The Experts below are selected from a list of 14421 Experts worldwide ranked by ideXlab platform
Lee T Zane - One of the best experts on this subject based on the ideXlab platform.
-
a novel nonsteroidal topical anti inflammatory phosphodiesterase 4 Inhibitor crisaborole ointment reduced pruritus and signs of atopic dermatitis in 2 phase 3 studies in children and adults
Pediatrics, 2018Co-Authors: Adelaide A Hebert, Eric L Simpson, Mark Lebwohl, Lawrence F Eichenfield, Amy S Paller, Wynnis L Tom, Matilda H Hughes, Lee T ZaneAbstract:Background: Atopic dermatitis (AD) is an inflammatory skin disease that presents with intense pruritus and red, inflamed lesions. Crisaborole Topical Ointment, 2% (Anacor Pharmaceuticals, Palo Alto, CA), is an investigational, nonsteroidal, topical anti-inflammatory, phosphodiesterase 4 Inhibitor for the treatment of AD. Objective: To evaluate the additional predefined efficacy endpoints on the impact of crisaborole ointment on pruritus and signs of AD from 2 Phase …
-
Early Relief of Pruritus in Atopic Dermatitis with Crisaborole Ointment, A Non-steroidal, Phosphodiesterase 4 Inhibitor
Society for Publication of Acta Dermato-Venereologica, 2018Co-Authors: Gil Yosipovitch, Linda F. Gold, Mark G. Lebwohl, Jonathan I. Silverberg, Anna M. Tallman, Lee T ZaneAbstract:Pruritus occurs in all patients with atopic dermatitis and requires quick relief to reduce disease exacerbation and improve quality of life. Crisaborole ointment is a non-steroidal phosphodiesterase 4 Inhibitor for the treatment of mild-to-moderate atopic dermatitis. This post hoc analysis explores crisaborole ointment for early relief of pruritus in patients with mild to moderate atopic dermatitis from 2 phase III studies. Patients received crisaborole or vehicle twice daily for 28 days. Pruritus was graded on a 4-point scale of none (0) to severe (3). Early improvement in pruritus required a score of none (0) or mild (1), with a ≥ 1-grade improvement from baseline on day 6. Significantly more patients experienced early improvement in pruritus with crisaborole than with vehicle (56.6% vs 39.5%; p
-
two phase 3 study results of children and adults with mild to moderate atopic dermatitis treated with crisaborole topical ointment 2 a novel nonsteroidal topical anti inflammatory phosphodiesterase 4 Inhibitor
Journal of Immunology, 2016Co-Authors: Lee T Zane, Mark Lebwohl, Lawrence F Eichenfield, Amy S Paller, Wynnis L Tom, Robin L Blumenthal, Mark Boguniewicz, Robert S Call, Douglass W Forsha, William C ReesAbstract:Up to 90% of children and adults with atopic dermatitis (AD), a chronic inflammatory skin disease, present with mild-to-moderate disease. Crisaborole Topical Ointment, 2%, is a novel, nonsteroidal, topical, anti-inflammatory, phosphodiesterase 4 Inhibitor being studied for the treatment of AD. The efficacy and safety of crisaborole was assessed in 2 identically designed, multicenter, vehicle-controlled, double-blind Phase 3 studies (301 and 302) that enrolled patients ≥2 years old with mild-to-moderate AD affecting ≥5% of body surface area (BSA). Patients were randomized 2:1 to receive crisaborole or vehicle twice daily and evaluated on Days 8, 15, 22, and 29. The primary endpoint defined success in the Investigator’s Static Global Assessment (ISGA) as “almost clear/1” or “clear/0” with ≥2-grade improvement from baseline at Day 29. Secondary endpoints analyzed the time to success and the percentage of patients achieving “almost clear/1” or “clear/0” on ISGA. At Day 29, more crisaborole-treated patients achieved ISGA success than vehicle (301: 32.8% vs 25.4%, P = 0.038; 302: 31.4% vs 18.0%, P P = 0.005; 302: 48.5% vs 29.7%, P P
-
crisaborole topical ointment 2 a novel nonsteroidal anti inflammatory topical phosphodiesterase 4 Inhibitor reduced pruritus and signs of atopic dermatitis in 2 phase 3 studies in children and adults with mild to moderate atopic dermatitis
Journal of Immunology, 2016Co-Authors: Lee T Zane, Eric L Simpson, Mark Lebwohl, Adelaide A Hebert, Lawrence F Eichenfield, Amy S Paller, Wynnis L Tom, Matilda H HughesAbstract:Atopic dermatitis (AD) is an inflammatory skin disease with intense pruritus and eczematous lesions. Crisaborole Topical Ointment, 2% (Anacor Pharmaceuticals, Palo Alto, CA), is an investigational, nonsteroidal, anti-inflammatory, topical, phosphodiesterase 4 Inhibitor for the treatment of AD. Here, we present the impact of crisaborole on pruritus and signs of AD evaluated as supportive efficacy endpoints for 2 Phase 3 studies (301, 302). Patients ≥2 years old with mild-to-moderate AD were enrolled in 2 double-blind, vehicle-controlled, multicenter Phase 3 studies of identical design. Patients were randomized 2:1 to receive crisaborole or vehicle twice daily for 28 days. Supportive efficacy endpoints examined severity of pruritus (measured twice daily) and signs of AD (measured weekly) on a 4-point scale (None [0] to Severe [3]). Success was defined for pruritus or each sign or symptom of AD as achievement of None (0) or Mild (1) with ≥1-grade improvement from baseline. Improvement in pruritus was achieved sooner in crisaborole-treated patients than vehicle-treated patients (pooled data: median, 1.37 vs 1.70 days; P = 0.001). A greater proportion of crisaborole-treated patients achieved success for all clinical signs of AD by Day 29 (301, 302; erythema: 62.8% vs 46.1%; 54.9% vs 33.9%; induration/papulation: 57.7% vs 54.8%; −51.9% vs 40.2%; exudation: 41.0% vs 33.3%; 38.1% vs 27.2%; excoriation: 63.0% vs 51.8%; 57.2% vs 44.2%; lichenification: 51.7% vs 46.5%; 51.4% vs 35.3%). In 2 large Phase 3 studies, crisaborole demonstrated early relief of pruritus and showed improvement in all measured signs of AD. Crisaborole Topical Ointment, 2%, may represent a safe and efficacious treatment for patients ≥2 years with mild-to-moderate AD.
