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Victoria P Werth - One of the best experts on this subject based on the ideXlab platform.

  • fri0307 Lenabasum a cannabinoid type 2 receptor agonist reduces cd4 cell populations and downregulates type 1 and 2 interferon activities in lesional dermatomyositis skin
    Annals of the Rheumatic Diseases, 2019
    Co-Authors: Kristen L Chen, Barbara White, Majid Zeidi, Nithin Reddy, Victoria P Werth
    Abstract:

    Background Lenabasum is a synthetic, non-immunosuppressive, selective cannabinoid receptor type 2 (CB2) agonist that activates resolution of innate immune responses. CB2 is a G-protein coupled receptor found primarily on activated immune cells. In vitro, it has shown to affect T-cell activity, alter Th1 and Th2 cytokine production, and decrease type 1 interferon activity. Objectives We sought to characterize the in vivo effect of Lenabasum on inflammatory cells and cytokines thought to be involved in the itch and disease pathogenesis of dermatomyositis (DM). Methods 22 adult patients with refractory, skin-predominant DM on stable standard-of-care treatments were recruited for a double-blind, placebo-controlled, randomized trial. Treatment was initially administered orally at a dose of 20 mg a day for 4 weeks, and subsequently raised to 20 mg twice a day for an additional 8 weeks. In a subset of subjects, lesional skin biopsies were collected at baseline and at Week 12. Tissues were stained via immunohistochemistry for IFN-beta, IFN-gamma, IL-4, IL-13, IL-33, IL-31, IL-31 RA, CB2 receptor, PPAR-gamma, CD4, CD8, CD69, CD11c, and mast cells. RT-PCR for IFN-beta, IFN-gamma, IL-31, IL-4, STAT6, and ST2 was performed on tissue RNA. Protein expression was quantified either by percent area positive or cells per HPF in the dermis. Statistical analyses were performed using the Wilcoxon signed-rank test. Results CD4 expression in the skin biopsies from Lenabasum-treated subjects significantly decreased at Week 12 compared to the placebo group (p Conclusion Lenabasum reduces Type 1 and 2 interferon levels as well as T-helper cell inflammation in subjects with DM. These effects have the potential to inhibit underlying disease pathways in DM, thus contributing to clinical improvement. References [1] Kim, H.J., Zeidi, M., Bonciani, D., Pena, S.M., Tiao, J., Sahu, S. and Werth, V.P. Itch in dermatomyositis: the role of increased skin interleukin-31. British Journal of Dermatology. 2018;179(3):669-678. [2] Robinson ES, Alves P, Bashir MM, Zeidi M, Feng R, Werth VP. Cannabinoid Reduces Inflammatory Cytokines, Tumor Necrosis Factor-α, and Type I Interferons in DermatomyositisInVitro. J Invest Dermatol. 2017;137(11):2445 [3] Wong D, Kea B, Pesich R, Higgs BW, Zhu W, Brown P, et al. Interferon and biologic signatures in dermatomyositis skin: specificity and heterogeneity across diseases. PLoS One. 2012;7(1):e29161. Disclosure of Interests Kristen Chen: None declared, Majid Zeidi: None declared, Nithin Reddy: None declared, Barbara White Shareholder of: Corbus Pharmaceuticals, Inc., Employee of: Corbus Pharmaceuticals, Inc., Victoria Werth: None declared

  • OP0241 SAFETY AND EFFICACY OF Lenabasum IN AN OPEN-LABEL EXTENSION OF A PHASE 2 STUDY OF Lenabasum IN REFRACTORY SKIN-PREDOMINANT DERMATOMYOSITIS (DM) SUBJECTS
    Oral Presentations, 2019
    Co-Authors: Victoria P Werth, S. Constantine, E Hejazi, Rui Feng, C Cornwall, David R. Pearson, Joyce Owaka, Josef Simon Concha, Basil Patel, Nancy Dgetluck
    Abstract:

    Background Lenabasum is a synthetic, non-immunosuppressive, selective cannabinoid receptor type 2 agonist that activates resolution of innate immune responses. Lenabasum had acceptable safety and tolerability and improved efficacy outcomes in the initial 16-week double-blinded, randomized, placebo-controlled Part A of Phase 2 trial JBT101-DM-001 (NCT02466243) in dermatomyositis (DM) subjects with refractory, skin-predominant involvement. Objectives To provide long-term safety and efficacy data in DM subjects in this study. Methods Subjects who completed Part A were eligible to receive oral Lenabasum 20 mg BID in an open-label extension (OLE) that assessed safety and efficacy at 4 weeks, then every 8 weeks. Results 20/22 (90.9%) eligible subjects received open-label Lenabasum, following a mean interval of 31 weeks from end of Part A, during which when they received only standard-of care, to start of OLE during which Lenabasum 20 mg BID was added. 17/20 (85.0%) subjects were on stable baseline immunosuppressive drugs. At the time of data cut-off, all subjects who entered OLE completed 12 months of dosing. Nineteen/20 (95%) of subjects experienced at least 1 AE, with 59 AEs occurring among the subjects during the OLE to date. The majority of AEs were mild (n = 16, 80%), with 1 severe AE (fatigue) considered unrelated to Lenabasum reported. AEs occurring in ≥ 2 subjects were: dermatomyositis worsening, dizziness, fatigue, herpes zoster, nasopharyngitis, nausea, upper respiratory tract infection, and urinary tract infection. No serious AEs related to Lenabasum have been reported. Improvement was seen in multiple physician- and patient-reported efficacy outcomes; selected outcomes are presented in Figure 1. Mean (SE) changes from study start at Week 52 in the OLE were: CDASI activity score = -17.6 (SD), Patient Skin Activity VAS = -2.6 (SD); Skindex-29 Symptoms Domain = -21.6 (SD); Patient Itch VAS = -2.8 (SD); Physician Overall Disease VAS = -3.0 (SD); and Patient Pain VAS = - 2.3 (SD). Improvements were seen in other efficacy outcomes. 12 subjects had no changes in immunosuppressive drugs during the OLE, 3 reduced chronic steroids, 2 reduced mycophenolate, 3 were switched from methotrexate to mycophenolate, 1 started methotrexate, and 1 had a burst and taper of steroids. Conclusion:  Lenabasum continues to have a favorable safety and tolerability profile in the OLE of the Phase 2 trial JBT101-DM-001 with no serious AEs or study discontinuations related to Lenabasum. The CDASI activity score and multiple other physician and patient-reported outcomes improved, although limitations of attributing efficacy to Lenabasum in the setting of open-label dosing is acknowledged. These data support further testing of Lenabasum for the treatment of DM, and a Phase 3 study of Lenabasum in DM has started.  Disclosure of Interests:   Victoria Werth: None declared, David Pearson: None declared, Joyce Owaka: None declared, Rui Feng: None declared, Josef Simon Concha: None declared, Basil Patel: None declared, Emily Hejazi: None declared, Caitlin Cornwall Shareholder of: Corbus Pharmaceuticals, Inc., Employee of: Corbus Pharmaceuticals, Inc., Scott Constantine Shareholder of: Corbus Pharmaceuticals, Inc., Employee of: Corbus Pharmaceuticals, Inc., Nancy Dgetluck Employee of: Corbus Pharmaceuticals, Inc., Barbara White Shareholder of: Corbus Pharmaceuticals, Inc., Employee of: Corbus Pharmaceuticals, Inc.

  • SAT0303 DESIGN OF PHASE 3 STUDY OF Lenabasum FOR THE TREATMENT OF DERMATOMYOSITIS
    Saturday 15 June 2019, 2019
    Co-Authors: Victoria P Werth, S. Constantine, C Cornwall, Nancy Dgetluck, Chester V. Oddis, Ingrid E. Lundberg, David Fiorentino, Barbara White
    Abstract:

    Background: To date, there has not been a Phase 3 study evaluating efficacy and safety of a new chemical entity solely in subjects with dermatomyositis (DM). There is no precedence for design of such a pivotal study, including selection of patients or efficacy outcomes. Objectives: Develop a Phase 3 study design for testing efficacy and safety of Lenabasum in DM that would be acceptable to experts and for registration purposes. Methods: Lenabasum is a synthetic, non-immunosuppressive, selective cannabinoid receptor type 2 agonist that activates resolution of innate immune responses. Lenabasum had acceptable safety and tolerability and improved multiple physician-reported and patient-reported efficacy outcomes in a 16-week double-blinded, randomized, placebo-controlled Phase 2 trial in DM subjects with refractory, skin-predominant involvement, as well as in the open-label extension of that study. The Phase 3 trial design was based on Phase 2 data, input from a steering committee of experts in DM clinical trials, and recommendations made by regulatory authorities in the US, EU, Sweden, and Japan. Results: A global, double-blind, randomized, interventional design was chosen to provide an unbiased assessment of the efficacy, safety and tolerability of Lenabasum 20 mg bid and 5 mg bid compared to placebo in the treatment of DM. A 52-week treatment duration was selected to provide safety and efficacy data adequate to support chronic treatment. Subjects with DM were classified by Peter and Bohan criteria or the 2017 EULAR/ACR classification criteria for DM (both amyopathic DM and classic DM). Subjects will be required to have active disease, as assessed by an expert and based on a range of muscle, skin, and other disease manifestations. Subjects must be on stable doses of current DM treatments with any background immunosuppressive medications allowed except prednisone ≥ 20 mg per day or equivalent. This inclusivity allows testing of efficacy and safety of Lenabasum in the setting of current treatment practice and reduces risk of disease flare early in the study. The primary efficacy outcome is change from baseline in 2016 ACR/EULAR Total Improvement Score (TIS) for DM and polymyositis. This composite outcome has six domains that broadly capture improvement in disease activity, is relevant to the range of manifestations in DM, and is applicable to the assessment of efficacy in the target patient population. Secondary efficacy outcomes were chosen to assess how the subject functions (Short Form – 36 physical functioning domain), major organ involvement (MMT-8, CDASI activity score, and a new Investigator Global Assessment scale of skin activity designed specifically for this study), and lung function (FVC). Change in oral corticosteroid dose also will be captured. Conclusion: To our knowledge, this is the first Phase 3 study in DM with a new molecular entity. As such, agreement with experts and regulatory authorities on design represents a step forward in the development pathway of new treatments for DM. Disclosure of Interests: Victoria Werth: None declared, Chester V Oddis Grant/research support from: Support of clinical research from Roche/Genentech and BMS, Consultant for: Corbus: Previous Steering Committee consultation; No longer being paid as a Corbus consultant, Ingrid E. Lundberg Grant/research support from: Dr. Lundberg has received honoraria from Bristol Myers Squibb and MedImmune and is currently receiving a research grant from Bristol Myers Squibb and from Astra Zeneca., Consultant for: She is a scientific advisor for Bristol Myers Squibb, and aTyr, David Fiorentino Grant/research support from: Pfizer - to support analysis of human tissue from patients with dermatomyositis, Consultant for: Pfizer—design and operation of clinical trial in DM Corbus—design of clinical trial in DM 23 and me—ad hoc consulting Admiryx—ad hoc consulting Janssen—SAB for PSOLAR database Beigene—paid consultant, Caitlin Cornwall Shareholder of: Corbus Pharmaceuticals, Inc., Employee of: Corbus Pharmaceuticals, Inc., Nancy Dgetluck Employee of: Corbus Pharmaceuticals, Inc., Scott Constantine Shareholder of: Corbus Pharmaceuticals, Inc., Employee of: Corbus Pharmaceuticals, Inc., Barbara White Shareholder of: Corbus Pharmaceuticals, Inc., Employee of: Corbus Pharmaceuticals, Inc.

