# EDGAR Filing Document

**Accession Number:** 0001580149
**File Stem:** 0001520138-23-000148
**Filing Date:** 2023-3
**Character Count:** 49807
**Document Hash:** 318d1b92007303b3569baa70f71ea767
**Contains OCR:** False
**Source Format:** 

## Filing Content

## Filing Summary
**0001520138-23-000148.hdr.sgml**: 20230323

**ACCESSION NUMBER**: 0001520138-23-000148

**CONFORMED SUBMISSION TYPE**: 8-K

**PUBLIC DOCUMENT COUNT**: 93

**CONFORMED PERIOD OF REPORT**: 20230323

**ITEM INFORMATION**: Regulation FD Disclosure

**ITEM INFORMATION**: Financial Statements and Exhibits

**FILED AS OF DATE**: 20230323

**DATE AS OF CHANGE**: 20230323

**FILER**: 

**COMPANY DATA:**
- **COMPANY CONFORMED NAME:** BIOVIE INC.
- **CENTRAL INDEX KEY:** 0001580149
- **STANDARD INDUSTRIAL CLASSIFICATION:** PHARMACEUTICAL PREPARATIONS [2834]
- **IRS NUMBER:** 462510769
- **STATE OF INCORPORATION:** NV
- **FISCAL YEAR END:** 0630

**FILING VALUES:**
- **FORM TYPE:** 8-K
- **SEC ACT:** 1934 Act
- **SEC FILE NUMBER:** 001-39015
- **FILM NUMBER:** 23757004

**BUSINESS ADDRESS:**
- **STREET 1:** 680 W NYE LANE
- **STREET 2:** SUITE 201
- **CITY:** CARSON CITY
- **STATE:** NV
- **ZIP:** 89703
- **BUSINESS PHONE:** 775-888-3162

**MAIL ADDRESS:**
- **STREET 1:** 680 W NYE LANE
- **STREET 2:** SUITE 201
- **CITY:** CARSON CITY
- **STATE:** NV
- **ZIP:** 89703

**FORMER COMPANY:**
- **FORMER CONFORMED NAME:** NANOANTIBIOTICS, INC.
- **DATE OF NAME CHANGE:** 20130625

?xml version="1.0" encoding="utf-8"?

**UNITED STATES SECURITIES AND EXCHANGE COMMISSION WASHINGTON, D.C. 20549**

**FORM 8-K**

**CURRENT REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934**

Date of Report (Date of earliest event reported) **March 23, 2023**

**<u>BioVie Inc.</u>** (Exact Name of Registrant as Specified in Its Charter)

---

| | | |
|:---|:---|:---|
| **Nevada** | **001-39015** | **46-2510769** |
| (State or Other Jurisdiction<br> of Incorporation)<br>| (Commission File Number) | (I.R.S. Employer Identification No.) |

---

---

| | |
|:---|:---|
| **680 W Nye Lane Suite 201**<br> **Carson City, NV** | **89703** |
| (Address of Principal Executive Offices) | (Zip Code) |

---

**(775) 888-3162** (Registrant's Telephone Number, Including Area Code)

(Former Name or Former Address, if Changed Since Last Report)

Securities registered pursuant to Section 12(b) of the Act:

---

| | | |
|:---|:---|:---|
| Title of each class | Trading Symbol(s) | Name of each exchange on which<br> registered |
| Class A Common Stock, par value $0.0001 per share | BIVI | The Nasdaq Stock Market, LLC |

---

Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions (see General Instruction A.2. below):

☐ Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425)

☐ Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12)

☐ Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b))

☐ Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c))

Indicate by check mark whether the registrant is an emerging growth company as defined in as defined in Rule 405 of the Securities Act of 1933 (§230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§240.12b-2 of this chapter).

Emerging growth company ☐

If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐

---

| | |
|:---|:---|
| **Item 7.01** | **Regulation FD Disclosure.** |

---

BioVie Inc. (the "Company") has updated its investor presentation (the "Investor Presentation"), a copy of which is furnished as Exhibit 99.1 to this Current Report on Form 8-K and is incorporated herein by reference. The Investor Presentation is also available under the "Events and Presentations" tab in the "Investors" section of the Company's website, located at www.biovie.com.

By filing this Current Report on Form 8-K and furnishing the information contained herein, the Company makes no admission as to the materiality of any information in this report (including Exhibit 99.1) that is required to be disclosed solely by reason of Regulation FD.

The information contained in the Investor Presentation is summary information that is intended to be considered in the context of the Company's Securities and Exchange Commission ("SEC") filings and other public announcements that the Company may make, by press release or otherwise, from time to time. The Company undertakes no duty or obligation to publicly update or revise the information contained in this report, although it may do so from time to time as its management believes is warranted. Any such updating may be made through the filing of other reports or documents with the SEC, through press releases or through other public disclosure.

The information presented in Item 7.01 of this Current Report on Form 8-K and Exhibit 99.1 shall not be deemed to be "filed" for purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the "Exchange Act"), or otherwise subject to the liabilities of that section, unless the Company specifically states that the information is to be considered "filed" under the Exchange Act or specifically incorporates it by reference into a filing under the Securities Act of 1933, as amended, or the Exchange Act.

---

| | |
|:---|:---|
| **Item 9.01** | **<u>Financial Statements and Exhibits</u>** |

---

(d) Exhibits

---

| | |
|:---|:---|
| **Exhibit No.** | **Description** |
| [99.1](bivi-20230323_8kex99z1.htm) | [Investor Presentation dated March 23, 2023](bivi-20230323_8kex99z1.htm) |

---

**SIGNATURE**

Pursuant to the requirements of the Securities Exchange Act of 1934, the Registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.

