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Randomized phase I trials of the safety/tolerability of anti-LINGO-1 monoclonal antibody BIIB033.

Tran JQ, Rana J, Barkhof F, Melamed I, Gevorkyan H, Wattjes MP, de Jong R, Brosofsky K, Ray S, Xu L, Zhao J, Parr E, Cadavid D - Neurol Neuroimmunol Neuroinflamm (2014)

Bottom Line: No clinically significant changes in any of the safety measures were observed.Doses of ≥10 mg/kg resulted in BIIB033 concentrations similar to or higher than the concentration associated with 90% of the maximum remyelination effect in rat remyelination studies.This study provides Class I evidence that BIIB033 is well tolerated and safe (serious adverse event rate 0%, 95% confidence interval 0-7.6%).

View Article: PubMed Central - PubMed

Affiliation: Biogen Idec (J.Q.T., J.R., S.R., L.X., D.C.), Cambridge, MA; VU Medical Center (F.B., M.P.W., R.D.), Amsterdam, the Netherlands; IMMUNOe (I.M.), Centennial, CO; PAREXEL International (H.G.), Glendale, CA; ALG Partners (K.B.), Natick, MA; and Excel Scientific Solutions (E.P.), Southport, CT. J.Z. is a former employee of Biogen Idec.

ABSTRACT

Objective: To evaluate the safety, tolerability, and pharmacokinetics (PK) of BIIB033 (anti-LINGO-1 monoclonal antibody) in healthy volunteers and participants with multiple sclerosis (MS).

Methods: In 2 separate randomized, placebo-controlled studies, single ascending doses (SAD; 0.1-100 mg/kg) of BIIB033 or placebo were administered via IV infusion or subcutaneous injection to 72 healthy volunteers, and multiple ascending doses (MAD; 0.3-100 mg/kg; 2 doses separated by 14 days) of BIIB033 or placebo were administered via IV infusion to 47 participants with relapsing-remitting or secondary progressive MS. Safety assessments included adverse event (AE) monitoring, neurologic examinations, conventional and nonconventional MRI, EEG, optical coherence tomography, retinal examinations, and evoked potentials. Serum and CSF PK as well as the immunogenicity of BIIB033 were also evaluated.

Results: All 72 healthy volunteers and 47 participants with MS were included in the safety analyses. BIIB033 infusions were well tolerated. The frequency of AEs was similar between BIIB033 and placebo. There were no serious AEs or deaths. No clinically significant changes in any of the safety measures were observed. BIIB033 PK was similar between healthy volunteers and participants with MS. Doses of ≥10 mg/kg resulted in BIIB033 concentrations similar to or higher than the concentration associated with 90% of the maximum remyelination effect in rat remyelination studies. The incidence of anti-drug antibody production was low.

Conclusions: The emerging safety, tolerability, and PK of BIIB033 support advancing BIIB033 into phase II clinical development as a potential treatment for CNS demyelination disorders.

Classification of evidence: This study provides Class I evidence that BIIB033 is well tolerated and safe (serious adverse event rate 0%, 95% confidence interval 0-7.6%).

No MeSH data available.


Related in: MedlinePlus

Mean serum concentrations of BIIB033 vs time(A) Single ascending dose study and (B) multiple ascending dose study. EC50 and EC90 values determined in rat lysolecithin-induced demyelination spinal cord model; values adjusted for 0.1% brain penetration. Abbreviations: EC50 and EC90 = 50% and 90% maximal effective concentrations; SC = subcutaneous.
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Figure 2: Mean serum concentrations of BIIB033 vs time(A) Single ascending dose study and (B) multiple ascending dose study. EC50 and EC90 values determined in rat lysolecithin-induced demyelination spinal cord model; values adjusted for 0.1% brain penetration. Abbreviations: EC50 and EC90 = 50% and 90% maximal effective concentrations; SC = subcutaneous.

Mentions: After IV infusion, serum BIIB033 concentration-time profiles in the PK population of both the SAD study (n = 53) and MAD study (n = 31) showed a multi-exponential decrease (figure 2, A and B). The PK values were similar between healthy adults (table 2) and participants with MS (tables 3 and e-4). In both studies, serum BIIB033 exposure (AUC, Cmax) increased in an approximately dose-proportional manner and mean t1/2 values spanned from 15 to 24 days (tables 2 and 3). The mean estimated values for Vss and mean values for clearance were both low. In the MAD study, serum BIIB033 PK was not detectably affected by concomitant treatment with interferon-β (n = 12) or glatiramer acetate (n = 14; table e-5). The Cmax and Tmax values for 100 mg/kg at the faster IV infusion rate (80 minutes) were similar to those observed for the 2.75-hour infusion, indicating that the PK was not affected by the duration of infusion.