  • Itch in dermatomyositis: the role of increased skin interleukin-31.
    The British journal of dermatology, 2018
    Co-Authors: Hee Joo Kim, S M Pena, Majid Zeidi, D. Bonciani, J. Tiao, S. Sahu, Victoria P Werth
    Abstract:

    Background Interleukin (IL)-31 is implicated in pruritus associated with pruritic skin diseases like atopic dermatitis. Although pruritus is a prominent feature in dermatomyositis (DM), few studies have evaluated the pathogenesis of DM-associated itch. Objectives To establish the prevalence of itch in DM, and to investigate the role of IL-31 in DM-related itch. Methods Pruritus and disease activity of DM were evaluated by a visual analogue scale (VAS) and the Cutaneous Disease and Activity Severity Index (CDASI), respectively. Expression of IL-31 and IL-31 receptor alpha (IL-31RA) in lesional DM, nonlesional DM and healthy control skin was evaluated by quantitative reverse-transcriptase polymerase chain reaction and immunofluorescence. Flow cytometry was performed on skin cells isolated from lesional DM skin to identify cellular sources of IL-31 in DM. Results Among 191 patients with DM, 50·8% had moderate-to-severe itch, and itch was correlated with increased cutaneous severity (r = 0·34). In patients with itchy DM, gene expression of IL31 and IL31RA in lesional skin was upregulated compared with nonlesional skin and healthy control skin. IL31 mRNA expression positively correlated with VAS itch score (r = 0·67). On immunofluorescence, immunoreactivity for IL-31 and IL-31RA was stronger in lesional skin. Flow cytometry showed that lesional DM skin contained significantly more IL-31-producing cells, and CD4+ cells were the most common cell type. Lenabasum, an emerging treatment for DM, significantly downregulated IL-31 from CpG-stimulated peripheral blood mononuclear cells. Conclusions Increased skin IL-31 may play a role in DM-associated itch, and ongoing trials will evaluate the effects of systemic treatment on IL-31 and itch in DM.

  • SAT0512 Safety and efficacy of Lenabasum in refractory skin-predominant dermatomyositis subjects treated in an open label extension of trial jbt101-dm-001
    Saturday 16 JUNE 2018, 2018
    Co-Authors: Victoria P Werth, E Hejazi, Joyce Okawa, Rui Feng, Josef Symon S Concha, C Cornwall, Nancy Dgetluck, David R. Pearson, Basil Patel, S. Constantine
    Abstract:

    Background Lenabasum (aka anabasum, JBT-101) is a selective cannabinoid receptor type 2 agonist that activates resolution of innate immune responses. It is a synthetic, oral, non-immunosuppressive small molecule. Lenabasum showed acceptable safety and tolerability and evidence of clinical benefit in 22 subjects with refractory, skin-predominant dermatomyositis (DM) in Phase 2 trial JBT101-DM-001 (NCT02466243). Objectives This study evaluated safety and efficacy of open-label dosing of Lenabasum in moderately-to-severely active skin-predominant DM in subjects who were refractory to or intolerant of hydroxychloroquine treatment. Methods Subjects who completed the double-blind placebo-controlled (DBPC) part of JBT101-DM-001 with 12 weeks of active dosing and 4 weeks of safety follow-up were eligible to receive Lenabasum 20 mg BID in an open-label extension (OLE). Safety and efficacy evaluations were done at Week 4 after the start of OLE, then every 8 weeks thereafter. Results 20/22 (91%) eligible subjects enrolled in the OLE and 17/20 (85%) were on baseline immunosuppressive drugs. There was a mean interval of 31 weeks (range 4–92 weeks) from the end of active DBPC dosing and the start of the OLE, during which time subjects remained on background medications prior to adding Lenabasum in the OLE. At the time of OLE data cut-off, no subjects had discontinued, all 20 subjects in the OLE completed visits through Week 12 and 11 subjects completed visits through Week 28. During the 28 weeks of OLE dosing, adverse events (AEs, n=30) occurred in 14/20 (70%) subjects. Only 1 subject had a moderate AE, all other AEs were mild. Four (20%) subjects had AEs considered related to Lenabasum. The only AE that occurred in more than 1 subject was DM flare (n=2, 10%). During the OLE, there was improvement from the beginning of the OLE dosing and from the study start in Cutaneous Dermatomyositis Activity and Severity Index (CDASI) Activity score and physician Likert assessments of global disease activity, skin disease activity and extramuscular disease activity. Similarly, there were improvements in multiple patient-reported outcomes, including patient 10 cm VAS scores of global disease activity, skin disease activity, itch and pain, as well as the Skin-dex-29 symptoms domain and PROMIS-29 physical function, fatigue, pain interference, and anxiety domains. Selected efficacy outcomes are shown in figure 1 as change from study start during two periods: 1) “off treatment” from the end of active DBPC dosing to the start of OLE, dotted line; and 2) OLE dosing, solid line. Conclusions Lenabasum continues to have a favourable safety and tolerability profile in the OLE of the Phase 2 trial JBT101-DM-001 with no severe or serious AEs or study discontinuations related to Lenabasum. The CDASI activity score and multiple other physician and patient-reported outcomes improved from study start and start of the OLE, although open-label nature of dosing with Lenabasum is acknowledged. These data support further testing of Lenabasum for the treatment of DM. Disclosure of Interest V. Werth Consultant for: Corbus Pharmaceuticals, Inc., B. Patel: None declared, J. Concha: None declared, J. Okawa: None declared, D. Pearson: None declared, E. Hejazi: None declared, R. Feng: None declared, C. Cornwall Employee of: Corbus Pharmaceuticals, Inc., N. Dgetluck Employee of: Corbus Pharmaceuticals, Inc., S. Constantine Employee of: Corbus Pharmaceuticals, Inc., A. Aggarwal Employee of: Corbus Pharmaceuticals, Inc., B. White Employee of: Corbus Pharmaceuticals, Inc.

Nancy Dgetluck - One of the best experts on this subject based on the ideXlab platform.

  • AB0568 BASELINE EUROPEAN PATIENT DEMOGRAPHICS AND DISEASE CHARACTERISTICS IN A PHASE 3 STUDY OF SAFETY AND EFFICACY OF Lenabasum, A CB2 AGONIST, IN DIFFUSE CUTANEOUS SYSTEMIC SCLEROSIS
    Annals of the Rheumatic Diseases, 2020
    Co-Authors: Christopher P. Denton, Nancy Dgetluck, B. Bloom, Barbara White, Robert Spiera
    Abstract:

    Background: We previously presented on the baseline characteristics of a large cohort of diffuse cutaneous systemic sclerosis (dcSSc) patients enrolled in a Phase 3 trial of Lenabasum, a selective cannabinoid receptor type 2 (CB2) agonist. Lenabasum, was safe and well-tolerated in a prior Phase 2 study in dcSSc patients and associated with improvements in ACR Combined Response Index Systemic Sclerosis (CRISS) score and multiple secondary efficacy outcomes. Objectives: We now report on the background standard of care and baseline disease characteristics of European (EU) patients in order to assess variability by geographic regions. Methods: The RESOLVE-1 Phase 3 study was designed with input from study investigators and regulatory authorities. An important intent of the design was to have eligibility criteria that allow testing of efficacy and safety of Lenabasum in an inclusive group of dcSSc subjects to maximize relevance to patients in current practice. The study is ongoing and remains blinded. Results: Primary efficacy outcome is the ACR CRISS score at 12 months, comparing Lenabasum 20 mg BID to placebo. Key inclusion criteria are males and females ≥ 18 years of age with dcSSc and disease duration ≤ 6 years who are on stable standard of care medicines, with background stable immunosuppressive mediations allowed. Baseline mRSS needed to be ≥ 15 if disease duration was > 3 to ≤ 6 years at enrollment. The study enrolled 110 EU subjects over 15 months who received ≥ 1 dose of study drug at 20 sites in 7 countries. Baseline characteristics as shown in Table 1. The majority were middle-aged, female, and white, and 80% were on immunosuppressive drugs in EU region; methotrexate (MTX) used in 30% of subjects, mycophenolate/mycophenolic acid (MMF) used in 46% of subjects, and 43% of subjects took ≥ 2 concurrent immunosuppressive drugs. There were regional differences in background immunosuppressive with use of MTX, MMF and corticosteroids highest in EU, NA and Asia, respectively. Conclusion: This is the first Phase 3 study to use ACR CRISS as the primary efficacy outcome, a composite outcome of multiple clinically relevant measures of SSc, and the largest interventional study to date in diffuse cutaneous SSc. While the use of background immunosuppressive therapies is significant irrespective of geographic regions, MTX use is highest in the EU. Benefits of having inclusive eligibility criteria are that they facilitated timely full enrollment and will make the study more relevant to real-world practice. This study provides a model for future Phase 3 trials in dcSSc and will afford valuable information regarding scleroderma care in practice as well as evaluating the efficacy and safety of Lenabasum. Disclosure of Interests: Christopher Denton Grant/research support from: GlaxoSmithKline, CSL Behring, and Inventiva, Consultant of: Medscape, Roche-Genentech, Actelion, GlaxoSmithKline, Sanofi Aventis, Inventiva, CSL Behring, Boehringer Ingelheim, Corbus Pharmaceuticals, Acceleron, Curzion and Bayer, Bradley Bloom Shareholder of: Corbus Pharmaceuticals, Inc., Employee of: Corbus Pharmaceuticals, Inc., Nancy Dgetluck Shareholder of: Corbus Pharmaceuticals, Inc., Employee of: Corbus Pharmaceuticals, Inc., Barbara White Shareholder of: Corbus Pharmaceuticals, Inc., Employee of: Corbus Pharmaceuticals, Inc., Robert Spiera Grant/research support from: Roche-Genetech, GSK, Boehringer Ingelheim, Chemocentryx, Corbus, Forbius, Sanofi, Inflarx, Consultant of: Roche-Genetech, GSK, CSL Behring, Sanofi, Janssen, Chemocentryx, Forbius, Mistubishi Tanabe

