Stealth BioTherapeutics CSO says bioenergetic dysfunction lies at the center of the aging process.
In a landmark moment for biotech, the FDA last year granted accelerated approval to elamipretide, now marketed as Forzinity, to improve muscle strength in patients with a rare disease called Barth syndrome. The drug, developed by Stealth BioTherapeutics, became the first approved mitochondria-targeted therapeutic, marking a major milestone for the company, and for mitochondrial medicine more broadly.
Longevity watchers may wonder why all the excitement over a drug approval for a disease that only affects a few hundred people worldwide, however mitochondrial dysfunction is increasingly viewed as a fundamental driver of many common diseases, particular those related to aging. Stealth is now seeking to build on its momentum with a pipeline includes age-related conditions such as dry age-related macular degeneration and neuromuscular disorders, while also advancing next-generation candidates aimed at neurological and cardiac indications.
With mitochondrial dysfunction recognized as one of the hallmarks of aging, could the first regulatory success in mitochondrial medicine open the door to a new class of therapies with relevance not only for rare disease, but for aging itself?
Longevity.Technology: The tiny mitochondria in our cells are responsible for the vast majority of cellular energy production, and when they fail to function properly, the consequences can ripple across body, especially in organ systems with high energy demands, including the heart, brain, eye, kidney and skeletal muscle. The result can be impaired ATP production, increased oxidative stress and a damaging cycle of inflammation, fibrosis, senescence and cell death that is increasingly implicated in both rare and common diseases.
By targeting the underlying bioenergetic decline that can cut across multiple tissues, Stealth is betting that mitochondrial therapies may offer a way to address common mechanisms that drive a range of degenerative disorders. We sat down with Chief Scientific Officer Dr David Brown to explore the role that mitochondrial dysfunction plays across age-related disease, and why targeting it therapeutically may one day benefit us all.
Reflecting broadly on mitochondria’s role in aging, Brown highlights the way that age-related diseases have typically been presented in literature – an anatomical sketch of a human, with balloon callouts from the various areas of the body indicating the disease affecting that area.
“We’re a bit siloed, and we often think of diseases in anatomical terms,” he says. “But if, instead of putting a body in the center of the sketch, you put mitochondrial dysfunction in the center, then you can see it manifesting itself in different tissues – whether in the brain, heart, or muscles.”
‘Life is bioenergetics’
Putting bioenergetic dysfunction at the center of aging and disease is what Stealth and several other longevity biotech companies are betting will lead to progress against some of the world’s most debilitating conditions. Of course, there are also 11 other hallmarks of aging that could potentially be viewed in the same way, but Brown has reason to believe that mitochondria may prove key in the battle against aging.
“Life is bioenergetics,” he says. “The basis of life is grounded in eating food and breathing air and having our mitochondria take those two things together and provide energy. To me, it’s the most natural thing to link what happens as we age, when pathology sets in, back to something so central to life.”
While Stealth is singularly focused on developing a clinical pipeline targeting multiple diseases, others are already investigating the potential of its technology from a broader aging perspective. University of Washington professor David Marcinek is collaborating on a project in the $101 million XPRIZE Healthspan competition, exploring whether treating older adults with elamipretide can counter aspects of functional decline associated with aging.
“The ultimate goal is to conduct a gold standard, randomized double-blind, placebo-controlled study on whether elamipretide improves function across muscle, cognitive, and inflammation aspects of aging,” Marcinek told us. , “Our previous research supports the view that mitochondria are a key link between the molecular drivers of aging and age-related pathology leading to reduced quality of life.”
The project has successfully advanced to the semifinal stage of the XPRIZE competition, where teams conduct early clinical studies to demonstrate feasibility and gather initial data on functional and biomarker outcomes.
“We just finished the data collection component of the pilot study and are very encouraged by our ability to recruit and safely deliver the elamipretide intervention in healthy older adults,” said Marcinek. “I think this reflects the enthusiasm of this population to support rigorous scientific tests of strategies for healthy aging. There is a lot of noise and promotion of unsubstantiated approaches to reverse aging so this type of study is critical for moving translational aging science forward.”