-
crisaborole topical ointment 2 a nonsteroidal topical anti inflammatory phosphodiesterase 4 Inhibitor in clinical development for the treatment of atopic dermatitis
Journal of Drugs in Dermatology, 2016Co-Authors: Kurt Jarnagin, Lee T Zane, Sanjay Chanda, Dina Coronado, E Guttmanyassky, Mark LebwohlAbstract:Crisaborole topical ointment, 2% (formerly known as AN2728) is a benzoxaborole, nonsteroidal, topical, anti-inflammatory phosphodiesterase 4 (PDE4) Inhibitor investigational compound that recently completed phase 3 studies for the treatment of mild to moderate atopic dermatitis (AD). The unique configuration of boron within the crisaborole molecule enables selective targeting and inhibition of PDE4, an enzyme that converts the intracellular second messenger 3'5'-cyclic adenosine monophosphate (cAMP) into the active metabolite adenosine monophosphate (AMP). By inhibiting PDE4 and thus increasing levels of cAMP, crisaborole controls inflammation. The use of boron chemistry enabled synthesis of a low-molecular-weight compound (251 daltons), thereby facilitating effective penetration of crisaborole through human skin. In vitro experiments showed that crisaborole inhibits cytokine production from peripheral blood mononuclear cells in a pattern similar to other PDE4 Inhibitors and distinct from corticosteroids. Crisaborole also displayed topical anti-inflammatory activity in a skin inflammation model. Once crisaborole reaches systemic circulation after topical application, it is metabolized to inactive metabolites. This limits systemic exposure to crisaborole and systemic PDE4 inhibition. In phase 1 and 2 clinical studies, crisaborole ointment, 2% was generally well tolerated and improved AD disease severity scores, pruritus, and all other AD signs and symptoms. Two large, randomized, controlled, phase 3, pivotal clinical trials assessing the efficacy and safety of crisaborole topical ointment, 2% in children, adolescents, and adults with mild to moderate AD were recently completed with positive results.
Philip J. Mease - One of the best experts on this subject based on the ideXlab platform.
-
fri0470 long term 156 week safety profile of apremilast an oral phosphodiesterase 4 Inhibitor in patients with psoriatic arthritis pooled safety analysis of 3 phase iii randomized controlled trials
Annals of the Rheumatic Diseases, 2016Co-Authors: Philip J. Mease, K Shah, Juan J Gomezreino, Dafna D Gladman, Eric Lespessailles, Stephen Hall, Georg Schett, A Kavanaugh, L Teng, J WollenhauptAbstract:Background Apremilast (APR), a phosphodiesterase 4 Inhibitor, acts to regulate immune activity in psoriatic arthritis (PsA) patients. PALACE 1 (NCT01172938), 2 (NCT01212757), and 3 (NCT01212770) compared the efficacy and safety of APR with placebo (PBO) in patients with active PsA despite prior conventional DMARDs and/or biologics. Objectives Assess the long-term safety of APR treatment for patients treated for up to 3 years with APR. Methods Patients were randomized (1:1:1) to PBO, APR 30 mg BID (APR30), or APR 20 mg BID (APR20) stratified by baseline DMARD use (yes/no). The PBO-controlled phase continued to Week 24; PBO patients were re-randomized to APR30 or APR20 at Week 16 (early escape) or Week 24. Double-blind APR treatment continued to Week 52; patients could continue to receive APR during an open-label, long-term treatment phase. Visits in years 2 and 3 were scheduled at 13-week intervals. Results 1493 patients were randomized and received ≥1 dose of study medication (PBO: n=495; APR30: n=497; APR20: n=501). At the studies9 3-year data cut, a total of 1441 (1209.3 patient-years), 1028 (937.8 patient-years), and 865 (790.4 patient-years) patients received APR in the Weeks 0 to ≤52, Weeks >52 to ≤104, and Weeks >104 to ≤156 periods, respectively, relative to the start of APR. During the Weeks 0 to ≤52 APR-exposure period, adverse events (AEs) occurring in ≥5% of APR-exposed patients were diarrhea, nausea, headache, upper respiratory tract infection, and nasopharyngitis (Table). Most diarrhea and nausea events were reported within the first 2 weeks of treatment and usually resolved in 4 weeks without medical intervention. The frequency of gastrointestinal AEs decreased with longer exposure (i.e., Weeks >52 to ≤104 or >104 to ≤156; Table); occurrence >5% of other common AEs either decreased in frequency or remained stable with prolonged exposure (Table). Most AEs were mild or moderate in severity up to 156 weeks of APR-exposure. Rates of depression remained very low, consistent with earlier findings. The rate of serious AEs (SAEs) was 8.1% during Weeks >104 to ≤156 of APR exposure; most SAEs occurred in 1 patient each. For SAEs of special interest (major cardiac events, malignant neoplasm, opportunistic infection), rates were very low and comparable to those in the first year of treatment. Discontinuation due to AEs was 1.6% during Weeks >104 to ≤156 of APR exposure. Marked laboratory