BioVie Inc. announced topline results from an investigator-Sponsored Phase 2 clinical trial of NE3107 for the treatment of Alzheimer's Disease (AD). Updates from other trials underway are also provided. AD research has largely focused on Amyloid Beta (Ab) and phospho-tau (p-tau) for decades and has resulted in a large number of trials targeting these mechanisms.1 More recently, however, research focus has shifted towards targeting neuroinflammation, as evidenced by the 23 disease-modifying agents listed in clinicaltrials.gov in 2021 investigating inflammation or the immune system.

NE3107 is the only molecule in this group that is pursuing a two-pronged approach targeting both neuroinflammation and insulin resistance. Furthermore, NE3107 is the only molecule in the group that is conducting a potentially pivotal Phase 3 trial (NCT04669028) that is currently underway in mild- to moderate-AD patients with co-primary endpoints of cognition, as measured by the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog12), and function, as measured by Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC), whereas 17 other agents are in Phase 2. This Phase 3 trial is expected to provide topline results in mid-2023. Tumor Necrosis Factor Alpha (TNFa) is a cytokine identified as a major regulator of inflammation given that its excessive activation is associated with chronic inflammation.2 It is considered to be the central mediator of inflammation due to its role at the top of the biochemical pathway that leads to the production of other inflammatory factors such as various cytokines (e.g., IFNg, IL-1b, IL23, IL-4, IL-17), neurotoxic Aß peptide oligomers, activation of IKK and JNK (that leads to insulin resistance), and others.

A large retrospective study analyzing the electronic medical records of 56 million unique patients demonstrated the linkage between TNFa and AD by showing that patients with rheumatoid arthritis and psoriasis taking TNF blocking agents had significantly lower AD risk.3 Preclinical studies showed NE3107 is a modulator of TNFa production through its ability to modulate the activation of the Extracellular Regulated Kinase (ERK) and Nuclear Factor kappa B (NFkB).4 By down regulating the activation of ERK and NFkB, NE3107 has been shown to reduce the production of TNFa.5 The Company's newly generated data supporting a new patent application show that NE3107 inhibits inflammatory ERK activation and blocks the phosphorylation of TNF receptor 1 (TNFR1) in an IKK-MAP3K8-MEK dependent pathway to decrease forward-feeding TNF inflammatory cascades, thereby lowering the expression of other downstream inflammatory factors. Since the NE3107 Phase 3 trial underway is focused on cognition and function and is not focused on collecting neuroinflammatory biomarkers, the Company supported a Phase 2 investigator-initiated trial (NCT05227820) to explore the link between NE3107's role in neuroinflammation and insulin resistance to the biomarkers historically used by the AD research community. It also was designed to provide, if possible, a glimpse into what can be expected regarding cognition and function when the Phase 3 trial reads out next year.

This was done by using a modified ADAS-Cog12 scale for cognition and the Global Rating of Change (GRoC), which is an instrument that can be administered more easily in general clinical practices than the ADCS-CGIC. The Phase 2 trial— A Phase II Open-Label Study for the Use of Anti-Inflammatory, Insulin-Sensitizing NE3107 for Treatment of Cognitive Decline Due to Degenerative Dementias (NCT05227820) — is an exploratory biomarker study conducted by Dr. Sheldon Jordan6, who served as principal investigator for the trial. The trial was intended to explore NE3107's potential role in real-world clinical practice as an exploratory precursor informing the design of subsequent placebo-controlled blinded studies.

Results from Phase 2 Exploratory Biomarker Trial: The trial enrolled a total of 23 patients – 17 patients with Mini-Mental State Examination (MMSE) scores greater than or equal to 20 (i.e., mild cognitive impairment [MCI] to mild AD) and 6 patients with MMSE <20 (i.e., moderate AD) – in an open-label, single arm study. The trial measured changes in cognition through verbal and visual test procedures, changes in biomarkers of Alzheimer's disease and inflammation that can be measured in cerebral spinal fluid (CSF) and serum samples, and with functional magnetic resonance imaging techniques in patients before and after treatment with 20 mg of NE3107 twice daily for 3 months.