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Princeton University Spinout KayoThera Marching Toward Clinic With Retinoid Pathway Inhibitor

DNA drug discovery

NEW YORK – Earlier this week, Princeton University spinout KayoThera announced plans to advance a lead candidate, KAYO-1609, toward first-in-human clinical trials in difficult-to-treat, genetically defined cancers including those with alterations in oncogenic driver genes TAL1, SS18, or KIT.

The drug's target, the retinoid pathway, is mired in a long history of promise and pitfalls but has for several decades been widely considered "undruggable."

A shift in the approach to this target might enable KAYO-1609 to succeed where other retinoid pathway inhibitors have failed, according to Mark Esposito, the cofounder and VP of R&D at Seattle-based KayoThera.

Reviving a failed approach

In the late 1980s and early 1990s, going after the retinoid pathway to treat cancers was all the rage. The approach had led to extremely encouraging responses among patients with acute promyelocytic leukemia (APL), and researchers sought to replicate that response broadly.

"There was this bonanza of clinicians going in and adding retinoic acid to every single cancer trial they could," Esposito said. But outside of the select cancers APL and cutaneous T-cell lymphoma, "every single cancer patient that they gave retinoids to did worse."

"There was a disconnect, and a lot of patients died because of these clinical trials," he said. Big drugmakers including Eli Lilly and Bristol Myers Squibb, among others, also launched retinoid antagonist programs, most going after nuclear receptors with their retinoid pathway inhibitors.

Here, too, the approach failed. "What wound up happening was that it was too hydrophobic of a binding pocket that kept on leading to nonspecific toxicity," Esposito said. Patients developed testicular toxicities, hepatitis, and other limiting adverse events. Even trying to administer the agonists topically, so as to avoid systemic toxicities, did not pan out.

"The summation of all of those results was that they were done there," he said. "The programs were buried."

Years later in 2015, however, Esposito and colleagues were conducting research at Princeton when they discovered two upstream enzymes that generated the ligand retinoic acid. "Those are actually the key point of flux for the pathway," he said.

Once Esposito and colleagues zeroed in on the functional element of these enzymes, they realized that they were driving retinoid signaling and altering the immune profile in tumors.

This research turned out to be the backbone on which KayoThera would emerge with what Esposito says is a less toxic approach to drugging the problem pathway. "Fundamentally, we're targeting enzymes, whereas the other [attempts] were targeting nuclear receptors, which are notorious for their druggability issues," he said. "The novelty was the target."

Spinning out KayoThera

It wasn't long before Esposito and colleagues realized that the discoveries they'd made at Princeton could have real potential for treating cancers with few available treatment options. They decided to spin the lab work into a biotech startup.

"It was a project with good academic promise, but really better translational promise," Esposito said. "I had this very interesting first-in-class compound — something that pharma had tried before and failed — and had some [early] evidence around it." Together, these factors made the project what he called an "interesting investment thesis."

The first real investment in the firm was $1 million from a nonprofit called the New Jersey Health Foundation. This gave KayoThera a launching pad to home in on a near-lead candidate and begin to attract Series A investors. The firm brought in $8 million in its Series A financing round, then an additional $3 million from a variety of grants.

According to Esposito, the firm now has a "great IND entry package" that includes demonstrated safety across various species in preclinical studies. KayoThera is accordingly planning to file its investigational new drug application in 2024 and begin dosing patients in its Phase I trial in 2025, assuming no bumps in the road.

While the exact protocol isn't finalized for the first-in-human trial of KAYO-1609, KayoThera is, as of now, planning to enroll 25 to 30 patients across four to five different cancer indications including T-cell acute lymphoblastic leukemia, synovial sarcomas, KIT-mutated gastrointestinal stromal tumors, and potentially mesothelioma, if the firm can identify the right mutational signature in advance of the trial. Eligible patients will have refractory cancers with confirmed alterations in TAL1 fusion oncogenes, genes leading to synovial sarcoma such as SS18, or KIT. 

"We're going to try to capture those cancers and then do post hoc discovery-based work to understand how [the biomarkers] correlate to any efficacy we're seeing," he said.

The alterations that KayoThera would be looking for in the eligible patient populations are already included in multigene panels, so it should be straightforward to enroll these patient populations, he predicted. Additionally, patients with the cancer types KayoThera is interested in including refractory sarcoma often have few treatment options should they relapse after chemotherapy. Esposito is hoping this will make recruitment go smoothly.

"These are patients who are always looking for new therapies, for whom it's 'cross your fingers and hope that salvage chemotherapy works,'" he said.

In the Phase I trial, KayoThera will administer KAYO-1609 as a single agent and then look at a dose-responsive biomarker that Esposito says will show whether the drug is actually interrogating the retinoid pathway. The main goal will be to assess safety and pharmacokinetics and pharmacodynamics, and secondary endpoints will include exploratory endpoints such as tumor response.

"Our hope is to show hints of efficacy in the Phase I and report on that, and then … we'd like to move into registrational trials with an orphan designation very early," he said. "We would definitely want a small but well-managed and randomized study that was registrational."

Policy flux brings uncertainty for future indications

KayoThera hopes its Phase I trial will be the first step in its plan to move KAYO-1609 into registrational trials with orphan drug designation in small, difficult-to-treat patient populations. But looking further ahead, expansion into additional patient populations could hinge on the ongoing and contentious debates surrounding the Inflation Reduction Act's Medicare drug price negotiation provisions. Many drugmakers, trade groups, and organizations have taken their concerns to court with lawsuits opposing the Inflation Reduction Act, several on the grounds that it conflicts with the goals of the Orphan Drug Act.

As the new Inflation Reduction Act is written, drugs are only exempt from Medicare price negotiations if they have a single orphan drug indication. Starting to develop the drug in an orphan drug-designated indication and then expanding it into larger patient populations could subject it to negotiated prices, which drugmakers argue harms profitability and commercial viability.

"You hate to say it, but we're as much bound by the financial and commercial considerations as we are by the true interest in R&D," Esposito said. "I just don't know what the landscape is going to be, and I don't know who does."

For now, KayoThera is focused on its march toward the clinic to prove the "undruggable" retinoid pathway is a viable and promising cancer treatment target after all.