Alefacept for Severe Alopecia Areata A Randomized, Double-blind, Placebo-Controlled Study

Transcription

STUDY
Alefacept for Severe Alopecia Areata
A Randomized, Double-blind, Placebo-Controlled Study
Bruce E. Strober, MD, PhD; Kavita Menon, MD; Amy McMichael, MD; Maria Hordinsky, MD; Gerald Krueger, MD;
Jackie Panko, MD; Kimberly Siu, MD; Jonathan L. Lustgarten, PhD; Elizabeth K. Ross, MD; Jerry Shapiro, MD
ment of severe alopecia areata (AA).
istration–approved T-cell biologic inhibitor for the treatment of moderate to severe plaque psoriasis.
Design: Multicenter, double-blind, randomized, placebocontrolled clinical trial.
Main Outcome Measure: Improved Severity of Alopecia Tool (SALT) score over 24 weeks.
Objective: To assess the efficacy of alefacept for the treat-
Setting: Academic departments of dermatology in the
United States.
Results: Participants receiving alefacept for 12 consecu-
tive weeks demonstrated no statistically significant improvement in AA when compared with a well-matched
placebo-receiving group (P =.70).
Participants: Forty-five individuals with chronic and
severe AA affecting 50% to 95% of the scalp hair and resistant to previous therapies.
severe AA.
Intervention: Alefacept, a US Food and Drug Admin-
Arch Dermatol. 2009;145(11):1262-1266
Conclusion: Alefacept is ineffective for the treatment of
A
Author Affiliations:
Departments of Dermatology,
New York University School of
Medicine, New York
(Drs Strober, Menon, Siu, and
Shapiro), Wake Forest
University, Winston-Salem,
North Carolina
(Dr McMichael), University of
Minnesota, Minneapolis
(Dr Hordinsky), University of
Utah, Salt Lake City
(Drs Krueger and Panko),
Biomedical Informatics,
University of Pittsburgh,
Pittsburgh, Pennsylvania
(Dr Lustgarten), Dermatology
and Laser Center NW,
Bellingham, Washington
(Dr Ross), and Dermatology
and Skin Science, University of
British Columbia, Vancouver,
Canada (Dr Shapiro).
LOPECIA AREATA (AA) IS A
chronic, potentially reversible autoimmune skin disease characterized by nonscarring patchy hair loss
involving any hair-bearing surface.1 Alopecia areata often causes considerable emotional distress and has limited treatment
options. The presentation and course of
AA differ from patient to patient and are
unpredictable.2 Most often involving the
scalp, AA typically presents as welldemarcated patches of hair loss that may
be either isolated or numerous.1 Patients
may develop total loss of scalp hair (alopecia totalis) or loss of all body hair (alopecia universalis).1,3 Alopecia areata has an
incidence rate of 0.1% to 0.2%, with a lifetime risk of roughly 1.7%.1,4 Most often it
is those with AA of the scalp who present
for evaluation.
T lymphocytes seem to play a central
role in AA through a targeted immunologic attack on the hair follicle leading to
anagen arrest.3,5-7 Histologically, lesions of
active AA reveal dense peribulbar lymphocytic infiltration, consisting of activated T lymphocytes and antigenpresenting Langerhans cells. 5-7 When
(REPRINTED) ARCH DERMATOL/ VOL 145 (NO. 11), NOV 2009
1262
lesions of AA are transplanted into mice
with severe combined immunodeficiency that lack T lymphocytes, hair
growth may resume, further confirming
the potential pathogenic role of T lymphocytes.8
Treatment options for more severe presentations of AA are limited, and neither
a cure nor preventive treatment is available. Most of the effective therapies for AA
are either immunosuppressive or immunomodulatory. Of the therapeutic options,
corticosteroids (topical and intralesional) remain the most popular, although other therapies, including anthralin, minoxidil, systemic corticosteroids,
topical immunotherapy, psoralen–UV-A
(PUVA), and cyclosporine are also commonly used with varying success.1 Interestingly, the biologic agents etanercept
and efalizumab—both effective in treating psoriasis, a T-cell–mediated disease—
demonstrate no efficacy in treating AA.3,9
Despite these failures, other biologic
agents with different mechanisms of action may be effective. Alefacept (Amevive; Astellas Pharma US Inc, Deerfield, Illinois) is a bioengineered lymphocyte
function–associated antigen-3/immuno-
WWW.ARCHDERMATOL.COM
©2009 American Medical Association. All rights reserved.
