Item 1A. Risk Factors 12
Item 1B. Unresolved Staff Comments 38
Item 1C. Cybersecurity 38
Item 2. Properties 38
Item 3. Legal Proceedings 39
Item 4. Mine Safety Disclosures 39
PART II
Item 6. [Reserved] 40
Item 7A. Quantitative and Qualitative Disclosures About Market Risk 44
Item 8. Financial Statements and Supplementary Data 44
Item 9A Controls and Procedures 44
Item 9B. Other Information 45
Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 45
PART III
Item 10. Directors, Executive Officers and Corporate Governance 46
Item 11. Executive Compensation 46
Item 14. Principal Accountant Fees and Services 46
PART IV
Item 15. Exhibits and Financial Statement Schedules 47
Item 16. Form 10-K Summary
(i)
BIOVIE INC.
FORWARD-LOOKING STATEMENTS
This report contains forward-looking statements within
the meaning of Section 21E of the Securities Exchange Act of 1934, and Section 27A of the Securities Act of 1933, as amended (the “Securities
Act”). Any statements contained in this report that are not statements of historical fact may be forward-looking statements. When
we use the words “intends,” “estimates,” “predicts,” “potential,” “continues,”
“anticipates,” “plans,” “expects,” “believes,” “should,” “could,”
“may,” “will” or the negative of these terms or other comparable terminology, we are identifying forward-looking
statements. Forward-looking statements involve risks and uncertainties, which may cause our actual results, performance or achievements
to be materially different from those expressed or implied by forward-looking statements. These factors include our research and development
activities, distributor channel; compliance with regulatory impositions; and our capital needs. Although we believe that the expectations
reflected in the forward-looking statements are reasonable, we cannot guarantee future results, levels of activity, performance or achievements.
Except as may be required by applicable law, we do
not undertake or intend to update or revise our forward-looking statements, and we assume no obligation to update any forward-looking
statements contained in this report as a result of new information or future events or developments. Thus, you should not assume that
our silence over time means that actual events are bearing out as expressed or implied in such forward-looking statements. You should
carefully review and consider the various disclosures we make in this report and our other reports filed with the Securities and Exchange
Commission (the “Commission”) that attempt to advise interested parties of the risks, uncertainties and other factors that
may affect our business.
All statements other than statements of historical
fact are statements that could be deemed forward-looking statements. The Company assumes no obligation and does not intend to update these
forward-looking statements, except as required by law. When used in this report, the terms “BioVie”, “Company”,
“we”, “our”, and “us” refer to BioVie, Inc.
(ii)
PART I
ITEM 1. BUSINESS
Overview
BioVie Inc. (the “Company” or “we”
or “our”) is a clinical-stage company developing innovative drug therapies for the treatment of neurological and neurodegenerative
disorders and advanced liver disease.
Neurodegenerative Disease Program
The Company acquired the biopharmaceutical assets
of NeurMedix, Inc. (“NeurMedix”) a privately held clinical-stage pharmaceutical company and a related party in June 2021.
The acquired assets included NE3107. In April 2024, the Company announced that the United States Adopted Names Council, and the World
Health Organization International Nonproprietary Names expert committee had approved “bezisterim” as the non-proprietary (generic)
name for NE3107. Bezisterim (NE3107) is an investigational, novel, orally administered small molecule that is thought to inhibit inflammation-driven
insulin resistance and major pathological inflammatory cascades with a novel mechanism of action. There is emerging scientific consensus
that both inflammation and insulin resistance may play fundamental roles in the development of Alzheimer’s disease (“AD”)
and Parkinson’s disease (“PD”), and bezisterim (NE3107) could, if approved by U.S. Food and Drug Administration (“FDA”),
represent an entirely new medical approach to treating these devastating conditions affecting an estimated 6 million Americans suffering
from AD and 1 million Americans suffering from PD.
In neurodegenerative disease, bezisterim (NE3107)
inhibits activation of inflammatory extracellular signal-regulated kinase (“ERK”) and nuclear factor kappa-light-chain-enhancer
of activated B cells (“NFκB”) (including interactions with tumor necrosis factor (“TNF”) signaling and other
relevant inflammatory pathways) that lead to neuroinflammation and insulin resistance. Bezisterim (NE3107) does not interfere with their
homeostatic functions (e.g., insulin signaling and neuron growth and survival). Both inflammation and insulin resistance are drivers of
AD and PD.
About Inflammation and Bezisterim’s (NE3107’s)
Mechanism of Action
Neuroinflammation, insulin resistance, and oxidative
stress are common features in the major neurodegenerative diseases, including AD, PD frontotemporal lobar dementia, and Amyotrophic lateral
sclerosis (“ALS”). Bezisterim (NE3107) is an orally bioavailable, blood-brain permeable, small molecule, with potential anti-inflammatory,
insulin sensitizing, and ERK-binding properties that may allow it to selectively inhibit ERK-, NFκB- and TNF-stimulated inflammation.
Bezisterim’s (NE3107’s) potential to inhibit neuroinflammation and insulin resistance forms the basis for the Company’s
work testing the molecule in AD and PD patients.
Parallels exist between AD and PD, among them activated
microglia driving inflammation, involvement of TNFα, oxidative stress, protein misfolding, mitochondrial dysfunction, and insulin
resistance. In preclinical and clinical studies, bezisterim (NE3107) reduced inflammation and enhanced insulin sensitivity, both of which
are important to PD pathology. Preclinical studies in marmoset monkeys have shown bezisterim (NE3107) administered alone to be as pro-motoric
as levodopa, underscoring the apparently critical role of inflammation in expression of PD motor symptoms. When bezisterim (NE3107) was
administered with levodopa, the combination improved motor control better than either drug alone. Furthermore, in the marmoset study,
bezisterim (NE3107) reduced the severity of levodopa induced dyskinesia (“LID”) concurrent with pro-motoric benefit and decreased
neurodegeneration, preserving twice as many dopaminergic neurons compared to control.
