Entinostat Fails. Again.

In P3 this time. So are we done here? This outcome would be much more satisfying if it weren’t so freaking obvious.

Syndax announced today that its baseless, vile devotion to HDAC inhibitor entinostat would not be rewarded. E2112, the company’s last hope at a big market for entinostat and that elusive NDA, failed to achieve its primary OS endpoint. If you’re just joining us now, entinostat already failed to prolong PFS in E2112’s hormone-positive breast population (N=600). Entinostat has previously failed in combination with immunotherapy in triple-negative breast and ovarian and is – wait for it – “on hold” in NSCLC, colorectal and melanoma. It’s also been tested and quietly brushed away elsewhere; I know because I tried it years ago in a small, investigator-led study evaluating it in combination with Herceptin and Tykerb. Not only did I not respond, it led to such severe bone marrow suppression that I was dose reduced after the first cycle, had several subsequent dose delays and was ultimately kicked off for “progression.”

Back to E2112. Their brief and asinine statement is titled “ECOG-ACRIN … Provides Syndax Pharmaceuticals with Results of Phase 3 E2112 Trial”, as if introducing another party will distract from the reality that Syndax were the sole actors dragging this poisonous shitshow along for all these years. The announcement is brief and features only one idiotic quote, from its CMO, who expresses how “disappointed” he is and, with a shake of the head, notes that it was a “historically difficult-to-treat” population.

Um. No. It’s not a “historically difficult-to-treat” population. All breast cancers are not equal. TNBC is a barren hellscape of treatment options; HER2+ disease can be manageable with a growing number of targeted options. Both subtypes tend to be aggressive and present in younger women. Hormone-positive breast cancer is the dull spinster aunt, the most indolent version of the disease as we know it, the most common subtype, and it appears in older patients. It responds well to anti-hormonals and aromatase inhibitors, even more so with the advent of CDK 4/6 inhibitors. No cancer is a good cancer, but, I mean, come on. “Difficult to treat” relative to what? This is important because companies sometimes dare to take on a difficult indication, and I applaud that risk. Syndax is not one of those companies.

I’ll leave you with this: they were quick to update the “About Syndax” footer of their press release. This was the footer on May 12, just one week ago:

Syndax Pharmaceuticals is a clinical stage biopharmaceutical company developing an innovative pipeline of cancer therapies. The Company’s lead product candidate, entinostat, a once-weekly, oral, small molecule, class I HDAC inhibitor, is being tested in a Phase 3 combination trial with exemestane for treatment of advanced HR+, HER2- breast cancer and has been evaluated in combination with several approved PD-1/PD-(L)1 antagonists. The Company’s pipeline also includes axatilimab (SNDX-6352), a monoclonal antibody that blocks the colony stimulating factor 1 (CSF-1) receptor, and SNDX-5613, a highly selective inhibitor of the menin–MLL binding interaction.

And this accompanied the E2112 announcement this morning, May 21:

Syndax Pharmaceuticals is a clinical stage biopharmaceutical company developing an innovative pipeline of cancer therapies. The Company’s pipeline includes SNDX-5613, a highly selective inhibitor of the Menin–MLL binding interaction, axatilimab, a monoclonal antibody that blocks the colony stimulating factor 1 (CSF-1) receptor, and entinostat, a class I HDAC inhibitor.

Let’s throw some dirt over this bullshit, and if there are any biotech gods to protect us, let it never rise again.

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