10-K
1
a10-k12312020.htm
PRIMARY DOCUMENT
a10-k12312020
UNITED
STATES
SECURITIES
AND EXCHANGE COMMISSION
Washington,
D.C. 20549
FORM
10-K
(Mark
One)
☒Annual Report Pursuant to Section 13 or 15(d)
of the Securities Exchange Act of 1934
For
the Fiscal Year Ended December 31, 2020
☐Transition
Report Pursuant to Section 13 or 15(d) of the Securities Exchange
Act of 1934
For the transition period from
_______________ to
________________
Commission
File Number: 001-39070
MONOPAR
THERAPEUTICS INC.
(Exact
name of registrant as specified in its charter)
(Address of principal executive offices) (zip code)
(847)
388-0349
(Registrant’s
telephone number, including area code)
Securities
registered pursuant to Section 12(b) of the Act:
Title of each class Trading Symbol(s) Name of each exchange on which registered
Securities
registered pursuant to section 12(g) of the Act:
None
Indicate by check mark if the registrant is a
well-known seasoned issuer, as defined in Rule 405 of the
Securities Act. Yes ☐ No ☒
Indicate by check mark if the registrant is not
required to file reports pursuant to Section 13 or Section 15(d) of
the Act. Yes ☐ No ☒
Indicate by check mark whether the registrant (1)
has filed all reports required to be filed by Section 13 or 15(d)
of the Securities Exchange Act of 1934 during the preceding 12
months (or for such shorter period that the registrant was required
to file such reports), and (2) has been subject to such filing
requirements for the past 90 days. Yes ☒ No ☐
Indicate by check mark whether the registrant has
submitted electronically every Interactive Data File required to be
submitted pursuant to Rule 405 of Regulation S-T (§ 232.405 of
this chapter) during the preceding 12 months (or for such shorter
period that the registrant was required to submit and post such
files). Yes ☒ No ☐
Indicate
by check mark whether the registrant is a large accelerated filer,
an accelerated filer, a non-accelerated filer, a smaller reporting
company or emerging growth company. See the definitions of
“large accelerated filer,” “accelerated
filer,” “smaller reporting company” and
“emerging growth company” in Rule 12b-2 of the Exchange
Act.
Large accelerated filer ☐ Accelerated filer ☐
Non-accelerated filer ☒ Smaller reporting company ☒
Emerging growth company ☒
If an emerging growth company, indicate by check
mark if the registrant has elected not to use the extended
transition period for complying with any new or revised financial
accounting standards provided pursuant to Section 13(a) of the
Exchange Act.☒
Indicate by check
mark whether the registrant has filed a report on and attestation
to its management’s assessment of the effectiveness of its
internal control over financial reporting under Section 404(b) of
the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered public
accounting firm that prepared or issued its audit
report.☐
Indicate by check mark whether the registrant is a
shell company (as defined in Rule 12b-2 of the Act). Yes
☐ No
☒
State the aggregate market value of the voting and non-voting
common equity held by non-affiliates computed by reference to the
price at which the common equity was last sold, or the average bid
and asked price of such common equity, as of the last business day
of the registrant’s most recently completed second fiscal
quarter. The aggregate market value of the voting and non-voting
common stock held by non-affiliates of the registrant as of
June 30, 2020 was $17,438,356, based on the closing price
reported for such date on the Nasdaq Capital Market.
The
number of shares outstanding with respect to each of the classes of
our common stock, as of March 5, 2021, is set forth
below:
Class Number of shares outstanding
The
documents incorporated by reference are as follows: portions of the
Registrant’s Proxy Statement for its 2021 annual meeting of
stockholders are incorporated by reference into Part
III.
MONOPAR
THERAPEUTICS INC.
