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Nested Therapeutics Looking to Stabilize Aberrant Ras Pathway With Molecular Glue


NEW YORK – Nested Therapeutics is hoping to move its lead investigational agent, a non-degrading molecular glue, into clinical trials in early 2024 and show its ability to target the challenging RAS-MAP kinase pathway.

Nested was founded by Klaus Hoeflich, a former senior VP at Blueprint Medicines, Kevan Shokat, a chemistry professor at the University of California, Berkeley, who discovered the first covalent KRAS inhibitors, and Arvin Dar, a professor of oncology and pharmacology at Icahn School of Medicine at Mount Sinai. They recognized that only about 50 cancer driver mutations had been identified out of nearly 10,000 known mutations and that there was an untapped opportunity in identifying and developing drugs against those targets. In forming Nested Therapeutics in March 2021, Hoeflich, Shokat, and Dar set out on a mission to find those still undiscovered, targetable driver mutations in cancer.

Since its founding, Nested has raised $125 million with which to fulfill its mission, most recently raising $90 million in an October 2022 Series A financing. The Cambridge, Massachusetts-based company has built a platform dedicated to finding the driver mutations "hiding in plain sight and being able to discern them from passenger mutations," said Nested CEO Darrin Miles.

"What really brought us together, the founders and original team at Nested, is that we've all worked for years in precision oncology," said Hoeflich. "For the most part, we've been going after active site inhibitors or targets that have very clear or hotspot mutations … but that's clearly now the low-hanging fruit, and those opportunities have been around for a long time."

Rather than developing drugs that target a single driver mutation, Nested is looking to target clusters of mutations that share the same oncogenic driver mechanism, and in this way, treat a broader patient population. "The opportunity here is to see if we could actually increase the size of the addressable population for a single precision oncology treatment," Miles said.

To find those key oncogenic driver mechanisms, Nested's founders applied artificial intelligence and machine learning to high resolution crystallographic structure data from the worldwide protein databank.

"In the early days of Nested, we ambitiously decided to map all recurring mutations from cancer to all protein structures, whether experimentally determined or predicted," Hoeflich said. "We thought this could point the way to new chemical biology strategies on targets that have previously been very challenging or even considered undruggable."

The result was a structural map that showed candidate driver mutations in relation to each other and specific structural features of the protein, and within that framework, clusters of mutations could be identified at key sites on the protein structure, such as pockets or loops, where different mutations would theoretically have the same effect on the protein's function.

This map allowed Nested's founders to identify driver mutations that could be good therapeutic targets. Hoeflich said Nested's founders wanted to start with "high conviction, high value" targets, on which a "substantial" amount of work had already been done to link that target to disease. As Nested researchers characterized the structural relationships of the proteins in the RAS/MAP kinase signal transduction pathway, which includes the RAS, RAF, MEK, and MAP proteins, they realized that it would be a good fit for their approach. "There was a beautiful connection there in terms of our platform approach and structural insights that were very novel," Hoeflich said. "That allowed us to get the first project up off the ground."

While RAS is a commonly mutated oncogene found in 25 percent to 30 percent of cancers, drugmakers have historically struggled to effectively target it for cancer therapy. Instead of going after RAS oncogenes, Nested is aiming to exploit the fact that RAF, in the same pathway, typically signals in the form of a dimer to perturb the same pathway but at a different entry point.

RAF inhibitors can paradoxically force dimerization, Hoeflich explained, which puts the protein in its active conformation and ends up being counterproductive to the inhibitory activity of the compound. Nested is taking a different approach with its lead compound, NST-628, a non-degrading molecular glue designed to stabilize the interaction of the RAF protein with MEK, preventing the formation of RAF dimers.

In KRAS-G13D tumor models in vitro and in vivo, NST-628 durably and robustly decreased RAS pathway reactivation. And in patient-derived xenografts, NST-628 inhibited growth of a range of tumors with RAS pathway mutations including multiple KRAS G12X, NRAS, and BRAF mutations. "These biomarkers we've chosen are the toughest in the field [to target]. The BRAF class II and III [mutations] are very challenging to go after," Hoeflich said. "It really points to our mechanism for the [molecular] glue being important."

Hoeflich said Nested is particularly interested in developing NST-628 in KRAS G12C mutated tumors and is exploring the activity of the drug in tumors that are refractory to KRAS G12C inhibitors such as Amgen's Lumakras (sotorasib) and Mirati's Krazati (adagrasib).

NST-628 also demonstrated similar efficacy and greater tolerability compared to Genentech's MEK inhibitor Cotellic (cobimetinib) and to its investigational Raf inhibitor belvarafenib. Nested has also demonstrated NS-628's brain penetration and central nervous system anti-tumor activity in mouse models.

Based on the data gathered so far, the company expects to submit an investigational new drug application for NST-628 in January with the US Food and Drug Administration. If cleared by the agency, Nested plans to launch its first clinical trial site in Australia in January and begin enrolling patients by the end of Q1 2024.

Miles said Nested will enroll patients with NRAS-, KRAS-, and BRAF-altered tumors in this trial, including individuals with melanoma who harbor BRAF class II and class III mutated tumors. Researchers are particularly interested in seeing the activity of NST-628 in this subset of patients based on the strong activity seen in patient-derived xenograft models. The investigators will also enroll patients with active but controlled central nervous system disease.

The development program for NST-628 is intended to test the activity of the drug as a monotherapy and in combination with other agents. "We made our glue compound [as a monotherapy] but also to be a preferred combination partner," Hoeflich said. "You could combine it with any RAS or receptor inhibitor that is upstream. We really want [NST-628] to be the preferred downstream agent in terms of treating patients with alterations in this pathway."

In addition to NST-628, Nested has another pipeline program targeting a mutated transcription factor. Miles said the company expects to nominate a development candidate in this program in the first half of 2024 and file an investigational new drug application in early 2025.

Miles expects the funds Nested raised in last year's Series A financing to carry the company into 2025. In that time, Nested expects to achieve clinical proof of concept for NST-628 and identify other pipeline candidates.

He noted that while Nested could commercialize NST-628 by itself, partnering with an organization with a global reach would allow it to reach more markets and more patients. "We'll make that call as we go forward."