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LB950 The potential impact on future fertility for biologics and emerging therapies for psoriasis and atopic dermatitis
ABSTRACTS | LB948
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Pharmacodynamic activity of a microRNA-29b mimic (MRG-201) in human skin incisions CL Gallant-Behm1, C Maari2, AL Jackson1, AG Seto1, JM Lynch1, J Ruckman1, ML Landry1, LA Pestano1, BA Dickinson1, CM Dalby1, M Sanseverino1, DM Rodman1, GG Gordon1, P Rubin1 and WS Marshall1 1 miRagen Therapeutics, Inc., Boulder, CO and 2 Innovaderm Research, Inc., Montreal, PQ, Canada MicroRNA-29 is an anti-fibrotic miRNA whose expression is downregulated in multiple fibrotic indications including in cutaneous scars and keloids. Its target genes include numerous collagens and other extracellular matrix molecules, suggesting that restoration of miR-29 expression in a skin wound or at the site of an excised scar could have a therapeutic benefit by reducing scarring and/or preventing scar regrowth. An oligonucleotide mimic of miR-29b (MRG-201) was studied in vivo in mouse, rats and rabbits as well as in vitro in human skin fibroblasts to identify a set of conserved pharmacodynamic biomarkers in the skin. MRG-201 was then evaluated in a Phase 1 double-blinded within-patient randomized clinical trial in 53 normal healthy volunteers (NCT02603224). Expression of miR-29b and its pharmacodynamic biomarkers was assessed in untreated skin incisions and following single or multiple administrations of MRG-201 at the site of a sutured skin incision. miR-29b expression was significantly decreased and direct miR-29 target genes were significantly upregulated with incision alone. Intradermal administration of MRG-201 resulted in a high local concentration of miR-29b with low systemic exposure and good safety/tolerability at all doses tested. Pharmacodynamic activity was seen after MRG-201 treatment: single and multiple doses of MRG-201 reduced collagen mRNA expression as compared to a placebo injected incision in the same subject. Additionally, multiple administrations of MRG-201 reduced fibroplasia as assessed by histopathology (p < 0.01). These findings support further investigation of MRG-201 as a novel therapeutic to inhibit scar formation or prevent hypertrophic scar or keloid recurrence following excision.
In vitro expansion of desmoglein specific peripheral blood B cells of patients with pemphigus S Mallam1, R Streilein2, H Suga3, TF Tedder2 and RP Hall2 1 Duke University School of Medicine, Durham, NC, 2 Duke University Medical Center, Durham, NC and 3 University of Tokyo, Tokyo, Japan B cells are known to play a major role in the pathogenesis of autoimmune diseases as precursors of autoantibody producing plasma cells. Pemphigus vulgaris (PV) and foliaceus (PF) are severe blistering diseases of the skin caused by autoantibodies directed against desmoglein-1 (DSG1) and desmoglein-3 (DSG3). The purpose of this study is to utilize in vitro expansion and differentiation of B cells from patients with PV and PF to help better understand the frequency of DSG1/DSG3 specific B cells in patients with active skin disease. B cells were isolated from peripheral blood (PB) samples from patients with clinically active PV (n¼2), PF (n¼2), and healthy controls (HC) (n¼2). B cells were expanded in vitro using a cell culture system that supports B cell proliferation and differentiation into immunoglobulinsecreting plasma cells. PB B cells (10/well) were cultured in 96 well plates for 12 days. Supernatants were tested for the presence of DSG1 or DSG3 antibodies by ELISA. The frequency of wells with ELISA values outside of 3x the interquartile range (IQR) were calculated for each subject. Supernatants from PV/PF patients showed a higher frequency of wells producing IgG anti DSG1 or DSG3 than controls (mean frequency wells>3x IQR: PV/ PF¼4.87%; HC¼1.89%, p¼0.03). This study demonstrates that in vitro stimulation of PB B cells from patients with PV/PF produce an increased frequency of IgG anti DSG1/DSG3 detected by ELISA compared to PB B cells from normal subjects. Utilizing these techniques, we will be able to analyze the change in antigen-specific B cell frequency in patients after treatment with rituximab compared to those treated with conventional therapy and increase the understanding of the mechanism of rituximab treatment failure and recurrences.