Dated: March 23, 2023

---

| | |
|:---|:---|
| **BIOVIE INC.** | **BIOVIE INC.** |
| By: | /s/ Joanne Wendy Kim |
| Name: | Joanne Wendy Kim |
| Title: | Chief Financial Officer |

---

## Exhibit 99.1

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### Attached PDF Documents

**Attachment 1:** `bivi-20230323_8kex99z1.pdf`

bioVie

# BioVie Day Presentation

March 23, 2023

# Forward-looking statements

This document contains forward-looking statements made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995 that involve risks, uncertainties and assumptions that could cause BioVie's actual results and experience to differ materially from anticipated results and expectations expressed in these forward-looking statements. BioVie has in some cases identified forward-looking statements by using words such as 'anticipates,' 'believes,' 'hopes,' 'estimates,' 'looks,' 'expects,' 'plans,' 'intends,' 'goal,' 'potential,' 'may,' 'suggest,' and similar expressions. Among other factors that could cause actual results to differ materially from those expressed in forward-looking statements are: BioVie's need for, and the availability of, substantial capital in the future to fund its operations and research and development. Other risks are that BioVie's compounds may not successfully complete pre-clinical or clinical testing or be granted regulatory approval to be sold and marketed in the United States or elsewhere. BioVie cannot guarantee the effectiveness of its patents or Orphan Drug designations. A more complete description of these risk factors is included in BioVie's filings with the Securities and Exchange Commission. In addition to the risks described above and in BioVie's filings with the Securities and Exchange Commission, other unknown or unpredictable factors also could affect BioVie's results. No forward-looking statements can be guaranteed and actual results may differ materially from such statements. You should not place undue reliance on any forward-looking statements. BioVie undertakes no obligation to release publicly the results of any revisions to any such forward-looking statements that may be made to reflect events or circumstances after the date that these slides are posted to BioVie's website or to reflect the occurrence of unanticipated events, except as required by applicable law or regulation.

©2022 BioVie Inc. | 1

# Agenda

- Overview
- Chronic Low-grade Inflammation Science
- Development programs

  - Alzheimer's Disease
  - Parkinson's Disease
  - Epigenetics & Longevity
  - Liver Disease

- Clinical & Regulatory Strategy
- Commercialization Roadmap
- Social Impact
- Recap

bioVie

©2022 BioVie Inc.

2

bioVie

# Overview

# Executive Summary

- • The company is in the early stages of multiple late-stage data readouts for multiple indications addressing great unmet medical needs
- • Early results in Alzheimer's Disease (AD), Parkinson's Disease (PD) and Ascites have all been encouraging, and our KOLs/SAB have encouraged us to move more assertively
- • Potentially pivotal registrational trials are underway or will begin in 2023 for all indications
- • Topline results from our Phase 3 AD trial expected to be announced October 2023. Regulatory submissions expected in 2024 and 2025
- • We believe our portfolio, if approved, will create a platform of great benefit to patients and economic value to shareholders
- • All development and commercialization options (including partnering) being considered
- • Our support of Social Impact Partners allows us to bring better patient-centered support to affected individuals/families, of which our future medication will be an important part

biovie

©2022 BioVie Inc. | 4

# Our journey thus far

- BioVie started with a single program in refractory ascites with the backdrop that terlipressin (or any treatment) has never been approved in the US
- Acquisition of the Neurmedix assets (including NE3107) expanded our horizons
  - The team that discovered NE3107 sought to develop a new therapy for diabetes
  - Their understanding of systems biology and metabolic syndromes led to the insights on NE3107's unique MOA and value in areas beyond diabetes, including AD and PD
- We took a more assertive approach than big-pharma
  - Proceeded straight to a potentially pivotal Phase 3 in mild- to moderate-AD as our first trial in AD
  - Supported exploratory biomarker Phase 2 started afterwards that associated NE3107 with reversed cognitive decline and reduced p-Tau in MCI and mild-AD
  - Conducted larger PD DDI study than required to seek an efficacy signal in humans, which revealed impact on greater motor control and morning "on time"
- Strong data and counsel from KOLs/SAB leading us to be more expansive with our aspirations than originally plan

biovie

©2022 BioVie Inc. | 5

# Our journey ahead

File NDA

Launch

|  | 2023 |  |  |  | 2024 |  |  |  | 2025 |  |  |  | 2026 |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  | Q1 | Q2 | Q3 | Q4 | Q1 | Q2 | Q3 | Q4 | Q1 | Q2 | Q3 | Q4 | Q1 | Q2 | Q3 | Q4 |
| Alzheimer's (NE3107) |  | Mild/Moderate AD Phase 3 (US) |  | Open label extension |  | ? |  | ? |  |  |  |  |  |  |  |  |
|  |  |  |  | Radiance-MCI 1 |  | Open label extension |  | ? |  | ? |  |  |  |  |  |  |
|  |  |  |  |  |  | Radiance-MCI 2 (Global) |  |  |  |  |  |  |  |  |  |  |
|  |  |  |  |  |  | Radiance-AD: Mild/Moderate AD Phase 3 (Global) |  |  |  |  |  | ◆ |  | ● |  |  |
| Parkinson's (NE3107) |  |  |  | SUNRISE-1 |  |  |  | Extension study |  |  |  |  | ◆ |  | ● |  |
|  |  |  |  |  |  | SUNRISE-2 (Global) |  |  |  |  |  | Extension study |  |  |  |  |
| Ascites (BIV201) |  | Phase 2b |  |  | Phase 3 |  |  |  |  |  | ◆ |  |  | ● |  |  |

bioVie

* Two Phase 3 trials are usually required for registration. However, the FDA has allowed filing based on strong data from a single pivotal trial in indications with few therapeutic options.

©2022 BioVie Inc.

6

bioVie

# Chronic Low-grade Inflammation Science

# Chronic low-grade inflammation

- Inflammation is the result of the body's natural protective processes

Insults

- Pathogens
- Trauma
- Ischemia
- Stress
- Radiation
- Obesity
- Cancer

Responders

- Blood proteins
- Platelets
- Granulocytes
- Monocytes
- Macrophages
- Microglia
- Endothelial cells

Master Alarms

- NFκB transcription factors
- Oxidative stress
- Reactive oxygen
- Reactive nitrogen

Pro-inflammatory

factors

- Cytokines
- Chemokines
- Receptors
- Complement factors
- Metalloprotinases
- Cell adhesion molecules

- If insults and pro-inflammatory factors eliminated, pathology addressed
- If not, low grade chronic inflammation and associated insulin resistance ensues
- Inflammation and insulin resistance go hand-in-hand

bioVie

©2022 BioVie Inc.

