Hepacid (pegargiminase)

P1/2, N=35, Recruiting, Washington University School of Medicine | Not yet recruiting --> Recruiting

P1/2, N=35, Not yet recruiting, Washington University School of Medicine | Trial completion date: Nov 2027 --> Feb 2028 | Initiation date: Jan 2024 --> Apr 2024 | Trial primary completion date: Nov 2025 --> Feb 2026

P1/2, N=30, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting

P2/3, N=1030, Recruiting, Global Coalition for Adaptive Research

P1/2, N=35, Not yet recruiting, Washington University School of Medicine | Trial completion date: Aug 2027 --> Nov 2027 | Initiation date: Oct 2023 --> Jan 2024 | Trial primary completion date: Aug 2025 --> Nov 2025

P1/2, N=0, Withdrawn, M.D. Anderson Cancer Center | N=10 --> 0 | Trial completion date: May 2025 --> Nov 2023 | Initiation date: Feb 2024 --> Aug 2023 | Not yet recruiting --> Withdrawn | Trial primary completion date: May 2025 --> Nov 2023

The combination of venetoclax (VEN), an inhibitor of the anti-apoptotic factor BCL2, with the hypomethylating agent (HMA) decitabine (DEC) is the current frontline standard therapy for elderly patients with acute myeloid leukemia (AML). In MV4-11, ADI-PEG 20 combination significantly facilitated cell growth inhibition by VEN/DEC (increased VEN/DEC growth inhibition by ADI: HL60, 7%; MV4-11, 57%, p < 0.05). Taken together, this study demonstrated that VEN/DEC treatment facilitates energy metabolism in AML cells through increased expression of PPARG and ASS1, which may in turn translate into therapeutic resistance, and that VEN/DEC /ADI-PEG 20 combination may represent a potential novel therapeutic strategy (Figure 1).

Comparisons of time-to-event endpoints by important subgroups will be made using the log-rank tests. The trial is currently enrolling and presents a novel and promising therapeutic strategy for patients with high-risk newly diagnosed and relapsed/refractory AML.

P1/2, N=30, Not yet recruiting, M.D. Anderson Cancer Center

Importantly, mechanistic analysis indicated that the processes of the cell cycle, ribonucleoprotein complex biogenesis, and ribosome biogenesis were upregulated after combination treatment. This study implied the possibility of L-Norvaline as a modulator of the immune response in cancer and provided a new potential therapy combined with ADI-PEG 20.

Collectively, our data indicate that ADI-PEG20-inducible cytokines orchestrate argininosuccinate fuelling of ASS1-deficient mesothelioma by macrophages. This novel stromal-mediated resistance pathway may be leveraged to optimize arginine deprivation therapy for mesothelioma and related arginine-dependent cancers.

P1/2, N=108, Recruiting, Washington University School of Medicine | Not yet recruiting --> Recruiting

Methods Cell lines were treated with ADI-PEG20 and A-1331852 (Bcl-xL inhibitor) and monitored for cell death using the Incucyte. Bcl-xL inhibition synergies with ADI-PEG20 to induce apoptosis. This study provides the preclinical rationale for combining ADI-PEG20 with next generation Bcl-xL inhibitors such as the Bcl-xL PROTAC in a phase I clinical trial.

P1, N=9, Completed, Memorial Sloan Kettering Cancer Center | Active, not recruiting --> Completed | Trial completion date: Apr 2024 --> Jan 2023 | Trial primary completion date: Apr 2024 --> Jan 2023

Alterations in arginine metabolism may sensitise cells to metabolic drugs and we find that BAP1-negative/ASS1-expressing MPM cell lines are more sensitive to ASS1 inhibition, although not to inhibition of purine synthesis by mizoribine. Importantly, BAP1w-/KO MeT5A become desensitised to arginine-deprivation by pegylated arginine deiminase (ADI-PEG20), phenocopying BAP1-negative/ASS1-expressing MPM cell lines. Implications: Our data reveal an inter-relationship between BAP1 and arginine metabolism, providing a potential means of identifying epithelioid MPM patients likely to benefit from ADI-PEG20.

P1, N=9, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Apr 2023 --> Apr 2024 | Trial primary completion date: Apr 2023 --> Apr 2024

The WWOX-rs13338697-GG genotype was associated with lower tissue WWOX and ASS1 levels and higher pretreatment plasma arginine levels, resembling an arginine auxotrophic phenotype requires excessive extracellular arginine supply. Silencing WWOX to mimic HCC with the WWOX-rs13338697-GG genotype further stimulated HCC cell response to hypoxia through increased HIF1A expression, leading to further reduction of ASS1 and thus increased cell susceptibility to ADI-PEG 20.

