Merck & Co. Inc.'s deal to take over Oncoethix SA for $110 million up front and $265 million in potential milestone payments raised not only the increasingly high profile of bromodomain (BET) inhibitors, but also the hopes of others in the space for similarly lucrative deals.
Lausanne, Switzerland-based Oncoethix has oral OTX015 in phase Ib trials for hematological malignancies and advanced solid tumors. BET proteins play a pivotal role in regulating the transcription of key regulators of cancer cell growth and survival, including c-Myc.
A number of players are trying their hands with the BET research. Farthest along clinically is Resverlogix Corp., of Calgary, Alberta. The firm has RVX-208 ready to enter phase III trials, not in cancer but in heart trouble. This fall, the firm disclosed data showing the compound gained a 77 percent reduction in major adverse cardiac events in diabetic patients, an "absolutely unprecedented" outcome, CEO Donald McCaffrey told BioWorld Today, adding that he was "very surprised" by the Oncoethix deal. "We're pretty excited about what a single molecule can do," he said.
Resverlogix spinout Zenith Epigenetics Inc., of San Francisco, has oncology work at the preclinical stage. "Zenith is actually the next generation," McCaffrey said. "It had to retool and head back to the clinic with a different molecule, but it will catch and surpass Oncoethix's molecule quite fast." McCaffrey, who served as CEO during Zenith's first year and still chairs the board, said his investigators have been watching the progress of Oncoethix. "We've run their data through our models," he said. "I'd much rather have our program, but we weren't up for sale right now. We're going to further develop value creation" with the platform.
In the oncology case with BET inhibitors, "you're turning off oncogenes that are not wanted," McCaffrey said. "In the cardiovascular [area], we're altering protein-to-protein interactions, increasing good cholesterol, decreasing thrombosis. There's a series of events that takes place. It's not a single target like most drug development, but a cascade-pathway effect in a positive manner."
Resverlogix's RVX-208 is a first-in-class small molecule that selectively inhibits BET bromodomains, removing atherosclerotic plaque via reverse cholesterol transport and boosting production of apolipoprotein A-I (ApoA-I), the building block of functional high-density lipoprotein, the "good" cholesterol. ApoA-I enhancement and glucose lowering also have been reported to help patients with Alzheimer's disease and diabetes, respectively. The compound also has anti-inflammatory effects, including effects on Interleukin-6 inhibition, vascular cell adhesion-1 and monocyte chemotactic protein-1, factors known to be involved in atherosclerosis and plaque stability. (See BioWorld Today, Aug. 28, 2012.)
Julie Cherrington, CEO of Zenith, noted "some subtle differences in the selectivity profiles" between the BET compounds pursued by Resverlogix and those with her firm. "There are four [bromodomain] family members and each one of them has three domains, but we really focus on two of those domains," she said. "Our inhibitors in oncology and in autoimmunity, which is another big area that our company is focused in inhibit all four family members in both domains. The Resverlogix inhibitors are more selective. There's a lot of biology yet to emerge on the relative applications of compounds that inhibit both of those domains vs. one or the other. That's an area we are hoping to lead the exploration of, and unravel some novel biology."
SHUTTING DOWN THE MUTATION ROUTE
Cherrington told BioWorld Today she was "certainly pleased with the [Merck/Oncoethix] news. It was a nice deal for a single compound with some clinical activity reported in hematological malignancies to date. We think we have some nice differentiating features, and we're focused a lot on the next-generation compounds, looking at covalent inhibitors and BD-1-specific inhibitors."
The BET space generally is of "hot interest among pharma and biotech," she said, and Whitehouse Station, N.J.-based Merck has put a lot of emphasis "and rightly so, on their immuno-oncology effort. To be able to test the BET inhibitors in combination there is going to hopefully provide additional benefit separate from either one of those alone, and potentially even get into new indications that aren't going to be approachable by either modality."
Oncoethix's OTX015 targets the BET bromodomain proteins 2, 3, and 4. "The reason all of the other [BET] companies except for Resverlogix are in oncology is because of the toxicology profile, mostly because they're pan inhibitors," McCaffrey said. "They're hitting more than they need to, and showing up with thrombocytopenia. All of the U.S.-based ones in clinical trials have been slapped with very serious extra cardiovascular monitoring. I don't know if that's something Oncoethix will face in the future or not."
Another BET player is Cambridge, Mass-based Constellation Pharmaceuticals Inc., which signed an epigenetics deal with Genentech, part of Roche AG, of Basel, Switzerland, in early 2012. Included in the arrangement is a buyout option that would bring aboard Constellation's BET program. "The interesting part about the Constellation deal is that it was $95 million in up-front fees for [preclinical work]," McCaffrey said. "That's amazing, about nine times higher than industry average. The excitement level here is quite high." (See BioWorld Today, Jan. 17, 2012.)
BET interest gained impetus in April 2013, with published research on "super-enhancer" sites that help cancers grow. "When you beat down a specific oncology gene, they mutate through other oncology genes via super-enhancer sites, which are highly sensitive to bromodomain inhibition," McCaffrey said. "So you're basically shutting down the mutation route at the same time you're killing the oncology cell."