TABLE
OF CONTENTS
Page
Part I Item 1. Business 3
Item 1A. Risk Factors 27
Item 2. Properties 55
Item 3. Legal Proceedings 55
Part II
Item 8. Financial Statements and Supplementary Data 73
Item 9A. Control and Procedures 74
Part III
Item 10. Directors, Executive Officers and Corporate Governance 75
Item 11. Executive Compensation 75
Item 14. Principal Accountant Fees and Services 75
Part IV
Item 15. Exhibits and Financial Statement Schedules 76
Item 16. Form 10-K Summary N/A
Forward-Looking
Statements
This
Annual Report on Form 10-K contains “forward-looking
statements” within the meaning of Section 27A of the
Securities Act of 1933, as amended (the “Act”) and
Section 21E of the Securities Exchange Act of 1934, as amended. All
statements other than statements of historical facts included in
this Annual Report on Form 10-K are forward-looking statements. The
words “hopes,” “believes,”
“anticipates,” “plans,”
“seeks,” “estimates,”
“projects,” “expects,”
“intends,” “may,” “could,”
“should,” “would,” “will,”
“continue,” and similar expressions are intended to
identify forward-looking statements. The following uncertainties
and factors, among others, could affect future performance and
cause actual results to differ materially from those matters
expressed in or implied by forward-looking statements:
● our ability
to raise sufficient funds in the next 12 months in order for us to
complete the Phase 3 portion of our Validive Phase 2b/3 clinical
trial and if required, complete a smaller second confirmatory Phase
3 clinical trial, to support further
development of camsirubicin beyond Phase 2 clinical trial, to
support further development of potential radio-immuno-therapeutics
to treat severe COVID-19 (patients with SARS-CoV-2 infection), to
support additional development of MNPR-101 and related compounds
and generally to support our current and any future product
candidates through completion of trials, approval processes and, if
applicable, commercialization;
● our ability
to find a suitable pharmaceutical partner to further our
development efforts, if we are unable to raise sufficient
additional financing;
● risks and
uncertainties associated with our research and development
activities, including our clinical trials;
● estimated
timeframes for our clinical trials and regulatory reviews for
approval to market products;
● plans to
research, develop and commercialize our current and future product
candidates;
● the rate
and degree of market acceptance and the competitive clinical
efficacy and safety of any products for which we receive marketing
approval;
● the
difficulties of commercialization, marketing and manufacturing
capabilities and strategy;
●
uncertainties of intellectual property position and
strategy;
● challenging
future financial performance;
● our ability
to attract and retain key personnel;
● the risks
inherent in our estimates regarding expenses, capital requirements
and need for additional financing;
● the impact
of government laws and regulations;
● the
uncertain impact of the COVID-19 pandemic on our ability to advance
our clinical programs and raise additional financing;
and
● uncertainty
of financial and operational projections.
Although we believe
that the expectations reflected in such forward-looking statements
are appropriate, we can give no assurance that such expectations
will be realized. Cautionary statements are disclosed in this
Annual Report on Form 10-K, including without limitation statements
in the section entitled “Risk Factors,” addressing
forward-looking statements. All subsequent written and oral
forward-looking statements attributable to us or persons acting on
our behalf are expressly qualified in their entirety by the
cautionary statements. We undertake no obligation to update any
statements made in this Annual Report on Form 10-K or elsewhere,
including without limitation any forward-looking statements, except
as required by law.
Any
forward-looking statements in this Annual Report reflect our
current views with respect to future events or to our future
financial performance and involve known and unknown risks,
uncertainties and other factors that may cause our actual results,
performance or achievements to be materially different from any
future results, performance or achievements expressed or implied by
these forward-looking statements. Information that is based on
estimates, forecasts, projections, market research or similar
methodologies is inherently subject to uncertainties and actual
events or circumstances may differ materially from events and
circumstances reflected in this information.
1
Risks Associated with our Business
Our
business is subject to numerous risks and uncertainties, including
those highlighted in “Item 1A - Risk Factors”. These
risks include, among others, the following:
● We are a
clinical stage biopharmaceutical company with a history of
financial losses. We expect to continue to incur significant losses
for the foreseeable future and may never achieve or maintain
profitability, which could result in a decline in the market value
of our common stock.
● Funds
raised to-date are not sufficient to complete the Validive Phase
2b/3 ("VOICE") clinical program, including, if required, completing
a smaller second Phase 3 confirmatory clinical trial, to support
further development of camsirubicin beyond Phase 2, or to support
continued development of MNPR-101 and related compounds. If we are
unable to raise enough funds in the next 12 months from the sale of
our common stock or other financing efforts, we may have to
consider strategic options such as out-licensing Validive or other
product candidates, entering into a clinical partnership, or
terminating one or more programs. There can be no assurance that we
can find a suitable partner on satisfactory terms.