  • OP0241 SAFETY AND EFFICACY OF Lenabasum IN AN OPEN-LABEL EXTENSION OF A PHASE 2 STUDY OF Lenabasum IN REFRACTORY SKIN-PREDOMINANT DERMATOMYOSITIS (DM) SUBJECTS
    Oral Presentations, 2019
    Co-Authors: Victoria P Werth, S. Constantine, E Hejazi, Rui Feng, C Cornwall, David R. Pearson, Joyce Owaka, Josef Simon Concha, Basil Patel, Nancy Dgetluck
    Abstract:

    Background Lenabasum is a synthetic, non-immunosuppressive, selective cannabinoid receptor type 2 agonist that activates resolution of innate immune responses. Lenabasum had acceptable safety and tolerability and improved efficacy outcomes in the initial 16-week double-blinded, randomized, placebo-controlled Part A of Phase 2 trial JBT101-DM-001 (NCT02466243) in dermatomyositis (DM) subjects with refractory, skin-predominant involvement. Objectives To provide long-term safety and efficacy data in DM subjects in this study. Methods Subjects who completed Part A were eligible to receive oral Lenabasum 20 mg BID in an open-label extension (OLE) that assessed safety and efficacy at 4 weeks, then every 8 weeks. Results 20/22 (90.9%) eligible subjects received open-label Lenabasum, following a mean interval of 31 weeks from end of Part A, during which when they received only standard-of care, to start of OLE during which Lenabasum 20 mg BID was added. 17/20 (85.0%) subjects were on stable baseline immunosuppressive drugs. At the time of data cut-off, all subjects who entered OLE completed 12 months of dosing. Nineteen/20 (95%) of subjects experienced at least 1 AE, with 59 AEs occurring among the subjects during the OLE to date. The majority of AEs were mild (n = 16, 80%), with 1 severe AE (fatigue) considered unrelated to Lenabasum reported. AEs occurring in ≥ 2 subjects were: dermatomyositis worsening, dizziness, fatigue, herpes zoster, nasopharyngitis, nausea, upper respiratory tract infection, and urinary tract infection. No serious AEs related to Lenabasum have been reported. Improvement was seen in multiple physician- and patient-reported efficacy outcomes; selected outcomes are presented in Figure 1. Mean (SE) changes from study start at Week 52 in the OLE were: CDASI activity score = -17.6 (SD), Patient Skin Activity VAS = -2.6 (SD); Skindex-29 Symptoms Domain = -21.6 (SD); Patient Itch VAS = -2.8 (SD); Physician Overall Disease VAS = -3.0 (SD); and Patient Pain VAS = - 2.3 (SD). Improvements were seen in other efficacy outcomes. 12 subjects had no changes in immunosuppressive drugs during the OLE, 3 reduced chronic steroids, 2 reduced mycophenolate, 3 were switched from methotrexate to mycophenolate, 1 started methotrexate, and 1 had a burst and taper of steroids. Conclusion:  Lenabasum continues to have a favorable safety and tolerability profile in the OLE of the Phase 2 trial JBT101-DM-001 with no serious AEs or study discontinuations related to Lenabasum. The CDASI activity score and multiple other physician and patient-reported outcomes improved, although limitations of attributing efficacy to Lenabasum in the setting of open-label dosing is acknowledged. These data support further testing of Lenabasum for the treatment of DM, and a Phase 3 study of Lenabasum in DM has started.  Disclosure of Interests:   Victoria Werth: None declared, David Pearson: None declared, Joyce Owaka: None declared, Rui Feng: None declared, Josef Simon Concha: None declared, Basil Patel: None declared, Emily Hejazi: None declared, Caitlin Cornwall Shareholder of: Corbus Pharmaceuticals, Inc., Employee of: Corbus Pharmaceuticals, Inc., Scott Constantine Shareholder of: Corbus Pharmaceuticals, Inc., Employee of: Corbus Pharmaceuticals, Inc., Nancy Dgetluck Employee of: Corbus Pharmaceuticals, Inc., Barbara White Shareholder of: Corbus Pharmaceuticals, Inc., Employee of: Corbus Pharmaceuticals, Inc.

  • SAT0303 DESIGN OF PHASE 3 STUDY OF Lenabasum FOR THE TREATMENT OF DERMATOMYOSITIS
    Saturday 15 June 2019, 2019
    Co-Authors: Victoria P Werth, S. Constantine, C Cornwall, Nancy Dgetluck, Chester V. Oddis, Ingrid E. Lundberg, David Fiorentino, Barbara White
    Abstract:

    Background: To date, there has not been a Phase 3 study evaluating efficacy and safety of a new chemical entity solely in subjects with dermatomyositis (DM). There is no precedence for design of such a pivotal study, including selection of patients or efficacy outcomes. Objectives: Develop a Phase 3 study design for testing efficacy and safety of Lenabasum in DM that would be acceptable to experts and for registration purposes. Methods: Lenabasum is a synthetic, non-immunosuppressive, selective cannabinoid receptor type 2 agonist that activates resolution of innate immune responses. Lenabasum had acceptable safety and tolerability and improved multiple physician-reported and patient-reported efficacy outcomes in a 16-week double-blinded, randomized, placebo-controlled Phase 2 trial in DM subjects with refractory, skin-predominant involvement, as well as in the open-label extension of that study. The Phase 3 trial design was based on Phase 2 data, input from a steering committee of experts in DM clinical trials, and recommendations made by regulatory authorities in the US, EU, Sweden, and Japan. Results: A global, double-blind, randomized, interventional design was chosen to provide an unbiased assessment of the efficacy, safety and tolerability of Lenabasum 20 mg bid and 5 mg bid compared to placebo in the treatment of DM. A 52-week treatment duration was selected to provide safety and efficacy data adequate to support chronic treatment. Subjects with DM were classified by Peter and Bohan criteria or the 2017 EULAR/ACR classification criteria for DM (both amyopathic DM and classic DM). Subjects will be required to have active disease, as assessed by an expert and based on a range of muscle, skin, and other disease manifestations. Subjects must be on stable doses of current DM treatments with any background immunosuppressive medications allowed except prednisone ≥ 20 mg per day or equivalent. This inclusivity allows testing of efficacy and safety of Lenabasum in the setting of current treatment practice and reduces risk of disease flare early in the study. The primary efficacy outcome is change from baseline in 2016 ACR/EULAR Total Improvement Score (TIS) for DM and polymyositis. This composite outcome has six domains that broadly capture improvement in disease activity, is relevant to the range of manifestations in DM, and is applicable to the assessment of efficacy in the target patient population. Secondary efficacy outcomes were chosen to assess how the subject functions (Short Form – 36 physical functioning domain), major organ involvement (MMT-8, CDASI activity score, and a new Investigator Global Assessment scale of skin activity designed specifically for this study), and lung function (FVC). Change in oral corticosteroid dose also will be captured. Conclusion: To our knowledge, this is the first Phase 3 study in DM with a new molecular entity. As such, agreement with experts and regulatory authorities on design represents a step forward in the development pathway of new treatments for DM. Disclosure of Interests: Victoria Werth: None declared, Chester V Oddis Grant/research support from: Support of clinical research from Roche/Genentech and BMS, Consultant for: Corbus: Previous Steering Committee consultation; No longer being paid as a Corbus consultant, Ingrid E. Lundberg Grant/research support from: Dr. Lundberg has received honoraria from Bristol Myers Squibb and MedImmune and is currently receiving a research grant from Bristol Myers Squibb and from Astra Zeneca., Consultant for: She is a scientific advisor for Bristol Myers Squibb, and aTyr, David Fiorentino Grant/research support from: Pfizer - to support analysis of human tissue from patients with dermatomyositis, Consultant for: Pfizer—design and operation of clinical trial in DM Corbus—design of clinical trial in DM 23 and me—ad hoc consulting Admiryx—ad hoc consulting Janssen—SAB for PSOLAR database Beigene—paid consultant, Caitlin Cornwall Shareholder of: Corbus Pharmaceuticals, Inc., Employee of: Corbus Pharmaceuticals, Inc., Nancy Dgetluck Employee of: Corbus Pharmaceuticals, Inc., Scott Constantine Shareholder of: Corbus Pharmaceuticals, Inc., Employee of: Corbus Pharmaceuticals, Inc., Barbara White Shareholder of: Corbus Pharmaceuticals, Inc., Employee of: Corbus Pharmaceuticals, Inc.