Alzheimer’s Disease
AD Pathophysiology and Bezisterim (NE3107) Treatment
Rationale
Alzheimer’s disease, which affects an estimated
6 million Americans, is a neuroinflammatory and neurodegenerative condition characterized by progressive deterioration of cognitive function
and loss of short-term memory and executive function. Cognitive tests quantifying AD severity have been exhaustively developed. Formal
diagnosis of AD has historically been dependent on the presence of extraneuronal amyloid beta (“Aβ”) plaques, which can
only be observed at autopsy or with the aid of sophisticated radioimaging techniques. However, diagnostic methods have recently been approved
that quantify Aβ in peripheral blood and correlate well with imaging results. Aβ plaques can also be found in people without
apparent AD symptoms, which has cast doubt about the role of Aβ as the central mediator of disease pathology.
Scientific investigations in the past twenty years
have provided strong evidence that inflammation, type 2 diabetes (“T2D”), and inflammation-driven insulin resistance are drivers
of AD through interplay with the major inflammation signaling node, NFkB, and the cytokine, TNF, the activities of which are modulated
by bezisterim (NE3107). The link between inflammation, T2D, and inflammation-driven insulin resistance and cognitive impairment are described
by relatively new terms, type 3 diabetes and metabolic-cognitive syndrome.
Inflammation, insulin resistance, and associated metabolic
dysregulation in the brain contribute to Aβ oligomerization and aggregation, phospho-tau formation, reduced neuron survival stimulus,
and a forward-feeding cycle of neuronal energy deficit and oxidative stress, causing neuronal dysfunction (cognitive impairment) and neurodegeneration.
Insulin has a major role in metabolic regulation and
neuron survival, while insulin resistance and T2D are closely linked to AD pathology. Insulin signaling is involved in synaptic plasticity,
learning, and memory. Exogenous insulin enhances cognition in normal and cognitively impaired subjects. Insulin resistance is linked to
cognitive impairment and senescence in the central nervous system (“CNS”).
Systemic inflammation from inflamed adipose tissue
and associated mononuclear cells promotes CNS inflammation and is linked to cognitive decline and neurodegeneration. In addition to the
afore mentioned factors contributing to AD pathophysiology, there is an extensive literature on the complex role of adipose tissue inflammation
in systemic inflammation, insulin resistance, hypothalamus-pituitary-adrenal axis (“HPA”) dysregulation and chronic cortisol
excess in cognitive impairment in AD. Obesity and inflammation are closely linked in expanding adipose tissue, where the production of
inflammatory cytokines and increased cortisol are driven though up-regulation of 11β-hydroxysteroid dehydrogenase type 1 and adipocyte
mineralocorticoid receptor activation. Inflamed adipose tissue interacts with the HPA axis and hippocampus to increase systemic cortisol,
and promote hippocampal inflammation through chronically elevated cortisol, which freely penetrates the blood-brain barrier. Hyperglycemia
(secondary to insulin resistance) exacerbates adrenal cortisol production and promotes forward feeding of inflammation and HPA-hippocampal
dysregulation.
Bezisterim (NE3107) is believed to inhibit ERK/NFkB
activation and TNF production stimulated by inflammatory stimuli, which includes oxidative stress. Inhibition of NFkB activation and TNF
production from this type of stimulation has broad potential implications for reduction of pathological peripheral and CNS inflammatory
signaling in AD, which includes reduction of inflammation-driven insulin resistance, decreased inflammatory cell infiltration into the
CNS, and decreased microglia activation. Reduction of systemic inflammation and inflammation-driven insulin resistance are also predicted
to have beneficial effects on HPA axis dysregulation and hippocampal dysregulation of cortisol secretion that are consequences of adipose
inflammation and insulin resistance, and as described above, are known to promote cognitive impairment and forward-feeding insulin resistance.
We believe bezisterim’s (NE3107’s) combination of anti-inflammatory and insulin sensitizing activity has the potential to
disrupt this forward-feeding cycle of AD pathology. The multifactorial influence of insulin signaling on neuron survival and cognition
suggests that correction of insulin signaling deficits with bezisterim (NE3107) in the target population may provide significant benefits
on both cognition and disease progression.
Company’s Progress with Alzheimer’s
Disease Clinical Trial
On November 29, 2023, the Company announced topline
efficacy data from its Phase 3 clinical trial (NCT04669028) of bezisterim (NE3107) in the treatment of mild to moderate AD. The study
had co-primary endpoints looking at cognition using the Alzheimer’s Disease Assessment Scale-Cognitive Scale (ADAS-Cog 12) and function
using the Clinical Dementia Rating-Sum of Boxes. Patients were randomly assigned, 1:1 versus placebo, to receive sequentially 5 mg of
bezisterim (NE3107) orally twice a day for 14 days, then 10 mg orally twice a day for 14 days, followed by 26 weeks of 20 mg orally twice
daily.
Upon trial completion, as the Company began the process
of analyzing the trial data, the Company found significant deviation from protocol and current good clinical practices (“cGCPs”)
violations at 15 study sites (virtually all of which were from one geographic area). This highly unusual level of suspected improprieties
led the Company to exclude all patients from these sites and to refer the sites to the FDA’s Office of Scientific Investigations
(“OSI”) for potential action.
After the patient exclusions, 81 patients remained
in the Modified Intent-to-Treat population, 57 of whom were in the Per-Protocol population which included those who completed the trial
and were verified to take study drug based on pharmacokinetic data. The trial was originally designed to be 80% powered with 125 patients
in each of the treatment and placebo arms. The unplanned exclusion of so many patients left the trial underpowered for its primary endpoints.
In the Per-Protocol population, which includes those
patients who completed the trial and who were further verified to have taken the study drug (based on pharmacokinetics data), an observed
but not statistically significant change from baseline appeared to suggest a slowing of cognitive loss; these same patients experienced
an advantage in age deceleration vs. placebo as measured by deoxyribonucleic acid (“DNA”) epigenetic change. Age deceleration
is used by longevity researchers to measure the difference between the patient’s biological age, in this case as measured by the
Horvath DNA methylation Skin Blood Clock, relative to the patient’s actual chronological age. This test was a non-primary/secondary
endpoint, other-outcome measure, done via blood test collected at week 30 (end of study).
Based on the efficacy signal seen in this trial, the
Company is exploring (1) a discussion with the FDA to potentially employ the adaptive trial feature of the protocol to continue enrolling
patients to achieve statistical significance; and/or (2) the design of a new Phase 3 study of bezisterim (NE3107) that leverages the most
recent data and understanding of the potential effects bezisterim (NE3107) may have in persons with AD.
