DDW speaks to Yasuo Nakamura, Senior Executive Officer at Pharmaceuticals R&D, Asahi Kasei Pharma Corporation about the challenges of treating chemotherapy-induced peripheral neuropathy (CIPN) and the company’s current pipeline targeting the condition.  

DDW: What makes chemotherapy-induced peripheral neuropathy (CIPN) such a persistent challenge in colorectal cancer care, and why has prevention proven so elusive? 

YN: Oxaliplatin is the key drug of chemotherapy for colorectal cancer, which is known to induce CIPN depending on the administered amount. Depending on the patient’s prognosis, it can be difficult to taper the dosage of oxaliplatin in colorectal cancer treatment regimens while maintaining effectiveness. Sometimes colorectal cancer patients must reduce the dose of oxaliplatin or stop its use entirely because of CIPN symptoms induced by it, which can negatively impact the patient’s treatment schedule. Currently, there still isn’t an effective drug to prevent and treat CIPN induced by oxaliplatin. 

DDW: How does ART-123 work mechanistically to protect nerves during oxaliplatin-based chemotherapy without compromising anticancer efficacy? 

YN: ART-123 has anti-inflammatory effects through activation of thrombin-activatable fibrinolysis inhibitor (TAFI) and protein C, and inactivation of high mobility group box 1 (HMGB1). ART-123 prevents oxaliplatin-induced peripheral neuropathy through the activation of TAFI and protein C, and potentially the inactivation of HMGB1 without affecting the anti-tumour activity of oxaliplatin in rodents1.

DDW: What were the key findings from earlier Phase II trials in Japan that supported the advancement of ART-123 into a Phase III study? What’s next? 

YN: The key findings from earlier Phase II trials in Japan are that ART-123 inhibited the decrease of FACT/GOG-Ntx-12 scores, a patient-reported outcome, and decreased the cumulative incidence of NCI-CTCAE grade 2 or higher sensory neuropathy, a physician-reported outcome. For more details, please refer to this publication2. Our next goal is to successfully complete the Phase III trials currently underway in Japan. 

DDW: In what ways could a successful CIPN prevention therapy like ART-123 improve adherence to chemotherapy regimens and patient quality of life? 

YN: CIPN causes huge disruptions to a patient’s quality of life (QOL), such as difficulty walking and grasping objects. This can then lead to decreased independence and significant frustration. In some cases, patients must reduce the dose of oxaliplatin and/or stop it because of CIPN symptoms. This change in treatment can have a negative impact on a patient’s care. ART-123 could improve patients’ QOL through its implementation into an oxaliplatin-based treatment regimen for the prevention of CIPN symptoms. 

DDW: How might ART-123, if approved, influence the global standard of care for oxaliplatin-based treatments beyond colorectal cancer? 

YN: Depending on its indication, we believe that ART-123 will be a game-changer for the standard of CIPN prevention in oxaliplatin-based treatment, regardless of cancer type. This is because we understand the mechanism of CIPN induced by oxaliplatin does not differ based on cancer types.  

DDW: What are the regulatory and clinical considerations in translating promising CIPN prevention strategies from regional trials to global oncology practice? 

YN: There is no international consensus on diagnostic criteria or assessment methods for CIPN at this time. However, the design of the Phase III study in Japan (regional trial) takes into account key resources such as the American Society of Clinical Oncology (ASCO) ‘Prevention and Management of Chemotherapy-Induced Peripheral Neuropathy in Survivors of Adult Cancers: ASCO Guideline Update’, the expert consensus paper ‘Trial designs for chemotherapy-induced peripheral neuropathy prevention – ACTTION recommendations’, and the US FDA draft guidance ‘Prevention and Treatment of Chemotherapy-Induced Peripheral Neuropathy: Developing Drug and Biological Products in Oncology’. Therefore, we do not anticipate any major challenges in expanding the development of ART-123 globally. That said, engaging in discussions with regulatory authorities in each country and building consensus on the development plan will be essential. 

References:

  1. 1: https://doi.org/10.1016/j.ejphar.2020.173196, https://doi.org/10.1186/s12974-019-1581-6
  2. 2: https://link.springer.com/article/10.1007/s00280-020-04135-8