Safety and tolerability of MEDI-551 in patients with relapsing forms of multiple sclerosis: results from a phase 1 randomised, placebo-controlled, escalating intravenous and subcutaneous dose study
Author(s): ,
M. Agius
Affiliations:
Department of Neurology, University of California at Davis, Sacramento, CA, United States
,
G. Klodowska-Duda
Affiliations:
Neuro-Care
,
M. Maciejowski
Affiliations:
KMK-Clinical Sp. z o.o., NZOZ RAWA-MED, Katowice
,
A. Potemkowski
Affiliations:
Osrodek Badan Klinicznych Indywidualnej Specjalistycznej Praktyki Lekarskiej, Szczecin, Poland
,
S. Sweeny
Affiliations:
MedImmune, Gaithersburg, MD
,
J. Li
Affiliations:
MedImmune, Mountain View, CA, United States
,
W. Yao
Affiliations:
MedImmune, Gaithersburg, MD
,
K. Patra
Affiliations:
MedImmune, Gaithersburg, MD
,
J.N. Ratchford
Affiliations:
MedImmune, Gaithersburg, MD
,
E. Katz
Affiliations:
MedImmune, Gaithersburg, MD
A. Flor
Affiliations:
MedImmune, Gaithersburg, MD
ECTRIMS Online Library. Agius M. 10/08/15; 115379; 210
Mark Agius
Mark Agius
Contributions
Abstract
Abstract: P528

Type: Poster

Abstract Category: Immunomodulation / Immunosuppression

Background: CD19+ B-cells play a role in the pathophysiology of multiple sclerosis (MS). MEDI-551, a humanised, afucosylated IgG1κ monoclonal antibody, binds to and depletes CD19+ B-cells.

Objectives: Assess safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of ascending intravenous (IV) and subcutaneous (SC) doses of MEDI‑551 in adults with relapsing forms of MS.

Methods: In this phase 1 trial (NCT01585766), patients in 5 cohorts were randomised 3:1 to receive MEDI-551, 2 doses (days 1 and 15) of 30, 100, or 600 mg IV, or a single dose (day 1) of 60 or 300 mg SC, or matching placebo (PBO). Only IV patients received premedication to reduce risk of possible infusion reactions. Adverse events (AEs) were monitored. Blood was collected for PK, PD, and antidrug antibodies (ADAs). MRI was performed periodically. Patients were followed until the CD19+ B-cell count returned to the lower limit of normal (80 cells/µL) or to the end of the treatment period (day 169), whichever was later.

Results: In total, 28 patients were randomised; 27 (MEDI-551, 20; PBO, 7) completed treatment (day 169). Nine patients remain in follow-up for B-cell recovery as of 1 April 2015. A rapid decline in B-cell counts was observed for all MEDI-551 dose groups. The mean drug half-life was 16 days. Higher doses caused longer B-cell depletion. Most related AEs seen only with MEDI-551 were single events, except for pyrexia, nasopharyngitis, oral herpes, and increased blood pressure (n=2 each). Infusion/injection reactions occurred in 6/15 MEDI-551 IV (40%), 2/6 MEDI-551 SC (33%), and 2/7 PBO patients (29%). Most injection/infusion reactions were grade 1 or grade 2 severity. Three serious AEs occurred in 2 patients in the MEDI-551 group (pyrexia, accidental opioid overdose, and death). The death was due to a mixed-drug intoxication that was not MEDI‑551 related (n=1, MEDI-551 30-mg IV cohort). ADAs were not observed in any patients. The mean number of cumulative new gadolinium-enhancing lesions over 169 days was 0.1 in the MEDI-551 group vs 1.1 in the PBO group. The mean number of new or newly enlarging T2 lesions at day 169 was 0.4 in the MEDI-551 group vs 2.2 in the PBO group.

Conclusions: MEDI-551 showed promising safety and tolerability in patients with relapsing MS. Two IV infusions with MEDI-551(30, 100, or 600 mg) or a single SC dose (60 or 300 mg) led to rapid, sustained B-cell depletion.

Disclosure:

M. Agius has served as a remunerated consultant and/or on advisory boards for Genzyme, Biogen Idec, and Novartis; served as a lecturer for Novartis, Genzyme, Biogen Idec, Bayer, and Teva; has received travel expenses from Novartis, Genzyme, and Biogen Idec; and has received research funding from Novartis, Genzyme, MedImmune, NIH, Roche, and Acorda.

