Novartis AG didn’t say why the FDA has put off action until September – a delay of three months – on the sBLA for multiple sclerosis (MS) prospect Arzerra (ofatumumab, OMB-157), first cleared in October 2009 for chronic lymphocytic leukemia, but the holdup brought renewed attention to the bustling space, and Immunic Inc. – which held its R&D Day on May 27 – is coming on strong.
New York-based Immunic is developing the phase II-stage, oral IMU-838, an inhibitor of the enzyme dihydro-orotate dehydrogenase (DHODH). That’s the same mechanism of action as oral, once-daily Aubagio (teriflunomide, Sanofi SA), cleared for relapsing MS in September 2012. Aubagio became a blockbuster in 2015 and is widely used.
Immunic’s IMU-838 is in phase II trials not only for relapsing/remitting MS but also inflammatory bowel disease (IBD) and primary sclerosing cholangitis (PSC). Wainwright analyst Raghuram Selvaraju, starting coverage May 11 with a “buy” rating and $45 price target, called Immunic a “fast follower” and said IMU-838 could have “best-in-class” characteristics in MS. Shares (NASDAQ:IMUX) closed at $12.19, down 67 cents. IMU-838’s predecessor molecule, vidofludimus, went through much clinical testing and was dosed in more than 300 humans, thereby derisking the drug, in his view.
IMU-838 bears a 30-hour half-life, still suited for once-daily dosing while less likely to cause the systemic accumulation problems brought by Aubagio with its 18-day half-life. Side effects noted with the latter include hepatotoxicity, immunosuppression, hair whitening and alopecia. Top-line data from the 210-patient phase II, fully enrolled Emphasis trial with IMU-838 in MS are due in the third quarter of this year. Selvaraju predicted in his report that “superior safety and tolerability of IMU-838 should permit it to gain traction in other autoimmune and inflammatory conditions as well, [such as] IBD and PSC.” Immunic could commercialize the drug in PSC, an orphan indication, on its own, and seek partners in MS and IBD, he said.
Approved in MS is Tecfidera (dimethyl fumarate, Biogen Inc.), believed to act centrally by enhancing the nuclear factor erythroid 2 related factor 2 transcriptional pathway, green-lighted in March 2013, and sphingosine 1-phosphate (S1P) receptor modulator Gilenya (fingolimod, Novartis AG), given the nod in September 2010. There’s also Ocrevus (ocrelizumab, Roche Holding AG), an anti-CD20 therapy like Arzerra, cleared in March 2017, and another S1P therapy, Mayzent (siponimod, Novartis AG). New York-based Bristol Myers Squibb Co. (BMS) just launched Zeposia (ozanimod) in MS.
Piquing investor interest as well is the possibility for a COVID-19 treatment in IMU-838. Recently, the drug showed promising antiviral impact in vitro against the SARS-CoV-2 coronavirus, the pathogen responsible for the pandemic, and German regulators have given Immunic their nod for a phase II study. Called Calvid-1, the experiment is a prospective, multicenter, randomized, placebo-controlled, double-blinded effort in about 230 patients, with top-line results due later this year. Immunic in its present form came into being in January 2019, when then-German Immunic AG reverse-merged with Vital Therapies Inc., of San Francisco.
DHODH, vital for de novo pyrimidine ribonucleotide biosynthesis, has lately become a popular target. Cambridge, Mass.-based Clear Creek Bio Inc. acquired the inhibitor brequinar from BMS in November 2017 and gained an active IND in October of the following year to test the candidate in relapsed/refractory acute myeloid leukemia (AML). A phase Ib/IIa multicenter, open-label, non-randomized study is gauging the safety, tolerability and efficacy of dose-adjusted brequinar in 27 adult subjects.
Also working with a DHODH inhibitor in AML is Rhizen Pharmaceuticals SA, of La Chaux-de-Fonds, Switzerland. The company highlighted intriguing preclinical results with RP-7214 in a poster last fall during the AACR-NCI-EORTC conference in Boston. Described as acting via suppression of cellular pyrimidine pools and promoting differentiation to fully mature cells, the compound demonstrated single-agent activity in AML cell lines and antitumor activities in size and weight in an MV-4-11 human leukemia xenograft model. It also potentiated the activity of Xospata (gilteritinib) in reducing cell growth and inducing apoptosis, among other effects. Xospata, a FLT3/AXL kinase inhibitor from Tokyo-based Astellas Pharma Inc., was approved in AML in late 2018. When combined with cytarabine, RP-7214 reduced tumor size and tumor weight in MV-4-11 human leukemia xenograft model.
Late last year, Aslan Pharmaceuticals Ltd., of Singapore, pointed to preclinical data characterizing its ASLAN-003 in AML. Published in the November 2019 issue of Haematologica Journal, the findings showed a favorable toxicity profile, inhibiting protein synthesis and inducing differentiation of AML cell lines via activation of AP-1 transcription factors. The investigation also confirmed that ASLAN-003-meditated AP-1 activation is important for the reversal of the blocked differentiation of AML cells. Still more preclinical findings – this time with small-cell lung cancer as the target – appeared in Science Translational Medicine. The work was done at the Massachusetts Institute of Technology. Research has gone beyond MS and cancer. A study published in Neuron a year ago found that inhibiting DHODH prevents seizures in mouse models of Dravet syndrome.