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uses them as “cellular flashlights” to see which genes they impact. The hope is to find drug targets for cancer that can’t be uncovered by traditional methods like the genetic sequencing of tumors, he says.
Through this method, Rgenix found, for instance, that certain microRNAs were altered in metastatic melanoma. That means the target of those microRNAs—a gene called apolipoprotein E (APOE), which Rgenix says is a tumor suppressor that regulates things like the immune system’s response to cancer—isn’t working the way it should. A drug like RGX-104 that dials up APOE, the thinking goes, could help the body’s defenses better respond to cancer.
Rgenix has found a few other targets this way, which have led to two other preclinical cancer drugs—RGS-202, and RGX-014. Neither are immunotherapies, which is why Tavazoie bristles at the idea that Rgenix is just trying to jump on the immuno-oncology bandwagon.
“We’re letting the science do the thinking—we’re not just a company that said, ‘oh we want to find immunotherapy drugs because they’re hot,” he says.
Yet immunotherapy is where Rgenix will have to start to make its mark. The startup found that a hormone receptor called liver X receptor (LXR), when activated with a drug, directly switches on APOE, and prompts an immune response. RGX-104, the company’s most advanced drug, is one such LXR activator.
But there’s a catch—LXR activators have a bit of a bad reputation in drug development. They’ve been studied as treatments for a variety of ailments—including heart disease, diabetes treatments, and prostate cancer—by several companies, among them GlaxoSmithKline. But not one has made it past Phase 1 testing.
LXR activators boosted triglyceride levels in animal tests—a worrisome sign for drugs meant to prevent heart attacks. One LXR drug, LXR-623, was tied in a Phase 1 trial to neurological problems like forgetfulness, confusion, and paranoia. The trial was stopped. Many of these LXR drugs were shelved as a result of such issues, according to University of Houston professor Chin-Yo Lin, who has published several papers on LXR and isn’t involved with Rgenix.
“Because of [these side effects], the enthusiasm for using these compounds in treating heart disease was dampened,” Lin says.
This checkered past is part of the reason Rgenix was able to scoop up RGX-104. GSK shelved that compound, as well as a group of other potential LXR drugs, a few years ago. But Rgenix, wanting to test its APOE hypothesis, found that GSK’s LXR drugs “were the most efficacious as anti-cancer agents,” Tavazoie says, and cut a deal for rights to them. “We tested [them] across multiple cancer types for which we found [they] were highly [effective],” he says.
Indeed, the FDA has given Rgenix orphan drug designations for RGX-104 in malignant melanoma (stages 2B through 4), glioblastoma, and ovarian cancer. The company has published several articles in peer-reviewed journals, among them a 2014 piece in Cell about switching on APOE with an LXR drug. Lin calls the Cell paper the best study he’s seen so far in terms of “characterizing and establishing LXR as a cancer target.”
“It’s very, very thorough work,” he says.
Importantly, Tavazoie notes, activating APOE, RGX-104 spurs on the innate immune system to fight cancer. That’s the body’s first line of defense, and an arm of the immune system that the “checkpoint inhibitor” cancer drugs like pembrolizumab (Keytruda) and nivolumab (Opdivo)—which have started to completely change cancer care—don’t impact. That’s important, because even with all the excitement surrounding checkpoint inhibitors, they don’t work for a majority of patients. RGX-104 could, in theory, complement and boost a checkpoint drug, enabling it to work in patients it otherwise wouldn’t. Tavazoie claims the company has seen additive potential in preclinical tests combining RGX-104 with some of the established immuno-oncology drugs.
Then again, Rgenix is a small player in a very big, competitive game. Companies all over the world are testing checkpoint inhibitors in tandem with a variety of molecules—IDO inhibitors, HDAC inhibitors, cancer vaccines, and more. Tavazoie counters that unlike some of these other approaches, that RGX-104 appears to shrink tumors—in animal studies, it should be noted—even on its own.
But is it safe? Tavazoie points out that elevated triglycerides for a late-stage cancer patient are a minor issue compared to the host of other side effects tied to chemotherapy and even checkpoint inhibitors, and that RGX-104 also hasn’t caused “clinically relevant increases” in triglycerides. He declined to comment on the neurological issues seen in LXR-623 trial, but said that preclinical data suggest RGX-104 will be safe and well tolerated in humans.
Lin is cautiously optimistic.
“The big question now is do they have the right compound to [activate LXR] without causing all the other problems?” he says. “Because if they can get past that, I think there’s some very promising Phase 2 and Phase 3 trials that we can look forward to.”
Photo of Manhattan courtesy of flickr user Jens karlsson via a Creative Commons license.