- Email: [email protected]
Rapid onset of action in patients with moderate-to-severe psoriasis treated with brodalumab: A pooled analysis of data from two phase 3 randomized clinical trials (AMAGINE-2 and AMAGINE-3)
372 Research Letters
REFERENCES 1. Ohata C, Ishii N, Koga H, et al. Coexistence of autoimmune bullous diseases (AIBDs) and psoriasis: a series of 145 cases. J Am Acad Dermatol. 2015;73(1):50-55. 2. Chen YJ, Wu CY, Lin MW, et al. Comorbidity profiles among patients with bullous pemphigoid: a nationwide populationbased study. Br J Dermatol. 2011;165(3):593-599. 3. Zhang LM, Wu J, Xiao T, et al. Treatment and mortality rate of bullous pemphigoid in China: a hospital-based study. Eur J Dermatol. 2013;23(1):94-98. 4. Joly P, Baricault S, Sparsa A, et al. Incidence and mortality of bullous pemphigoid in France. J Invest Dermatol. 2012;132(8): 1998-2004. 5. Vaccaro M, Magaudda L, Cutroneo G, et al. Changes in the distribution of laminin alpha1 chain in psoriatic skin: immunohistochemical study using confocal laser scanning microscopy. Br J Dermatol. 2002;146(3):392-398. http://dx.doi.org/10.1016/j.jaad.2017.02.057
Rapid onset of action in patients with moderate-to-severe psoriasis treated with brodalumab: A pooled analysis of data from two phase 3 randomized clinical trials (AMAGINE-2 and AMAGINE-3) To the Editor: Brodalumab, a human monoclonal antibody that binds to interleukin (IL)-17RA (receptor subunit utilized by pro-inflammatory cytokines IL-17A, IL-17F, and IL-17A/F), has been shown at doses of 210 mg every 2 weeks to be superior to ustekinumab and placebo in treating moderate-to-severe plaque psoriasis in 2 large phase 3 studies: AMAGINE-2 and AMAGINE-3.1,2 Time to achieve significant improvements in psoriasis disease severity is an important aspect of patient treatment and education. Our objective was to evaluate the speed of action of brodalumab with the use of data from AMAGINE-2 and AMAGINE-3. Detailed study designs are reported elsewhere.2 In these analyses, efficacy assessments included median times for 25% of patients to achieve Psoriasis Area and Severity Index (PASI) 75, static Physician’s Global Assessment (sPGA) success (score 0/1), and median times to achieve 25%, 50%, and 75% reductions in baseline PASI. Estimated times for 25% of patients to achieve PASI 75 were 2.1 (95% confidence interval [CI], 2.0-2.3) weeks for brodalumab and 4.8 (95% CI, 4.55.1) weeks for ustekinumab (Fig 1, A); times for 25% of patients to achieve sPGA success were 2.5 (95% CI, 2.4-2.6) weeks and 5.6 (95% CI, 5.2-6.0) weeks, respectively (Fig 1, B). Differences in speed of efficacy between brodalumab and ustekinumab were evident as early as week 1, whereas 3.5% (95% CI, 2.5-4.7) of brodalumab-treated patients achieved sPGA success and PASI 75 in individual
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independent assessments, compared with 0.7% (sPGA success; 95% CI, 0.2-1.7) and 0.2% (PASI 75; 95% CI, 0.0-0.9) of ustekinumab-treated patients (PASI 75 and sPGA success, both P \.001). By week 12, 85.7% (95% CI, 83.6-87.6) and 79.1% (95% CI, 76.8-81.4) of patients treated with brodalumab achieved PASI 75 and sPGA success, respectively, compared with 69.7% (95% CI, 65.8-73.3) and 59.1% (95% CI, 55.0-63.0) of patients treated with ustekinumab (both P \.001). Improvement in baseline PASI over time also revealed rapid and sustained brodalumab efficacy. Median time to achieve a 75% improvement in baseline PASI (PASI 75) was estimated at 4.2 weeks for brodalumab and 9.4 weeks for ustekinumab (Fig 2). Furthermore, times needed to achieve 25% and 50% median improvement in baseline PASI were 0.8 [95% CI, 0.8-0.8] and 1.8 [95% CI, 1.8-1.9] weeks, respectively, for brodalumab compared with 1.8 (95% CI, 1.7-2.0) and 4.5 (95% CI, 4.24.8) weeks for ustekinumab (all P \ .0001). Our data suggest that