Contributions
Abstract: P926
Type: Poster Sessions
Abstract Category: Therapy - Risk management for disease modifying treatments
Introduction: There is strong enthusiasm for applying precision medicine (such as genetic markers) in selecting disease modifying therapies (DMTs) in multiple sclerosis (MS). However, clinicians remain in the dark about the possible effects of sex/gender, which play a well established role in MS risk and course, on DMT efficacy and toxicity, and about optimal sex-specific therapeutic approaches.
Objective: To systematically evaluate the DMT pivotal trials in their reporting on sex differences in DMT efficacy and safety.
Methods: We reviewed published analyses from all Phase III pivotal trials for FDA or EMA-approved MS DMTs, and additional relevant information requested from medical scientific liaisons for all pharmaceutical companies that sponsored these studies. We evaluated results based on the following criteria (1) availability of pre-specified or post-hoc sex-related analyses; (2) evaluation of sex differences in (a) baseline disease characteristics and (b) MS course during the trial; (3) stratification of efficacy and safety outcomes by sex; and (4) other sex-specific concerns.
Results: Twenty-eight Phase III randomized controlled clinical trials were evaluated. Participants were 65-78% female in relapsing MS trials, and 50% in progressive trials. No trial reported comparisons of baseline clinical characteristics, adverse events or safety. One reported sex differences in disease trajectory. More recent trials reported stratification of treatment efficacy by sex. None reported on efficacy or safety during specific hormonal windows (postpartum period with higher risk of MS activity, post-menopausal stage with higher risk of MS progression).
For illustration purposes, its 2017 FDA label reported no efficacy for ocrelizumab vs. placebo in women with progressive MS, but a possible increased risk of breast cancer. Without a report of sex differences in baseline or longitudinal clinical features, a clinician is unable to evaluate whether the stratified analyses reflect a true sex difference in efficacy, or whether the study was underpowered to evaluate DMT effects on progression in the slower-progressing sex.
Conclusions: Sex/gender is a concrete factor affecting clinical course, yet its possible effects are incompletely evaluated to date in clinical trials. Adequately powered, pre-specified analyses accounting for sex differences in clinical course are required to maximize safety and efficacy in specific patient populations.
Disclosure: RB has received research support from Akili Interactive; and has received personal compensation for medical legal consulting and for serving on the advisory boards of Roche-Genentech, Genzyme-Sanofi and Novartis.
MH has served as a consultant for Biogen, Genzyme, Serono, Teva, Genentech. She received research support from Genzyme, Biogen and Teva.
Abstract: P926
Type: Poster Sessions
Abstract Category: Therapy - Risk management for disease modifying treatments
Introduction: There is strong enthusiasm for applying precision medicine (such as genetic markers) in selecting disease modifying therapies (DMTs) in multiple sclerosis (MS). However, clinicians remain in the dark about the possible effects of sex/gender, which play a well established role in MS risk and course, on DMT efficacy and toxicity, and about optimal sex-specific therapeutic approaches.
Objective: To systematically evaluate the DMT pivotal trials in their reporting on sex differences in DMT efficacy and safety.
Methods: We reviewed published analyses from all Phase III pivotal trials for FDA or EMA-approved MS DMTs, and additional relevant information requested from medical scientific liaisons for all pharmaceutical companies that sponsored these studies. We evaluated results based on the following criteria (1) availability of pre-specified or post-hoc sex-related analyses; (2) evaluation of sex differences in (a) baseline disease characteristics and (b) MS course during the trial; (3) stratification of efficacy and safety outcomes by sex; and (4) other sex-specific concerns.
Results: Twenty-eight Phase III randomized controlled clinical trials were evaluated. Participants were 65-78% female in relapsing MS trials, and 50% in progressive trials. No trial reported comparisons of baseline clinical characteristics, adverse events or safety. One reported sex differences in disease trajectory. More recent trials reported stratification of treatment efficacy by sex. None reported on efficacy or safety during specific hormonal windows (postpartum period with higher risk of MS activity, post-menopausal stage with higher risk of MS progression).
For illustration purposes, its 2017 FDA label reported no efficacy for ocrelizumab vs. placebo in women with progressive MS, but a possible increased risk of breast cancer. Without a report of sex differences in baseline or longitudinal clinical features, a clinician is unable to evaluate whether the stratified analyses reflect a true sex difference in efficacy, or whether the study was underpowered to evaluate DMT effects on progression in the slower-progressing sex.
Conclusions: Sex/gender is a concrete factor affecting clinical course, yet its possible effects are incompletely evaluated to date in clinical trials. Adequately powered, pre-specified analyses accounting for sex differences in clinical course are required to maximize safety and efficacy in specific patient populations.
Disclosure: RB has received research support from Akili Interactive; and has received personal compensation for medical legal consulting and for serving on the advisory boards of Roche-Genentech, Genzyme-Sanofi and Novartis.
MH has served as a consultant for Biogen, Genzyme, Serono, Teva, Genentech. She received research support from Genzyme, Biogen and Teva.