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The potential impact on future fertility for biologics and emerging therapies for psoriasis and atopic dermatitis BY Kong1, S Immaneni1, TK Woodruff2, AS Paller2 and S Xu1 1 Northwestern University Feinberg School of Medicine, Chicago, IL and 2 Northwestern University, Chicago, IL Recently, the impact of therapeutics on future fertility has received wider recognition in oncology, including melanoma. Unlike methotrexate, which has an adverse effect on male fertility, there is relatively little known how newer systemic and biologic drugs for psoriasis and atopic dermatitis affect future fertility. We conducted a retrospective review of FDA, European Union, and Health Canada regulatory data, as well as the medical literature to assess the fertility risk of biologics and new medications approved after 2004 for psoriasis and atopic dermatitis. Off-label drugs were also included. We used a previously reported fertility risk system (A/B/C/D/X/N), which is analogous to the FDA’s former pregnancy risk category system. IL-17 inhibitors (brodalumab, ixekizumab, secukinumab), TNF-a inhibitors (adalimumab, etanercept, infliximab), JAK-inhibitors (tofacitinib/ruxolitinib), apremilast, and topical crisaborole were reviewed. For females, 27% (3/11) of medications represented a potential fertility risk in animal studies without human data (Category C - apremilast, tofacitinib, and ruxolitinib), 55% (6/11) did not show ovarian toxicity in animal studies without human data (Category B), and 18% (2/11) had an unknown risk (Category N - adalimumab/ etanercept). For males, all medications were Category B. 82% (9/11) of the systemic medications did not show toxicity to sperm in animal studies. Adalimumab and etanercept lacked animal data, but the available human data did not reveal significant gonadal toxicity (Category B). The impact of new biologics and systemic drugs for psoriasis and atopic dermatitis on future fertility is largely unknown but the available data suggests that most of the treatments have no adverse effects. The paucity of data, particularly for female fertility, underscores the need for longer outcome tracking and the further assessment of existing registries.
Establishing a roadmap for therapeutics development for cutaneous neurofibromas S Verma1, P Wolkenstein2, LQ Le3, J Lee4, B Widemann5, I Brownell6, K Jarnagin7, RM Lavker8, E Legius9, R Anderson10, S Plotkin11, H Weinberg12, D Casey13, H Ko13, S LaRosa14, P Knight14, M Parides12, N Bora15, J Morris16, V Riccardi17, B Korf18 and J Blakeley1 1 Johns Hopkins School of Medicine, Baltimore, MD, 2 Universite´ de Paris XII Val de Marne, Paris, France, 3 University of Texas Southwestern Medical Center, Dallas, TX, 4 Roivant Sciences Inc, Durham, NC, 5 NCI, Bethesda, MD, 6 Dermatology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, 7 Pfizer, Cambridge, MA, 8 Northwestern University, Chicago, IL, 9 University of Leuven, Belgium, Lueven, Belgium, 10 Wellman Center for Photomedicine/MGH, Boston, MA, 11 Harvard (Mass Gen Hospital), Cambridge, MA, 12 Mount Sinai, New York, NY, 13 FDA, Rockville, MD, 14 CTF, New York, NY, 15 Department of Defense, Bethesda, MD, 16 NIH, Bethesda, MD, 17 NF Institute, Los Angeles, CA and 18 UAB, Birmingham, AL Cutaneous neurofibromas (cNF) are multicellular tumors involving the skin that are one of the hallmark findings of neurofibromatosis type 1 (NF1), and patients with NF1 often identify these tumors as their greatest burden. As there is no known way to prevent these tumors from developing and current treatments are limited to regional procedure based approaches that have uncertain efficacy, the Neurofibromatosis Therapy Acceleration Program (NTAP) has undertaken the targeting of cNF as part of its strategic mission. Recently, NTAP hosted a cNF summit comprised of leading experts from a range of disciplines representing the ranks of academia, industry, and public agencies in order to create a community of invested experts in this space and identify the key areas of research priority for developing therapies for cNF. This group drafted core questions, reviewed published and unpublished materials, and created summaries about the material that may influence therapeutic development for cNF. Key focus areas for understanding disease pathogenesis, therapies development, and clinical trial optimization were identified and represent a ‘road map’ for accelerating the development of therapies for cNF.
