Immunomet Therapeutics Inc.’s chief scientific officer, Sanghee Yoo, told BioWorld Today that $5.2 million in series A money will take the company to the start of phase I trials with oxidative phosphorylation (OXPHOS) inhibitor IM156 and fund operations into 2017, though the firm has “not provided specific details” on an immuno-oncology program, also in the pipeline, he said.
Spun from Hanall Pharmaceutical Co. Ltd., of Seoul, South Korea, in July 2015, Immunomet has taken aim at cancer metabolism with backing from round leader Mirae Asset Venture Investments plus participants Aju Tech, Gntech and Metavest. As part of the deal, Jae Joon Kim, director at Mirae, has joined the company’s board.
“We believe the OXPHOS technology may be applicable to a broad range of cancers,” Yoo said, and the first indication is likely a particularly problematic tumor type: glioblastoma. The technology was developed by Hanall scientists who have migrated to Immunomet. “The spinoff allows the company to focus and fully capitalize in the areas of cell metabolism, including cancer cells or immune cells and immuno-oncology, which our scientists have been working on for more than six years at Hanall and now bring this expertise to Immunomet,” he said.
OXPHOS has made headlines before, and with another tough oncology target. Scientists at the University of Texas MD Anderson Cancer Center published in 2014 their findings that, when a genetic mutation that propels pancreatic cancer is knocked out, remaining cells in the scar tissue can stay quietly alive, and later return as worsened disease that uses mitochondria to burgeon, as regular cells do.
The paper that appeared in Nature showed that, while effective therapies targeting specific genes can work very well at first, a mechanism remained in place that allowed the cancerous lesions to arise again, just as strong or even stronger. Enter OXPHOS inhibitors, which could help overcome that resistance to targeted therapies. However impressive, they often don’t get the job done completely.
Andrea Viale, the author of the paper, sought to find out whether pancreatic cancer stem cells need an active oncogene to survive, and began investigating KRAS, which mutated is known to be implicated in pancreatic ductal adenocarcinoma, an especially deadly form that promises only a 6 percent five-year survival rate.
In a mouse model, researchers induced KRAS-driven pancreatic cancer by giving mice doxycycline, and then turned KRAS off by taking away the antibiotic. Tumors dwindled in two or three weeks, but – with KRAS still turned off – returned in four or five months. It turned out that nests of surviving cells, kept vital by feeding off themselves, were found in fibrotic scar tissue left behind after KRAS-deprived tumors had appeared to regress completely. It wasn’t because of genetically selected new, dominant mutations, either, Viale found.
His lab was able to identify strong expression of genes that govern mitochondrial function and mitochondrial respiration, processes that operate by way of OXPHOS. His work also determined that the newly resistant cells relied less on glycolysis, the conversion of glucose to energy in the absence of oxygen, which is cancer’s usual modus operandi.
Acting on those discoveries, the team treated resistant cells and KRAS-dependent cells with the OXPHOS inhibitor oligomycin and saw mitochondrial respiration drop in both cell types. In time, oligomycin treatment reduced the ability of cells to form tumor spheres, boosting the mice’s survival. Two pathways regulated by KRAS, MEK and PI3K, are targeted by various drugs, and Viale’s group since has been studying combinations of MEK, PI3K and OXPHOS inhibitors to learn whether they might work synergistically. That is where the likes of newly funded Immunomet’s IM156 enter the picture. (MD Anderson’s Institute of Applied Cancer Science is developing an OXPHOS inhibitor.)
“There are currently less than 15 people in [Immunomet], but we are now headquartered in Houston where we will be conducting our development work at JLABS,” Yoo said. “Going forward, we plan to grow the company in Houston,” and already a strong scientific advisory board is in place, he said. The firm recently appointed Anthony Hoerning, who formerly led alliance management at Basel, Switzerland-based Novartis AG, as head of business development and licensing.
Another firm busy in the OXPHOS space is Khondrion BV, of Nijmegen, the Netherlands, which last December completed phase I trials with KH176, described as an orally bioavailable small molecule for the treatment of mitochondrial-related diseases. Khondrion said KH176 is a member of a new class of drugs for the control of oxidative and oxidation-reduction reaction pathologies. The phase I trials consisted of single ascending and multiple dosing arms, both of them randomized, placebo-controlled and double-blinded. Khondrion determined that KH176 is well tolerated by healthy volunteers and has an excellent pharmacokinetic profile, the firm said, noting that mitochondrial failure, due to either mutations in the mitochondrial genome or the nuclear DNA, is associated with a broad range of diseases, including orphan diseases of the OXPHOS system such as Leigh disease, and the syndromes MELAS (mitochondrial encephalopathy lactic acidosis with stroke-like episodes) and LHON (Leber hereditary optic neuropathy).