8

# TNFα-mediated inflammation leads to many downstream consequences

TNFα

![img-0.jpeg](img-0.jpeg)

- Cytokine and chemokine production (more inflammation)
- Systems dysregulation (diabetes, dyslipidemia, cardiovascular, etc.)
- Hypermethylation of DNA
- IKKβ and JNK activation → insulin resistance
- More APP → more Aβ (more inflammation)
- Serine/threonine kinase activation (Tau → pTau)

- Various forms of cancers
- Age-related cognitive impairment and dementia
- Parkinson's disease
- Cardiovascular disease
- COPD and respiratory disease
- Chronic kidney disease
- Inflammatory bowel disease
- Sepsis
- Many others

bioVie

Wang Z Nucleic Acids Research, 2020, Vol. 48, No. 5; Sugden K Neurology 2022;99:e1402-e1413; Tang X DOI: 10.1002/mds.29157; Tabaeia S Artificial Cells, Nanomedicine, and Biotechnology, 47:1, 2031-2041; Qiu W Am J Respir Crit Care Med Vol 185, Iss. 4, pp 373-381, Feb 15, 2012; Rysz C Int J Mol Sci, 2022, 23(13), 7108; Kraiczy J Mucosal Immunology volume 9, pages 647-658 (2016); Rump K Sci Rep 9, 18511 (2019)

©2022 BioVie Inc.

9

# NE3107 blocks inflammatory (but not homeostatic) ERK and NFkB, which play pivotal roles in AD pathogenesis

![img-0.jpeg](img-0.jpeg)

bioVie

©2022 BioVie Inc.

10

# Activation of Inflammatory Signaling

Inflammatory signals (Amyloid beta, TNF, LPS, fatty acids, others) interact with toll-like receptor 4 (TLR4) and with TNF Receptor 1 (TNFR1) leading to:

01 Activation of I kappa B kinase beta (IKKβ)
02 Phosphorylation of NFκB p105, which is degraded to p50
03 Release of MAP3K8 phosphorylation of MEK, ERK, RSK, MSK, NFκB3 (RelA p65)
04 Nuclear localization of p50 and phospho-p65
05 Transcription of kappa B (κB) promoter sites for inflammatory genes (e.g., TNF, IL-1, IL-6)

06 Translation, maturation and secretion of inflammatory mediators (e.g., TNF)
07 TNF binding to TNFR1
08 MAP3K8-dependent ERK phosphorylation of TNFR1
09 Internalization of the TNF/TNFR1 complex leading to further inflammatory signaling

bioVie

©2022 BioVie Inc.

11

# ERK plays a critical role in the NFκB scaffold complex

![img-1.jpeg](img-1.jpeg)

bioVie

©2022 BioVie Inc.

12

# We believe NE3107 alters the NFκB scaffold complex

![img-2.jpeg](img-2.jpeg)

bioVie

©2022 BioVie Inc.

13

# Normal insulin signaling

![img-3.jpeg](img-3.jpeg)

bioVie

©2022 BioVie Inc.

14

# Inflammation-mediated insulin resistance

![img-4.jpeg](img-4.jpeg)

bioVie

©2022 BioVie Inc.

15

# NE3107 believed to modulates inflammation at the central hub, thereby reducing downstream inflammatory cascade

![img-5.jpeg](img-5.jpeg)

bioVie

©2022 BioVie Inc.

16

# Expanding beyond NE3107

- HE3291 is a sister molecule with similar activity profile as NE3107
- We are resuming discovery research to explore additional molecules and indications

  - We now have a much better understanding of NE3107's presumed MOA
  - Enables even more precise medicinal chemistry to target binding sites

- Focus areas will be communicated in due course

bioVie

©2022 BioVie Inc.

17

bioVie

# Alzheimer's Disease

# Alzheimer's Disease program overview

- Results from NE3107 Phase 2 exploratory biomarker trial in Mild Cognitive Impairment (MCI)/mild-AD reported at the CTAD Annual Conference in December 2022

- First data set showing impact on cognition, p-tau, and imaging biomarkers
- Impact on biological aging created new program on epigenetics & longevity

- NM101 Phase 3 in mild- to moderate-AD fully enrolled

- Last patient visit expected in September 2023. Topline data readout expected October 2023

- Future clinical trials

- Radiance-MCI 1 being launched by June 2023 to focus on US registration
- Follow-on trials for global registrations in MCI and mild/moderate AD targeted for early 2024

biovie

©2022 BioVie Inc.

19

# NE3107 Phase 2 exploratory biomarker trial

Open-Label Single-Arm 3-Month Study

Inclusion criteria

- 50-89 years old
- Cognitive decline due to dementia
- QDRS score: 1.5-12.5
- CDR score: 0.5 (MCI) or 1 (mild dementia)

Exclusion criteria

- Prior imaging inconsistent with AD
- History of stroke that resulted in cognitive or motor deficits
- MRI/CT evidence of moderate/large cerebral infarct

![img-0.jpeg](img-0.jpeg)

N=23

Active Treatment, 3 Months

NE3107
20 mg

BID
12 hours apart

![img-1.jpeg](img-1.jpeg)

Change from baseline assessments

Neuroimaging

- MRS
- Relative CBF
- Anatomical imaging
- BOLD imaging*
- DTI-NODDI†

Clinical Assessments

- MMSE
- ADAS-Cog12
- MoCA
- QDRS and CDR
- ADCOMS

Biomarker Assessments

- Plasma TNF-α
- CSF Aβ42
- CSF p-tau
- P-tau:Aβ42 ratio
- Brain glutathione (by MRS)

*Preliminary data; †Data analysis ongoing.

ADAS-Cog, Alzheimer's Disease Assessment Scale-Cognitive Subscale; ADCOMS, AD Composite Score; ASL, arterial spin labeling; BID, twice per day; BOLD, blood-oxygen level dependent; CBF, cerebral blood flow; CDR, Clinical Dementia Rating; CSF, cerebrospinal fluid; DTI-NODDI, diffusion tensor imaging - neurite orientation dispersion and density imaging; MMSE, Mini-Mental State Examination; MoCA, Montreal Cognitive Assessment; MRS, magnetic resonance spectroscopy; NMR, nuclear magnetic resonance; QDRS, Quick Dementia Rating Scale.

biovie

©2022 BioVie Inc. | 20

# Clinical outcomes assessments

NE3107 Was Associated With Improvements From Baseline in Clinical Outcomes of Neuropsychological and Cognitive Assessments after 3 months of Treatment

## Changes from Baseline in Clinical Assessments

| Assessment | All Patients (N=23) | MCI/Mild AD (n=18) |
| --- | --- | --- |
| ADAS-Cog12 | -0.913 | -2.167* |
| MMSE | -0.74 | -0.39 |
| MoCA | -0.04 | 0.56 |
| QDRS | -0.54 | -1.56* |
| CDR | 0.04 | -0.11* |
| ADCOMS | 0.0049 | -0.07* |

In the patients with baseline MMSE ≥20 (indicating MCI or mild dementia), NE3107 was associated with statistically significantly improved cognitive functioning vs baseline, in ADAS-Cog12, QDRS, CDR, ADCOMS.

