Item 1. Business
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
In neurodegenerative disease, the Company’s
drug candidate NE3107 inhibits inflammatory activation of extracellular single-regulated kinase (“ERK”) and Nuclear factor kappa-light-chain-enhancer
of activated B cells (“NFkB”) (e.g., tumor necrosis factor (“TNF”) signaling) that leads to neuroinflammation
and insulin resistance, but not their homeostatic functions (e.g., insulin signaling and neuron growth and survival). Both inflammation
and insulin resistance are drivers of Alzheimer’s disease (“AD”) and Parkinson’s disease (“PD”).
The
Company is conducting a potentially pivotal Phase 3 randomized, double-blind, placebo-controlled, parallel-group, multicenter study to
evaluate NE3107 in patients who have mild to moderate Alzheimer’s disease (NCT04669028). The Company is targeting primary completion
of this study in the fourth quarter of calendar year 2023.
In
December 2022, topline results were released from the Company’s Phase 2 study assessing NE3107’s safety and tolerability
and potential pro-motoric impact in PD patients. The NM201 study (NCT05083260) 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:NE3107 20 mg twice daily for 28 days. The trial was launched with two design objectives:
1) the primary objective was safety and a drug-drug interaction study (as requested by the U.S. Food and Drug Administration (“FDA”)) to demonstrate the absence of adverse interactions of NE3107 with levodopa; and 2) the secondary objective was to determine
if preclinical indications of promotoric activity and apparent enhancement of levodopa activity observed in a Parkinson’s disease
model in monkeys can be seen in humans. Both objectives of the study were met. Patients treated with NE3107 experienced greater motor
control.
The
Company provided the financial support and the use of our NE3107 formulated drug product for an open-label phase 2, Investigator-Initiated
Trial in mild cognitive impairment (“MCI”) and Mild AD, NCT05227820, conducted by (“The Regenesis Project”)
of Dr. Sheldon Jordan. The study received FDA authorization on December 12, 2021 and was designed to measure NE3107’s effect on cognition,
cerebral spinal fluid (“CSF”) and blood biomarkers, and neuro-imagining endpoints. Topline results were released September
7, 2022, and additional data was presented at the Clinical Trial in Alzheimer’s Disease (“CTAD”) annual conference in
December 2022. The data showed that three months of treatment with NE3107 in patients with MCI and mild AD enhanced cognition compared
to baseline, as measured using multiple rating scales, had improvement in daily function and improvements in inflammation correlated with
improved cognition. No drug-related adverse events were observed.
The
Company acquired the biopharmaceutical assets of NeurMedix, Inc. (“NeurMedix”), from a related party privately held clinical-stage
pharmaceutical company, in June 2021. The acquired assets included NE3107, a potentially selective inhibitor of inflammatory ERK signaling that, based on animal studies and Dr. Jordan’s study, is believed to reduce
neuroinflammation. NE3107 is a 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 AD and PD, and NE3107 could, if approved by the FDA represent
a new medical approach to treating these devastating conditions affecting an estimated 6 million Americans suffering from AD and 1 million
Americans suffering from PD.
Inflammation-driven
insulin resistance is believed to be implicated in a broad range of serious diseases, and we plan to begin exploring these opportunities
in the coming months using NE3107 or related compounds acquired in the NeurMedix asset purchase. NE3107 is patented in the United States
(“U.S.”), Australia, Canada, Europe and South Korea.
1
Liver
Disease Program
In liver disease, our Orphan Drug candidate BIV201
(continuous infusion terlipressin), with FDA Fast Track status, has been evaluated in a U.S. Phase 2b study (NCT04112199) for the treatment
of refractory ascites due to liver cirrhosis. BIV201 is administered as a patent-pending liquid formulation. The study was closed before
full enrollment, without clinically meaningful adverse effects associated with BIV201 treatment and data that appeared to show that treatment
with BIV201 plus standard-of-care (“SOC”) resulted in a reduction in ascites fluid accumulation during treatment versus pre-treatment.
In June 2023, we requested 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.
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 U.S. FDA has not approved any drug to treat
refractory ascites.
The
BIV201 development program was initiated by LAT Pharma LLC. On April 11, 2016, the Company acquired LAT Pharma LLC and the rights to
its BIV201 development program. The Company currently owns all development and marketing rights to this drug candidate. Pursuant to the
Agreement and Plan of Merger entered into on April 11, 2016, between our predecessor entities, LAT Pharma LLC and NanoAntibiotics, Inc.,
BioVie is obligated to pay a low single digit royalty on net sales of BIV201 (continuous infusion terlipressin) to be shared among LAT
Pharma Members, PharmaIn Corporation, and The Barrett Edge, Inc.
