Alx Oncology Inc. pulled down a $105 million series C equity financing to support the expansion into phase II trials with ALX-148, described as a next-generation CD47 myeloid checkpoint inhibitor, paired with other cancer therapeutics.
ALX-148 uses a “dead” Fc domain that does not bind to macrophages, thus reducing cytopenia and other toxicities associated with the class. “If you do what every other company does and simply go into this pathway with an antibody that has a functional Fc domain – and I’m defining function by the sequence that’s going to bind to the receptor on macrophages – if you go in with one molecule to do that, I think it’s a fool’s errand,” said Corey Goodman, Alx’s executive chairman and managing partner at Venbio Partners. “You are always going to be up against the difference of whether the macrophages are going to kill the cancer cell vs. whether they’re going to kill your own host cells. You’re always going to be up against this very narrow therapeutic index.”
Companies may “try to play games, titrate, dose and all of this mishigas,” but will run up against such bedevilments as anemia and thrombocytopenia if the Fc domain is active. “They’ll go with some different Fc domain, but all Fc domains, trust me, bind the Fc gamma receptor of macrophages. They may have eliminated binding to complement, this and that, but: Smokescreen. It all binds to the Fc receptor of macrophages,” which means researchers must resort to strategies such as alternative dosing schemes and selecting patients with very high red blood cells counts.
“You’re talking about terminal cancer patients,” he said. “These are often third-line, they’ve been through the kitchen sink, they’re within months of going to hospice. You have to cherry-pick patients who otherwise have normal hemoglobin levels.”
Vivo Capital was the lead investor in the series C round with other new investors including funds managed by Logos Capital, Janus Henderson, Foresite Capital, Cormorant Asset Management, BVF Partners and investor HBM Healthcare Investments. Existing investors Venbio and Lightstone Ventures also participated in the financing, Alx said.
Alx, of Burlingame, Calif., “went 200-fold higher in monkeys, above the dose where everybody else was getting these serious side effects,” and turned up no toxicities, Goodman noted. “That was the indication to us that this hypothesis was working.” Three phase Ib trials – in non-Hodgkin lymphoma, gastric cancer, and head and neck cancer, 140 patients total – have been conducted so far. “The company found early on, before it even went into the clinic, that there was remarkable synergy between our agent and the adaptive immunity checkpoint pathway, PD-1 and PD-L1,” he said.
“There’s no reason to do it as one molecule,” Goodman added. “In fact, everybody else who made the mistake of going in with a molecule that had a functional Fc domain are all doing combination studies – combinations with anticancer antibodies, with checkpoints, with chemo. We argued very simply that the way to turn this into a real drug that wouldn’t have side effects [and] that you could combine with any other anticancer antibody, any other checkpoint inhibitor of the PD-1, PD-L1 family, any cancer agent, the way to do it was to separate those functions.”
Alx unveiled data at the latest meetings of the American Society of Clinical Oncology and the American Society of Hematology. “Of course, there’s even more complete data today that investors saw,” Goodman said. The company, started in 2015, was two-and-a-half years behind its CD47 competition, including Forty Seven Inc., of Menlo Park, Calif., and Cambridge, Mass.-based Trillium Therapeutics Inc. “They were already in the clinic,” he said. “We hadn’t even made our protein yet. We were able to catch up so effectively because we’re safe,” thanks to the dead Fc domain.
There’s one company doing work similar to Alx’s, though: Celgene Corp., now part of Bristol-Myers Squibb Co., of New York. Two summers ago, Goodman said, he was chatting with a Celgene exec who “turned to me over drinks and said, ‘Corey, you guys were right. The way to go after this is with a dead Fc. We’re going to become your competition.’” In 2019, Celgene entered the clinic with a compound “slightly different but [designed according to] the same principle.” Celgene’s antibody targets the SIRP alpha receptor. “We also have such antibodies. We’ve never taken them to the clinic because we’ve seen no difference vs. blocking the signal, the ligand. I assumed they were going to take their CD47 antibody and simply mutate the Fc domain. I can only guess they chose the [strategy] they did because the molecule they put in the clinic was ready to go,” he said.
“We don’t know what they’re seeing [in the study],” Goodman said. “They’re quite stealth, so when people write reviews about CD47, half the time I don’t even see them mention what Celgene/BMS is doing” in the space. “There’s no motivation for them to discuss it anywhere.” Alx is “still sorting out some of the details” of its phase II campaign, he said, noting that the series C round was oversubscribed. “At least one trial with liquid cancers” is planned, with a push likely in acute myeloid leukemia. “We’re trying to sort that out.” There will be at least one experiment with an anti-PD-1 checkpoint inhibitor, too. “It may very well be head and neck again, but we haven’t had the FDA discussions.” At least one if not more trials will involve cancer antibodies. “The more money we raise, the more trials we will do,” he said.