brodalumab 210 mg every 2 weeks provides rapid improvement in disease severity of moderate-to-severe plaque psoriasis. In addition, comparative data suggest that brodalumab may have the most rapid onset of action of any biologic therapy used in psoriasis (2.1 weeks versus 2.4 weeks for ixekizumab,3 3.0 weeks for high-dose secukinumab),4 when using the measure of the time required for 25% of patients to achieve PASI 75. Brodalumab also demonstrates shorter time to achieve a 50% improvement in baseline PASI (1.8 weeks) compared with that reported for ixekizumab (1.9 weeks)5 or high-dose secukinumab (3 weeks).4 In addition, the median time to achieve PASI 75 with brodalumab in our study was 4.2 weeks compared with 4.4 weeks, previously reported for ixekizumab.5 The authors acknowledge Brian Bulley, MSc, of Konic Limited for medical writing support. Valeant Pharmaceuticals North America LLC funded Konic’s activities pertaining to this report.
Andrew Blauvelt, MD, MBA,a Kim A. Papp, MD, PhD,b Mark G. Lebwohl, MD,c Lawrence J. Green, MD,d Sylvia Hsu, MD,e Varsha Bhatt, PhD,f Shipra Rastogi, PhD, MBA,g Radhakrishnan Pillai, PhD,f and Robert Israel, MDg Oregon Medical Research Center, Portland, Oregona; Probity Medical Research, Waterloo, Ontario, Canadab; Icahn School of Medicine at Mount Sinai, New York, New Yorkc; Department of Dermatology, Temple University School, Philadelphia, Pennsylvaniad; Department of
J AM ACAD DERMATOL VOLUME 77, NUMBER 2
Research Letters 373
Fig 1. Percentage of patients achieving Psoriasis Area and Severity Index (PASI) 75 (nonresponder imputation) in induction phase (baseline to week 12, pooled data) (A). Time for 25% of patients to achieve PASI 75 was estimated from bootstrap samples with the use of linear interpolation between time points. Percentage of patients achieving Physician’s Global Assessment (sPGA) success (0 or 1) (nonresponder imputation) in induction phase (baseline to week 12, pooled data) (B). Time for 25% of patients to achieve sPGA was estimated from bootstrap samples with the use of linear interpolation between time points.
Dermatology, Baylor College of Medicine, Houston, Texase; Dow Pharmaceutical Sciences (a division of Valeant Pharmaceuticals North America, LLC), Petaluma, Californiaf; and Valeant Pharmaceuticals North America LLC, Bridgewater, New Jersey.g This work was supported by Valeant Pharmaceuticals North America LLC, Bridgewater, New Jersey. Conflicts of interest: Dr Blauvelt has served as a scientific adviser and clinical study investigator for AbbVie, Inc, Amgen, Inc, Boehringer Ingelheim, Celgene Corporation, Dermira, Inc,
Genentech, Inc, GlaxoSmithKline, Janssen Pharmaceutica, Eli Lilly & Co, Merck & Co, Inc, Novartis AG, Pfizer, Inc, Regeneron Pharmaceuticals, Inc, Sandoz, Sanofi Genzyme, Sun Pharmaceutical Industries, Ltd, UCB, and Valeant Pharmaceuticals North America LLC, and, as a paid speaker for Eli Lilly & Co, Regeneron Pharmaceuticals, Inc, and Sanofi Genzyme, Dr Papp is a consultant, an investigator, and on the speakers bureau for AbbVie, Amgen, Astellas, Bayer, Boehringer Ingelheim, Celgene, Eli Lilly, Forward, Galderma, Janssen, LEO, Merck, Novartis, Pfizer, Roche, and UCB. Dr Lebwohl is an
374 Research Letters
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Fig 2. Change from baseline Psoriasis Area and Severity Index (PASI) in induction phase (baseline to week 12, pooled data). A repeated-measures, mixed-effects model was used to analyze the percentage change from baseline in the PASI. Symbols without black outlining indicate least-squares means; I-bars, 95% confidence intervals (CIs). Median time to 75%, 50%, and 25% reduction in mean PASI was estimated from bootstrap samples with the use of linear interpolation between time points. Multiple imputation was used to impute missing data with 3 imputed datasets.