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globulin fusion protein that interrupts T-lymphocyte activation by binding to CD2 on T lymphocytes and consequently interrupting the costimulation between antigenpresenting cells and T lymphocytes.10,11 Perhaps more
important, alefacept specifically induces the apoptosis of
both CD4⫹ and CD8⫹ memory effector T lymphocytes,
cells that comprise the peribulbar lymphocytic infiltrate
and have been implicated in the pathogenesis of AA.10-14
Case reports15,16 have shown that alefacept may be effective in the treatment of AA. Herein, we report the results of a double-blind, randomized, placebo-controlled
study of alefacept in patients with severe AA.
METHODS
The primary objective of this study was to assess the safety and
therapeutic efficacy of a weekly regimen of intramuscular (IM)
alefacept compared with placebo over a course of 12 weeks in patients with chronic, severe scalp AA. This was a double-blind, randomized, placebo-controlled, multicenter, investigator-initiated
study in a voluntary population of patients with chronic, severe
scalp AA. There were 5 participating study sites. The study was
approved by the institutional review boards at each of the study
sites and was conducted in accordance with Good Clinical Practice guidelines, the US Food and Drug Administration (FDA)
guidelines for clinical trials, and the principles set forth by the
Declaration of Helsinki. All participants provided written informed consent prior to the initiation of any study procedures.
Eligible individuals were randomized to receive either weekly
IM administration of placebo or alefacept,15 mg, for 12 weeks,
followed by a 12-week, posttreatment observation period. Safety
and efficacy were assessed throughout the 24-week study period. Randomization lists detailing the person’s identification
(ID) number and medication allocation were provided by a coordinating monitor. An unblinded study coordinator or pharmacist maintained the randomization lists responsible for participant ID number assignment and drug shipment and
management. Once an individual was deemed eligible for study
entry, the unblinded study coordinator or pharmacist assigned the participant an ID number and dispensed study medication as listed in the randomization list. Participants were monitored for safety and efficacy throughout the entire study by a
blinded investigator. Efforts were made to ensure that the same
investigator monitored any specific participant for the entire
study period.
PATIENT ELIGIBILITY
Eligible individuals were 18 to 65 years of age, with a diagnosis of chronic, severe, scalp AA defined as at least a 50% to 95%
patchy scalp hair loss of at least 6 months’ duration. Patients
with alopecia totalis, alopecia universalis, or coexisting significant androgenetic alopecia (Norwood-Hamilton stage IV or
greater in males, Ludwig stage III in females) were excluded.
Individuals with CD4⫹ T-lymphocyte counts below the lower
limit of the reference range at screening (as determined by the
local laboratory) were not included, nor were those with either
abnormal hepatic function or hematologic test results. In addition, individuals were not enrolled if they had a known history of unstable cardiovascular or pulmonary disease, or poorly
controlled diabetes mellitus; were seropositive for human immunodeficiency, hepatitis C, or hepatitis B viruses; had a history of recurrent bacterial, fungal, atypical mycobacterial, viral or opportunistic infections; a history of lymphoproliferative
or malignant disease (other than treated basal cell carcinoma
or ⱕ3 squamous cell carcinomas); a history of active tuberculosis (TB) or were currently undergoing treatment for active
TB; or were pregnant or breastfeeding. Individuals with a history of treatment with alefacept or treatment with another investigational medication also were not allowed to participate
in the study. Systemic therapies (eg, corticosteroids, fumaric
acid derivatives, cyclosporine A, methotrexate, biologic medications, retinoids, azathioprine) and phototherapy (UV-B,
PUVA) were discontinued for 1 month prior and during the
entire study treatment period. Topical therapies (corticosteroids, contact sensitizing agents, tacrolimus, or pimecrolimus) were discontinued for 2 weeks prior to and during the
entire study treatment period. The use of prescription medications for conditions unrelated to AA was permitted.