abnormalities were infrequent, and most returned to baseline with continued treatment. Conclusions APR demonstrated a favorable safety profile and was well tolerated for up to 156 weeks. These data continue to support the lack of accumulation of immunosuppression and a need for specific laboratory monitoring with APR. The incidence of AEs remained stable or decreased with long-term exposure to APR. Acknowledgement We thank Adewale O. Adebajo for his work on the original abstract. Disclosure of Interest P. Mease Grant/research support from: Abbott, Amgen, Biogen Idec, Bristol-Myers Squibb, Genentech, Janssen, Eli Lilly, Pfizer, Celgene Corporation, Novartis, Roche, Consultant for: Abbott, Amgen, Biogen Idec, Bristol-Myers Squibb, Genentech, Janssen, Eli Lilly, Pfizer, Celgene Corporation, Novartis, Roche, Speakers bureau: Abbott, Amgen, Biogen Idec, Bristol-Myers Squibb, Genentech, Janssen, Eli Lilly, Pfizer, D. Gladman Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Celgene Corporation, Janssen, Pfizer, Novartis, UCB, Consultant for: AbbVie, Amgen, Bristol-Myers Squibb, Celgene Corporation, Janssen, Pfizer, Novartis, UCB, J. Gomez-Reino Grant/research support from: Roche, Schering-Plough, Consultant for: Bristol-Myers Squibb, Pfizer Inc, Roche, Schering-Plough, UCB, Speakers bureau: Bristol-Myers Squibb, Roche, Schering-Plough, Wyeth, S. Hall Grant/research support from: Celgene Corporation, Pfizer, UCB, Bristol-Myers Squibb, Glaxo-Smith Kline, Roche, Janssen, Novartis, Merck, Consultant for: Celgene Corporation, Pfizer, UCB, Bristol-Myers Squibb, Glaxo-Smith Kline, Roche, Janssen, Novartis, Merck, A. Kavanaugh Grant/research support from: Abbott, Amgen, Astra-Zeneca, Bristol-Myers Squibb, Celgene Corporation, Centocor-Janssen, Pfizer, Roche, UCB, Consultant for: Abbott, Amgen, Astra-Zeneca, Bristol-Myers Squibb, Celgene Corporation, Centocor-Janssen, Pfizer, Roche, UCB, E. Lespessailles Grant/research support from: Amgen, Eli Lilly, Novartis, Servier, Speakers bureau: Amgen, Eli Lilly, Novartis, Servier, G. Schett Grant/research support from: Abbott, Celgene Corporation, Roche, UCB, Consultant for: Abbott, Celgene Corporation, Roche, UCB, K. Shah Employee of: Celgene Corporation, L. Teng Employee of: Celgene Corporation, J. Wollenhaupt Grant/research support from: Abbott, Bristol-Myers Squibb, MSD, Pfizer, UCB, Consultant for: Abbott, Bristol-Myers Squibb, MSD, Pfizer, UCB
-
thu0432 long term 104 week safety profile of apremilast an oral phosphodiesterase 4 Inhibitor in patients with psoriatic arthritis pooled safety analysis of three phase 3 randomized controlled trials
Annals of the Rheumatic Diseases, 2015Co-Authors: Philip J. Mease, K Shah, Juan J Gomezreino, A O Adebajo, Dafna D Gladman, Eric Lespessailles, Stephen Hall, Georg Schett, A Kavanaugh, L TengAbstract:Background Apremilast (APR), a phosphodiesterase 4 Inhibitor, helps regulate the immune responses in psoriatic arthritis (PsA). PALACE 1-3 compared APR efficacy/safety with placebo (PBO) in patients (pts) with active PsA despite prior conventional DMARDs and/or biologics. Objectives Overall APR safety/tolerability was assessed in a pooled analysis of PALACE 1-3, with APR exposure ≤104 wks. Methods Pts were randomized (1:1:1) to PBO, APR 20 mg BID (APR20), or APR 30 mg BID (APR30) stratified by baseline DMARD use (yes/no). The PBO-controlled phase continued to Wk 24, with an early escape option at Wk 16. Double-blind APR treatment continued to Wk 52; pts could continue to receive APR during an open-label, long-term treatment phase. We report safety findings from the APR-exposure period (Wks 0 to ≤104). Results 1493 pts were randomized and received ≥1 dose of study medication (PBO: n=495; APR20: n=501; APR30: n=497). A total of 1441 (1209.3 pt-yrs) and 1028 (907.7 pt-yrs) pts received APR in the Wk 0 to ≤52 and Wk >52 to ≤104 periods, respectively. During Wks 0 to ≤52, AEs occurring in ≥5% of APR-exposed pts were diarrhea, nausea, headache, URTI, and nasopharyngitis (Table). Most AEs were mild/moderate in severity during the Wk 0 to ≤104 APR-exposure period; in general, no increase was seen in the incidence/severity of AEs with longer term exposure. During Wks >52 to ≤104, diarrhea (2.9%), nausea (1.8%), and headache (3.0%) occurred at lower rates vs Wks 0 to ≤52 (Table). In Wks 0 to ≤52, 87 pts reported serious AEs (SAEs) vs 71 pts in Wks >52 to ≤104. In few system organ classes, there were numerically more pts reporting SAEs but it did not indicate any specific organ involvement. The vast majority of the SAEs were reported by 1 pt each. There was no increase in cardiac, malignant neoplasm, opportunistic infection, or psychiatric disorder related SAEs and no cases of tuberculosis (new/reactivation) reported with either APR dose. Discontinuations due to AEs occurred at a lower rate (2.3%) during Wks >52 to ≤104. Marked laboratory abnormalities were generally infrequent and most returned to baseline with