Small cell lung cancer (SCLC) displays marked arginine auxotrophy due to inactivation of the rate-limiting enzyme argininosuccinate synthetase 1 (ASS1), and as a consequence may be targeted with pegylated arginine deiminase or ADI-PEG20 (pegargiminase) and human recombinant pegylated arginases (rhArgPEG, BCT-100 and pegzilarginase). Moreover, recent work has identified an intriguing role for targeting arginine in combination with PD-1/PD-L1 immune checkpoint inhibitors and clinical trials are in progress. Thus, future studies of arginine-depleting agents with chemoimmunotherapy, the current standard of care for SCLC, may lead to enhanced disease control and much needed improvements in long-term survival for patients.

Imaging with proliferation biomarker 3'-deoxy-3'-[F] fluorothymidine (F-FLT) positron emission tomography (PET)-computed tomography (CT) was performed in a phase 1 study of pegargiminase with pemetrexed and cisplatin (ADIPemCis). Both early and late FLT PET-CT provide evidence of response to ADIPemCis therapy in MPM and NSCLC. We provide first-in-human FLT PET-CT data in MPM, indicating it is comparable with modified RECIST.

This study aims at investigating the safety and tolerability of a triple combination consisting of ipilimumab and nivolumab immunotherapy and the metabolic therapy, ADI-PEG 20. Further, an IFNg-dependent inflammatory signature was observed in metastatic lesions in patients pre-treated with ICB compared with patients with no pretreatment. Multiplex immunohistochemistry demonstrated variable presence of tumor infiltrating CD8 lymphocytes and PD-L1 expression at the baseline in metastases.

ADIPemCis was well tolerated with modest disease stabilisation in metastatic UM. Further investigation of arginine deprivation is indicated in UM including combinations with immune checkpoint blockade and additional antimetabolite strategies.

P1, N=9, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Apr 2022 --> Apr 2023 | Trial primary completion date: Apr 2022 --> Apr 2023

Concurrent IM injection of ADI-PEG 20 at 36 mg/m weekly and intravenous infusion of PLD at 20 mg/m biweekly had an acceptable safety profile in patients with advanced ASS1-deficient solid tumors. Further evaluation of this combination is under discussion.

Arginine deprivation with the therapeutic enzyme ADI-PEG20 (pegylated arginine deiminase) sensitises cancers deficient in the enzyme argininosuccinate synthase (ASS1) to the apoptosis initiating activity of TRAIL through tumour cell surface upregulation of death receptors DR4 and DR5...Conclusion Our study proposes a synergistic interaction between the arginine depleting enzyme ADI-PEG20 and anti-CD19 CAR-T for the treatment of ASS1 deficient B-ALL, whereby priming of death receptor signalling may underlie enhanced CAR-T cytotoxicity against CD19 + tumour cells. These data support an emerging framework for CAR-T optimisation based on targeting of the death receptor mediated extrinsic apoptosis pathway and can inform future refinements in the development of cellular immunotherapy.

The dose expansion of ADIPemCis confirmed the high clinical activity and good tolerability in ASS1-deficient poor-prognosis mesothelioma, underpinning an ongoing phase 3 study (ClinicalTrials.govNCT02709512). Notably, resistance to pegargiminase correlated with marked macrophage recruitment and-along with the tumor immune microenvironment-warrants further study to optimize arginine deprivation for the treatment of mesothelioma.

In the TRAP Phase 1 trial (NCT02029690) ADI-PEG 20 combined with 1st-line pemetrexed (PEM) and cisplatin (CDDP) chemotherapy revealed a 94% disease control rate (34/36) in MPM with a 33.3% partial response rate in biphasic and sarcomatoid subtypes...Patients who developed CDDP toxicity were switched to carboplatin... ATOMIC-meso is the largest first-line triplet chemotherapy study to assess the role of targeted arginine deprivation in aggressive subtypes of mesothelioma on a global scale (US, Europe, and Australasia). The overall blinded data is encouraging and an interim analysis for ORR is planned once the 176 patients have reached the first CT treatment response assessment scan. Pending a Go decision, a total of up to 386 patients will be randomized to complete ATOMIC-meso (NCT02709512).

