Vandria reports VNA-318’s first-in-human data in Alzheimer’s

Vandria has taken a step forward in its bid to bring a new kind of Alzheimer’s treatment into the clinic. The Lausanne-based company shared first-in-human data for its lead candidate VNA-318 ahead of its presentation at the Clinical Trials on Alzheimer’s Disease (CTAD) meeting, positioning the small molecule as part of a growing interest in targeting mitochondrial health in neurodegenerative disease.

While most Alzheimer’s drug development still centers on amyloid and tau, relatively few programmes have advanced into the clinic with a focus on mitophagy or broader mitochondrial pathways. Vandria’s early results suggest the company’s approach is behaving in humans as it did in preclinical models, adding momentum to the idea that restoring cellular energy balance could complement existing Alzheimer’s disease (AD) strategies.

Vandria’s VNA-318: what the drug does

VNA-318 is designed to shift how cells produce energy. The compound temporarily slows down glycolysis, the process by which cells break down glucose, creating a short-lived energetic signal that pushes them to rely more heavily on mitochondrial oxidative phosphorylation instead.

“Inhibition of the target results in a temporary reduction in glycolysis, leading to transient energetic stress. This prompts cells that are capable of shifting toward the more efficient energy production pathway of mitochondrial oxidative phosphorylation,” explained Vandria’s chief executive officer (CEO), Klaus Dugi.

This shift is important because oxidative phosphorylation is tightly linked to mitophagy, the cellular mechanism that identifies and removes damaged mitochondria. Increased mitochondrial reliance signals the cell to clean out dysfunctional organelles and renew its energy-producing network. Research has shown that metabolic cues can directly regulate autophagy and mitophagy pathways, with energetic stress often serving as an upstream trigger for mitochondrial turnover.

According to Vandria, this metabolic switch has a second effect: reduced inflammation. Many pro-inflammatory or aged cells rely heavily on glycolysis, and lowering glycolytic activity can suppress inflammatory signalling.

“This metabolic switch not only induces mitophagy and autophagy, supporting cellular health, but also has a rejuvenating (senomorphic) and anti-inflammatory effect by reducing reliance on glycolysis,” said Dugi.

Vandria refers to this profile as “mitophagy-plus”, meaning the drug acts upstream of classical mitophagy pathways like PINK1/Parkin or USP30. The company argues this broader mechanism allows both mitochondrial cleanup and a direct anti-inflammatory component.

“Our mode of action is upstream of mitophagy and has a mitophagy-independent direct anti-inflammatory effect, through the reduction in glycolysis. In addition, mitophagy and subsequently improved mitochondrial respiration will have an additional anti-neuroinflammatory effect,” explained Vandria’s chief scientific officer (CSO), Penelope Andreux.

Why mitophagy matters in Alzheimer’s disease

Mitophagy is the quality-control system cells use to identify and remove damaged mitochondria. When this process breaks down, defective mitochondria accumulate, energy production falters, and reactive oxygen species and stress signals build up, all of which are increasingly seen as early features of neurodegenerative diseases, including Alzheimer’s.

Vandria leans heavily on this biology. “There is a large body of evidence linking impaired mitophagy to Alzheimer’s Disease. For instance, in a 2019 study, Evandro Fang et al. demonstrated that in patients suffering from AD, about 80% of mitochondria in the hippocampus were damaged, while in age-matched healthy control subjects, this value was only 20%,” noted Andreux. That work by Fang and colleagues showed that defective mitophagy in AD models leads to a buildup of damaged mitochondria, and that experimentally boosting mitophagy can reduce amyloid-beta and tau pathology and reverse cognitive deficits in animals.

More recent reviews reinforce the idea that mitophagy failure is intertwined with classical AD hallmarks. The broader hypothesis is that restoring mitochondrial quality and energy metabolism could make neurons more resilient, rather than only neutralizing one specific pathological protein.

Dugi doesn’t think one approach will necessarily prevail over the other in the treatment of Alzheimer’s disease. “I believe it is fair to say that most experts agree that treating AD patients will eventually be done via a combination of therapies with different modes of action. A compound such as VNA-318, after we have hopefully demonstrated it has efficacy as a monotherapy in patients with AD, could potentially become an ideal combination partner due to its unique mode of action, excellent tolerability, and once-daily oral dosing.”

Who else is working on mitophagy?

Mitophagy has emerged across multiple research groups and companies as a promising therapeutic lever for neurodegeneration, yet only a handful of efforts combine mitophagy activation with neurodegenerative-disease ambitions, and even fewer make an explicit push toward Alzheimer’s as a target. 

Indeed, beyond Vandria, most mitophagy work in Alzheimer’s remains academic, supported by a growing body of research linking impaired mitochondrial quality control to aging and neurodegeneration.

One often-cited example is urolithin A, a gut-metabolite-derived compound that stimulates mitophagy. Urolithin A has been tested in humans, primarily in aging and muscle-health contexts, where it showed safety and biomarkers of improved mitochondrial and cellular health. Yet while preclinical data in Alzheimer’s models show positive effects, reduced amyloid/tau and improved memory, the compound is not currently developed by a company with a declared Alzheimer’s clinical-trial programme.

Another active track involves inhibition of USP30, a deubiquitinase that negatively regulates the mitophagy machinery. Companies such as Mission Therapeutics have developed USP30 inhibitors, and recently published a review outlining how enhancing mitophagy could address a broad range of neurodegenerative diseases. Current clinical-stage programs are more clearly geared toward Parkinson’s and mitochondrial disorders.

Overall, while there is genuine scientific momentum behind mitophagy as a neuroprotective strategy, very few efforts have combined mitophagy-enhancing chemistry, brain penetration, and an explicit Alzheimer’s clinical-development plan.

That is where Vandria’s VNA‑318 emerges as novel, one of the rare small molecules designed for mitophagy-plus activity in the central nervous system (CNS), now advanced into first-in-human trials with Alzheimer’s disease in view.

One of the well-known challenges in CNS diseases is crossing the blood-brain barrier. “For compounds to pass the blood-brain barrier by passive diffusion, they need to exhibit a very high level of permeability, which is typically linked to lipophilicity/hydrophobicity. The latter, however, makes it very difficult to make the compounds sufficiently soluble to allow for oral dosing,” explained Dugi.

“VNA-318 does have very high permeability but rather poor solubility. Luckily, this is a known problem in pharmaceutical development, and solutions exist to improve the solubility and absorption of such compounds. We are working with leading experts in the field,” Dugi added.

Mitophagy remains niche and relatively unadvanced in Alzheimer’s disease, but it represents a promising direction in a field that needs new ideas. Whether metabolic reprogramming can deliver clinical benefit will now depend on phase 2, but Vandria’s early results suggest the concept is finally moving from academic interest into real therapeutic experimentation.