ompenaclid (RGX-202) / Inspirna, EMD Serono - LARVOL DELTA

Structure-Based Search for Novel Creatine Transporter Inhibitors. (PubMed, ACS Med Chem Lett) - "Retrospective comparison confirmed good agreement between our models and the experimental structures. These findings provide a computational-experimental framework for CT1 inhibitor discovery and support future structure-based drug design."

Journal • CNS Disorders • Oncology

Targeting the creatine transporter SLC6A8: Mechanisms and emerging therapeutic strategies for multiple diseases. (PubMed, Biochem Pharmacol) - "SLC6A8 is aberrantly expressed across numerous cancer types, and its inhibitor RGX-202 (also termed ompenaclid, chemically identified as β-GPA) exerts broad antitumor activity in preclinical models of colorectal cancer and hepatocellular carcinoma. This review summarizes recent advances delineating the involvement of SLC6A8 in neurological disorders, cancer, and other pathological conditions, with a particular emphasis on its translational potential as a therapeutic target. Clarifying the research status of SLC6A8 in various systemic diseases enables subsequent researchers to comprehensively understand its biological functions and clinical translational value from a more systematic perspective."

Journal • Review • Cardiovascular • CNS Disorders • Colorectal Cancer • Congestive Heart Failure • Diabetes • Gene Therapies • Genetic Disorders • Heart Failure • Hepatocellular Cancer • Metabolic Disorders • Obesity • Oncology • Solid Tumor

Anti-tumor efficacy of ompenaclid, a creatine transporter inhibitor, in KRAS mutant tumors, including NSCLC (AACR 2024) - "Ompenaclid is currently in a Phase 2 trial, in combination with FOLFIRI and bevacizumab, in patients with RAS-mutated second-line advanced/metastatic colorectal cancer...Combination treatment with MRTX849, a KRAS G12C inhibitor, was conducted in a pancreatic MiaPaca xenograft model. Our studies demonstrate ompenaclid anti-tumor efficacy in NSCLC and pancreatic xenografts... Our studies demonstrate ompenaclid anti-tumor efficacy in NSCLC and pancreatic xenografts. Notably, and consistent with findings in CRC, efficacy in NSCLC was more robust in RAS mutant cancer models, relative to those bearing KRAS WT tumors. Metabolite analysis of the plasma of tumor-bearing mice at baseline revealed that mice harboring RAS mutant tumors had higher levels of p-creatine and lower levels of ATP, indicating that RAS mutant tumors utilize higher amounts of ATP, which may be converted to phosphocreatine by tumoral CKB, as confirmed by qPCR analysis."

Clinical • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CKB • KRAS

Targeting SLC6A8 suppresses tumor growth and enhances ferroptosis in hepatocellular carcinoma. (PubMed, J Cancer Res Clin Oncol) - No abstract available

Journal • Hepatocellular Cancer • Oncology • Solid Tumor

A Study to Investigate Ompenaclid Combined With FOLFIRI Plus Bevacizumab in Advanced/Metastatic Colorectal Cancer (clinicaltrials.gov) - P2 | N=76 | Terminated | Sponsor: Inspirna, Inc. | Active, not recruiting ➔ Terminated; At the time of the primary analysis, results did not meet the primary endpoint

Trial termination • Colon Cancer • Colorectal Cancer • Oncology • Solid Tumor • MSI • PD-1 • PD-L1

Carboxylic Acid Bioisosteres of Creatine as Novel and Selective Substrate Competitive Inhibitors of the Creatine Transporter SLC6A8. (PubMed, J Med Chem) - "A bioisostere approach was used by replacing the carboxylic acid of β-GPA with surrogate functional groups to achieve these improvements. Docking of these inhibitors into the recently published SLC6A8 cryo-EM structure reveals key binding contacts and supports the observed structure-activity relationships."

Journal • Colorectal Cancer • Oncology • Solid Tumor

Structural insights into the substrate uptake and inhibition of the human creatine transporter (hCRT). (PubMed, Proc Natl Acad Sci U S A) - "Creatine is coordinated in the central substrate-binding site through interactions with transmembrane helices TM1, TM3, TM6, and TM8, while the inhibitor RGX202 occupies the same binding pocket, engaging in overlapping contacts that competitively block creatine access. Our structural and mechanistic findings clarify substrate recognition and inhibitory binding of hCRT, providing a molecular rationale for targeting hCRT in both inherited metabolic diseases and cancer therapy."