G. Klodowska-Duda has nothing to disclose.

M. Maciejowski has nothing to disclose.

A. Potemkowski has nothing to disclose.

S. Sweeny has nothing to disclose.

J. Li is an employee of MedImmune and holds stock and/or stock options in the company.

W. Yao has nothing to disclose.

K. Patra is an employee of MedImmune and holds stock and/or stock options in the company.

J.N. Ratchford has served as a remunerated consultant and/or on advisory boards for Biogen Idec and Genzyme; has developed educational presentations for Prime Education; has received research funding from Novartis, Biogen Idec, and Sun Pharmaceuticals; and is an employee of MedImmune and holds stock and/or stock options in the company.

E. Katz is an employee of MedImmune.

A. Flor is an employee of MedImmune and has stock and/or stock options in the company.

Abstract: P528

Type: Poster

Abstract Category: Immunomodulation / Immunosuppression

Background: CD19+ B-cells play a role in the pathophysiology of multiple sclerosis (MS). MEDI-551, a humanised, afucosylated IgG1κ monoclonal antibody, binds to and depletes CD19+ B-cells.

Objectives: Assess safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of ascending intravenous (IV) and subcutaneous (SC) doses of MEDI‑551 in adults with relapsing forms of MS.

Methods: In this phase 1 trial (NCT01585766), patients in 5 cohorts were randomised 3:1 to receive MEDI-551, 2 doses (days 1 and 15) of 30, 100, or 600 mg IV, or a single dose (day 1) of 60 or 300 mg SC, or matching placebo (PBO). Only IV patients received premedication to reduce risk of possible infusion reactions. Adverse events (AEs) were monitored. Blood was collected for PK, PD, and antidrug antibodies (ADAs). MRI was performed periodically. Patients were followed until the CD19+ B-cell count returned to the lower limit of normal (80 cells/µL) or to the end of the treatment period (day 169), whichever was later.

Results: In total, 28 patients were randomised; 27 (MEDI-551, 20; PBO, 7) completed treatment (day 169). Nine patients remain in follow-up for B-cell recovery as of 1 April 2015. A rapid decline in B-cell counts was observed for all MEDI-551 dose groups. The mean drug half-life was 16 days. Higher doses caused longer B-cell depletion. Most related AEs seen only with MEDI-551 were single events, except for pyrexia, nasopharyngitis, oral herpes, and increased blood pressure (n=2 each). Infusion/injection reactions occurred in 6/15 MEDI-551 IV (40%), 2/6 MEDI-551 SC (33%), and 2/7 PBO patients (29%). Most injection/infusion reactions were grade 1 or grade 2 severity. Three serious AEs occurred in 2 patients in the MEDI-551 group (pyrexia, accidental opioid overdose, and death). The death was due to a mixed-drug intoxication that was not MEDI‑551 related (n=1, MEDI-551 30-mg IV cohort). ADAs were not observed in any patients. The mean number of cumulative new gadolinium-enhancing lesions over 169 days was 0.1 in the MEDI-551 group vs 1.1 in the PBO group. The mean number of new or newly enlarging T2 lesions at day 169 was 0.4 in the MEDI-551 group vs 2.2 in the PBO group.

Conclusions: MEDI-551 showed promising safety and tolerability in patients with relapsing MS. Two IV infusions with MEDI-551(30, 100, or 600 mg) or a single SC dose (60 or 300 mg) led to rapid, sustained B-cell depletion.

Disclosure:

M. Agius has served as a remunerated consultant and/or on advisory boards for Genzyme, Biogen Idec, and Novartis; served as a lecturer for Novartis, Genzyme, Biogen Idec, Bayer, and Teva; has received travel expenses from Novartis, Genzyme, and Biogen Idec; and has received research funding from Novartis, Genzyme, MedImmune, NIH, Roche, and Acorda.

G. Klodowska-Duda has nothing to disclose.

M. Maciejowski has nothing to disclose.

A. Potemkowski has nothing to disclose.

S. Sweeny has nothing to disclose.

J. Li is an employee of MedImmune and holds stock and/or stock options in the company.

W. Yao has nothing to disclose.

K. Patra is an employee of MedImmune and holds stock and/or stock options in the company.

J.N. Ratchford has served as a remunerated consultant and/or on advisory boards for Biogen Idec and Genzyme; has developed educational presentations for Prime Education; has received research funding from Novartis, Biogen Idec, and Sun Pharmaceuticals; and is an employee of MedImmune and holds stock and/or stock options in the company.

E. Katz is an employee of MedImmune.

A. Flor is an employee of MedImmune and has stock and/or stock options in the company.

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