Neurodegenerative
Disease Program
The Company is conducting a potentially pivotal
Phase 3 randomized, double blind, placebo controlled, parallel group, multicenter study to evaluate NE3107 in patients who have mild to
moderate AD (NCT04669028). The study has co-primary endpoints looking at cognition using the Alzheimer’s Disease Assessment Scale-Cognitive
Scale (ADAS-Cog 12) and function using the Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC).
The program is fully enrolled and is targeting primary completion in the fourth quarter of the calendar 2023 year.
The Company supported a Phase 2 exploratory biomarker
study (Investigator-Initiated Trial in MCI and Mild Alzheimer’s Disease, NCT05227820) showing that patients treated with NE3107
experienced improved cognition as measured by a modified ADAS-Cog12 score, reduced TNF- a (i.e.,
inflammation) in a manner that’s correlated to improvements in cognition, reduced CSF p-tau levels and the ratio of p-tau to A b 42 ,
and imaging findings suggestive of improved neuronal health. Despite the open-label nature of the exploratory study, the emerging data
and correlations provide encouraging signs of what we may see in the upcoming Phase 3 data reveal. The Phase 2 Study enrolled a total
of 23 patients – 17 patients with Mini-Mental State Examination (“MMSE”) scores greater than or equal to 20 (i.e., MCI
to mild AD) and 6 patients with MMSE <20 (i.e., moderate AD) – with an average age of 71.1 years. This open-label, single arm
study was designed to measure changes in cognition through verbal and visual test procedures and changes in biomarkers of AD and inflammation
that can be measured in cerebral spinal fluid (“CSF”), blood samples, and functional magnetic resonance imaging in patients
before and after treatment with 20 mg of NE3107 twice daily for 3 months. This data showed the following among patients with MMSE<20
(i.e., mild cognitive impairment and mild AD):
● NE3107
showed the potential to enhance cognition as measured by multiple assessment tools, including
a 2.1 point improvement (p=0.0173) on the modified ADAS-Cog12 scale equating to a 21.1% (p=0.0079)
change compared to baseline, a 0.11 point improvement (p=0.0416) on the Clinical Dementia
Rating scale (CDR), equating to 19.4% (p=0.0416) change from baseline, and a 0.07 point improvement
in the ADCOMS scale, equating to 27.4% improvement (p=0.009).
● NE3107
reduced CSF phospho-tau levels by -1.66 pg/mL (p=0.0343) and the ratio of p-tau to A b 42
by -0.0024 (p=0.0401)
● 18
of 22 patients with abnormal baseline scans showed improvement in one or more brain regions
as seen from advanced functional MRI studies.
● No
drug-related adverse events were observed.
Other potential NE3107 effects on biomarkers of
aging-related disease states were indicated. Blood samples were taken from the patients who participated in the investigator-initiated
Alzheimer’s Phase 2 trial before and after three months of treatment with NE3107, and these samples were analyzed to assess NE3107’s
potential to alter DNA methylation associated with epigenetic biological clocks. The resulting data for patients
treated with NE3107 for three months showed an average reduction of 3.3 years (p=0.0021) on the Horvath DNA methylation SkinBlood clock.
Furthermore, 19 out of the 22 patients experienced a reduction in the SkinBlood clock score.
2
In July 2023, the Company presented a poster detailing
the epigenetic basis for how its drug candidate NE3107 may have the potential to regulate methylation of specific genes in a manner that
significantly correlated with observed cognitive and biomarker improvements at the Alzheimer’s Associate’s International Conference
(AAIC) held in Amsterdam from July 16 through July 20, 2023.
The poster presentation titled Treatment-Induced
Epigenetic Modifications in MCI and Probable Alzheimer’s (Reading C, et al.), showed how patients with clinical dementia treated
with NE3107 for three months saw significant reductions in the level of DNA methylation, and that such reductions were, in some cases,
significantly correlated with observed improvements in various cognitive measures (e.g., ADAS-Cog11, CDR, ADCOMS, QDRS) and biomarkers
(including TNFα, CSF p-Tau/Aβ 42 , precuneus glutathione).
Inflammation has been shown to be associated with
the hypermethylation of our DNA, [1] which in turn has been shown to impact a wide range of diseases, including various forms
of cancers, [2] age-related cognitive impairment and dementia, [3] Parkinson’s disease, [4] cardiovascular
disease, [3,5] COPD and respiratory disease, [6] chronic kidney disease, [7] inflammatory bowel disease, [8]
sepsis, [9] and many others. The new data to be presented details how NE3107 may potentially change or affect the degree of
methylation of specific genes that are correlated with various markers of disease.
