In the Lab
Beyond dealmaking, a dive into the science
For decades, the fight against neurodegenerative diseases like Alzheimer’s, Parkinson’s and Multiple Sclerosis was waged against pathologies visible under the microscope: the plaques and tangles in Alzheimer’s, the loss of dopamine-producing neurons in Parkinson’s, and the damaged myelin sheaths in Multiple Sclerosis.
Though traditionally viewed as a bystander, evidence suggests that chronic inflammation within the central nervous system (neuroinflammation) is a crucial driver of disease onset and progression. New therapeutics are increasingly targeting inflammation as a core pathology, which could change the narrative of neurogenerative disease moving forward.
The inflammatory cycle
Neuroinflammation involves the activation of the brain’s resident immune cells, microglia and astrocytes. While this response is protective in the short term against injury or infection, chronic activation becomes detrimental. In neurodegenerative diseases, factors like misfolded protein aggregates (amyloid-beta, tau, alpha-synuclein) trigger persistent immune activation. Activated microglia and astrocytes release a cascade of pro-inflammatory molecules, including cytokines like Tumor Necrosis Factor-alpha (TNF-α), Interleukin-1 beta (IL-1β), and Interleukin-6 (IL-6). These molecules, particularly TNF-α, perpetuate neuronal dysfunction, damage, and cell death, creating a vicious cycle where inflammation drives further neurodegeneration, which in turn fuels more inflammation.
Alzheimer’s Disease: Beyond plaques and tangles
While Alzheimer’s disease (AD) pathogenesis is not completely understood, there are patterns shared amongst all Alzheimer’s patients, which led to the treatments we have today. AD progresses in a loop. A protein called amyloid-beta, which normally plays a helpful role in memory and the brain’s immune defense, starts to build up and form sticky clumps, or plaques. These plaques interfere with how brain cells (neurons) communicate and can overstimulate them to the point of damage or death. Another protein called tau, which normally helps keep the structure inside neurons stable, becomes overactive and twists into tangles. These tangles block important transport systems in the cell and eventually cause the cells to die, a driver of memory loss. As damage builds, the brain’s immune cells—microglia—detect something is awry and release proteins to clean up the mess. Over time, their response becomes chronic and overactive, triggering long-lasting inflammation in the brain.
Traditional AD treatments focus on amyloid plaques and tau tangles. However, "despite recent approvals of lecananab and donanemab, their 30% slowing of cognition vs. placebo suggests that plaques and tangles are not the true drivers of Alzheimer’s," emphasized Cuong Do, president and CEO of Biovie.
The true driver? Inflammation. Inflammation activates signaling pathways like ERK and NF-κB, which lead to the release of TNF-alpha, the master regulator of inflammation. High levels of TNF-alpha cause insulin resistance in neurons and promote further cell death. This stress on brain cells leads to increased production of amyloid precursor protein (APP) and more amyloid beta. Inflammation accelerates AD. The cycle of inflammation creating plaques and tangles is seen as a central mechanism of AD, and it is shaping the direction of new treatments that aim to break the loop by targeting inflammation. Biovie’s Bezisterim targets neuroinflammation: “In a six-month trial, patients on Bezisterim experienced a 68% slowing of cognitive decline versus placebo,” demonstrated Do.
Aphios, another biotech, focuses on mitigating neuroinflammation in AD but using a different target. “In aging brains, the CCR5 gene becomes increasingly active, contributing significantly to inflammation that disrupts synaptic connectivity and accelerates cognitive decline,” explained Trevor Castor, founder, president and CEO of Aphios.
By repurposing Maraviroc, an HIV drug that blocks CCR5 by encapsulating it in nanoparticles designed to cross the blood-brain barrier, Aphios aims to reduce neuroinflammation and slow AD progression.
Multiple Sclerosis: long- term treatments
Inflammation is the cornerstone of Multiple Sclerosis (MS), a disorder where the immune system attacks the myelin sheath (protective outer coating) that insulates nerve fibers. This effectively ‘unwraps’ the outer coating of neurons and leads to progressive disability. Existing treatments primarily target the inflammatory relapses, but significant unmet needs remain in preventing long-term disability progression.
Immunic is developing Vidofludimus Calcium, an oral therapy currently in phase 3 trials for relapsing MS (RMS) and phase 2 for progressive MS (PMS). According to CEO Daniel Vitt, the drug possesses a unique dual mechanism: “It was initially developed as a DHODH inhibitor, which is excellent for treating inflammation and reducing brain lesions and relapses.”
The path forward
The growing understanding of neuroinflammation’s central role across diverse neurodegenerative diseases is paving the way for a new generation of therapies. By addressing inflammation – a common thread linking AD, MS and PD – these approaches hold the potential to move beyond symptom management and tackle the underlying drivers of neurodegeneration. As these therapies progress through clinical trials, the coming years will be critical in determining if targeting inflammation can truly change the trajectory for patients living with these devastating conditions.
Article header image courtesy of Dipharma