● We have a
limited operating history, no revenues from operations, and are
dependent upon raising capital to continue our drug development
programs.
● We do not
have and may never have any approved products on the market. Our
business is highly dependent upon receiving approvals from various
U.S. and international governmental agencies and will be severely
harmed if we are not granted approval to manufacture and sell our
product candidates.
● Our
clinical trials may not yield sufficiently conclusive results for
regulatory agencies to approve the use of our
products.
● If we
experience delays or difficulties in the enrollment of subjects in
clinical trials, our receipt of necessary regulatory approvals will
be delayed or prevented, which will materially delay our program
schedules and adversely affect our financial
condition.
● We rely on
third parties to conduct our manufacturing, non-clinical studies,
and our clinical trials. If these third parties do not successfully
carry out their contractual duties or meet expected deadlines or
performance goals, the initiation or conduct of our clinical trials
may be delayed and we may be unable to obtain regulatory approval
for, or commercialize our, current product candidates or any future
products, and our financial condition will be adversely
affected.
● We face
significant competition from other biotechnology and pharmaceutical
companies, and our operating results will suffer if we fail to
compete effectively. Competition and technological change may make
our product candidates obsolete or non-competitive.
● The
termination of third-party licenses will adversely affect our
rights to important compounds or technologies.
● If we and
our third-party licensors do not obtain and preserve protection for
our respective intellectual property rights, our competitors may be
able to take advantage of our development efforts to develop
competing drugs.
● If we lose
key management leadership, and/or scientific personnel, and if we
cannot recruit qualified employees or other significant personnel,
we may experience program delays and increased compensation costs,
and our business will be materially disrupted.
● The
COVID-19 pandemic could have a substantial negative impact on our
business, financial condition, operating results, stock price and
ability raise additional funds.
2
PART
I
Item 1. Business
You should read the following
discussion in conjunction with our financial statements as of
December 31, 2020 and the notes to such financial statements
included elsewhere in this Annual Report on Form 10-K.
Overview
We are a clinical stage
biopharmaceutical company focused on developing proprietary
therapeutics designed to extend life or improve quality of life for
cancer patients. We are building a drug development pipeline
through the licensing and acquisition of oncology therapeutics in
late preclinical and clinical development stages. We leverage our
scientific and clinical experience to help reduce the risk and
accelerate the clinical development of our drug product
candidates.
Given the COVID-19 pandemic
and its effects on clinical trials, we have adjusted and simplified
the design of the clinical trial for our lead product candidate,
Validive (clonidine mucobuccal tablet; clonidine MBT) for the
prevention of chemoradiotherapy (“CRT”)-induced
severe
oral
mucositis in patients with
oropharyngeal cancer
(“VOICE”), to a seamless Phase 2b/3 design. This design
is based on a binary primary endpoint, incidence of severe oral
mucositis (“SOM”), and will minimize touch points with
the clinical trial sites and patients. The VOICE trial
(NCT04648020) is randomized, placebo-controlled and double blinded
and allows a sample size adjustment for the Phase 3 portion of the
trial if supported by the interim analysis at the end of Phase 2b.
The entire trial has been designed to enroll up to 260 evaluable
patients. This modification in design allowed us to activate and
commence dosing the VOICE trial without requiring near-term
financing. To complete the VOICE clinical program, including, if
required, completing a smaller second Phase 3 confirmatory clinical
trial, we will require additional funding in the millions or tens
of millions of dollars (depending on if we have consummated a
collaboration or partnership or neither for Validive) which we are
planning to pursue in the next 12 months.
Along with our VOICE trial,
we continue to prioritize supporting the camsirubicin Phase 2
clinical trial for which we signed a collaboration agreement in
June 2019 with Grupo Español de Investigación en Sarcomas
(“GEIS”), discussed in further detail below. We believe
we have funds sufficient to enable GEIS to commence its open label
Phase 2 clinical trial in the second quarter of 2021 and to obtain
results from the run-in portion of the trial.
Additionally, we continue to
develop MNPR-101 in several indications as discussed
below.