continued treatment or were associated with a concurrent medical condition. Conclusions APR demonstrated an acceptable safety profile and was generally well tolerated for up to 104 wks, with no new safety concerns identified with long-term exposure. These data continue to support the lack of a need for specific laboratory monitoring with APR. Disclosure of Interest P. Mease Grant/research support from: Abbott, Amgen, Biogen Idec, Bristol-Myers Squibb, Genentech, Janssen, Eli Lilly, Pfizer Inc, UCB, Celgene Corporation, Novartis, and Roche, Consultant for: Abbott, Amgen, Biogen Idec, Bristol-Myers Squibb, Genentech, Janssen, Eli Lilly, Pfizer Inc, UCB, Celgene Corporation, Novartis, and Roche, Speakers bureau: Abbott, Amgen, Biogen Idec, Bristol-Myers Squibb, Genentech, Janssen, Eli Lilly, Pfizer Inc, and UCB, A. Adebajo: None declared, D. Gladman Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Celgene Corporation, Janssen, Pfizer Inc, Novartis, and UCB, Consultant for: AbbVie, Amgen, Bristol-Myers Squibb, Celgene Corporation, Janssen, Pfizer Inc, Novartis, and UCB, J. Gomez-Reino Grant/research support from: Roche and Schering-Plough, Consultant for: Bristol-Myers Squibb, Pfizer Inc, Roche, Schering-Plough, and UCB SA, Speakers bureau: Bristol-Myers Squibb, Roche, Schering-Plough, and Wyeth, S. Hall Consultant for: Boehringer Ingelheim, MSD, Roche Schering Plough, Servier, and Wyeth., Paid instructor for: Amgen, AstraZeneca, Boehringer Ingelheim, Centocor, GlaxoSmithKline, MSD, Pfizer, Sanofi Aventis, Sanofi Pasteur, Schering-Plough, Serono, and Wyeth, Speakers bureau: Boehringer Ingelheim, GlaxoSmithKline, MSD, Pfizer, Roche, Sanofi Aventis, Schering-Plough, and Wyeth;, A. Kavanaugh Grant/research support from: Abbott, Amgen, Astra-Zeneca, Bristol-Myers Squibb, Celgene Corporation, Centocor-Janssen, Pfizer Inc, Roche, and UCB, E. Lespessailles Grant/research support from: Amgen, Eli Lilly, Novartis, and Servier, Speakers bureau: Amgen, Eli Lilly, Novartis, and Servier, G. Schett Grant/research support from: Abbott, Celgene Corporation, Roche, and UCB, Consultant for: Abbott, Celgene Corporation, Roche, and UCB, K. Shah Employee of: Celgene Corporation, L. Teng Employee of: Celgene Corporation, J. Wollenhaupt Grant/research support from: Abbott, Bristol-Myers Squibb, MSD, Pfizer Inc, and UCB, Consultant for: Abbott, Bristol-Myers Squibb, MSD, Pfizer Inc, and UCB
-
thu0420 long term 104 week efficacy and safety profile of apremilast an oral phosphodiesterase 4 Inhibitor in patients with psoriatic arthritis results from a phase iii randomised controlled trial and open label extension palace 1
Annals of the Rheumatic Diseases, 2015Co-Authors: A Kavanaugh, K Shah, Philip J. Mease, Juan J Gomezreino, A O Adebajo, Dafna D Gladman, Eric Lespessailles, Stephen Hall, Georg Schett, J WollenhauptAbstract:Background Apremilast (APR), an oral phosphodiesterase 4 Inhibitor, helps regulate immune responses in psoriatic arthritis (PsA). PALACE 1 compared the efficacy and safety of APR with placebo (PBO) in patients with active PsA despite prior conventional disease-modifying antirheumatic drugs (DMARDs) and/or biologics. Objectives Evaluate the efficacy and safety of APR treatment over 104 weeks. Methods Patients were randomized (1:1:1) to PBO, APR 20 mg BID (APR20), or APR 30 mg BID (APR30) stratified by baseline DMARD use (yes/no). Patients whose swollen/tender joint counts (SJC/TJC) had not improved ≥20% at Week 16 were considered non-responders and were required to be re-randomized (1:1) to APR20 or APR30 if they were initially randomized to PBO, or continued on their initial APR dose. At Week 24, all remaining PBO patients were re-randomized to APR20 or APR30. Double-blind APR treatment continued to Week 52; patients could continue APR for up to 4 additional years. Results 504 randomized patients received ≥1 dose of study medication (PBO: n=168; APR20: n=168; APR30: n=168). At Week 52, 53.2% of patients receiving APR30 and 59.6% of patients receiving APR20 achieved a modified ACR20 response (Table); $≈ $80% (285/344) of patients completing Week 52 were still receiving APR at the data cutoff during their second year of APR exposure. Patients taking APR demonstrated sustained improvements at Week 104 as shown by modified ACR20/ACR50/ACR70 response rates, SJC/TJC mean percent change, HAQ-DI mean change, proportion of patients with HAQ-DI exceeding the minimal clinically important difference (MCID) ≥0.30 threshold, mean change in DAS-28 (CRP), achievement of DAS (CRP) 52 to ≤104, adverse events (AEs) occurring in ≥5% of APR-exposed patients were nasopharyngitis and upper respiratory tract infection; most AEs were mild/moderate in severity. Diarrhea (1.7%) and nausea (1.2%) occurred at lower rates in Weeks >52 to ≤104 than in Weeks 0 to ≤52 (15.3% and 12.4%, respectively). Serious AEs occurred in 4.7% (APR30) and 6.4% (APR20) of patients over Weeks >52 to ≤104. Fewer discontinuations due