BioVie Inc. announced encouraging data suggesting that NE3107 has an impact on improving patients' DNA methylation profiles, potentially impacting biomakers of aging-related disease states. The Phase 2 Investigator-Sponsored Trial (NCT05227820) enrolled a total of 23 patients with an average age of 71.1 years in an open-label, single arm study to measure changes in cognition through verbal and visual test procedures and changes in biomarkers of Alzheimer's Disease (AD) and inflammation that can be measured in cerebral spinal fluid, blood samples, and functional magnetic resonance imaging in patients before and after treatment with 20 mg of NE3107 twice daily for 3 months. Dr. Sheldon Jordan (the Principal Investigator) and his team presented detailed data through posters and a platform presentation at the Clinical Trial in Alzheimer's Disease (CTAD) annual conference, held in San Francisco, CA that ended December 2, 2022.

These data showed the following among patients with MMSE>=20 (i.e., mild cognitive impairment and mild AD): NE3107 showed the potential to enhance cognition as measured by multiple assessment tools, including a 2.2 point improvement (p=0.0173) on the modified ADAS-Cog12 scale equating to a 21.1% (p=0.0079) change compared to baseline, a 0.11 point improvement (p=0.0416) on the Clinical Dementia Rating scale (CDR), equating to 19.4% (p=0.0416) change from baseline, and a 0.07 point improvement in the ADCOMS scale, equating to 27.4% improvement (p=0.009); NE3107 reduced CSF phospho-tau levels by -1.66 pg/mL (p=0.0343) and the ratio of p-tau to A42 by -0.0024 (p=0.0401); 18 of 22 patients with abnormal baseline scans showed improvement in one or more brain regions as seen from advanced functional MRI studies; No drug-related adverse events were observed. NE3107's Potential Impact on Biomakers of Aging-related Disease States: Blood samples were taken from the patients who participated in the Alzheimer's Phase 2 trial before and after 3 months of treatment with NE3107, and these samples were analyzed to assess NE3107's potential to reduce inflammation and alter DNA methylation associated with epigenetic biological clocks. The resulting data for patients treated with NE3107 for three months showed a reduction of 3.3 years (p=0.0021) on the Horvath DNA methylation SkinBlood clock.

Furthermore, 19 out of the 22 patients experienced this reduction in the SkinBlood clock score. The finding that NE3107 affects the SkinBlood clock provides an impetus to explore further the relationship between NE3107 improving neurodegeneration and other inflammation-driven diseases. Epigenetics is the study of how behavior (e.g., diet, exercise) and environment affect the way genes work in addition to the genetic code itself, and there's an increasing body of evidence that signs of aging are epigenetic in nature.

Perhaps the most studied area of epigenetics involves DNA methylation, which is the process of how methyl groups are added or removed from DNA and thus regulate the expression of various genes in bodies. Many studies have shown that genes become over- or under-methylated as age, thereby suggesting that the modulation of DNA methylation could enable the up- or down-regulation of specific genes and thus modulate the aging process. Dr. Steven Horvath, Professor of Human Genetics at the UCLA David Geffen School of Medicine and Professor of Human Genetics & Biostatistics at the UCLA Field School of Public Health, is a leading authority on the study of DNA methylation, and his research publications have been cited nearly 90,000 times in peer-reviewed articles.

Dr. Horvath studied a large number of datasets comprised of most tissue and cell types to create the first epigenetic clock (or “biological clock” to measure “biological age”) to measure the cumulative methylation of selected sites in the genome and how this could differ from a person's “chronological age.” This finding that NE3107 may affect DNA methylation would be consistent with the understanding of its mechanism of action. NE3107 has been shown to modulate the expression of TNF, which is considered to be the master regulator of inflammation.7 Inflammation has been shown to be associated with hypermethylation of DNA, which in turn has been shown to impact a wide range of diseases, including various forms of cancers, age-related cognitive impairment and dementia,10 Parkinson's disease, cardiovascular disease, COPD and respiratory disease, chronic kidney disease, inflammatory bowel disease, sepsis, and many others. Contributory Explanation for Alzheimer's and Parkinson's Findings: Patients treated with NE3107 demonstrated enhanced cognition as evidenced by improvements on multiple assessment scales in this Phase 2 study, and the Company's confirmatory double-blind, randomized controlled study involving subjects who have mild to moderate Alzheimer's disease is expected to read out in 3Q2023.

Patients also saw improvements in their inflammation (i.e., reduction in TNF) in a manner that is correlated with improvements in cognition, reduction of CSF phospho-tau levels and the ratio of p-tau to A42, and improvements in neuronal health as seen from functional MRI studies. The Company announced topline results from its NM201 double-blind, placebo-controlled, proof of concept study (NCT05083260) in Parkinson's disease (PD) on December 5, 2022 showing that symptomatic patients treated with NE3107 in addition to their stable dose of levodopa (and other Parkinson's therapies) showed superior motor control compared to levodopa alone (trend level). Patients treated with NE3107/levodopa saw improvements of UPDRS part 3 (motor) score on Day 28 compared to Day 0 that is 3+ points better than those treated with levodopa alone at the 2 and 3 hour marks.

Furthermore, patients under 70 years of age treated with NE3107/levodopa scored roughly 6 points superiority compared to levodopa alone. This level of improvement is considered by PD experts to be clinically meaningful.