Concurrent mFOLFOX6 plus ADI-PEG 20 exhibited limited antitumor activity in patients with treatment-refractory HCC. The study was terminated early, and no further evaluation of the combination will be pursued.

ADIPemCis was safe and highly active in patients with ASS1-deficient non-squamous NSCLC, however, survival was poor overall. ASS1 loss was co-associated with p53 mutations. Therapies incorporating pegargiminase merit further evaluation in ASS1-deficient and treatment-refractory NSCLC.

ADI-PEG 20 treatment increased T cell infiltration in the low PD-L1 tumor microenvironment. The recommended phase 2 doses are 36 mg/m weekly for ADI-PEG 20 and 200 mg every 3 weeks for pembrolizumab.

Further combination studies are warranted. (This trial was registered in ClinicalTrials.gov as a Ph1 Study of ADI-PEG20 Plus Low-Dose Cytarabine in Older Patients With AML, NCT02875093).

Concurrently administered ADI-PEG20 and cisplatin had an acceptable safety profile and had shown antitumour activity against metastatic ASS1-deficient solid tumours. Further evaluation of this treatment combination is warranted.

One challenge of ADI-PEG20 (pegylated ADI) therapy is the development of drug resistance caused by restoration of ASS1 expression and other factors...The present study sheds light on the detailed mechanisms of resistance to arginine-deprivation therapy and uncovers novel targets to overcome resistance. We uncovered TREM1/CCL2 activation, in addition to restored ASS1 expression, as a key pathway involved in full ADI-resistance in breast and prostate cancer models.

In conclusion, we describe, for the first time, that NAC in combination with ADI-PEG 20 not only possesses unique cytotoxic anticancer properties but also triggers the hallmarks of immunogenic cell death. Hence, ADI-PEG 20 in combination with NAC may represent a promising approach to treat ADI-sensitive tumors while preventing relapse and metastasis.

The translation-dependent sensor developed here is able to accurately track the development of resistance in ASS1-deficient cells treated with ADI-PEG20. Its ability to track single cells over time allowed the determination that resistance is not present in the naïve population, as well as elucidating the heterogeneity of the timing and extent of resistance. This tool represents a useful advance in the study of arginine deprivation, while its design has potential to be adapted to other amino acids.

P1, N=9, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Apr 2021 --> Apr 2022 | Trial primary completion date: Apr 2021 --> Apr 2022

Molecular block adamantane-grafted poly(ethylene glycol) (Ad-PEG) was modified with epidermal growth factor receptor (EGFR)-specific binding ligand GE11 or pH-sensitive fusogenic peptide GALA and then used for self-assembly with cyclodextrin-grafted branched polyethylenimine (CD-PEI), adamantane-grafted polyamidoamine dendrimer (Ad-PAMAM), and plasmid DNA containing a small hairpin RNA expression cassette against vascular endothelial growth factor (VEGF) into functional DNA-loaded supramolecular nanoparticles (GE11&GALA-pshVEGF@SNPs) based on molecular recognition and charge interaction...The systemic delivery of the GE11&GALA-pshVEGF@SNPs can efficiently downregulate the intratumoral VEGF protein levels, reduce blood vessel formation, and significantly inhibit A549 xenograft tumor growth. These results reveal the potential of these multifunctional self-assembled nanoparticles as a nucleic acid drug delivery system for the treatment of lung cancer.

P1, N=85, Terminated, Polaris Group | Trial completion date: Jun 2019 --> Jun 2020

Targeted TRK inhibition with larotrectinib in PDAC harbouring a CTRC-NTRK1 gene fusion is well tolerated and can improve quality of life for the patient. However, acquired resistance to therapy can emerge in some patients. Next-generation TRK inhibitors such as selitrectinib are currently in development to overcome this resistance (NCT02576431; NCT03215511).

Although pegargiminase monotherapy in SCLC failed to meet its primary endpoint of RECIST-confirmed responses, more recent molecular stratification, including MYC status, may provide new opportunities moving forward.

Arginine deiminase (ADI-PEG20) therapy exploits this metabolic vulnerability by depleting extracellular arginine, causing arginine starvation...Concomitantly, these data elucidate proteomic changes that facilitate oxaloacetate production by enhancing glutamine and pyruvate anaplerosis and altering lipid metabolism to recycle citrate for oxidative glutaminolysis. Based on the complexity of metabolic and cellular signaling interactions, these multi-omic approaches could provide valuable tools for evaluating response to metabolically targeted therapies.