Our
Product Pipeline
3
Our Product Candidates
Validive (clonidine mucobuccal tablet; clonidine MBT)
Validive is designed to be
used prophylactically to prevent SOM in patients undergoing CRT for
oropharyngeal cancer (“OPC”). SOM is a painful and
debilitating inflammation and ulceration of the mucous membranes
lining the oral cavity and oropharynx in response to
chemoradiation. The majority of patients receiving CRT to treat
their OPC develop SOM, which remains one of the most common and
devastating side effects of treatment in this indication. The
potential clinical benefits to preventing SOM in patients include:
reduced treatment discontinuations leading to potentially improved
overall survival outcomes; reduced mouth and throat pain avoiding
the need for feeding tube intervention; decreased long-term and
often permanent debilitation arising from swallowing difficulties,
neck and throat spasms, and lung complications due to food
aspiration; and decreased reliance on pain medication. Our
mucobuccal tablet (“MBT”) formulation is a novel
delivery system for clonidine that allows for prolonged and
enhanced local delivery of drug in the regions of mucosal radiation
damage in patients with OPC. Validive has been granted fast track
designation in the U.S., orphan drug designation in the EU, and has
global intellectual property patent protection through mid-2029 not
accounting for possible extensions.
In September 2017, we
exercised an option to license Validive from Onxeo S.A., the
company that developed Validive through its Phase 2 clinical trial.
In the completed Phase 2 clinical trial, Validive demonstrated
clinically meaningful efficacy signals within the 64-patient OPC
population randomized to placebo, Validive 50 μg dose and
Validive 100 μg dose. The absolute incidence of SOM in OPC
patients who received a dose of Validive 100 μg once per day
was reduced by 26.3% (incidence rate of 65.2% in placebo, 45.0% in
Validive 50 μg group, and 38.9% in Validive 100 μg
group). The median time to onset of SOM was 37 days in the placebo
cohort; 45 days in the Validive 50 μg cohort and no median
time of onset was reached in the Validive 100 μg group since
fewer than half of this cohort of patients developed SOM. There was
also a 37.8% reduction in the median duration of the SOM for the
Validive 100 μg group versus placebo (41.0 days placebo group,
34.0 days Validive 50 μg group, and 25.5 days Validive 100
μg group) in patients that developed SOM. Median duration of
SOM across all patients, inclusive of both those that did and did
not develop SOM, was 17 days in the placebo group and 0 days in
each of the Validive 50 and 100 μg groups. A positive dose
response was seen in each of these three clinical endpoints.
Additionally, patients in the Validive cohorts in the Phase 2
clinical trial demonstrated a safety profile similar to that of
placebo. Onxeo’s promising preclinical studies and Phase 2
clinical trial have informed the design and conduct of what we
believe will be an effective Phase 2b/3 and smaller confirmatory
Phase 3 clinical program.
SOM typically arises in the
immune tissue at the back of the tongue and throat, which comprise
the oropharynx, and consists of acute severe tissue damage and pain
that prevents patients from swallowing, eating and drinking.
Validive stimulates the alpha-2 adrenergic receptor (alpha-2AR) on
macrophages (white blood cells present in the immune tissues of the
oropharynx) suppressing pro-inflammatory cytokine expression.
Validive exerts its effects locally in the oral cavity and
oropharynx over a prolonged period of time through its unique MBT
formulation. Patients who develop SOM are also at increased risk of
developing late onset toxicities, including trismus (jaw, neck, and
throat spasms), dysphagia, and lung complications, which are often
irreversible and lead to increased hospitalization and the need for
further interventions sometimes years after completion of CRT. We
believe that the prevention of SOM by Validive will have the
potential to reduce treatment discontinuation and/or treatment
delays potentially leading to improved survival outcomes, and
reducing or eliminating these long-term morbidities resulting from
CRT.
The OPC target population for
Validive is the most rapidly growing segment of head and neck
cancer (“HNC”) patients, with an estimated greater than
40,000 new cases of OPC in the U.S alone in 2021. The growth in OPC
is driven by the increasing prevalence of oral human papilloma
virus (“HPV”) infections in the U.S. and around the
world. Despite the availability of a pediatric/adolescent HPV
vaccine, the rate of OPC incidence in adults is not anticipated to
be materially reduced for decades due to low adoption of the
vaccine to date. As a result, the incidence of HPV-driven OPC is
projected to increase for years to come and will continue to
represent a clinical need for Validive for the prevention of
CRT-induced SOM in patients with OPC since CRT is the standard of
care treatment, and we anticipate that radiation will remain an
important treatment modality for these patients for years to
come.
