sirpiglenastat (DRP-104)

Using multimodal single-cell sequencing and ex vivo functional assays, we demonstrate that DRP-104 reverses T cell exhaustion, decreases Tregs, and enhances the function of CD4 and CD8 T cells, culminating in an improved response to anti-PD1 therapy. Our preclinical findings provide compelling evidence that DRP-104, currently in clinical trials, offers a promising therapeutic approach for treating patients with KEAP1 mutant lung cancer.

The glutamine antagonist DRP-104 blocks purine synthesis and combines with checkpoint inhibitors to promote antitumor immunity in KEAP1/NRF2-mutant lung cancers.

P1/2, N=27, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Phase classification: P1b/2 --> P1/2

P1/2, N=27, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Not yet recruiting --> Recruiting

P1/2, N=27, Not yet recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Preclinical work from our laboratory and others has revealed that the DNAJB1-PRKACA fusion results in a metabolic rewiring of the tumor characterized by glutamine dependence. This study has been registered under NCT06027086 and is expected to begin enrollment in December 2023. Clinical trial information: NCT06027086.

P2a, N=61, Terminated, Dracen Pharmaceuticals, Inc. | N=246 --> 61 | Trial completion date: Dec 2023 --> Mar 2023 | Active, not recruiting --> Terminated; Company decision to closing study and discontinue further patient enrollment.

Overall, we find that DRP-104 impairs the growth of KEAP1 mutant tumors through both targeting of tumor intrinsic metabolic vulnerabilities and through tumor extrinsic immunostimulatory mechanisms such as promoting the expansion of functional anti-tumor T cell populations. This data provides additional rationale for the ongoing phase I/II clinical trial (NCT04471415) using DRP-104 in NSCLC with mutations in KEAP1 as well as for combining DRP-104 with checkpoint blockade.

P2a, N=246, Active, not recruiting, Dracen Pharmaceuticals, Inc. | Recruiting --> Active, not recruiting

Our data suggest that broad glutamine antagonism using sirpiglenastat (DRP-104) has therapeutic potential in HNSCC by dismantling cancer metabolism and sensitizing cells to additional perturbations leading to specific cell death. A clinical trial of sirpiglenastat (DRP-104) is currently ongoing (NCT04471415).

Our studies will provide a rationale for sub-stratification of KEAP1-mutant patients with hyperactivation of the NRF2 pathway, which is a genetic subset of NSCLC with great clinical need, as treatment candidates for sirpiglenastat. A first-in-human clinical trial of sirpiglenastat (DRP-104) is currently ongoing and will further explore this hypothesis in a LUAD cohort (NCT04471415).

However, less than 20% of HNSCC patients respond to FDA-approved anti-PD1 immune checkpoint blockade (ICB) (pembrolizumab and nivolumab), often not leading to durable responses. Our data suggest that broad glutamine antagonism using DRP-104 has therapeutic potential in HNSCC by both dismantling cancer metabolism and enhancing the anti-tumor immune response of immune checkpoint blockade. Clinical trials of DRP-104 are currently ongoing.

Importantly, this metabolic signature is predictive of either response or resistance to targeted therapies that inhibit glucose and glutamine metabolism that may be exploited in a clinical setting.We previously reported that combined targeting of glucose and glutamine metabolism with mTOR kinase inhibitor TAK228 or TKI in combination with the selective glutaminase (GLS) inhibitor CB-839 was required to significantly suppress glucose and glutamine metabolism in both LUSC and EGFR mutant LUADs resulting in metabolic crisis and tumor cell death3,5. Overall, DRP-104 showed great potential to treat hypermetabolic therapy-resistant LUSC and EGFR mutant LUAD as a single-agent therapy and in combination with immune CPI. Further clinical development of DRP-104 in this patient population is warranted and clinical trials are currently ongoing.

This unique and non-overlapping mechanism of action supports clinical development of DRP-104 alone and in combination with immune checkpoint inhibitors. The first in human clinical study of DRP-104 is ongoing.

P2a, N=246, Recruiting, Dracen Pharmaceuticals, Inc. | N=160 --> 246 | Trial completion date: Jul 2023 --> Dec 2023

P2a, N=160, Recruiting, Dracen Pharmaceuticals, Inc. | Not yet recruiting --> Recruiting

P2a, N=160, Not yet recruiting, Dracen Pharmaceuticals, Inc.

Combination therapy of DRP-104 with anti-PD-1/PD-L1 achieved significantly enhanced anti-tumor efficacy including long-term durable cures even in checkpoint inhibitor resistant models. This unique and non-overlapping mechanism of action supports clinical development of DRP-104 alone and in combination with PD-1/PD-L-1 checkpoint inhibitors.