Green=Improvement

## Clinician-Rated Global Rating of Change

![img-2.jpeg](img-2.jpeg)

biovie

*p<0.05

©2022 BioVie Inc. | 21

# Biomarker improvements

Changes from baseline in biomarkers

| Assessment | All Patients (N=23) | MCI/Mild AD (n=18) |
| --- | --- | --- |
| TNF-α, pg/mL | -0.452 | -0.563 |
| CSF p-tau, pg/mL | -1.1 | -1.66* |
| P-tau:Aβ42 ratio | -0.0033 | -0.0024* |

In the MMSE ≥20 patients, NE3107 was associated with statistically significant improvements in p-tau and the p-tau:Aβ42 ratio

Correlations between biomarkers and clinical outcomes

|  | All Patients | MMSE ≥20 n=18 |
| --- | --- | --- |
| ADAS-Cog12 |  |  |
| TNF-α | r=0.46 | r=0.59* |
| ADCOMS |  |  |
| Aβ42 | r=0.53* | r=0.31 |
| P-tau | r=0.49* | r=0.37 |

NE3107 was associated with statistically significant correlations between several clinical assessments and biomarkers

Green=Improvement

biovie

*p<0.05

©2022 BioVie Inc.

22

# Neuroimaging methodology

- Functional MRI data were submitted to blinded review and scoring by two independent clinician-readers. Inter-rater reliability was 96%; in the event of disagreement between raters, data were subjected to additional review and ultimately scored by consensus
- Criteria for “Improved,” “Stable,” or “Declined”
  - Improved: No longer meets criteria for abnormality
  - Declined: Previously ‘normal’ scan met criteria for abnormality at follow-up OR • Abnormality becomes more extensive in an abnormal patient
  - Stable: No significant change between baseline and follow-up scans

![img-3.jpeg](img-3.jpeg)

![img-4.jpeg](img-4.jpeg)

**Criteria for Abnormality:** Perfusion / Relative cerebral blood flow (CBF): 30% decrease in signal intensity in the temporal, parietal, or occipital lobes (in at least one hemisphere) was scored as abnormal.

Examples shows a subject that had decreased perfusion (abnormal) that improved at follow-up

bioVie

©2022 BioVie Inc. | 23

# NE3107 increased functional connectivity from baseline in group analysis using BOLD imaging

Precuneus ROI

![img-5.jpeg](img-5.jpeg)

Right HC ROI

Left HC ROI

![img-6.jpeg](img-6.jpeg)

Statistically significant regions of increased connectivity

![img-7.jpeg](img-7.jpeg)

![img-8.jpeg](img-8.jpeg)

bioVie

©2022 BioVie Inc.

24

# NE3107 associated with reduced oxidative stress in the brain

Brain glutathione assessed by MRS of Precuneus

![img-9.jpeg](img-9.jpeg)

11/17 (59%) improved
mean +59% change
P=0.069

![img-10.jpeg](img-10.jpeg)

Significant correlation of Glutathione with:

TNF-α (r=-0.44)

ADAS-Cog12 (r=-0.45)

bioVie

©2022 BioVie Inc.

25

# Update on NM101 Phase 3 in Mild/Moderate

- Trial fully enrolled as of February 28, 2023

  - 100 patients completed treatment at that time
  - Top-line data readout expected in October 2023

- Trial continues to have a good safety profile and low discontinuation rate
- Blinded baseline data shows evidence of metabolic inflammation in amyloid β positive and negative, and APOEε4 positive and negative subjects submitted for presentation at the American Diabetes Association's 83rd Scientific Sessions in San Diego, June 23-26, 2023

biovie

©2022 BioVie Inc.

26

# Radiance-MCI 1 Trial

- A potentially pivotal Phase 2/3, double-blind, randomized, placebo-controlled, parallel group, multicenter study of NE3107 in MCI subjects
  - MCI patients have a measurable loss of memory, but have not yet shown significant functional impairment
  - MCI is defined by Stage 2 and Stage 3 diagnostic criteria in Draft Guidance for Industry- Early AD: Developing Drugs for Treatment (February 2018)
  - Most patients with MCI continue to degenerate to AD. Inflammation drives both conditions
  - Arresting/reversing at the MCI stage (CDR less than 0.5) has the potential for the greatest long term patient benefit
- Patients 50-80 years old qualify with computer-based tests of cognitive impairment
- Patients will receive 20 mg NE3107 or placebo for 6 months for CDR-SB primary endpoint
  - Patients randomized to NE3107 will continue receiving drug for 1 year to observe effect on disease progression
  - Patients randomized to placebo at the start crosses over to NE3107 for 6 months (delayed start)
- Anticipate first patient enrollment by June 2023
- Trial approach provides maximum flexibility to work with FDA for approval
  - Single MCI trial in combination with mild-/moderate-AD Phase 3 for full approval in MCI in the US
  - A second MCI trial to be started in 2024 for as second trial for full approval in MCI globally

biovie

©2022 BioVie Inc. | 27

bioVie

# Parkinson's Disease

# Parkinson's Disease program overview

- Clinical development was initiated based on strong data from preclinical studies
- Phase 2 NM201 trial launched with 2 main objectives
  - Primary: safety and drug-drug-interaction study (as requested by FDA) to demonstrate the absence of adverse interactions with levodopa
  - Secondary: detect efficacy signal in humans
  - Small study not powered for statistical significance
- NM201 objectives were both met
  - 3+ points greater motor control vs. placebo on the UPDRS Part 3 score. 6+ point among <70 years old
  - Statistically significant fraction of patients experienced morning “on” state with levodopa withheld overnight and prior to receiving their morning medication
- Clinical studies in levodopa naïve patients being launched
  - SUNRISE-1 is a potentially pivotal Phase 2b starting 3Q2023
  - SUNRISE-2 is a potentially pivotal Phase 3 starting late 1Q2024

bioVie

©2022 BioVie Inc. | 29

# NE3107 has similar promotoric activity to L-dopa in rodent* and marmoset* models

Funded by

THE MICHAEL I. FOX FOUNDATION

FOR PARKINSON'S RESEARCH

MPTP Mouse

![img-0.jpeg](img-0.jpeg)

