"If we were to treat patients for a longer period of time than we've been able to treat them so far, we'd begin to see these disease-modifying effects in biomarkers and in clinical outcomes."
Dr. Gabriel Vargas has watched the field chase amyloid for 30 years. He was part of it — at Roche in 2008, he worked on crenezumab, one of the early anti-amyloid monoclonal antibodies, convinced that earlier intervention would finally make the hypothesis work. What he's seen since has changed his view.
The biomarker data on lecanemab and donanemab is impressive — plaques come down dramatically. The cognitive data isn't. The minimally clinically important difference on the CDR sum of boxes is 0.5 to 1 point. The approved drugs are producing about 0.45 — below the threshold, and in some analyses, less effective than Aricept, a cholinesterase inhibitor developed three decades ago.
His conclusion: the field is removing plaques. It is not modifying disease.
At CuraSen, he's betting on a different mechanism entirely: the adrenergic system. And he thinks it may be both faster to show symptomatic benefit and — if the trials run long enough — capable of something the amyloid drugs haven't yet delivered: genuine disease modification.
The Adrenergic System: An Overlooked Lever
The adrenergic system drives the fight-or-flight response — it's one of the most fundamental physiological systems in the body. But its role in neurodegeneration has been largely overlooked in favor of amyloid and dopamine pathways.
The connection runs deep. James McGaugh's research at UC Irvine, spanning four decades, established that the adrenergic system is central to memory formation and valence — the process by which the brain tags certain memories as important and worth retaining. Noradrenaline release improves attention, mood, and apathy. And the adrenergic system has meaningful effects on neuroinflammation and autophagy — processes directly relevant to long-term disease modification.
CuraSen's core strategy: target beta-2 adrenergic receptors in the brain to improve cognition, attention, and mood. The challenge is that a systemic oral beta-2 agonist produces cardiovascular side effects — heart rate increases, palpitations, tremor, electrolyte shifts — that would limit dose. Their solution: co-dose the beta-2 agonist (clenbuterol) with nadolol, a peripherally restricted beta-blocker that doesn't cross the blood-brain barrier. Nadolol neutralizes all peripheral effects, leaving brain-selective beta-2 agonism intact.
Why Direct Agonism Changes the Game
Most existing neuropsychiatric drugs — SSRIs, noradrenergic reuptake inhibitors, cholinesterase inhibitors — are indirect agonists. Their mechanism depends on endogenous levels of the neurotransmitter they're targeting. If you don't have serotonin available, a reuptake inhibitor does nothing. If acetylcholine is already severely depleted, as it is in advanced Alzheimer's, donepezil's ceiling is low.
CuraSen's approach is direct agonism — bypassing endogenous neurotransmitter levels entirely and acting directly on the downstream postsynaptic receptor. This matters most in severe neurodegenerative states where neurotransmitter systems are already substantially depleted. The mechanism still works.
The phase 2 data supports this. In signal-seeking studies at the Center for Human Drug Research in Leiden — one of the premier early-phase human drug research centers globally — oral beta-2 agonists increased the number of words subjects recalled in a standard word list test versus placebo. Pindolol, a beta-1 agonist and beta-2 blocker with opposite pharmacology, produced the opposite effect: impaired recall. Mechanistically clean.
Arterial spin labeling MRI showed that all tested beta-2 agonists, including CuraSen's novel chemical entity, increased cerebral blood flow. The correlation between improved cerebral blood flow and better cognition — and between declining cerebral blood flow and neurodegenerative disease — is well established.
The Amyloid Paradox
Dr. Vargas doesn't dismiss the amyloid hypothesis entirely. The genetic grounding is real for early-onset familial Alzheimer's. But familial Alzheimer's is under 10% of cases. The other 90% is late-onset sporadic disease, and 30+ years of trials in that population have not delivered cognitive benefit proportionate to plaque removal.
Lecanemab and donanemab are extraordinarily effective at removing amyloid plaques. The biomarker story is compelling. But the cognitive improvement at 18 months sits below the minimally clinically important difference. The field is calling it disease modification. Dr. Vargas doesn't believe it yet.
What he does believe: with a mechanism that produces fast symptomatic benefit and has a credible long-term disease-modification hypothesis through neuroinflammation and autophagy pathways, you can demonstrate value much earlier in the trial timeline — and potentially show what anti-amyloid drugs haven't shown yet.
From Signal-Seeking Studies to Phase 2 Data
In Parkinson's patients with cognitive impairment and mild depression, CuraSen used the facial expression recognition test (FERT) — a validated measure developed at Oxford by Catherine Harmer — to capture antidepressant signal. Depressed patients recognize happy faces at about 40% accuracy; non-depressed individuals at ~70%. After medication, scores returned to essentially normal. It's a fast, clean signal that predicts antidepressant response weeks before MADRS scores would move — making it ideal for early-phase trial design.
In a separate trial using their novel chemical entity CST-2032 paired with nadolol, the digit symbol substitution task — a highly sensitive cognitive endpoint capturing executive function, working memory, processing speed, and complex attention — showed positive effects.
Taken together: fast cognitive signal, antidepressant signal, mechanistic brain imaging confirmation, and a disease-modification hypothesis supported by the biology. The question, as Dr. Vargas frames it, is whether the trials run long enough to show what he believes the drug will demonstrate.
What You'll Learn
- How translational medicine bridges preclinical science and first-in-human trials — and why it's essential for determining real-world therapeutic viability
- Why the adrenergic system may unlock both symptomatic improvement and long-term disease-modifying potential for neurodegenerative disorders
- How pairing beta-2 agonists with peripherally restricted beta-blockers enables brain-selective targeting while eliminating systemic side effects
- Why direct agonist therapies may succeed where SSRIs and amyloid-focused drugs fall short — especially in severe neurodegenerative states where endogenous neurotransmitters are already depleted
- The clinical difference between symptomatic relief and true disease modification — and why the amyloid hypothesis hasn't delivered after 30+ years of trials
- How PTRS (Probability of Technical & Regulatory Success) guides strategic decisions, regulatory alignment, and investment in new drug development
- Why the facial expression recognition test is a better early-phase biomarker for antidepressant response than waiting for MADRS results
Episode Highlights
- [00:41] Intro: From Academic Science to Industry Drug Development
- [06:55] Translational Medicine: Bridging Preclinical Discovery to First-in-Human Trials
- [10:03] Understanding the Adrenergic System and Its Role in Brain Health
- [15:27] Strategic Drug Design: Coupling Beta-2 Agonists with Peripheral Beta-Blockers
- [19:23] Direct Agonism: Why It Works When Neurotransmitters Are Depleted
- [23:33] Disease Modification vs. Symptomatic Treatment: The Amyloid Therapy Paradox
- [33:28] PTRS Framework: Balancing Medical Need with Regulatory Success
- [39:09] Pharmacokinetics and Patient Adherence: Daily Dosing Requirements
- [43:14] Psychedelics, Non-Hallucinogenic Neuroplastogens, and Digital Biomarkers
- [48:30] Digital Health Technologies as Clinical Trial Endpoints
- [48:59] Career Defining Moments: From Erenumab to Impacting Millions of Patients
- [52:41] Closing Thoughts: Neurogenic Orthostatic Hypotension and Future Research