Parkinson’s Disease
Parkinson’s disease (PD), which affects an estimated
1 million Americans, is driven in large part by neuroinflammation and activation of brain microglia, leading to increased proinflammatory
cytokines (particularly TNF). Multiple daily administrations of levodopa (converted to dopamine in the brain) is the current standard
of care treatment for this movement disorder, but levodopa effectiveness diminishes over time necessitating increased dosage and prolonged
daily administration leads to side effects of uncontrolled movements called levodopa-induced dyskinesia, commonly referred to as LID,
which is exacerbated by high dose levodopa. Although levodopa provides symptomatic benefit, it does not slow PD progression.
The Company’s Phase 2 study of bezisterim (NE3107)
for the treatment of PD (NCT05083260), completed in January 2023, was a double-blind, placebo-controlled, safety, tolerability, and pharmacokinetics
study in PD participants treated with carbidopa/levodopa and NE3107. Forty-five patients with a defined L-dopa “off state”
were randomized 1:1 to placebo or bezisterim (NE3107) 20 mg twice daily for 28 days. This trial was launched with two design objectives:
(1) the primary objective was safety and drug-drug interaction, as requested by the FDA, to assess the potential for adverse interactions
between bezisterim (NE3107) and carbidopa/ levodopa; and (2) the secondary objective was to determine if preclinical indications of promotoric
activity and apparent enhancement of levodopa activity could be seen in humans. Both objectives were met. Results of the study include:
To extend this Phase 2 data in progressed patients,
the Company has designed a new Phase 2 study of bezisterim (NE3107) as a potential first line therapy to treat patients with new onset
PD. In July 2024, the Company submitted the protocol for this new study to the FDA for regulatory review.
Bezisterim (NE3107) may have the potential to become
a non-dopaminergic alternative to PD patients. There are numerous scientific reports that support the critical role of inflammation in
the manifestation of PD symptoms in addition to the essential role of inflammation in driving disease progression. We have shown in a
mouse model of PD that bezisterim (NE3107) decreases inflammation and TNF in the brain and increases neuron survival (Nicoletti, 2012
Parkinson’s Disease 969418). In this neurotoxin induced model, bezisterim (NE3107) decreased clinical signs of disease and neuronal
death compared to placebo treated mice. An unpublished study of a neurotoxin induced marmoset model of PD reported that administration
of bezisterim (NE3107) decreased movement abnormalities that are the clinical signs of the disease. In the same study, bezisterim (NE3107)
in combination with levodopa had a stronger effect on clinical signs of disease than levodopa or bezisterim (NE3107) alone, while marmosets
treated with bezisterim (NE3107) developed less LID. Bezisterim (NE3107)-treated monkeys also exhibited neuroprotective activity that
promoted the survival of twice as many neurons in the substantia nigra (primary region of the brain that degenerates to cause parkinsonism)
as monkeys treated with placebo. The results from the marmoset study suggest that bezisterim (NE3107) may decrease clinical signs of disease
in humans (improve motor function), which if true could enable a straightforward clinical development strategy to test bezisterim (NE3107)
in PD patients needing promotoric therapy. If approved as a promotoric agent, NE3107 would provide a non-dopaminergic alternative to Parkinson’s
patients, and an opportunity to significantly delay the need to start levodopa therapy. This could represent a first step toward supplanting
levodopa as the primary PD therapy, and in addition to delaying the emergence of LID, could also slow disease progression, the most important
and still unmet objective of PD drug development.
Long COVID Program
In April 2024, the Company announced the grant of a clinical trial award of up to $13.1 million from the U.S. Department of Defense (“DOD”),
awarded through the Peer Reviewed Medical Research Program of the Congressionally Directed Medical Research Programs. In August 2024,
U.S. Army Medical Research and Development Command, Office of Human Research Oversight (“OHRO”) approved the Company’s
plan to evaluate bezisterim (NE3107) for the treatment of neurological symptoms that are associated with long COVID. The FDA
had previously reviewed and approved the study as “Safe to Proceed” in August 2024. The approval form OHRO is the last scientific
review milestone needed for the Company to receive the additional $12.6 million of the aggregate $13.1 million in grant funding from the
DOD. The award can provide up to 2 years of non-dilutive funding for a Phase 2 clinical trial that will assess bezisterim (NE3107) for
the treatment of neurological symptoms that are associated with long COVID. The Company anticipates the trial to commence by early 2025.
The study protocol was finalized and submitted to the FDA for regulatory review in July 2024 and on August 22, 2024 the FDA authorized
our IND application for Bezisterim (NE3107) allowing us to study a novel, anti-inflammatory approach or the treatment of the debilitating
neurocognitive symptoms associated with long covid.
Long COVID is a condition in which symptoms of COVID-19,
the acute respiratory disease caused by the SARS-CoV-2 virus, persist for an extended period of time, generally three months or more.
The Centers for Disease Control recently reported that 6.8% of adults in the United States (more than 17 million individuals) currently
or previously had long COVID. Symptoms, which include fatigue, cognitive dysfunction and sleep disturbances, are debilitating. The loss
in quality of life and earnings and increased medical costs has an enormous economic impact estimated to be 3.7 trillion dollars. To date
there are no therapies proven effective for treatment.
Chronic inflammation is one of the main hypotheses
that researchers have proposed to explain the persistence of symptoms in long COVID. Specifically in individuals with “brain fog,”
sustained systemic inflammation and persistent localized blood-brain-barrier (“BBB”) dysfunction are key physiological features.
Bezisterim (NE3107) permeates the BBB and has been shown to modulate inflammation via the inhibition of NF-kB activation, thus representing
a novel oral treatment targeting an underlying cause of long COVID symptoms.
Chronic neuroinflammation, insulin resistance, and
oxidative stress are common features in the major neurodegenerative diseases, including AD, PD, frontotemporal lobar dementia, and ALS.
Bezisterim (NE3107) is an investigational oral small molecule, blood-brain permeable, compound with potential anti-inflammatory, insulin
sensitizing, and ERK-binding properties that may allow it to selectively inhibit ERK-, NFκB- and TNF-stimulated inflammation. Bezisterim’s
(NE3107) potential to inhibit neuroinflammation and insulin resistance forms the basis for the Company’s work testing the molecule
in AD, PD, and long COVID patients. Bezisterim (NE3107) is patented in the United States, Australia, Canada, Europe and South Korea.