MPTP Marmoset treated at Week 8

![img-1.jpeg](img-1.jpeg)

*p<0.001 compared to other treatment arm in time period

** L-Dopa at week 11 not statistically different from NE3107 at weeks 8 and 9

NE3107's promotoric effects observed within 4 days of treatment

biovie

* Funded by MJFF for Parkinson's Research, MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a toxin used to mimic many aspects of PD

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# NE3107 decreases L-Dopa-induced dyskinesia (LID) in marmosets*

Funded by

THE MICHAEL J. FOUNDATION

FOR PARKINSON & RESEARCH

Distribution of AIMS Scores

![img-2.jpeg](img-2.jpeg)

biovie

* Funded by MJFF for Parkinson's Research

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# NE3107 preserved ~2X TH+ (dopaminergic) neurons in MPTP marmosets*

![img-3.jpeg](img-3.jpeg)

Control moneys (M09100 and M11008)

![img-4.jpeg](img-4.jpeg)

![img-5.jpeg](img-5.jpeg)

HE3286 (M11007)

![img-6.jpeg](img-6.jpeg)

Amantadine (M10084)

![img-7.jpeg](img-7.jpeg)

Funded by

THE MICHAEL I. FOX FOUNDATION
FOR PARKINSON'S RESEARCH

biovie

Note: NE3107 was originally known as HE3286 from Hollis Eden Pharmaceuticals. *Funded by MJFF for Parkinson's Research

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# Parkinson's disease clinical development program

- NM201 sought to satisfy FDA requirement for drug-drug interaction (DDI) study with L-Dopa and assess NE3107 promotoric and anti-LID activity
- 45 patients with defined L-Dopa "off state" randomized 1:1 active:placebo, 20 mg BID for 28 days
- Primary endpoints: Safety, L-Dopa PK and DDI
- Secondary endpoint: MDS-UPDRS* part 1-3 and NMSS**

biovie

* Movement Disorder Society-Unified Parkinson's Disease Rating Scale

** Non-Motor Assessment Scale for Parkinson's Disease

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# NE3107-treatment patients experienced fewer motor symptoms before morning drug administration

Day 28 Improvement in Motor Control vs. Day 1

![img-8.jpeg](img-8.jpeg)

|  | NE3107 | Placebo |
| --- | --- | --- |
| "On" at t=0 | 6 | 0 |
| Total patients | 20 | 19 |
| P-value* | 0.02 |  |

* Fisher's exact test

biovie

©2022 BioVie Inc. | 34

# Desirable pharmacokinetics - no observed DDI

0-8 hr 231 ngh/mL (SD 22.38)

![img-9.jpeg](img-9.jpeg)

NE3107 Treated Plasma Levodopa

![img-10.jpeg](img-10.jpeg)

Day 1 ave Day 14 ave

Placebo Treated Plasma Levodopa

![img-11.jpeg](img-11.jpeg)

Hr Post Levodopa Administration

Day 1 ave Day 14 ave

bioVie

2 BioVie Inc.

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# Collaboration with Parkinson Study Group

![img-12.jpeg](img-12.jpeg)

- • The largest, pro-active, not-for-profit scientific network of Parkinson Centers in North America for over 30 years
- • Strict credentialing process, with over 150 Credentialed PSG Centers in North America, Hawaii, and the Caribbean
- • Over 350 credentialed investigators and 245 coordinators and growing
- • Strong partnerships with both the **Michael J Fox Foundation** and the **Parkinson's Foundation**
- • International collaborations in India, China, Scandinavia, & Germany
- • Partners receive support from credentialed coordination & biostatistics centers: **CTCC** at the University of Rochester, **NCRI** at Massachusetts General Hospital, and the **Columbia University Biostatistics Center**

biovie

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# BioVie's Parkinson's Advisory Committee

- **Anthony Lang** (co-chair), MD. Author of 950+ peer-reviewed papers and 100+ book chapters in Parkinson's Disease
  - Director, the Morton and Gloria Shulman Movement Disorders Clinic at Toronto Western Hospital
  - Jack Clark Chair for Parkinson's Disease Research at the University of Toronto
  - Lily Safra Chair in Movement Disorders at the University Health Network in Toronto
  - Director, the University Health Network and the University of Toronto Edmond J. Safra Program in Parkinson's Disease
  - Director, Division of Neurology at the University of Toronto
- **Hubert Fernandez** (co-chair), MD. Director, Center for Neurological Restoration, Cleveland Clinic
- **Tanya Simuni**, MD, FAAN. Arthur C. Nielsen Jr Professor of Neurology and the Director of the Parkinson's disease and Movement Disorders Center at Northwestern University Feinberg School of Medicine
- **Rajesh Pahwa**, MD. Laverne and Joyce Rider Professor of Neurology, chief of the Parkinson's and Movement Disorder Division and director of Parkinson Foundation Center of Excellence at the University of Kansas Medical Center
- **Sheng Luo**, PhD. Professor of Biostatistics & Bioinformatics, Duke University

bioVie

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## Strong support from advisors for a more aggressive plan to address significant unmet medical needs

"The Parkinson's Study Group (PSG) has provided guidance to many industry partners who have successfully brought to market Parkinson's therapeutics that address the unmet needs of patients. The PSG members unanimously recommended that the company accelerate plans to explore the potential efficacy of NE3107 in levodopa naïve Parkinson's patients due to the current unmet need. With great enthusiasm, the PSG advisory members look forward to collaborating with BioVie and seeing the results of clinical trials in this patient population"

Dr. Hubert Fernandez on behalf of the Parkinson's Study Group,
Co-Chair PSG and Director of the Center for Neurological Restoration at Cleveland Clinic

March 15, 2023

biovie

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# SUNRISE 1 and 2 in Treatment Naïve PD Patients

![img-13.jpeg](img-13.jpeg)

