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Clinical Trial
. 2024 Jul 26;103(30):e39027.
doi: 10.1097/MD.0000000000039027.

A phase 2, open-label study of anti-inflammatory NE3107 in patients with dementias

Jonathan Haroon  1 , Kaya Jordan  1 , Kennedy Mahdavi  1   2 , Elisabeth Rindner  1 , Sergio Becerra  2 , Jean Rama Surya  1 , Margaret Zielinski  1 , Victoria Venkatraman  1   2 , Dayan Goodenowe  3 , Kaitlyn Hofmeister  3 , Jeffrey Zhang  4 , Clarence Ahlem  5 , Christopher Reading  5 , Joseph Palumbo  5 , Bijan Pourat  6 , Taylor Kuhn  7 , Sheldon Jordan  1   2
Affiliations
Clinical Trial

A phase 2, open-label study of anti-inflammatory NE3107 in patients with dementias

Jonathan Haroon et al. Medicine (Baltimore). .

Abstract

Background: Alzheimer's disease (AD) is a progressive, multifactorial, neurodegenerative disorder affecting >6 million Americans. Chronic, low-grade neuroinflammation, and insulin resistance may drive AD pathogenesis. We explored the neurophysiological and neuropsychological effects of NE3107, an oral, anti-inflammatory, insulin-sensitizing molecule, in AD.

Methods: In this phase 2, open-label study, 23 patients with mild cognitive impairment or mild dementia received 20-mg oral NE3107 twice daily for 3 months. Primary endpoints assessed changes from baseline in neurophysiological health and oxidative stress (glutathione level) using advanced neuroimaging analyses. Secondary endpoints evaluated changes from baseline in neuropsychological health using cognitive assessments, including the 11-item Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11), Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment, Clinical Dementia Rating, Quick Dementia Rating Scale, Alzheimer's Disease Composite Score, and Global Rating of Change (GRC). Exploratory endpoints assessed changes from baseline in neuroinflammation biomarkers (tumor necrosis factor alpha, TNF-α) and AD (amyloid beta and phosphorylated tau [P-tau]).

Results: NE3107 was associated with clinician-rated improvements in cerebral blood flow and functional connectivity within the brain. In patients with MMSE ≥ 20 (mild cognitive impairment to mild AD; n = 17), NE3107 was associated with directional, but statistically nonsignificant, changes in brain glutathione levels, along with statistically significant improvements in ADAS-Cog11 (P = .017), Clinical Dementia Rating (P = .042), Quick Dementia Rating Scale (P = .002), Alzheimer's Disease Composite Score (P = .0094), and clinician-rated GRC (P < .001), as well as in cerebrospinal fluid P-tau levels (P = .034) and P-tau:amyloid beta 42 ratio (P = .04). Biomarker analyses also demonstrated directional, but statistically non-significant, changes in plasma TNF-α, consistent with the expected mechanism of NE3107. Importantly, we observed a statistically significant correlation (r = 0.59) between improvements in TNF-α levels and ADAS-Cog11 scores (P = .026) in patients with baseline MMSE ≥ 20.

Conclusion: Our results indicate that in this study NE3107 was associated with what appear to be positive neurophysiological and neuropsychological findings, as well as evidence of improvement in biomarkers associated with neuroinflammation and AD in patients diagnosed with dementia. Our findings are consistent with previous preclinical and clinical observations and highlight a central role of neuroinflammation in AD pathogenesis.

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Conflict of interest statement

As employees of The Regenesis Group, Mr. Haroon, Ms. Jordan, Ms. Mahdavi, Ms. Rindner, Mr. Becerra, Mr. Surya, and Dr. Jordan report receiving grant funding from BioVie Inc. for this study. Mr. Becerra is CTO at Synaptec Network. Dr. Goodenowe has been paid fees for processing blood samples. Ms. Hofmeister’s institution has received partial grant support from Dr. Jordan. Dr. Kuhn, through Kuhn Consulting LLC, has received consulting fees from Synaptec Network, Synaptec Research, and The Regenesis Project. Dr. Jordan is CEO and founder of Synaptec Network and was responsible for processing of fMRIs on this study. Ms. Zielinski, Ms. Venkatraman, and Dr. Pourat have nothing to disclose. Dr. Zhang has received consulting fees from BioVie Inc. to prepare the data analysis of the manuscript and has stock or stock options with BioVie Inc. Mr. Ahlem and Dr. Reading are employees, stockholders, and have stock options with BioVie Inc. Dr. Palumbo is an employee and stockholder at BioVie Inc.; he has multiple patents filed as a full time compensated employee: formerly—Johnson & Johnson, Mitsubishi Tanabe, and Zynerba Pharmaceuticals; currently—BioVie Inc.; he is also an unpaid voluntary member of Dean’s Advisory Council of the George Washington University School of Medicine and Health Sciences, Washington, DC.

Figures

Figure 1.
Figure 1.
Flowchart of the study selection process.
Figure 2.
Figure 2.
The neurophysiological health of patients before and after treatment with NE3107 was evaluated using advanced MRI of the brain. (A–E) Statistically significant regions of increased connectivity for (A) precuneus ROI (z-score > 3.1), (B) left HC ROI (z-score > 2.3), (C) right HC ROI (z-score > 2.3), (D) left NBM ROI (z-score > 2.3), and (E) right NBM ROI (z-score > 2.3); (F) Percent change from baseline in glutathione levels in the precuneus as measured by MRS (P = .069). HC = hippocampus; MMSE = Mini-Mental State Examination; MRI = magnetic resonance imaging; MRS = magnetic resonance spectroscopy; NBM = nucleus basalis of Meynert; ROI = region of interest.
Figure 3.
Figure 3.
Secondary endpoints evaluated changes, after treatment with NE3107, in neuropsychological health using various cognitive assessments. (A–E) Change from baseline in (A) ADAS-Cog11 scores (all patients, P = .29; MMSE ≥ 20 patients, P = .017); (B) MMSE scores (all patients, P = .20; MMSE ≥ 20 patients, P = .55); (C) MoCA scores (all patients; P = .92; MMSE ≥ 20 patients, P = .23); (D) QDRS scores (all patients, P = .37; MMSE ≥ 20 patients, P = .002); (E) CDR scores (all patients, P = .63; MMSE ≥ 20 patients, P = .042). (F) Change from baseline in ADCOMS in patients with clinician-rated improvements in any fMRI analyses. ADAS-Cog11 = 11-item Alzheimer’s Disease Assessment Scale-Cognitive Subscale; ADCOMS = Alzheimer’s Disease Composite Score; CDR = Clinical Dementia Rating; fMRI = functional magnetic resonance imaging; MMSE = Mini-Mental State Examination; MoCA = Montreal Cognitive Assessment; QDRS = Quick Dementia Rating Scale.
Figure 4.
Figure 4.
Exploratory endpoints assessed changes in biomarkers associated with neuroinflammation and AD in patients after treatment with NE3107. (A) Change from baseline in plasma TNF-α for all patients (P = .23) and patients with MMSE ≥ 20 (P = .24). (B–D) Change from baseline in CSF levels of B. P-tau:Aβ42 ratio (all patients, P = .18; MMSE ≥ 20 patients, P = .04); (C) P-tau levels (all patients, P = .26; MMSE ≥ 20 patients, P = .034); (D) Aβ42 levels (all patients, P = .77; MMSE ≥ 20 patients, P = .80). Aβ42 = amyloid beta peptide 42; CSF = cerebrospinal fluid; MMSE = Mini-Mental State Examination; P-tau = phosphorylated tau protein; TNF-α = tumor necrosis factor alpha.
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