employee of the Mount Sinai Medical Center, which receives research funds from Amgen, Anacor, Aqua, Canfite Biopharma, Celgene, Clinuvel, Coronado Biosciences, Eli Lilly, Ferndale, Janssen, Leo, Merck, Novartis, Pfizer, Sandoz, and Valeant. Dr Green is an investigator, consultant, and/or speaker for AbbVie, Amgen, Celgene, Merck, Novartis, and Valeant. Dr Hsu is a consultant for AbbVie, Amgen, Novartis, Eli Lilly, Janssen, Regeneron, Sanofi, and Valeant. Drs Bhatt, Rastogi, Pillai, and Israel are employees of Valeant Pharmaceuticals. Reprint requests: Andrew Blauvelt, MD, MBA, Oregon Medical Research Center, 9495 SW Locust Street, Suite G, Portland, OR 97223. E-mail: [email protected] REFERENCES 1. Papp KA, Reich K, Paul C, et al. A prospective phase III, double-blind, placebo-controlled study of brodalumab in patients with moderate-to-severe plaque psoriasis. Br J Dermatol. 2016;175:273-286. 2. Lebwohl M, Strober B, Menter A, et al. Phase 3 studies comparing brodalumab with ustekinumab in psoriasis. N Engl J Med. 2015;373:1318-1328. 3. Griffiths CEM, Reich K, Lebwohl M, et al. Comparison of ixekizumab with etanercept or placebo in moderateto-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials. Lancet. 2015;386(9993): 541-551. 4. Langley RG, Elewski BE, Lebwohl M. Secukinumab in plaque psoriasis: results of two phase 3 trials. N Engl J Med. 2014; 371(4):326-338.
5. Leonardi C, Langley R, Blauvelt A, et al. Rapid onset of efficacy in patients with psoriasis treated with ixekizumab: a pooled analysis of data from two randomized clinical trials (UNCOVER-2 and UNCOVER-3). Poster presented at Am Acad Dermatol Annual Meeting, March 2016, Washington, DC. http://dx.doi.org/10.1016/j.jaad.2017.03.026
The quinacrine experience in a population of patients with cutaneous lupus erythematosus and dermatomyositis To the Editor: Quinacrine, a compounded antimalarial, has been used for patients intolerant or unresponsive to hydroxychloroquine. In March 2016, the Pharmacy Compounding Advisory Committee raised safety concerns about quinacrine-associated aplastic anemia. In addition, the Office of New Drugs advised that although quinacrine might be safe at the 100 mg/ day dose prescribed for rheumatic skin diseases, generalists might prescribe this drug at higher doses and for alternative indications that have yet to be formally studied. As a consequence, this orphan drug may no longer be compounded and might become effectively unavailable with a prescription, requiring an Investigational New Drug, institutional review board approval, patient consent, and toxicity reporting.1 To evaluate the need for continued access, we surveyed providers at various institutions to determine their quinacrine prescribing practices. Two rheumatologic skin disease specialists (Drs Costner and Bangert) from Texas estimated having seen 96 and 30 patients on quinacrine within the last year but
REFERENCES 1. Ohata C, Ishii N, Koga H, et al. Coexistence of autoimmune bullous diseases (AIBDs) and psoriasis: a series of 145 cases. J Am Acad Dermatol. 2015;73(1):50-55. 2. Chen YJ, Wu CY, Lin MW, et al. Comorbidity profiles among patients with bullous pemphigoid: a nationwide populationbased study. Br J Dermatol. 2011;165(3):593-599. 3. Zhang LM, Wu J, Xiao T, et al. Treatment and mortality rate of bullous pemphigoid in China: a hospital-based study. Eur J Dermatol. 2013;23(1):94-98. 4. Joly P, Baricault S, Sparsa A, et al. Incidence and mortality of bullous pemphigoid in France. J Invest Dermatol. 2012;132(8): 1998-2004. 5. Vaccaro M, Magaudda L, Cutroneo G, et al. Changes in the distribution of laminin alpha1 chain in psoriatic skin: immunohistochemical study using confocal laser scanning microscopy. Br J Dermatol. 2002;146(3):392-398. http://dx.doi.org/10.1016/j.jaad.2017.02.057