4
Validive is an MBT of
clonidine. The MBT formulation was developed to enhance drug
delivery to the oral mucosa while minimizing systemic absorption.
The Validive tablet is tasteless and odorless and is
self-administered once daily by affixing it to the outside of the
patient’s upper gum where it dissolves slowly over a period
of several hours, resulting in the extended release of clonidine
into the oral cavity and oropharynx, the sites of SOM following CRT
for OPC. Validive treatment begins on the first day of CRT and
continue daily through the last day of radiation.
The VOICE trial is a double blinded, placebo
controlled Phase 2b/3 clinical trial of Validive which is estimated
to recruit up to 260 OPC patients receiving CRT. The VOICE trial
has been activating sites and dosing has begun. An interim analysis
at the end of Phase 2b is anticipated in Q1, 2022 with the Phase 3
portion of the trial to immediately follow. To complete the
VOICE clinical program, including, if required, completing a
smaller second Phase 3 confirmatory clinical trial, we will require
additional funding in the millions or tens of millions of dollars
(depending on if we have consummated a collaboration or partnership
or neither for Validive), which we are planning to pursue in the
next 12 months.
Validive U.S. Market Opportunity
The incidence of HNC (all
anatomical types, including larynx, oral cavity, oropharynx, etc.)
in the U.S. was estimated to be approximately 65,630 cases in 2020
(American Society of Clinical Oncology, cancer.net). The most
rapidly growing type of HNC is OPC. The oropharynx is comprised
largely of immune tissue and includes the soft palate, the base
(rear one third) of the tongue, and the tonsils. In the U.S., the
incidence of OPC is estimated to be greater than 40,000 cases in
2021. The majority of these OPC patients (approximately 70%) are
human papilloma virus positive (“HPV+”). The incidence
of OPC is also increasing in the rest of the world (>30% of
HNC), with >50% of all OPC being HPV+. While certain types of
HNC have been in decline in the U.S., such as laryngeal cancer as a
result of a reduction in the smoking population, the total
incidence of HNC has been growing steadily primarily due to OPC.
The increase in OPC is directly associated with increased infection
with the human papilloma virus. The incidence of HPV+ OPC has
outpaced the incidence of HPV– HNC by 4-5-fold over the past
decade. This trend of HPV+ OPC driving an increase in overall HNC
is expected to continue for some time as the relatively recent
introduction of a vaccine designed to prevent the transfer and
colonization with HPV is only effective if administered prior to
infection, and until October 2018, it was only recommended for
those under the age of 26 (newer FDA guidelines include those up to
age 45). Even for those under the age of 26 who are eligible for
the vaccine, oral HPV infections are predicted to increase due to
the lack of adequate use of HPV vaccinations. Approximately 50% of
eligible females and 33% of eligible males are presently being
vaccinated.
Most OPC is caused by the
HPV16 strain, with virus detectable in the tumor. More than 3% of
adult men and 1% of adult woman have HPV16 detectable in their
saliva at any one time. The virus is transmitted through sexual
contact and CDC estimates 10% of men and 3.6% of women in the U.S.
have an active oral HPV infection. The latency period for that
proportion that do go on to develop HPV+ OPC is 15-20+ years. This
HPV+ OPC population is expected to be a long-term driver of the
incidence of OPC and the resultant SOM associated with what is
frequently curative therapy for this serious
malignancy.
In previous studies describing SOM in OPC
patients receiving the CRT regimen we are using in our VOICE
clinical program, patients had a SOM incidence rate of 55-90%
across studies. In the Validive Phase 2 trial, the incidence of SOM
in OPC patients receiving placebo was 65.2% (see
“Validive Phase 2 Clinical
Trial Data” section
below). Currently there is no way to predict which patients will
develop SOM, so any active preventive treatment for SOM will likely
be used in most OPC patients receiving CRT. With the consistently
growing incidence of OPC as a result of the human papillomavirus,
there is the potential for a substantial and growing market for
Validive.