Liver Cirrhosis Program
In liver disease, our investigational drug candidate
BIV201 (continuous infusion terlipressin), which has been granted both FDA Fast Track designation status and FDA Orphan Drug status, is
being evaluated and discussed after receiving guidance from the FDA regarding the design of Phase 3 clinical testing for the treatment
of ascites due to chronic liver cirrhosis. BIV201 is administered as a patent-pending liquid formulation.
Ascites is a common complication of advanced liver
cirrhosis involving the accumulation of large volumes of fluid in the abdomen, often exceeding five liters, due to liver and kidney dysfunction.
The FDA has never approved a drug to treat ascites, and once patients reach the refractory stage the estimated one-year survival rate
is only approximately 50%[10]. BIV201 is a continuous infusion of terlipressin, a drug used in over 40 countries to treat related
complications of liver cirrhosis (Type 1 hepatorenal syndrome and bleeding esophageal varices) that was recently approved in the U.S.
but is not approved in Japan. With the novel room temperature stable formulation in a pre-filled syringe, BIV201 could potentially provide
a superior terlipressin drug delivery system throughout the world. The goal of BIV201 therapy is to interrupt the ascites disease pathway,
thereby halting the cycle of accelerated fluid generation in ascites patients.
In June 2021, the Company initiated a Phase 2 study
(NCT04112199) designed to evaluate the efficacy of BIV201 (terlipressin, administered by continuous infusion for two 28-day treatment
cycles) combined with standard-of-care (“SOC”), compared to SOC alone, for the treatment of refractory ascites. The primary
endpoints of the study are the incidence of ascites-related complications and change in ascites fluid accumulation during treatment compared
to a pre-treatment period.
In March 2023, the Company announced enrollment was
paused and that data from the first 15 patients treated with BIV201 plus SOC appeared to show at least a 30% reduction in ascites fluid
during the 28 days after treatment initiation compared to the 28 days prior to treatment. The change in ascites volume was significantly
different from those patients receiving SOC treatment. Patients who completed the treatment with BIV201 experienced a 53% reduction in
ascites fluid, which was sustained (43% reduction) during the three months after treatment initiation as compared to the three-month pre-treatment
period.
In June 2023, the Company requested and subsequently
received guidance from the FDA regarding the design and endpoints for definitive clinical testing of BIV201 for the treatment of ascites
due to chronic liver cirrhosis. The Company is currently finalizing protocol designs for the Phase 3 study of BIV201 for the treatment
of ascites due to chronic liver cirrhosis.
While the active agent, terlipressin, is approved
in the U.S. and in about 40 countries for related complications of advanced liver cirrhosis, treatment of ascites is not included in these
authorizations. Patients with refractory ascites suffer from frequent life-threatening complications, generate more than $5 billion in
annual treatment costs, and have an estimated 50% mortality rate within 6 to 12 months. The FDA has not approved any drug to treat refractory
ascites.
Our proprietary novel liquid formulation of terlipressin
is designed to improve convenience for outpatient administration and avoid potential formulation errors when pharmacists reconstitute
the current powder version of terlipressin. To date, analytical testing results have confirmed room temperature stability of the prefilled
syringe in storage for 18 months, with the potential for up two years stability. Room temperature storage presents a key product differentiation
versus terlipressin products in countries where the drug is approved. To the best of the Company’s knowledge, all other terlipressin
products sold globally must be stored under refrigeration and there is no prefilled syringe format of terlipressin available for treating
patients in these countries. BioVie has also filed a Patent Cooperation Treaty (“PCT”) application covering our novel liquid
formulations of terlipressin (international patent application PCT/US2020/034269, published as WO2020/237170) and we are seeking patent
protection in at least the U.S., Europe, China, Japan and other jurisdictions.
BIV201 (continuous infusion terlipressin) has the
potential to improve the health of thousands of patients suffering from life-threatening complications of liver cirrhosis due to hepatitis,
nonalcoholic steatohepatitis, and alcoholism. The FDA has granted Fast-Track status and Orphan Drug designation for the most common of
these complications, ascites, which represents a significant unmet medical need. Patients with cirrhosis and ascites account for an estimated
116,000 U.S. hospital discharges annually, with frequent early readmissions. According to the HCUP Nationwide Readmissions Database 2016,
those requiring paracentesis (removal of ascites fluid) experience an average hospital stay lasting eight days incurring over $86,000
in medical costs. This translates into a total potentially addressable ascites market size for BIV201 therapy exceeding $650 million based
on Company estimates. The FDA has never approved any drug specifically for treating ascites. For patients with refractory ascites the
mean one-year survival rate is only 50% (Bureau et al. 2017). BIV201 has also received Orphan Drug designation for hepatorenal
syndrome (“HRS”). Patients with refractory ascites often progress to HRS which is the onset of kidney failure and requires
emergency hospitalization.
The BIV201 development program began at LAT Pharma
LLC. On April 11, 2016, we acquired LAT Pharma LLC and the rights to its BIV201 development program and currently own all development
and marketing rights to the product candidate. We and PharmaIN, LAT Pharma’s former partner focused on the development of new modified
product candidates in the same therapeutic field but not including BIV201, have agreed to pay royalties equal to less than 1% of future
net sales of each company’s ascites drug development programs, or if such program is licensed to a third party, less than 5% of
each company’s net license revenues. On December 24, 2018, we returned our partial ownership rights to the PharmaIN modified terlipressin
development program and simultaneously paid the remaining balance due on a related debt. PharmaIN’s rights to our program remain
unchanged.
About Ascites and Liver Cirrhosis
Cirrhosis is a leading cause of death in the U.S.
The condition results primarily from hepatitis, alcoholism, and fatty liver disease linked to obesity. Ascites is a common complication
of advanced liver cirrhosis, involving kidney dysfunction and the accumulation of large amounts of fluid in the abdominal cavity.
The Need for an Ascites Therapy
With no medications approved by the FDA specifically
for treating ascites, an estimated 40% of patients die within two years of diagnosis. Certain drugs approved for other uses such as diuretics
may provide initial relief, but patients may fail to respond to treatment as ascites worsens. This represents a critical unmet medical
need, reflected by the Fast Track designation granted to BIV201 by the FDA as a treatment for ascites refractory to or intolerant of diuretic
therapy. U.S. treatment costs for liver cirrhosis, including ascites and other complications, are estimated at more than $5 billion annually.
