Contributions
Abstract: P1251
Type: Poster
Abstract Category: Therapy - disease modifying - Risk management for disease modifying treatments
Background: Blockade of the α4 integrin by natalizumab (NTZ) affects immune cell trafficking into the central nervous system (CNS). Extended interval dosing (EID) has been proposed as a potential risk mitigation strategy for NTZ induced progressive multifocal leukoencephalopathy (PML), with maintained efficacy and a trend toward reduced PML risk observed in a retrospective multi-center trial. The pharmacological response of NTZ EID remains poorly characterized.
Methods: A total of 445 NTZ-infusing patients were evaluated, with 323 on standard interval dosing (SID; every 28-30 days), and 122 on EID (every 33-51 days). NTZ serum concentrations and α4 integrin occupancy were measured at dosing trough prior to infusion in all patients, and at additional timepoints between infusions in a subset of patients.
Results: At 2 hours after NTZ administration, NTZ serum concentrations were similar between the SID and EID cohorts (median=120.5 versus 138.0 mg/ml, respectively; p=0.304), and receptor occupancy was also not different between the two cohorts (median=97% for both; p=0.821). At 4 weeks post-infusion, NTZ concentration remained similar in SID versus EID patients (median= 27.7 versus 25.6 mg/ml, respectively; p= 0.117), as did receptor occupancy (median= 89 versus 88%, respectively; p=0.700). However, by weeks 5 and 6, EID patients exhibited lower trough NTZ concentration (median=16.4 mg/ml) and receptor occupancy (median=80%) compared to that observed at 4 weeks (trough) in SID patients (p< 0.001 for both comparisons). Also, the proportion of patients with maximal α4 integrin occupancy (at least 95% saturation) was 3-fold lower at trough EID timepoints versus the trough timepoint for SID (9% versus 24%, respectively; p= 0.013).
Conclusions: EID reduces both NTZ serum concentrations and α4 integrin occupancy levels at trough timepoints, though receptor occupancy was still generally maintained within the range considered to be protective against disease. Further research is needed to determine if these reductions lead to an increase in immunological trafficking into the CNS, and could serve as a potential mechanism to reduce PML risk.
Disclosure: John F. Foley Dr. Foley participates in the Speakers´ Bureaus for Biogen, Genentech-Roche, Genzyme and Accorda. Dr. Foley advises for Biogen, Genentech-Roche, and Genzyme.
Tamara Hoyt has nothing to disclose.
Angelene Christensen has nothing to disclose.
Laura Seawright has nothing to disclose.
Ryan Metzger owns stock in Biogen.
Evan Riddle is an employee of and hold stock in Biogen.
Tatiana Plavina is an employee of and hold stock in Biogen.
This study was supported by Biogen.
Abstract: P1251
Type: Poster
Abstract Category: Therapy - disease modifying - Risk management for disease modifying treatments
Background: Blockade of the α4 integrin by natalizumab (NTZ) affects immune cell trafficking into the central nervous system (CNS). Extended interval dosing (EID) has been proposed as a potential risk mitigation strategy for NTZ induced progressive multifocal leukoencephalopathy (PML), with maintained efficacy and a trend toward reduced PML risk observed in a retrospective multi-center trial. The pharmacological response of NTZ EID remains poorly characterized.
Methods: A total of 445 NTZ-infusing patients were evaluated, with 323 on standard interval dosing (SID; every 28-30 days), and 122 on EID (every 33-51 days). NTZ serum concentrations and α4 integrin occupancy were measured at dosing trough prior to infusion in all patients, and at additional timepoints between infusions in a subset of patients.
Results: At 2 hours after NTZ administration, NTZ serum concentrations were similar between the SID and EID cohorts (median=120.5 versus 138.0 mg/ml, respectively; p=0.304), and receptor occupancy was also not different between the two cohorts (median=97% for both; p=0.821). At 4 weeks post-infusion, NTZ concentration remained similar in SID versus EID patients (median= 27.7 versus 25.6 mg/ml, respectively; p= 0.117), as did receptor occupancy (median= 89 versus 88%, respectively; p=0.700). However, by weeks 5 and 6, EID patients exhibited lower trough NTZ concentration (median=16.4 mg/ml) and receptor occupancy (median=80%) compared to that observed at 4 weeks (trough) in SID patients (p< 0.001 for both comparisons). Also, the proportion of patients with maximal α4 integrin occupancy (at least 95% saturation) was 3-fold lower at trough EID timepoints versus the trough timepoint for SID (9% versus 24%, respectively; p= 0.013).
Conclusions: EID reduces both NTZ serum concentrations and α4 integrin occupancy levels at trough timepoints, though receptor occupancy was still generally maintained within the range considered to be protective against disease. Further research is needed to determine if these reductions lead to an increase in immunological trafficking into the CNS, and could serve as a potential mechanism to reduce PML risk.
Disclosure: John F. Foley Dr. Foley participates in the Speakers´ Bureaus for Biogen, Genentech-Roche, Genzyme and Accorda. Dr. Foley advises for Biogen, Genentech-Roche, and Genzyme.
Tamara Hoyt has nothing to disclose.
Angelene Christensen has nothing to disclose.
Laura Seawright has nothing to disclose.
Ryan Metzger owns stock in Biogen.
Evan Riddle is an employee of and hold stock in Biogen.
Tatiana Plavina is an employee of and hold stock in Biogen.
This study was supported by Biogen.