course C (n = 88)
75 (62) 46 (38)
53 (60) 35 (40)
(95) 115 (5) 6 (12.6) 45.6 (6e64) 21
(95) 85 (5) 3 (12.7) 45.3 (6e53) 23
(97) (3) (11.9) (6e48)
(1e99) 14 (1e85) 10 (2e90) (42)
35 (29)
22 (25)
(34) (17) (7)
45 (37) 25 (21) 16 (13)
35 (40) 19 (22) 11 (13)
No. (%) of patients
Any adverse event Withdrawal because of adverse event Adverse event Nasopharyngitis Influenza Upper respiratory tract infection Arthralgia Headache Cough Injection site bruising Bronchitis Hypertension Herpes simplex
Course A (n = 175)
Course B (n = 121)
Course C (n = 88)
141 (81) 4 (2)
96 (79) 1 (\1)
57 (65) 0
21 (12) 15 (9) 14 (8)
15 (12) 9 (7) 11 (9)
8 (9) 3 (3) 5 (6)
12 11 10 9 5 5 4
4 14 4 5 6 7 6
4 (5) 5 (6) 1 (1) 2 (2) 0 1 (1) 4 (5)
(7) (6) (6) (5) (3) (3) (2)
(3) (12) (3) (4) (5) (6) (5)
Adverse events are presented by decreasing incidence in course A. BSA, Body surface area; PGA, Physician Global Assessment.
On average, the time of year when each alefacept treatment course was initiated did not appear to affect the incidence of infection observed. Infections were reported by 47%, 51%, and 33% of patients in courses A, B, and C, respectively. The proportion of patients with an infection did not increase with additional courses. All infections were uncomplicated and readily controlled by conventional therapy. One serious infection, mycoplasmal tracheobronchitis, developed in a 66-year-old man 31 weeks after his last dose of alefacept; he was hospitalized for 2 days and discharged on clarithromycin. This infection was considered to be unrelated to treatment by the investigator. No opportunistic infections were reported. Overall incidence rates of infections were similar in patients whose CD41 Tcell counts ever fell below 250 cells/mm3 compared with those whose CD41 T-cell counts were always above 250 cells/mm3: 7 (44%) vs 73 (46%) patients in course A, 3 (38%) vs 58 (51%) patients in course B, and 3 (50%) vs 25 (31%) patients in courses C, respectively (P $ .05). The proportion of patients testing positive for anti-alefacept antibodies remained low (\1%-1%) throughout all courses, suggesting that multiple courses of alefacept or treatment-free intervals between courses did not elicit an immune response. Anti-alefacept antibodies were detected in only two of 175 patients at any time during the study and were of low titer in both patients. One patient tested positive for anti-alefacept antibodies in course A, but was not dosed in courses B or C. This patient had
tested negative for anti-alefacept antibodies in the antecedent qualifying trials. The other patient tested positive for anti-alefacept antibodies in all 3 courses. The incidence of malignancies was 3% or less in each of the 3 treatment courses of alefacept. Malignancies were diagnosed in 7 patients during the study. Nine nonmelanoma skin cancers (3 squamous cell and 6 basal cell carcinomas) were reported in 5 patients with a long-standing history of psoriasis (18-50 years) and prior exposure to phototherapy (PUVA, UVB, or both) and systemic immunosuppressive therapy including methotrexate and cyclosporine. Two of these 5 patients also had a history of squamous cell carcinomas. Non-Hodgkin lymphoma was diagnosed in a 68-year-old woman who had psoriasis for 64 years and had previously been treated with methotrexate, retinoids, and PUVA; the diagnosis was 72 weeks after her first dose and 2 weeks after her last dose of alefacept. A 52-year-old man with a 44-year history of psoriasis was diagnosed with Hodgkin disease 93 weeks after his first dose and 1 week after his last dose of alefacept. He had been treated with immunosuppressive agents for an extended period of time, specifically methotrexate for 180 months and cyclosporine for 6 months. Pharmacodynamics Within each course, the mean counts of circulating lymphocytes, and CD41 and CD81 T lymphocytes (Fig 3), decreased during the active treatment phase, and gradually increased during the follow-up
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Fig 3. Mean total lymphocyte, CD41, and CD81 T-cell counts during each course.