About
Inflammation and NE3107s Mechanism of Action
Neuroinflammation,
insulin resistance, and oxidative stress are common features in the major neurodegenerative diseases, including Alzheimers Disease
(AD), Parkinsons Disease (PD), frontotemporal lobar dementia, and Amyotrophic lateral sclerosis (ALS). 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. NE3107s potential to inhibit
neuroinflammation and insulin resistance forms the basis for the Companys 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, NE3107 reduced inflammation and enhanced insulin sensitivity,
both of which are important to PD pathology. Preclinical studies in marmoset monkeys have shown NE3107 administered alone to be as pro-motoric
as levodopa, underscoring the apparently critical role of inflammation in expression of PD motor symptoms. When NE3107 was administered
with levodopa, the combination improved motor control better than either drug alone. Furthermore, in the marmoset study, 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.
Alzheimers
Disease
Alzheimers
disease (AD), 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. The link between these factors and cognitive impairment are described by relatively new terms,
type 3 diabetes and metabolic-cognitive syndrome.
1 Stenvinkel
P doi: 10.1111/j.1365-2796.2007.01777.x
2 Wang
Z Nucleic Acids Research, 2020, Vol. 48, No. 5
3 Sugden K Neurology 2022;99:e1402-e1413
4 Tang X DOI: 10.1002/mds.29157
5 Tabaeia S Artificial Cells, Nanomedicine,
and Biotechnology, 47:1, 2031-2041
6 Qiu W Am J Respir Crit Care Med
Vol 185, Iss. 4, pp 373–381, Feb 15, 2012
7 Rysz C Int. J. Mol. Sci. 2022,
23(13), 7108
8 Kraiczy J Mucosal Immunology volume
9, pages 647–658 (2016)
9 Rump K Sci Rep
9, 18511 (2019)
3
A large body of evidence supports inflammation
as a primary driver of pathology in AD. The major inflammation signaling node, NFkB, and the cytokine tumor necrosis factor (TNF) are
important initiators of inflammatory signaling in AD pathology. NE3107 is believed to inhibit extracellular signal regulated kinase (ERK)/NFkB
activation and TNF production stimulated by inflammatory mediators, such as lipopolysaccharide. Inhibition of NFkB activation and TNF
production from this type of stimulation has broad potential implications for reduction of pathological peripheral and central nervous
system (CNS) inflammatory signaling in AD, which include 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 hypothalamus-pituitary-adrenal (HPA) axis dysregulation and hippocampal dysregulation
of cortisol secretion that are consequences of adipose inflammation and insulin resistance, and are known to promote cognitive impairment,
and are also forward-feeding for insulin resistance.
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. We believe NE3107’s combination of anti-inflammatory and insulin sensitizing activity has the potential to
disrupt this forward-feeding cycle of AD pathology.
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.
The multifactorial influence of insulin signaling
on neuron survival and cognition suggests that correction of insulin signaling deficits with NE3107 in the target population may provide
significant benefits on both cognition and disease progression. Additional rationale for targeting metabolic dysregulation with NE3107
has come from recent work showing that peripheral insulin resistance promotes insulin resistance and senescence in the CNS.
There is also 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.
Systemic inflammation from inflamed adipose and
associated mononuclear cells, promotes CNS inflammation with associated cognitive decline and neurodegeneration. We believe NE3107’s
anti-inflammatory activity against systemic/adipose inflammation and factors that dysregulate cortisol secretion, such as hyperglycemia,
has the potential to decrease cognitive impairment and neurodegenerative mechanisms that have been linked to cortisol excess.
Parkinsons
Disease
The Company completed its Phase 2 study assessing
NE3107 in Parkinson’s disease patients in the fourth quarter of calendar year 2022. The NM201 study (NCT05083260) was a double-blind,
placebo-controlled, safety, tolerability, and pharmacokinetics study in Parkinson’s disease (PD) participants treated with carbidopa/levodopa
and NE3107. Forty-five patients with a defined L-dopa morning “off state” were randomized 1:1 to placebo:NE3107 20 mg twice
daily for 28 days. The trial was launched with two design objectives: 1) the primary objective was safety and a drug-drug interaction
study (as requested by FDA) to demonstrate the absence of adverse interactions of NE3107 with levodopa; and 2) the secondary objective
was to determine if preclinical indications of promotoric activity and apparent enhancement of levodopa activity observed in a PD model
in monkeys can be seen in humans. Both objectives were met. Highlighted results of the study were:
● Patients
treated with NE3107 + C/L experienced greater improvements in their Motor Disease Society-
Unified Parkinsons Disease Rating Scale (MDS UPDRS) Part III score than patients treated
with placebo + C/L at the 2- and 3-hour marks after administration of the first daily
dose of C/L.
