MetaShape’s PNP inhibitor technology aims to restore NAD+ levels to combat LDL cholesterol, cognitive decline and neurodegeneration.
At the recent Longevity Investors Conference in Switzerland, we came across a new longevity therapeutics company with a fascinating technology. MetaShape Pharma, a clinical-stage biotech company based in Basel, Switzerland, is developing therapies to combat age-related diseases by restoring nicotinamide adenine dinucleotide (NAD+) levels in the body.
MetaShape’s approach centers on inhibiting purine nucleoside phosphorylase (PNP), an enzyme that limits the body’s capacity to synthesize NAD+. The company is initially targeting well-defined age-related conditions, such as high cholesterol, the prevention of cognitive decline, and the treatment of neurodegenerative diseases. A clinical trial in LDL cholesterol reduction is planned for as early as next year, although MetaShape’s longer-term vision is to address the wider complexities of aging itself.
Longevity.Technology: NAD+ is a vital coenzyme required by all living cells to perform essential functions, supporting cellular metabolism, DNA repair, and immune responses, effectively acting as the fuel that powers biological systems. However, the natural decline in NAD+ levels as we age impairs these processes, leading to cellular exhaustion and dysfunction, and is linked to a host of age-related conditions. We caught up with MetaShape founder and CEO, Dr Thomas Mehrling to learn more about how the company aims to combat diseases and aging through NAD+ restoration.
The origins of MetaShape began back in 2007, when Mehrling, then head of the European oncology division of the Mundipharma Group, first became aware of PNP inhibitors through a collaboration with US biotech company BioCryst. While the company ultimately didn’t end up pursing the technology, Mehrling was convinced it had potential for something significant.
“When I left Mundipharma in 2019, I joined up with my co-founder Shanta Bantia who was the head of biology at BioCryst, and we both felt that something may have been overlooked,” he says. “So, we linked up with a team of UCLA researchers that specialized in nucleoside metabolism, and we discovered intriguing other capabilities of these drugs.”
The role of PNP in NAD+ synthesis
In 2022, a breakthrough study conducted by Russian researchers gave Mehrling and Bantia the hypothesis on which to build MetaShape. The paper discovered that PNP plays a role in limiting the metabolism of NAD+ precursors – chemicals that our bodies can use to synthesize NAD+.
“It appears that NAD precursors, once they get into the intracellular space, are rapidly degraded, and one of the enzymes that degrades them very effectively is PNP,” says Mehrling. “So, our hypothesis was – if we inhibit PNP, then we prevent the degradation, and then supplementing with precursors will enable restoration of the biological system.”
MetaShape’s founders then began work on developing their own, proprietary technology, essentially reworking the most promising candidates from their previous collaboration. The company’s lead compound, MS 001, is a selective and potent inhibitor of PNP.
MS 001 is designed to disrupt pathways that degrade key NAD+ precursors, while also preserving the availability of essential cofactors like phosphoribosyl pyrophosphate (PRPP) that enhance the body’s ability to regenerate NAD+. Mehrling says its mechanism is designed to deliver sustained NAD+ elevation in critical tissues such as the brain, muscles, and blood, which are often the first to suffer from cellular exhaustion.
Early studies show promise
In MetaShape’s preclinical research, MS 001 restored NAD+ levels to their prime state in animal models, and significantly reduced LDL cholesterol and blood glucose levels. The company is collaborating on this work with renowned longevity researcher, Professor Vincenzo Sorrentino at the National University of Singapore.
“What we’ve seen in our studies in mice is that NAD+ levels are not just going up in blood, we have also observed them going up in brain and in muscle,” says Mehrling. “These are two very important areas that are also sensitive to energy production and being able to restore the functionality of cellular energy production in these areas is potentially very meaningful, especially as we age.”
Given the broad potential scope of its technology, Mehrling explains that MetaShape’s strategy is to first target a well-recognized area of drug development, starting with reduction of LDL cholesterol in patients with statin intolerance, before moving into additional areas, such as prevention of cognitive decline and treatments for neurodegenerative diseases.
“We see that market is now starting to move, and it is moving towards repurposed drugs like Metformin,” he says. “We believe that, in addition to its LDL-lowering potential, our drug is also tapping into what is probably one of the best researched biological systems for generating energy. We’re aiming to get an approved drug that has a marked potential in preventing multiple diseases that are associated with aging.”
Seeking rapid approval
Given the well-trodden path of cholesterol-lowering drugs, Mehrling hopes that the route to the company’s first approval could be as short as three years.
“From a regulatory perspective, we wanted to find an accepted indication where we can prove that the drug has efficacy, and expand into longevity or neurodegeneration trials from there,” he says. “When it comes to cholesterol, you just need to demonstrate that you lower LDL cholesterol, because it’s now widely accepted that by lowering LDL cholesterol, you’re preventing cardiovascular events.”
Mehrling expects that the MetaShape should be able to commence its first clinical trial in about a year, which he says will be a “classical Phase 1” looking at different dose levels and their effect on lowering cholesterol.
“Once we identify appropriate doses, we will straight go to Phase 2, which has a very clear endpoint of percentage lowering of LDL cholesterol,” he adds. “And that’s basically already something that is potentially approvable –we just have to discuss with regulators how many patients they want to see.”
Having raised $1.1 million in funding to date, MetaShape is now in the process of raising a Series A round to take the company through its initial Phase 1 trials.
