Endurance Bio ready for Phase 2 trials of drug targeting ‘master regulator’ of cell energy metabolism.
Last year, a study published in the European Journal of Pharmacology highlighted the potential of targeting a protein called PGC-1α as an “effective strategy for the treatment of neurological disorders.” PGC-1α, a so-called “transcriptional coactivator,” meaning it helps activate gene transcription, is increasingly recognized as playing a central role in pathways that deteriorate with age.
Building on research that started at Stanford University, a new biotech focused on neurodegeneration and aging believes PGC-1α could prove to be one of the most important targets in age-related disease biology. Endurance Bio, which recently launched as a management buyout of Palo Alto biotech Tranquis Therapeutics, is advancing a therapeutic strategy based around restoring mitochondrial and lysosomal health through upregulation of the protein, described by the company as a “master regulator” of cellular metabolism and mitochondrial biogenesis.
Initially focused on neurodegeneration, the company is already gearing up for Phase 2 trials of its lead program in Parkinson’s disease. With Endurance’s founders claiming the approach has shown promise in animal studies of neurodegeneration, metabolic disorders, muscle degeneration and frailty, it’s clear that PGC-1α is a target with significant longevity potential.
Longevity.Technology: It’s easy to see why the longevity field is getting excited about PGC-1α. A wealth of research has indicated the protein’s role in everything from mitochondrial function and autophagy, to whole-body metabolic fitness – all key factors when it comes to addressing age-related decline. While Endurance Bio is initially pursuing neurodegenerative diseases, the company sees PGC-1α less as a disease-specific target and more as a “metabolic integrator” whose modulation could, in principle, impact multiple age-related diseases. To learn more, we sat down with Endurance’s Frederic Godderis, who founded the company alongside former Tranquis execs Sanjay Kakkar, Enchi Liu and Andrew Lam.
Endurance Bio builds on discoveries made in the Stanford lab of Dr Edgar Engleman, a world-renowned expert in immunology, whose research has led to significant breakthroughs in oncology and neuroscience. Engleman confirmed metabolic reprogramming of microglia could reverse neurotoxicity and inflammation in neurodegeneration.
“We know dysfunctional microglia are key contributors to disease progression in neurodegenerative diseases – they throw fuel on the fire instead of acting as fire extinguishers in the brains of patients with neurodegeneration,” explains Godderis. “Dr Engleman found that by upregulating PGC-1α with our small molecule T-168, he could shift cellular metabolism from dysfunctional glycolysis toward oxidative phosphorylation, essentially restoring cells from an inflamed, dysfunctional state to their normal, homeostatic one.”
Restoring power and waste management
Investigators at the Kyoto Prefectural University of Medicine in Japan also observed T-168 downstream activation of key regulators of lysosomal biogenesis and acidification, hinting at a dual mechanism that could simultaneously address mitochondrial dysfunction and defective cellular waste clearance.
“If you think about it in simple terms, restoring PGC-1α levels within cells is like restoring the power grid, activating emergency response services and organizing the waste management system of a city after a natural disaster – mitochondrial energy and cellular cleanup working together to restore health,” says Godderis.
Engleman’s research into PGC-1a upregulation continued through multiple studies across a variety of animal models, exploring its potential in ALS, Parkinson’s, and other conditions.
“Across all studies, we saw consistent outcomes: improved survival, better motor and cognitive function, reduced neurotoxicity, reduced oxidative stress and reduced inflammation,” says Godderis. “We’re now building on these significant scientific breakthroughs and bringing them over the finish line by testing them as potential new medicines.”
For Endurance, this means generating human clinical data that validate Engleman’s discoveries, and to show that the approach can provide disease-modifying benefits to patients with neurodegenerative and other aging-related diseases.
“What’s interesting is how our understanding has evolved since the early days,” says Godderis. “Initially we focused on microglia, but now we see effects in other cell types as well – improved cell energy metabolism, cleanup of misfolded proteins, and broader cellular impacts. We’re only scratching the surface.”
Initial focus on Parkinson’s
While Tranquis had initially focused on ALS, the Endurance team decided to shift strategy to Parkinson’s as its first clinical indication after being selected to participate in a Phase 2 platform trial organized by Professor Charalampos Tzoulis, an expert in Parkinson’s and mitochondrial biology at the Neuro-SysMed Centre of the University of Bergen.
“They invited us to participate after reviewing our data, which drove our pivot toward Parkinson’s disease as the first indication,” explains Godderis. “The biomarker-rich data from that trial will de-risk development not only in Parkinson’s disease but will also help us accelerate development in ALS, which remains a very high priority for us, and other neurodegenerative diseases. And it’s important to note that we’re not talking about just one product. Our second molecule is already in IND enabling studies and we have a library of analogues and derivatives ready for further exploration.”
Godderis suggests that the company’s approach could potentially work synergistically with other treatments, including antibody therapies.
“We believe combination therapies will ultimately deliver the best outcomes for patients with neurodegenerative diseases,” he says. “These are multi-faceted and complex diseases that can’t be solved with a single silver bullet. We look forward to exploring this with pharma and biotech partners.”
Longevity in its sights
Ultimately, Endurance’s vision extends beyond neurodegeneration, and Godderis says the company can be considered as a “longevity play”.
“If you look at the mechanism – the mitochondrial component, the lysosomal component – it hits several hallmarks of aging,” he says. “We have substantial data suggesting the mechanism could be useful not only in neurodegeneration but also in aging-related conditions like sarcopenia, type 2 diabetes and other diseases.”
The company claims to have observed “significant and meaningful effects” in type 2 diabetes and weight-loss, having observed reduction of fat mass combined with reduced frailty, increased muscle strength, and improved endurance in normal aging mice.
“So our data strongly suggest we’re talking about something much broader than neurodegeneration, but the need is so high in neurodegenerative diseases that this is absolutely our initial focus,” says Godderis. “We’re not a well-known company and flying under the radar right now, but this is real transformational science, we’re working on a real product, and a well-designed clinical trial addressing a huge unmet need in Parkinson’s disease.”
“To our knowledge, we’re the only ones with a clinical Phase 2-ready molecule targeting PGC-1α. Big pharma recognizes it as a target of interest, but we’re a small company – we won’t change the paradigm by talking about it; we’ll change it by showing clinical data.”
Endurance is currently exploring a range of partnership and funding opportunities as it seeks to continue its clinical development and expand its pipeline.