to AEs occurred during Weeks >52 to ≤104 (1.5%) vs. Weeks 0 to ≤52 (8.2%). Conclusions Over 104 weeks, APR demonstrated sustained clinically meaningful improvements in signs and symptoms of PsA, including physical function, and associated psoriasis. APR continued to demonstrate an acceptable safety profile and was generally well tolerated. Disclosure of Interest A. Kavanaugh Grant/research support from: Abbott, Amgen, Astra-Zeneca, Bristol-Myers Squibb, Celgene Corporation, Centocor-Janssen, Pfizer Inc, Roche, and UCB, A. Adebajo: None declared, D. Gladman Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Celgene Corporation, Janssen, Pfizer Inc, Novartis, and UCB, Consultant for: AbbVie, Amgen, Bristol-Myers Squibb, Celgene Corporation, Janssen, Pfizer Inc, Novartis, and UCB, J. Gomez-Reino Grant/research support from: Roche and Schering-Plough, Consultant for: Bristol-Myers Squibb, Pfizer Inc, Roche, Schering-Plough, and UCB SA, Speakers bureau: Bristol-Myers Squibb, Roche, Schering-Plough, and Wyeth; S. Hall Consultant for: Amgen, AstraZeneca, Boehringer Ingelheim, Centocor, GlaxoSmithKline, MSD, Pfizer, Sanofi Aventis, Sanofi Pasteur, Schering-Plough, Serono, and Wyeth; Paid instructor for: Boehringer Ingelheim, MSD, Roche Schering Plough, Servier, and Wyeth., Speakers bureau: Boehringer Ingelheim, GlaxoSmithKline, MSD, Pfizer, Roche, Sanofi Aventis, Schering-Plough, and Wyeth, E. Lespessailles Grant/research support from: Amgen, Eli Lilly, Novartis, and Servier, Speakers bureau: Amgen, Eli Lilly, Novartis, and Servier, P. Mease Grant/research support from: Abbott, Amgen, Biogen Idec, Bristol-Myers Squibb, Genentech, Janssen, Eli Lilly, Pfizer Inc, UCB, Celgene Corporation, Novartis, and Roche, Consultant for: Abbott, Amgen, Biogen Idec, Bristol-Myers Squibb, Genentech, Janssen, Eli Lilly, Pfizer Inc, UCB, Celgene Corporation, Novartis, and Roche, Speakers bureau: Abbott, Amgen, Biogen Idec, Bristol-Myers Squibb, Genentech, Janssen, Eli Lilly, Pfizer Inc, UCB, G. Schett Grant/research support from: Abbott, Celgene Corporation, Roche, and UCB, Consultant for: Abbott, Celgene Corporation, Roche, and UCB, K. Shah Employee of: Celgene Corporation, C. Hu Employee of: Celgene Corporation, J. Wollenhaupt Grant/research support from: Abbott, Bristol-Myers Squibb, MSD, Pfizer Inc, and UCB, Consultant for: Abbott, Bristol-Myers Squibb, MSD, Pfizer Inc, and UCB
-
apremilast a phosphodiesterase 4 Inhibitor for the treatment of psoriatic arthritis
Rheumatology and Therapy, 2014Co-Authors: Philip J. MeaseAbstract:Introduction Psoriatic arthritis (PsA) is a spondyloarthritis that occurs in up to 30% of psoriasis patients. Patients with PsA are at risk for decreased quality of life due to both joint and skin symptoms, impaired physical function and disease progression. Treatments include non-steroidal anti-inflammatory drugs, conventional systemic disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate, and biologic agents, including tumor necrosis factor-α Inhibitors. The most recently introduced treatment option is apremilast, an oral phosphodiesterase 4 Inhibitor.
-
treatment of psoriatic arthritis in a phase 3 randomised placebo controlled trial with apremilast an oral phosphodiesterase 4 Inhibitor
Annals of the Rheumatic Diseases, 2014Co-Authors: Philip J. Mease, Juan J Gomezreino, A O Adebajo, J Wollenhaupt, Dafna D Gladman, Eric Lespessailles, Stephen Hall, Marla Hochfeld, Douglas R HoughAbstract:Objectives Apremilast, an oral phosphodiesterase 4 Inhibitor, regulates inflammatory mediators. Psoriatic Arthritis Long-term Assessment of Clinical Efficacy 1 (PALACE 1) compared apremilast with placebo in patients with active psoriatic arthritis despite prior traditional disease-modifying antirheumatic drug (DMARD) and/or biologic therapy. Methods In the 24-week, placebo-controlled phase of PALACE 1, patients (N=504) were randomised (1:1:1) to placebo, apremilast 20 mg twice a day (BID) or apremilast 30 mg BID. At week 16, patients without ≥20% reduction in swollen and tender joint counts were required to be re-randomised equally to either apremilast dose if initially randomised to placebo or remained on their initial apremilast dose. Patients on background concurrent DMARDs continued stable doses (methotrexate, leflunomide and/or sulfasalazine). Primary outcome was the proportion of patients achieving 20% improvement in modified American College of Rheumatology response criteria (ACR20) at week 16. Results At week 16, significantly more apremilast 20 mg BID (31%) and 30 mg BID (40%) patients achieved ACR20 versus placebo (19%) (p Conclusions Apremilast was effective in the treatment of psoriatic arthritis, improving signs and symptoms and physical function. Apremilast demonstrated an acceptable safety profile and was generally well tolerated. Clinical trial registration number NCT01172938.
Mark Lebwohl - One of the best experts on this subject based on the ideXlab platform.