  • OP0069 PERFORMANCE OF AMERICAN COLLEGE OF RHEUMATOLOGY (ACR) COMBINED RESPONSE INDEX IN DIFFUSE CUTANEOUS SYSTEMIC SCLEROSIS (CRISS) SCORE IN PHASE 2 TRIAL OF Lenabasum IN DIFFUSE CUTANEOUS SYSTEMIC SCLEROSIS (DCSS)
    Oral Presentations, 2019
    Co-Authors: Robert Spiera, B. Conley, Nancy Dgetluck, Dinesh Khanna, Barbara White
    Abstract:

    Background Change in modified Rodnan skin score (mRSS) has been used as primary efficacy outcome in at least 13 failed controlled studies in dcSSc. In 2016, the CRISS score was provisionally accepted by ACR as a primary efficacy outcome for clinical trials in dcSSc. Its performance as a primary efficacy outcome has not been tested in a clinical trial. Objectives To evaluate performance of ACR CRISS outcome measure in the Lenabasum Phase 2 study in dcSSc, the first study in which it was used prospectively as the primary efficacy outcome. Methods The Phase 2 study JBT101-SSc-001 (NCT02465437) included a 16-week, double-blinded, randomized, placebo-controlled Part A followed by an open-label extension (OLE). ACR CRISS score is calculated from a weighted exponential formula that includes change in mRSS, Patient Global Assessment (PtGA), HAQ-DI, Physician Global Assessment (MDGA), and FVC% predicted. Spearman correlations were determined for: pairs of core items at Baseline; change in pairs of core items; and change in a given core item and calculated ACR CRISS score. Median ACR CRISS scores were determined in subjects with different levels of improvement in patient-reported outcomes (PROs). Results Correlations among pairs of CRISS core items at baseline and change in core items were all Median ACR CRISS scores increased with increasing levels of improvement in PROs that were core items (HAQ-DI and PtGA) and even PROs (PROMIS-29 domains) that were not core items. Median ACR CRISS score associated with improvement in HAQ-DI at least -0.250 points was 0.82 and associated with at least 1-point improvement in PtGA was 0.53 at 12 months. Conclusion In the context of the Lenabasum Phase 2 clinical trial, ACR CRISS core items at baseline and change in ACR core items were not redundant (r Disclosure of Interests Robert Spiera Grant/research support from: Roche-Genentech, GlaxoSmithKline, Bristol-Myers Squibb, Boehringer Ingelheim, Cytori, Chemocentryx, Corbux, Consultant for: Roche-Genentech, GlaxoSmithKline, CSL Behring, Sanofi Aventis, Dinesh Khanna Shareholder of: Eicos Sciences, Inc, Grant/research support from: Bayer, BMS, Pfizer, Horizon, Consultant for: Actelion Acceleron, Arena, Bayer, BI, BMS, CSL Behring, Corbus, Cytori, GSK, Genentech/Roche, Galapagos, Employee of: Elcos Sciences, Inc, Nancy Dgetluck Employee of: Corbus Pharmaceuticals, Inc., Brian Conley Employee of: Corbus Pharmaceuticals, Inc., Barbara White Shareholder of: Corbus Pharmaceuticals, Inc., Employee of: Corbus Pharmaceuticals, Inc.

  • FRI0334 PERFORMANCE OF THE SCLERODERMA SKIN PATIENT-REPORTED OUTCOME (SSPRO) IN A PHASE 2 TRIAL WITH Lenabasum
    Scleroderma myositis and related syndromes, 2019
    Co-Authors: Ada Man, B. Conley, Nancy Dgetluck, Barbara White
    Abstract:

    Background Skin thickening is a distressing feature of systemic sclerosis (SSc). The severity and extensiveness of skin thickening, as traditionally assessed by mRSS, may not directly correlate with its effect on patients’ health related quality of life (HRQoL). The Scleroderma Skin Patient-reported Outcome (SSPRO) was specifically developed to assess the skin-related HRQoL in SSc. No skin-specific PRO in SSc has been prospectively validated in a clinical trial. Objectives Validate the SSPRO prospectively in a clinical trial. Methods The SSPRO, Patient Global Assessment (PtGA), Physician Global Assessment (MDGA), HAQ-DI, mRSS, FVC% predicted, PROMIS-29 questionnaire, and ACR CRISS were assessed prospectively in a Phase 2 study of Lenabasum in dcSSc. SSPRO has 18 items that assess four SSc skin-related HRQoL domains. The Phase 2 study of Lenabasum had a 4-month double-blinded portion (N = 41 completers) followed by an open-label extension (N = 38 entered). Spearman correlations of baseline values and change values were determined for SSPRO and other outcome measures. Mean change in SSPRO scores were determined in subjects with increasing levels of improvement in other efficacy outcomes. Results At baseline, SSPRO correlated moderately with all other outcome measures except for FVC%, as expected, with strongest correlations with PtGA, HAQ-DI, and PROMIS-29 pain interference and social role domains (Table 1). The mean change in SSPRO scores at 3 and 12 months correlated mostly moderately (r = 0.25 to 0.62) with the mean change in other outcome scores, but correlations were low or inconsistent with mRSS, FVC%, and PROMIS-29 anxiety domain (Table 1). Significance of correlations in some outcomes was hampered by small magnitudes of change. Mean SSPRO generally increased in subjects with increasing levels of improvement in HAQ-DI, PtGA, mRSS, and ACR CRISS, although less consistently with mRSS and ACR CRISS at 3 months (Table 2). Conclusion SSPRO score correlates with both physician and patient-reported outcomes at baseline, though correlations with the latter were stronger. Change in SSPRO reflects changes in how the patient feels (PtGA, PROMIS-29 pain interference and depression domains) and functions (HAQ-DI, PROMI-29 physical function and social role domains) and less consistently with physician-assessed outcomes. Subjects with improvement ≥ MID levels of –0.250 in HAQ-DI, -1 in PtGA, and –5 in mRSS had SSPRO improvements of -22 to -23 points at 12 months. Disclosure of Interests Ada Man Consultant for: Advisory Board Fee: Abbvie, Janssen, Boeringer Ingelheim, Nancy Dgetluck Employee of: Corbus Pharmaceuticals, Inc., Brian Conley Employee of: Corbus Pharmaceuticals, Inc., Barbara White Shareholder of: Corbus Pharmaceuticals, Inc., Employee of: Corbus Pharmaceuticals, Inc.

Robert Spiera - One of the best experts on this subject based on the ideXlab platform.

  • Response to Mittal and Sharma Letter to the Editor
    Arthritis & rheumatology (Hoboken N.J.), 2021
    Co-Authors: Robert Spiera, Lorinda Chung, Tracy M. Frech, Robyn T. Domsic, Vivien Hsu, Daniel E. Furst, Maureen D. Mayes, Robert W. Simms, Viktor Martyanov, Michael L. Whitfield
    Abstract:

    On behalf of the authors, we appreciate the interest from Mittal and Sharma in the Phase 2 study results of Lenabasum for the treatment of diffuse cutaneous systemic sclerosis (dcSSc) [1]. The small sample size and specified set of efficacy analyses done in this study preclude separate subset analyses of the course of interstitial lung disease, pulmonary artery hypertension, gastrointestinal involvement, or all efficacy analyses by disease duration or background immunosuppressant use, over 16 weeks.

  • Safety and Efficacy of Lenabasum in a Phase II, Randomized, Placebo-Controlled Trial in Adults With Systemic Sclerosis.
    Arthritis & rheumatology (Hoboken N.J.), 2020
    Co-Authors: Robert Spiera, Laura K. Hummers, Lorinda Chung, Tracy M. Frech, Robyn T. Domsic, Vivien Hsu, Daniel E. Furst, Jessica K. Gordon, Maureen D. Mayes, Robert W. Simms
    Abstract:

    Objective To assess the safety and efficacy of Lenabasum in diffuse cutaneous systemic sclerosis (dcSSc). Methods A randomized, double-blind, placebo-controlled, phase II study was conducted at 9 SSc clinics in the US. Adults with dcSSc of ≤6 years' duration who were receiving stable standard-of-care treatment were randomized to receive Lenabasum (n = 27) or placebo (n = 15). Lenabasum doses were 5 mg once daily, 20 mg once daily, or 20 mg twice daily for 4 weeks, followed by 20 mg twice daily for 8 weeks. Safety and efficacy were assessed at weeks 4, 8, 12, and 16. Results Adverse events (AEs) occurred in 63% of the Lenabasum group and 60% of the placebo group, with no serious AEs related to Lenabasum. Compared to placebo, Lenabasum treatment was associated with greater improvement in the American College of Rheumatology Combined Response Index in diffuse cutaneous Systemic Sclerosis (CRISS) score and other efficacy outcome measures that assessed overall disease, skin involvement, and patient-reported function. The median CRISS score increased in the Lenabasum group during the study, reaching 0.33, versus 0.00 in the placebo group, at week 16 (P = 0.07 by 2-sided mixed-effects model repeated-measures analysis). Gene expression in inflammation and fibrosis pathways was reduced, and inflammation and fibrosis were improved on histologic evaluation of skin biopsy specimens, in the Lenabasum group compared to the placebo group (all P ≤ 0.05). Conclusion Despite a short trial duration in a small number of patients in this phase II study in dcSSc, our findings indicate that Lenabasum improves efficacy outcomes and underlying disease pathology with a favorable safety profile.