● Patients
<70 years old treated with NE3107 + C/L experienced improvements that were ~6 points better
than those who received placebo + C/L.
4
● Five
(26%) of the 19 patients treated with NE3107, compared to none of the 19 placebo treated
patients, who had a baseline of morning OFF experienced a morning ON state prior to receiving
their morning medications on day 28; this difference was statistically significant (p=0.046).
● The
study met its endpoints; investigators concluded that NE3107 + C/L combination treatment
was associated with clinically meaningful and superior improvements (3+ points) on the motor
examination part (Part III) of the MDS UPDRS.
● NE3107
produced statistically significant improvements in nonmotor symptoms scale assessments (NMSS)
for fatigue (Q4) p=0.02, urge to move legs (Q6) p=0.0036, and saliva dribbling (Q19) p= 0.0395.
Neuroinflammation and activation of brain microglia,
leading to increased proinflammatory cytokines (particularly TNF) that play a pivotal role in PD, which affects an estimated 1 million
Americans. Multiple daily administrations of levodopa (converted to dopamine in the brain) is the current standard of care treatment for
this movement disorder, but prolonged daily administration leads to side effects of uncontrolled movements called levodopa-induced dyskinesia,
commonly referred to as LID. Recent evidence demonstrates that daily administration of levodopa further increases neuroinflammation, microglia
activation, and TNF inflammatory damage in neurons.
We
have shown in a mouse model of PD that NE3107 decreases inflammation and TNF in the brain and increases neuron survival (Nicoletti, 2012
Parkinsons Disease 969418.) In this neurotoxin induced model, NE3107 decreased clinical signs of disease and neuronal death compared
to placebo treated mice.
An
unpublished study in a neurotoxin induced marmoset model of Parkinsons disease reported that administration of NE3107 decreased
movement abnormalities that are the clinical signs of the disease. In the same study, NE3107 in combination with levodopa had a stronger
effect on clinical signs of disease than levodopa or NE3107 alone, while marmosets treated with NE3107 developed less LID. 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 NE3107 may decrease clinical signs of disease in humans (improve motor function), which if true could enable a straightforward clinical
development strategy to test NE3107 in PD patients needing promotoric therapy.
If
approved as a promotoric agent, NE3107 would provide a non-dopaminergic alternative to Parkinsons 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 imply a slowing of disease progression, the most important and
still unmet objective of PD drug development.
5
Liver Cirrhosis Program
BioVie’s orphan drug candidate BIV201 (continuous
infusion terlipressin) represents a novel approach to the treatment of ascites due to chronic liver cirrhosis. 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 a series of interactions between June
2019 and April 2020, representatives of BioVie and the FDA communicated regarding the design and endpoints for the Phase 2 study (NCT04112199).
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 enrolment
was paused and that data from the first 15 patients treated with BIV201 plus SOC appeared to show a 34% reduction in ascites fluid during
the 28 days after treatment initiation compared to the 28 days prior to treatment (p=0.0046). This improvement was significantly different
from those patients receiving SOC treatment. Patients who completed the treatment with BIV201 experienced a 53% reduction in ascites fluid
(p=0.001), which was sustained during the three months after treatment initiation as compared to the three-month pre-treatment period
(43% reduction, p=0.06).
In June 2023, the Company requested 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. FDA accepted the request and intends to send written comments in the third quarter of calendar year 2023.
10 Bureau
et al. 2017
6
Our proprietary novel liquid formulation of terlipressin
in a prefilled syringe 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 plan to seek 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 (“NASH”), 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.
7
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 patients 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.
8
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 (received November 21, 2018) and treatment of ascites due to all etiologies except
cancer (received 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 at least the U.S., Europe, China,
Japan and other jurisdictions. Also, we own U.S. Patent 11,364,277, which is directed to a method of treating ascites with BIV201, and
we are pursuing similar patent coverage in Japan, Europe, and China.