Table IV. Proportion of patients with total, CD41, and CD81 T-lymphocyte counts below the lower limit of normal Type of lymphocyte count below LLN Time point
Total
CD41
CD81
Patients, No. (%) Course A Course B Course C (n = 175) (n = 120) (n = 87)
At Emax 11 (6) 12 wk 3 (2) posttreatment At Emax 63 (36) 12 wk 19 (12) posttreatment At Emax 102 (58) 12 wk 44 (29) posttreatment
12 (10) 0
6 (7) 0
42 (35) 12 (11)
31 (36) 10 (12)
69 (58) 38 (34)
53 (61) 28 (34)
Fig 4. Proportion of patients who achieved clear or almost clear (C/AC ) across 3 treatment courses. PGA, Physician Global Assessment.
Emax, Maximum reduction of lymphocytes; LLN, lower limit of normal.
phase. The mean counts of total, CD41, and CD81 lymphocytes at Emax and at 12 weeks postdosing were not appreciably different across the treatment courses. There were no differences in total, CD41, and CD81 T-lymphocyte counts obtained by lymphocyte monitoring performed once weekly (course A) or once every 2 weeks (courses B and C). The percentage of patients with counts below the LLN at Emax and at 12 weeks after the last dose in each course was similar across courses for total lymphocytes, CD41 T lymphocytes, and CD81 T lymphocytes (Table IV). Efficacy Disease status. The proportion of patients achieving C/AC at 2 weeks postdosing was 16%,
22%, and 19% in courses A, B, and C, respectively (Fig 4). At 12 weeks postdosing (ie, end of treatment course), 29%, 31%, and 31% had a PGA of C/AC in courses A, B, and C, respectively. The proportion of patients achieving C/AC at any time during the treatment course was 35%, 42%, and 42% for courses A, B, and C, respectively. Patients across all levels of disease severity responded to alefacept. Among patients whose baseline disease severity for individual courses was rated moderate or worse, 29%, 35%, and 30% achieved C/AC during courses A, B, and C, respectively. Patients who attained C/AC in one course were eligible for the next course when they ceased to maintain this response. Of the patients who achieved C/AC in course A, 68% and 59%, respectively, achieved the same response in courses B and C. Similarly, 69% of patients who achieved C/AC in
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Fig 5. Duration of clear or almost clear (C/AC ) and mild or better (MOB) responses in patients who achieved C/AC. At 2 weeks postdosing for each course (A) and any time during treatment course (B). CI, Confidence interval; PGA, Physician Global Assessment.
course B also achieved it in course C, indicating that a majority of patients who achieved C/AC did so consistently and reproducibly over multiple courses of treatment. In addition, among patients who did not achieve C/AC in course A and received subsequent courses, 21 of 77 (27%) patients and 18 of 56 (32%) patients achieved this response in courses B and C, respectively. Similarly, 10 of 49 (20%) patients who did not achieve C/AC in course B achieved it in course C. Duration of response. Patients who achieved C/AC at 2 weeks postdosing in response to course A maintained this response for a median duration of 214 days, whereas those who achieved C/AC at 2 weeks postdosing in response to course B maintained this response for a median duration of 126 days (Fig 5, A). Furthermore, these patients remained at MOB for median durations of 340 days in response to course A and 283 days in response to course B. Patients who achieved C/AC at any time during a treatment course maintained this response for median durations of 146 days after treatment in course A
and 123 days after treatment in course B. The median duration of MOB response in these patients was 287 days after treatment in course A and 221 days after treatment in course B (Fig 5, B). Patients who achieved C/AC in response to course A were further evaluated for duration of response based on whether or not they received course B (Table V). All patients receiving course A and achieving C/AC had a longer median duration of treatment response than the subset that also received course B. Because of censoring caused by study termination prior to the patients’ requiring retreatment, the duration of response for patients who received only course A could be determined only for one of 4 response categories (Table V). Among responding patients who received only course A and achieved C/AC, the lower limits of the confidence intervals (CIs) ranged from 112 to 540 days, which was 2 to 5 times greater than the corresponding values for patients who received course B (range: 68-173 days). This may be explained by the finding that only 21 of the 28 patients who were rated C/AC at 2 weeks postdosing in course A were dosed in course B, and only 44 of the 61 patients who were rated C/AC at any time during course A were dosed in course B. Thus, patients with a positive outcome in course A may not have received course B possibly contributing to the observed shorter median duration of response in the latter course. Sustained duration of C/AC response was observed for both courses A and B in the subset of patients who achieved C/AC in both courses (Fig 6). For patients who achieved C/AC at 2 weeks postdosing in both courses (n = 11), the median duration of