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Impilo Therapeutics Bets on Stroma-Penetrating Platform to Bring Nucleic Acid Therapies to Cancer

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NEW YORK – Nucleic acid-based therapies haven't had much success treating cancer, but newly launched Impilo Therapeutics wants to change that.

San Diego-based Impilo, which officially launched this week, aims to develop nucleic acid-based therapies against solid tumors, beginning with a treatment that targets androgen receptor splice variants in patients with previously treated castration-resistant prostate cancer.

Impilo CEO David Slack has been working with nucleic acid-based therapies — including antisense oligonucleotides, small-interfering RNAs, messenger RNAs, and treatments that involve in vivo gene editing — for several decades and considers himself well positioned to finally bring this type of therapy into the commercial market for oncology. Slack has been pursuing this goal since the 1990s, when he worked for what is now Ionis Pharmaceuticals, a big name among nucleic acid-based therapeutics developers. Ionis' US Food and Drug Administration-approved drugs are all marketed to patients with genetic conditions, and its pipeline is not cancer-focused either, but this wasn't always the case, Slack recalled.

"Back in the mid-'90s, half of Ionis' pipeline was focused on oncology, predicated on early mouse data," he said, explaining that at the time, the company and several partners were enthusiastic enough about nucleic acid-based treatments to try to test them in the clinic against anti-cancer targets. But as time went on, researchers developed more sophisticated preclinical techniques. Instead of "putting a chunk of tumor in a mouse and getting the drug in there somehow," Slack said animal tumor models started to resemble and behave more and more like patients' tumors, including mice with specific genetic features that form tumors gradually. Within these advanced mouse models, researchers were able to identify the main barrier to treating solid tumors with nucleic acid-based therapies: the tumor stroma and microenvironment.

"Those models stopped looking so good," Slack said. "We would find most of the oligonucleotide, either antisense or siRNA, was sequestered in the outer layers of the stroma forming a kind of capsule layer around the primary tumor and metastases, as well. We found hardly any of the drug actually penetrated the tumor to get to the target."

This realization, alongside "many painful failures in the clinic," led companies in the space to largely abandon their oncology development programs, Slack said, and focus on other disease types where they had more success.

After living through those failures with colleagues who are now leading Impilo, Slack said he recognized that if the drug delivery method could penetrate the stroma, nucleic acid-based therapies might still have a shot at treating cancer.

Eventually, Impilo's scientific founder, Erkki Ruoslahti, landed on a peptide that could target its effects to the tumor through its affinity for certain integrins including alpha-v beta-3 and alpha-v beta-5, which are selectively expressed on tumor vasculature but not on normal, healthy vasculature elsewhere in the body. Once this peptide, called an internalizing RGD peptide, binds to these integrins, it gets cleaved by proteases upregulated in tumors and releases a peptide fragment that binds to a second receptor. This second receptor, called neuropilin, activates what Slack called an "active transport pathway" that a tumor normally uses for nutrient uptake through its outer layers.

"It's unique and really cool biology," Slack said of the science, which is now the basis of Impilo. He added that the penetration method that Impilo's agents use — namely the cleaved protein releasing a peptide fragment that penetrates via a pathway — are similar to how the SARS-CoV-2 virus gets into respiratory and other tissues. "That's how the virus penetrates tissues for its pathological impact," Slack said. "But we, of course, are trying to harness this to target tumors and to get our peptide through the layers of the tumor."

Impilo's approach involves conjugating this peptide to a nucleic acid-based therapy such that it delivers the treatment to the tumor. The firm believes this approach can deliver nucleic acid-based therapies including single-stranded antisense, double-stranded siRNA, immunostimulatory oligonucleotides, and gene-editing constructs.

Importantly, the platform — dubbed the tumor-penetrating nanocomplex, or TPN, platform — already has clinical data backing its activity, since Impilo's partner, Lisata Therapeutics, has been using this delivery method within an investigational drug it is developing, called LSTA1, for treating pancreatic and other solid tumors in combination with immunotherapy or chemotherapy.

'Both a product and a platform'

Scientifically, Impilo's platform for penetrating tumors and delivering these nucleic acid-based therapies is the core of the company's approach, but from a business standpoint, Slack said he envisions two simultaneous paths. On the one hand, Impilo will develop its own products using the TPN platform, but on the other, it also plans to license the platform to external partners that want to improve their chances of successfully getting their therapies into the tumor.

"We [have] both a product and a platform play," Slack said. For its internal programs, Impilo is focused mostly on developing antisense and siRNA therapies.

The lead program in mCRPC involves a drug for treating patients whose tumors are confirmed to have specific androgen receptor splice variants. These variants cause patients to become resistant to anti-androgen therapies. The oligonucleotide that Impilo is developing targets the androgen receptor splice variants 1, 6, and 9, among others. "Our oligo targets a common site where these splice variants occur," Slack said. While he was unable to share additional information about what that site is, Slack said Impilo will test patients for these variants in clinical trials and select those most likely to benefit.

"These patients do represent a very high unmet need population because the existing treatments no longer benefit them," he said. Impilo is now working on optimizing the therapy's delivery format and aiming to bring it into clinical trials in 2025.

Beyond mCRPC, the firm is in the process of working with an undisclosed partner on a treatment that targets a certain long noncoding RNA biomarker, though Slack was unable to share more. Impilo is also in the very early stages of research to determine if it can develop nucleic acid-based therapies against difficult-to-treat tumors harboring KRAS mutations. "We may have advantages, or at least different mechanisms of action, than the small molecule approaches to those KRAS mutations," Slack said, adding that this could be valuable since patients eventually develop resistance to these otherwise promising KRAS-targeting drugs.

"We still have to prove that we can adequately achieve a level of selectivity before we put that one on a path towards the clinic, but I'm hopeful that we will," he said.

Beyond these internal programs, Slack said the company is eager to exploit its technologies broadly. "We don't envision becoming an in vivo gene editing company, but we can help those folks deliver their [treatments]," he said. "We're not likely to become a messenger RNA company, but we do have delivery formats that can carry such large constructs."

As for the siRNAs and antisense therapies against a "litany of high-interest cancer targets" that have either failed in the clinic or haven't made it to the clinic at all because of delivery limitations, Slack believes Impilo can help partners by removing that limitation with its TPN platform.

As excited as Slack is about all these potential applications down the line, he recognizes that in these early days of the company, the priority is ensuring it has adequate resources to make these applications a reality. "We're in fundraising mode," he said, noting that although the firm has a "significant amount of seed funding," it is looking to raise more funds through Series A financing to fast track its lead program in prostate cancer to the clinic.

"We want to optimize that to make sure we're giving the best we can give to these patients," he said.