I was prompted to write this summary of the IDO inhibitor field by a recent, excellent, review by G. Prendergast and A. Muller about the history of IDO1 inhibitors. I can only urge anyone who wants to obtain deeper knowledge on the topic to read this review. In the following, I am going to focus on the different mechanism of action between the most advanced IDO1 inhibitors currently in clinical trials and compare, wherever feasible, clinical trials of IDO inhibitors with each other and with anti-PD1/CTLA4 combinations.
Indoleamine 2,3-dioxygenase-1 (IDO1) is an enzyme that breaks down the amino acid tryptophan. This has two significant consequences for the immune system: low levels of tryptophan 1) impair the activation of anti-tumor T cells and 2) cause the activation of immune-suppressive cells like regulatory T cells and myeloid-derived suppressor cells.
IDO1 is expressed in many human tumors, either on the tumor cells themselves or on surrounding cells. Importantly, unlike general suppressors of the immune system, like PD-1 and especially CTLA-4, the IDO-1 expression is only induced by an activated immune system. This predicts a more benign safety profile for the pharmacologic inhibition of IDO1 as compared to anti-PD-1/CTLA-4 which e.g. in melanoma have Grade ≥ 3 treatment-related adverse events in 55% of cases.
Indeed, all 4 IDO inhibitors mentioned in this article (Epacadostat, Indoximod, Navoximod and BMS-986205) are well tolerated with Grade ≥ 3 treatment-related adverse events ranging from 11-26% (here, here, here, and here).
IDO inhibition on its own has only limited anti-tumor efficacy. However, the real value of IDO inhibitors shows by combinations with other drugs, most importantly anti-PD-1.
Mechanism of action and potency
I want to focus on the following on the IDO inhibitors that progressed furthest in clinical trials: Epacadostat, Indoximod, Navoximod and BMS-986205.
Epacadostat, developed by Incyte (NASDAQ:INCY), is a highly selective inhibitor of tryptophan binding to IDO1 with an IC50 of 12 nmol/L (IC50 is a measure of how much of a substance is needed to inhibit a biological process by half; so the lower the IC50, the better). In preclinical assays in tumor-bearing mice, Epacadostat reduced kynurenine levels, which is the degradation product of tryptophan, by about 90%.
Indoximod (1-methyl-D-tryptophan), developed by NewLink Genetics (NASDAQ:NLNK), in comparison to all other IDO1 inhibitors has a different mechanism of action. It is not a direct inhibitor of IDO1 but instead acts as a high-potency mimetic of tryptophan. Indoximod re-activates signaling that was abolished by tryptophan depletion and counters the adverse effects of IDO1 expression on T-cells. Thus, in distinction to other IDO1 inhibitors, Indoximod acts directly on the T cells. Theoretically, this would allow Indoximod to be active in tumors that are driven by IDO2 or TDO as well.
Navoximod is a direct IDO1 inhibitor also from NewLink Genetics. Navoximod inhibits IDO1 with an IC50 of only 75 nmol/L, which is 6-fold higher than Epacadostat. In preclinical tests, Navoximod reduced plasma kynurenine by just 50% (compared to 90% of Epacadostat) in mice. Navoximod was licensed to Genentech, which however returned the license to NewLink Genetics, after disappointing phase 1 results. I think that the low IDO inhibition is a plausible reason for the mediocre efficacy results.
BMS-986205 is a direct IDO inhibitor from Bristol-Myers Squibb (NASDAQ:BMY) (which it bought in a 1.25 billion deal from Flexus Biosciences). It is an irreversible IDO1 inhibitor with an IC50 of 2 nmol/L. So clearly, BMS-986205 is the best IDO1 inhibitor tested right now. While there appears to be a critical IDO1 inhibition threshold somewhere between the 12 nmol/L of Epacadostat and 75 nmol/L of Navoximod, it remains to be seen whether an even stronger IDO1 inhibitor will have a benefit on the clinical outcome.
