J. Gelfand 1, A. Joshi 2, D. Shin 1, A. Dey 2, D. Torigian 1, D. Rader 1, M. Playford 2, M. Ahlman 2, A. Alavi 1, N. Mehta 2.

Transcription

1 A Trial to Determine the Effect of Psoriasis Treatment (Adalimumab, Phototherapy, and placebo) on Cardiometabolic Disease: The Vascular Inflammation in Psoriasis (VIP) Trial Abstract 393 J. Gelfand 1, A. Joshi 2, D. Shin 1, A. Dey 2, D. Torigian 1, D. Rader 1, M. Playford 2, M. Ahlman 2, A. Alavi 1, N. Mehta 2 1. University of Pennsylvania Perelman School of Medicine 2. National Heart Lung Blood Institute

2 Disclosure Statement Consultant for BMS, Boehringer Ingelheim, Coherus (DSMB), Dermira, GSK, Janssen Biologics, Menlo Therapeutics, Novartis Corp, Regeneron, Dr Reddy s labs, Sanofi and Pfizer Inc., receiving honoraria; and Research grants (to the Trustees of the University of Pennsylvania) from Abbvie, Janssen, Novartis Corp, Regeneron, Sanofi, Celgene, Ortho Dermatologics, and Pfizer Inc.; and received payment for continuing medical education work related to psoriasis that was supported indirectly by Lilly, Ortho Dermatologics, and Abbvie. Co-patent holder of resiquimod for treatment of cutaneous T cell lymphoma. Deputy Editor for the Journal of Investigative Dermatology receiving honoraria from the Society for Investigative Dermatology. VIP trial supported by a NIH grant UPENN R01HL and Abbvie. VIP-E suported by a grant to UPENN from Abbvie. Design, execution, and analysis conducted by Dr. Gelfand and colleagues at PENN and NIH This presentation is the sole work of Dr. Gelfand

3 Risk of Cardiometabolic Disease in Psoriasis Mortality Curve Kivelevitch et al Circ 2017;136: Abuabara, K., et al. Br. J. Dermatol. 2010; 163(3):586 Moderate to severe psoriasis is associated with an increased risk for major cardiovascular events and mortality independent of traditional risk factors resulting in a 5 year reduction in life expectancy Chronic inflammation and metabolic abnormalities are common to psoriasis and cardiovascular disease IL-1 beta inhibition prevents MACE in CANTOS RCT, TNFi lowers MACE in observational studies Azfar RS, Gelfand JM. Curr Opin Rheum 2008;20: Ridker PM et al NEJM 2017; 377: Yang ZS et al Clin Rev Allergy Immunol Oct;51(2):240-7

4 18-FDG PET/CT A Novel Imaging Biomarker of Inflammation Biomarker for CD68+ macrophages in fatty plaques Elevated vascular inflammation is Predictive of future CV events Associated with psoriasis and its severity Increased vascular inflammation improves with treatments known to lower CV risk (statins) within 4-12 weeks Increasingly used as a surrogate for cardiovascular trials Mehta NN et al. Arch Derm. 2011;147: Naik HB et al Arterioscler Thromb Vasc Biol Dec;35(12): Rudd et al. J Am Coll Cardiol Aug 28;50(9): Tahara et al. J Am Coll Cardiol Nov 7;48(9): Lee et al. J Nucl Med Aug;49(8): Rominger et al. J Nucl Med Oct;50(10):

5 Vascular Inflammation in Psoriasis Trials (VIP) RCT: adalimumab or phototherapy v placebo (NCT ) (VIP) RCT: ustekinumab v placebo (NCT ) (VIP-U) RCT: secukinumab v placebo (NCT ) (VIP-S) Open label: apremilast (NCT ) (VIP-A)

6 FDG PET/CT FDG PET/CT FDG PET/CT Screening Period Up to 180 days for treatment washout 96 Patients Vascular Inflammation in Psoriasis (VIP & VIP-E) FDG-PET scan CV biomarkers Randomization Double-blind, placebocontrolled period 12 Weeks n=32 Adalimumab n=32 UVB n=32 Placebo weeks Assessments every 4 weeks FDG-PET scan CV biomarkers Open label period Weeks 40 Weeks Adalimumab 52 Weeks Adalimumab Assessments every 10 weeks FDG-PET scan CV biomarkers Key inclusion criteria: BSA of 10%; PASI of 12% Diagnosis of Psoriasis > 6 months Candidate for systemic and phototherapy

7 VIP Main Inclusion/Exclusion Criteria Inclusion Criteria or older 2. Psoriasis for at least 6M, stable for 2M 3. PASI 12, BSA Candidate for systemic therapy Exclusion Criteria 1. Previous TNFi or phototherapy treatment that contraindicates additional use due to poor safety or efficacy in past 2. Phototherapy or topical prescriptions in 14 days prior to baseline 3. Oral psoriasis treatment in prior 30 days, biologics in prior 90 days, Ustekinumab in prior 180 days to baseline 4. Poorly controlled medical conditions 5. Internal malignancy in previous 5 years 6. HIV, Hep B, C or active TB See for details

