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Newlink Genetics Corp


NewLink Genetics Corp. CEO Chuck Link says he believes the company's IDO pathway inhibitor indoximod still has potential and is differentiated from direct inhibitors of the target, even after news of Genentech Inc.'s exit from an IDO/TDO development deal.

Indoleamine 2,3-dioxygenase (IDO) is an enzyme that plays an important part in immune response. NewLink has developed a direct inhibitor of IDO called navoximod, as well as the unpartnered indoximod, which targets the mechanism indirectly.

Link believes there may still be a path forward for this class of drugs, although with a more measured approach to clinical development.

NewLink reported the end of its partnership with Roche subsidiary Genentech to develop navoximod (GDC-0919, NLG919) as well as other IDO/TDO inhibitors in a May 15 US Securities and Exchange Commission (SEC) filing. The company's stock closed down 3.5% at $5.18 following the disclosure.

Genentech paid NewLink $150m up front under their 2014 agreement to develop navoximod as well as other IDO inhibitors and tryptophan 2,3-dioxygenase (TDO) inhibitors. (Also see "NewLink-Genentech deal could be worth more than $1bn " - Scrip, 21 Oct, 2014.) Genentech announced in June 2017 that it was ending an agreement to co-develop navoximod after a lackluster presentation of results at the annual American Society of Clinical Oncology annual meeting. 

As NewLink noted in the SEC filing, "the agreement remained in force with respect to next-generation IDO/TDO inhibitors identified through the research program conducted under the Genentech Agreement."

The rights to the next-generation compounds now revert to NewLink, which will pay a low single-digit royalty to Genentech on any sales, should the compounds be developed and commercialized, according to the filing.

"These licenses, royalty obligations and assignments for next-generation compounds are in addition to the licenses, royalty obligations and assignments for NLG919 that went into effect in December 2017 when the Genentech Agreement terminated with respect to NLG919," the filing states.

Class Takes A Beating

IDO as a class looked enormously promising and big pharmas bought in fast and at high cost based on very early data, skipping mid-stage development. In addition to Roche, Merck & Co. Inc. and Bristol-Myers Squibb Co. started Phase III trials in a range of tumor types testing their PD-1 inhibitors in combination with Incyte Corp.'s epacadostat, the most advanced IDO inhibitor in the class. (Also see "Incyte Eyes Big Phase III IDO Expansion, NewLink Plans First Pivotal Trial" - Scrip, 4 May, 2017.)

The big wake-up call came in early April when Incyte and Merck announced that the combination of the PD-1 inhibitorKeytruda (pembrolizumab) and epacadostat failed against the Keytruda monotherapy comparator arm in the Phase III ECHO-201/KEYNOTE-252 study of 700 patients with metastatic melanoma. (Also see "Incyte/Merck's ECHO-301 Failure Casts More Shadow On IDO Space" - Scrip, 6 Apr, 2018.)

Bristol subsequently terminated Phase III studies of its in-house IDO inhibitor BMS-986205 in melanoma, head and neck, and lung cancer – an asset acquired through a high-priced acquisition of Flexus Biosciences in 2015. (Also see "Flexus flips IDO inhibitors to Bristol-Myers for up to $1.25bn" - Scrip, 24 Feb, 2015.) And Incyte announced the end of a number of pivotal trials involving epacadostat in its first quarter earnings call, though it will press on with development in some tumor types. (Also see " Merck's Keytruda Keeps Nipping At Opdivo's Heels" - Scrip, 1 May, 2018.)

NewLink Mulls Options

NewLink has ended plans to test indoximod in a Phase III study of melanoma and is reviewing the strategy for its programs after the wave of announcements terminating IDO development.

The company also “deprioritized” pancreatic cancer and will not proceed with a planned Phase II study of indoximod with AstraZeneca PLC's PD-L1 inhibitorImfinzi (durvalumab). (Also see "More IDO Issues: NewLink Drops Pancreatic Cancer Indication For Indoximod" - Scrip, 4 May, 2018.) The focus of Roche, Merck and Bristol was on building upon PD-1 blockade, but there are alternative development possibilities in combination with other types of therapies, commented NewLink CEO Chuck Link in an interview withScrip.

It's not just about combinations with PD-1 inhibitors and, furthermore, indoximod functions differently than specific enzymatic inhibitors, Link said. Whereas navoximod binds directly to IDO, indoximod interacts with multiple places along the IDO pathway to elicit immune responses.

At a high level, indoximod "mimics tryptophan, so the immune cells sense a normal level of tryptophan and stay active, not suppressed. Indoximod counteracts the consequences of IDO being expressed," the company has explained. ( (Also see "Scrip's Rough Guide To IDO" - Scrip, 18 May, 2017.))

"Our viewpoint is that there is still opportunity to evaluate indoximod, since it does have such a different mechanism of action," Link said.

During the company's first-quarter earnings call on May 3, NewLink said that its indoximod program continues to show promise. At the American Association for Cancer Research annual meeting in April, NewLink presented data showing what the company views as encouraging early data from a Phase Ib study of indoximod with radiation, followed by followed by maintenance indoximod and chemotherapy in diffuse intrinsic pontine glioma (DIPG), a fatal pediatric brain tumor. NewLink views these data as supportive of indoximod's differentiated IDO mechanism. The company has also developed a new formulation of indoximod that minimizes the pill burden.

Link noted that the company has data suggesting that indoximod is complementary to specific IDO inhibitors, perhaps targeting the pathway more completely, and that the combination might have potential for use in the salvage setting after PD-1 failures, Link said. Outside of melanoma, most tumors don't respond to PD-1 therapy and in those who do respond, the majority recur, he added.

It will also be important going forward to gather biomarker data to help identify who will respond to treatment.

"Maybe you could figure out the right salvage setting in PD-1 failures," Link told Scrip.

Further analyses of Merck/Incyte's failed ECHO-201/KEYNOTE-252 study – the largest study every done of the mechanism – may be helpful in this regard.

A More Cautious Path Forward?

With IDO, companies jumped over randomized Phase II studies and jumped into randomized Phase III trials.

"Now there is clearly diminished enthusiasm for the specific enzymatic inhibitors," Link said.

People are going back to the first principle of clinical trials, where you get a signal in a single-arm study then you proceed to a Phase II randomized study to assess how strong that signal is and identify biomarkers to understand which patients are more likely to respond, he said.

William Blair analyst Matt Phipps shared similar sentiments in a May 14 note based on a presentation by melanoma expert Jason Luke, assistant professor of medicine at the University of Chicago.

"Following the ECHO-301 trial failure with epacadostat and Keytruda, Dr. Luke feels it is important for clinicians and the industry to slow down in pushing cancer immunotherapy combinations forward and ensure proper diligence is done in early clinical stages. In particular, he looks for fundamental principles such as monotherapy activity, responses in refractory patients, and supporting biomarker data; and he encourages randomized Phase II data prior to Phase III trials, particularly in treatment-naïve melanoma patients," Phipps wrote.

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