  • AB0568 BASELINE EUROPEAN PATIENT DEMOGRAPHICS AND DISEASE CHARACTERISTICS IN A PHASE 3 STUDY OF SAFETY AND EFFICACY OF Lenabasum, A CB2 AGONIST, IN DIFFUSE CUTANEOUS SYSTEMIC SCLEROSIS
    Annals of the Rheumatic Diseases, 2020
    Co-Authors: Christopher P. Denton, Nancy Dgetluck, B. Bloom, Barbara White, Robert Spiera
    Abstract:

    Background: We previously presented on the baseline characteristics of a large cohort of diffuse cutaneous systemic sclerosis (dcSSc) patients enrolled in a Phase 3 trial of Lenabasum, a selective cannabinoid receptor type 2 (CB2) agonist. Lenabasum, was safe and well-tolerated in a prior Phase 2 study in dcSSc patients and associated with improvements in ACR Combined Response Index Systemic Sclerosis (CRISS) score and multiple secondary efficacy outcomes. Objectives: We now report on the background standard of care and baseline disease characteristics of European (EU) patients in order to assess variability by geographic regions. Methods: The RESOLVE-1 Phase 3 study was designed with input from study investigators and regulatory authorities. An important intent of the design was to have eligibility criteria that allow testing of efficacy and safety of Lenabasum in an inclusive group of dcSSc subjects to maximize relevance to patients in current practice. The study is ongoing and remains blinded. Results: Primary efficacy outcome is the ACR CRISS score at 12 months, comparing Lenabasum 20 mg BID to placebo. Key inclusion criteria are males and females ≥ 18 years of age with dcSSc and disease duration ≤ 6 years who are on stable standard of care medicines, with background stable immunosuppressive mediations allowed. Baseline mRSS needed to be ≥ 15 if disease duration was > 3 to ≤ 6 years at enrollment. The study enrolled 110 EU subjects over 15 months who received ≥ 1 dose of study drug at 20 sites in 7 countries. Baseline characteristics as shown in Table 1. The majority were middle-aged, female, and white, and 80% were on immunosuppressive drugs in EU region; methotrexate (MTX) used in 30% of subjects, mycophenolate/mycophenolic acid (MMF) used in 46% of subjects, and 43% of subjects took ≥ 2 concurrent immunosuppressive drugs. There were regional differences in background immunosuppressive with use of MTX, MMF and corticosteroids highest in EU, NA and Asia, respectively. Conclusion: This is the first Phase 3 study to use ACR CRISS as the primary efficacy outcome, a composite outcome of multiple clinically relevant measures of SSc, and the largest interventional study to date in diffuse cutaneous SSc. While the use of background immunosuppressive therapies is significant irrespective of geographic regions, MTX use is highest in the EU. Benefits of having inclusive eligibility criteria are that they facilitated timely full enrollment and will make the study more relevant to real-world practice. This study provides a model for future Phase 3 trials in dcSSc and will afford valuable information regarding scleroderma care in practice as well as evaluating the efficacy and safety of Lenabasum. Disclosure of Interests: Christopher Denton Grant/research support from: GlaxoSmithKline, CSL Behring, and Inventiva, Consultant of: Medscape, Roche-Genentech, Actelion, GlaxoSmithKline, Sanofi Aventis, Inventiva, CSL Behring, Boehringer Ingelheim, Corbus Pharmaceuticals, Acceleron, Curzion and Bayer, Bradley Bloom Shareholder of: Corbus Pharmaceuticals, Inc., Employee of: Corbus Pharmaceuticals, Inc., Nancy Dgetluck Shareholder of: Corbus Pharmaceuticals, Inc., Employee of: Corbus Pharmaceuticals, Inc., Barbara White Shareholder of: Corbus Pharmaceuticals, Inc., Employee of: Corbus Pharmaceuticals, Inc., Robert Spiera Grant/research support from: Roche-Genetech, GSK, Boehringer Ingelheim, Chemocentryx, Corbus, Forbius, Sanofi, Inflarx, Consultant of: Roche-Genetech, GSK, CSL Behring, Sanofi, Janssen, Chemocentryx, Forbius, Mistubishi Tanabe

  • OP0325 SAFETY AND EFFICACY OF Lenabasum IN AN OPEN-LABEL EXTENSION OF A PHASE 2 STUDY IN DIFFUSE CUTANEOUS SYSTEMIC SCLEROSIS SUBJECTS (DCSSC)
    Oral Presentations, 2019
    Co-Authors: Robert Spiera, Laura K. Hummers, Lorinda Chung, Tracy M. Frech, Daniel E. Furst, Jessica K. Gordon, Maureen D. Mayes, R.t. Domsic, Vivian C. Hsu, Robert W. Simms
    Abstract:

    Background Lenabasum is a synthetic, non-immunosuppressive, selective cannabinoid receptor type 2 agonist that activates resolution of innate immune responses and limits fibrosis in animal models of SSc. Lenabasum had acceptable safety and tolerability, and improved efficacy outcomes in the 16-week, double-blinded, randomized, placebo-controlled Part A of Phase 2 trial JBT101-SSc-001 (NCT02465437) in dcSSc subjects. Objectives To provide long-term open-label safety and efficacy data in dcSSc subjects in study JBT101-SSc-001. Methods Subjects who completed Part A were eligible to receive oral Lenabasum 20 mg BID in an open-label extension (OLE) that assessed safety and efficacy at 4 weeks, then every 8 weeks. Results 36/38 (95%) eligible subjects enrolled in the OLE, with mean interval of 134 (range 33-392) days or 19.1 weeks from end of dosing in Part A to start of OLE when subjects received only standard-of care drugs. 34/36 (94%) subjects were on stable doses of immunosuppressive drugs. At safety data cut-off, 31 (86%) subjects finished 1 year, 30 (83%) finished 18 months, and 24 finished ≥ 2 years in the OLE. Thirty-five (97%) subjects experienced at least 1 AE; 239 AEs have occurred during the OLE to date. Seven (19%) subjects had ≥ 1 AE considered related to Lenabasum in the OLE. Only fatigue (1 subject) was considered definitely-related, none of the related AEs were serious or severe. Most subjects experienced AEs that were mild (n = 6, 17%) to moderate (n = 24, 67%) in maximum severity. Four (11%) had severe AEs and 1 (3%) had a life-threating AE of renal crisis caused by high-dose steroids. AEs in ≥ 10% of subjects: upper respiratory tract infection (n = 11, 31%), skin ulcer and arthralgia (each n = 6, 17%), urinary tract infection (n = 5, 14%), and diarrhea, nasopharyngitis, and cough (each n = 4, 11%). Dizziness and fatigue occurred in 3 (8.3%) subjects each. At the time of efficacy data cut-off, 30/36 (83%) subjects had completed ≥ 18 months in the OLE. Improvement was seen in multiple physician- and patient-reported efficacy outcomes; selected outcomes are shown in Figure 1 Compared to Baseline at study start, the CRISS median score (primary efficacy outcome) was 0.99 (0.43 IQR) at Week 76 and mRSS declined by mean (SD) = -10.7 (7.2) points. HAQ-DI, Physician Global Assessment, Patient Global Assessment, skin symptoms, itch, and multiple PROMIS-29 domains also improved. FVC% predicted was relatively stable during the OLE; mean (SD) FVC% predicted decreased by 2.5% from study start. Conclusion Lenabasum continues to have a favorable safety and tolerability profile in the OLE of Phase 2 trial JBT101-SSc-001 with no Lenabasum-related serious AEs or study discontinuations. Only 7 (19%) subjects had an AE related to Lenabasum in ≥ 18 months of OLE dosing. ACR CRISS score, mRSS, Physician Global Assessment, and multiple patient-reported outcomes show continued improvement, although background therapy, potential for spontaneous improvement, and open-label dosing limit what can be definitely attributed to Lenabasum. Disclosure of Interests:  Robert Spiera Grant/research support from: Roche-Genentech, GlaxoSmithKline, Bristol-Myers Squibb, Boehringer Ingelheim, Cytori, Chemocentryx, Corbux, Consultant for: Roche-Genentech, GlaxoSmithKline, CSL Behring, Sanofi Aventis, Laura Hummers Grant/research support from: Site PI for phase 2 and 3 clinical trials (Cumberland, Glaxo Smith Kline, Boerhinger Ingleheim, Corbus, Cytori), Consultant for: CSL Behring, Lorinda Chung Grant/research support from: United Therapeutics, Consultant for: Reata, Bristol Meyers Squibb, Boehringer Ingelheim, Mitsubishi Tanabe, Eicos, Tracy Frech: None declared, Robin Domsic Consultant for: Eicos Sciences Inc/Civi Biopharma and Boehringer-Ingelheim., Vivian Hsu: None declared, Daniel Furst Grant/research support from: F. Hoffmann-La Roche, Genentech, Jessica Gordon Grant/research support from: Corbus Pharmaceuticals Cumberland Pharmaceuticals, Maureen Mayes Grant/research support from: Maureen Mayes is a clinical trial investigator for Boehringer-Ingelheim; Galapagos, Reata, Sanofi, Merck-Serono, Consultant for: Maureen Mayes is a member of scientific advisory boards for Galapagos NV (Pharma), Boehringer-Ingelheim, Mitsubishi-Tanabe, Astellas: Grant Review Board for Actelion., Speakers bureau: Maureen Mayes received personal fees for being a conference speaker on the use of autoantibodies in connective tissue diseases for Medtelligence, Robert Simms: None declared, Elizabeth Lee Shareholder of: Corbus Pharmaceuticals, Inc., Employee of: Corbus Pharmaceuticals, Inc., Scott Constantine Shareholder of: Corbus Pharmaceuticals, Inc., Employee of: Corbus Pharmaceuticals, Inc., Nancy Dgetluck Employee of: Corbus Pharmaceuticals, Inc., Barbara White Shareholder of: Corbus Pharmaceuticals, Inc., Employee of: Corbus Pharmaceuticals, Inc.