Due to this strong IDO inhibition, BMS-986205 is tested in a once a day setting, in contrast to Epacadostat and Indoximod, which are supposed to be taken in a BID schedule (=twice a day). This could be an important differentiator in a crowded IDO inhibitor space.
Efficacies of IDO inhibitors with anti-PD-1
Since IDO1 inhibitors + anti-PD-1 combinations are perceived as the new, but safer, anti-PD-1/CTLA-4 combo, I want to compare the so far reported efficacies of IDO inhibitors + anti-PD-1 and contrast them to the Nivolumab + Ipilimumab combination (Table 1). It is always to be taken with caution, if different, early stage, clinical trials are compared to each other, but in general, the IDO/PD-1 combinations have a remarkably similar efficacy compared with Nivo+Ipi.
|Epacadostat||56% ORR (n=63) 12.4m PFS 1||35% ORR (n=40) 2||35% ORR (n=37) 2|| |
47% ORR (n=19)* 2
|Indoximod||61% ORR (n=51) 12.9m PFS 3||-||-||-|
|BMS-986205||-||-||32% ORR (n=25) 4||-|
|Nivolumab + Ipilimumab||58% ORR (n=314) 11.5m PFS 5||47% ORR (n=78)** 6||39% ORR (n=26) 4.3m PFS 7||42% ORR (n=550) 11.6m PFS** 8|
Table 1. Efficacies of IDO1 inhibitor + anti-PD-1 combinations compared to results from Nivolumab + Ipilimumab. *Patients with 0-1 prior treatments. **Treatment-naive patients only.
Comparing Epacadostat and Indoximod in melanoma with each other, it is of note that they have virtually identical response rates and median progression-free survival (PFS). Given their different mechanism of action on the IDO pathway, I find it quite remarkable (and encouraging) how similar they are.
One notable distinction between the Epacadostat and Indoximod trials is the number of treatment-naive patients. While in the phase II Epacadostat trial about 83% of patients were treatment naive, only 55% of patients hadn’t received any treatment in the phase II trial of Indoximod.
I mentioned before that it remains to be seen whether the superior IDO1 inhibition of BMS-986205 would result in higher response rates. In bladder cancer, it doesn’t seem that BMS-986205 increases the ORR as compared to Epacadostat. Again, it is always problematic to compare two early-stage trials with each other, but I think it is an interesting aspect to keep in mind.
Epacadostat will be the first IDO1 inhibitor to complete a phase III trial in melanoma, which has, based on clinicaltrials.gov, an expected primary completion date of May 2018. Indoximod follows more than a year later with the primary phase 3 completion expected in December 2019. Notably, while BMS-986205 has no efficacy data available in melanoma as of yet, Bristol-Myers Squibb has started a Phase 3 trial in melanoma, with the primary completion expected to be in August 2020 (notably only a couple of months later than the completion of Indoximod). So in this regard, BMS has done an excellent job to not fall behind the competition too far.
In general, I see a bright future for IDO inhibitor combinations (except for Navoximod) since they achieve similar response rates as anti-PD-1/CTLA-4 combos throughout different indications, with significantly lower treatment-related toxicities. If the observed objective responses and median progression-free survivals convert into similar overall survival benefits as with anti-PD1/CTLA-4, then I see no reason why IDO1 inhibitors should not be approved.
Last but not least, I think that all the IDO inhibitors (again, except Navoximod) have a good chance of approval. Since, so far, Epacadostat and Indoximod produce virtually identical results in melanoma, I see no reason why Epacadostat should have a higher likelihood of approval than Indoximod in this particular indication. As Bristol-Myers Squibb aggressively presses forward with the phase 3 trial of BMS-986205 in melanoma, I also expect similar or even better data compared to the other two IDO inhibitors.
Obviously, IDO inhibitors are still in development, and it is not a given that they will be approved. The failure to obtain approval will result in a reduced market capitalization. Especially for smaller companies like NewLink Genetics, there is always the risk of dilution. BMS faces a lawsuit from Incyte, which claims that intellectual property belonging to Incyte was used by Flexus Biosciences.
Disclosure: I am/we are long NLNK.
I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.