Contributions
Abstract: P1249
Type: Poster
Abstract Category: Therapy - disease modifying - Risk management for disease modifying treatments
Background: Previous PML risk estimates in natalizumab-treated patients using postmarketing data were stratified by 3 established risk factors: presence of anti-JCV antibodies, prior immunosuppressant (IS) use, and treatment duration. As individual risk factor information was not available for all patients, population-based assumptions were needed. While essential since 2012 in guiding patient care, these estimates can now be made more precise using patient-level clinical trial data to assess risk associated with anti-JCV antibody levels ("index").
Objective: To derive annual index-stratified PML risk estimates from clinical trials stratified by the 3 risk factors and based on individual patient data.
Methods: Data were pooled from the STRATIFY-2 (N=24,402), TOP (N=5691), TYGRIS (N=6489), and STRATA (N=1094) trials. The life-table method provided forward-looking PML risk estimates for anti-JCV antibody positive patients in yearly epochs. Further index-stratified risk estimates for patients without prior IS were derived by combining these risk estimates with the probability distribution of index values in patients with/without PML using Bayes rule.
Results: The pooled cohort comprised 37,249 natalizumab-treated patients, including 156 patients with confirmed PML. Patients received a median (range) of 42 (1-129) natalizumab doses, 58% were anti-JCV antibody positive, and 14% had prior IS use. For patients with index ≤0.9, estimated PML risks (per 1000 patients) in yearly epochs 1, 2, 3, 4, 5, and 6 of natalizumab exposure were 0.1, 0.1, 0.2, 0.4, 0.5, 0.6, respectively; for those with index >0.9 to ≤1.5, respective estimated risks were 0.1, 0.3, 0.8, 2, 2, 3; for those with index >1.5, respective estimated risks were 0.2, 0.9, 3, 7, 8, 10; for those with prior IS use, respective estimated risks were 0.3, 0.4, 4, 8, 8, 6. Cumulative PML risk over time will be presented.
Conclusions: Although consistent with previous risk estimates from postmarketing data, these updated risk estimates achieve greater temporal precision in yearly treatment epochs using individual patient data and do not require population-based assumptions. By incorporating index in the algorithm, PML risk can be further stratified for anti-JCV antibody positive patients without prior IS use. In the prior algorithm, the largest numeric increase in PML risk occurred after >2 years of treatment; with increased precision using clinical trial data, the largest increase is observed after >3 years.
Disclosure:
Supported by Biogen
Harold Koendgen: employee of and may hold stock and/or stock options in Biogen.
Ih Chang: employee of and may hold stock and/or stock options in Biogen.
Bjoern Sperling: employee of and may hold stock and/or stock options in Biogen.
Gary Bloomgren: employee of and may hold stock and/or stock options in Biogen.
Bill Haddock: employee of and may hold stock and/or stock options in Biogen.
Sandra Richman: employee of and may hold stock and/or stock options in Biogen.
Pei-Ran Ho: employee of and may hold stock and/or stock options in Biogen.
Nolan Campbell: employee of and may hold stock and/or stock options in Biogen.
Abstract: P1249
Type: Poster
Abstract Category: Therapy - disease modifying - Risk management for disease modifying treatments
Background: Previous PML risk estimates in natalizumab-treated patients using postmarketing data were stratified by 3 established risk factors: presence of anti-JCV antibodies, prior immunosuppressant (IS) use, and treatment duration. As individual risk factor information was not available for all patients, population-based assumptions were needed. While essential since 2012 in guiding patient care, these estimates can now be made more precise using patient-level clinical trial data to assess risk associated with anti-JCV antibody levels ("index").
Objective: To derive annual index-stratified PML risk estimates from clinical trials stratified by the 3 risk factors and based on individual patient data.
Methods: Data were pooled from the STRATIFY-2 (N=24,402), TOP (N=5691), TYGRIS (N=6489), and STRATA (N=1094) trials. The life-table method provided forward-looking PML risk estimates for anti-JCV antibody positive patients in yearly epochs. Further index-stratified risk estimates for patients without prior IS were derived by combining these risk estimates with the probability distribution of index values in patients with/without PML using Bayes rule.
Results: The pooled cohort comprised 37,249 natalizumab-treated patients, including 156 patients with confirmed PML. Patients received a median (range) of 42 (1-129) natalizumab doses, 58% were anti-JCV antibody positive, and 14% had prior IS use. For patients with index ≤0.9, estimated PML risks (per 1000 patients) in yearly epochs 1, 2, 3, 4, 5, and 6 of natalizumab exposure were 0.1, 0.1, 0.2, 0.4, 0.5, 0.6, respectively; for those with index >0.9 to ≤1.5, respective estimated risks were 0.1, 0.3, 0.8, 2, 2, 3; for those with index >1.5, respective estimated risks were 0.2, 0.9, 3, 7, 8, 10; for those with prior IS use, respective estimated risks were 0.3, 0.4, 4, 8, 8, 6. Cumulative PML risk over time will be presented.
Conclusions: Although consistent with previous risk estimates from postmarketing data, these updated risk estimates achieve greater temporal precision in yearly treatment epochs using individual patient data and do not require population-based assumptions. By incorporating index in the algorithm, PML risk can be further stratified for anti-JCV antibody positive patients without prior IS use. In the prior algorithm, the largest numeric increase in PML risk occurred after >2 years of treatment; with increased precision using clinical trial data, the largest increase is observed after >3 years.
Disclosure:
Supported by Biogen
Harold Koendgen: employee of and may hold stock and/or stock options in Biogen.
Ih Chang: employee of and may hold stock and/or stock options in Biogen.
Bjoern Sperling: employee of and may hold stock and/or stock options in Biogen.
Gary Bloomgren: employee of and may hold stock and/or stock options in Biogen.
Bill Haddock: employee of and may hold stock and/or stock options in Biogen.
Sandra Richman: employee of and may hold stock and/or stock options in Biogen.
Pei-Ran Ho: employee of and may hold stock and/or stock options in Biogen.
Nolan Campbell: employee of and may hold stock and/or stock options in Biogen.