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Reply to “Cardiovascular Safety of Nilotinib in Alzheimer's Disease”

We thank the authors for the constructive comment regarding cardiovascular safety in Turner et al report of safety, tolerability, and biomarker effects of the tyrosine kinase inhibitor Nilotinib in Alzheimer’s disease (AD). The authors recommend caution regarding the risk and incidence of cardiovascular events (CVEs) and cite the Evaluating Nilotinib Efficacy and Safety in Clinical Trials – Newly Diagnosed Patients (ENESTnd) trial, which investigated the safety and tolerability of Nilotinib in chronic myelogenous leukemia (CML) using Nilotinib, 600 mg and 800 mg, daily. Furthermore, the authors recognize that a lower dose of Nilotinib, 150 mg and 300 mg, daily was given to patients with AD with mean age of 72 years. We agree with the authors that monitoring CVEs and the risks associated with CVEs are paramount in any study using Nilotinib in a geriatric population that may already have increased CVE risk due to comorbidities. We also agree that CVE risks should be monitored with lower doses of Nilotinib, 150 mg and 300 mg, daily because long-term administration of Nilotinib may increase CVE risks in this population. Indeed, this study followed strict safety guidelines according to all grades and Common Terminology Criteria for Adverse Events (CTCAE), and excluded patients with hypokalemia, hypomagnesemia, or long corrected QT (QTc) syndrome according to the protocol. Concomitant drugs known to prolong the QTc interval (≥ 460 ms) were not allowed. Patients with history of CVEs, including (e.g., myocardial infarction, unstable angina, or stroke), congestive heart failure, first, second-degree or thirddegree atrioventricular block, sick sinus syndrome, or other serious cardiac rhythm disturbances, and any history of Torsade de Pointes were excluded. The study did not allow drug contraindications, including anticoagulants (Coumadin [warfarin], heparin, enoxaparin, daltiparin, xarelto, etc.). The baseline QTc range for inclusion into this study was 350 to 460 ms. A serious adverse event (SAE) was defined as QTc prolongation ≥ 60 ms from baseline of individual participants AND to a value ≥ 480 ms or corrected QT Fridericia’s formula (QTcF) prolongs ≥ 500 ms. Lack of QTc prolongation is supported by > 2,000 patient visits in this study with patients with AD, as well as patients with Parkinson’s disease (PD) with a similar mean age of 70 years treated with Nilotinib, 150 mg and 300 mg, for 12 months, and 27 months (manuscript under review). Importantly, newly diagnosed or worsened ischemic vascular or CVEs have occurred in patients treated with Nilotinib in CML and caution should be exercised in neurodegeneration. Therefore, it is highly recommended that regular laboratory tests to monitor AEs and stopping rules for individual patients should follow common toxicity criteria and grade (< grade 3) classification of organ toxicity of AEs according to CTCAE. Nilotinib toxicity may not only be due to inhibition of plasma Abelson but some other off-target tyrosine inhibition of Nilotinib. Inhibition of either Abelson or other tyrosine kinases cannot be ruled out. Nilotinib inhibits several tyrosine kinases, including c-KIT and platelet-derived growth factor (PDGF) receptors, which play a crucial role in normal hematopoiesis.