The Ascites Development Pathway
Most experts agree that ascites develops through a
sequence of events illustrated by the above diagram. High blood pressure in the vein that supplies blood to the liver, called “portal
hypertension,” occurs as increasing liver damage (fibrosis) impedes blood flow through the liver. This causes vasodilation
and blood pooling in the central or “splanchnic” region of the body and low blood volume in the arteries. The decrease in
effective blood volume activates a signaling pathway (“neurohormonal systems”) which tells the kidneys to retain large amounts
of salt and water in an effort to increase blood volume. Ultimately the retention of excess sodium and water leads to the formation of
ascites as these substances “weep” from the liver and lymph system and collect in the patient’s abdomen.
The BIV201 Proposed Mechanism of Action
BIV201 is being developed with the goal of alleviating
portal hypertension and correcting splanchnic vasodilation, thereby increasing effective blood volume and reducing the signals
to the kidneys to retain excess salt and water. If successful, BIV201 could halt the cycle of accelerating fluid generation in ascites
patients and reduce the need for the frequent and painful paracentesis procedures many of these patients currently require.
Future Possible BIV201 Indications
Based on international investigative studies of the
active agent in BIV201, terlipressin, we believe our drug candidate has potential future applications in other life-threatening conditions
due to liver cirrhosis. Securing marketing approvals for any of these new uses will require well-controlled clinical trials to satisfy
the FDA and/or other countries’ regulatory requirements, none of which have commenced at this time. The Company continues to evaluate
other indications for the use of terlipressin continuous infusion. BioVie will discuss such indications if and when selected for testing.
Intellectual Property
BIV201
BioVie relies on a combination of patent, trade secret,
other intellectual property laws (such as FDA data exclusivity), nondisclosure agreements, and other measures to protect our proposed
products. We require our employees, consultants, and advisors to execute confidentiality agreements and to agree to disclose and assign
to us all inventions conceived during the workday, using our property, or which relate to our business. Despite any measures taken to
protect our intellectual property (IP), unauthorized parties may attempt to copy aspects of our products or to obtain and use information
that we regard as proprietary.
BIV201 was awarded Orphan Drug Designations in the
U.S. for the treatment of hepatorenal syndrome on November 21, 2018 and treatment of ascites due to all etiologies except cancer on September
8, 2016. We also filed a PCT application covering our novel liquid formulations of terlipressin (international patent application PCT/US2020/034269,
published as WO2020/237170) and are seeking patent protection in U.S., Europe, China, Japan and other jurisdictions. To date patents have
been granted in India (Patent No. 540813) and Chile (Patent No. 68965). Also, we own U.S. Patent 11,364,277, and European patent EP3347032,
which is directed to a method of treating ascites with BIV201, and we are pursuing additional patent coverage in U.S., Japan, Europe,
and China.
Bezisterim (NE3107) and related compounds
As of August 15, 2024, we have twelve (12) issued U.S. patents, six (6)
pending U.S. patent applications, three (3) pending U.S. PCT applications, six (6) issued foreign patents, and six (6) pending foreign
patent applications directed to protecting NE3107 and related compounds and methods of making and using thereof. The U.S. patents and
pending patent applications and their projected expiration dates are provided below.
Title Patent Application Number Patent Number Expiration Date
Compositions for Treatment of Neurodegenerative Conditions 18/511,027 pending —
Methods of Treating Long COVID 63/621,280 pending —
Modified C19 Steroids and Methods of Using the Same 63/610,915 pending —
Methods for the Treatment of Biological Aging 63/561,157 pending —
** Foreign counterparts issued in Europe and Japan projected to expire 6/5/2029.
Government Regulation
Government authorities in the United States, at the
federal, state and local level, and in other countries extensively regulate, among other things, the research, development, testing, manufacture,
quality control, approval, labeling, packaging, storage, record-keeping, promotion, advertising, distribution, post-approval monitoring
and reporting, marketing and export and import of products such as those we are developing. Any pharmaceutical candidate that we develop
must be approved by the FDA before it may be legally marketed in the United States and by the appropriate foreign regulatory agency before
it may be legally marketed in foreign countries.
United States Drug Development Process
In the United States, the FDA regulates drugs under
the Federal Food, Drug and Cosmetic Act (“FDCA”), and implements regulations. Drugs are also subject to other federal, state
and local statutes and regulations. Biologics are subject to regulation by the FDA under the FDCA, the Public Health Service Act (the
“PHSA”), and related regulations, and other federal, state and local statutes and regulations. Biological products include,
among other things, viruses, therapeutic serums, vaccines and most protein products. The process of obtaining regulatory approvals and
the subsequent compliance with appropriate federal, state, local and foreign statutes and regulations require the expenditure of substantial
time and financial resources. Failure to comply with the applicable United States requirements at any time during the product development
process, approval process or after approval, may subject an applicant to administrative or judicial sanctions. FDA sanctions could include
refusal to approve pending applications, withdrawal of an approval, a clinical hold, warning letters, product recalls, product seizures,
total or partial suspension of production or distribution, injunctions, fines, refusals of government contracts, restitution, disgorgement
or civil or criminal penalties. Any agency or judicial enforcement action could have a material adverse effect on us.
The process required by the FDA before a drug or biological
product may be marketed in the United States generally involves the following:
● FDA review and approval of the NDA or BLA.
The lengthy process of seeking required approvals
and the continuing need for compliance with applicable statutes and regulations require the expenditure of substantial resources. There
can be no certainty that approvals will be granted.
Clinical trials involve the administration of the
drug or biological candidate to healthy volunteers or patients having the disease being studied under the supervision of qualified investigators,
generally physicians not employed by or under the trial sponsor’s control. Clinical trials are conducted under protocols detailing,
among other things, the objectives of the clinical trial, dosing procedures, subject selection and exclusion criteria, and the parameters
to be used to monitor subject safety. Each protocol must be submitted to the FDA as part of the IND. Clinical trials must be conducted
in accordance with the FDA’s cGCP requirements. Further, each clinical trial must be reviewed and approved by an independent institutional
review board (“IRB”), at or servicing each institution at which the clinical trial will be conducted. An IRB is charged with
protecting the welfare and rights of trial participants and considers such items as whether the risks to individuals participating in
the clinical trials are minimized and are reasonable in relation to anticipated benefits. The IRB also approves the informed consent form
that must be provided to each clinical trial subject or his or her legal representative and must monitor the clinical trial until it is
completed.