Journal • Brain Cancer • CNS Disorders • Colorectal Cancer • Developmental Disorders • Epilepsy • Glioblastoma • Mental Retardation • Metabolic Disorders • Oncology • Solid Tumor

Hypoxia-Induced Creatine Uptake Reprograms Metabolism to Antagonize PARP1-Mediated Cell Death and Facilitate Tumor Progression in Hepatocellular Carcinoma. (PubMed, Cancer Res) - "The SLC6A8 inhibitor RGX-202 exerted potent antitumor activity alone and in combination with lenvatinib in patient-derived xenografts and primary HCC mouse models. Overall, this study identified intracellular creatine accumulation as a mechanism that allows hypoxic cancer cells to circumvent parthanatos and as a therapeutic target in HCC."

Journal • Hepatocellular Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • HIF1A • PARP1 • SERPINE1

RGX-202-001: A Study of RGX-202-01 (Ompenaclid) as Combination Therapy in RAS Mutant Advanced Colorectal Cancer (clinicaltrials.gov) - P1 | N=89 | Completed | Sponsor: Inspirna, Inc. | Trial completion date: Dec 2024 ➔ Mar 2025 | Recruiting ➔ Completed | Trial primary completion date: Dec 2024 ➔ Mar 2025

Trial completion • Trial completion date • Trial primary completion date • Colorectal Adenocarcinoma • Colorectal Cancer • Gastric Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Oncology • Solid Tumor • MSI

A Study to Investigate Ompenaclid Combined With FOLFIRI Plus Bevacizumab in Advanced/Metastatic Colorectal Cancer (clinicaltrials.gov) - P2 | N=70 | Active, not recruiting | Sponsor: Inspirna, Inc. | Trial completion date: Dec 2026 ➔ Mar 2025 | Trial primary completion date: Sep 2025 ➔ Jan 2025

Trial completion date • Trial primary completion date • Colon Cancer • Colorectal Cancer • Oncology • Solid Tumor • MSI

A Study to Investigate Ompenaclid Combined With FOLFIRI Plus Bevacizumab in Advanced/Metastatic Colorectal Cancer (clinicaltrials.gov) - P2 | N=70 | Active, not recruiting | Sponsor: Inspirna, Inc. | Recruiting ➔ Active, not recruiting | Trial completion date: Aug 2028 ➔ Dec 2026 | Trial primary completion date: Aug 2026 ➔ Sep 2025

Combination therapy • Enrollment closed • Metastases • Trial completion date • Trial primary completion date • Colon Cancer • Colorectal Cancer • Oncology • Solid Tumor • MSI

A randomized blinded phase II study of ompenaclid (RGX-202-01) vs placebo in combination with FOLFIRI plus bevacizumab (BEV) in patients (pts) with previously treated RAS mutated (RASmt) advanced/metastatic colorectal cancer (mCRC) (ESMO 2024) - P2 | "In an open-label single arm study (RGX-202-001) as 2L treatment in pts with RASmt mCRC, ompenaclid at 2400 mg and 3000 mg orally twice-daily (BID) in combination with FOLFIRI/BEV was shown to have potential clinical benefit with a tolerable safety profile (ESMO 2023, abstract 646P).Trial design: Key eligibility criteria: measurable disease per RECIST v1.1, disease progression after 1L oxaliplatin-based therapy and ECOG performance status 0–1. Treatment consists of FOLFIRI/BEV (irinotecan intravenously [IV] 180 mg/m2, 5-FU 46-hour IV 2400 mg/m2, leucovorin IV 400 mg/m2, BEV IV 5 mg/kg every 2 weeks), with double-blind 1:1 randomization to either ompenaclid 3000 mg PO BID or placebo, stratified by prior exposure to 1L BEV...The study will enroll 70 pts and is conducted in Spain, Belgium and France. Study enrollment is ongoing."