-
a novel nonsteroidal topical anti inflammatory phosphodiesterase 4 Inhibitor crisaborole ointment reduced pruritus and signs of atopic dermatitis in 2 phase 3 studies in children and adults
Pediatrics, 2018Co-Authors: Adelaide A Hebert, Eric L Simpson, Mark Lebwohl, Lawrence F Eichenfield, Amy S Paller, Wynnis L Tom, Matilda H Hughes, Lee T ZaneAbstract:Background: Atopic dermatitis (AD) is an inflammatory skin disease that presents with intense pruritus and red, inflamed lesions. Crisaborole Topical Ointment, 2% (Anacor Pharmaceuticals, Palo Alto, CA), is an investigational, nonsteroidal, topical anti-inflammatory, phosphodiesterase 4 Inhibitor for the treatment of AD. Objective: To evaluate the additional predefined efficacy endpoints on the impact of crisaborole ointment on pruritus and signs of AD from 2 Phase …
-
two phase 3 study results of children and adults with mild to moderate atopic dermatitis treated with crisaborole topical ointment 2 a novel nonsteroidal topical anti inflammatory phosphodiesterase 4 Inhibitor
Journal of Immunology, 2016Co-Authors: Lee T Zane, Mark Lebwohl, Lawrence F Eichenfield, Amy S Paller, Wynnis L Tom, Robin L Blumenthal, Mark Boguniewicz, Robert S Call, Douglass W Forsha, William C ReesAbstract:Up to 90% of children and adults with atopic dermatitis (AD), a chronic inflammatory skin disease, present with mild-to-moderate disease. Crisaborole Topical Ointment, 2%, is a novel, nonsteroidal, topical, anti-inflammatory, phosphodiesterase 4 Inhibitor being studied for the treatment of AD. The efficacy and safety of crisaborole was assessed in 2 identically designed, multicenter, vehicle-controlled, double-blind Phase 3 studies (301 and 302) that enrolled patients ≥2 years old with mild-to-moderate AD affecting ≥5% of body surface area (BSA). Patients were randomized 2:1 to receive crisaborole or vehicle twice daily and evaluated on Days 8, 15, 22, and 29. The primary endpoint defined success in the Investigator’s Static Global Assessment (ISGA) as “almost clear/1” or “clear/0” with ≥2-grade improvement from baseline at Day 29. Secondary endpoints analyzed the time to success and the percentage of patients achieving “almost clear/1” or “clear/0” on ISGA. At Day 29, more crisaborole-treated patients achieved ISGA success than vehicle (301: 32.8% vs 25.4%, P = 0.038; 302: 31.4% vs 18.0%, P P = 0.005; 302: 48.5% vs 29.7%, P P
-
crisaborole topical ointment 2 a novel nonsteroidal anti inflammatory topical phosphodiesterase 4 Inhibitor reduced pruritus and signs of atopic dermatitis in 2 phase 3 studies in children and adults with mild to moderate atopic dermatitis
Journal of Immunology, 2016Co-Authors: Lee T Zane, Eric L Simpson, Mark Lebwohl, Adelaide A Hebert, Lawrence F Eichenfield, Amy S Paller, Wynnis L Tom, Matilda H HughesAbstract:Atopic dermatitis (AD) is an inflammatory skin disease with intense pruritus and eczematous lesions. Crisaborole Topical Ointment, 2% (Anacor Pharmaceuticals, Palo Alto, CA), is an investigational, nonsteroidal, anti-inflammatory, topical, phosphodiesterase 4 Inhibitor for the treatment of AD. Here, we present the impact of crisaborole on pruritus and signs of AD evaluated as supportive efficacy endpoints for 2 Phase 3 studies (301, 302). Patients ≥2 years old with mild-to-moderate AD were enrolled in 2 double-blind, vehicle-controlled, multicenter Phase 3 studies of identical design. Patients were randomized 2:1 to receive crisaborole or vehicle twice daily for 28 days. Supportive efficacy endpoints examined severity of pruritus (measured twice daily) and signs of AD (measured weekly) on a 4-point scale (None [0] to Severe [3]). Success was defined for pruritus or each sign or symptom of AD as achievement of None (0) or Mild (1) with ≥1-grade improvement from baseline. Improvement in pruritus was achieved sooner in crisaborole-treated patients than vehicle-treated patients (pooled data: median, 1.37 vs 1.70 days; P = 0.001). A greater proportion of crisaborole-treated patients achieved success for all clinical signs of AD by Day 29 (301, 302; erythema: 62.8% vs 46.1%; 54.9% vs 33.9%; induration/papulation: 57.7% vs 54.8%; −51.9% vs 40.2%; exudation: 41.0% vs 33.3%; 38.1% vs 27.2%; excoriation: 63.0% vs 51.8%; 57.2% vs 44.2%; lichenification: 51.7% vs 46.5%; 51.4% vs 35.3%). In 2 large Phase 3 studies, crisaborole demonstrated early relief of pruritus and showed improvement in all measured signs of AD. Crisaborole Topical Ointment, 2%, may represent a safe and efficacious treatment for patients ≥2 years with mild-to-moderate AD.