Rapid onset of action in patients with moderate-to-severe psoriasis treated with brodalumab: A pooled analysis of data from two phase 3 randomized clinical trials (AMAGINE-2 and AMAGINE-3) To the Editor: Brodalumab, a human monoclonal antibody that binds to interleukin (IL)-17RA (receptor subunit utilized by pro-inflammatory cytokines IL-17A, IL-17F, and IL-17A/F), has been shown at doses of 210 mg every 2 weeks to be superior to ustekinumab and placebo in treating moderate-to-severe plaque psoriasis in 2 large phase 3 studies: AMAGINE-2 and AMAGINE-3.1,2 Time to achieve significant improvements in psoriasis disease severity is an important aspect of patient treatment and education. Our objective was to evaluate the speed of action of brodalumab with the use of data from AMAGINE-2 and AMAGINE-3. Detailed study designs are reported elsewhere.2 In these analyses, efficacy assessments included median times for 25% of patients to achieve Psoriasis Area and Severity Index (PASI) 75, static Physician’s Global Assessment (sPGA) success (score 0/1), and median times to achieve 25%, 50%, and 75% reductions in baseline PASI. Estimated times for 25% of patients to achieve PASI 75 were 2.1 (95% confidence interval [CI], 2.0-2.3) weeks for brodalumab and 4.8 (95% CI, 4.55.1) weeks for ustekinumab (Fig 1, A); times for 25% of patients to achieve sPGA success were 2.5 (95% CI, 2.4-2.6) weeks and 5.6 (95% CI, 5.2-6.0) weeks, respectively (Fig 1, B). Differences in speed of efficacy between brodalumab and ustekinumab were evident as early as week 1, whereas 3.5% (95% CI, 2.5-4.7) of brodalumab-treated patients achieved sPGA success and PASI 75 in individual
J AM ACAD DERMATOL
AUGUST 2017
independent assessments, compared with 0.7% (sPGA success; 95% CI, 0.2-1.7) and 0.2% (PASI 75; 95% CI, 0.0-0.9) of ustekinumab-treated patients (PASI 75 and sPGA success, both P \.001). By week 12, 85.7% (95% CI, 83.6-87.6) and 79.1% (95% CI, 76.8-81.4) of patients treated with brodalumab achieved PASI 75 and sPGA success, respectively, compared with 69.7% (95% CI, 65.8-73.3) and 59.1% (95% CI, 55.0-63.0) of patients treated with ustekinumab (both P \.001). Improvement in baseline PASI over time also revealed rapid and sustained brodalumab efficacy. Median time to achieve a 75% improvement in baseline PASI (PASI 75) was estimated at 4.2 weeks for brodalumab and 9.4 weeks for ustekinumab (Fig 2). Furthermore, times needed to achieve 25% and 50% median improvement in baseline PASI were 0.8 [95% CI, 0.8-0.8] and 1.8 [95% CI, 1.8-1.9] weeks, respectively, for brodalumab compared with 1.8 (95% CI, 1.7-2.0) and 4.5 (95% CI, 4.24.8) weeks for ustekinumab (all P \ .0001). Our data suggest that brodalumab 210 mg every 2 weeks provides rapid improvement in disease severity of moderate-to-severe plaque psoriasis. In addition, comparative data suggest that brodalumab may have the most rapid onset of action of any biologic therapy used in psoriasis (2.1 weeks versus 2.4 weeks for ixekizumab,3 3.0 weeks for high-dose secukinumab),4 when using the measure of the time required for 25% of patients