- SUNRISE-1 and Sunrise-2 have the same design in levodopa naïve PD patients
- 20 mg NE3107 or placebo BID, rescue medication permitted as directed by the investigator
- 6-month to primary endpoint (UPDRS Part 3 score) and secondary endpoint PADLS*
  - Placebo-cross over to NE3107 for 12-month extension to demonstrate disease modification
- Sunrise-1 to enroll 100 patients randomized 1:1, first patient enrollment 3Q2023
  - Blinded interim at 3 months to repower if needed
- Sunrise-2 expected to enroll an estimated 200 patients (to be repowered from Sunrise-1)
  - Start late 1Q2024 with primary endpoint readout 3Q2025
  - Sunrise-1 results in 3Q2024 will be used to re-power SUNRISE-2 Phase 3, if necessary

bioVie

* Parkinson's Disease Activities of Daily Living Scale, a patient reported outcome

©2022 BioVie Inc. | 39

# Additional endpoints

## Secondary endpoints

- Parkinson's Disease Activities of Daily Living Scale* (PADLS)
- Time to initiation of PD therapy
- Parkinson's sleep scale

## Exploratory endpoints

- Rate of disease progression defined by:
- Change in MDS-UPDRS Part 3 score compared to baseline after withholding all PD and study medications for 24 hours in treatment compared to placebo groups at 26, 52, and 56 weeks
- Change in MDS-UPDRS Part 3 score compared to baseline after withholding all PD and study medications for 24 hours in NE3107 patients after 26 and 52 weeks of treatment compared to historical controls, and at week 56
- Plasma levels of inflammatory biomarkers (adiponectin, leptin, CRP, ceruloplasmin, C1q, IFNγ, IL1β, IL6, IL17, IL23, MCP1, RANTES, and TNFα)
- Change in heart rate variability compared to baseline
- Changes in DNA methylation compared to baseline

biovie

*Patient reported outcome

©2022 BioVie Inc. | 40

bioVie

# Epigenetics & Longevity

# Epigenetics & Longevity program overview

- Early stages of program initiated based on early findings that NE3107 may affect the biological aging process
- We have identified the nucleus of academic collaborators to steer this program

- Ekaterina Rogaeva, Ph.D., Professor, Department of Medicine University of Toronto; Chair Research on Dementia with Lewy Bodies; Tanz Center for Research in Neurodegenerative Diseases.
- Nikolaos Daskalakis Ph.D., M.D., Assist. Prof. Psychiatry; Director Neurogenomics and Translational Bioinformatics Lab, McLean Hospital, Harvard Medical School

bioVie

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# Genome reacts to environment, mutations & aging: epigenetics

![img-0.jpeg](img-0.jpeg)

DNA

- 25,000 genes
- 6 billion base pairs
- 4% code for proteins
- 100 million variations

![img-1.jpeg](img-1.jpeg)

## DNAm controls gene-expression

- 28 million CpGs in genome
- DNAm arrays: <1 million CpGs
- DNAm levels at some CpGs are age-related, affecting expression of >2000 genes

Protein

- Diet and exercise remains the most accepted tool for influencing epigenetics
- Clinicians have experimented with metformin and rapomycin

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# DNA methylation clocks and their predictive capacity for aging phenotypes and health span

![img-2.jpeg](img-2.jpeg)

![img-3.jpeg](img-3.jpeg)

- DNAm clocks are based on cumulative assessment of the methylation levels of many age-related CpGs
- DNAm clocks reflect biological aging, the pace of which varies among individuals
- 15 reported DNAm clocks reflect different mechanisms of aging

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# Each DNAm clock is built according to a unique training method

![img-4.jpeg](img-4.jpeg)

bioVie

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# NE3107 decreased biological age in MCI/AD subjects

- Dr. Steve Horvath* developed an extremely precise Biological age DNA methylation clock, the **DNAmSkinBloodAge**
- The biological clock age was in close agreement with the chronological age (72.3 vs 71.6; +0.98%) at baseline
- After 3 months treatment with NE3107 there was a decrease in DNA methylation commensurate with 3.3 years reduction on the Skin Blood Clock (68.1 vs 71.6; -4.9%)

![img-5.jpeg](img-5.jpeg)

bioVie

* 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

©2022 BioVie Inc. | 46

# Next steps

- Additional results of NE3107 modulation of DNA methylation pertaining to immunomodulatory cells, endocrine mediator expression, and their correlates will be presented at the Alzheimer's Association International Conference (AAIC) July 16-20, 2023
- Along with Drs. Rogaeva and Daskalakis, we are assembling longevity advisors, collaborators and team

- To deepen Biovie's current epigenetic analyses in three diseases of aging: MCI, Mild-moderate AD, and PD
- To broaden to additional areas of exploration

biovie

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bioVie

# Liver Disease

# Refractory Ascites

- Fluid build-up in the abdomen of patients with advanced cirrhosis
  - Cannot be controlled with an effective dose of diuretics
- No approved pharmacological treatments - unmet need
- First line treatment is repeated mechanical draining by paracentesis
  - Surgically implanted shunts an option in select patients
- Mortality > 40% in 12 months*

![img-6.jpeg](img-6.jpeg)

Very poor quality of life
Not typically hospitalized

bioVie

* 1 Will et al. Dig Liver Dis. 2022 Aug;54(8):1007-1014.

©2022 BioVie Inc.

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# Ascites Pathophysiology

![img-0.jpeg](img-0.jpeg)

bioVie

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# BIV201

- Terlipressin administered as a continuous infusion
  - Outpatient treatment with small ambulatory infusion pump
- Targets the pathophysiology of ascites
  - Multiple small trials and Phase 2a support efficacy in reducing ascites
- Orphan and Fast Track Designations for the treatment of ascites due to all etiologies except cancer
- Mallinckrodt's Terlivaz approved in US 2022 indicated to improve kidney function in adults with hepatorenal syndrome with rapid reduction in kidney function. Does not impact BIV201 Clinical Program
  - Approved for different indication - Orphan market exclusivity for HRS
  - Administered in conjunction with daily albumin
  - Different dosage form and administration (intermittent bolus injections)
  - Restricted to hospital setting - black box warning
- Impacts BIV201's regulatory pathway and non-clinical package for NDA (505(b)(1))

bioVie

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# BIV201 Program Update

- Phase 2b - Originally targeted 30 patients randomized 2:1
- Paused enrollment based on encouraging data from the first 15 patients informing next steps

- 10 randomized to BIV201; 5 randomized to standard of care
- 5 completed 2 X 28-day cycles
- 5 discontinued treatment during or at end of Cycle 1

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# BIV201-treated patients experienced a 37% advantage in ascites fluid reduction compared to SOC

![img-1.jpeg](img-1.jpeg)

BIV201 + SOC

Mean: 34 % reduction

5/10 (50%) with >40% reduction

P=0.0046

SOC only

Mean: 3.1 % increase

0/5 (0%) with >40% reduction

P=0.8

BIV201 vs SOC

P value = 0.05 for difference

bioVie

©2022 BioVie Inc.