Clinical • Combination therapy • Metastases • P2 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • RAS

Phase Ib/II study of ompenaclid (RGX-202-01), a first-in-class oral inhibitor of the creatine transporter SLC6A8, in combination with FOLFIRI and bevacizumab (BEV) in RAS mutated (RASmt) second-line (2L) advanced/metastatic colorectal cancer (mCRC): Updated results (ESMO 2024) - P1 | "Pts must have had progression after a 1L oxaliplatin-containing regimen... Ompenaclid + FOLFIRI/BEV was well tolerated. Encouraging efficacy was observed in pts with RASmt mCRC, with ORR, mPFS and mOS exceeding that expected with standard of care. This preferential RASmt activity is consistent with preclinical and Ph 1a data."

Clinical • Combination therapy • Metastases • P1/2 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CKB • KRAS

A Study to Investigate Ompenaclid Combined With FOLFIRI Plus Bevacizumab in Advanced/Metastatic Colorectal Cancer (clinicaltrials.gov) - P2 | N=70 | Recruiting | Sponsor: Inspirna, Inc. | N=50 ➔ 70

Combination therapy • Enrollment change • Metastases • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • MSI

RGX-202-001: A Study of RGX-202-01 (Ompenaclid) as Combination Therapy in RAS Mutant Advanced Colorectal Cancer (clinicaltrials.gov) - P1 | N=108 | Recruiting | Sponsor: Inspirna, Inc. | N=60 ➔ 108 | Trial primary completion date: Dec 2023 ➔ Dec 2024

Combination therapy • Enrollment change • Metastases • Trial primary completion date • Colorectal Adenocarcinoma • Colorectal Cancer • Gastric Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Oncology • Solid Tumor • MSI

Merck KGaA, Darmstadt, Germany, Expands Colorectal Cancer Portfolio Through Licensing Agreement with Inspirna (Businesswire) - "Merck KGaA, Darmstadt, Germany...today announced a licensing agreement with Inspirna, Inc...for ompenaclid (RGX-202), a first-in-class oral inhibitor of the creatine transport channel SLC6A8, and SLC6A8-targeting follow-on compounds...2024 marks the 20th anniversary of the introduction of ERBITUX^®, for which the company has marketing rights outside the U.S. and Canada, as a backbone treatment in mCRC; today, multiple active clinical trials continue to evaluate ERBITUX^® in this disease...Under the terms of the license agreement, Merck KGaA, Darmstadt, Germany will receive an exclusive license to ompenaclid outside of the United States and an option to co-develop and co-promote ompenaclid in the US....the parties agreed to collaborate on Inspirna’s SLC6A8 follow-on compounds for which Inspirna will retain US co-development and co-commercialization rights."

Clinical • Licensing / partnership • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Myeloid cell-derived creatine in the hypoxic niche promotes glioblastoma growth. (PubMed, Cell Metab) - "Lastly, inhibition of creatine transport using the clinically relevant compound, RGX-202-01, blunted tumor growth and enhanced radiation therapy in vivo. This work highlights that myeloid-to-tumor transfer of creatine promotes tumor growth in the hypoxic niche."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

A Study to Investigate Ompenaclid Combined With FOLFIRI Plus Bevacizumab in Advanced/Metastatic Colorectal Cancer (clinicaltrials.gov) - P2 | N=50 | Recruiting | Sponsor: Inspirna, Inc.

Trial completion date • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • MSI

Inspirna Announces Clinical Data from Phase 1b/2 Study of Ompenaclid (RGX-202) in Advanced Colorectal Cancer at ESMO Congress 2023 (Businesswire) - "'We are excited to share the clinical data being presented at ESMO, further demonstrating the clear potential of ompenaclid to improve on the standard-of-care for advanced CRC, especially for the approximately 40-45% of CRC patients whose tumors harbor a RAS mutation,' said Andrew Hendifar, MD...'Encouraging efficacy was observed in patients with RASm second-line metastatic CRC with a response rate exceeding that expected with the standard-of-care regimen FOLFIR/BEV alone. At the evaluated dose levels, ompenaclid plus FOLFIRI/BEV was also well tolerated and induced potent inhibition of SLC6A8, consistent with preclinical and previously presented Phase 1 data.'"