-
crisaborole topical ointment 2 a nonsteroidal topical anti inflammatory phosphodiesterase 4 Inhibitor in clinical development for the treatment of atopic dermatitis
Journal of Drugs in Dermatology, 2016Co-Authors: Kurt Jarnagin, Lee T Zane, Sanjay Chanda, Dina Coronado, E Guttmanyassky, Mark LebwohlAbstract:Crisaborole topical ointment, 2% (formerly known as AN2728) is a benzoxaborole, nonsteroidal, topical, anti-inflammatory phosphodiesterase 4 (PDE4) Inhibitor investigational compound that recently completed phase 3 studies for the treatment of mild to moderate atopic dermatitis (AD). The unique configuration of boron within the crisaborole molecule enables selective targeting and inhibition of PDE4, an enzyme that converts the intracellular second messenger 3'5'-cyclic adenosine monophosphate (cAMP) into the active metabolite adenosine monophosphate (AMP). By inhibiting PDE4 and thus increasing levels of cAMP, crisaborole controls inflammation. The use of boron chemistry enabled synthesis of a low-molecular-weight compound (251 daltons), thereby facilitating effective penetration of crisaborole through human skin. In vitro experiments showed that crisaborole inhibits cytokine production from peripheral blood mononuclear cells in a pattern similar to other PDE4 Inhibitors and distinct from corticosteroids. Crisaborole also displayed topical anti-inflammatory activity in a skin inflammation model. Once crisaborole reaches systemic circulation after topical application, it is metabolized to inactive metabolites. This limits systemic exposure to crisaborole and systemic PDE4 inhibition. In phase 1 and 2 clinical studies, crisaborole ointment, 2% was generally well tolerated and improved AD disease severity scores, pruritus, and all other AD signs and symptoms. Two large, randomized, controlled, phase 3, pivotal clinical trials assessing the efficacy and safety of crisaborole topical ointment, 2% in children, adolescents, and adults with mild to moderate AD were recently completed with positive results.
Ieharu Hishinuma - One of the best experts on this subject based on the ideXlab platform.
-
a putative antipruritic mechanism of the phosphodiesterase 4 Inhibitor e6005 by attenuating capsaicin induced depolarization of c fibre nerves
Experimental Dermatology, 2015Co-Authors: Hisashi Wakita, Ieharu Hishinuma, Naoto Ishii, Masayoshi Ohkuro, Manabu ShiratoAbstract:E6005, a potent, selective phosphodiesterase (PDE) 4 Inhibitor, has been developed as a novel topical agent of atopic dermatitis (AD). It has been shown to inhibit itching in patients with AD as well in mouse models. To study the mechanism underlying the anti-pruritic effect of E6005, we examined its effect on the activation of dorsal root ganglion (DRG) neurons associated with the itch sensation. Depolarization of DRG neurons by a transient receptor potential vanilloid 1 (TRPV 1) activator, capsaicin was attenuated by E6005 as well as by a 3′,5′-cyclic adenosine monophosphate (cAMP) elevator, forskolin. E6005 elevated intracellular levels of cAMP in DRG cells. Taken together, these results suggest that E6005 suppresses TRPV1-mediated C-fibre depolarization through elevation of cAMP levels, thereby exerting an anti-pruritic effect. Thus, E6005 shows the potential to be a new agent for managing pruritus in various skin disorders, including AD.
-
antipruritic effect of the topical phosphodiesterase 4 Inhibitor e6005 ameliorates skin lesions in a mouse atopic dermatitis model
Journal of Pharmacology and Experimental Therapeutics, 2013Co-Authors: Naoto Ishii, Manabu Shirato, Hisashi Wakita, Kazuki Miyazaki, Yasutaka Takase, Kazutomi Kusano, Chiharu Inoue, Eiichi Yamamoto, Osamu Asano, Ieharu HishinumaAbstract:Phosphodiesterase (PDE) 4 inhibition is a well-known anti-inflammatory mechanism, but the development of PDE4 Inhibitors has been hampered by side effects such as nausea and emesis. Local delivery of a PDE4 Inhibitor to the site of inflammation may overcome these issues. The purpose of this study was to assess the therapeutic potential of E6005 (methyl 4-[({3-[6,7-dimethoxy-2-(methylamino)quinazolin-4-yl]phenyl}amino)carbonyl]benzoate), a novel PDE4 Inhibitor developed as a topical agent for atopic dermatitis (AD). E6005 potently and selectively inhibited human PDE4 activity with an IC50 of 2.8 nM and suppressed the production of various cytokines from human lymphocytes and monocytes with IC50 values ranging from 0.49 to 3.1 nM. In mice models, the topical application of E6005 produced an immediate antipruritic effect as well as an anti-inflammatory effect with reduced expression of cytokines/adhesion molecules. On the basis of these observed effects, topical E6005 ameliorated the appearance of atopic dermatitis-like skin lesions in two types of AD models, hapten- and mite-elicited models, exhibiting Inhibitory effects comparable to that of tacrolimus. The use of 14C-labeled E6005 showed rapid clearance from the blood and low distribution to the brain, contributing to the low emetic potential of this compound. These results suggest that E6005 may be a promising novel therapeutic agent with antipruritic activity for the treatment of AD.
-
Antipruritic Effect of the Topical Phosphodiesterase 4 Inhibitor E6005 Ameliorates Skin Lesions in a Mouse Atopic Dermatitis Model s
2013Co-Authors: Naoto Ishii, Manabu Shirato, Hisashi Wakita, Kazuki Miyazaki, Yasutaka Takase, Kazutomi Kusano, Chiharu Inoue, Eiichi Yamamoto, Osamu Asano, Ieharu HishinumaAbstract:Phosphodiesterase (PDE) 4 inhibition is a well-known anti-inflam-matory mechanism, but the development of PDE4 Inhibitors has been hampered by side effects such as nausea and emesis. Local delivery of a PDE4 Inhibitor to the site of inflammation may overcome these issues. The purpose of this study was to assess the therapeutic potential of E6005 (methyl 4-[({3-[6,7-dimethoxy-2-(methylamino)quinazolin-4-yl]phenyl}amino)carbonyl]ben-zoate), a novel PDE4 Inhibitor developed as a topical agent for atopic dermatitis (AD). E6005 potently and selectively inhibited human PDE4 activity with an IC50 of 2.8 nM and suppressed the production of various cytokines from human lymphocytes and monocytes with IC50 values ranging from 0.49 to 3.1 nM. In mice models, the topical application of E6005 produced an immediate antipruritic effect as well as an anti-inflammatory effect with re-duced expression of cytokines/adhesion molecules. On the basis of these observed effects, topical E6005 ameliorated the appearance of atopic dermatitis-like skin lesions in two types of AD models, hapten- and mite-elicited models, exhibiting in-hibitory effects comparable to that of tacrolimus. The use of 14C-labeled E6005 showed rapid clearance from the blood and low distribution to the brain, contributing to the low emetic potential of this compound. These results suggest that E6005 may be a promising novel therapeutic agent with antipruritic activity for the treatment of AD
Lawrence F Eichenfield - One of the best experts on this subject based on the ideXlab platform.
