"These are tough-to-treat cancers and we knew they were tough-to-treat cancers going in," Oncomed Pharmaceuticals Inc. CEO Paul Hastings said, but results "all the way back to our xenograft data, as well as our phase Ib data, gave us every indication that these were indications which we should go forward with," and the company "did the right thing" by pursuing them, he said.

But it didn't work out. Hastings' remarks came as the Redwood City, Calif.-based company suffered setback number two in as many weeks, disclosing topline results from the randomized 145-patient phase II PINNACLE trial of anti-cancer stem cell antibody tarextumab (anti-Notch2/3, OMP-59R5), partnered with London-based Glaxosmithkline plc, in combination with etoposide plus either cisplatin or carboplatin chemotherapy in previously untreated patients with extensive-stage small-cell lung cancer.

Results with tarextumab showed no difference between the drug arm and the arm that used chemo plus placebo, thereby missing the primary endpoint of progression-free survival (PFS) and secondary endpoints of overall survival and biomarkers reflective of Notch pathway gene activation. Shares of Oncomed (NASDAQ:OMED) closed Monday at $4.01, down 83 cents, or 17.2 percent, after trading as low as $3.76.

"Given all the recent developments, we are currently carefully reviewing our portfolio and resource allocations," Hastings said, a process that began with the phase II miss last week when Notch-targeting demcizumab failed to outperform standard-of-care gemcitabine and Abraxane (nab-paclitaxel, Celgene Corp.) in pancreatic cancer on the trial's primary endpoint of PFS. Bayer AG, of Leverkusen, Germany, also walked away from an option to license Oncomed's early stage Wnt pathway inhibitors vantictumab and ipafricept. (See BioWorld Today, April 11, 2017.)

Monday's news grew slightly worse. "Simultaneously [with the missed endpoint in the phase II with tarextumab], we learned something and have decided to discontinue enrollment in the phase Ib trial of brontictuzumab, an anti-Notch1 antibody," Hastings said. "We were conducting a small and focused phase Ib trial of brontictuzumab in combination with Lonsurf [trifluridine and tipiracil, the colorectal cancer (CRC) drug from Taiho Oncology Inc. a subsidiary of Tokyo-based Taiho Pharmaceutical Co.] in third-line CRC patients. Based on initial early results from the first cohort of that trial, which showed that the combination of brontictuzumab and Lonsurf caused grade 3 diarrhea at the lowest doses of brontictuzumab, we've concluded [that] the combination of brontictuzumab plus chemotherapy is not tolerable in this patient population and we'll be discontinuing this trial also."

Jefferies analyst Brian Abrahams wanted specifics about what might be next. "You guys obviously have a lot of other pipeline candidates," he said. "As you take a look through the evolving preclinical and clinical data, I know there's still work to do to figure out the full plan, but [I'm] just wondering if you could give us some flavor for how you're thinking about potential prioritization, and then maybe how we should think about go-forward research and development expenses as you retool some of the earlier-stage programs."

Hastings said the company needs to "take a little bit of time and put our heads down and look at this pipeline and how to prioritize it." Officials will sort through "the discovery efforts we have ongoing as well as the clinical programs we have ongoing," he said. Oncomed "continue[s] to develop our immuno-oncology [I/O] pipeline, which gets a lot of attention and [represents] a lot of opportunity for us. That's as much as I can say on that right now, and we'll be talking about that real soon." The company expects to dose the first patient in the anti-TIGIT (T-cell immunoreceptor with Ig and ITIM domains) phase Ia trial – Oncomed's first I/O agent to reach the clinic – and to file the IND for its GITRL-Fc program soon as well. GITRL is a member of the tumor necrosis factor family of ligands and activates the co-stimulatory receptor glucocorticoid-induced tumor necrosis factor receptor, or GITR, to enhance T-cell modulated immune responses. Oncomed's GITRL-Fc agent is engineered using a single-gene, linkerless GITRL trimer.

'SOME TIME' TO WAIT FOR NEW VALUE: ANALYST

JMP Securities analyst Michael King pressed on the I/O program, asking what makes Oncomed's effort different from others. "There are obviously a number of different entities that are developing either TIGIT or GITR antibodies," he noted. Hastings acknowledged as much, saying that "each one of them has different targets and many of them have similar targets to each other. I think the jury is still out. Preclinically, we could sit here and tell you why we think [our approaches] would be better," but the proof won't come until the mechanisms are tested clinically, he said. "And that's what we're going to have to do."

Whatever else might be said, Oncomed pursued broad enough work to be able quit as necessary before the phase III stage, and Wells Fargo analyst Jim Birchenough offered "kudos for doing early randomized phase II studies. At least you've had the answers relatively early." Asked about the burn rate given recent discontinuations, CEO Hastings said he didn't "have anything to give you specifically right now." The firm surely will "spend less than we expected to spend," he added, "but the thing that's really important about doing these shot-on-goal trials is that you have to close them out." Good Clinical Practice rules bring to bear specific ways of finishing up, "so that's the tricky part there," he said. "What we're trying to do is extend our cash as much as we can. We have $156.9 million of cash at the end of the first quarter, which represents [as of] today cash through the third quarter of 2018."

Overall, Piper Jaffray analyst Edward Tenthoff didn't much like the picture. He downgraded his rating on Oncomed to "neutral" and dropped his price target to $5 from $17, given that the firm is now left with an early stage pipeline that includes an anti-DLL4/VEGF bispecific antibody navicixizumab, plus anti-RSPO antibody and the two I/O assets. Oncomed has started two phase Ib studies with navicixizumab combined with the FOLFIRI chemo regimen in second-line CRC and with paclitaxel in platinum-resistant ovarian cancer, which could trigger a $25 million opt-in payment from Summit, N.J.-based Celgene Corp. next year. (See BioWorld Today, Dec. 4, 2013.)

Also leery was Leerink analyst Michael Schmidt. "We've historically been cautious on the probability-of-success of Oncomed's cancer stem cell-targeting agents, and see more promise in the company's recent efforts in building a second area of focus in I/O," adding that "it will take some time until value-creating catalysts emerge." He said in a report that his firm is "less enthused about the anti-RSPO3 agent and the bispecific DLL4/VEGF inhibitor," given the recent stumbles, and held to his "market perform" rating on Oncomed shares.

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