A peek into the pipeline: Expert views on emerging therapies

Abstract

Alzheimer's disease (AD) trials: A field in (r)evolution AD remains a major societal challenge, but more than a century of research is gradually leading to an exciting (r)evolution in AD and other tauopathy trials. Initially, amyloid-beta-targeting trials faced significant failures, but recent successes with lecanemab (Clarity AD) and donanemab (TRAILBLAZER-ALZ 2) demonstrated substantial amyloid clearance and significant clinical benefits. These breakthroughs marked the first disease-modifying effects in AD trials, leading to FDA approval (Leqembi in 2023; Kisunla in 2024). While available in the US, China, and Japan, Europe has yet to approve them. Acknowledging the need for more effective disease-modifying therapies, research is including tau-targeting treatments. First-generation tau immunotherapies failed to meet primary endpoints, but next-generation approaches may show promise (CTAD 2024). Bepranemab (TOGETHER, MTBR-tau immunotherapy) significantly slowed tau pathology progression, as measured by PET, for the first time (Alzforum). While the primary endpoint (CDR-SB) was not met, subtle cognitive improvements (ADAS-cog-14) were observed in predefined subgroups with low tau and non-ApoE4 carriers. Antisense oligonucleotide therapy (e.g., BIIB080, NIO752) is also emerging as a promising tau-targeting strategy for slowing tau pathology and symptom progression. This (r)evolution in tau therapies and their outcomes provides a foundation for developing next-generation, more effective tau therapies, possibly in combination with anti-amyloid treatments. Beyond amyloid and tau, new targets, like inflammation, ApoE, and TREM2, are under investigation. Biomarker research has (r)evolved from amyloid-/tau-CSF to amyloid-/tau-PET and recently to blood-based biomarkers. Clinical trial designs have also transformed, accelerating the development of disease-modifying treatments. These advances provide a solid foundation for developing more-effective therapies. The cardiorenal benefits of glucagon-like peptide 1 (GLP-1) medicines Initially developed as glucose-lowering medicines for type 2 diabetes (T2D), GLP-1 therapies were subsequently approved for weight loss over a decade ago. The requirement for cardiovascular safety trials for T2D therapies ushered in a new evidence based era for GLP-1 medicines, demonstrating a reduction in myocardial infarction, stroke, cardiovascular death, and all-cause mortality in people with T2D treated with long-acting GLP-1 medicines. More recently, the cardiorenal benefits of semaglutide were extended to encompass a 24% reduction in rates of progression to chronic kidney disease and cardiovascular death in the FLOW trial, a dedicated renal outcomes trial studying semaglutide 1 mg once weekly in people with T2D. Equally exciting are the results of the SELECT trial studying the safety of semaglutide 2.4 mg once weekly in subjects with overweight or obesity and a history of atheroscleoritc cardiovascular disease. Semaglutide reduced the rate of the composite primary outcome, myocardial infarction, stroke, and cardio-vascular death, by 20%, associated with a 19% reduction in all cause mortality. Notably, scrutiny of adverse events across the FLOW and SELECT trials revealed a favorable benefit-risk profile of semaglutide therapy, without evidence for new concerning adverse events. These two landmark trials continue a promising shift away from a historical glucose-or weight loss-centric focus in the treatment of T2D and obesity, respectively, further emphasizing the substantial benefits of GLP-1 medicines in reducing serious cardiorenal complications, morbity, and mortality in people living with T2D and/or obesity.