C/AC response was longer in course A (238 days; 95% CI: 105-488) than in course B (164 days; 95% CI: 123-225). Similar results were obtained for patients who achieved C/AC at any time during both courses (n = 30) with median duration of C/AC response being 169 days (95% CI: 105-222) for course A vs 133 days (95% CI: 119-200) for course B. The median durations at MOB for this subpopulation were similar in courses A (287 days; 95% CI: 173-399) and B (283 days; 95% CI: 221-332) for patients who responded at any time during both courses. A similar comparison could not be made for patients who responded at 2 weeks postdosing, because almost all of the patients were censored and the median duration for course B could not be estimated by Kaplan-Meier analysis. The duration of follow-up for these patients ranged from 121 to 545 days. Time to retreatment. The mean times to retreatment among patients who achieved C/AC at 2 weeks postdosing were 282 days (n = 21) after course A and 219 days (n = 17) after course B (Table VI).
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Table V. Duration of clear or almost clear and mild or better response in course A, summarized by dosing in course B Time of C/AC response
2 wk postdosing
Rating at which duration was measured
C/AC
MOB
Any time during treatment course
C/AC
MOB
No. and duration
Course A
Dosed in course B
No. (%) Censoring rate, No. (%) Median duration of response, d 95% CI, d
28 (100) 5 (18) 213.5
21 (100) 0 182.0
7 (100) 5 (71) NE
168.5e436.5
105.0e242.5
491.0eNE
28 (100) 11 (39) 340.0
21 (100) 5 (24) 330.5
7 (100) 6 (86) NE
185.5e540.0
172.5e371.0
540.0eNE
61 (100) 9 (15) 146.0
44 (100) 2 (5) 129.5
17 (100) 7 (41) 224.0
97.0e208.5
68.0e172.5
112.0e611.5
61 (100) 22 (36) 286.5
44 (100) 10 (23) 193.5
17 (100) 12 (71) NE
182.5e399.0
150.5e330.5
433.0eNE
No. (%) Censoring rate, No. (%) Median duration of response, d 95% CI, d No. (%) Censoring rate, No. (%) Median duration of response, d 95% CI, d No. (%) Censoring rate, No. (%) Median duration of response, d 95% CI, d
Not dosed in course B
C/AC, Clear or almost clear; CI, confidence interval; MOB, mild or better; NE, cannot be estimated from Kaplan-Meier curve. Duration of C/AC and MOB response was measured in patients who achieved C/AC in course A.
DISCUSSION Alefacept, a biological agent that inhibits activation of pathogenic T lymphocytes and induces their apoptosis,9,10 is exceptional in its ability to offer an extended treatment-free interval for those patients with psoriasis who experience a good response to a treatment course.4,11 When psoriasis reappears on termination of treatment, it does so without rebound flares. Furthermore, when psoriasis recurs, retreatment with alefacept appears to offer similar subsequent improvement in the majority of responders.6 The safety and efficacy of up to two courses of alefacept have previously been demonstrated in prospective, randomized, double-blind trials.6-8,12 An integrated analysis of 13 trials showed that up to 9 courses of alefacept can be safely administered to patients.13 This report presents, to our knowledge, the results of the first clinical trial designed to evaluate the safety and efficacy of up to 5 courses of alefacept for the treatment of psoriasis. Overall, up to 3 additional treatment courses of alefacept IM were safe and well tolerated in patients with plaque psoriasis. The incidence of adverse events (including infections), serious adverse events (including serious infections), discontinuations of alefacept, and study withdrawals were similar for all
courses in this study, supporting the lack of cumulative toxicity or nonspecific immunosuppressive effects. The incidence of anti-alefacept antibodies was low across all courses. In this study, the overall number of patients with malignancies was 4% (7 of 175), the majority of which were nonmelanoma skin cancers. Patients with psoriasis and a history of PUVA exposure are reported to have an increased risk of nonmelanoma skin cancers, with a relative risk of 17.6 for squamous cell carcinoma and 4.1 for basal cell carcinoma compared with the general population.14 Similarly, patients with psoriasis, especially those with a high exposure to methotrexate ( $ 36 months), are reported to have an increased risk for developing lymphoma, with an estimated 2- to 4-fold higher incidence compared with the rate in the general population.15,16 Based on these reports, the rate of malignancies observed in this study appears to be within the expected incidence rates for patients with psoriasis. Safety profiles of additional courses of alefacept were similar to those previously reported in patients receiving up to two courses of alefacept.6-8 It would be intuitive that only patients who experienced some improvement of their psoriasis without any adverse effects from a prior treatment with a therapeutic agent would participate or
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Fig 6. Duration of response in patients who achieved clear or almost clear (C/AC ) in both courses A and B at 2 weeks postdosing (A) and at any time during treatment course (B). CI, Confidence interval; MOB, mild or better; PGA, Physician Global Assessment.
