ASCO: Don’t write off IDO yet, says NewLink

NewLink CMO Eugene Kennedy, M.D. (NewLink/LaVoie)

At last year’s ASCO, IDO inhibitors were being hailed as the next big thing in cancer immunotherapy, but a series of trial setbacks took that optimism down a notch. Now, armed with new data on its lead IDO drug indoximod, NewLink Genetics insists there is still hope for the class.

Today, the company revealed data from a single-arm phase 2 trial of indoximod given alongside checkpoint inhibitor drugs in 102 patients with advanced melanoma, suggesting that the combination achieved an overall response rate of 56%, with 19% of patients achieving a complete response. The median progression-free survival was greater than one year.

Out of the total group, 70 patients were treated with indoximod alongside Merck & Co’s Keytruda (pembrolizumab), with a small number also receiving Bristol-Myers Squibb’s Opdivo (nivolumab) and Yervoy (ipilumumab).

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It’s a welcome bit of positive news for NewLink, which has been one of the pathfinders for the IDO inhibitor class. It saw enthusiasm wane however, after a failed phase 3 trial of rival Incyte’s candidate epacadostat paired with Merck & Co’s Keytruda (pembrolizumab)—as well as negative data from other studies including a breast cancer trial with indoximod—was followed by the shuttering of IDO programs at Merck and Bristol-Myers Squibb, among others. It also cost NewLink a $1 billion partnership with Roche on indoximod follow-up navoximod.

While the run of bad news prompted a rethink at NewLink, which is in the midst of a review of all its clinical programs, it would be premature to write off IDO as target, the firm’s chief medical officer Eugene Kennedy, M.D., tells FierceBiotech from the side-lines at ASCO.

The results of the new melanoma trial as well as earlier data in acute myeloid leukemia (AML) and diffused intrinsic pontine glioma (DIPG), a form of brain cancer, are all cause for optimism about the program, he suggested.

“A sizable amount of data has been generated over approximately 20 years describing the central role of the IDO pathway in immune response,” according to Kennedy. “We continue to believe that indoximod, with its unique mechanism of action, may show efficacy in multiple combination therapies across a broad range of cancer indications.”

So what makes indoximod different? According to NewLink, it’s because the drug has a mechanism of action that differs from direct enzymatic inhibitors—a group that includes epacadostat—and may explain its efficacy where other drugs have failed.

Our work on the MOA of indoximod presented at AACR 2018 suggests indoximod mimics tryptophan, causing the immune cells to sense a normal level of tryptophan and remain active,” said Kennedy. “In so doing, indoximod increases the proliferation of effector T cells, appears to re-program the regulatory T-cells towards helper T-cells, and, finally, downregulates the IDO expression in dendritic cells—activity not seen in the presence of direct IDO inhibitors.”

Kennedy said it is notable that there was a lower percentage of PD-L1 positive patients in the trial, and higher response rates in the PD-L1 negative cohort, than those seen in trials with direct enzymatic inhibitors for patients with advanced melanoma.

Looking ahead, he says the next data read-out will be an update on the phase 1b study of indoximod in combination with radiation and maintenance chemotherapy for pediatric patients with DIPG at ISPNO in July. It will also be presenting updated data from its phase 1b/2 study of indoximod plus standard-of-care chemotherapy for patients with AML at a medical conference at the end of 2018.

NewLink has generated data in a number of clinical trials suggesting an improvement in response rates and patient outcomes when indoximod is administered in combination with multiple treatment regimens across a number of cancer indications thus far, including PD-1 inhibitors, chemotherapy, and radiation,” according to Kennedy.

“We believe that indoximod’s mechanism may be a contributing factor to the differentiated outcomes of cancer patients.”

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