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Postsurgical Biopsy Shows Viability of NEO 100 Internasal Delivery

May 26, 2022

Detection of Perillyl Alcohol and Its Metabolite Perillic Acid in Postsurgical Glioblastoma Tissue After Intranasal Administration of NEO100

Authors: Axel H. Sch€onthal, PhD,1, Steve Swenson, PhD,2, Phillip A. Bonney, MD,2, Naveed Wagle, MD,3, Vincent F. Simmon, PhD,4, Anna J. Mathew, MD,5, Kyle M. Hurth, MD, PhD,5, and Thomas C. Chen, MD, PhD2,4–6

In a recent case trial followup of a patient with a recurring glioblastoma (GBM) tumor who had been undergoing NEO 100 internasal treatment, a postsurgical biopsy of the tumor showed the definitive presence of NEO 100 which is the first in-human clinical evidence of the viability of NEO 100 internasal delivery as a delivery mechinism for chemotherapeutic treatment of GBM. 

A 39-year-old woman was diagnosed with a left frontal lowgrade glioma upon workup for new-onset seizure. She was initially treated with two craniotomies over a 4-year period, with histopathological examination revealing World Health Organization (WHO) grade 2 oligoastrocytoma. Upon second recurrence, she underwent gross-total resection of recurrent disease, with histological and molecular features demonstrating WHO grade 3 anaplastic gemistocytic astrocytoma, IDH1 (R132H) mutant, with no evidence of 1p/19q codeletion. The patient received standard of care intensity-modulated radiotherapy (57 Gy in 30 fractions) with concomitant temozolomide followed by six cycles of adjuvant temozolomide. Radiographic recurrence was demonstrated 10 months from the time of the last resection. The patient then underwent subtotal resection with a small volume of residual enhancing disease. Pathological examination at that time revealed grade IV glioma, MGMT unmethylated, IDH1 mutant. The patient was enrolled in an open-label, phase I/IIa trial (NCT02704858),12 in which she self-administered intranasal NEO100 using a nebulizer and nasal mask. Dosing was four times a day, every day, at 144 mg/dose (576 mg/day). Plasma levels of POH and PA at different time intervals after dosing were shown, confirming uptake of NEO100 into the systemic circulation. PA plasma levels were approximately 100-fold higher than POH plasma levels. Despite being much lower, POH levels were readily detectable at the 5-minute time point, but in two of three serial samplings the levels dropped below the detection threshold within 30 minutes, consistent with the known very short half-life of POH in plasma and the resulting difficulty of detecting it in biological systems.

An excellent clinical outcome was achieved, with tumor regression and lack of progression for more than 3 years. No significant toxicities were appreciated, based on physical examination, vital signs, clinical laboratory test results, and National Cancer Institute Common Terminology Criteria for Adverse Events. Mild dermatitis related to the inhalation mask was successfully treated with cortisone during cycle 21. Tumor recurrence was demonstrated after 40 months, and the patient was taken for reresection given good performance status. On the day of surgery, the patient self-administered one dose of 144 mg intranasal NEO100. After surgery, the resected GBM tissue was processed for pharmacoanalytical examination and for molecular analysis, which revealed MGMT methylated, IDH1 mutant disease. High-performance liquid chromatography was applied to two separate regions of the tumor tissue, both of which readily revealed the presence of POH and its metabolite PA. This result is especially notable on two accounts: (1) despite the unavoidable delay between NEO100 administration and retrieval of the tissues sample (approximately 4 hours), POH was still present in the tissue and (2) the ratio of PA to POH was very low (approximately 1.4), altogether indicating a very slow metabolism of POH in this tissue.

This is the first demonstration of POH and PA in brain tumor tissue from any patient. It reveals that intranasal administration of NEO100 is a valid approach to achieve delivery of this agent to a brain tumor. In view of the noninvasive and safe nature of this method, along with tentative indications of activity, our findings add confidence to the notion that intranasal administration of NEO100 holds potential as a new treatment option for brain-localized malignancies.


1Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, 2Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California, 3Pacific Brain Tumor Center, Pacific Neuroscience Institute, Santa Monica, California, 4NEONC Technologies, Inc., Los Angeles, California,5 Departments of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California, 6USC/Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California