  • OP0069 PERFORMANCE OF AMERICAN COLLEGE OF RHEUMATOLOGY (ACR) COMBINED RESPONSE INDEX IN DIFFUSE CUTANEOUS SYSTEMIC SCLEROSIS (CRISS) SCORE IN PHASE 2 TRIAL OF Lenabasum IN DIFFUSE CUTANEOUS SYSTEMIC SCLEROSIS (DCSS)
    Oral Presentations, 2019
    Co-Authors: Robert Spiera, B. Conley, Nancy Dgetluck, Dinesh Khanna, Barbara White
    Abstract:

    Background Change in modified Rodnan skin score (mRSS) has been used as primary efficacy outcome in at least 13 failed controlled studies in dcSSc. In 2016, the CRISS score was provisionally accepted by ACR as a primary efficacy outcome for clinical trials in dcSSc. Its performance as a primary efficacy outcome has not been tested in a clinical trial. Objectives To evaluate performance of ACR CRISS outcome measure in the Lenabasum Phase 2 study in dcSSc, the first study in which it was used prospectively as the primary efficacy outcome. Methods The Phase 2 study JBT101-SSc-001 (NCT02465437) included a 16-week, double-blinded, randomized, placebo-controlled Part A followed by an open-label extension (OLE). ACR CRISS score is calculated from a weighted exponential formula that includes change in mRSS, Patient Global Assessment (PtGA), HAQ-DI, Physician Global Assessment (MDGA), and FVC% predicted. Spearman correlations were determined for: pairs of core items at Baseline; change in pairs of core items; and change in a given core item and calculated ACR CRISS score. Median ACR CRISS scores were determined in subjects with different levels of improvement in patient-reported outcomes (PROs). Results Correlations among pairs of CRISS core items at baseline and change in core items were all Median ACR CRISS scores increased with increasing levels of improvement in PROs that were core items (HAQ-DI and PtGA) and even PROs (PROMIS-29 domains) that were not core items. Median ACR CRISS score associated with improvement in HAQ-DI at least -0.250 points was 0.82 and associated with at least 1-point improvement in PtGA was 0.53 at 12 months. Conclusion In the context of the Lenabasum Phase 2 clinical trial, ACR CRISS core items at baseline and change in ACR core items were not redundant (r Disclosure of Interests Robert Spiera Grant/research support from: Roche-Genentech, GlaxoSmithKline, Bristol-Myers Squibb, Boehringer Ingelheim, Cytori, Chemocentryx, Corbux, Consultant for: Roche-Genentech, GlaxoSmithKline, CSL Behring, Sanofi Aventis, Dinesh Khanna Shareholder of: Eicos Sciences, Inc, Grant/research support from: Bayer, BMS, Pfizer, Horizon, Consultant for: Actelion Acceleron, Arena, Bayer, BI, BMS, CSL Behring, Corbus, Cytori, GSK, Genentech/Roche, Galapagos, Employee of: Elcos Sciences, Inc, Nancy Dgetluck Employee of: Corbus Pharmaceuticals, Inc., Brian Conley Employee of: Corbus Pharmaceuticals, Inc., Barbara White Shareholder of: Corbus Pharmaceuticals, Inc., Employee of: Corbus Pharmaceuticals, Inc.

C Cornwall - One of the best experts on this subject based on the ideXlab platform.

  • OP0241 SAFETY AND EFFICACY OF Lenabasum IN AN OPEN-LABEL EXTENSION OF A PHASE 2 STUDY OF Lenabasum IN REFRACTORY SKIN-PREDOMINANT DERMATOMYOSITIS (DM) SUBJECTS
    Oral Presentations, 2019
    Co-Authors: Victoria P Werth, S. Constantine, E Hejazi, Rui Feng, C Cornwall, David R. Pearson, Joyce Owaka, Josef Simon Concha, Basil Patel, Nancy Dgetluck
    Abstract:

    Background Lenabasum is a synthetic, non-immunosuppressive, selective cannabinoid receptor type 2 agonist that activates resolution of innate immune responses. Lenabasum had acceptable safety and tolerability and improved efficacy outcomes in the initial 16-week double-blinded, randomized, placebo-controlled Part A of Phase 2 trial JBT101-DM-001 (NCT02466243) in dermatomyositis (DM) subjects with refractory, skin-predominant involvement. Objectives To provide long-term safety and efficacy data in DM subjects in this study. Methods Subjects who completed Part A were eligible to receive oral Lenabasum 20 mg BID in an open-label extension (OLE) that assessed safety and efficacy at 4 weeks, then every 8 weeks. Results 20/22 (90.9%) eligible subjects received open-label Lenabasum, following a mean interval of 31 weeks from end of Part A, during which when they received only standard-of care, to start of OLE during which Lenabasum 20 mg BID was added. 17/20 (85.0%) subjects were on stable baseline immunosuppressive drugs. At the time of data cut-off, all subjects who entered OLE completed 12 months of dosing. Nineteen/20 (95%) of subjects experienced at least 1 AE, with 59 AEs occurring among the subjects during the OLE to date. The majority of AEs were mild (n = 16, 80%), with 1 severe AE (fatigue) considered unrelated to Lenabasum reported. AEs occurring in ≥ 2 subjects were: dermatomyositis worsening, dizziness, fatigue, herpes zoster, nasopharyngitis, nausea, upper respiratory tract infection, and urinary tract infection. No serious AEs related to Lenabasum have been reported. Improvement was seen in multiple physician- and patient-reported efficacy outcomes; selected outcomes are presented in Figure 1. Mean (SE) changes from study start at Week 52 in the OLE were: CDASI activity score = -17.6 (SD), Patient Skin Activity VAS = -2.6 (SD); Skindex-29 Symptoms Domain = -21.6 (SD); Patient Itch VAS = -2.8 (SD); Physician Overall Disease VAS = -3.0 (SD); and Patient Pain VAS = - 2.3 (SD). Improvements were seen in other efficacy outcomes. 12 subjects had no changes in immunosuppressive drugs during the OLE, 3 reduced chronic steroids, 2 reduced mycophenolate, 3 were switched from methotrexate to mycophenolate, 1 started methotrexate, and 1 had a burst and taper of steroids. Conclusion:  Lenabasum continues to have a favorable safety and tolerability profile in the OLE of the Phase 2 trial JBT101-DM-001 with no serious AEs or study discontinuations related to Lenabasum. The CDASI activity score and multiple other physician and patient-reported outcomes improved, although limitations of attributing efficacy to Lenabasum in the setting of open-label dosing is acknowledged. These data support further testing of Lenabasum for the treatment of DM, and a Phase 3 study of Lenabasum in DM has started.  Disclosure of Interests:   Victoria Werth: None declared, David Pearson: None declared, Joyce Owaka: None declared, Rui Feng: None declared, Josef Simon Concha: None declared, Basil Patel: None declared, Emily Hejazi: None declared, Caitlin Cornwall Shareholder of: Corbus Pharmaceuticals, Inc., Employee of: Corbus Pharmaceuticals, Inc., Scott Constantine Shareholder of: Corbus Pharmaceuticals, Inc., Employee of: Corbus Pharmaceuticals, Inc., Nancy Dgetluck Employee of: Corbus Pharmaceuticals, Inc., Barbara White Shareholder of: Corbus Pharmaceuticals, Inc., Employee of: Corbus Pharmaceuticals, Inc.

  • SAT0303 DESIGN OF PHASE 3 STUDY OF Lenabasum FOR THE TREATMENT OF DERMATOMYOSITIS
    Saturday 15 June 2019, 2019
    Co-Authors: Victoria P Werth, S. Constantine, C Cornwall, Nancy Dgetluck, Chester V. Oddis, Ingrid E. Lundberg, David Fiorentino, Barbara White
    Abstract:

    Background: To date, there has not been a Phase 3 study evaluating efficacy and safety of a new chemical entity solely in subjects with dermatomyositis (DM). There is no precedence for design of such a pivotal study, including selection of patients or efficacy outcomes. Objectives: Develop a Phase 3 study design for testing efficacy and safety of Lenabasum in DM that would be acceptable to experts and for registration purposes. Methods: Lenabasum is a synthetic, non-immunosuppressive, selective cannabinoid receptor type 2 agonist that activates resolution of innate immune responses. Lenabasum had acceptable safety and tolerability and improved multiple physician-reported and patient-reported efficacy outcomes in a 16-week double-blinded, randomized, placebo-controlled Phase 2 trial in DM subjects with refractory, skin-predominant involvement, as well as in the open-label extension of that study. The Phase 3 trial design was based on Phase 2 data, input from a steering committee of experts in DM clinical trials, and recommendations made by regulatory authorities in the US, EU, Sweden, and Japan. Results: A global, double-blind, randomized, interventional design was chosen to provide an unbiased assessment of the efficacy, safety and tolerability of Lenabasum 20 mg bid and 5 mg bid compared to placebo in the treatment of DM. A 52-week treatment duration was selected to provide safety and efficacy data adequate to support chronic treatment. Subjects with DM were classified by Peter and Bohan criteria or the 2017 EULAR/ACR classification criteria for DM (both amyopathic DM and classic DM). Subjects will be required to have active disease, as assessed by an expert and based on a range of muscle, skin, and other disease manifestations. Subjects must be on stable doses of current DM treatments with any background immunosuppressive medications allowed except prednisone ≥ 20 mg per day or equivalent. This inclusivity allows testing of efficacy and safety of Lenabasum in the setting of current treatment practice and reduces risk of disease flare early in the study. The primary efficacy outcome is change from baseline in 2016 ACR/EULAR Total Improvement Score (TIS) for DM and polymyositis. This composite outcome has six domains that broadly capture improvement in disease activity, is relevant to the range of manifestations in DM, and is applicable to the assessment of efficacy in the target patient population. Secondary efficacy outcomes were chosen to assess how the subject functions (Short Form – 36 physical functioning domain), major organ involvement (MMT-8, CDASI activity score, and a new Investigator Global Assessment scale of skin activity designed specifically for this study), and lung function (FVC). Change in oral corticosteroid dose also will be captured. Conclusion: To our knowledge, this is the first Phase 3 study in DM with a new molecular entity. As such, agreement with experts and regulatory authorities on design represents a step forward in the development pathway of new treatments for DM. Disclosure of Interests: Victoria Werth: None declared, Chester V Oddis Grant/research support from: Support of clinical research from Roche/Genentech and BMS, Consultant for: Corbus: Previous Steering Committee consultation; No longer being paid as a Corbus consultant, Ingrid E. Lundberg Grant/research support from: Dr. Lundberg has received honoraria from Bristol Myers Squibb and MedImmune and is currently receiving a research grant from Bristol Myers Squibb and from Astra Zeneca., Consultant for: She is a scientific advisor for Bristol Myers Squibb, and aTyr, David Fiorentino Grant/research support from: Pfizer - to support analysis of human tissue from patients with dermatomyositis, Consultant for: Pfizer—design and operation of clinical trial in DM Corbus—design of clinical trial in DM 23 and me—ad hoc consulting Admiryx—ad hoc consulting Janssen—SAB for PSOLAR database Beigene—paid consultant, Caitlin Cornwall Shareholder of: Corbus Pharmaceuticals, Inc., Employee of: Corbus Pharmaceuticals, Inc., Nancy Dgetluck Employee of: Corbus Pharmaceuticals, Inc., Scott Constantine Shareholder of: Corbus Pharmaceuticals, Inc., Employee of: Corbus Pharmaceuticals, Inc., Barbara White Shareholder of: Corbus Pharmaceuticals, Inc., Employee of: Corbus Pharmaceuticals, Inc.