to achieve PASI 75. Brodalumab also demonstrates shorter time to achieve a 50% improvement in baseline PASI (1.8 weeks) compared with that reported for ixekizumab (1.9 weeks)5 or high-dose secukinumab (3 weeks).4 In addition, the median time to achieve PASI 75 with brodalumab in our study was 4.2 weeks compared with 4.4 weeks, previously reported for ixekizumab.5 The authors acknowledge Brian Bulley, MSc, of Konic Limited for medical writing support. Valeant Pharmaceuticals North America LLC funded Konic’s activities pertaining to this report.
Andrew Blauvelt, MD, MBA,a Kim A. Papp, MD, PhD,b Mark G. Lebwohl, MD,c Lawrence J. Green, MD,d Sylvia Hsu, MD,e Varsha Bhatt, PhD,f Shipra Rastogi, PhD, MBA,g Radhakrishnan Pillai, PhD,f and Robert Israel, MDg Oregon Medical Research Center, Portland, Oregona; Probity Medical Research, Waterloo, Ontario, Canadab; Icahn School of Medicine at Mount Sinai, New York, New Yorkc; Department of Dermatology, Temple University School, Philadelphia, Pennsylvaniad; Department of
J AM ACAD DERMATOL VOLUME 77, NUMBER 2
Research Letters 373
Fig 1. Percentage of patients achieving Psoriasis Area and Severity Index (PASI) 75 (nonresponder imputation) in induction phase (baseline to week 12, pooled data) (A). Time for 25% of patients to achieve PASI 75 was estimated from bootstrap samples with the use of linear interpolation between time points. Percentage of patients achieving Physician’s Global Assessment (sPGA) success (0 or 1) (nonresponder imputation) in induction phase (baseline to week 12, pooled data) (B). Time for 25% of patients to achieve sPGA was estimated from bootstrap samples with the use of linear interpolation between time points.
Dermatology, Baylor College of Medicine, Houston, Texase; Dow Pharmaceutical Sciences (a division of Valeant Pharmaceuticals North America, LLC), Petaluma, Californiaf; and Valeant Pharmaceuticals North America LLC, Bridgewater, New Jersey.g This work was supported by Valeant Pharmaceuticals North America LLC, Bridgewater, New Jersey. Conflicts of interest: Dr Blauvelt has served as a scientific adviser and clinical study investigator for AbbVie, Inc, Amgen, Inc, Boehringer Ingelheim, Celgene Corporation, Dermira, Inc,
Genentech, Inc, GlaxoSmithKline, Janssen Pharmaceutica, Eli Lilly & Co, Merck & Co, Inc, Novartis AG, Pfizer, Inc, Regeneron Pharmaceuticals, Inc, Sandoz, Sanofi Genzyme, Sun Pharmaceutical Industries, Ltd, UCB, and Valeant Pharmaceuticals North America LLC, and, as a paid speaker for Eli Lilly & Co, Regeneron Pharmaceuticals, Inc, and Sanofi Genzyme, Dr Papp is a consultant, an investigator, and on the speakers bureau for AbbVie, Amgen, Astellas, Bayer, Boehringer Ingelheim, Celgene, Eli Lilly, Forward, Galderma, Janssen, LEO, Merck, Novartis, Pfizer, Roche, and UCB. Dr Lebwohl is an
374 Research Letters
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Fig 2. Change from baseline Psoriasis Area and Severity Index (PASI) in induction phase (baseline to week 12, pooled data). A repeated-measures, mixed-effects model was used to analyze the percentage change from baseline in the PASI. Symbols without black outlining indicate least-squares means; I-bars, 95% confidence intervals (CIs). Median time to 75%, 50%, and 25% reduction in mean PASI was estimated from bootstrap samples with the use of linear interpolation between time points. Multiple imputation was used to impute missing data with 3 imputed datasets.