Serum samples, measuring hepatic, renal and hematologic
function, and CD4⫹ T-lymphocyte count, were drawn throughout the study, and participants were assessed for signs and symptoms of infection. Study medication was withheld if the CD4⫹
T-lymphocyte count fell below 250 cells/mm3.
The severity of AA and clinical response were measured with
the Severity of Alopecia Tool (SALT) as detailed in the Alopecia Areata Investigational Guidelines.17 The SALT score is computed by measuring the percentage of hair loss in each of 4 areas
of the scalp—vertex (40%), right profile (18%), left profile (18%),
and posterior (24%)—and adding the total to achieve a composite score. Hair regrowth is reflected by a decrease in the SALT
score (eg, complete hair regrowth would confer a SALT score
of 0). The primary efficacy end point was the percentage of participants with at least a 50% improvement from the baseline in
their SALT score at week 24. Treatment response was also measured at week 12. The SALT score was measured visually by
the study physician and corroborated by photographic analysis. The participant’s perception of the extent of scalp disease
on completion of the treatment phase and at the end of the posttreatment, observational phase was also assessed.
STATISTICAL ANALYSIS
Efficacy and safety analyses were based on the modified intentto-treat population, which included all randomized patients who
received at least 1 dose of the study medication. For the population and safety analyses, patients were separated based on the
treatment groups to which they were randomized. The proportion of patients who achieved a 50% or greater reduction
in their SALT scores in the alefacept and placebo groups was
analyzed using the ␹2 test. Participants’ assessment of disease
was analyzed by the Wilcoxon rank-sum test. All statistical tests
were 2-sided, and all tests for efficacy were performed at the
␣=.05 level. The planned sample size was 76, with 38 patients
expected in each treatment arm in order to detect a 30% difference between treatment and placebo groups with 80% power
and a 2-sided test at a significance level of P=0.05. Difficulty
with participant enrollment necessitated reducing the study
population to a total of 45 individuals. We were unable to perform statistical tests for those persons who achieved greater than
50% improvement in SALT scores owing to the low sample size.
RESULTS
Forty-five participants were enrolled, of whom 23 (51%)
were randomized to receive alefacept and 22 (49%) to
receive placebo (Figure 1). All participants received at
least 1 treatment with study medication. In the placebotreated group, 3 patients withdrew after day 29, and 2
patients withdrew after day 92. No patients from the alefacept treatment group withdrew from the study. The alef-
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Table 2. Therapeutic Efficacy
78 Assessed for eligibility
33 Excluded
SALT Score
45 Randomized
23 Allocated to alefacept
23 Received alefacept
0 Did not receive alefacept
0 Lost to follow-up
Placebo
Treatment
Group
(n=22)
P
Value
71.1
61.8
67.3
67.0
65.7
64.4
.58
.70
2
1
2
3
NA
NA
SALT score, mean for entire group
Baseline
Week 12 a
Week 24 a
Participants who had ⱖ50%
improvement in SALT score, No.
Week 12
Week 24
22 Allocated to placebo
22 Received placebo
0 Did not receive placebo
5 Lost to follow-up
23 Analyzed
Alefacept
Treatment
Group
(n=23)
22 Analyzed
Abbreviations: NA, not applicable; SALT, Severity of Alopecia Tool.
a Intent to treat, last observation carried forward used for noncompleters.
Figure 1. Disposition of screened patients.
Table 3. Participant Self-Assessment of Disease
Table 1. Participant Characteristics
Characteristic
All
Randomized
Participants
(N=45)
Alefacept
Treatment
Group
(n=23)
Placebo
Treatment
Group
(n=22)
Age, mean (SD), y
36.3 (11.1)
38.3 (10.3)
34.2 (11.8)
Sex, No.
Male
13
5
8
Female
32
18
14
Ethnicity, No.
White
25
13
12
Black
12
8
4
Hispanic
7
2
5
Asian
1
0
1
Age at onset,
21.0 (13.0)
22.5 (14.6)
19.4 (11.1)
mean (SD), y
Duration of disease,
180.7 (154.7) 182.6 (175.6) 178.8 (133.4)
mean (SD), mo
Baseline SALT score,
69.1 (15.6)
71.1 (15.5)
67.0 (15.8)
mean (SD)
1132.8 (440.4) 1186.0 (459.5) 1077.2 (423.0)
Baseline CD4 count,
mean (SD), cells/mm3
Abbreviation: SALT, Severity of Alopecia Tool.
acept and placebo treatment groups had comparable baseline demographics and disease characteristics (Table 1).