Table VI. Time to retreatment among patients who achieved clear or almost clear at 2 weeks postdosing Time to retreatment, d
Mean SD Median Range
Course A (n = 21)
281.9 155.24 249.0 99e608
Course B (n = 17)
218.8 133.39 173.0 84e517
SD, Standard deviation.
continue to participate in a trial evaluating additional doses of that agent. However, interestingly, approximately 70% (69%-76% across all groups) of all patients in each of courses A and B continued to receive a subsequent course of alefacept irrespective of whether or not they derived clinical benefit from the prior course. These data suggest that selection bias of patients, if any, was minimal. Consistent with previous reports,5,9 the decrease in numbers of circulating T lymphocytes during the
active treatment phase of each course was followed by a recovery during the follow-up phase in the same course. Repeated courses of alefacept did not result in a progressive reduction in total lymphocytes, CD41 T lymphocytes, or CD81 T lymphocytes. As with previous studies, there was no increased incidence of adverse events (including infections or malignancies) in those patients whose CD41 Tlymphocyte counts ever decreased below 250 cells/mm3. These data are consistent with the selective reduction of pathogenic memory T cells by alefacept, which may help explain the absence of correlation between reduced peripheral T-lymphocyte counts and infection.9,10,17 The results of this study demonstrate that alefacept continues to be effective in up to 3 additional courses in patients who had previously received one or two treatment courses. The proportion of patients who achieved C/AC in this study was similar to that in previous studies of patients receiving up to two courses of alefacept IM,6,7 or intravenously.8 Similar proportions of patients achieved C/AC in each of the 3 courses (Fig 4). Patients who achieved C/AC in one course generally had a similar response to a subsequent course. Some patients who did not achieve C/AC in one course achieved it in a subsequent course, a result consistent with a previous report showing that among patients who did not achieve PASI 50 with one treatment course, 53% achieved PASI 50 (vs 33% in the placebo group) and 19% achieved PASI 75 (vs 8% in the placebo group) with the second course of treatment.18 Thus, additional courses of alefacept may be valuable both for patients who achieve the desired response in a course and for those who do not. In addition, patients responded to alefacept regardless of baseline disease severity. Alefacept yielded extended response times among patients who achieved C/AC in course A (214 days) and those who achieved it in course B (126 days). There was a decrease in the median duration of response in course B compared with course A, possibly, in part, because of the differences in patient populations entering each course. The initial baseline severity of psoriasis, before the first alefacept treatment course in the antecedent trials, was similar between patients who received course A and those who received course B. Course A consisted of all study participants, whereas those in course B were patients who either did not achieve C/AC in course A, or did not maintain this PGA status during the study. Thus, some of the best responders received only course A. This may also explain the shorter time to retreatment in responders after course B, compared with course A. Comparison of duration
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of response in patients who achieved C/AC at 2 weeks postdosing in both courses A and B could not be made because of censoring. Overall, these data suggest that patients who are most likely to respond well to alefacept treatment may do so with fewer courses of treatment and have longer treatment-free intervals (ie, remissions). The similarity of efficacy, safety, and pharmacodynamic profiles reported in previous studies of up to two courses of alefacept IM,6,7 and the subpopulations assessed in this study suggests that repeated courses of alefacept IM may be an effective therapeutic option for these responding patients. In conclusion, up to 5 courses of alefacept IM were safe and effective in treating plaque psoriasis. For those patients who achieved significant improvement, additional courses of alefacept yielded sustained responses with remissions of up to 7 months. Among this subset of responders, multiple courses of alefacept IM can help achieve long-term control of plaque psoriasis without requiring continuous treatment, while maintaining the safety profile. Editorial assistance in the preparation of this manuscript was provided by Sudha Srinivasan, PhD, and Mukund Nori, PhD, MBA, Envision Pharma Inc, Southport, CT. Barabara Mathes, MD, and Rita Kristy, MS, of Astellas Pharma US, Inc provided assistance in writing this manuscript. REFERENCES 1. Nijsten T, Looman CW, Stern RS. Clinical severity of psoriasis in last 20 years of PUVA study. Arch Dermatol 2007;143:111321. 2. Kazlow Stern D, Tripp JM, Ho VC, Lebwohl M. The use of systemic immune moderators in dermatology: an update. Dermatol Clin 2005;23:259-300. 3. 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. 4. Langley RG, Gupta AK, Cherman AM, Inniss KA. Biologic therapeutics in the treatment of psoriasis, part 1: review. J Cutan Med Surg 2007;11:99-122.