Findings from the study are expected to be presented at the American Aging Association annual meeting in June.
From the eye to the brain
When it comes to Stealth’s ongoing programs in age-related disease, the most advanced is bevemipretide (SBT-272). The compound is currently in Phase 1 clinical testing for ophthalmic use in dry AMD, and preclinical studies have also explored its potential in models of neurodegenerative diseases such as ALS and Parkinson’s disease.
Building on insights gained from elamipretide, bevemipretide is designed to achieve higher concentrations in certain tissues, particularly the central nervous system.
“The exciting thing about bevemipretide is that we seem to be able to get therapeutic levels into tissue compartments that we wouldn’t with either the route of administration or the concentrations used for other compounds,” says Brown. “The brain is a great example. One of the things that we know is that we can target mitochondria in the brain, and that’s a unique opportunity for our developmental programs.”
In dry AMD, bevemipretide is being delivered as an eye drop to target mitochondria in the retina.
“People don’t often think of the eyes as something that generates tons of energy,” says Brown. “But the eyes are one of the more energetically consuming organs in the body when you normalize for organ weight. If you think about every hour that we’re awake, we’ve got constant impulses lighting up our cones and rods, sending nerve impulses constantly to our brain to be processed.”
“So the eye has an enormous bioenergetic need, and hence there’s a very high density of mitochondria in certain parts of the eye, particularly around the photoreceptors. For us, knowing that there are parts of the eye that are energetically demanding, that decline with age, and that are associated with age-related macular degeneration, targeting mitochondria is really exciting.”
Stealth expects results from the Phase 1 trial of bevemipretide “later this year.”
Next-generation programs underway
On the preclinical front, the company has two other programs under development, including SBT-255, another mitochondrial peptide that shows strong tissue distribution in the heart and skeletal muscle. Because these tissues are particularly vulnerable to age-related declines in mitochondrial bioenergetics, the compound is being positioned primarily for cardiomyopathies and other disorders involving impaired cardiac energetics.
Brown says studies in aged rodent models have shown improvements in key measures of cardiac function, and additional laboratory studies using mitochondria isolated from failing human hearts have demonstrated improvements in mitochondrial respiration and reductions in reactive oxygen species production.
“We presented a poster at a meeting in Colorado in February showing that in these failing human heart mitochondria, we can improve mitochondrial function and reduce the amount of reactive oxygen species leaking from the electron transport chain,” says Brown. “So that’s also been really exciting for us: seeing benefits not only in an aged rodent model, but also in human heart mitochondria with this newer compound.”
Finally, a compound called SBT-589 represents a newer class of mitochondrial therapies within the Stealth pipeline that act through a different mechanism than its other programs. The compound is designed to target dysfunction in Complex I of the mitochondrial electron transport chain, a defect that has been implicated in several neurodegenerative and mitochondrial disorders. Although the program is currently focused on the rare neurological condition Friedreich’s Ataxia, Complex I dysfunction is also implicated in more common age-related diseases, including Parkinson’s.
“I think there’s a really nice scientific story emerging that in common neurodegenerative diseases, as well as more rare mitochondrial diseases, Complex I is something that should be in the crosshairs in terms of what to try to target,” says Brown.
Ultimately, what’s clear is that the FORZINITY approval is just the beginning for the mitochondrial therapy landscape, and that age-related diseases are squarely in the sights of companies like Stealth.
“What’s really exciting is the idea that a rising tide raises all boats,” says Brown. “Now that we’ve shown that there can be success in this area, what’s most exciting, both for us and for other companies in the space, is that there is now a visible path.”
“We’re really hopeful and optimistic that, with all the companies out there working on therapies to target mitochondria, more will jump in. And more companies addressing more and more unmet needs should ultimately mean better treatments for patients.”
