AJ302 is a novel selective histone deacetylase 6 inhibitor (HDAC6i) under development for the prevention and/or treatment of chemotherapy-induced peripheral neuropathy (CIPN). AJ302, selected for its safety profile and drug-like physiochemical properties, substantially reduces drug toxicity commonly associated with non-selective HDAC inhibitors that deacetylate histone proteins in the genome. Recent studies have indicated that HDAC6 may be a drug target for the protection and regeneration of damaged peripheral nerves by enhancing microtubule-based axonal transport and mitochondrial dynamics. Scientists at AnnJi have demonstrated that AJ302 increases a-tubulin acetylation in microtubule, promotes neurite outgrowth and branching in paclitaxel-induced dorsal root ganglion (DRG) neurons in vitro. In a rat model of CIPN, AJ302 was shown to reverse paclitaxel-induced mechanical allodynia in a dose-dependent manner. The improvement in sensory functions was sustained after the treatment stopped.

Chemotherapy-Induced Peripheral Neuropathy (CIPN)

CIPN is a common, painful, dose-limiting adverse effect associated with chemotherapy in cancer patients. Major symptoms include pain and sensory impairments, such as tingling, numbness, and burning, often described as “stocking-glove distribution”. It is estimated that CIPN occurs in up to 40% of patients undergoing chemotherapy and is one of the main reasons for dose adjustment and cancer treatment disruption. Several molecular mechanisms have been proposed based on the cytotoxic properties of the chemotherapeutic agents, including axonal degeneration mediated by disruption in microtubule dynamics and axonal transport, mitochondrial dysfunction, alterations in neural excitability, and activation of the immune and inflammatory responses. To date, there are no approved treatments for CIPN. Management of neuropathic pain mainly relies on off-label use of anti-depressants but often with limited benefits.

Selective targeting HDAC6 to reduce the risk of epigenetic toxicity commonly associated with other HDACs

Clinical Development

1. Comprehensive IND package to support safety and clinical study is under preparation for the initiation of the first-in-human clinical trial in 2022

References

1. Novel HDAC6 Inhibitors Increase Tubulin Acetylation and Rescue Axonal Transport of Mitochondria in a Model of Charcot–Marie–Tooth Type 2F. ACS Chem Neurosci. 2020 Feb 5;11(3):258-267
2. HDAC6 inhibition effectively reverses chemotherapy-induced peripheral neuropathy. 2017 Jun;158(6):1126-1137
3. HDAC6 is a target for protection and regeneration following injury in the nervous system. Proc Natl Acad Sci USA. 2009 Nov 17;106(46):19599-604
4. HDAC6 is a microtubule-associated deacetylase. Nature. 2002 May 23;417(6887):455-8