On October 23, 2023 Inspirna, Inc., a clinical stage biopharmaceutical company developing first-in-class cancer therapeutics, reported 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) (Free ESMO Whitepaper) Congress 2023 being held October 20-24, 2023 in Madrid, Spain (Press release, Inspirna, OCT 23, 2023, View Source [SID1234636249]).

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"We are excited to share the clinical data being presented at ESMO (Free ESMO Whitepaper), 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, M.D., Assistant Professor of Medicine at Cedars-Sinai Medical Center and Principal Investigator on the study. "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."

Ompenaclid is a first-in-class oral inhibitor of the creatine transport channel SLC6A8, a novel target that is enriched under hypoxic conditions and provides tumor cells with an additional energy source. Ompenaclid triggers tumor regressions in CRC patients by inducing apoptosis of tumor cells. The Phase 1b/2 study of ompenaclid in combination with FOLFIRI/BEV in second-line (2L) advanced or metastatic CRC patients has completed enrollment, with an ongoing follow up period. The primary endpoint of the study is to determine maximum tolerated dose (MTD), objective response rate (ORR), and treatment-emergent adverse events (TEAEs). In the dose escalation stage of the study, two dose levels of ompenaclid with FOLFIRI/BEV have been evaluated in patients with CRC with disease progression after a first-line oxaliplatin-containing regimen.

"There is a high unmet need for a safe and effective pan-RASm treatment in the advanced or metastatic CRC setting, and these data continue to show the potential of ompenaclid as a novel therapy that can improve upon the current standard-of-care," said Dr. Usman "Oz" Azam, M.D., Chief Executive Officer of Inspirna. "In addition to fully enrolling this Phase 1b/2 study, we are excited to announce that we have begun enrollment in a randomized controlled trial in the same indication and expect to have interim efficacy data in the second half of 2024."

Inspirna hosted a virtual KOL panel on Sunday, October 22, 2023, with Andrew Hendifar, M.D., to discuss these clinical data. The event replay may be accessed by registering at View Source

Key findings presented at ESMO (Free ESMO Whitepaper) Congress 2023:

As of September 18, 2023, 50 patients in the dose escalation/expansion cohorts received either 2400mg twice daily (BID) of ompenaclid plus FOLFIRI/BEV (n = 27) or 3000mg BID ompenaclid plus FOLFIRI/BEV (n = 23). 39 patients were evaluable for RECIST 1.1 response if they completed at least one treatment cycle and had at least one follow-up on treatment scan.
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.
Across safety-evaluable patients (n = 48), ompenaclid was well-tolerated, and its safety profile in combination was similar to FOLFIRI/BEV alone, demonstrating its potential to be added to standard-of-care treatments.
The most common Grade ≤2 TEAEs were diarrhea (58%) and nausea (52%), frequent Grade ≥3 TEAEs were neutropenia (18%), diarrhea (13%), fatigue (10%) and abdominal pain (10%).
At both doses, systemic exposure was comparable and resulted in up to a 48x increase in urine creatine, suggesting robust SLC6A8 target inhibition.
No DLTs were observed in the dose escalation cohort, and MTD was not reached.
The abstract is published in the ESMO (Free ESMO Whitepaper) Congress 2023 Abstract Book, a supplement to the official ESMO (Free ESMO Whitepaper) journal, Annals of Oncology. The poster is available at the Annals of Oncology website and View Source

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, M.D., Assistant Professor of Medicine at Cedars-Sinai Medical Center and Study Principal Investigator

Onsite Poster Display Date: Sunday, October 22, 2023 at 9:00 AM CEST

Presentation Number: 646P