# Patients completing BIV201 treatment experienced 56% advantage in ascites fluid reduction compared to SOC

![img-2.jpeg](img-2.jpeg)

- 53% reduction in ascites volume among patient completing BIV201 treatment
- 15% reduction among patients who started but did not complete treatment
- 3.1% increase for SOC patients
- p<0.001

bioVie

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# Safety

- Incidence of treatment emergent adverse events similar in both groups
- Overall safety consistent with patient population with advanced cirrhosis
- No unexpected SAEs

bioVie

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# Conclusions

- BIV201 treatment resulted in a reduction in ascites
- Treatment appears to be well tolerated
- Engaging FDA in discussions on next steps

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bioVie

# Clinical & Regulatory Strategy

# Alzheimer's Clinical Program creates maximum optionality for approval

![img-3.jpeg](img-3.jpeg)

## Potential paths to approval

- Conditional approval based on strong clinical, functional, and objective results from single US Phase 3 pivotal in mild/moderate AD
- Regular approval for broad indication in dementia (MCI through Moderate) based on combination of positive outcomes from Phase 3 in mild/moderate and Sunrise-MCI 1
- Regular approval for mild/moderate AD from US and Global Phase 3 trials in mild/moderate

bioVie

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# Parkinson's clinical program is straight forward

![img-4.jpeg](img-4.jpeg)

- Both SUNRISE-1 and SUNRISE-2 are designed to serve as pivotal studies
  - Primary end-point of UPDRS Part 3 (motor) scores at 6 months
  - Extension to 18 months to demonstrate disease modification
- SUNRISE-1 adaptive design enables sample size adjustment (if needed) at 3 months
- SUNRISE-2 sample adjustment (if needed) based on SUNRISE-1 results

File NDA

Launch

biovie

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# Ascites program

![img-0.jpeg](img-0.jpeg)

- Phase 2b paused with only one-half targeted patients enrolled due to statistically significant results demonstrating reduction of ascites fluid with BIV201 treatment
- Discussions initiated with FDA on path forward

File NDA

Launch

bioVie

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bioVie

# Commercialization Roadmap

# Commercialization approach

- All options are open
- Partnering is an option

- Initial conversation have been held

  - Some companies interested in global collaboration
  - Others in geographic rights

- Most companies are intrigued and awaiting Phase 3 data readout

- Go-alone is always an option

bioVie

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# Commercial potential in US market alone

Ascites

$1.6B

US peak sales

- $45K/year
- 45% market penetration
- 2026 launch
- 2032 peak sales

Alzheimer's

$30B

Annual sales for every
1 million people treated

- 15% market penetration
- $30K/year - much lower all-in cost vs. competition

Parkinson's

$3B

Annual sales for every
100,000 people treated

- 10% penetration of US market
- $30K/ year

bioVie

Source: Company estimates

©2022 BioVie Inc. | 63

# Current finances

- $44 million cash balance as of February 28, 2023
- We have resources to fund operations through most of the year and could extend through first part of 2024 if necessary

bioVie

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bioVie

# Social Impact

# BioVie is the founding backer of Social Impact Partners

![img-1.jpeg](img-1.jpeg)

Social Impact Partners

Mission:

To combat Alzheimer's and other neurodegenerative conditions and enable people to lead better and healthier lives by 1) working collaboratively, 2) raising awareness, and 3) mobilizing resources that drive innovation and new solutions.

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# SIP's Goals

Mobilizing Resources & Driving Innovation

1. Mobilize 1 million new healthcare workers to support individuals and families.
2. Increase public/private funding of Alzheimer's medical research 3x in 5 years and expand Medicaid/Insurance Coverage for services needed.
3. Invest and grow in 10 companies annually who advance innovative solutions.

Working Collaboratively

4. Connect a global coalition of partners and individuals to promote a public and private collaboration to positively impact healthy aging and brain health.
5. Create college campus networks with Youth Ambassadors across the all countries.
6. Encourage industry collaboration (PPP's sharing preclinical models and resources).

Raising Awareness & Education

7. Implement a significant public service ad campaign to build universal awareness of Alzheimer's.
8. Draft legislation with "Youth Board" in conjunction with consortium to present in DC & globally.
9. Support "turning passion into action" with speaker series and educational programs for universities.

bioVie

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# Meet our global consortium and youth board schools

![img-2.jpeg](img-2.jpeg)

![img-3.jpeg](img-3.jpeg)

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bioVie

**Recap**

# Executive Summary

- • The company is in the early stages of multiple late-stage data readouts for multiple indications addressing great unmet medical needs
- • Early results in Alzheimer's Disease (AD), Parkinson's Disease (PD) and Ascites have all been encouraging, and our KOLs/SAB have encouraged us to move more assertively
- • Potentially pivotal registrational trials are underway or will begin in 2023 for all indications
- • Topline results from our Phase 3 AD trial expected to be announced October 2023. Regulatory submissions expected in 2024 and 2025
- • We believe our portfolio, if approved, will create a platform of great benefit to patients and economic value to shareholders
- • All development and commercialization options (including partnering) being considered
- • Our support of Social Impact Partners allows us to bring better patient-centered support to affected individuals/families, of which our future medication will be an important part

biovie

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# Expected Catalysts & anticipated timelines

File NDA

Launch

|  | 2023 |  |  |  | 2024 |  |  |  | 2025 |  |  |  | 2026 |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  | Q1 | Q2 | Q3 | Q4 | Q1 | Q2 | Q3 | Q4 | Q1 | Q2 | Q3 | Q4 | Q1 | Q2 | Q3 | Q4 |
| Alzheimer's (NE3107) |  | Mild/Moderate AD Phase 3 (US) |  | Open label extension |  | ? |  | ? |  |  |  |  |  |  |  |  |
|  |  |  |  | Radiance-MCI 1 |  | Open label extension |  | ? |  | ? |  |  |  |  |  |  |
|  |  |  |  |  |  | Radiance-MCI 2 (Global) |  |  |  |  |  |  |  |  |  |  |
|  |  |  |  |  |  | Radiance-AD: Mild/Moderate AD Phase 3 (Global) |  |  |  |  |  | ◆ |  | ● |  |  |
| Parkinson's (NE3107) |  |  |  | SUNRISE-1 |  |  |  | Extension study |  |  |  |  | ◆ |  | ● |  |
|  |  |  |  |  |  | SUNRISE-2 (Global) |  |  |  |  |  | Extension study |  |  |  |  |
| Ascites (BIV201) |  | Phase 2b |  |  | Phase 3 |  |  |  |  | ◆ |  |  | ● |  |  |  |

bioVie

* Two Phase 3 trials are usually required for registration. However, the FDA has allowed filing based on strong data from a single pivotal trial in indications with few therapeutic options.