Human clinical trials prior to approval are typically
conducted in three sequential phases that may overlap or be combined:
Post-approval studies, or Phase 4 clinical trials,
may be conducted after initial marketing approval. These studies are used to gain additional experience from the treatment of patients
in the intended therapeutic indication and may be required by the FDA as part of the approval process.
Progress reports detailing the results of the clinical
trials must be submitted at least annually to the FDA and written IND safety reports must be submitted to the FDA by the investigators
for serious and unexpected adverse events or any finding from tests in laboratory animals that suggests a significant risk for human subjects.
Phase 1, Phase 2 and Phase 3 clinical trials may not be completed successfully within any specified period, if at all.
The FDA or the sponsor or its data safety monitoring board may suspend a clinical trial at any time on various grounds, including a finding
that the research subjects or patients are being exposed to an unacceptable health risk. Similarly, an IRB can suspend or terminate approval
of a clinical trial at its institution if the clinical trial is not being conducted in accordance with the IRB’s requirements or
if the drug or biologic has been associated with unexpected serious harm to patients.
Concurrent with clinical trials, companies usually
complete additional animal studies and develop additional information about the chemistry and physical characteristics of the drug or
biologic as well as finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements. The
manufacturing process must be capable of consistently producing quality batches of the drug or biological candidate and, among other things,
must include methods for testing the identity, strength, quality and purity of the final drug or biologic. Additionally, appropriate packaging
must be selected and tested and stability studies must be conducted to demonstrate that the drug or biological candidate does not undergo
unacceptable deterioration over its shelf life.
U.S. Review and Approval Processes
The results of product development, preclinical studies
and clinical trials, along with descriptions of the manufacturing process, analytical tests conducted on the chemistry of the drug or
biologic, proposed labeling and other relevant information are submitted to the FDA as part of an NDA or BLA requesting approval to market
the product. The submission of an NDA or BLA is subject to the payment of substantial user fees; a waiver of such fees may be obtained
under certain limited circumstances.
The FDA reviews all NDAs and BLAs submitted before
it accepts them for filing and may request additional information rather than accepting an NDA or BLA for filing. Once the submission
is accepted for filing, the FDA begins an in-depth review of the NDA or BLA.
After the NDA or BLA submission is accepted for filing,
the FDA reviews the NDA to determine, among other things, whether the proposed product is safe and effective for its intended use, and
whether the product is being manufactured in accordance with cGMP to assure and preserve the product’s identity, strength, quality
and purity. The FDA reviews a BLA to determine, among other things, whether the product is safe, pure and potent and the facility in which
it is manufactured, processed, packaged or held meets standards designed to assure the product’s continued safety, purity and potency.
In addition to its own review, the FDA may refer applications for novel drug or biological products or drug or biological products which
present difficult questions of safety or efficacy to an advisory committee, typically a panel that includes clinicians and other experts,
for review, evaluation and a recommendation as to whether the application should be approved and under what conditions. The FDA is not
bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions. During the
approval process, the FDA also will determine whether a risk evaluation and mitigation strategy, or REMS, is necessary to assure the safe
use of the drug or biologic. If the FDA concludes that a REMS is needed, the sponsor of the NDA or BLA must submit a proposed REMS; the
FDA will not approve the NDA or BLA without a REMS, if required.
Before approving an NDA or BLA, the FDA will inspect
the facilities at which the product is to be manufactured. The FDA will not approve the product unless it determines that the manufacturing
processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required
specifications. Additionally, before approving an NDA or BLA, the FDA will typically inspect one or more clinical sites to assure compliance
with cGMP. If the FDA determines the application, manufacturing process or manufacturing facilities are not acceptable it will outline
the deficiencies in the submission and often will request additional testing or information.
The NDA or BLA review and approval process is lengthy
and difficult and the FDA may refuse to approve an NDA or BLA if the applicable regulatory criteria are not satisfied or may require additional
clinical data or other information. Even if such data and information is submitted, the FDA may ultimately decide that the NDA or BLA
does not satisfy the criteria for approval. Data obtained from clinical trials are not always conclusive and may be susceptible to varying
interpretations, which could delay, limit or prevent regulatory approval. The FDA will issue a “complete response” letter
if the agency decides not to approve the NDA or BLA. The complete response letter describes all of the specific deficiencies in the NDA
or BLA identified by the FDA. The deficiencies identified may be minor, for example, requiring labeling changes, or major, for example,
requiring additional clinical trials. Additionally, the complete response letter may include recommended actions that the applicant might
take to place the application in a condition for approval. If a complete response letter is issued, the applicant may either resubmit
the NDA or BLA, addressing all of the deficiencies identified in the letter, or withdraw the application.
If a product receives regulatory approval, the approval
may be limited to specific diseases and dosages or the indications for use may otherwise be limited, which could restrict the commercial
value of the product. Further, the FDA may require that certain contraindications, warnings or precautions be included in the product
labeling. In addition, the FDA may require Phase 4 testing which involves clinical trials designed to further assess a product’s
safety and effectiveness and may require testing and surveillance programs to monitor the safety of approved products that have been commercialized.
Orphan Drug Designation
Under the Orphan Drug Act, the FDA may grant orphan
designation to a drug or biological product intended to treat a rare disease or condition, which is generally a disease or condition that
affects fewer than 200,000 individuals in the United States, or more than 200,000 individuals in the United States and for which there
is no reasonable expectation that the cost of developing and making a drug or biological product available in the United States for this
type of disease or condition will be recovered from sales of the product. Orphan product designation must be requested before submitting
an NDA or BLA. After the FDA grants orphan product designation, the identity of the therapeutic agent and its potential orphan use are
disclosed publicly by the FDA. Orphan product designation does not convey any advantage in or shorten the duration of the regulatory review
and approval process.
If a product that has Orphan designation subsequently
receives the first FDA approval for the disease or condition for which it has such designation, the product is entitled to orphan product
exclusivity, which means that the FDA may not approve any other applications to market the same drug or biological product for the same
indication for seven years, except in limited circumstances, such as a showing of clinical superiority to the product with orphan exclusivity.
