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Immuneering Takes Lead Agent Into Phase II Trial Betting on Universal RAS Inhibition in Solid Tumors

Cancer genetics

NEW YORK – Immuneering Corp. has scored back-to-back milestones this month within the development program for its lead oncology candidate IMM-1-104.

First, the US Food and Drug Administration granted fast-track designation to the RAS inhibitor in pancreatic cancer. Then, the Cambridge, Massachusetts-based firm treated the first patient with RAS-mutant cancer with IMM-1-104 in the Phase IIa portion of an ongoing clinical trial and, just days later, reported encouraging preliminary Phase I data from the first part of that trial.

"We're really excited to have the Phase II underway," said Ben Zeskind, CEO, president, and cofounder of Immuneering. The company launched 16 years ago, Zeskind recalled, when everyone had begun talking about personalized medicine.

According to Zeskind, back then, everyone was focused on using genomics and informatics to target drugs to narrower and narrower patient populations, "until eventually, there'd be one bespoke pill for every patient." But Immuneering wanted to use biomarkers, molecular tests, and informatics tools to develop drugs that facilitated personalized treatments for a wider population.

In line with the founding vision for the company, the ongoing IMM-1-104 clinical trial began with a biomarker-guided but tumor-agnostic approach. Patients were eligible if they had any advanced, previously treated solid tumor harboring a RAS activating mutation, including in KRAS, NRAS, or HRAS. In the Phase IIa portion of the trial, Immuneering is enrolling patients to histology-specific arms, including advanced, RAS-mutant melanoma, RAS-mutant non-small cell lung cancer, or pancreatic cancer patients regardless of mutation status.

Depending on the number of prior treatments patients have received, they will receive either IMM-1-104 monotherapy or the agent combined with one of two chemotherapy regimens. Immuneering expects to enroll 210 patients into the trial and to share Phase IIa data from multiple arms this year.

Although the firm opted to advance its lead candidate in specific cancer types, Zeskind said Immuneering believes IMM-1-104 has tissue-agnostic potential. "Any patient with any mutation in RAS has the potential to respond [to this drug]," he said. "It doesn't mean every patient will, but there's nothing in the mechanism that is inherently specific to any one RAS mutation over another."

This is because the drug is designed to target the pathway at the level of MEK, which is downstream of RAS and RAF. "In theory, any mutation in either of those genes should be blocked," he said, adding that first-generation MEK inhibitors had limitations that Immuneering believes its agent, dubbed a "universal RAS inhibitor," can overcome.

"Prior MEK inhibitors have been very poorly tolerated and limited to RAF-mutant disease, mainly in combination with BRAF inhibitors," he noted.

The reason for this is because most of those earlier MEK inhibitors were chronic inhibitors, meaning they shut down the pathway 24/7, he said. "And the thing is, we have the MAP kinase pathway for reasons other than for cancer cells to hijack it. … There are a lot of healthy cells that use the MAP kinase pathway, and if you completely shut it down permanently, it has a lot of harmful effects on those healthy cells."

Using a computational platform to analyze informatics data, Immuneering found that the time of administration was crucial for the activity of MEK inhibitors. "At early time points, like three hours and six hours [post-treatment], those first-generation MEK inhibitors were doing a good job of counteracting disease-associated gene expression profiles, but by 24 hours, they were actually making things worse," Zeskind said. This led to the discovery that healthy cells and cancer cells rely on the MAP kinase pathway differently.

Zeskind likes to use an analogy to explain these differences. Cancer cells, he said, are "always on" and "need MAP kinase signaling the way a person needs air." Healthy cells, on the other hand, also need MAP kinase signaling, but more sporadically, akin to the way a person needs hydration.

"A couple hours without a drink of water, you're fine. Then, a few hours later, you start to get pretty thirsty," Zeskind said, continuing the analogy. "Then, it's really not until 24 hours that it becomes a medical dehydration situation."

