UNITED
STATES
SECURITIES
AND EXCHANGE COMMISSION
Washington,
D.C. 20549
Form
10-K
For
the fiscal year ended December 31, 2023
For
the transition period from ________to_________
Commission
file number 001-31361
MIRA
Pharmaceuticals, Inc.
(Exact
name of registrant as specified in its charter)
(Address of principal executive offices) (Zip Code)
Registrant’s
telephone number, including area code: 786-432-9792
Securities
registered pursuant to Section 12(b) of the Act:
Title of each class Trading Symbol(s) Name of exchange on which registered
Common stock, par value $0.0001 MIRA The Nasdaq Capital Market
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 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 an emerging growth company. See definition 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. ☒
If
securities are registered pursuant to Section 12(b) of the Act, indicate by check mark whether the financial statements of the registrant
in the filing reflect the correction of an error to previously issued financial statements. ☐
Indicate
by check mark whether any of those error corrections are restatements that required a recovery analysis of incentive-based compensation
received by any of the registrant’s executive officers during the relevant recovery period pursuant to §240.10D-1(b). ☐
Indicate
by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Exchange Act). Yes ☐ No ☒
The
aggregate market value of the voting and non-voting common equity held by non-affiliates as of June 30, 2023, was $0 based on the closing
sale price of the company’s common stock on such date of $0.00 per share, as reported by the NASDAQ Capital Market.
As
of March 28, 2024, there were 14,780,885 shares of common stock, par value $0.0001, issued and outstanding.
Mira
Pharmaceuticals, Inc.
Annual
Report on Form 10-K
For
the fiscal year ended December 31, 2023
TABLE
OF CONTENTS
Cautionary Note Regarding Forward-Looking Statements 1
PART I 4
Item 1. Description of Business 4
Item 1A. Risk Factors 34
Item 1B. Unresolved Staff Comments 67
Item 1C. Cyber Disclosure 67
Item 2. Description of Property 67
Item 3. Legal Proceedings 67
Item 4. Mine Safety Disclosure 67
Item 5. Market for Common Equity and Related Stockholder Matters 68
Item 6. Reserved 68
Item 7A. Quantitative and Qualitative Disclosures About Market Risk 76
Item 8. Financial Statements 76
Item 9A. Controls and Procedures 76
Item 9B. Other Information 77
Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 77
PART III 78
Item 10. Directors, Executive Officers and Corporate Governance 78
Item 11. Executive Compensation 84
Item 14. Principal Accountant Fees and Services 97
Item 15. Exhibits, Financial Statement Schedules 98
Unless
we have indicated otherwise, or the context otherwise requires, references in this Report to “MIRA,” the “Company,”
“we,” “us” and “our” or similar terms refer to Mira Pharmaceuticals, Inc., a Florida corporation.
From
time to time, we may use our website, our Facebook page at https://www.facebook.com/people/Mira-Pharmaceuticals-Inc/100087641460083,
our Twitter at https://twitter.com/PharmaMira and on our LinkedIn account at www.linkedin.com/company/mira-pharmaceuticals-inc to distribute
material information. Our financial and other material information is routinely posted to and accessible on the Investors section of
our website, available at www.mirapharmaceuticals.com. Investors are encouraged to review the Investors section of our website because
we may post material information on that site that is not otherwise disseminated by us. However, information that is contained in and
can be accessed through our website, our Facebook page, our Twitter posts and our LinkedIn posts are not incorporated into, and does
not form a part of, this Annual Report.
i
CAUTIONARY
NOTE REGARDING FORWARD-LOOKING STATEMENTS
This
Annual Report on Form 10-K (this “Report”) contains forward-looking statements (as defined in Section 27A of the Securities
Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended (the “Exchange Act) that reflect our
current expectations and views of future events. In some cases, you can identify forward-looking statements by terms such as “may,”
“will,” “should,” “expect,” “plan,” “anticipate,” “could,” “intend,”
“target,” “project,” “contemplate,” “believe,” “estimate,” “predict,”
“potential”, or “continue” or the negative of these terms or other similar expressions. In particular, statements
about our pre-clinical and clinical trials and expectations regarding such trials, the markets in which we operate, including growth
of such markets, and our expectations, beliefs, plans, strategies, objectives, prospects, assumptions, or future events or performance
contained in this Report generally under the headings “Risk Factors,” “Management’s Discussion and Analysis of
Financial Condition and Results of Operations” and “Business” are forward-looking statements.