Competitors, however, may receive approval of different products for the indication for which the Orphan product has exclusivity or obtain
approval for the same product but for a different indication for which the Orphan product has exclusivity. Orphan product exclusivity
also could block the approval of one of our products for seven years if a competitor obtains approval of the same drug or biological product
as defined by the FDA or if our drug or biological candidate is determined to be contained within the competitor’s product for the
same indication or disease. If a drug or biological product designated as an orphan product receives marketing approval for an indication
broader than what is designated, it may not be entitled to orphan product exclusivity. Orphan Drug status in the European Union has similar
but not identical benefits in the European Union.
Expedited Development and Review Programs
The FDA has a Fast Track program that is intended
to expedite or facilitate the process for reviewing new drug and biological products that meet certain criteria. Specifically, new drug
and biological products are eligible for Fast Track designation if they are intended to treat a serious or life-threatening condition
and demonstrate the potential to address unmet medical needs for the condition. Fast Track designation applies to the combination of the
product and the specific indication for which it is being studied. Unique to a Fast Track product, the FDA may consider for review sections
of the NDA or BLA on a rolling basis before the complete application is submitted, if the sponsor provides a schedule for the submission
of the sections of the NDA or BLA, the FDA agrees to accept sections of the NDA or BLA and determines that the schedule is acceptable,
and the sponsor pays any required user fees upon submission of the first section of the NDA or BLA.
Any product submitted to the FDA for marketing approval,
including those submitted to a Fast Track program, may also be eligible for other types of FDA programs intended to expedite development
and review, such as priority review and accelerated approval. Any product is eligible for priority review if it has the potential to provide
safe and effective therapy where no satisfactory alternative therapy exists or a significant improvement in the treatment, diagnosis or
prevention of a disease compared with marketed products. The FDA will attempt to direct additional resources to the evaluation of an application
for a new drug or biological product designated for priority review in an effort to facilitate the review. Additionally, a product may
be eligible for accelerated approval. Drug or biological products studied for their safety and effectiveness in treating serious or life-threatening
illnesses and that provide meaningful therapeutic benefit over existing treatments may receive accelerated approval, which means that
they may be approved on the basis of adequate and well-controlled clinical studies establishing that the product has an effect on a surrogate
endpoint that is reasonably likely to predict a clinical benefit, or on the basis of an effect on a clinical endpoint other than survival
or irreversible morbidity. As a condition of approval, the FDA generally requires that a sponsor of a drug or biological product receiving
accelerated approval perform adequate and well-controlled post-marketing clinical studies to establish safety and efficacy for the approved
indication. Failure to conduct such studies or conducting such studies that do not establish the required safety and efficacy may result
in revocation of the original approval. In addition, the FDA currently requires as a condition for accelerated approval pre-approval of
promotional materials, which could adversely impact the timing of the commercial launch or subsequent marketing of the product. Fast Track
designation, priority review and accelerated approval do not change the standards for approval but may expedite the development or approval
process.
Post-Approval Requirements
Any drug or biological products for which we receive
FDA approvals are subject to continuing regulation by the FDA, including, among other things, record-keeping requirements, reporting of
adverse experiences with the product, providing the FDA with updated safety and efficacy information on an annual basis or as required
more frequently for specific events, product sampling and distribution requirements, complying with certain electronic records and signature
requirements and complying with FDA promotion and advertising requirements, which include, among others, standards for direct-to-consumer
advertising, prohibitions against promoting drugs and biologics for uses or in patient populations that are not described in the drug’s
or biologic’s approved labeling (known as “off-label use”), rules for conducting industry-sponsored scientific and educational
activities, and promotional activities involving the internet. Failure to comply with FDA requirements can have negative consequences,
including the immediate discontinuation of noncomplying materials, adverse publicity, enforcement letters from the FDA, mandated corrective
advertising or communications with doctors, and civil or criminal penalties. Although physicians may prescribe legally available drugs
and biologics for off-label uses, manufacturers may not market or promote such off-label uses.
We will need to rely on third parties for the production
of our product candidates. Manufacturers of our product candidates are required to comply with applicable FDA manufacturing requirements
contained in the FDA’s cGMP regulations. cGMP regulations require among other things, quality control and quality assurance as well
as the corresponding maintenance of comprehensive records and documentation. Drug and biologic manufacturers and other entities involved
in the manufacture and distribution of approved drugs and biologics are also required to register their establishments and list any products
made there with the FDA and comply with related requirements in certain states, and are subject to periodic unannounced inspections by
the FDA and certain state agencies for compliance with cGMP and other laws. Accordingly, manufacturers must continue to expend time, money
and effort in the area of production and quality control to maintain cGMP compliance. Discovery of problems with a product after approval
may result in serious and extensive restrictions on a product, manufacturer, or holder of an approved NDA or BLA, including suspension
of a product until the FDA is assured that quality standards can be met, continuing oversight of manufacturing by the FDA under a “consent
decree,” which frequently includes the imposition of costs and continuing inspections over a period of many years, and possible
withdrawal of the product from the market. In addition, changes to the manufacturing process generally require prior FDA approval before
being implemented and other types of changes to the approved product, such as adding new indications and additional labeling claims, are
also subject to further FDA review and approval.
The FDA also may require post-marketing testing, known
as Phase 4 testing, risk minimization action plans and surveillance to monitor the effects of an approved product or place conditions
on an approval that could otherwise restrict the distribution or use of the product.
Employees
Our business is managed by our officers who consist
of Mr. Cuong Do, Chief Executive Officer & President; Dr. Joseph M Columbo, Executive Vice President -Chief Medical Officer; and Wendy
Kim, our Chief Financial Officer and Corporate Secretary. These individuals devote their full-time efforts to the Company activities.
The Company has 14 employees which are all full time. We also rely on a team of highly experienced scientific, medical, and regulatory
consultants to conduct product development activities.
ITEM 1A. RISK FACTORS
Our business, financial condition, operating results
and prospects are subject to the following risks. Additional risks and uncertainties not presently foreseeable to us may also impair our
business operations. If any of the following risks or the risks described elsewhere in this report actually occurs, our business, financial
condition or operating results could be materially adversely affected. In such case, the trading price of our Company’s Class A
Common Stock, par value $0.0001 (“Common Stock”) Common Stock could decline, and our stockholders may lose all or part of
their investment in the shares of our Common Stock.
