Limits...
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

Disposition of participants(A) Single ascending dose study and (B) multiple ascending dose study. Abbreviations: AE = adverse event; SC = subcutaneous. a 80-minute infusion time.
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4202679&req=5

Figure 1: Disposition of participants(A) Single ascending dose study and (B) multiple ascending dose study. Abbreviations: AE = adverse event; SC = subcutaneous. a 80-minute infusion time.

Mentions: Of the 72 healthy volunteers enrolled, randomized, and dosed in the SAD study between January 2010 and October 2011, 71 completed the study (figure 1). One participant in the 3.0-mg/kg SC group was withdrawn owing to severe AEs (affective disorder and toxicity) after consuming amphetamines and alcohol (protocol violation). Of the 47 participants with MS who were dosed in the MAD study between October 2010 and April 2012, 46 completed the study. One participant in the placebo group withdrew consent (relocated). Overall, SAD participants were about 10 years younger (mean ± SD, 36.7 ± 9.6 years) than MAD participants (mean ± SD, 47.7 ± 8.8 years). A notably larger percentage of participants were female in the MAD vs SAD studies (77% vs 10%) due to exclusion of females of childbearing potential from the SAD study. Other baseline demographic and clinical characteristics for SAD and MAD participants are presented in table e-1.


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)

Disposition of participants(A) Single ascending dose study and (B) multiple ascending dose study. Abbreviations: AE = adverse event; SC = subcutaneous. a 80-minute infusion time.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Disposition of participants(A) Single ascending dose study and (B) multiple ascending dose study. Abbreviations: AE = adverse event; SC = subcutaneous. a 80-minute infusion time.
Mentions: Of the 72 healthy volunteers enrolled, randomized, and dosed in the SAD study between January 2010 and October 2011, 71 completed the study (figure 1). One participant in the 3.0-mg/kg SC group was withdrawn owing to severe AEs (affective disorder and toxicity) after consuming amphetamines and alcohol (protocol violation). Of the 47 participants with MS who were dosed in the MAD study between October 2010 and April 2012, 46 completed the study. One participant in the placebo group withdrew consent (relocated). Overall, SAD participants were about 10 years younger (mean ± SD, 36.7 ± 9.6 years) than MAD participants (mean ± SD, 47.7 ± 8.8 years). A notably larger percentage of participants were female in the MAD vs SAD studies (77% vs 10%) due to exclusion of females of childbearing potential from the SAD study. Other baseline demographic and clinical characteristics for SAD and MAD participants are presented in table e-1.

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