8 95% Completed RCT 75% completed open label portion

9 Baseline Demographics Age, Mean (SD) Sex Male N (%) BMI Mean (SD) Placebo (15) 20 (65) 32 (8) Adalimumab (14) 24 (73) 31 (7) Phototherapy (14) 23 (70) 33 (9) Total (14) 67 (69) 32 (8) Pso Dur. Mean (SD) H/o PsA N (%) BSA Mean (SD) PASI Mean (SD) 19 (14) 2 (6) 26 (15) 18 (8) 15 (15) 4 (13) 23 (14) 19 (6) 16 (13) 3 (10) 23 (13) 19 (8) 17 (14) 9 (10) 24 (14) 19 (7) H/o Phototx N (%) H/o Oral Tx N (%) H/o Biologics N (%) 11 (35) 10 (32) 11 (35) 5 (16) 10 (32) 10 (32) 13 (42) 11 (35) 8 (26) 29 (31) 31 (33) 29 (31)

10 Physician reported psoriasis endpoints: Week 12 Placebo Adalimumab Phototherapy PASI75 N (%) 2 (7%) 15 (47%) p= (47%) p=0.002 PGA Clear/Almost Clear N (%) 2 (7%) 14 (44%) p= (27%) p= 0.053

11 Physician reported psoriasis endpoints: End of extension End of study (N=67) PASI 75 N (%) (95% CI) 40 (61%) (CI: 48, 72) PGA clear/almost clear N (%) (95% CI) 35 (53% ) (CI: 40, 65)

12 18-FDG PET/CT Endpoint: Total aortic vascular inflammation week 12 Adalimumab Phototherapy Placebo Global change compared to baseline within group Mean % change (95% CI) -1.85% (-7.17%, 3.47%) p= % (-7.78%, -0.39%) p= % (-6.29%, 1.31%) p=0.191 Global Change compared to placebo Difference of % change (95% CI) 0.64% (-5.84%, 7.12%) p= % (-6.78%, 3.59%) p=0.540 No evidence of an effect of adalimumab or phototherapy on aortic inflammation but cannot rule out a statin like effect based on CI s NA

13 No evidence of an effect of adalimumab on aortic vascular inflammation and 95% CI rule out a statin like effect Total aortic vascular inflammation end of extension Global Change Adalimumab treatment period only % Change, (95% CI), p value 0.02% (-2.85%, 2.90%) p=0.987

14 Change in advanced lipoprotein characterization between Baseline and Week 12, by treatment group during RCT period Adalimumab vs Placebo Phototherapy vs Placebo Total cholesterol (p=0.386) (p=0.280) Efflux (p=0.357) (p=0.496) LDL-P (p=0.897) (p=0.467) HDL-P (p=0.089) (p=0.030)

15 Change in advanced glucose metabolism between baseline and Week 12, by treatment group during RCT period Adalimumab vs Placebo Phototherapy vs Placebo Log Insulin (p=0.934) (p=0.679) Log Adiponectin (p=0.672) (p=0.655) Log Leptin (p=0.504) (p=0.695)

16 Change in inflammation between baseline and Week 12, by treatment group during RCT period Adalimumab vs Placebo Phototherapy vs Placebo Log CRP (p=0.002) (p=0.009) Log TNF-alpha (p<0.001) (p=0.065) Log IL (p=0.007) (p=0.019) GlycA (p=0.006) (p=0.628)

17 Change in advanced lipoprotein characterization, glucose metabolism, and inflammation between start of adalimumab and end of open label extension Class Biomarker Start of adalimumab (SD) End of Study (SD) Diff (SE) p-value Total Cholesterol (37.236) (34.347) (4.004) Lipoproteins Efflux (0.235) (0.163) (0.032) <0.001 LDL-P ( ) ( ) (40.416) HDL-P (7.220) (6.721) (0.824) Glucose metabolism Log Insulin (0.772) (0.795) (0.128) Log Adiponectin (0.792) (0.571) (0.071) Log Leptin (1.334) (1.233) (0.197) Log CRP (1.441) (1.383) (0.184) <0.001 Inflammation Log TNF-alpha (0.571) (0.867) (0.126) Log IL (1.734) (1.152) (0.235) <0.001 GlycA (80.882) (65.916) (9.022) <0.001

18 Discussion Adalimumab has a neutral impact aortic vascular inflammation Over 12 weeks Adalimumab has neutral impact on markers of lipoprotein characterization and glucose metabolism but improves inflammation (CRP, TNF-alpha, IL-6, GlycA) Over 12 weeks phototherapy improves HDL-P, has a neutral effect on glucose metabolism, and improves inflammation (CRP, IL-6) Over 52 weeks adalimumab is associated with impairments in HDL function and HDL-P, has neutral impact on insulin metabolism, and has mixed effects on inflammation (CRP, TNF-alpha, GlycA improve, IL-6 goes up)

19 1. Aortic inflammation results are similar to a prior RCT of adalimumab for psoriasis (Bissonnette NCT ) 2. Results are in contrast to preliminary findings from VIP-U (NCT ) 12 week findings in which ustekinumab was associated with a 19% improvement in aortic vascular inflammation compared to placebo (p=0.001) 3. Improvement in MACE outcomes in observational studies of TNFi may be mediated through mechanism beyond aortic inflammation including reductions in CV risk biomarkers such as GlycA Conclusions To refer patients for the VIP trials: SKIN or SkinVIP@upenn.edu

20 Co-PI: Mehta NN Co-investigators: AW Armstrong, K Callis Duffin, ZC Fuxench,, RA Hubbard, RE Kalb, A Menter, EL Simpson, J Takeshita, DA Torigian, AB Troxel, SK Tyring, AS Van Voorhees, A. Alavi Coordinators/fellows: M Papadopolous, J Alvarez, S Baez Vanderbeek Funding support from NHLBI, Abbvie Acknowledgements Funding support for Dr. Gelfand s career from NIH/FDA/Foundations/PCORI