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To: Art Bechhoefer who wrote (52148)	8/5/2025 4:09:49 PM
From: Ian@SI	Read Replies (1) \| Respond to of 52153

Art, I’ve updated my data as it was a month or two old. I had misunderstood the 98 number of failures. I suspect that Gemini‘s response below is only covering the data up until 2022. I’m too lazy to look at the detailed references that came with that response. :-). Ian Based on a comprehensive review of clinical trials for Alzheimer's disease, the figure of 98 failures, specifically for Phase II and III trials targeting amyloid-beta and tau, has been cited in a significant scientific review article published in 2022. This number, which included both Phase II and III trials, reflected the state of research up to that point. These failures, often resulting from futility analyses, underscore the immense challenge of developing effective treatments for Alzheimer's disease. A futility analysis is a statistical check during a trial to see if it's likely to succeed. If the chance of success is too low, the trial is stopped early. The key takeaways from these numerous failures are: * High Failure Rate: The vast majority of trials, particularly those focused on the amyloid-beta and tau hypotheses, have not yielded a successful drug. * Futility as a Major Cause: A large number of these trials were terminated early based on futility analyses, indicating that the drugs were unlikely to show a meaningful benefit to patients. * Re-evaluation of the Hypotheses: The consistent failures have led researchers to question the long-standing amyloid and tau hypotheses as the sole drivers of the disease, prompting a shift toward exploring other therapeutic targets and more complex disease mechanisms. It's important to note that the exact number can fluctuate as new trials begin, fail, or succeed. However, the number 98 represents a key milestone in the history of Alzheimer's research and highlights the monumental challenges that the field has faced.

To: Art Bechhoefer who wrote (52148)	8/5/2025 4:41:55 PM
From: Ian@SI	Read Replies (1) \| Respond to of 52153

Here’s a quick response from Gemini to my first question on Tau tangle research. Attempts to develop drugs targeting tau tangles have been a significant part of Alzheimer's research, especially as the failures of amyloid-targeting drugs became more apparent. However, the path has been similarly challenging. Attempts that have made it to Phase 2 or Phase 3: * LMTM (Hydromethylthionine mesylate): This tau aggregation inhibitor developed by TauRx reached Phase 3 trials. * Gosuranemab (BIIB092): A monoclonal antibody designed to clear tau from the brain, it advanced to Phase 2 trials. * *Tilavonemab (ABBV-8E12): Another monoclonal antibody targeting tau, which also reached Phase 2 trials. Semorinemab (RO7109575): This antibody from Genentech and AC Immune made it to Phase 2. * Tideglusib: A GSK-3ß inhibitor, which is an enzyme involved in tau phosphorylation, that went into Phase 2 trials. * ACI-35: A vaccine targeting phosphorylated tau, which has been in Phase 2 trials. It is difficult to provide a precise, up-to-the-minute number for all tau-specific trials as new studies are constantly being registered, initiated, or terminated. However, based on available data from scientific reviews and clinical trial registries, a number of tau-targeting drugs have reached late-stage development. Failures between Phase 1 and Phase 3 The number of failed trials is substantial. A significant portion of the tau-targeting drugs that reached Phase 2 or 3 have ultimately failed to demonstrate clinical efficacy. * Gosuranemab: Was terminated after a Phase 2 trial failed to show a benefit in slowing cognitive decline. * Semorinemab: A Phase 2 trial for this drug failed to meet its primary efficacy endpoint. * Tilavonemab: A Phase 2 trial for this drug was also stopped due to futility. * LMTM: The Phase 3 trials for this drug failed to meet their primary endpoints. * Tideglusib: Clinical trials were terminated after it failed to show a significant benefit. These examples represent some of the most notable failures, but they are not exhaustive. Many other tau-related compounds, including various aggregation inhibitors, microtubule stabilizers, and other antibodies, have also been discontinued in earlier phases (Phase 1 or 2) due to a lack of efficacy, safety concerns, or futility. The experience with tau-targeting drugs is mirroring the amyloid story, where many promising candidates in preclinical studies have not translated into successful treatments for patients.