Once Daily Oral CHS-131, a Novel PPARγ Agonist, Reduces Both Neuroinflammation and Gray Matter Volume Depletion in Patients with Relapsing-Remitting Multiple Sclerosis: a Randomized, Placebo Controlled Double-blind, Phase 2b, Multicenter Study
ECTRIMS Online Library. Weinstein D. 10/26/17; 200368; P713
David Weinstein
David Weinstein
Contributions
Abstract

Abstract: P713

Type: Poster

Abstract Category: Therapy - disease modifying - 27 Neuroprotection and Repair

Background: We recently completed a successful Phase 2B study of oral CHS-131, a novel, first-in-class, highly-selective partial PPARγ agonist, for the treatment of Relapsing Remitting Multiple Sclerosis (RRMS). In preclinical studies CHS-131 crossed the intact blood-brain barrier and attained pharmacologically relevant levels in the neural parenchyma. In PLP-induced RREAE CHS-131 reversed neuroinflammation and blocked relapse. Phase 1 and 2 human studies to date have included > 600 subjects in RRMS, Type 2 Diabetes and healthy volunteers. The current study is a 2-part design: Part 1 was double-blind, placebo-controlled, three arm design (1 mg/day CHS-131; 3mg/day CHS-131; or placebo) to evaluate safety and efficacy of CHS-131 in treatment-naïve subjects with RRMS. In Part 2 the subjects were given the choice to continue treatment with 1mg daily of CHS-131. The results of Part 1 are reported here.
Methods: 227 treatment-naive adult subjects (mean age 31 [range 18-50]; 65% female) were randomized into one of three arms: oral CHS-131 at 3 mg (n=76); oral CHS-131 at 1 mg (n=76); placebo (n=75), at 21 sites in Russia. 97% completed Part 1. Inclusion criteria: RRMS for ≤3 years, ≥1 gadolinium-positive lesion within 1-year of enrollment, and an EDSS ≤ 6 at screening. The patients underwent monthly MRI examinations with contrast to identify new inflammatory lesions. All MRIs were read blinded at the Buffalo Neuroimaging Center (Buffalo, NY). In addition to CE lesions the images were scored for cumulative new/enlarged T2 lesions, and serial cortical and whole brain volumetric analysis.
Results: CHS-131 treatment resulted in a dose-dependent reduction in cumulative CE lesions over 6 months (complete case analysis). 3 mg daily reduced CE lesion burden by 52% (4.2 lesions [LSMean 3.10]) vs. placebo (7.8 [LSMean 6.49]) (p=0.003). 1mg treatment was less robust- 21% reduction vs. placebo (7.6 [LSMean 5.15] (p=ns). New/enlarged T2 lesions were reduced by 30% (3mg)(p=0.0767) and 14% (1mg)(p=ns) compared to placebo. In addition to the dose-dependent anti-neuroinflammatory effects, CHS-131 treatment appeared to attenuate gray matter volume loss at 6-months. Compared to placebo, there was 34.2% less cortical volume loss and 50% less whole brain volume loss in the 3mg cohort. Volume losses in the 1mg treatment group were similar to placebo at 6 months.
CHS-131 was safe and well-tolerated, and was without treatment-emergent serious adverse events.
Disclosure:
•D. Weinstein is a consultant, and stock holder in Coherus Biosciences, and a stock holder and former employee of InteKrin Therapeutics, Inc, which is a wholly owned subsidiary of Coherus Biosciences
L. Pugliese is an employee and stock holder for Coherus Biosciences
H. Tang is an employee and stock holder for Coherus Biosciences
D. Lanfear is an employee and stock holder for Coherus Biosciences
B. Finck is an employee and stock holder for Coherus Biosciences
A. Boyko is a consultant for ZAO InteKrin
R Zivadinov is an employee of the Buffalo Neuroimaging Analysis Center which provided services to ZAO InterKrin

Abstract: P713

Type: Poster

Abstract Category: Therapy - disease modifying - 27 Neuroprotection and Repair

Background: We recently completed a successful Phase 2B study of oral CHS-131, a novel, first-in-class, highly-selective partial PPARγ agonist, for the treatment of Relapsing Remitting Multiple Sclerosis (RRMS). In preclinical studies CHS-131 crossed the intact blood-brain barrier and attained pharmacologically relevant levels in the neural parenchyma. In PLP-induced RREAE CHS-131 reversed neuroinflammation and blocked relapse. Phase 1 and 2 human studies to date have included > 600 subjects in RRMS, Type 2 Diabetes and healthy volunteers. The current study is a 2-part design: Part 1 was double-blind, placebo-controlled, three arm design (1 mg/day CHS-131; 3mg/day CHS-131; or placebo) to evaluate safety and efficacy of CHS-131 in treatment-naïve subjects with RRMS. In Part 2 the subjects were given the choice to continue treatment with 1mg daily of CHS-131. The results of Part 1 are reported here.
Methods: 227 treatment-naive adult subjects (mean age 31 [range 18-50]; 65% female) were randomized into one of three arms: oral CHS-131 at 3 mg (n=76); oral CHS-131 at 1 mg (n=76); placebo (n=75), at 21 sites in Russia. 97% completed Part 1. Inclusion criteria: RRMS for ≤3 years, ≥1 gadolinium-positive lesion within 1-year of enrollment, and an EDSS ≤ 6 at screening. The patients underwent monthly MRI examinations with contrast to identify new inflammatory lesions. All MRIs were read blinded at the Buffalo Neuroimaging Center (Buffalo, NY). In addition to CE lesions the images were scored for cumulative new/enlarged T2 lesions, and serial cortical and whole brain volumetric analysis.
Results: CHS-131 treatment resulted in a dose-dependent reduction in cumulative CE lesions over 6 months (complete case analysis). 3 mg daily reduced CE lesion burden by 52% (4.2 lesions [LSMean 3.10]) vs. placebo (7.8 [LSMean 6.49]) (p=0.003). 1mg treatment was less robust- 21% reduction vs. placebo (7.6 [LSMean 5.15] (p=ns). New/enlarged T2 lesions were reduced by 30% (3mg)(p=0.0767) and 14% (1mg)(p=ns) compared to placebo. In addition to the dose-dependent anti-neuroinflammatory effects, CHS-131 treatment appeared to attenuate gray matter volume loss at 6-months. Compared to placebo, there was 34.2% less cortical volume loss and 50% less whole brain volume loss in the 3mg cohort. Volume losses in the 1mg treatment group were similar to placebo at 6 months.
CHS-131 was safe and well-tolerated, and was without treatment-emergent serious adverse events.
Disclosure:
•D. Weinstein is a consultant, and stock holder in Coherus Biosciences, and a stock holder and former employee of InteKrin Therapeutics, Inc, which is a wholly owned subsidiary of Coherus Biosciences
L. Pugliese is an employee and stock holder for Coherus Biosciences
H. Tang is an employee and stock holder for Coherus Biosciences
D. Lanfear is an employee and stock holder for Coherus Biosciences
B. Finck is an employee and stock holder for Coherus Biosciences
A. Boyko is a consultant for ZAO InteKrin
R Zivadinov is an employee of the Buffalo Neuroimaging Analysis Center which provided services to ZAO InterKrin

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