Rise of the WormBots: it’s time to scale up longevity R&D

Ora Biomedical aims to screen over 100,000 compounds a year for longevity potential in worm models – cherry picking the best for clinical development.

Seattle-based startup Ora Biomedical is on a mission to develop a “new generation of broad use small molecule healthy aging interventions.” The company emerged earlier this year from the laboratory of University of Washington professor and renowned longevity researcher Matt Kaeberlein.

The company aims to conduct the largest preclinical longevity drug screening operation of its kind through the automated high-throughput robotics and AI platform known as WormBot-AI. The company has an exclusive agreement for the technology, also developed in Kaeberlein’s lab, which automates the study of the effects of longevity interventions on the transparent nematode (worm) model Caenorhabditis elegans.

Longevity.Technology: Measuring health and survival in the short-lived C elegans model is a popular choice for preclinical screening of longevity compounds, but such studies have historically been a highly manual, time-consuming process. This has meant that worm studies have not been conducted at scale. Ora Biomedical says it can screen up to 144 worm populations in parallel with a single WormBot-AI, and it aims to use multiple WormBots to screen tens of thousands of compounds to identify small molecule gerotherapeutics that modify normal aging and age-related disease pathology. To learn more, we caught up with Dr Mitchell Lee, Ora’s co-founder and CEO.

Ora Biomedical co-founders Dr Mitchell Lee and Dr Ben Blue

The longevity biotech field is, according to Lee, still very much in its infancy.

“I feel that we are still in longevity biotech 1.0, which is testing what we know and getting some proof of principle studies out there,” he says. “But we’re aiming for longevity biotech 2.0, which is really going to be discovering the next generation, most efficacious interventions. And this is probably going to be going through combination research – taking what’s already known and combining it with new interventions and aging targets.”

Seeking longevity interventions at scale

It was this fundamental principle that brought Lee together with his co-founders – Kaeberlein himself, AI specialist Dr Ben Blue, WormBot inventor Dr Jason Pitt, and Professors Brian Kennedy and Jan Gruber of National University Singapore.

“We all felt that this was the right time right place to really start developing a longevity biotech company based on large scale drug screening, utilising the WormBot technology,” says Lee.

University of Washington professor Matt Kaeberlein

And so, Ora Biomedical was born, taking its name from the word meaning “healthy, alive” in the language spoken by the people of Easter Island, where the longevity-linked compound rapamycin was first discovered. The company places itself firmly in the geroscience category, guided by the principle that targeting aging will not only affect lifespan – it will also improve disease resistance.

“We consider ourselves a pharmaceutical company that identifies interventions that are going to broadly fight disease and extend healthy lifespan,” says Lee. “We do that by looking at standard aging models and age-associated disease models in nematodes via the WormBots.”

“Looking for interventions that ameliorate those disease models, and combining those with tests in standard aging models, will let us know that we are hitting age-regulating mechanisms. It will also lead us to the pathways for indications that we can pursue in clinical trials and give us the best chance of finding those broad-acting, healthspan-modifying interventions.” 

Screening 100,000 interventions per year

Ora Biomedial spun-out earlier this year, announcing pre-seed funding from Optispan Ventures, which included the leasing of a space to build its high-throughput longevity drug discovery facility.

Wormbot-AI in action

“The big thing that sets us apart is the scale of our operations,” says Lee. “We’re just getting things underway, but our headquarters is going to house 30 WormBot platforms, which will allow us to hit a throughput of screening at least 100,000 interventions per year. And we think we can even do better than that.”

Lee says that Ora is already focusing on compounds that have the “shortest runway” to getting into humans.

“We’re currently going through approved FDA drug libraries, which have some known mechanism behind them, and natural products are another big early focus of ours as well,” he says. “For longevity interventions, there just has not been a lot of coverage to date. The largest drug database right now only has about 3,200 drug entries in it, so there’s really a dearth of early leads.”

While some of those early leads are being pursued through by the first longevity companies, Lee says there is a lot more still to learn.

“There’s a big open chemical space to discover,” he says. “So, we’re finding the largest, most diverse drug libraries that we can start with, and then going from there to find hits. Then we’ll either go through different sorts of novel medicinal chemistry approaches to find composition of matter IP, or just find different ways to combine those novel hits with existing hits.”

Ora’s development strategy

The company’s early screening has been using an Alzheimer’s disease model that means the worms undergo a rapid onset of paralysis.

“We’ve been taking known lifespan-extending interventions, and screening those across compounds in the FDA drug library to find synergistic interactions that strongly delay paralysis in this model, and we’ve identified some great hits already,” says Lee. “So now we’re working with researchers who have Alzheimer’s patient-derived cell culture models to test these interventions.”

Wormbot-AI monitoring C Elegans activity

This approach is reflective of how Ora plans to move forward with its programmes in other indications.

“We’ll go from worms to mammalian systems, either cell-culture or small mammals, and then IND-enabling studies to get us down the road to clinical trials,” says Lee. “We’re going to carry forward the most efficacious interventions ourselves, but at any point along that pathway, we also have the option of out licensing interventions to other companies for further development.”

WormBots at the ready

Next year will be a big one for Ora, as the company aims to deploy its WormBot army and start screening at scale.

“By the end of 2023, we will have put together our factory, we’ll have 30 WormBots up and running and I would estimate that we’ll have about 50,000 or so interventions screened, if not more,” says Lee. “We’re thinking that out of 100,000 interventions screened per year, we’ll get about 100 to 300 hits. Out of those, we expect maybe 10 to 30 new interventions to validate in mammals.”

While Lee expects some of those interventions will be for existing aging targets, he also expects Ora will uncover new aging targets.

“It’s hard to estimate how many new targets are out there, but it’s very clear that the field has focused its efforts on just a small handful of aging targets,” he says. “There are many more druggable mechanisms out there to be discovered, we just haven’t had that focus on discovery that we’ve needed to really build them out.”

Until now, perhaps?