Contributions
Abstract: P1658
Type: LB Poster
Abstract Category: Late Breaking News
Background: Oxidative stress secondary to cell-mediated inflammation plays an important role in the pathology of multiple sclerosis (MS). Sulforaphane, a naturally occurring isothiocyanate, has dual therapeutic potential in MS by upregulating Nrf2-mediated anti-oxidant cytoprotective mechanisms and inhibiting NF-kB-mediated inflammatory responses. Activation of Nrf2 by sulforaphane is an order of magnitude higher compared to dimethyl fumarate (BG-12). SFX-01 is a proprietary, synthetic and stabilized form of sulforaphane, developed as a pharmaceutical product. First-in-man trials have documented safety and the product is in Phase II clinical trials for other indications. Here the efficacy of SFX-01 is tested in experimental autoimmune encephalomyelitis (EAE), a mouse model recapitulating some features of MS.
Methods: EAE was induced in 72 female SJL mice using PLP139-151 and pertussis toxin. Groups of 12 mice received vehicle, SFX-01 at 10, 50 or 300 mg/kg or BG-12 at 15mg/kg. The experiment was performed with two different dosing schedules: prophylactic (Day 0 to Day 19) and therapeutic (after recovery and before relapse, ie Day 19 to Day 41). Clinical scores and weights were measured, and tissue prepared for histological analysis.
Results: With prophylactic dosing:
(1) SFX-01 caused a dose-dependent reduction in EAE scores but this did not reach significance even at 300mg/kg;
(2) 300mg/kg of SFX-01 was equivalent to BG-12.
With therapeutic dosing:
(1) neither SFX-01 nor BG-12 affected relapse rate;
(2) SFX-01 caused a dose-dependent reduction in relapse severity and end score, which achieved significance at the 300 mg/kg dose;
(3) BG-12 did not significantly affect EAE relapse measures.
Histological examination of the lumbar, thoracic, and cervical spinal cord were consistent with the clinical findings. In SFX-01 treated animals, all histological readouts including demyelination and the number of apoptotic cells were significantly improved compared to the vehicle group. In BG-12 treated animals, only demyelination was statistically improved.
Conclusions: SFX-01 appears to be superior to BG-12 in the therapeutic EAE model. SFX-01 appears to exert maximum effects later in the course of the disease by enabling superior neurological recovery in the chronic stage after relapse. SFX-01 is a promising drug candidate in MS, and warrants further investigation.
Disclosure:
Ian Galea receives research support from Medical Research Council, Engineering and Physical Sciences Research Council, Multiple Sclerosis Society, Wellcome Trust, National Institute for Health Research, Bio Products Laboratory Limited, Evgen, Merck-Serono, Spire, IQ Products, Peel Medical Research Trust, Royal College of Surgeons of Edinburgh, Association of British Neurologists, Wessex Medical Research, Smile for Wessex, University of Southampton.
Ian Copple receives research support from Evgen, Medical Research Council, Pancreatic Cancer Research Fund, North West Cancer Research, Amgen, University of Liverpool.
David Howat is an employee of Evgen plc and does not receive any other financial support from other sources.
Abstract: P1658
Type: LB Poster
Abstract Category: Late Breaking News
Background: Oxidative stress secondary to cell-mediated inflammation plays an important role in the pathology of multiple sclerosis (MS). Sulforaphane, a naturally occurring isothiocyanate, has dual therapeutic potential in MS by upregulating Nrf2-mediated anti-oxidant cytoprotective mechanisms and inhibiting NF-kB-mediated inflammatory responses. Activation of Nrf2 by sulforaphane is an order of magnitude higher compared to dimethyl fumarate (BG-12). SFX-01 is a proprietary, synthetic and stabilized form of sulforaphane, developed as a pharmaceutical product. First-in-man trials have documented safety and the product is in Phase II clinical trials for other indications. Here the efficacy of SFX-01 is tested in experimental autoimmune encephalomyelitis (EAE), a mouse model recapitulating some features of MS.
Methods: EAE was induced in 72 female SJL mice using PLP139-151 and pertussis toxin. Groups of 12 mice received vehicle, SFX-01 at 10, 50 or 300 mg/kg or BG-12 at 15mg/kg. The experiment was performed with two different dosing schedules: prophylactic (Day 0 to Day 19) and therapeutic (after recovery and before relapse, ie Day 19 to Day 41). Clinical scores and weights were measured, and tissue prepared for histological analysis.
Results: With prophylactic dosing:
(1) SFX-01 caused a dose-dependent reduction in EAE scores but this did not reach significance even at 300mg/kg;
(2) 300mg/kg of SFX-01 was equivalent to BG-12.
With therapeutic dosing:
(1) neither SFX-01 nor BG-12 affected relapse rate;
(2) SFX-01 caused a dose-dependent reduction in relapse severity and end score, which achieved significance at the 300 mg/kg dose;
(3) BG-12 did not significantly affect EAE relapse measures.
Histological examination of the lumbar, thoracic, and cervical spinal cord were consistent with the clinical findings. In SFX-01 treated animals, all histological readouts including demyelination and the number of apoptotic cells were significantly improved compared to the vehicle group. In BG-12 treated animals, only demyelination was statistically improved.
Conclusions: SFX-01 appears to be superior to BG-12 in the therapeutic EAE model. SFX-01 appears to exert maximum effects later in the course of the disease by enabling superior neurological recovery in the chronic stage after relapse. SFX-01 is a promising drug candidate in MS, and warrants further investigation.
Disclosure:
Ian Galea receives research support from Medical Research Council, Engineering and Physical Sciences Research Council, Multiple Sclerosis Society, Wellcome Trust, National Institute for Health Research, Bio Products Laboratory Limited, Evgen, Merck-Serono, Spire, IQ Products, Peel Medical Research Trust, Royal College of Surgeons of Edinburgh, Association of British Neurologists, Wessex Medical Research, Smile for Wessex, University of Southampton.
Ian Copple receives research support from Evgen, Medical Research Council, Pancreatic Cancer Research Fund, North West Cancer Research, Amgen, University of Liverpool.
David Howat is an employee of Evgen plc and does not receive any other financial support from other sources.