9
NE3107 and related compounds
As
of August 15, 2023, we have fifteen (15) issued U.S. patents, six (6) pending U.S. patent applications, one (1) pending U.S. PCT application
and six (6) issued foreign patents 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
Steroids
Having 7-Oxygen and 17-Heteroaryl Substitution
13/095,528
14/027,825
14/027,842
8,569,275
9,102,702
9,115,168
2/14/2024
3/28/2024
3/28/2024
Unsaturated
Steroid Compounds
13/030,326
8,586,770
6/2/2026
Solid
State Forms of a Pharmaceutical
12/418,559
8,252,947*
4/18/2030
Crystalline
Anhydrate Forms of a Pharmaceutical
14/459,528
15/348,107
16/598,694
17/240,728
9,555,046
9,850,271
10,995,112
pending
4/3/2029
4/3/2029
4/3/2029
—
Pharmaceutical
Solid State Forms
12/370,510
8,518,922
9/24/2031
Methods
of Preparing Pharmaceutical Solid State Forms
13/919,593
9,314,471
6/28/2029
Steroid
Tetrol Solid State Forms
12/272,767
8,486,926
1/10/2030
Drug
Identification and Treatment Method
11/941,936
8,354,396
7/7/2031
Method
For Preparing Substituted 3,7-Dihydroxy Steroids
13/664,304
14/886,738
9,163,059**
9,994,608
6/5/2029
6/5/2029
Treatment
Methods Using Pharmaceutical Solid State Forms
14/459,493
9,877,972
4/3/2029
Compositions
for Treatment of Neurodegenerative Conditions
PCT/US2022/027294
pending
—
Methods
for the Treatment of Mild Cognitive Impairment
63/374631
pending
—
Methods
for the Treatment of Mild Cognitive Impairment
63/498703
pending
—
Assay
and Methods for Drug Discovery
63/479973
pending
—
Methods
for the Treatment of Biological Aging
63/381521
pending
—
Methods
for the Treatment of Biological Aging
63/508856
pending
—
*
Foreign
counterparts issued in Australia, Canada, Europe and South Korea expire 4/3/2029.
**
Foreign
counterparts issued in Europe and Japan 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, or 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, or 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.
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The
process required by the FDA before a drug or biological product may be marketed in the United States generally involves the following:
●
Completion
of preclinical laboratory tests, animal studies and formulation studies according to Good Laboratory Practices or other applicable
regulations;
●
Submission
to the FDA of an Investigational New Drug Application, or an IND, which must become effective before human clinical trials may begin;
●
Performance
of adequate and well-controlled human clinical trials according to the FDAs current good clinical practices, or GCPs, to establish
the safety and efficacy of the proposed drug or biologic for its intended use;
●
Submission
to the FDA of a New Drug Application, or an NDA, for a new drug product, or a Biologics License Application, or a BLA, for a new
biological product;
●
Satisfactory
completion of an FDA inspection of the manufacturing facility or facilities where the drug or biologic is to be produced to assess
compliance with the FDAs current good manufacturing practice standards, or cGMP, to assure that the facilities, methods and
controls are adequate to preserve the drugs or biologics identity, strength, quality and purity;
●
Potential
FDA audit of the nonclinical and clinical trial sites that generated the data in support of the NDA or BLA; and
●
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 sponsors 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 FDAs good clinical practices requirements. Further,
each clinical trial must be reviewed and approved by an independent institutional review board, or 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:
●
Phase 1. The
drug or biologic is initially introduced into healthy human subjects and tested for safety, dosage tolerance, absorption, metabolism,
distribution and excretion. In the case of some products for severe or life-threatening diseases, especially when the product may
be too inherently toxic to ethically administer to healthy volunteers, the initial human testing is often conducted in patients having
the specific disease.
●
Phase 2. The
drug or biologic is evaluated in a limited patient population to identify possible adverse effects and safety risks, to preliminarily
evaluate the efficacy of the product for specific targeted diseases and to determine dosage tolerance, optimal dosage and dosing
schedule for patients having the specific disease.
●
Phase 3. Clinical
trials are undertaken to further evaluate dosage, clinical efficacy and safety in an expanded patient population at geographically
dispersed clinical trial sites. These clinical trials, which usually involve more subjects than earlier trials, are intended to establish
the overall risk/benefit ratio of the product and provide an adequate basis for product labeling. Generally, at least two adequate
and well-controlled Phase 3 clinical trials are required by the FDA for approval of an NDA or BLA.
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.
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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 IRBs 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 products 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 products 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.
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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 data and 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 usually 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 products 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 competitors 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.
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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 drugs or biologics 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 FDAs 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 18 employees which are all full time. We also rely on a team of highly experienced
scientific, medical, and regulatory consultants to conduct its product development activities.
14
Text extracted from the filing as submitted to EDGAR. Formatting, tables and exhibits are simplified for reading; the original document is authoritative for anything you rely on.