Carbazole-Based Therapy Carba1 Demonstrates Improvement of Chemotherapy-Induced Neuropathy

Lauriane Bosc, co-founder of Saxol

Preclinical data presented at the 2025 Peripheral Nerve Society (PNS) Annual Meeting, held May 17-20, in Edinburgh, Scotland, demonstrated the therapeutic potential of Carba1 (Saxol), a novel bi-functional carbazole, in the treatment of chemotherapy-induced neuropathy (CIPN). Overall, the agent demonstrated neuroprotective effects against CIPN by both reducing the required dose of toxic taxanes through tubulin interaction and activating nicotinamide phosphoribosyltansferase (NAMPT) to promote cellular resistance.

CIPN is a severe adverse effect of neurotoxic anticancer drugs, affecting millions of patients annually. Current treatments focus on pain relief with opioids, antidepressants, and antiepileptics; however, these medications only reduce symptoms without treating the cause and have serious adverse events, such as addition, drowsiness, and digestive problems.

Presented by Lauriane Bosc, co-founder of Saxol, the analysis comprised several in vitro and in vivo models ranging from cultured dorsal root ganglion neurons and explants to an animal models. Here, investigators found that Carba1 activated NAMPT, initiating metabolic reprogramming that enhanced neuronal and Schwann cell resistance to chemotherapy-induced toxicity.

In vitro, it effectively mitigated neurotoxicity across several CIPN models, including those triggered by paclitaxel (PTX), cisplatin, and bortezomib. In a rat model of PTX-induced neuropathy, Carba1 significantly reduced neurotoxic damage. Notably, these protective effects occurred without compromising PTX’s anticancer efficacy or promoting tumor progression. Structure-activity analyses of Carba1 derivatives further suggest potential for developing compounds with either dual anticancer and neuroprotective effects or selective neuroprotection alone.

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PTX, which binds to the taxane site tubulin and stabilizes the microtubules (MT) lattice by strengthening tubulin contacts, stands out as one of the most successful chemotherapeutic agents. At stoichiometric concentrations, PTX promotes MT assembly whereas at low and clinically relevant concentrations, PTX primarily suppresses MT dynamics without significantly affecting MT polymer mass. Despite these prominent effects, MT-interfering drugs have been known to face resistance and cause AEs like neutropenia, gut toxicity, alopecia, and peripheral neuropathies.

Carba1’s effects on preclinical models were described in a recently published paper, with data highlighting the neuroprotective action of the agent. In vitro, Carba1 was shown to synergize with compounds targeting the tubulin taxane site, but not with other chemotherapeutic agents, Cis or Bort, with different mechanisms of action. The study authors noted that these findings further support the belief that Carba1 experts its effects by perturbing MT dynamics at the growing end, promoting the binding of non-saturating doses of PTX.

In a rat model of PTX-induced neuropathy, Carba1 fully prevented tactile hypersensitivity and preserved nerve endings for up to 14 days, indicating sustained action. At high doses, the agent showed no detectable toxicity in ice, as confirmed by blood markers. Overall, these data suggest Carba1 has a favorable pharmacokinetic and pharmacodynamic properties for therapeutic use, with no observed toxicity.

CIPN remains a major concern in the United States, as nearly 30-40% of patients undergoing chemotherapy develop CIPN, with prevalence rates varying based on the specific chemotherapeutic agents used.³ Patients with CIPN often require additional medical interventions, including pain management and physical therapy, contributing to increased healthcare expenditures. CIPN symptoms, such as pain, tingling, and numbness in the extremities, can impair daily activities, reduce balance, and increase the risk of falls, leading to decreased overall quality of life.

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REFERENCES
1. Bosc L, Elena PM, Balayssac D, et al. Preventing Neuropathy and Improving Anti-cancer Chemotherapy With a Carbazole-based Compound. Presented at: 2025 PNS Annual Meeting; May 17-20. Edinburgh, Scotland. Abstract O573
2. Bosc L, Pero ME, Balayssac D, et al. Preventing neuropathy and improving anti-cancer chemotherapy with a carbazole-based compound. bioRxiv. Published online March 13, 2025. doi:10.1101/2025.03.10.642317
3. Staff NP, Grisold A, Grisold W, Windebank AJ. Chemotherapy-induced peripheral neuropathy: A current review. Ann Neurol. 2017;81(6):772-781. doi:10.1002/ana.24951.