AACR 2019 – Entinostat turns Syndax’s frown upside down

After two checkpoint combo trials flopped last month Syndax celebrates an unexpected win in a third.

Syndax Pharmaceuticals has not had much to write home about since floating on Nasdaq in 2016, and is currently trading at less than half of its IPO price. Results of a mid-stage melanoma study combining its lead asset, entinostat, with Keytruda, presented today at AACR, could give it hope.

That said, the company remains focused primarily on interim readout of a pivotal breast cancer trial of entinostat plus exemestane. It effectively suspended further work on anti-PD-(L)1 combo approaches after last month’s failure of two studies testing its asset with Bavencio and with Tecentriq.

Syndax says it remains optimistic about overall survival data from the exemestane combo trial, E2112, specifically testing entinostat in ER-positive, Her2-negative subjects. “Following availability of positive E2112 OS results, the company will determine whether to advance its entinostat-PD-1 combination programs into one or more registration trials,” Syndax said last month.

As such it is unclear whether the AACR data could focus Syndax’s mind a little more quickly. The fact that the company chose not to wait for the data presentation before raising $26.2m in stock and warrants last week suggests not.

Encore

The latest results come from the melanoma cohort of the Encore-601 trial, in which entinostat was combined with Keytruda. Since much of biotech is obsessed with overcoming resistance to checkpoint blockade, the study design’s most salient feature was that subjects had progressed on anti-PD-1 therapy.

Not only that, but 70% of the 53 evaluable patients had failed Yervoy too. Treatment with the entinostat/Keytruda combo resulted in one complete and nine partial confirmed responses, equivalent to a 19% overall remission rate.

This seems impressive, especially given the failures in the Tecentriq and Bavencio combo trials, Encore-602 and 603 respectively (Syndax suspends entinostat work after two trial flops, March 8, 2019).

Encore-601 too was on shaky ground, having had its colorectal cancer cohort shelved. A separate AACR abstract detailed a cohort of 72 NSCLC subjects who had received prior anti-PD-(L)1 therapy; entinostat plus Keytruda yielded a 10% overall response rate.

Entinostat’s clinical programme
Study Combination Details Trial ID
Encore-601 Keytruda combo NSCLC & melanoma data at AACR; colorectal cancer cohort shelved NCT02437136
Encore-602 Tecentriq combo PD-1-naive triple-negative breast cancer – failed NCT02708680
Encore-603 Bavencio combo epithelial ovarian cancer – failed NCT02915523
Encore-607 Keytruda combo NSCLC post Keytruda – deferred n/a
E2112* Exemestane combo HR+, Her2- breast cancer – interim analysis Q2 2019 NCT02115282
*Sponsored by the NCI.

It is not clear why Encore-601 succeeded when the Tecentriq and Bavencio combo trials failed. And being an HDAC inhibitor entinostat carries a lot of baggage.

Merck & Co’s Zolinza, one of the first HDAC inhibitors, failed to make an impression in its approved indication, non-Hodgkin’s lymphoma; other approved HDAC inhibitors include Spectrum’s Beleodaq, Novartis’s Farydak and Celgene’s Istodax, none of which has set the market alight.

HDAC (histone deacetylase) is an enzyme that affects the tightness with which DNA is wrapped around histones, and targeting it is therefore an example of an epigenetics-based approach.

Researchers at AACR suggested that blocking the enzyme could suppress myeloid-derived suppressor cells and T regulatory cells – both types damp down immune response – and increase the expression of target antigens. Such traits could make HDAC inhibition particularly relevant in the checkpoint blockade combo setting.

Encore-601’s lead investigator, Dr Ryan Sullivan, from Massachusetts General Hospital Cancer Center, said adding HDAC inhibition to anti-PD-1 treatment in PD-1-resistant tumours could “lead to re-recognition of the tumour by the immune system”. This would explain the pairing of entinostat with checkpoint blockade, in preference to entinostat monotherapy.

If the theory holds true it could reinvigorate other developers of HDAC inhibitors too. Over to Syndax.

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