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Omalizumab for the treatment of chronic severe atopic dermtitis and urticaria RK Murakawa1, MD Tharp2 and GJ Murakawa3 1 Somerset Skin Centre and Derm Center, Troy, MI, 2 Rush Medical College, Chicago, IL and 3 Michigan State University, Troy, MI Omalizumab, a humanized monoclonal antibody targeted against IgE, is clinically indicated for the treatment of chronic idiopathic urticaria, but not severe atopic dermatitis. In this retrospective review, we identified a total of 43 people who were treated with omalizumab at a private practice clinic in Troy, MI. Five patients had only chronic idiopathic urticaria and 3 patients were given omalizumab by other physicians; these patients were excluded from the study. The remaining 35 patients were diagnosed with both dermatographic chronic idiopathic urticaria and atopic dermatitis. Patients ranged in age from 32 to 89 with an average age of 61.7. There were 19 males and 16 females in this study. The group was comprised of 32 Caucasians, 1 African American, 1 Asian, and1 Indian, Efficacy was determined by the Investigator’s Global Assessment (0-4). The average initial Investigator’s Global Assessment (IGA) score was 3.91. The average final IGA score was 1.17. 31/35 patients (88.57%) had an IGA improvement of 2. Patients were asked to complete a survey regarding their experience with omalizumab on a scale from 1-10 with 1 being no itch and 10 as a severe itch. The results demonstrated a significant improvement for both the pruritius and rash. Of the patients who took the survey, the average initial scores of the itch and rash were 9.52 and 9.04, respectively. After the first month, the itch and rash improved to 5.81 and 6.44. The end of the second month showed continued progress with an itch of 5.34 and rash of 5.74. The patients rated their itch after their most recent shot as 3.37 and rash as 3.42. These data suggest that omalizumab is a promising therapeutic option for treating patients with severe atopic dermatitis and dermatographic chronic idiopathic urticaria.
B4 Journal of Investigative Dermatology (2017), Volume 137
Spironolactone and psoriasis outcome in young adult women: A report from the RADAR (Research on Adverse Drug events And Reports) project P Vakharia1, E Lund2, S Rangel3, W Temps2, DP West4 and S Belknap2 1 Northwestern University Department of Dermatology, Rochester, MI, 2 Northwestern University Department of Dermatology, Chicago, IL, 3 Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL and 4 Department of Dermatology, Northwestern University Feinberg School of Medicine, Robert H Lurie Cancer Center, Chicago, IL Epstein-Barr virus (EBV) has been implicated in the pathogenesis of psoriasis. Spironolactone inhibits the function of EBV SM protein and also inhibits production of pro-inflammatory cytokines. The aim of this study was to determine if exposure to spironolactone is associated with an effect on psoriasis outcome in young adult women. We queried an electronic medical record (EMR) database repository for a large, urban, U.S. patient population to detect data for young female patients with psoriasis (aged 18-40 years), who had exposure to spironolactone. Additional inclusion criteria were patients with 3 consecutive months of spironolactone exposure and a description of psoriasis extent and severity, both before and after spironolactone initiation, with no initiation of new psoriasis medications at or after the time of spironolactone initiation. Improvement in psoriasis was designated as either 1) psoriasis medication change from systemic to topical or no medication, or 2) objective or physiciandetermined improvement in EMR. We identified 65 eligible patients, of whom 22 met inclusion criteria. Of these, 4 patients (18.2%) had noted improvement in psoriasis extent and severity, 17 (77.3%) had no detectable change, and 1 (4.5%) had noted worsening of psoriasis. Given the limitations of this retrospective research, these findings of no demonstrable effect on outcome warrant further research to more precisely assess the relationship between spironolactone exposure and psoriasis outcome.