employee of the Mount Sinai Medical Center, which receives research funds from Amgen, Anacor, Aqua, Canfite Biopharma, Celgene, Clinuvel, Coronado Biosciences, Eli Lilly, Ferndale, Janssen, Leo, Merck, Novartis, Pfizer, Sandoz, and Valeant. Dr Green is an investigator, consultant, and/or speaker for AbbVie, Amgen, Celgene, Merck, Novartis, and Valeant. Dr Hsu is a consultant for AbbVie, Amgen, Novartis, Eli Lilly, Janssen, Regeneron, Sanofi, and Valeant. Drs Bhatt, Rastogi, Pillai, and Israel are employees of Valeant Pharmaceuticals. Reprint requests: Andrew Blauvelt, MD, MBA, Oregon Medical Research Center, 9495 SW Locust Street, Suite G, Portland, OR 97223. E-mail: [email protected] REFERENCES 1. Papp KA, Reich K, Paul C, et al. A prospective phase III, double-blind, placebo-controlled study of brodalumab in patients with moderate-to-severe plaque psoriasis. Br J Dermatol. 2016;175:273-286. 2. Lebwohl M, Strober B, Menter A, et al. Phase 3 studies comparing brodalumab with ustekinumab in psoriasis. N Engl J Med. 2015;373:1318-1328. 3. Griffiths CEM, Reich K, Lebwohl M, et al. Comparison of ixekizumab with etanercept or placebo in moderateto-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials. Lancet. 2015;386(9993): 541-551. 4. Langley RG, Elewski BE, Lebwohl M. Secukinumab in plaque psoriasis: results of two phase 3 trials. N Engl J Med. 2014; 371(4):326-338.
5. Leonardi C, Langley R, Blauvelt A, et al. Rapid onset of efficacy in patients with psoriasis treated with ixekizumab: a pooled analysis of data from two randomized clinical trials (UNCOVER-2 and UNCOVER-3). Poster presented at Am Acad Dermatol Annual Meeting, March 2016, Washington, DC. http://dx.doi.org/10.1016/j.jaad.2017.03.026
The quinacrine experience in a population of patients with cutaneous lupus erythematosus and dermatomyositis To the Editor: Quinacrine, a compounded antimalarial, has been used for patients intolerant or unresponsive to hydroxychloroquine. In March 2016, the Pharmacy Compounding Advisory Committee raised safety concerns about quinacrine-associated aplastic anemia. In addition, the Office of New Drugs advised that although quinacrine might be safe at the 100 mg/ day dose prescribed for rheumatic skin diseases, generalists might prescribe this drug at higher doses and for alternative indications that have yet to be formally studied. As a consequence, this orphan drug may no longer be compounded and might become effectively unavailable with a prescription, requiring an Investigational New Drug, institutional review board approval, patient consent, and toxicity reporting.1 To evaluate the need for continued access, we surveyed providers at various institutions to determine their quinacrine prescribing practices. Two rheumatologic skin disease specialists (Drs Costner and Bangert) from Texas estimated having seen 96 and 30 patients on quinacrine within the last year but