Safety/tolerability of the anti-semaphorin 4D antibody VX15/2503 in a randomized phase 1 trial

Christopher LaGanke, Lawrence Samkoff, Keith Edwards, Lily Jung Henson, Pavle Repovic, Sharon Lynch, Lael Stone, David Mattson, Aaron Galluzzi, Terrence L. Fisher, Christine Reilly, Laurie A. Winter, John E. Leonard, Maurice Zauderer

Research output: Contribution to journalArticle

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Abstract

Objective: To evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of VX15/2503 in a randomized, single-dose, dose-escalation, double-blind, placebo-controlled study enrolling adult patients with MS. Methods: Single IV doses of VX15/2503 or placebo were administered. Ten patients each were randomized (4:1 randomization ratio) into 5 ascending dose cohorts of 1, 3, 6, 10, or 20 mg/kg. Safety, immunogenicity, PK/PD, MRI, ECG, and lymphocyte subset levels were evaluated. A Dose Escalation Safety Committee (DESC) approved each dose escalation. Results: VX15/2503 was well tolerated, and all participants completed the study. Antibody treatment-related adverse events were primarily grade 1 or 2 and included urinary tract infection (12.5%) and muscle weakness, contusion, and insomnia (each 7.5%). No dose-limiting toxicities were observed, and no maximum tolerated dose was determined. One subject (20 mg/kg) experienced disease relapse 3 months before study entry and exhibited a grade 3 (nonserious) increase in brain lesions by day 29, possibly related to VX15/2503. Twenty-nine patients exhibited human anti-humanized antibody responses; 5 with titer $100. No anti-VX15/2503 antibody responses were fully neutralizing. VX15/2503 Cmax, area under the time-concentration curve, and mean half-life increased with dose level; at 20 mg/kg, the T1/2 was 20 days. Cellular SEMA4D saturation occurred at serum antibody concentrations #0.3 mg/mL, resulting in decreased cSEMA4D expression. At 20 mg/kg, cSEMA4D saturation persisted for $155 days. Total sSEMA4D levels increased with dose level and declined with antibody clearance. Conclusions: These results support the continued investigation of VX15/2503 in neurodegenerative diseases.

Original languageEnglish (US)
JournalNeurology: Neuroimmunology and NeuroInflammation
Volume4
Issue number4
DOIs
StatePublished - 2017

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Safety
Antibody Formation
Antibodies
Pharmacokinetics
Placebos
Antibodies, Monoclonal, Humanized
Maximum Tolerated Dose
Contusions
Muscle Weakness
Lymphocyte Subsets
Sleep Initiation and Maintenance Disorders
Random Allocation
Urinary Tract Infections
Neurodegenerative Diseases
Half-Life
Anti-Idiotypic Antibodies
Electrocardiography
Recurrence
Brain
Serum

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology

Cite this

Safety/tolerability of the anti-semaphorin 4D antibody VX15/2503 in a randomized phase 1 trial. / LaGanke, Christopher; Samkoff, Lawrence; Edwards, Keith; Henson, Lily Jung; Repovic, Pavle; Lynch, Sharon; Stone, Lael; Mattson, David; Galluzzi, Aaron; Fisher, Terrence L.; Reilly, Christine; Winter, Laurie A.; Leonard, John E.; Zauderer, Maurice.

In: Neurology: Neuroimmunology and NeuroInflammation, Vol. 4, No. 4, 2017.

Research output: Contribution to journalArticle

LaGanke, C, Samkoff, L, Edwards, K, Henson, LJ, Repovic, P, Lynch, S, Stone, L, Mattson, D, Galluzzi, A, Fisher, TL, Reilly, C, Winter, LA, Leonard, JE & Zauderer, M 2017, 'Safety/tolerability of the anti-semaphorin 4D antibody VX15/2503 in a randomized phase 1 trial', Neurology: Neuroimmunology and NeuroInflammation, vol. 4, no. 4. https://doi.org/10.1212/NXI.0000000000000367
LaGanke, Christopher ; Samkoff, Lawrence ; Edwards, Keith ; Henson, Lily Jung ; Repovic, Pavle ; Lynch, Sharon ; Stone, Lael ; Mattson, David ; Galluzzi, Aaron ; Fisher, Terrence L. ; Reilly, Christine ; Winter, Laurie A. ; Leonard, John E. ; Zauderer, Maurice. / Safety/tolerability of the anti-semaphorin 4D antibody VX15/2503 in a randomized phase 1 trial. In: Neurology: Neuroimmunology and NeuroInflammation. 2017 ; Vol. 4, No. 4.
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abstract = "Objective: To evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of VX15/2503 in a randomized, single-dose, dose-escalation, double-blind, placebo-controlled study enrolling adult patients with MS. Methods: Single IV doses of VX15/2503 or placebo were administered. Ten patients each were randomized (4:1 randomization ratio) into 5 ascending dose cohorts of 1, 3, 6, 10, or 20 mg/kg. Safety, immunogenicity, PK/PD, MRI, ECG, and lymphocyte subset levels were evaluated. A Dose Escalation Safety Committee (DESC) approved each dose escalation. Results: VX15/2503 was well tolerated, and all participants completed the study. Antibody treatment-related adverse events were primarily grade 1 or 2 and included urinary tract infection (12.5{\%}) and muscle weakness, contusion, and insomnia (each 7.5{\%}). No dose-limiting toxicities were observed, and no maximum tolerated dose was determined. One subject (20 mg/kg) experienced disease relapse 3 months before study entry and exhibited a grade 3 (nonserious) increase in brain lesions by day 29, possibly related to VX15/2503. Twenty-nine patients exhibited human anti-humanized antibody responses; 5 with titer $100. No anti-VX15/2503 antibody responses were fully neutralizing. VX15/2503 Cmax, area under the time-concentration curve, and mean half-life increased with dose level; at 20 mg/kg, the T1/2 was 20 days. Cellular SEMA4D saturation occurred at serum antibody concentrations #0.3 mg/mL, resulting in decreased cSEMA4D expression. At 20 mg/kg, cSEMA4D saturation persisted for $155 days. Total sSEMA4D levels increased with dose level and declined with antibody clearance. Conclusions: These results support the continued investigation of VX15/2503 in neurodegenerative diseases.",
author = "Christopher LaGanke and Lawrence Samkoff and Keith Edwards and Henson, {Lily Jung} and Pavle Repovic and Sharon Lynch and Lael Stone and David Mattson and Aaron Galluzzi and Fisher, {Terrence L.} and Christine Reilly and Winter, {Laurie A.} and Leonard, {John E.} and Maurice Zauderer",
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T1 - Safety/tolerability of the anti-semaphorin 4D antibody VX15/2503 in a randomized phase 1 trial