Most of the participants were female (71%). Of the participants, 56% were white, 27% black, 16% Hispanic, and
2% Asian. The mean age of the participants was 36 years,
with a mean age at onset of AA of 21 years. All 45 individuals had received prior treatment for AA, including
systemic and topical immunosuppressant therapies and
phototherapy.
At baseline, the mean SALT scores were comparable:
71.1 in the alefacept treatment group and 67.0 in the placebo treatment group. The mean percentage of hair regrowth as measured by the SALT score was not significantly different (P ⬎ .05) in either treatment group
(Table 2). Neither group achieved the primary efficacy
end point of at least a 50% improvement in SALT scores
at the end of the treatment and observation periods. By
the end of the treatment period at week 12, the alefacepttreated group, when compared with the placebo group,
did not demonstrate a statistically relevant treatment re-
Distribution
of Alopecia
Scalp
Screening
Week 11
Week 24
Nonscalp
Screening
Week 11
Week 24
Alefacept Treatment
Group
(n = 23)
Placebo Treatment
Group
P
(n = 22)
Value
Moderate to severe
Moderate to severe
Moderate to severe
Moderate to severe
Moderate to severe
Moderate to severe
.26
.13
Mild to moderate
Mild to moderate
Mild to moderate
Mild to moderate
Mild to moderate
Mild to moderate
.43
.54
sponse (P ⬎ .05). Specifically, only 2 patients in the alefacept treatment group and 2 patients in the placebo group
achieved at least 50% improvement in their SALT scores
at week 12. Of the 2 alefacept-treated patients who had
at least 50% improvement in their SALT scores at week
12, only 1 patient maintained this improvement at week
24. We were unable to perform statistical tests for those
patients who achieved greater than 50% improvement in
SALT scores owing to the low sample size.
Participant assessment of disease (Table 3) was analyzed by grading patient perception of the extent of hair
loss on a 7-point qualitative scale (none, trace, mild, mild
to moderate, moderate, moderate to severe, severe). Participants graded both scalp and nonscalp hair loss. The
mean participant assessment of disease scores was unchanged throughout the study duration, from screening
to study completion, for both the placebo and alefacept
treatment groups. In both treatment groups, the mean
patient rating of scalp hair loss remained moderate to severe from screening to week 24.
Adverse events (AEs) occurring in the group receiving alefacept were similar to those occurring in the placebo group and to those noted in clinical trials of alefacept for moderate to severe psoriasis (Table 4). Most
AEs were rated as mild and considered unrelated to study
medication. The most frequently reported AEs in both
treatment groups were infections (upper respiratory infections, influenza), headaches, and nasal congestion.
Three serious adverse events (SAEs) occurred during the course of the study. None of the SAEs had an in-
1264
Table 4. Adverse Events a
Event
a Data
Placebo Treatment
Group
20
8
4
4
4
2
20
2
3
2
3
1
are given as number of patients.
1400
1200
COMMENT
Anecdotal experience and case reports15,16 have noted an
improvement of AA following alefacept treatment. With this
randomized, double-blind, placebo-controlled trial, we demonstrate that a 12-week course of IM alefacept, 15 mg, does
not effectively treat severe AA. In the enrolled population
of patients, treatment with alefacept was well tolerated. Most
AEs were rated as mild, and the AE profile was comparable with those from previous clinical studies of alefacept.11,13,18 Serious infections in persons receiving alefacept were not observed. Alefacept may reduce CD4⫹
T-lymphocyte counts, but most participants who received alefacept demonstrated a CD4⫹ count that remained higher than 250 cells/mm3. In the 1 patient whose
CD4⫹ count transiently fell below 250 cells/mm3, no infections or other adverse events were observed.
