Contributions
Abstract: P1209
Type: Poster
Abstract Category: Therapy - disease modifying - Neurorepair
Background: ABT-555 is a fully human, high-affinity repulsive guidance molecule a (RGMa) specific monoclonal antibody. In rodent models of demyelination and nerve injury, ABT-555 demonstrated axon regeneration, neuroprotection, remyelination, and immune modulation. (Mueller. Mult Scler 2015;21(11suppl):P582.)
Method: In the single ascending dose (SAD) study, healthy adults were randomized 3:1 to ABT-555 or placebo (5 intravenous [IV] 50 - 1600mg, n=8/group; 1 subcutaneous [SC] dose, n=7). Safety and pharmacokinetic (PK) assessments were performed ≤140 days post-dose. In the ongoing multiple ascending dose (MAD) study, subjects with relapsing MS (RMS) receive 1 of 5 ABT-555 doses or placebo IV once monthly plus maintenance glatiramer acetate (n=8/group, 3:1 ratio) for 4 months. The effect of ABT-555 on axon and myelin pathophysiology measured by magnetization transfer ratio, fractional anisotropy and radial diffusivity are being assessed. In a PET study, ABT-555"s effect on translocator protein (TSPO) expression and thus CNS inflammation is being assessed with [11C]-PBR28 volume of distribution (VT) in brain regions of interest (ROIs) in RMS subjects; Part 1 (n=4, completed), assesses the test-retest variability of VT, and Part 2 (n=14, ongoing) examines the effect of a single dose of ABT-555 on VT in brain ROIs.
Results: In the completed SAD study, a total of 65 adverse events (AE) were reported in 28/47 subjects with no trend in frequency of adverse events with each ascending dose group. The most frequently reported AEs were headache, nausea and local back pain. All treatment-related AEs assessed by the investigator were minor in severity and spontaneously resolved without treatment. There was no discontinuation due to treatment related AEs, nor major dose-related biochemical or hematological alterations. Two subjects had SAEs resulting in death; one due to coronary artery disease and toxicity of multiple illicit drugs and one due to toxicity of cocaine and oxycodone, both determined to be unrelated to ABT-555. The mean plasma half-life ranged from approximately 20 to 40 days with an estimated CSF to serum ratio of approximately 0.2%. In Part 1 of the ongoing TSPO PET study, the intra-subject coefficient of variation of lesion and perilesion VT was estimated to be 15%.
Conclusion: In the SAD study, ABT-555 was well tolerated in healthy subjects up to 1600 mg. PK data were consistent with monoclonal antibody administration and CSF to serum distribution.
Disclosure: AbbVie Inc participated in the study design, research, writing, reviewing, and approving the publication. B.A.C. Cree has received personal compensation for consulting from Abbvie, Biogen, EMD Serono, MedImmune, Novartis, Sanofi Genzyme, Shire and Teva. G.Giovannoni has received fees for participation in advisory board for AbbVie Biotherapeutics Inc., Biogen, Canbex, Ironwood, Novartis, Merck, Merck Serono, Roche, Sanofi-Genzyme, Synthon, Teva, and Vertex; speaker fees from AbbVie Biotherapeutics Inc., Biogen, Bayer HealthCare, Genzyme, Merck Serono, Sanofi-Aventis, and Teva; coeditor in chief of Multiple Sclerosis and Related Disorders; research support unrelated to study from Biogen, Genzyme, Ironwood, Merck Serono, and Novartis. B.K.Mueller, R. Rajagovindan, J. Beaver, C. Locke, B. Barger, M. Rosebraugh, S. Goss, J. Genius, G. Haig, and S.J. Greenberg are full-time employees of AbbVie Inc and may hold stock or stock options.
Abstract: P1209
Type: Poster
Abstract Category: Therapy - disease modifying - Neurorepair
Background: ABT-555 is a fully human, high-affinity repulsive guidance molecule a (RGMa) specific monoclonal antibody. In rodent models of demyelination and nerve injury, ABT-555 demonstrated axon regeneration, neuroprotection, remyelination, and immune modulation. (Mueller. Mult Scler 2015;21(11suppl):P582.)
Method: In the single ascending dose (SAD) study, healthy adults were randomized 3:1 to ABT-555 or placebo (5 intravenous [IV] 50 - 1600mg, n=8/group; 1 subcutaneous [SC] dose, n=7). Safety and pharmacokinetic (PK) assessments were performed ≤140 days post-dose. In the ongoing multiple ascending dose (MAD) study, subjects with relapsing MS (RMS) receive 1 of 5 ABT-555 doses or placebo IV once monthly plus maintenance glatiramer acetate (n=8/group, 3:1 ratio) for 4 months. The effect of ABT-555 on axon and myelin pathophysiology measured by magnetization transfer ratio, fractional anisotropy and radial diffusivity are being assessed. In a PET study, ABT-555"s effect on translocator protein (TSPO) expression and thus CNS inflammation is being assessed with [11C]-PBR28 volume of distribution (VT) in brain regions of interest (ROIs) in RMS subjects; Part 1 (n=4, completed), assesses the test-retest variability of VT, and Part 2 (n=14, ongoing) examines the effect of a single dose of ABT-555 on VT in brain ROIs.
Results: In the completed SAD study, a total of 65 adverse events (AE) were reported in 28/47 subjects with no trend in frequency of adverse events with each ascending dose group. The most frequently reported AEs were headache, nausea and local back pain. All treatment-related AEs assessed by the investigator were minor in severity and spontaneously resolved without treatment. There was no discontinuation due to treatment related AEs, nor major dose-related biochemical or hematological alterations. Two subjects had SAEs resulting in death; one due to coronary artery disease and toxicity of multiple illicit drugs and one due to toxicity of cocaine and oxycodone, both determined to be unrelated to ABT-555. The mean plasma half-life ranged from approximately 20 to 40 days with an estimated CSF to serum ratio of approximately 0.2%. In Part 1 of the ongoing TSPO PET study, the intra-subject coefficient of variation of lesion and perilesion VT was estimated to be 15%.
Conclusion: In the SAD study, ABT-555 was well tolerated in healthy subjects up to 1600 mg. PK data were consistent with monoclonal antibody administration and CSF to serum distribution.
Disclosure: AbbVie Inc participated in the study design, research, writing, reviewing, and approving the publication. B.A.C. Cree has received personal compensation for consulting from Abbvie, Biogen, EMD Serono, MedImmune, Novartis, Sanofi Genzyme, Shire and Teva. G.Giovannoni has received fees for participation in advisory board for AbbVie Biotherapeutics Inc., Biogen, Canbex, Ironwood, Novartis, Merck, Merck Serono, Roche, Sanofi-Genzyme, Synthon, Teva, and Vertex; speaker fees from AbbVie Biotherapeutics Inc., Biogen, Bayer HealthCare, Genzyme, Merck Serono, Sanofi-Aventis, and Teva; coeditor in chief of Multiple Sclerosis and Related Disorders; research support unrelated to study from Biogen, Genzyme, Ironwood, Merck Serono, and Novartis. B.K.Mueller, R. Rajagovindan, J. Beaver, C. Locke, B. Barger, M. Rosebraugh, S. Goss, J. Genius, G. Haig, and S.J. Greenberg are full-time employees of AbbVie Inc and may hold stock or stock options.