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  Protecting Sponsor Capital, Managing Risk, and Maximizing Probability of Success Denis Katz, MD, MHA Clinical Scientist & Development Strategist Founder, Salience Clinical, LLC Executive Summary Alzheimer’s disease (AD) drug development remains the most capital-intensive and failure-prone domain in biopharma. The so-called “Alzheimer’s graveyard” reflects decades of scientific promise undermined by regulatory, operational, and strategic misalignment. Yet the landscape is shifting. The emergence of amyloid- and tau-targeting therapies has demonstrated that regulatory approval is achievable but only when supported by disciplined development architecture. Success in 2026 is defined by translational clarity : the ability to demonstrate that biological modification leads to measurable and meaningful functional benefit in patients. The Success Gap 99.6% historical failure rate (2002–2012) 18-year gap between novel disease-modifying approvals (2003–2021) $300M+ average s...

  By Denis Katz, MD, MHA Founder, Salience Clinical For decades, psychiatry has framed major depressive disorder (MDD) as a disorder of neurochemistry—an imbalance of serotonin, norepinephrine, or dopamine. This paradigm has delivered meaningful therapeutic advances. Yet it has not consistently achieved durable remission for a substantial proportion of patients. Approximately one-third remain treatment-resistant, and relapse among responders is common. Incremental modulation of synaptic signaling appears to be approaching a ceiling in its capacity to transform long-term outcomes at scale. The next shift in neuropsychiatry will not be chemical. It will be architectural. By “architectural,” we refer to the topology, coupling, and dynamic switching behavior of large-scale brain networks that govern how information is processed and regulated. From Neurotransmitters to Networks Advances in high-resolution functional MRI, multimodal imaging, and computational modeling have fundamentall...

  Protecting Sponsor Capital, Managing Risk, and Maximizing Probability of Success Denis Katz, MD, MHA Clinical Scientist & Development Strategist Founder, Salience Clinical, LLC Executive Summary Alzheimer’s disease (AD) drug development remains the highest-stakes arena in biopharma. While the "Alzheimer’s Graveyard" is littered with multi-billion dollar failures, a new era of amyloid and tau-targeting therapies has proven that the regulatory path is navigable—but only for those with a disciplined risk architecture. Success in 2026 is driven by Translational Clarity : the ability to prove that biological changes translate into human functional benefit. The Success Gap ●        99.6%: Historical failure rate (2002–2012). ●        18 Years: The approval drought between novel disease-modifying therapies (2003–2021). ●        $300M+: The average sunk R&D cost of...