Gender-based approach to MS therapeutics: a missed opportunity

Most pivotal disease-modifying treatment (DMT) trials miss an opportunity to evaluate and understand sex differences. There seem to be unexplored sources of bias in observational and interventional studies. Greater attention is warranted to evaluate sex-specific experiences, especially regarding safety and side effects. This was argued by Dr Riley Bove (Weil Institute for the Neurosciences, USA) in an invited lecture [1].

The female:male ratio is about 3:1 in MS. Overall, men and women tend to reach disability milestones at a similar age, despite numerous differences in the disease course. For example, men tend to be older at diagnosis, have more often a progressive onset of MS, have a lower relapse rate (with a greater proportion of motor relapses), and experience more rapid disability progression in relapsing-onset MS. In women, the risk of developing adverse health outcomes is nearly doubled compared with men. After menopause, women may experience increased disability progression, but also less inflammatory activity. Many gaps in scientific knowledge surround postmenopausal women, including the unknown effectiveness of hormone supplementation in stabilising symptoms or even offering neuroprotection.

Drug volume of distribution, metabolism, and elimination are likely to be influenced by sex differences in anatomy, body composition, and physiology. Despite known differences, most drugs have had no sex-specific dosage recommendations in their labels.

In the major clinical trials, evaluation of sex differences in enrolment characteristics, DMT efficacy, and/or side effects are incomplete. Dr Bove described in detail a study she recently published, reporting sex differences in a total of 29 clinical MS trials of DMT [2]. She found that:

• 0 of 29 trials reported baseline comparison of demographic or clinical characteristics according to sex;
• 10 of 29 trials reported a pre-planned analysis of efficacy based on sex (but without evaluating baseline sex differences);
• 0 of 29 trials performed a pre-planned analysis of major adverse events based on sex;
• 8 of 29 trials published post-hoc comparisons of sex differences in efficacy and safety outcomes; and
• 0 of 29 trials commented on statistical power to report sex differences.

Dr Bove also stressed that adjusting for sex differences is not the same as evaluating and understanding these differences. She would recommend at a minimum the following steps for reporting sex differences in future trials:

• giving attention to statistical power and pharmacokinetics/pharmacodynamics;
• harmonisation of baseline characteristics;
• evaluation of efficacy and safety; and
• consideration of sex-specific experiences or risks.

Ethical concerns complicate proper research in the area of pregnancy and lactation, but it could also be argued that it is the status quo which is “unethical”. An example of an ethical approach in research is to evaluate transfer of DMT into breast milk without exposing the infant. Obviously, DMT selection in women of childbearing potential is very important, including the issue of whether and when to discontinue a DMT, and how to avoid rebound risk. Dr Bove added that there is mounting evidence that B cell-depleting agents support disease control surrounding pregnancy, as B cell depletion can extend well beyond drug elimination.

1. Bove R. Gender Based Approach to MS Therapeutics. MSVirtual 2020, Abstract PS12.01.
2. Houtchens MK & Bove R. Front Neuroendocrinol. 2018;50:123-34.

 



Posted on 25 November 202019 November 2021