Validive Mechanism of Action
Validive is designed to
deliver high local concentrations of clonidine, an agonist of
alpha-2AR, to the oral cavity and oropharynx, the site of
irradiation in the treatment of OPC. In the oropharynx, alpha-2AR
is expressed on macrophages, immune cells that produce inflammatory
cytokines, the molecules that are responsible for the development
of SOM, in response to CRT. Several published clinical reports have
demonstrated that chemoradiation treatment substantially increased
salivary cytokine levels and a recent study demonstrated that these
were positively associated with the formation of SOM in patients
with head and neck cancer. Patients with HPV+ OPC demonstrate an
increased accumulation of macrophages in the tumor microenvironment
compared to patients with OPC that were negative for human
papilloma virus (“HPV–”), thus further priming
HPV+ OPC patients for the development of SOM. The alpha-2AR
regulates the expression of cytokines by macrophages, and clonidine
reduces this cytokine production. Macrophages are the primary
immune cells in the oropharynx that express alpha-2AR, making
clonidine’s mechanism of cytokine suppression macrophage
selective and distinct from the mechanism of other
anti-inflammatory drugs. Further, Validive delivers clonidine to
the mucosal surface, the site most affected by chemoradiation
treatment in OPC. This results in high salivary concentrations of
clonidine, minimizing systemic absorption, and allowing for maximal
exposure the at-risk oral mucosa and the OPC microenvironment to
drug. Preclinical studies and a Phase 2 clinical trial of Validive
have provided data that support Validive’s mechanism of
action and therapeutic potential for reducing the incidence of SOM
in patients with OPC, improving oral mucositis-related symptoms,
and decreasing CRT-related adverse events, while exhibiting a
favorable safety profile and high compliance rate in
patients.
5
Validive Phase 2 Clinical Trial Data
In October 2015, the results
from an international Phase 2 clinical trial of Validive were
announced, demonstrating promising signs of clinical activity and
safety compared to placebo. The trial enrolled 183 patients and was
conducted in more than thirty centers in Europe and the United
States. HNC patients who had undergone surgical resection of their
head and neck cancer with curative intent and who were planned to
receive at least 50 Gray (Gy) of radiation in combination with
chemotherapy, regardless of anatomical location of disease, were
included in this study. This global, multi-center, double-blind,
randomized, placebo-controlled, three-arm study (NCT01385748)
compared the efficacy and safety of Validive 50 μg and 100
μg to placebo in patients with HNC receiving CRT. Of the 183
HNC patients, 64 had OPC (placebo = 24, Validive 50 μg = 21,
Validive 100 μg = 19). Validive and placebo were administered
once daily beginning 1 to 3 days prior to CRT and continuing until
the end of chemoradiation.
We believe
the Phase 2 clinical trial data support the development of Validive
for the prevention of SOM in OPC patients. The analysis of OPC
patients in this study showed:
●
The incidence of SOM (primary endpoint) was reduced by 26.3% (40%
relative to placebo) in OPC patients treated with Validive 100
μg (p=0.09, a meaningful trend but not statistically
significant). 65.2% of OPC patients on placebo experienced SOM
compared to only 38.9% of OPC patients on Validive 100
μg.
■
Incidence of SOM in OPC Patients
Validive has
demonstrated reduced incidence of SOM in a Phase 2 clinical trial
(p=0.09)
●
Patients on Validive experienced a delay in the time to onset of
SOM. Patients receiving placebo experienced a median time to onset
of SOM of 37 days; patients receiving Validive (50 μg one per
day) experienced a 45 day median time to onset of SOM; and patients
receiving Validive (100 μg once per day) did not reach a
median time to onset. A comparison of hazards for time to onset
demonstrated that patients that received Validive 100 μg had a
hazard ratio (HR)=0.48 compared to placebo.
●
Patients receiving Validive experienced a decrease in the median
duration of SOM. In patients that developed SOM, a 15.5 day
reduction (by 37.8%) in the median duration of SOM was observed in
patients treated with Validive 100 μg (41 day median duration
with placebo, 34 days in the Validive 50 μg group, and 25.5
days in the Validive 100 μg group). Median duration across all