-
a novel nonsteroidal topical anti inflammatory phosphodiesterase 4 Inhibitor crisaborole ointment reduced pruritus and signs of atopic dermatitis in 2 phase 3 studies in children and adults
Pediatrics, 2018Co-Authors: Adelaide A Hebert, Eric L Simpson, Mark Lebwohl, Lawrence F Eichenfield, Amy S Paller, Wynnis L Tom, Matilda H Hughes, Lee T ZaneAbstract:Background: Atopic dermatitis (AD) is an inflammatory skin disease that presents with intense pruritus and red, inflamed lesions. Crisaborole Topical Ointment, 2% (Anacor Pharmaceuticals, Palo Alto, CA), is an investigational, nonsteroidal, topical anti-inflammatory, phosphodiesterase 4 Inhibitor for the treatment of AD. Objective: To evaluate the additional predefined efficacy endpoints on the impact of crisaborole ointment on pruritus and signs of AD from 2 Phase …
-
two phase 3 study results of children and adults with mild to moderate atopic dermatitis treated with crisaborole topical ointment 2 a novel nonsteroidal topical anti inflammatory phosphodiesterase 4 Inhibitor
Journal of Immunology, 2016Co-Authors: Lee T Zane, Mark Lebwohl, Lawrence F Eichenfield, Amy S Paller, Wynnis L Tom, Robin L Blumenthal, Mark Boguniewicz, Robert S Call, Douglass W Forsha, William C ReesAbstract:Up to 90% of children and adults with atopic dermatitis (AD), a chronic inflammatory skin disease, present with mild-to-moderate disease. Crisaborole Topical Ointment, 2%, is a novel, nonsteroidal, topical, anti-inflammatory, phosphodiesterase 4 Inhibitor being studied for the treatment of AD. The efficacy and safety of crisaborole was assessed in 2 identically designed, multicenter, vehicle-controlled, double-blind Phase 3 studies (301 and 302) that enrolled patients ≥2 years old with mild-to-moderate AD affecting ≥5% of body surface area (BSA). Patients were randomized 2:1 to receive crisaborole or vehicle twice daily and evaluated on Days 8, 15, 22, and 29. The primary endpoint defined success in the Investigator’s Static Global Assessment (ISGA) as “almost clear/1” or “clear/0” with ≥2-grade improvement from baseline at Day 29. Secondary endpoints analyzed the time to success and the percentage of patients achieving “almost clear/1” or “clear/0” on ISGA. At Day 29, more crisaborole-treated patients achieved ISGA success than vehicle (301: 32.8% vs 25.4%, P = 0.038; 302: 31.4% vs 18.0%, P P = 0.005; 302: 48.5% vs 29.7%, P P
-
crisaborole topical ointment 2 a novel nonsteroidal anti inflammatory topical phosphodiesterase 4 Inhibitor reduced pruritus and signs of atopic dermatitis in 2 phase 3 studies in children and adults with mild to moderate atopic dermatitis
Journal of Immunology, 2016Co-Authors: Lee T Zane, Eric L Simpson, Mark Lebwohl, Adelaide A Hebert, Lawrence F Eichenfield, Amy S Paller, Wynnis L Tom, Matilda H HughesAbstract:Atopic dermatitis (AD) is an inflammatory skin disease with intense pruritus and eczematous lesions. Crisaborole Topical Ointment, 2% (Anacor Pharmaceuticals, Palo Alto, CA), is an investigational, nonsteroidal, anti-inflammatory, topical, phosphodiesterase 4 Inhibitor for the treatment of AD. Here, we present the impact of crisaborole on pruritus and signs of AD evaluated as supportive efficacy endpoints for 2 Phase 3 studies (301, 302). Patients ≥2 years old with mild-to-moderate AD were enrolled in 2 double-blind, vehicle-controlled, multicenter Phase 3 studies of identical design. Patients were randomized 2:1 to receive crisaborole or vehicle twice daily for 28 days. Supportive efficacy endpoints examined severity of pruritus (measured twice daily) and signs of AD (measured weekly) on a 4-point scale (None [0] to Severe [3]). Success was defined for pruritus or each sign or symptom of AD as achievement of None (0) or Mild (1) with ≥1-grade improvement from baseline. Improvement in pruritus was achieved sooner in crisaborole-treated patients than vehicle-treated patients (pooled data: median, 1.37 vs 1.70 days; P = 0.001). A greater proportion of crisaborole-treated patients achieved success for all clinical signs of AD by Day 29 (301, 302; erythema: 62.8% vs 46.1%; 54.9% vs 33.9%; induration/papulation: 57.7% vs 54.8%; −51.9% vs 40.2%; exudation: 41.0% vs 33.3%; 38.1% vs 27.2%; excoriation: 63.0% vs 51.8%; 57.2% vs 44.2%; lichenification: 51.7% vs 46.5%; 51.4% vs 35.3%). In 2 large Phase 3 studies, crisaborole demonstrated early relief of pruritus and showed improvement in all measured signs of AD. Crisaborole Topical Ointment, 2%, may represent a safe and efficacious treatment for patients ≥2 years with mild-to-moderate AD.