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Pharmacodynamic activity of a microRNA-29b mimic (MRG-201) in human skin incisions CL Gallant-Behm1, C Maari2, AL Jackson1, AG Seto1, JM Lynch1, J Ruckman1, ML Landry1, LA Pestano1, BA Dickinson1, CM Dalby1, M Sanseverino1, DM Rodman1, GG Gordon1, P Rubin1 and WS Marshall1 1 miRagen Therapeutics, Inc., Boulder, CO and 2 Innovaderm Research, Inc., Montreal, PQ, Canada MicroRNA-29 is an anti-fibrotic miRNA whose expression is downregulated in multiple fibrotic indications including in cutaneous scars and keloids. Its target genes include numerous collagens and other extracellular matrix molecules, suggesting that restoration of miR-29 expression in a skin wound or at the site of an excised scar could have a therapeutic benefit by reducing scarring and/or preventing scar regrowth. An oligonucleotide mimic of miR-29b (MRG-201) was studied in vivo in mouse, rats and rabbits as well as in vitro in human skin fibroblasts to identify a set of conserved pharmacodynamic biomarkers in the skin. MRG-201 was then evaluated in a Phase 1 double-blinded within-patient randomized clinical trial in 53 normal healthy volunteers (NCT02603224). Expression of miR-29b and its pharmacodynamic biomarkers was assessed in untreated skin incisions and following single or multiple administrations of MRG-201 at the site of a sutured skin incision. miR-29b expression was significantly decreased and direct miR-29 target genes were significantly upregulated with incision alone. Intradermal administration of MRG-201 resulted in a high local concentration of miR-29b with low systemic exposure and good safety/tolerability at all doses tested. Pharmacodynamic activity was seen after MRG-201 treatment: single and multiple doses of MRG-201 reduced collagen mRNA expression as compared to a placebo injected incision in the same subject. Additionally, multiple administrations of MRG-201 reduced fibroplasia as assessed by histopathology (p < 0.01). These findings support further investigation of MRG-201 as a novel therapeutic to inhibit scar formation or prevent hypertrophic scar or keloid recurrence following excision.
In vitro expansion of desmoglein specific peripheral blood B cells of patients with pemphigus S Mallam1, R Streilein2, H Suga3, TF Tedder2 and RP Hall2 1 Duke University School of Medicine, Durham, NC, 2 Duke University Medical Center, Durham, NC and 3 University of Tokyo, Tokyo, Japan B cells are known to play a major role in the pathogenesis of autoimmune diseases as precursors of autoantibody producing plasma cells. Pemphigus vulgaris (PV) and foliaceus (PF) are severe blistering diseases of the skin caused by autoantibodies directed against desmoglein-1 (DSG1) and desmoglein-3 (DSG3). The purpose of this study is to utilize in vitro expansion and differentiation of B cells from patients with PV and PF to help better understand the frequency of DSG1/DSG3 specific B cells in patients with active skin disease. B cells were isolated from peripheral blood (PB) samples from patients with clinically active PV (n¼2), PF (n¼2), and healthy controls (HC) (n¼2). B cells were expanded in vitro using a cell culture system that supports B cell proliferation and differentiation into immunoglobulinsecreting plasma cells. PB B cells (10/well) were cultured in 96 well plates for 12 days. Supernatants were tested for the presence of DSG1 or DSG3 antibodies by ELISA. The frequency of wells with ELISA values outside of 3x the interquartile range (IQR) were calculated for each subject. Supernatants from PV/PF patients showed a higher frequency of wells producing IgG anti DSG1 or DSG3 than controls (mean frequency wells>3x IQR: PV/ PF¼4.87%; HC¼1.89%, p¼0.03). This study demonstrates that in vitro stimulation of PB B cells from patients with PV/PF produce an increased frequency of IgG anti DSG1/DSG3 detected by ELISA compared to PB B cells from normal subjects. Utilizing these techniques, we will be able to analyze the change in antigen-specific B cell frequency in patients after treatment with rituximab compared to those treated with conventional therapy and increase the understanding of the mechanism of rituximab treatment failure and recurrences.
