Contributions
Abstract: EP1554
Type: ePoster
Abstract Category: Therapy - disease modifying - Others
Background: Natalizumab"s effects on MRI disease activity and annualized relapse rate (ARR) in RRMS patients have been described; however, no quantitative models define the relationship between natalizumab time-averaged exposure and MRI.
Objectives: The analysis quantified the relationship between exposure and T1 gadolinium-enhancing (Gd) lesion count or ARR following phase 2, 3, or 4 clinical trial dosing of 3 mg/kg, 6 mg/kg, 300 mg q4wk, 150 mg q12wk, or 300 mg q12wk natalizumab, or placebo.
Methodology: Gd lesion observations (n=6913) from 1512 RRMS patients from 4 studies (AN100226-231, C1801, 101MS205, 101MS206) and ARR observations from 1270 RRMS patients from 3 studies (AN100226-231, C1802, 101MS206) were analyzed. Gd lesion observations were collected monthly for 6 months (AN100226-231, 101MS205) or every 3 months for 15 months to every 12 months for 2 years (101MS206, C1801). Natalizumab exposure was predicted using a previously developed PK model; effect on Gd lesion count and ARR was evaluated. Here, model-estimated individual average concentration (Cavg=AUCτ/τ [τ=dosing interval]) was utilized as the exposure parameter. To characterize exposure-response relationship, 2 models were developed (exposure-Gd model, exposure-ARR model).
Results: From the exposure-response model, it can be observed that with increasing exposure, Gd lesion count was increasingly reduced, with a maximal reduction of 96% observed with a 300 mg dose. Similarly, ARR decreased with increasing steady-state exposure. Based on long-term clinical studies (C1802, 101MS206), the lowest ARR of 0.240 was achieved with a 300 mg dose. Further, it can be inferred that, at steady state with the approved clinical dose (300 mg q4wk), a 90% decrease in Gd lesion count is expected in >90% of enrolled subjects vs other evaluated clinical doses, and the 300 mg q4wk arm is expected to be associated with a mean ARR of 0.242, representing a 61% ARR reduction vs placebo (baseline ARR λio =0.618).
Conclusions: In RRMS patients, this model characterizes the relationship between exposure and Gd lesions or ARR, confirming the efficacy observed in the 300mg q4wk IV dosing regimen.
Disclosure: Supported by Biogen.
KKM, DS, JE, PRH, DA, HK, KE: employees of and may hold stock and/or stock options in Biogen
DM: employee of Biogen at the time of the analysis
Abstract: EP1554
Type: ePoster
Abstract Category: Therapy - disease modifying - Others
Background: Natalizumab"s effects on MRI disease activity and annualized relapse rate (ARR) in RRMS patients have been described; however, no quantitative models define the relationship between natalizumab time-averaged exposure and MRI.
Objectives: The analysis quantified the relationship between exposure and T1 gadolinium-enhancing (Gd) lesion count or ARR following phase 2, 3, or 4 clinical trial dosing of 3 mg/kg, 6 mg/kg, 300 mg q4wk, 150 mg q12wk, or 300 mg q12wk natalizumab, or placebo.
Methodology: Gd lesion observations (n=6913) from 1512 RRMS patients from 4 studies (AN100226-231, C1801, 101MS205, 101MS206) and ARR observations from 1270 RRMS patients from 3 studies (AN100226-231, C1802, 101MS206) were analyzed. Gd lesion observations were collected monthly for 6 months (AN100226-231, 101MS205) or every 3 months for 15 months to every 12 months for 2 years (101MS206, C1801). Natalizumab exposure was predicted using a previously developed PK model; effect on Gd lesion count and ARR was evaluated. Here, model-estimated individual average concentration (Cavg=AUCτ/τ [τ=dosing interval]) was utilized as the exposure parameter. To characterize exposure-response relationship, 2 models were developed (exposure-Gd model, exposure-ARR model).
Results: From the exposure-response model, it can be observed that with increasing exposure, Gd lesion count was increasingly reduced, with a maximal reduction of 96% observed with a 300 mg dose. Similarly, ARR decreased with increasing steady-state exposure. Based on long-term clinical studies (C1802, 101MS206), the lowest ARR of 0.240 was achieved with a 300 mg dose. Further, it can be inferred that, at steady state with the approved clinical dose (300 mg q4wk), a 90% decrease in Gd lesion count is expected in >90% of enrolled subjects vs other evaluated clinical doses, and the 300 mg q4wk arm is expected to be associated with a mean ARR of 0.242, representing a 61% ARR reduction vs placebo (baseline ARR λio =0.618).
Conclusions: In RRMS patients, this model characterizes the relationship between exposure and Gd lesions or ARR, confirming the efficacy observed in the 300mg q4wk IV dosing regimen.
Disclosure: Supported by Biogen.
KKM, DS, JE, PRH, DA, HK, KE: employees of and may hold stock and/or stock options in Biogen
DM: employee of Biogen at the time of the analysis