©2022 BioVie Inc. | 71

bioVie

# Appendix

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# Inflammation drives systems dysregulation

- Patients with increasing metabolic disease show greater variability for individual hematology, metabolic and chemistry values
- Indicates increasing dysregulation

![img-0.jpeg](img-0.jpeg)

![img-1.jpeg](img-1.jpeg)

![img-2.jpeg](img-2.jpeg)

![img-3.jpeg](img-3.jpeg)

![img-4.jpeg](img-4.jpeg)

![img-5.jpeg](img-5.jpeg)

![img-6.jpeg](img-6.jpeg)

![img-7.jpeg](img-7.jpeg)

![img-8.jpeg](img-8.jpeg)

![img-9.jpeg](img-9.jpeg)

![img-10.jpeg](img-10.jpeg)

![img-11.jpeg](img-11.jpeg)

DL: dyslipidemic placebo group, IGT: impaired glucose tolerant placebo group, Naive: treatment-naive uncontrolled T2DM placebo group, MET: uncontrolled T2DM placebo group on a stable dose of metformin

RBC: red blood cell count, Hct: hematocrit, MCV: mean cell volume, MCH: mean corpuscular hemoglobin, MCHC: mean corpuscular hemoglobin concentration, Hb: hemoglobin, HbA1c: hemoglobin A1c, HDL: high density lipoprotein cholesterol, LDL: low density lipoprotein cholesterol.

If Statistically Significant Welch ANOVA).

* Statistically significant 2-sided \(F\)-test.

Reading 2013 Mediators Inflamm 814989

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# NE3107 decreased systems dysregulation in a Phase 2 study

- Heteroscedasticity* investigated by analyzing data distributions for normality (Shapiro-Wilks W test)

- Deviations from normal distribution represents dysregulation

- Placebo patients had significantly abnormal data distributions after 84 days of treatment whereas NE3107 subjects did not

- Placebo patients had many parameters that significantly deviated from normal distribution (i.e., dysregulated)

- NE3107 treatment reduced systems dysregulation

| Group | Day | Parameter | HE3286 W test P | Placebo W test P |
| --- | --- | --- | --- | --- |
| Cohort 1 | 84 | ΔInsulin d | >0.1 | <0.0001 |
|  |  | ΔC-peptide | >0.1 | <0.0001 |
|  |  | ΔFasting glucose | >0.1 | 0.02 |
|  |  | ΔHOMA2 %B | >0.1 | <0.0001 |
|  |  | ΔHOMA2 IR | >0.1 | 0.002 |
|  |  | Δleptin | >0.1 | 0.005 |
| Cohort 1 MCP-1 > 40 b | 84 | ΔHbA1c | >0.1 | 0.006 |
|  |  | ΔFasting glucose | >0.1 | 0.02 |
|  |  | ΔHOMA2 %B | >0.1 | <0.0001 |
| Cohort 2 | 84 | ΔnHbA1c | >0.1 | 0.04 |
|  |  | ΔInsulin | >0.1 | >0.1 |
|  |  | ΔFasting glucose | >0.1 | 0.03 |
|  |  | ΔHOMA2 %B | >0.1 | >0.1 |
|  |  | ΔMCP-1 | >0.1 | 0.005 |
|  |  | ΔTriglycerides | >0.1 | <0.0001 |
|  | 112 | ΔnHbA1c | >0.1 | 0.0007 |
|  |  | ΔInsulin | >0.1 | >0.1 |
|  |  | ΔFructosamine | >0.1 | 0.002 |
|  |  | ΔHOMA2 %B | >0.1 | <0.0001 |
| Cohort 2 BMI > 31 c | 84 | ΔHOMA2 %B | >0.1 | 0.007 |
|  |  | ΔMCP-1 | >0.1 | >0.1 |
|  |  | ΔTriglycerides | >0.1 | >0.1 |
|  | 112 | ΔInsulin | >0.1 | <0.0001 |
|  |  | ΔC-peptide | >0.1 | <0.0001 |
|  |  | ΔHOMA2 %B | >0.1 | <0.0001 |
|  |  | ΔHOMA2 IR | >0.1 | <0.0001 |

* Heteroscedasticity describes differences in variances between groups.

Reading 2013 Mediators Inflamm 814989

Note: NE3107 was originally known as HE3286 from Hollis Eden Pharmaceuticals

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# NE3107's inhibition of inflammatory signaling

NE3107 binds to ERK in the NFκB scaffold complex, and alters the scaffold conformation, inhibiting

![img-12.jpeg](img-12.jpeg)

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# Homeostatic insulin signaling

![img-13.jpeg](img-13.jpeg)

01

Hyperglycemia increases insulin, which binds to the insulin receptor (IR) on cells in muscle, liver, adipose tissue, brain, pancreas, etc.

02

Insulin binding to IR triggers IR phosphorylation of insulin receptor substrate 1 & 2 (IRS1/2) on tyrosine, activating Phospho-inositol 3 kinase (PI3K) and MAPKs RAF, MEK and ERK

03

PI3K feeds back to phosphorylate IRS1/2 on serine, inhibiting further stimulation as glucose is taken up in cells in response to insulin

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# Inflammatory inhibition of Insulin signaling

As in macrophage lineage cells, the NFκB resting scaffold is present in these insulin target cells

Inflammatory mediators (e.g., Amyloid β, alpha-synuclein, TNF, fatty acids) activate NFκB, IKKβ, as in macrophages

IKKβ is a serine kinase, and phosphorylates serine on IR, blocking PI3K and ERK homeostatic signaling and resulting in insulin resistance

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# NE3107 restoration of Insulin sensitivity

![img-14.jpeg](img-14.jpeg)

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