LB950
LB951
The potential impact on future fertility for biologics and emerging therapies for psoriasis and atopic dermatitis BY Kong1, S Immaneni1, TK Woodruff2, AS Paller2 and S Xu1 1 Northwestern University Feinberg School of Medicine, Chicago, IL and 2 Northwestern University, Chicago, IL Recently, the impact of therapeutics on future fertility has received wider recognition in oncology, including melanoma. Unlike methotrexate, which has an adverse effect on male fertility, there is relatively little known how newer systemic and biologic drugs for psoriasis and atopic dermatitis affect future fertility. We conducted a retrospective review of FDA, European Union, and Health Canada regulatory data, as well as the medical literature to assess the fertility risk of biologics and new medications approved after 2004 for psoriasis and atopic dermatitis. Off-label drugs were also included. We used a previously reported fertility risk system (A/B/C/D/X/N), which is analogous to the FDA’s former pregnancy risk category system. IL-17 inhibitors (brodalumab, ixekizumab, secukinumab), TNF-a inhibitors (adalimumab, etanercept, infliximab), JAK-inhibitors (tofacitinib/ruxolitinib), apremilast, and topical crisaborole were reviewed. For females, 27% (3/11) of medications represented a potential fertility risk in animal studies without human data (Category C - apremilast, tofacitinib, and ruxolitinib), 55% (6/11) did not show ovarian toxicity in animal studies without human data (Category B), and 18% (2/11) had an unknown risk (Category N - adalimumab/ etanercept). For males, all medications were Category B. 82% (9/11) of the systemic medications did not show toxicity to sperm in animal studies. Adalimumab and etanercept lacked animal data, but the available human data did not reveal significant gonadal toxicity (Category B). The impact of new biologics and systemic drugs for psoriasis and atopic dermatitis on future fertility is largely unknown but the available data suggests that most of the treatments have no adverse effects. The paucity of data, particularly for female fertility, underscores the need for longer outcome tracking and the further assessment of existing registries.
Establishing a roadmap for therapeutics development for cutaneous neurofibromas S Verma1, P Wolkenstein2, LQ Le3, J Lee4, B Widemann5, I Brownell6, K Jarnagin7, RM Lavker8, E Legius9, R Anderson10, S Plotkin11, H Weinberg12, D Casey13, H Ko13, S LaRosa14, P Knight14, M Parides12, N Bora15, J Morris16, V Riccardi17, B Korf18 and J Blakeley1 1 Johns Hopkins School of Medicine, Baltimore, MD, 2 Universite´ de Paris XII Val de Marne, Paris, France, 3 University of Texas Southwestern Medical Center, Dallas, TX, 4 Roivant Sciences Inc, Durham, NC, 5 NCI, Bethesda, MD, 6 Dermatology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, 7 Pfizer, Cambridge, MA, 8 Northwestern University, Chicago, IL, 9 University of Leuven, Belgium, Lueven, Belgium, 10 Wellman Center for Photomedicine/MGH, Boston, MA, 11 Harvard (Mass Gen Hospital), Cambridge, MA, 12 Mount Sinai, New York, NY, 13 FDA, Rockville, MD, 14 CTF, New York, NY, 15 Department of Defense, Bethesda, MD, 16 NIH, Bethesda, MD, 17 NF Institute, Los Angeles, CA and 18 UAB, Birmingham, AL Cutaneous neurofibromas (cNF) are multicellular tumors involving the skin that are one of the hallmark findings of neurofibromatosis type 1 (NF1), and patients with NF1 often identify these tumors as their greatest burden. As there is no known way to prevent these tumors from developing and current treatments are limited to regional procedure based approaches that have uncertain efficacy, the Neurofibromatosis Therapy Acceleration Program (NTAP) has undertaken the targeting of cNF as part of its strategic mission. Recently, NTAP hosted a cNF summit comprised of leading experts from a range of disciplines representing the ranks of academia, industry, and public agencies in order to create a community of invested experts in this space and identify the key areas of research priority for developing therapies for cNF. This group drafted core questions, reviewed published and unpublished materials, and created summaries about the material that may influence therapeutic development for cNF. Key focus areas for understanding disease pathogenesis, therapies development, and clinical trial optimization were identified and represent a ‘road map’ for accelerating the development of therapies for cNF.