This study was limited by the number of patients randomized to receive treatment. The planned sample size
was 76 participants, with 38 patients in each group to
detect at least a 30% difference at the primary end point
between the treatment and placebo groups. Owing to slow
enrollment, only 45 participants were enrolled. Consequently, the study may be underpowered to detect a statistically significant treatment effect of alefacept. However, given the negligible response rate in either group
of this study, a larger sample size likely would not significantly change the nature of the results.
It is unclear why alefacept failed to treat AA. Alefacept
is an FDA-approved therapy for psoriasis, which also is a
T-lymphocyte–mediated disease. The failure of alefacept
to treat AA in this setting suggests that AA has a more complex pathophysiologic mechanism that may not be driven
by memory-effector T lymphocytes.3,15 Studies from animal models indicate that the inhibition of T-lymphocyte
activation may not completely treat AA.15,19 Blocking costimulatory signals and thereby inhibiting T-lymphocyte
activation in mice with chronic AA had little effect on the
course of AA.15,19 However, inhibiting costimulation did
prevent the development of AA in the skin-grafted mouse
model, suggesting that the maintenance of chronic AA requires multiple mechanisms.15,19 Indeed, single-agent thera-
Alefacept Treatment
Group
Any adverse event
Congestion
Infection
Cold
Headaches
Nausea
Mean CD4 Count, Cells/mm3
fectious etiology or were thought to be related to the study
medication. Of the 3 SAEs, 2 occurred in participants receiving placebo—an episode of asthma exacerbation and
an episode of vomiting and dehydration. The alefaceptreceiving individual was hospitalized for right elbow arthropathy without evidence of bacterial or viral infection. The patient’s symptoms were not considered by the
investigator to be related to the study medication.
Laboratory tests revealed no clinically significant
changes in findings for serum chemical analysis. CD4⫹
T-lymphocyte counts were monitored throughout the
study, and the mean CD4 counts remained higher than
250 cells/mm3 (Figure 2). Only 1 person in the alefacept treatment group developed a CD4 count lower than
250 cells/mm3 (239 cells/mm3). Alefacept was held for 1
dose, after which the patient’s CD4 count returned to normal (658 cells/mm3). This individual experienced no further declines in CD4 count.
1000
800
600
400
200
Alefacept group
Placebo group
0
CD4
CD4
(Screening) (wk 1)
CD4
(wk 3)
CD4
(wk 5)
CD4
(wk 7)
CD4
(wk 9)
CD4
CD4
(wk 12) (wk 24)
Week of Measurement
Figure 2. Mean CD4 counts of alefacept- and placebo-treated individuals
throughout the treatment and posttreatment observation periods.
pies,includingefalizumab,alsoaninhibitorofT-lymphocyte
function, are ineffective in treating AA.3
Because AA may have multiple effectors, successful
treatment for AA may require combination therapy with
mechanistically different agents; perhaps alefacept in combination with other modalities would be effective. Because active AA is characterized by a type-1 immune response, future use of therapies that inhibit this response
may prove successful.15,20 Also, successful therapy may
involve the shifting from a type 1 to a type 2 immune
response.15,20 Clearly, AA is a complex disease, and further research into both understanding its pathophysiologic mechanism and the development of effective therapies is needed.
Accepted for Publication: February 1, 2009.
Correspondence: Bruce E. Strober, MD, PhD, Department of Dermatology, New York University Medical Center, 550 First Ave, TCH-158, New York, NY 10016 (strober
@nyc.rr.com).
Author Contributions: Drs Strober and Menon had full
access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the
data analysis. Study concept and design: Strober,
McMichael, Krueger, and Shapiro. Acquisition of data:
Strober, Menon, McMichael, Hordinsky, Krueger, Panko,
and Lustgarten. Analysis and interpretation of data: Strober,
Menon, Hordinsky, Siu, and Ross. Drafting of the manuscript: Strober, Menon, and Hordinsky. Critical revision
of the manuscript for important intellectual content:
1265
McMichael, Hordinsky, Krueger, Panko, Siu, Lustgarten, Ross, and Shapiro. Statistical analysis: Strober, Menon, and Ross. Administrative, technical, and material support: Menon, McMichael, Hordinsky, Krueger, Panko, and
Shapiro. Study supervision: Strober. Drafting and design
of patient case report form files and protocol: Ross.
