linrodostat (BMS-986205)

Linrodostat + nivolumab ± ipilimumab demonstrated a manageable safety profile. Kynurenine changes supported IDO1 pathway inhibition but did not correlate with response. A composite biomarker of low TDO2 expression plus high IFN-γ gene expression may predict response to linrodostat + nivolumab.

Response-adaptive surgical timing enhanced treatment response. IDO-inhibitor BMS986205 augmented pTR in patients with high IDO1-expression in baseline samples, indicating a need for identifying and targeting resistant nodes to immunotherapy. HPV-status-dependent signatures predicting response to immunotherapy in HNSCC warrant further study.

P1/2, N=255, Active, not recruiting, Bristol-Myers Squibb | Trial primary completion date: Apr 2024 --> Nov 2026

P1, N=18, Active, not recruiting, Northwestern University | Trial completion date: Jun 2025 --> Jun 2027 | Trial primary completion date: Feb 2024 --> Feb 2025

P2, N=45, Terminated, Thomas Jefferson University | Trial completion date: Dec 2025 --> Jun 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Dec 2025 --> Jun 2024; toxicity - per sponsor

P2, N=24, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Sep 2024 --> Sep 2025 | Trial primary completion date: Sep 2024 --> Sep 2025

P3, N=861, Active, not recruiting, Bristol-Myers Squibb | Trial primary completion date: Nov 2023 --> Apr 2025

Efforts are underway to identify the proteome-wide direct target of BMS in CLL cells. In conclusion, our limited and preliminary data suggest that BMS could be considered as a potential therapeutic strategy to target CLL cells with a double hit: by blocking the pro-survival effect of BCR signaling, one of the driving forces for CLL cell survival and proliferation, and by inhibiting IDO1/kynurenine action to restore sensitivity to key leukemia treatments.

The quantitative method was validated according to FDA, ICH and EMA guidelines, later applied: i) to assess the impact of selective inhibition of hIDO1 or hTDO (human tryptophan 2,3-dioxygenase) on the kynurenine pathway in A375 (melanoma), MDA-MB-231 (breast cancer), and U87 (glioblastoma) cell lines using multivariate analysis (MVA); ii) to determine the IC values of both well-known (i.e., epacadostat, linrodostat) and the novel hIDO1 inhibitor (i.e., BL5) in the aforementioned cell lines. The proposed LC-MS/MS method is reliable and robust. Furthermore, it is highly versatile and suitable for applications in the preclinical drug research and in vitro assays.

P1, N=18, Active, not recruiting, Northwestern University | N=30 --> 18 | Trial primary completion date: Feb 2022 --> Feb 2024

P2, N=24, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Sep 2023 --> Sep 2024 | Trial primary completion date: Sep 2023 --> Sep 2024

P2, N=142, Terminated, Bristol-Myers Squibb | N=69 --> 142 | Completed --> Terminated; Insufficient Enrollment

P1, N=30, Active, not recruiting, Northwestern University | Recruiting --> Active, not recruiting | Trial completion date: Jun 2023 --> Jun 2025

In this study, we compared the anti-tumor effects of YH29407, the best-in-class IDO1 inhibitor with improved pharmacodynamics and pharmacokinetics, with first and second-generation IDO1 inhibitors (epacadostat and BMS-986205, respectively). Our results suggest that an IDO1 inhibitor, YH29407, has enhanced PK/PD compared to previous IDO1 inhibitors by causing a change in the population of CD8 T cells including infiltrating T cells into the tumor. Ultimately, YH29407 overcame the limitations of the competing drugs and displayed potential as an immunotherapy strategy in combination with aPD-1.

P2, N=45, Active, not recruiting, Thomas Jefferson University | Recruiting --> Active, not recruiting

Taken together, we suggest that YH29407 is the best combination partner with immune checkpoint inhibitors for solid tumor.

Biolayer interferometry (BLI) studies show that IDO-PROTAC forms a binary complex with IDO protein with similar affinity comparable to parental compound – BMS986205. IDO-PROTACs induced IDO ubiquitination and the pretreatment with ubiquitin proteasome inhibitors, MG132 or MLN4924, inhibited IDO protein degradation...CONCLUSIONS This study developed a lead IDO-PROTAC compound that efficiently degrades IDO protein in human GBM cells with a moderate bioavailability and blood-brain barrier (BBB) penetration. Future work will focus on the enhancement of BBB penetration, increased bioavailability, and route of administration to improve IDO-PROTAC potency for combination with other forms of immunotherapy for GBM patient treatment.

CONCLUSIONS Similar to what was reported in older adult mice treated with simultaneous RT, anti-PD-1 mAb, and IDO enzyme inhibitor, advanced age negatively affected the survival in older adult human GBM patients treated with an analogous clinical approach. Future determination of whether the age-related biomarker profile can be used diagnostically and therapeutically is now under investigation.

BACKGROUND IDHwt glioblastoma with unmethylated MGMT gene promoter carries a poor prognosis. Accrual is ongoing for the MGMT promoter methylated cohort using the same regimen without withholding temozolomide. A randomized phase 2/3 trial is approved within the NRG network.

P2, N=295, Terminated, Bristol-Myers Squibb | N=504 --> 295 | Active, not recruiting --> Terminated; The standard of care for the patient population changed and we were unable to accrue any longer.

This work focuses on the identification of IDO1 inhibitors containing replacements or isosteres for the amide found in BMS-986205, an amide-containing, IDO1-selective inhibitor currently in phase III clinical trials. Detailed subsequently are efforts to identify a structurally differentiated IDO1 inhibitor via the pursuit of a variety of heterocyclic isosteres, leading to the discovery of highly potent, imidazopyridine-containing IDO1 inhibitors.

The novel IDO1 inhibitor, YH29407, with improved pharmacokinetic and pharmacodynamic profiles, showed antitumor inflammatory reprogramming leading to enhanced antitumor efficacy.

Given the substantial interest around this target for cancer immunotherapy, we sought to identify a structurally differentiated clinical candidate that performs comparably to linrodostat (BMS-986205) in terms of both in vitro potency and in vivo pharmacodynamic effect in a mouse xenograft model. On the basis of its preclinical profile, BMS-986242 was selected as a candidate for clinical development.

This global study in 14 countries is underway, with a target enrollment of 436 pts. Research Funding: Bristol Myers Squibb