  • SAT0512 Safety and efficacy of Lenabasum in refractory skin-predominant dermatomyositis subjects treated in an open label extension of trial jbt101-dm-001
    Saturday 16 JUNE 2018, 2018
    Co-Authors: Victoria P Werth, E Hejazi, Joyce Okawa, Rui Feng, Josef Symon S Concha, C Cornwall, Nancy Dgetluck, David R. Pearson, Basil Patel, S. Constantine
    Abstract:

    Background Lenabasum (aka anabasum, JBT-101) is a selective cannabinoid receptor type 2 agonist that activates resolution of innate immune responses. It is a synthetic, oral, non-immunosuppressive small molecule. Lenabasum showed acceptable safety and tolerability and evidence of clinical benefit in 22 subjects with refractory, skin-predominant dermatomyositis (DM) in Phase 2 trial JBT101-DM-001 (NCT02466243). Objectives This study evaluated safety and efficacy of open-label dosing of Lenabasum in moderately-to-severely active skin-predominant DM in subjects who were refractory to or intolerant of hydroxychloroquine treatment. Methods Subjects who completed the double-blind placebo-controlled (DBPC) part of JBT101-DM-001 with 12 weeks of active dosing and 4 weeks of safety follow-up were eligible to receive Lenabasum 20 mg BID in an open-label extension (OLE). Safety and efficacy evaluations were done at Week 4 after the start of OLE, then every 8 weeks thereafter. Results 20/22 (91%) eligible subjects enrolled in the OLE and 17/20 (85%) were on baseline immunosuppressive drugs. There was a mean interval of 31 weeks (range 4–92 weeks) from the end of active DBPC dosing and the start of the OLE, during which time subjects remained on background medications prior to adding Lenabasum in the OLE. At the time of OLE data cut-off, no subjects had discontinued, all 20 subjects in the OLE completed visits through Week 12 and 11 subjects completed visits through Week 28. During the 28 weeks of OLE dosing, adverse events (AEs, n=30) occurred in 14/20 (70%) subjects. Only 1 subject had a moderate AE, all other AEs were mild. Four (20%) subjects had AEs considered related to Lenabasum. The only AE that occurred in more than 1 subject was DM flare (n=2, 10%). During the OLE, there was improvement from the beginning of the OLE dosing and from the study start in Cutaneous Dermatomyositis Activity and Severity Index (CDASI) Activity score and physician Likert assessments of global disease activity, skin disease activity and extramuscular disease activity. Similarly, there were improvements in multiple patient-reported outcomes, including patient 10 cm VAS scores of global disease activity, skin disease activity, itch and pain, as well as the Skin-dex-29 symptoms domain and PROMIS-29 physical function, fatigue, pain interference, and anxiety domains. Selected efficacy outcomes are shown in figure 1 as change from study start during two periods: 1) “off treatment” from the end of active DBPC dosing to the start of OLE, dotted line; and 2) OLE dosing, solid line. Conclusions Lenabasum continues to have a favourable safety and tolerability profile in the OLE of the Phase 2 trial JBT101-DM-001 with no severe or serious AEs or study discontinuations related to Lenabasum. The CDASI activity score and multiple other physician and patient-reported outcomes improved from study start and start of the OLE, although open-label nature of dosing with Lenabasum is acknowledged. These data support further testing of Lenabasum for the treatment of DM. Disclosure of Interest V. Werth Consultant for: Corbus Pharmaceuticals, Inc., B. Patel: None declared, J. Concha: None declared, J. Okawa: None declared, D. Pearson: None declared, E. Hejazi: None declared, R. Feng: None declared, C. Cornwall Employee of: Corbus Pharmaceuticals, Inc., N. Dgetluck Employee of: Corbus Pharmaceuticals, Inc., S. Constantine Employee of: Corbus Pharmaceuticals, Inc., A. Aggarwal Employee of: Corbus Pharmaceuticals, Inc., B. White Employee of: Corbus Pharmaceuticals, Inc.

  • fri0470 a phase 2 study of safety and efficacy of Lenabasum jbt 101 a cannabinoid receptor type 2 agonist in refractory skin predominant dermatomyositis
    Annals of the Rheumatic Diseases, 2018
    Co-Authors: Victoria P Werth, E Hejazi, S M Pena, J S Haber, Joyce Okawa, Rui Feng, K Gabre, Josef Symon S Concha, C Cornwall, Nancy Dgetluck
    Abstract:

    Background Effective treatment options are limited for refractory skin disease in dermatomyositis (DM). Lenabasum is a non-immunosuppressive, synthetic, oral preferential CB2 agonist that triggers resolution of innate immune responses and reduces cytokine production by PBMC from DM patients. Objectives The purpose of this study was to test safety and efficacy of Lenabasum (aka JBT-101, anabasum) in DM subjects with refractory, moderate-to-severely active skin disease. Methods A double-blind, randomised placebo-controlled 16 week Phase 2 trial (JBT101-DM-001; NCT02466243) enrolled adults with documented DM and a Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) activity score ≥14, minimal active muscle involvement and failure or intolerance to hydroxychloroquine and stable DM medications including immunosuppressants. Subjects received 2 escalating dose levels of Lenabasum (20 mg QD X 4 weeks, then 20 mg BID X 8 weeks) or PBO X 12 weeks. Subjects were followed off study drug X 4 weeks. Safety and efficacy outcomes were assessed from Day 1 through end of study at Week 16. The primary efficacy objective was to assess efficacy of Lenabasum using CDASI activity score. Results 11 adults each received Lenabasum and PBO (n=22). Demographic and disease characteristics were similar in both cohorts. Both cohorts had mean CDASI activity scores in the severe range33–35 despite immunosuppressants (19/22 subjects). Lenabasum subjects had clinically meaningful improvement in CDASI activity scores with mean reduction ≥5 points at all visits after 4 weeks. Improvement had statistical significance at end of study (figure 1, p=0.02, 2-sided MMRM) that first became apparent after 4 weeks. Lenabasum provided greater improvement than placebo in CDASI damage index, patient-reported global skin disease and overall disease assessments, skin symptoms including photosensitivity and itch, fatigue, sleep, pain interference with activities, pain, and physical function (examples in figure 1). Improvements in secondary efficacy outcomes reached statistical significance (p≤0.1, 1-sided MMRM) at multiple visits after week 4 (figure 1). There were no serious, severe or unexpected adverse events (AEs) related to Lenabasum. Tolerability of Lenabasum was excellent with no study drop-outs. Subjects in the Lenabasum cohort had numerically more mild AEs than placebo subjects (29 vs. 19) and fewer moderate AEs (4 vs. 7). AEs in ≥3 subjects in any cohort were diarrhoea, dizziness (lightheadedness), fatigue and dry mouth. Conclusions Lenabasum demonstrated consistent evidence of clinical benefit across multiple efficacy outcomes and had acceptable safety and tolerability in this Phase 2 trial in refractory skin disease in DM. Further evaluation of Lenabasum in the treatment of DM is warranted. Disclosure of Interest V. Werth Consultant for: Corbus Pharmaceuticals, Inc., E. Hejazi: None declared, S. Pena: None declared, J. Haber: None declared, J. Okawa: None declared, R. Feng: None declared, K. Gabre: None declared, J. Concha: None declared, C. Cornwall Employee of: Corbus Pharmaceuticals, Inc., N. Dgetluck Employee of: Corbus Pharmaceuticals, Inc., S. Constantine Employee of: Corbus Pharmaceuticals, Inc., B. White Employee of: Corbus Pharmaceuticals, Inc.

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  • OP0241 SAFETY AND EFFICACY OF Lenabasum IN AN OPEN-LABEL EXTENSION OF A PHASE 2 STUDY OF Lenabasum IN REFRACTORY SKIN-PREDOMINANT DERMATOMYOSITIS (DM) SUBJECTS
    Oral Presentations, 2019
    Co-Authors: Victoria P Werth, S. Constantine, E Hejazi, Rui Feng, C Cornwall, David R. Pearson, Joyce Owaka, Josef Simon Concha, Basil Patel, Nancy Dgetluck
    Abstract:

    Background Lenabasum is a synthetic, non-immunosuppressive, selective cannabinoid receptor type 2 agonist that activates resolution of innate immune responses. Lenabasum had acceptable safety and tolerability and improved efficacy outcomes in the initial 16-week double-blinded, randomized, placebo-controlled Part A of Phase 2 trial JBT101-DM-001 (NCT02466243) in dermatomyositis (DM) subjects with refractory, skin-predominant involvement. Objectives To provide long-term safety and efficacy data in DM subjects in this study. Methods Subjects who completed Part A were eligible to receive oral Lenabasum 20 mg BID in an open-label extension (OLE) that assessed safety and efficacy at 4 weeks, then every 8 weeks. Results 20/22 (90.9%) eligible subjects received open-label Lenabasum, following a mean interval of 31 weeks from end of Part A, during which when they received only standard-of care, to start of OLE during which Lenabasum 20 mg BID was added. 17/20 (85.0%) subjects were on stable baseline immunosuppressive drugs. At the time of data cut-off, all subjects who entered OLE completed 12 months of dosing. Nineteen/20 (95%) of subjects experienced at least 1 AE, with 59 AEs occurring among the subjects during the OLE to date. The majority of AEs were mild (n = 16, 80%), with 1 severe AE (fatigue) considered unrelated to Lenabasum reported. AEs occurring in ≥ 2 subjects were: dermatomyositis worsening, dizziness, fatigue, herpes zoster, nasopharyngitis, nausea, upper respiratory tract infection, and urinary tract infection. No serious AEs related to Lenabasum have been reported. Improvement was seen in multiple physician- and patient-reported efficacy outcomes; selected outcomes are presented in Figure 1. Mean (SE) changes from study start at Week 52 in the OLE were: CDASI activity score = -17.6 (SD), Patient Skin Activity VAS = -2.6 (SD); Skindex-29 Symptoms Domain = -21.6 (SD); Patient Itch VAS = -2.8 (SD); Physician Overall Disease VAS = -3.0 (SD); and Patient Pain VAS = - 2.3 (SD). Improvements were seen in other efficacy outcomes. 12 subjects had no changes in immunosuppressive drugs during the OLE, 3 reduced chronic steroids, 2 reduced mycophenolate, 3 were switched from methotrexate to mycophenolate, 1 started methotrexate, and 1 had a burst and taper of steroids. Conclusion:  Lenabasum continues to have a favorable safety and tolerability profile in the OLE of the Phase 2 trial JBT101-DM-001 with no serious AEs or study discontinuations related to Lenabasum. The CDASI activity score and multiple other physician and patient-reported outcomes improved, although limitations of attributing efficacy to Lenabasum in the setting of open-label dosing is acknowledged. These data support further testing of Lenabasum for the treatment of DM, and a Phase 3 study of Lenabasum in DM has started.  Disclosure of Interests:   Victoria Werth: None declared, David Pearson: None declared, Joyce Owaka: None declared, Rui Feng: None declared, Josef Simon Concha: None declared, Basil Patel: None declared, Emily Hejazi: None declared, Caitlin Cornwall Shareholder of: Corbus Pharmaceuticals, Inc., Employee of: Corbus Pharmaceuticals, Inc., Scott Constantine Shareholder of: Corbus Pharmaceuticals, Inc., Employee of: Corbus Pharmaceuticals, Inc., Nancy Dgetluck Employee of: Corbus Pharmaceuticals, Inc., Barbara White Shareholder of: Corbus Pharmaceuticals, Inc., Employee of: Corbus Pharmaceuticals, Inc.

  • SAT0512 Safety and efficacy of Lenabasum in refractory skin-predominant dermatomyositis subjects treated in an open label extension of trial jbt101-dm-001
    Saturday 16 JUNE 2018, 2018
    Co-Authors: Victoria P Werth, E Hejazi, Joyce Okawa, Rui Feng, Josef Symon S Concha, C Cornwall, Nancy Dgetluck, David R. Pearson, Basil Patel, S. Constantine
    Abstract:

    Background Lenabasum (aka anabasum, JBT-101) is a selective cannabinoid receptor type 2 agonist that activates resolution of innate immune responses. It is a synthetic, oral, non-immunosuppressive small molecule. Lenabasum showed acceptable safety and tolerability and evidence of clinical benefit in 22 subjects with refractory, skin-predominant dermatomyositis (DM) in Phase 2 trial JBT101-DM-001 (NCT02466243). Objectives This study evaluated safety and efficacy of open-label dosing of Lenabasum in moderately-to-severely active skin-predominant DM in subjects who were refractory to or intolerant of hydroxychloroquine treatment. Methods Subjects who completed the double-blind placebo-controlled (DBPC) part of JBT101-DM-001 with 12 weeks of active dosing and 4 weeks of safety follow-up were eligible to receive Lenabasum 20 mg BID in an open-label extension (OLE). Safety and efficacy evaluations were done at Week 4 after the start of OLE, then every 8 weeks thereafter. Results 20/22 (91%) eligible subjects enrolled in the OLE and 17/20 (85%) were on baseline immunosuppressive drugs. There was a mean interval of 31 weeks (range 4–92 weeks) from the end of active DBPC dosing and the start of the OLE, during which time subjects remained on background medications prior to adding Lenabasum in the OLE. At the time of OLE data cut-off, no subjects had discontinued, all 20 subjects in the OLE completed visits through Week 12 and 11 subjects completed visits through Week 28. During the 28 weeks of OLE dosing, adverse events (AEs, n=30) occurred in 14/20 (70%) subjects. Only 1 subject had a moderate AE, all other AEs were mild. Four (20%) subjects had AEs considered related to Lenabasum. The only AE that occurred in more than 1 subject was DM flare (n=2, 10%). During the OLE, there was improvement from the beginning of the OLE dosing and from the study start in Cutaneous Dermatomyositis Activity and Severity Index (CDASI) Activity score and physician Likert assessments of global disease activity, skin disease activity and extramuscular disease activity. Similarly, there were improvements in multiple patient-reported outcomes, including patient 10 cm VAS scores of global disease activity, skin disease activity, itch and pain, as well as the Skin-dex-29 symptoms domain and PROMIS-29 physical function, fatigue, pain interference, and anxiety domains. Selected efficacy outcomes are shown in figure 1 as change from study start during two periods: 1) “off treatment” from the end of active DBPC dosing to the start of OLE, dotted line; and 2) OLE dosing, solid line. Conclusions Lenabasum continues to have a favourable safety and tolerability profile in the OLE of the Phase 2 trial JBT101-DM-001 with no severe or serious AEs or study discontinuations related to Lenabasum. The CDASI activity score and multiple other physician and patient-reported outcomes improved from study start and start of the OLE, although open-label nature of dosing with Lenabasum is acknowledged. These data support further testing of Lenabasum for the treatment of DM. Disclosure of Interest V. Werth Consultant for: Corbus Pharmaceuticals, Inc., B. Patel: None declared, J. Concha: None declared, J. Okawa: None declared, D. Pearson: None declared, E. Hejazi: None declared, R. Feng: None declared, C. Cornwall Employee of: Corbus Pharmaceuticals, Inc., N. Dgetluck Employee of: Corbus Pharmaceuticals, Inc., S. Constantine Employee of: Corbus Pharmaceuticals, Inc., A. Aggarwal Employee of: Corbus Pharmaceuticals, Inc., B. White Employee of: Corbus Pharmaceuticals, Inc.

  • fri0470 a phase 2 study of safety and efficacy of Lenabasum jbt 101 a cannabinoid receptor type 2 agonist in refractory skin predominant dermatomyositis
    Annals of the Rheumatic Diseases, 2018
    Co-Authors: Victoria P Werth, E Hejazi, S M Pena, J S Haber, Joyce Okawa, Rui Feng, K Gabre, Josef Symon S Concha, C Cornwall, Nancy Dgetluck
    Abstract:

    Background Effective treatment options are limited for refractory skin disease in dermatomyositis (DM). Lenabasum is a non-immunosuppressive, synthetic, oral preferential CB2 agonist that triggers resolution of innate immune responses and reduces cytokine production by PBMC from DM patients. Objectives The purpose of this study was to test safety and efficacy of Lenabasum (aka JBT-101, anabasum) in DM subjects with refractory, moderate-to-severely active skin disease. Methods A double-blind, randomised placebo-controlled 16 week Phase 2 trial (JBT101-DM-001; NCT02466243) enrolled adults with documented DM and a Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) activity score ≥14, minimal active muscle involvement and failure or intolerance to hydroxychloroquine and stable DM medications including immunosuppressants. Subjects received 2 escalating dose levels of Lenabasum (20 mg QD X 4 weeks, then 20 mg BID X 8 weeks) or PBO X 12 weeks. Subjects were followed off study drug X 4 weeks. Safety and efficacy outcomes were assessed from Day 1 through end of study at Week 16. The primary efficacy objective was to assess efficacy of Lenabasum using CDASI activity score. Results 11 adults each received Lenabasum and PBO (n=22). Demographic and disease characteristics were similar in both cohorts. Both cohorts had mean CDASI activity scores in the severe range33–35 despite immunosuppressants (19/22 subjects). Lenabasum subjects had clinically meaningful improvement in CDASI activity scores with mean reduction ≥5 points at all visits after 4 weeks. Improvement had statistical significance at end of study (figure 1, p=0.02, 2-sided MMRM) that first became apparent after 4 weeks. Lenabasum provided greater improvement than placebo in CDASI damage index, patient-reported global skin disease and overall disease assessments, skin symptoms including photosensitivity and itch, fatigue, sleep, pain interference with activities, pain, and physical function (examples in figure 1). Improvements in secondary efficacy outcomes reached statistical significance (p≤0.1, 1-sided MMRM) at multiple visits after week 4 (figure 1). There were no serious, severe or unexpected adverse events (AEs) related to Lenabasum. Tolerability of Lenabasum was excellent with no study drop-outs. Subjects in the Lenabasum cohort had numerically more mild AEs than placebo subjects (29 vs. 19) and fewer moderate AEs (4 vs. 7). AEs in ≥3 subjects in any cohort were diarrhoea, dizziness (lightheadedness), fatigue and dry mouth. Conclusions Lenabasum demonstrated consistent evidence of clinical benefit across multiple efficacy outcomes and had acceptable safety and tolerability in this Phase 2 trial in refractory skin disease in DM. Further evaluation of Lenabasum in the treatment of DM is warranted. Disclosure of Interest V. Werth Consultant for: Corbus Pharmaceuticals, Inc., E. Hejazi: None declared, S. Pena: None declared, J. Haber: None declared, J. Okawa: None declared, R. Feng: None declared, K. Gabre: None declared, J. Concha: None declared, C. Cornwall Employee of: Corbus Pharmaceuticals, Inc., N. Dgetluck Employee of: Corbus Pharmaceuticals, Inc., S. Constantine Employee of: Corbus Pharmaceuticals, Inc., B. White Employee of: Corbus Pharmaceuticals, Inc.