In Chapter 2 of our 2017 book-length report, Cancer Immunotherapy: Building on Initial Successes to Improve Clinical Outcomes (published by Insight Pharma Reports), we discussed the major approved and emerging checkpoint inhibitors and checkpoint inhibitor modulators. Most of these, exemplified by the PD-1 inhibitors pembrolizumab (Merck’s Keytruda) and nivolumab (BMS’ Opdivo), and the PD-L1 inhibitor atezolizumab (Roche/ Genentech’s Tecentriq), are monoclonal antibodies (mAbs). Chapter 2 also included discussions of several small-molecule checkpoint inhibitor modulators, notably NewLink Genetics’ indoximod (D-1-methyl-tryptophan). Indoximod is an inhibitor of tryptophan catabolism via the kynurenine pathway (also known as the IDO pathway). IDO1 (indoleamine 2,3-dioxygenase 1) is the enzyme that catalyzes the first and rate-limiting step of that pathway.
We also discussed NewLink’s IDO pathway programs in the November 25, 2014 article on this blog.
Recently, on July 31, 2018, NewLink announced that it has decided to focus its indoximod clinical programs on treatment of three specific indications:
- recurrent pediatric brain tumors,
- front-line treatment of diffuse intrinsic pontine glioma (DIPG),
- front-line treatment of acute myeloid leukemia (AML).
These are relatively rare cancer indication with high unmet medical need. NewLink will also continue to advance NLG802, a prodrug of indoximod. NLG802 has demonstrated significantly higher pharmacokinetic exposure in preclinical models.
This program is in contrast to NewLink’s previous clinical trial focus on advanced metastatic melanoma, a more “mainstream” target for cancer immunotherapy. Specifically, the company had been conducting Phase 1/2 studies of combinations of indoximod with the leading checkpoint inhibitors pembrolizumab (Merck’s Keytruda) or nivolumab (Bristol-Myers Squibb’s Opdivo). On April 16, 2018, NewLink announced that it would not proceed to the randomization portion of these Phase 1/2 studies.
NewLink’s change in its clinical trial strategy, as well as its organizational and financial restructuring, was in reaction to the recent Phase 3 failure of Incyte’s IDO-inhibitor drug epacadostat (in combination with pembrolizumab), in late-stage melanoma.
At the time of NewLink’s initial announcement of its change in clinical trial strategy (April 18, 2018), the company’s shares were down 8% premarket. This was despite the simultaneous release of positive preliminary Phase 1 data on the effect of indoximod treatment of children with progressive brain tumors.
Organizational changes in support of NewLink’s new strategy
NewLink has completed a set of organizational changes designed to support its new strategy within its current financial capacity, to substantially cut future expenses, and to extend its cash runway into the second half of 2021. The company is reducing its headcount by approximately 30%, and has made several changes to its senior management, in support of its strategic realignment.
As a result of its organizational changes, NewLink anticipates its current cash runway to extend into the second half of 2021. This excludes any additional financings, proceeds from strategic alliances, and other receipts or expenditures. NewLink expects to expend approximately $10 million per quarter after completing its restructuring.
Mechanistic difference between epacadostat and indoximod
As we discussed in our November 25, 2104 blog post, IDO [and the related enzyme tryptophan-2,3-dioxygenase (TDO)] are enzymes that catalyze the first and rate-limiting step of tryptophan catabolism through the IDO pathway. The resulting depletion of tryptophan, an essential amino acid, inhibits T-cell proliferation. Moreover, the tryptophan metabolite kynurenine can induce development of immunosuppressive regulatory T cells (Tregs), as well as causing apoptosis of effector T cells, especially Th1 cells.
The IDO pathway is active in many types of cancer both within tumor cells and within antigen presenting cells (APCs) in tumor draining lymph nodes. This pathway can suppress T-cell activation within tumors, and also promote peripheral tolerance to tumor associated antigens. Via both of these mechanisms, the IDO pathway may enable the survival, growth, invasion and metastasis of malignant cells by preventing their recognition and destruction by the immune system. Inhibitors of the IDO pathway may therefore block these immunosuppressive pathways, and may therefore enhance the efficacy of checkpoint inhibitor drugs. Development of IDO pathway inhibitors thus constitute an immunotherapy 2.0 strategy.
Epacadostat, Incyte’s drug candidate that failed in the Phase 3 clinical trial, is a direct inhibitor of IDO1.
In contrast, D-1-methyl-tryptophan (NewLink’s indoximod) does not inhibit IDO at all, but inhibits the IDO-related enzyme IDO2. Indoximod also works to reverse the IDO-mediated inhibition of the immunoregulatory kinase mTOR (mammalian target of rapamycin), and specifically of mammalian target of rapamycin complex 1 (mTORC1), a protein complex that functions as a nutrient/energy/redox sensor and controls protein synthesis. mTORC1 appears to interpret indoximod as a highly potent mimetic of the amino acid L-tryptophan. It thus can reverse the effects of tryptophan catabolism mediated by the IDO pathway. It is possible that indoximod may be active against tumors driven by any tryptophan catabolic pathway. Indoximod’s unique and complex mechanism of action is not fully understood. Further investigations could thus result in new therapeutic insights. However, current results of mechanistic studies indicate the possibility that indoximod may be a superior agent to epacadostat in potentiating immunotherapeutic efficacy of checkpoint inhibitors.
Moreover, early Phase 2 clinical data on treatment of advanced melanoma patients with a combination of indoximod and the PD-1 inhibitor pembrolizumab indicated that after a median follow-up of 10.5 months, 60 evaluable patients experienced an overall response rate (ORR) of 52%, including six complete and 25 partial responses. The combination therapy was well tolerated.
However, as we discussed earlier, NewLink has shifted its clinical trial program away from melanoma to three rarer cancer indications with high unmet medical need. The outcome of the company’s efforts to develop indoximod awaits the results of the clinical trials in these cancer indications, which are now in the Phase 1b stage.
As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to your company, please contact us by phone or e-mail. We also welcome your comments on this or any other article on this blog.