AU - LaGanke, Christopher

AU - Samkoff, Lawrence

AU - Edwards, Keith

AU - Henson, Lily Jung

AU - Repovic, Pavle

AU - Lynch, Sharon

AU - Stone, Lael

AU - Mattson, David

AU - Galluzzi, Aaron

AU - Fisher, Terrence L.

AU - Reilly, Christine

AU - Winter, Laurie A.

AU - Leonard, John E.

AU - Zauderer, Maurice

PY - 2017

Y1 - 2017

N2 - Objective: To evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of VX15/2503 in a randomized, single-dose, dose-escalation, double-blind, placebo-controlled study enrolling adult patients with MS. Methods: Single IV doses of VX15/2503 or placebo were administered. Ten patients each were randomized (4:1 randomization ratio) into 5 ascending dose cohorts of 1, 3, 6, 10, or 20 mg/kg. Safety, immunogenicity, PK/PD, MRI, ECG, and lymphocyte subset levels were evaluated. A Dose Escalation Safety Committee (DESC) approved each dose escalation. Results: VX15/2503 was well tolerated, and all participants completed the study. Antibody treatment-related adverse events were primarily grade 1 or 2 and included urinary tract infection (12.5%) and muscle weakness, contusion, and insomnia (each 7.5%). No dose-limiting toxicities were observed, and no maximum tolerated dose was determined. One subject (20 mg/kg) experienced disease relapse 3 months before study entry and exhibited a grade 3 (nonserious) increase in brain lesions by day 29, possibly related to VX15/2503. Twenty-nine patients exhibited human anti-humanized antibody responses; 5 with titer $100. No anti-VX15/2503 antibody responses were fully neutralizing. VX15/2503 Cmax, area under the time-concentration curve, and mean half-life increased with dose level; at 20 mg/kg, the T1/2 was 20 days. Cellular SEMA4D saturation occurred at serum antibody concentrations #0.3 mg/mL, resulting in decreased cSEMA4D expression. At 20 mg/kg, cSEMA4D saturation persisted for $155 days. Total sSEMA4D levels increased with dose level and declined with antibody clearance. Conclusions: These results support the continued investigation of VX15/2503 in neurodegenerative diseases.

AB - Objective: To evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of VX15/2503 in a randomized, single-dose, dose-escalation, double-blind, placebo-controlled study enrolling adult patients with MS. Methods: Single IV doses of VX15/2503 or placebo were administered. Ten patients each were randomized (4:1 randomization ratio) into 5 ascending dose cohorts of 1, 3, 6, 10, or 20 mg/kg. Safety, immunogenicity, PK/PD, MRI, ECG, and lymphocyte subset levels were evaluated. A Dose Escalation Safety Committee (DESC) approved each dose escalation. Results: VX15/2503 was well tolerated, and all participants completed the study. Antibody treatment-related adverse events were primarily grade 1 or 2 and included urinary tract infection (12.5%) and muscle weakness, contusion, and insomnia (each 7.5%). No dose-limiting toxicities were observed, and no maximum tolerated dose was determined. One subject (20 mg/kg) experienced disease relapse 3 months before study entry and exhibited a grade 3 (nonserious) increase in brain lesions by day 29, possibly related to VX15/2503. Twenty-nine patients exhibited human anti-humanized antibody responses; 5 with titer $100. No anti-VX15/2503 antibody responses were fully neutralizing. VX15/2503 Cmax, area under the time-concentration curve, and mean half-life increased with dose level; at 20 mg/kg, the T1/2 was 20 days. Cellular SEMA4D saturation occurred at serum antibody concentrations #0.3 mg/mL, resulting in decreased cSEMA4D expression. At 20 mg/kg, cSEMA4D saturation persisted for $155 days. Total sSEMA4D levels increased with dose level and declined with antibody clearance. Conclusions: These results support the continued investigation of VX15/2503 in neurodegenerative diseases.

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