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Omalizumab for the treatment of chronic severe atopic dermtitis and urticaria RK Murakawa1, MD Tharp2 and GJ Murakawa3 1 Somerset Skin Centre and Derm Center, Troy, MI, 2 Rush Medical College, Chicago, IL and 3 Michigan State University, Troy, MI Omalizumab, a humanized monoclonal antibody targeted against IgE, is clinically indicated for the treatment of chronic idiopathic urticaria, but not severe atopic dermatitis. In this retrospective review, we identified a total of 43 people who were treated with omalizumab at a private practice clinic in Troy, MI. Five patients had only chronic idiopathic urticaria and 3 patients were given omalizumab by other physicians; these patients were excluded from the study. The remaining 35 patients were diagnosed with both dermatographic chronic idiopathic urticaria and atopic dermatitis. Patients ranged in age from 32 to 89 with an average age of 61.7. There were 19 males and 16 females in this study. The group was comprised of 32 Caucasians, 1 African American, 1 Asian, and1 Indian, Efficacy was determined by the Investigator’s Global Assessment (0-4). The average initial Investigator’s Global Assessment (IGA) score was 3.91. The average final IGA score was 1.17. 31/35 patients (88.57%) had an IGA improvement of 2. Patients were asked to complete a survey regarding their experience with omalizumab on a scale from 1-10 with 1 being no itch and 10 as a severe itch. The results demonstrated a significant improvement for both the pruritius and rash. Of the patients who took the survey, the average initial scores of the itch and rash were 9.52 and 9.04, respectively. After the first month, the itch and rash improved to 5.81 and 6.44. The end of the second month showed continued progress with an itch of 5.34 and rash of 5.74. The patients rated their itch after their most recent shot as 3.37 and rash as 3.42. These data suggest that omalizumab is a promising therapeutic option for treating patients with severe atopic dermatitis and dermatographic chronic idiopathic urticaria.
B4 Journal of Investigative Dermatology (2017), Volume 137
Spironolactone and psoriasis outcome in young adult women: A report from the RADAR (Research on Adverse Drug events And Reports) project P Vakharia1, E Lund2, S Rangel3, W Temps2, DP West4 and S Belknap2 1 Northwestern University Department of Dermatology, Rochester, MI, 2 Northwestern University Department of Dermatology, Chicago, IL, 3 Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL and 4 Department of Dermatology, Northwestern University Feinberg School of Medicine, Robert H Lurie Cancer Center, Chicago, IL Epstein-Barr virus (EBV) has been implicated in the pathogenesis of psoriasis. Spironolactone inhibits the function of EBV SM protein and also inhibits production of pro-inflammatory cytokines. The aim of this study was to determine if exposure to spironolactone is associated with an effect on psoriasis outcome in young adult women. We queried an electronic medical record (EMR) database repository for a large, urban, U.S. patient population to detect data for young female patients with psoriasis (aged 18-40 years), who had exposure to spironolactone. Additional inclusion criteria were patients with 3 consecutive months of spironolactone exposure and a description of psoriasis extent and severity, both before and after spironolactone initiation, with no initiation of new psoriasis medications at or after the time of spironolactone initiation. Improvement in psoriasis was designated as either 1) psoriasis medication change from systemic to topical or no medication, or 2) objective or physiciandetermined improvement in EMR. We identified 65 eligible patients, of whom 22 met inclusion criteria. Of these, 4 patients (18.2%) had noted improvement in psoriasis extent and severity, 17 (77.3%) had no detectable change, and 1 (4.5%) had noted worsening of psoriasis. Given the limitations of this retrospective research, these findings of no demonstrable effect on outcome warrant further research to more precisely assess the relationship between spironolactone exposure and psoriasis outcome.