5. Ellis CN, Krueger GG. Treatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes. N Engl J Med 2001;345:248-55. 6. Gordon KB, Langley RG. Remittive effects of intramuscular alefacept in psoriasis. J Drugs Dermatol 2003;2:624-8. 7. Lebwohl M, Christophers E, Langley R, Ortonne JP, Roberts J, Griffiths CE. An international, randomized, double-blind, placebocontrolled phase 3 trial of intramuscular alefacept in patients with chronic plaque psoriasis. Arch Dermatol 2003;139:719-27. 8. Krueger GG, Papp KA, Stough DB, Loven KH, Gulliver WP, Ellis CN. A randomized, double-blind, placebo-controlled phase III study evaluating efficacy and tolerability of 2 courses of alefacept in patients with chronic plaque psoriasis. J Am Acad Dermatol 2002;47:821-33. 9. Gordon KB, Vaishnaw AK, O’Gorman J, Haney J, Menter A. Treatment of psoriasis with alefacept: correlation of clinical improvement with reductions of memory T-cell counts. Arch Dermatol 2003;139:1563-70. 10. Gottlieb AB, Casale TB, Frankel E, Goffe B, Lowe N, Ochs HD, et al. Cd41 T-cell-directed antibody responses are maintained in patients with psoriasis receiving alefacept: results of a randomized study. J Am Acad Dermatol 2003;49:816-25. 11. Langley RG, Gordon KB. Duration of remission of biologic agents for chronic plaque psoriasis. J Drugs Dermatol 2007;6: 1205-12. 12. Krueger GG. Clinical response to alefacept: results of a phase 3 study of intravenous administration of alefacept in patients with chronic plaque psoriasis. J Eur Acad Dermatol Venereol 2003;17(Suppl):17-24. 13. Goffe B, Papp K, Gratton D, Krueger GG, Darif M, Lee S, et al. An integrated analysis of thirteen trials summarizing the long-term safety of alefacept in psoriasis patients who have received up to nine courses of therapy. Clin Ther 2005;27:1912-21. 14. Stern RS, Liebman EJ, Vakeva L. Oral psoralen and ultraviolet-A light (PUVA) treatment of psoriasis and persistent risk of nonmelanoma skin cancer. PUVA follow-up study. J Natl Cancer Inst 1998;90:1278-84. 15. Gelfand JM, Berlin J, Van Voorhees A, Margolis DJ. Lymphoma rates are low but increased in patients with psoriasis: results from a population-based cohort study in the United Kingdom. Arch Dermatol 2003;139:1425-9. 16. Stern RS. Lymphoma risk in psoriasis: results of the PUVA follow-up study. Arch Dermatol 2006;142:1132-5. 17. Scheinfeld N. Alefacept: a safety profile. Expert Opin Drug Saf 2005;4:975-85. 18. Menter A, Cather JC, Baker D, Farber HF, Lebwohl M, Darif M. The efficacy of multiple courses of alefacept in patients with moderate to severe chronic plaque psoriasis. J Am Acad Dermatol 2006;54:61-3.