Insitro, Inc.

The AI-focused biotech insitro is advancing a new idea to potentially treat ALS, one of the most intractable and brutal diseases. The South San Francisco-based startup has identified a new drug target against the neurodegenerative disease, CEO Daphne Koller exclusively told Endpoints News . And it’s the first public update to a 2020 research collaboration with Bristol Myers Squibb that is focused on ALS, or amyotrophic lateral sclerosis, and frontotemporal dementia. Bristol Myers has also paid a $25 million milestone to insitro, as the two companies are now working on identifying and advancing a small molecule against the target. Specifics on the target and a timeline for next steps were not disclosed. ALS — and more broadly, neurodegeneration — remains one of the toughest areas of drug development. It’s a field littered with disappointments, most notably the Phase 3 failure and subsequent market withdrawal of Amylyx Pharmaceuticals’ Relyvrio earlier this year. ALS patients have been left with exceedingly few options to stave off a disease that deteriorates their nerve cells and eventually leads to death. Insitro’s strategy of diving into diseases like ALS diverges from many AI-focused peers that have focused on familiar, already-drugged targets. Biotechs like Iambic Therapeutics , Generate:Biomedicines and Atomwise have lead programs in well-trodden lanes of biology, like HER2, TSLP and TYK2. Insitro was built to discover new, high-conviction drug targets instead of designing molecules against familiar targets. “When you go after a target everyone and their cousin is going after, and you’re fifth in line to the clinic, then what value have you brought to patients? What value will subsequently accrue to you?” Koller said. “This lemming-like approach of, ‘Here’s a target that others have de-risked, so we’re going to be third in line, fifth in line, 10th in line, to make a molecule and hope we can be best-in-class so we can eke out a small percentage of the market’ — sure, you could do that. There’s a business in that, but it’s not going to transform the industry.” New biology requires money and time, and insitro has raised over $700 million over its six-year history with a team that is now about 300 people. In addition to the collaboration with Bristol Myers, insitro aims to enter the clinic in 2026 with its own drug candidates. That includes three metabolic programs involved in an Eli Lilly partnership announced in October. In the case of ALS, insitro built over 200 cell lines, some from ALS patients, to study the genetics of the disease. The biotech used high-content imaging of cells and proprietary optical screening techniques to eventually find genes that, when knocked out, restored some level of function to these cells. For next steps, insitro will search for small molecules against the new ALS target, according to Koller, using parts of its platform the company has not talked about much. That includes DNA-encoded library screening, a technique that shows how billions of molecules bind to a protein of interest. The biotech can run multiple rounds of so-called DEL screens, followed by virtual tests to find strong binders that are also easy to make and have drug-like properties. The plan is to test those drug candidates in the lab to see if certain compounds result in the same benefits that the company’s researchers saw in the genetic knockdown experiments that helped identify the target. None of that has been easy — nor has it been particularly fast compared to peer biotechs that have opted to focus on already validated targets. But Koller said that approach is now starting to deliver. “It takes a while to figure out exactly what you need, to build it and refine it,” Koller said about building insitro’s technology over the years. “We built it, and it has delivered a truly novel target in this really, really hard-to-tackle disease.”

