After years of clinical setbacks and deprioritization in neuro drug development, could targeting the brain’s immune system as a new therapeutic hypothesis spark the next wave of FDA approvals?
Good piece here! Fully agree with the reversal issue vs. slow progression of neurodegeneration.
A key challenge seems to be when to target the glial cells too. Too early/ too late? TREM2 is a good example; too much agonism shuts down downstream signaling (desensitization).
Not to mention, which biomarkers to think about for neuroinflammation or how to consider (or if?) oligodendrocytes.
See recent papers & reviews from Li Huei Tsai et. al for impact of oligos.
Super insightful. I really appreciate the point you're making about accessible/known PD biomarkers from I&I. Sure, it's unlikely that these biomarkers serve as efficacy or disease modification markers, and those will continue to be difficult to identify in diseases like AD&PD. But given the uncertain dynamics of brain delivery (at tissue & cell level), having strong confidence PK:PD understanding == better science.
Great piece! as a former neuroscientist, a lot of this resonates. There is a mounting body of evidence that neurodegeneration is a symptom of over-active immune cells in the brain.
I wonder in your research for this piece if you came across any evidence in sex differences in prevalence or pathology for neurodegenerative disease. It is well-characterized now that auto-immune condition prevalence in women is far higher than in men; some clinical trials for IBD, for example, enroll on the order of 80% women. If AD was re-classified to something that "looked" more auto-immune for example, would it follow then that we expect more women to suffer from it or that disease progression in female patients is more rapid or carries any hallmarks of other auto-immune disorders? Curious if you found any evidence of anything like this at the macro-level, or even if any of the immune targets listed demonstrate any sex-specific bifurcation in function or expression.
A valuable piece. Also worth mentioning the forthcoming readout in AD of Semaglutide (Novo) as well as the potential utility of the GLP-1 class in various addiction disorders. One minor point; although it’s true that the cost and time to run a P3 trial for Disease Modification in either PD of AD is significant (thereby limiting entrants), the timelines are quite different in depression and schizophrenia (mostly small molecule approaches).
Good piece here! Fully agree with the reversal issue vs. slow progression of neurodegeneration.
A key challenge seems to be when to target the glial cells too. Too early/ too late? TREM2 is a good example; too much agonism shuts down downstream signaling (desensitization).
Not to mention, which biomarkers to think about for neuroinflammation or how to consider (or if?) oligodendrocytes.
See recent papers & reviews from Li Huei Tsai et. al for impact of oligos.
Super insightful. I really appreciate the point you're making about accessible/known PD biomarkers from I&I. Sure, it's unlikely that these biomarkers serve as efficacy or disease modification markers, and those will continue to be difficult to identify in diseases like AD&PD. But given the uncertain dynamics of brain delivery (at tissue & cell level), having strong confidence PK:PD understanding == better science.
Great piece! as a former neuroscientist, a lot of this resonates. There is a mounting body of evidence that neurodegeneration is a symptom of over-active immune cells in the brain.
I wonder in your research for this piece if you came across any evidence in sex differences in prevalence or pathology for neurodegenerative disease. It is well-characterized now that auto-immune condition prevalence in women is far higher than in men; some clinical trials for IBD, for example, enroll on the order of 80% women. If AD was re-classified to something that "looked" more auto-immune for example, would it follow then that we expect more women to suffer from it or that disease progression in female patients is more rapid or carries any hallmarks of other auto-immune disorders? Curious if you found any evidence of anything like this at the macro-level, or even if any of the immune targets listed demonstrate any sex-specific bifurcation in function or expression.
A valuable piece. Also worth mentioning the forthcoming readout in AD of Semaglutide (Novo) as well as the potential utility of the GLP-1 class in various addiction disorders. One minor point; although it’s true that the cost and time to run a P3 trial for Disease Modification in either PD of AD is significant (thereby limiting entrants), the timelines are quite different in depression and schizophrenia (mostly small molecule approaches).