While working as a principal scientist at Celgene in the mid-2010s, Tomas Babak, PhD, found himself deeply frustrated with consistently failing at translational development—taking knowledge of a disease target to develop a human-compatible drug.
“I got a chance to work on drugs that were going straight into phase one clinical trials, and my job was to try to help figure out how we select the right patients for these drugs,” said Babak. “Long story short, it all failed. I worked on three drugs that ended up being pretty safe, but just none of the patients responded. I started thinking, is this something that I screwed up, or is this something that’s more general?”
It turns out to be pretty general, as most drugs that enter clinical development are never approved. The number that’s usually thrown around is 90% for drug candidates that fail in clinical trials, and for the drugs that do get approved, they typically take 10 to 15 years and around $1 billion.
In trying to find a better way, Babak, who described himself as “a risk-averse person,” began to think about how he could up the odds for successful cancer drugs. In boiling cancer conceptually down to a genetic disease, Babak was struck by the idea of creating a drug-screening platform consisting of genetically engineering cells to carry all known oncogenic mutations. And he didn’t want to just test any drug—Babak decided to start with drugs that had already made it to Phase II but had failed. Instead of trying to drug biological pathway-associated targets, Babak’s platform was made to pin down safe drugs for patient populations with specific genotypes that are likely to be responsive.
The result was the launching of a company, fittingly named Leapfrog Bio, that was essentially a clinical-stage oncology company straight out of the gate without ever having developed a drug. In an NPJ Precision Oncology article, Babak details proof-of-concept retrospective analyses performed on currently marketed cancer drugs to demonstrate the clinical relevance of the platform’s predictions, called the Precision PGx Platform. With the pharmacogenomic platform, Leapfrog Bio is screening clinically actionable molecules to target major solid tumor markets in a condensed timeline, requiring far fewer resources.
Leapfrog CEO Greg Vontz said, “Thomas always said he’s a skeptic and wants to rigorously always test and make sure that the platform is really delivering what we believe it is. One of the things I’m most excited about is that we have now conducted internally over 20 or more cancer cell-derived xenograft (CDX) [experiments] in-house, and every one of these that the platform has predicted has read out extremely well in line with or better than current targeted therapy. I know we’re on to something big here.”
A new approach to synthetic lethality
What really makes Leapfrog’s Precision PGx platform stand out is its ability to rapidly discover novel therapeutic options for cancers caused by loss-of-function mutations. Approximately two-thirds of cancers result from a loss-of-function mutation in a tumor suppressor gene, yet approved drugs can only treat about two percent of tumor suppressor gene-driven cancers.
Vontz puts the value of Leapfrog’s approach in the context of PARP inhibitors, the first clinically approved drugs designed to exploit synthetic lethality, a genetic concept proposed nearly a century ago. Tumors arising in patients who carry germline mutations in either BRCA1 or BRCA2 are sensitive to PARPi because they have a specific type of DNA repair defect. Olaparib was the first PARP inhibitor to be developed (2005) and was approved 13 years later by the FDA in 2018 as monotherapy for the first-line maintenance treatment of BRCA-mutated advanced ovarian cancer.
“We don’t really understand cells very well at all, or cancer cells for that matter, so we have to ask the cells,” Vontz said. “The hyper-complex biology of cancer is such that we almost seem arrogant as humans to try and want to draw one or a part of this pathway and think we can control something. Yes, it does work on occasion, but more times than not, the body has many redundant systems.”
But even with the massive and ongoing efforts by large consortia to comprehensively map synthetic lethal networks in hundreds of cancer cell lines to identify drug targets and the patients who are expected to respond best to targeted treatment, the needle has hardly moved. This failure can be explained by two findings: that pharmacologic inhibition of a cell line rarely reproduces the phenotype induced by genetic knockout of the drug target and that it is not possible to identify drugs with the potential to be repurposed as genetically targeted therapies by simply aligning drugs against novel targets discovered based on genetically defined synthetic lethality.
However, performing a drug screen on cancer cell lines carrying a genetically edited driver mutation has shown promise in defining druggable targets essential for a particular loss of function tumor suppressor genes. That concept is at the heart of Babak’s innovation—a clinically optimized driver-associated pharmacogenomic (CODA-PGx) platform. According to the research article, Babak’s CODA-PGx has replicated known synthetic lethal interactions, such as PARP with BRCA, and has made discoveries.
“This took a lot of work to figure out—doing [the screen] in a context where that perturbation that we put in replicates a loss of tumor suppressor biology,” said Babak. “We’re not going to believe every single perturbation in every single cancer cell line. Most of them don’t. It has actually to replicate a driver event. If we’re interested in some obscure tumor suppressor gene, we’ll try to find a cell line where it leads to increased proliferation if you knock it out. That’s how we know this is actually a genuine tumor suppressor in that context, and in that context, we can trust it. Then, we can add the drug on top and see if there’s an interaction. If you have the driver mutation, you want to see which ones get killed off by the drug.”
And, if you limit the pharmacological candidates to phase II candidates, which is on the order of several thousand, any successes in CODA-PGx could help Leapfrog get a targeted therapy through clinical trials and to market in a fraction of the time it has taken others.
Vontz said, “We look at today’s public synthetic lethality companies; they’re building their pipeline very traditionally. They identify an important target, and then they begin the process of drugging it and taking that long journey. We feel this tool can quickly bring a tremendous number of new target therapies to patients. It’s part of the thesis, the leaping of the leapfrog, taking phase II drugs that have already run the gauntlet of safety and been well tested. This allows us to potentially bring a drug to the market in half the time and, we believe, with considerably less risk than starting with a target ID and building a molecule from scratch.”
Searching for the next blockbuster cancer drug
With this approach, Leapfrog has selected a lead drug that remains confidential. Vontz said Leapfrog plans to take this compound into the clinic for three solid cancer types: lung, colon, and bladder. Given the “substantive frequency” of the loss-of-function mutations in the yet-to-be-revealed tumor suppressor genes, Vontz thinks they’re onto something big.
“The term blockbuster is trite and overused, but this has the potential to be if it’s as successful as we think,” said Vontz. “We’re feverishly building a pipeline. It’s early days, but we have an exciting clinical program that could be on the cusp of moving into the clinic in the next 18 months, and we’re making discoveries every day. Then it becomes a process really of prioritizing our work.”
Babak said he’s already filed for five methods of treatment patents that are completely first-in-class and unrelated to the PARP inhibitor space. But it’s all for nothing if they don’t have the proper prospective validation.
With future clinical trials in mind, the next step for Leapfrog, according to Vontz, is to complete Series A financing. If they can pull it off, Leapfrog may have a lot of potential cancer drugs on their hands, as, according to Babak, they’ve only screened two percent of the catalog of drugs that made it to phase II. Leapfrog Bio is ready to jump through clinical trial hoops, and with Babak’s newly published proof-of-concept article on Leapfrog’s platform, it’s more likely for investors to start walking through the door.