If all goes according to plan, insitro could finally start testing its first drug in clinical trials in 2026, eight years after Daphne Koller founded the AI-powered biotech. To get there, it’s teaming up with Eli Lilly to access a key technology to make its experimental genetic medicine a reality. The South San Francisco-based startup has identified two genes with its machine learning tools that it believes are linked to metabolic diseases, including fatty liver diseases. While insitro has designed gene-silencing siRNA molecules to target those genes, it still needs a chemical conjugate called GalNAc to shuttle those treatments into liver cells. Through the deal, insitro will have the option to license Lilly’s GalNAc molecules. Insitro will also work with Lilly to develop an antibody against a secreted target. For all three programs, insitro is responsible for running clinical tests. There is no upfront money, but Lilly will get milestone and royalty payments if the drugs are successful. It’s an arrangement that flips the normal order of partnerships between biotech and pharma, which usually sees the bigger company run expensive clinical trials and dole out payments to the smaller company upon positive clinical trial results and FDA approval. “I think they recognize that even the biggest pharma companies in the world can’t do everything internally,” Koller told Endpoints News in an interview. “We were able to really come to a set of economic terms that are very beneficial to both sides.” The siRNA drugs are insitro’s most advanced programs. Koller said she hopes to announce the development candidates later this year or early next, then file an IND for the first one within 12 months after that — a timeline that could lead to a clinical trial in 2026. The second siRNA drug will be a few months behind. Koller is one of the biggest names at the intersection of AI and biology, particularly after raising $643 million across three funding rounds since 2018. Despite that, she’s developing a reputation for warning about the dangers of overhyping AI and insitro has been quiet about the specifics of its research. The company started to open up a bit more in January when it published a trio of preprints showing how it used machine learning to predict genetic details about cancer cells just by analyzing stained biopsies, develop a new screening method for ALS drug discovery, and identify hundreds of genetic loci linked to metabolic dysfunction-associated steatotic liver disease. That common condition, also called MASLD, is one focus of the Lilly partnership. The company’s fatty liver disease work is furthest along. “These are novel targets with strong genetic support,” Koller said of the program. “The genetics of fatty liver disease have been largely uncharted territory, because there’s just not a lot of patients in which the disease has been officially diagnosed.” One of the January preprints shows how insitro used machine learning to predict liver fat in UK Biobank participants by looking at data from bone density scans and molecules in the blood. “It turns out that AI could read liver fat quite reliably from that,” Koller said. “We now have liver fat measurements — even if not 100% accurate — not for a few thousand people, but for a few hundred thousand people,” she added That helped insitro uncover new genetic links that would have been difficult or impossible to find with a smaller dataset, Koller said. But since the company’s AI advantage is largely centered around finding a new drug target before someone else, she isn’t saying what those genes are just yet. Getting scooped is a big concern. “As soon as there is a good drug against a biology, you have 20 other companies that are making drugs against that same thing,” Koller said.

Dive Brief:Eli Lilly and Insitro said they have entered into three drug development deals that offer a new paradigm for collaborations between major pharmaceutical companies and smaller biotechs.Insitro, which specializes in applying machine learning to drug discovery, will get an option to license delivery technology from Lilly as part of the first two agreements. The third pact lays the groundwork for Lilly and Insitro to work together to discover a metabolic disease treatment.The alliance allows Insitro to retain full global rights to all of its research programs, while Lilly will be eligible for payments for reaching certain milestones. Lilly may also receive royalties from products that win regulatory approval, Insitro said Wednesday. Insitro will be working with Lilly Catalyze 360, a unit designed to collaborate with biotechs.Dive Insight:The deal highlights the growing importance of artificial intelligence in drug discovery. The announcement arrived on the same day that three scientists won the Nobel Prize in Chemistry for their work with computational protein design and an AI model that predicts protein structure.Insitro integrates machine learning with data from human and cellular research, coming up with new genetic targets and hypotheses for treatments. Its technology has drawn interest around the pharmaceutical industry; in recent years, its inked development deals with both Gilead and Bristol Myers Squibb.The Lilly alliance focuses on metabolic diseases, including metabolic dysfunction-associated steatotic liver disease. Insitro plans to combine Lillys GalNAc delivery technology with two different small interfering ribonucleic acid, or siRNA, molecules Insitro developed to target the liver. The company will also collaborate with Lilly on preclinical work to develop an antibody for a third metabolic target.AI proponents tout its tremendous promise to find better drug candidates more quickly and cheaply, potentially accelerating the discovery process. And companies such as Nvidia and Recursion Pharmaceuticals have been priming investors to rethink traditional research models.But AI-discovered medicines still need to be proven in clinical trials, which remain expensive and time-consuming. Recursions first big readout from a mid-stage trial yielded mixed results. The study showed its lead experimental drug is safe but provided little information on effectiveness, prompting a drop in the companys stock price.Insitro said its agreements with Lilly will support research that could lead to human trials for its first set of programs. In addition to metabolic diseases, the company is also working in neurodegeneration and oncology. '