Media quote

Phase Ib/II study of ompenaclid (RGX-202-01), afirst-in-class oral inhibitor of the creatine transporter SLC6A8, in combination with FOLFIRI and bevacizumab (BEV) in RAS mutated (RASm) second-line (2L) advanced/metastatic colorectal cancer (mCRC) (ESMO 2023) - P1 | "Eligible pts had disease progression after a 1L oxaliplatin-containing regimen...There is a high unmet need for a safe and combinable oral pan-RASm therapy in mCRC. Recruitment of RASm pts continues and a randomized controlled trial in 2L RASm mCRC is planned."

Clinical • Combination therapy • Metastases • P1/2 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CKB • KRAS

Inspirna Announces Clinical Data from Phase 1b/2 Study of Ompenaclid (RGX-202) in Advanced Colorectal Cancer at ESMO Congress 2023 (Businesswire) - P1b/2 | N=60 | NCT03597581 | Sponsor: Inspirna, Inc. | "Inspirna, Inc...announced today data from the ongoing Phase 1b/2 study of ompenaclid (RGX-202) in combination with FOLFIRI and bevacizumab (BEV) in RAS-mutated (RASm) advanced or metastatic colorectal cancer (CRC) presented at the European Society for Medical Oncology (ESMO) Congress 2023 being held October 20-24, 2023 in Madrid, Spain....41 patients had RASm CRC. ORR was 37% including 8 confirmed partial responses (PR) and 3 unconfirmed PRs (all 3 patients are ongoing) in the 30 evaluable patients. Median progression-free survival (mPFS) was 10.2 months, and median overall survival (mOS) was 19.1 months across all 41 patients in the intention to treat population. 9 patients (all evaluable) had RAS-wildtype (RAS-wt) CRC. ORR was 22%, including 1 confirmed PR and 1 unconfirmed PRs. mPFS was 7.5 months and mOS was 14.5 months."

P1/2 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Inspirna to Present Clinical Data from Phase 1b/2 Study of Ompenaclid (RGX-202) in Advanced Colorectal Cancer at ESMO Congress 2023 (BioSpace) - "Inspirna, Inc...announced today that data from the ongoing Phase 1b/2 study of ompenaclid (RGX-202) in combination with FOLFIRI and bevacizumab (BEV) in RAS-mutated (RASm) advanced or metastatic colorectal cancer (CRC) will be presented at the European Society for Medical Oncology (ESMO) Congress 2023 being held October 20-24, 2023 in Madrid, Spain...Poster Presentation Details Title: Phase 1b/2 study of ompenaclid (RGX-202-01), a first-in-class oral inhibitor of the creatine transporter SLC6A8, in combination with FOLFIRI and bevacizumab (BEV) in RAS mutated (RASm) second-line (2L) advanced/metastatic colorectal cancer (mCRC) Presenter: Andrew Hendifar, MD..."

Inspirna to Present Clinical Data from Phase 1b/2 Study of Ompenaclid (RGX-202) in Advanced Colorectal Cancer at ESMO Congress 2023 (Businesswire) - "Inspirna, Inc...announced today that data from the ongoing Phase 1b/2 study of ompenaclid (RGX-202) in combination with FOLFIRI and bevacizumab (BEV) in RAS-mutated (RASm) advanced or metastatic colorectal cancer (CRC) will be presented at the European Society for Medical Oncology (ESMO) Congress 2023 being held October 20-24, 2023 in Madrid, Spain."

P1/2 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

A Study to Investigate Response to Ompenaclid Combined With FOLFIRI Plus Bevacizumab in Patients With Advanced or Metastatic Colorectal Cancer (clinicaltrials.gov) - P2 | N=50 | Recruiting | Sponsor: Inspirna, Inc. | Not yet recruiting ➔ Recruiting

Combination therapy • Enrollment open • Metastases • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • MSI

A Study to Investigate Response to Ompenaclid Combined With FOLFIRI Plus Bevacizumab in Patients With Advanced or Metastatic Colorectal Cancer (clinicaltrials.gov) - P2 | N=50 | Not yet recruiting | Sponsor: Inspirna, Inc.

Combination therapy • Metastases • New P2 trial • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • MSI