Randomized phase I trials of the safety/tolerability of anti-LINGO-1 monoclonal antibody BIIB033.

Tran JQ, Rana J, Barkhof F, Melamed I, Gevorkyan H, Wattjes MP, de Jong R, Brosofsky K, Ray S, Xu L, Zhao J, Parr E, Cadavid D - Neurol Neuroimmunol Neuroinflamm (2014)

Mean serum concentrations of BIIB033 vs time(A) Single ascending dose study and (B) multiple ascending dose study. EC50 and EC90 values determined in rat lysolecithin-induced demyelination spinal cord model; values adjusted for 0.1% brain penetration. Abbreviations: EC50 and EC90 = 50% and 90% maximal effective concentrations; SC = subcutaneous.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4202679&req=5

Figure 2: Mean serum concentrations of BIIB033 vs time(A) Single ascending dose study and (B) multiple ascending dose study. EC50 and EC90 values determined in rat lysolecithin-induced demyelination spinal cord model; values adjusted for 0.1% brain penetration. Abbreviations: EC50 and EC90 = 50% and 90% maximal effective concentrations; SC = subcutaneous.
Mentions: After IV infusion, serum BIIB033 concentration-time profiles in the PK population of both the SAD study (n = 53) and MAD study (n = 31) showed a multi-exponential decrease (figure 2, A and B). The PK values were similar between healthy adults (table 2) and participants with MS (tables 3 and e-4). In both studies, serum BIIB033 exposure (AUC, Cmax) increased in an approximately dose-proportional manner and mean t1/2 values spanned from 15 to 24 days (tables 2 and 3). The mean estimated values for Vss and mean values for clearance were both low. In the MAD study, serum BIIB033 PK was not detectably affected by concomitant treatment with interferon-β (n = 12) or glatiramer acetate (n = 14; table e-5). The Cmax and Tmax values for 100 mg/kg at the faster IV infusion rate (80 minutes) were similar to those observed for the 2.75-hour infusion, indicating that the PK was not affected by the duration of infusion.

Bottom Line: No clinically significant changes in any of the safety measures were observed.Doses of ≥10 mg/kg resulted in BIIB033 concentrations similar to or higher than the concentration associated with 90% of the maximum remyelination effect in rat remyelination studies.This study provides Class I evidence that BIIB033 is well tolerated and safe (serious adverse event rate 0%, 95% confidence interval 0-7.6%).

View Article: PubMed Central - PubMed

Affiliation: Biogen Idec (J.Q.T., J.R., S.R., L.X., D.C.), Cambridge, MA; VU Medical Center (F.B., M.P.W., R.D.), Amsterdam, the Netherlands; IMMUNOe (I.M.), Centennial, CO; PAREXEL International (H.G.), Glendale, CA; ALG Partners (K.B.), Natick, MA; and Excel Scientific Solutions (E.P.), Southport, CT. J.Z. is a former employee of Biogen Idec.

ABSTRACT

Objective: To evaluate the safety, tolerability, and pharmacokinetics (PK) of BIIB033 (anti-LINGO-1 monoclonal antibody) in healthy volunteers and participants with multiple sclerosis (MS).

Methods: In 2 separate randomized, placebo-controlled studies, single ascending doses (SAD; 0.1-100 mg/kg) of BIIB033 or placebo were administered via IV infusion or subcutaneous injection to 72 healthy volunteers, and multiple ascending doses (MAD; 0.3-100 mg/kg; 2 doses separated by 14 days) of BIIB033 or placebo were administered via IV infusion to 47 participants with relapsing-remitting or secondary progressive MS. Safety assessments included adverse event (AE) monitoring, neurologic examinations, conventional and nonconventional MRI, EEG, optical coherence tomography, retinal examinations, and evoked potentials. Serum and CSF PK as well as the immunogenicity of BIIB033 were also evaluated.

Results: All 72 healthy volunteers and 47 participants with MS were included in the safety analyses. BIIB033 infusions were well tolerated. The frequency of AEs was similar between BIIB033 and placebo. There were no serious AEs or deaths. No clinically significant changes in any of the safety measures were observed. BIIB033 PK was similar between healthy volunteers and participants with MS. Doses of ≥10 mg/kg resulted in BIIB033 concentrations similar to or higher than the concentration associated with 90% of the maximum remyelination effect in rat remyelination studies. The incidence of anti-drug antibody production was low.

Conclusions: The emerging safety, tolerability, and PK of BIIB033 support advancing BIIB033 into phase II clinical development as a potential treatment for CNS demyelination disorders.

Classification of evidence: This study provides Class I evidence that BIIB033 is well tolerated and safe (serious adverse event rate 0%, 95% confidence interval 0-7.6%).

No MeSH data available.


Related in: MedlinePlus