A Phase 1, multiple-dose study of elezanumab (ABT-555) in patients with relapsing forms of multiple sclerosis
Author(s): ,
B. Cree
Affiliations:
University of California San Francisco, Weill Institute for Neurosciences, San Francisco, CA
,
M. Rosebraugh
Affiliations:
AbbVie, Inc., North Chicago, IL, United States
,
B. Barger
Affiliations:
AbbVie, Inc., North Chicago, IL, United States
A. Ziemann
Affiliations:
AbbVie, Inc., North Chicago, IL, United States
ECTRIMS Online Library. Cree B. 10/11/18; 228742; P899
Bruce A. Cree
Bruce A. Cree
Contributions
Abstract

Abstract: P899

Type: Poster Sessions

Abstract Category: Therapy - Neuroprotection and Repair

Background and goals: Elezanumab is a fully humanized monoclonal antibody directed against repulsive guidance molecule A (RGMa). Studies in patients with multiple sclerosis (MS) demonstrate RGMa upregulation, which inhibits axonal growth and myelination, oligodendroglial regeneration and functional recovery after trauma or inflammation.1 Elezanumab treatment promoted axon regeneration, neuroprotection, remyelination, and immune modulation in several MS-relevant preclinical models.1 Elezanumab was previously administered as a single dose to healthy volunteers and was well-tolerated.2 This study evaluated multiple doses of elezanumab to determine its safety and tolerability in patients with relapsing forms of MS.
Methods: In this phase 1, double-blind, placebo-controlled, randomized, escalating multiple-dose 29-week study, patients were randomized into 3 treatment groups and 1 placebo group. Of the 20 patients enrolled (12 female, 8 male), 18 had relapsing-remitting MS and 2 had secondary progressive MS. Elezanumab doses were given intravenously every 4 weeks for a total of 4 doses, with a loading dose of double the maintenance dose given on Day 1. Maintenance doses were 150 mg, 600 mg, and 1800 mg elezanumab for Groups 1, 2, and 3, respectively. Assessments included treatment-emergent adverse events (TEAEs), cerebral spinal fluid (CSF) and plasma biomarker analysis, and Expanded Disability Status Score (EDSS). Subsequently, magnetic resonance imaging and serum pharmacokinetics data will be reported.
Results: The most common TEAE reported was headache (25% of all patients). Free soluble RGMA decreased with increasing levels of elezanumab in CSF, while total RGMA (both free and antibody-bound) increased linearly with CSF elezanumab exposure. Interleukin-10 also increased in the CSF following elezanumab administration compared with placebo. From baseline through the end of the follow-up period, the majority of patients receiving elezanumab did not experience a clinically significant worsening or improvement in EDSS scores.
Conclusions: Elezanumab was well-tolerated and did not consistently result in symptom worsening in patients who received multiple doses of up to 1800 mg. Additional long-term studies are required to elucidate elezanumab efficacy in a more robust patient population.
References:
1. Mueller BK, et al. Mult Scler J. 2015;21(S11):76‒653. Poster #582.
2. Cree BAC, et al. Mult Scler J. 2016;22(S3):400‒705. Poster #1209.
Disclosure: BACC has received honoraria for consulting services from AbbVie, Inc., Akili, Biogen, EMD Serono, GeNeuro, Novartis, and Sanofi Genzyme. MR, BB, and AZ are full-time employees of AbbVie and may own stock and/or stock options. AbbVie, Inc., funded this study and participated in the study design, research, data collection, analysis and interpretation of data, and writing, reviewing, and approving this abstract for presentation. All authors had access to the data; participated in the development, review, and approval of the abstract; and agreed to submit this abstract to ECTRIMS for consideration. The authors would like to thank Thomas P. Misko, PhD for his contributions to the abstract. Editorial assistance provided by Jennifer Dreyer, PhD and Kristy A. Grabowski, PhD, of JB Ashtin; funded by AbbVie, Inc.

Abstract: P899

Type: Poster Sessions

Abstract Category: Therapy - Neuroprotection and Repair

Background and goals: Elezanumab is a fully humanized monoclonal antibody directed against repulsive guidance molecule A (RGMa). Studies in patients with multiple sclerosis (MS) demonstrate RGMa upregulation, which inhibits axonal growth and myelination, oligodendroglial regeneration and functional recovery after trauma or inflammation.1 Elezanumab treatment promoted axon regeneration, neuroprotection, remyelination, and immune modulation in several MS-relevant preclinical models.1 Elezanumab was previously administered as a single dose to healthy volunteers and was well-tolerated.2 This study evaluated multiple doses of elezanumab to determine its safety and tolerability in patients with relapsing forms of MS.
Methods: In this phase 1, double-blind, placebo-controlled, randomized, escalating multiple-dose 29-week study, patients were randomized into 3 treatment groups and 1 placebo group. Of the 20 patients enrolled (12 female, 8 male), 18 had relapsing-remitting MS and 2 had secondary progressive MS. Elezanumab doses were given intravenously every 4 weeks for a total of 4 doses, with a loading dose of double the maintenance dose given on Day 1. Maintenance doses were 150 mg, 600 mg, and 1800 mg elezanumab for Groups 1, 2, and 3, respectively. Assessments included treatment-emergent adverse events (TEAEs), cerebral spinal fluid (CSF) and plasma biomarker analysis, and Expanded Disability Status Score (EDSS). Subsequently, magnetic resonance imaging and serum pharmacokinetics data will be reported.
Results: The most common TEAE reported was headache (25% of all patients). Free soluble RGMA decreased with increasing levels of elezanumab in CSF, while total RGMA (both free and antibody-bound) increased linearly with CSF elezanumab exposure. Interleukin-10 also increased in the CSF following elezanumab administration compared with placebo. From baseline through the end of the follow-up period, the majority of patients receiving elezanumab did not experience a clinically significant worsening or improvement in EDSS scores.
Conclusions: Elezanumab was well-tolerated and did not consistently result in symptom worsening in patients who received multiple doses of up to 1800 mg. Additional long-term studies are required to elucidate elezanumab efficacy in a more robust patient population.
References:
1. Mueller BK, et al. Mult Scler J. 2015;21(S11):76‒653. Poster #582.
2. Cree BAC, et al. Mult Scler J. 2016;22(S3):400‒705. Poster #1209.
Disclosure: BACC has received honoraria for consulting services from AbbVie, Inc., Akili, Biogen, EMD Serono, GeNeuro, Novartis, and Sanofi Genzyme. MR, BB, and AZ are full-time employees of AbbVie and may own stock and/or stock options. AbbVie, Inc., funded this study and participated in the study design, research, data collection, analysis and interpretation of data, and writing, reviewing, and approving this abstract for presentation. All authors had access to the data; participated in the development, review, and approval of the abstract; and agreed to submit this abstract to ECTRIMS for consideration. The authors would like to thank Thomas P. Misko, PhD for his contributions to the abstract. Editorial assistance provided by Jennifer Dreyer, PhD and Kristy A. Grabowski, PhD, of JB Ashtin; funded by AbbVie, Inc.

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