rucosopasem manganese (GC4711)

This study presents a novel role for selective superoxide dismutase mimetics, such as RUC, in protecting against CTI-induced cardiovascular toxicities. As RUC dismutates superoxide, the results suggest superoxide plays a key part in the modulation of mitochondrial oxidative phosphorylation, activation of the canonical TGF-β/Smad pathway, and ionizing radiation cardiovascular side effects. These findings suggest an association between RUC treatment and TGF-β pathway antagonism that requires additional mechanistic validation.

Most importantly, the combination of RUC + P-AscH‾ was found to sensitize both H1299T and A549 cell types to radio-chemotherapy with cisplatin (CIS) + etoposide (ETOP). Finally, in H1299T NSCLC xenografts the combination of RUC + P-AscH‾ with CIS + ETOP and 12 × 2 Gy radiation significantly inhibits tumor growth and increased median overall over survival. These results support the hypothesis that selective MnPAM dismutase mimetic + P-AscH‾ enhances the efficacy of radio-chemotherapy in NSCLC through a mechanism governed by redox active metals and H2O2 production.

P1/2, N=47, Terminated, Galera Therapeutics, Inc. | N=71 --> 47 | Trial completion date: Dec 2025 --> Nov 2023 | Recruiting --> Terminated | Trial primary completion date: Jun 2024 --> Nov 2023; Development GC4711 was halted after the lead study in pancreatic cancer was stopped early due to meeting the requirements of a futility analysis

P2, N=177, Terminated, Galera Therapeutics, Inc. | Phase classification: P2b --> P2 | Trial completion date: Oct 2027 --> Nov 2023 | Recruiting --> Terminated | Trial primary completion date: Oct 2024 --> Nov 2023; Futility Analysis

Co-treatment with DMs and P-AscH selectively enhanced tumor radiosensitization by increasing oxygen consumption and H0 fluxes even in tumor models which are known to be resistant to oxidative stressors (HT29). In contrast, each agent conferred a radioprotective effect in the rectum. Combination therapy with DMs and P-AscH may represent a novel, potent approach to target dysregulated redox metabolism in colorectal tumors.

The radiotherapeutic effect can be vastly increased with superoxide dismutase mimetics, both within and outside the treatment field. Combination therapy requires screening of schedules regarding timing, drug dosage, and IR dose and fractionation to achieve optimal tumoricidal effects. SODm synergize with IR acting on various molecular targets that can be harnessed to overcome treatment resistance.

In a pilot Phase 1/2 trial (GC4419-101), subjects with locally advanced PC were randomized to receive SBRT with a selective dismutase mimetic or placebo... GC4711 may improve the benefit-risk ratio of 5-fraction SBRT and drive survival benefit of local treatment of chemotherapy responsive PC patients.

GC4711 may improve the benefit-risk ratio of 5-fraction SBRT and drive survival benefit of local treatment of chemotherapy responsive PC patients.