Key Points:
- MetaShape’s new compound, MS 001, disrupts pathways that degrade key NAD+ precursors to thereby elevate cellular NAD+.
- More specifically, MS 001 inhibits purine nucleoside phosphorylase (PNP)—a potent NAD+ precursor-degrading enzyme.
- MetaShape plans to target well-defined age-related conditions like high cholesterol, cognitive decline, and neurodegenerative diseases with its new approach to boosting NAD+.
A new longevity therapeutics-focused biotech company called MetaShape Pharma, based in Basel, Switzerland, is developing new therapeutics targeting NAD+ to fight age-related diseases. The company’s approach encompasses the inhibition of an enzyme—PNP— that limits cells’ capacity to synthesize NAD+.
To start their NAD+-related pharmaceutical venture, the company will target well-defined age-related conditions like high cholesterol, cognitive decline, and neurodegenerative diseases. However, their long-term aspirations center on addressing the complex intricacies of aging itself.
For some background, NAD+ is a crucial molecule found in every cell in the body with essential functions like supporting metabolism, DNA repair, and immunity. Not only that but NAD+ serves in cell energy-generating reactions within cell powerhouses—mitochondria—acting as a fuel of sorts to power biological systems. Moreover, a decline in cellular NAD+ with age impairs these processes, leading to cellular dysfunction, which has been tied to an array of age-related diseases.
MetaShape’s Beginning and Development of PNP Inhibitors
MetaShape was founded in 2023; however, its origins go way back to 2007 when the company’s CEO, Dr. Thomas Mehrling, first became aware of PNP inhibitors. He was working as the head of the European oncology division of the Mundipharma group when, through a collaboration with US biotech company BioCryst, his team decided not to pursue new drugs based on PNP inhibitors. All the same, Dr. Mehrling was convinced that PNP inhibitors had substantial potential.
“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,” says Dr. Mehrling in a press release. “So, we linked up with a team of UCLA researchers that specialized in nucleoside metabolism, and we discovered intriguing other capabilities of these drugs.”
Inhibiting PNP Boosts NAD+ Synthesis
A study from Russia, published in 2022, spurred Mehrling’s and Bantia’s hypothesis that inhibiting PNP may work to boost cellular NAD+. In their study, Russian researchers uncovered that PNP plays a key role in degrading NAD+ precursors—molecules cells 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.”
Following their hypothesis, Mehrling and other MetaShape founders began the development of their own proprietary technology. Essentially, they reworked previously-designed technologies from their collaboration at Mundipharma. Their efforts led to the development of the company’s lead compound, MS 001, which selectively and potently inhibits PNP.
Not only does MS 001 disrupt pathways that degrade NAD+ precursors but it also preserves cellular concentrations of molecules that enhance NAD+ regeneration like phosphoribosyl pyrophosphate (PRPP). In this way, MS 001’s mechanism of action is meant to deliver sustained, elevated NAD+ in crucial tissues like the brain, muscles, and blood, which are often some of the first tissues to bear the brunt of cellular exhaustion, according to Dr. Mehrling.
Promise from Early Studies
In preclinical research, MS 001 has been shown to restore aged animals’ NAD+ to levels seen in younger ones. What’s more, the compound lowered LDL cholesterol (the harmful type) and decreased blood glucose.
“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 spectrum of age-related diseases that MS 001 may address, Mehrling has explained that MetaShape’s strategy entails first targeting well-established areas of drug development. Along those lines, MetaShape’s researchers are aiming to reduce LDL cholesterol levels in patients with statin intolerance. Once they can confirm MS 001’s cholesterol-lowering capabilities, the MetaShape team will move into other areas like preventing cognitive decline and treating neurodegenerative diseases.
“We see that market is now starting to move, and it is moving towards repurposed drugs like Metformin,” says Mehrlin. “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.”
MS 001 May Receive Approval within Three Years
As for how long it may take for a drug like MS 001 to receive approval for widespread use, Mehrling hopes the route to first approval may happen within the next 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 and the MetaShape researchers expect to finish their first human trial in about a year. That study will be a “classical Phase I,” which looks at different MS 001 doses as well as their effects on lowering LDL cholesterol. Then, once appropriate doses are identified, Mehrling says the team will move on to Phase II trials, which have a clearly defined endpoint percentage goal for lowering LDL cholesterol. Mehrling has also said that once MS 001 has been shown to lower LDL cholesterol to that endpoint, the compound will be potentially approvable—MetaShape just needs to establish with regulators how many patients they need for their human trial.
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