Financial Disclosure: Dr Strober serves as a speaker for
Astellas Pharma US. Dr McMichael serves on the Scientific Advisory Council to the National Alopecia Areata
Foundation.
Funding/Support: This research was supported by a grant
from the National Alopecia Areata Foundation, San Rafael, California, and by Biogen Idec and Astellas Pharma
US.
Role of the Sponsors: The sponsors had no role in the
design and conduct of the study; in the collection, analysis, and interpretation of data; or in the preparation, review, or approval of the manuscript.
Additional Contributions: Vicki Kalabokes, BA, of the
National Alopecia Areata Foundation, provided encouragement and tireless organizational support throughout
the duration of this study.
REFERENCES
1. Wasserman D, Guzman-Sanchez DA, Scott K, McMichael A. Alopecia areata. Int
J Dermatol. 2007;46(2):121-131.
2. Dudda-Subramanya R, Alexis AF, Siu K, Sinha AA. Alopecia areata: genetic complexity underlies clinical heterogeneity. Eur J Dermatol. 2007;17(5):367-374.
3. Price VH, Hordinsky MK, Olsen EA, et al. Subcutaneous efalizumab is not effective in the treatment of alopecia areata. J Am Acad Dermatol. 2008;58(3):395402.
4. McDonagh AJ, Tazi-Ahnini R. Epidemiology and genetics of alopecia areata. Clin
Exp Dermatol. 2002;27(5):405-409.
5. Lu W, Shapiro J, Yu M, et al. Alopecia areata: pathogenesis and potential for therapy.
Expert Rev Mol Med. 2006;8(14):1-19.
6. Christoph T, Müller-Röver S, Audring H, et al. The human hair follicle immune
system: cellular composition and immune privilege. Br J Dermatol. 2000;142
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7. Whiting DA. Histopathologic features of alopecia areata: a new look. Arch Dermatol.
2003;139(12):1555-1559.
8. Gilhar A, Ullmann Y, Berkutzki T, Assy B, Kalish RS. Autoimmune hair loss (alopecia areata) transferred by T lymphocytes to human scalp explants on SCID mice.
J Clin Invest. 1998;101(1):62-67.
9. Strober BE, Siu K, Alexis AF, et al. Etanercept does not effectively treat moderate
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10. Amevive [package insert]. Cambridge, MA: Biogen Inc; 2003.
11. Strober BE, Menon K. Alefacept for the treatment of psoriasis and other dermatologic diseases. Dermatol Ther. 2007;20(4):270-276.
12. Vaishnaw AK, TenHoor CN. Pharmacokinetics, biologic activity, and tolerability
of alefacept by intravenous and intramuscular administration. J Pharmacokinet
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13. Gottlieb AB. Alefacept is well tolerated in patients with chronic plaque psoriasis.
J Cutan Med Surg. 2004;8(suppl 2):14-19.
14. Lebwohl M, Christophers E, Langley RG, Ortonne JP, Roberts J, Griffiths CE; Alefacept Clinical Study Group. An international, randomized, double-blind, placebocontrolled phase 3 trial of intramuscular alefacept in patients with chronic plaque
psoriasis. Arch Dermatol. 2003;139(6):719-727.
15. Heffernan MP, Hurley MY, Martin KS, Smith DI, Anadkat MJ. Alefacept for alopecia areata. Arch Dermatol. 2005;141(12):1513-1516.
16. Bui K, Polisetty S, Gilchrist H, Jackson SM, Frederic J. Successful treatment of
alopecia universalis with alefacept: a case report and review of the literature. Cutis.
2008;81(5):431-434.
17. Olsen E, Hordinsky M, McDonald-Hull S, et al; National Alopecia Areata Foundation. Alopecia areata investigational assessment guidelines. J Am Acad Dermatol.
1999;40(2, pt 1):242-246.
18. Scheinfeld N. Alefacept: a safety profile. Expert Opin Drug Saf. 2005;4(6):975-985.
19. McElwee KJ, Freyschmidt-Paul P, Zöller M, Hoffmann R. Alopecia areata susceptibility in rodent models. J Investig Dermatol Symp Proc. 2003;8(2):182187.
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Alefacept for Severe Alopecia Areata A Randomized, Double-blind, Placebo-Controlled Study

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