With a mechanism called deep cyclic inhibition, Zeskind said Immuneering is trying to "come in with a pulse of very high inhibition to really shut down the pathway hard … and really choke the tumor for several hours of its supply of MAP kinase signaling, but then release."

This represents a departure from what many others in the field have tried to do with small molecule inhibitors, which is extend the half-life longer and longer, he said. Immuneering's approach involves a short, but more potent, half-life.

"You give the healthy cells the pathway back by the end of the day — their drink of water, if you will — and the hypothesis is that would provide improved tolerability over chronic inhibition of MEK," he explained.

Up to this point, Immuneering has explored that hypothesis largely preclinically. Now, with the Phase I/IIa trial underway, the firm has some data on the preliminary safety and tolerability of IMM-1-104. Earlier this month, the firm reported that, of 41 patients on IMM-1-104 in the Phase I portion of this trial, no one experienced grade 4 treatment-related adverse events, and only one patient experienced grade 3 rash that was reversible. The firm has selected a recommended Phase II dose for IMM-1-104 based on the Phase I data and is moving ahead with further testing.

The preliminary Phase I readout also showed that, of 22 patients who underwent circulating tumor DNA analysis, none acquired RAS mutations after getting IMM-1-104. Only two patients acquired alterations in MAPK pathway genes, but Zeskind noted that these patients had received a dose of IMM-1-104 that Immuneering considered to be "sub-clinical."

Although the data from this trial is still too early for the firm to draw any definitive efficacy conclusions, Immuneering is encouraged by the fact that 53 percent of patients treated with IMM-1-104 experienced a regression of at least one target lesion when given one of two higher dose levels of the drug, and that one patient received the treatment for over five months with no treatment-related adverse events.

In the Phase II portion of the trial, Zeskind said the decision to focus on patients with pancreatic cancer, melanoma, and non-small cell lung cancer was rooted in extensive preclinical modeling. "We were able to say which types of cancer were most likely to have the largest numbers of patients whose tumors are dependent on the MAP kinase pathway," he said.

Zeskind underscored that the decision to narrow the trial to specific histologies wasn't because the firm thought that patients with other types of tumors wouldn't respond, but rather the aim was to home in on patient subgroups likely to be best responders to IMM-1-104.

Plus, tumor-agnostic drug development, from a regulatory standpoint, is trickier, Zeskind acknowledged. "We're open to that at the right time," he said. "It's just that the clinical development path is a little more complicated [with a tumor-agnostic indication]. … When you go with specific tumor types, there's a clear standard of care established and clear benchmarks to improve on."

As for the choice to broaden the enrollment criteria to include pancreatic cancer patients with those with known RAS mutations but limit the melanoma and NSCLC enrollment to those with confirmed mutations, Zeskind reasoned "that approximately 90 percent of pancreatic cancer patients have RAS mutations at baseline, and even among the other 10 percent, a lot of them are also dependent on the MAP kinase pathway."

Further biomarker testing will be necessary for pancreatic cancer patients once they're enrolled on the trial, he clarified, but not requiring it at the outset is expected to speed up and streamline the enrollment process. "We're very engaged in the genetics of these patients," he said. "Just because [RAS mutation testing] is not an enrollment criteria, doesn't mean we're not looking at it."

IMM-1-104 is Immuneering's most advanced therapeutic candidate, but the firm is eager to advance earlier-stage molecules including another RAS inhibitor, IMM-6-415, which it expects to enter a Phase I/IIa trial in RAS- or RAF-mutant solid tumors any day now.

"This is also a deep cyclic inhibitor of the MAP kinase pathway, but it has a different, faster cadence," Zeskind said. The drug is designed to be given twice daily, and the firm thinks that the faster cadence can be "optimized for different biologies," including BRAF-mutant cancers. "We'll take patients with any mutations in RAS or RAF," he noted. "We're really aiming for a broad, inclusive group."

Beyond those two drugs, the firm has several discovery-stage programs which aren't public yet, but that use the same concept of deep cyclic inhibition. "We believe we can hit at these pathways very hard and do it in a way that is well tolerated," Zeskind said.