This Form 10-K contains forward-looking statements
that involve risks and uncertainties. These statements can be identified by the use of forward-looking terminology such as “believes,”
“expects,” “intends,” “plans,” “may,” “will,” “should,” “predict”
or “anticipation” or the negative thereof or other variations thereon or comparable terminology. Actual results could differ
materially from those discussed in the forward- looking statements as a result of certain factors, including those set forth below and
elsewhere in this Form 10-K.
Risk Factor Summary
Our business operations are subject to numerous risks,
factors and uncertainties, including those outside of our control, which could cause our actual results to be harmed, including risks
regarding the following:
Risks Relating to Our Business and Industry
· We may not be able to attract and retain highly skilled personnel.
Risks Relating to Our Intellectual Property
· Intellectual property rights do not necessarily address all potential threats.
Risks Relating to Our Common Stock
· The market price and trading volume of our Common Stock may be volatile.
Risks Relating to Our Business and Industry
We rely and will continue to rely on third parties
to conduct our clinical trials. If these third parties do not successfully carry out their contractual duties or meet expected deadlines
or do not successfully perform and comply with regulatory requirements, we may not be able to obtain regulatory approval of or commercialize
our product candidates.
We depend, and will
continue to depend, on third parties, including, but not limited to, contract research organizations (“CROs”), clinical
trial sites and clinical trial principal investigators, contract laboratories, IRBs, manufacturers, suppliers, and other third
parties to conduct our clinical trials, including those for our drug candidates bezisterim (NE3107) and BIV201. We rely heavily on
these third parties over the course of our clinical trials, and we control only certain aspects of their activities. Nevertheless,
we retain ultimate responsibility for ensuring that each of our studies is conducted in accordance with the protocol and applicable
legal, regulatory, and scientific standards and regulations, and our reliance on third parties does not relieve us of our regulatory
responsibilities. We and these third parties are required to comply with cGCPs, which are regulations and guidelines enforced by the
FDA and comparable foreign regulatory authorities for the conduct of clinical trials on product candidates in clinical development.
Regulatory authorities enforce cGCPs through periodic inspections and for-cause inspections of clinical trial principal
investigators and trial sites. If, due to the failure of either the Company or a third party, a clinical trial fails to comply with
applicable cGCPs, FDA’s IND requirements, other applicable regulatory requirements, or requirements set forth in the
applicable IRB-approved protocol, the Company may be required to conduct additional clinical trials to support our marketing
applications, which would delay the regulatory approval process. For example, our drug product candidate bezisterim (NE3107) was
cleared by FDA for use in a Phase 3, randomized, double blind, placebo controlled, parallel group, multicenter study in subjects who
have mild to moderate AD. Enrollment in that trial began in August 2021, with a planned primary completion in late 2022/early 2023.
On November 29, 2023, the Company announced topline efficacy data from its Phase 3 clinical trial (NCT04669028) of bezisterim
(NE3107) in the treatment of mild to moderate AD. Upon trial completion, as the Company began the process of analyzing the trial
data, the Company found significant deviations from the protocol and cGCP violations at 15 study sites (virtually all of which were
from one geographic area). This highly unusual level of suspected improprieties led the Company to exclude all patients from these
sites. We subsequently notified FDA’s OSI of such significant deviations from study protocol, the suspected improprieties, and
the study sites involved. The identification of significant deviations from study protocol and numerous GCP violations at multiple
study sites raised questions regarding the validity and robustness of data from these study sites. The unplanned exclusion of so
many patients left the trial underpowered for its primary endpoints. However, based on the remaining dataset from those other sites
determined to be in compliance with the protocol and GCP’s, a preliminary signal of efficacy was detected. The Company is
considering: (1) employing the adaptive trial feature of the protocol to continue enrolling patients to achieve statistical
significance; and/or (2) designing a new Phase 3 study of bezisterim (NE3107) that leverages the most recent scientific literature
relating to AD along with the company's understanding regarding the effects of bezisterim (NE3107) in persons with mild-moderate
AD.
Although we design the clinical
trials for our product candidates, our CROs are tasked with facilitating and monitoring these trials. As a result, many aspects
of our clinical development programs, including site and investigator selection, and the conduct, timing, and monitoring of the study,
is outside our direct control, either partially or in whole. Our reliance on third parties to conduct clinical trials also results
in less direct control over the collection, management, and quality of data developed through clinical trials than would be the case if
we were relying entirely upon our own employees. Communicating with third parties can also be challenging, potentially leading to mistakes
as well as difficulties in coordinating activities. Our business may be impacted if any of these third parties violates applicable federal, state, or foreign laws and/or regulations, including
but not limited to FDA’s IND regulations, cGCPs, fraud and abuse or false claims laws, healthcare privacy and data security laws,
or provide us or government agencies with inaccurate, misleading, or incomplete data.
Successful development of biopharmaceuticals
is highly uncertain and is dependent on numerous factors, many of which are beyond our control.
Product candidates that appear promising in the early
phases of development may fail to reach the market for several reasons. Pre-clinical study results may show the product candidate to be
less effective than desired (e.g., the study failed to meet its primary endpoints) or to have harmful or problematic side effects. Product
candidates may fail to receive the necessary regulatory approvals or may be delayed in receiving such approvals. Among other things, such
delays may be caused by slow enrollment in clinical studies; length of time to achieve study endpoints; additional time requirements for
data analysis; IND and later new drug application preparation; discussions with the FDA; an FDA request for additional pre-clinical or
clinical data; unexpected safety or manufacturing issues; manufacturing costs; pricing or reimbursement issues; clinical sites deviating
from the trial protocol, committing scientific misconduct, or other violations of regulatory requirements - which can render data from
those sites unusable in support of regulatory approval; or other factors that make the product not economical. Proprietary rights of others
and their competing products and technologies may also prevent the product from being commercialized.
Success in pre-clinical and early clinical studies
does not ensure that large-scale clinical studies will be successful. Clinical results are frequently susceptible to varying interpretations
that may delay, limit or prevent regulatory approvals. The length of time necessary to complete clinical studies and to submit an application
for marketing approval for a final decision by a regulatory authority varies significantly from one product to the next, and may be difficult
to predict. There can be no assurance that any of our products will develop successfully, and the failure to develop our products will
have a materially adverse effect on our business and will cause you to lose all of your investment.
The concentration of our assets within a
certain financial institution could have a material adverse effect on its business, financial condition and results of
operations.
As of August 30, 2024, the Company had cash