Genentech, a member of the Roche Group, has terminated its four-year-old collaboration with NewLink Genetics to discover next-generation combination IDO-TDO (indoleamine-pyrrole 2,3-dioxygenase–tryptophan-2,3-dioxygenase) therapy compounds, nearly a year after the Roche subsidiary returned to NewLink rights to the cancer candidate GDC-0919 (navoximod).

The collaboration had been expected to generate more than $1.15 billion for NewLink when launched in October 2014, with Genentech paying NewLink $150 million upfront.

At the time, the companies reasoned that IDO pathway inhibitors represented a breakthrough approach to cancer therapy, as did treatments that combined IDO with TDO-specific inhibitors.

The companies cited earlier studies showing that the IDO pathway was active both within tumor cells as a direct defense against T-cell attack and within antigen-presenting cells in tumor-draining lymph nodes.

However, that thinking changed following a series of clinical trial setbacks experienced by Genentech/NewLink and other developers of IDO inhibitor treatments.

In June 2017, Genentech returned its GDC-0919 rights to NewLink, while agreeing to continue partnering with NewLink on discovering IDO-TDO treatment candidates.

That decision came almost a week after NewLink acknowledged that a Phase II study of another IDO inhibitor, indoximod, plus taxane chemotherapy—either docetaxel or paclitaxel—failed to meet its primary endpoints of a statistically significant difference in progression-free survival (PFS) compared with placebo plus taxane chemotherapy in patients with metastatic breast cancer.

In a regulatory filing today, NewLink disclosed that on May 10, it received notice from Genentech that it will terminate their collaboration effective in 180 days.

As a result, NewLink said, it will regain rights to IDO inhibitors, and receive from Genentech an “exclusive, worldwide, royalty-bearing, sublicensable license, under certain Genentech intellectual property, to research, develop, manufacture, and commercialize such next-generation compounds.” NewLink said it will be required to pay Genentech a low single-digit royalty on any sales of the compounds should it proceed to develop and commercialize them.

Also as a result of the termination, Genentech must assign to NewLink data arising from research that Genentech conducted on IDO inhibitors, NewLink added.

Retreat from IDO Inhibitors

Genentech follows the pattern of other biopharma giants in retreating from IDO inhibitor development.

On April 6, Incyte and Merck & Co. halted the Phase III ECHO-301/KEYNOTE-252 study (NCT02752074) assessing the combination of Incyte’s lead cancer immunotherapy candidate, the IDO1 inhibitor epacadostat (INCB024360), with Merck’s marketed blockbuster cancer immunotherapy Keytruda® (pembrolizumab) in melanoma.

The combination missed its first primary endpoint of improving PFS in the overall population compared to Keytruda monotherapy, the companies acknowledged.

Later last month, Bristol-Myers Squibb (BMS) halted two Phase III trials of its IDO1 inhibitor BMS-986205, which it acquired when it bought Flexus Biosciences for up-to-$1.25 billion in 2015, in combination with its blockbuster cancer immunotherapy Opdivo® (nivolumab) in head-and-neck cancer (NCT03386838), and in non-small-cell lung cancer (NCT03417037).

“Business objectives have changes,” BMS stated on the pages for both trials on

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