We
have based these forward-looking statements on our current expectations, assumptions, estimates and projections. While we believe these
expectations, assumptions, estimates, and projections are reasonable, such forward-looking statements are only predictions and involve
known and unknown risks and uncertainties, many of which are beyond our control. These and other important factors, including those discussed
in this Report under the headings “Risk Factors,” “Management’s Discussion and Analysis of Financial Condition
and Results of Operations” and “Business,” may cause our actual results, performance, or achievements to differ materially
from any future results, performance or achievements expressed or implied by these forward-looking statements, or could affect our share
price. Important factors that could cause actual results or events to differ materially from those expressed in forward-looking statements
include, but are not limited to, the following:
● the timing of anticipated regulatory filings;
● the timing of availability of data from our clinical trials;
● our ability to recruit and enroll suitable patients in our clinical trials;
● the pricing and reimbursement of our product candidates, if approved;
● developments relating to our competitors and our industry;
Given
the risks and uncertainties set forth in this Report, you are cautioned not to place undue reliance on such forward-looking statements.
The forward-looking statements contained in this Report are not guarantees of future performance and our actual results of operations,
financial condition, and liquidity, and the development of the industry in which we operate, may differ materially from the forward-looking
statements contained in this Report. In addition, even if our results of operations, financial condition and liquidity, and events in
the industry in which we operate, are consistent with the forward-looking statements contained in this Report, they may not be predictive
of results or developments in future periods.
Any
forward-looking statement that we make in this Report speaks only as of the date of such statement. Except as required by federal securities
laws, we do not undertake any obligation to update or revise, or to publicly announce any update or revision to, any of the forward-looking
statements, whether as a result of new information, future events or otherwise, after the date of this Report.
Summary
of Principal Risks
Our
business is subject to numerous risks and uncertainties that represent challenges that we face in connection with the implementation
of our strategy and the growth of our business. In particular, the following are the principal risks which could cause a decline in the
price of shares of our common stock:
PART
I
ITEM
1. Description of Business
Overview
We
are a pre-clinical-stage pharmaceutical development company with two neuroscience programs targeting a broad range of neurologic and
neuropsychiatric disorders. We hold exclusive license rights in the U.S., Canada and Mexico for Ketamir-2, a novel,
patent pending oral ketamine analog under pre-clinical investigation to potentially deliver ultra-rapid antidepressant effects,
providing hope for individuals battling treatment-resistant depression (or TRD), major depressive disorder with suicidal ideation
(or MDSI) and potentially post-traumatic stress disorder (or PTSD).
Additionally,
our novel oral pharmaceutical marijuana molecule, MIRA-55, is being studied for its potential to alleviate neuropathic pain, as well as anxiety and cognitive decline, symptoms
commonly associated with early-stage dementia.
MIRA-55, if approved by the U.S. Food and Drug Administration (or FDA), could mark a significant advancement in addressing various
neuropsychiatric, inflammatory, and neurologic diseases and disorders.
The
U.S. Drug Enforcement Administration (DEA)’s scientific review of Ketamir-2 concluded that it would not be considered a controlled
substance or listed chemical under the Controlled Substances Act (CSA) and its governing regulations. Additionally, we have submitted
the required paperwork for MIRA-55 to be evaluated by the DEA.
We
were incorporated under the laws of the State of Florida in September 2020 and commenced substantive operations, including our pharmaceutical
development program, in late 2020.
Our
Product Candidates in Development
KETAMIR-2
Major
Depressive Disorder (or MDD) is a significant global health concern, affecting over 264 million people worldwide and ranking among the
leading causes of disability according to the World Health Organization. In the United States alone, it impacts nearly 21.1 million adults,
accounting for about 8.3 % of the adult population in 2-2021 according to data form the National Institutes of Health. This widespread
mental health disorder not only undermines the quality of life and daily functioning of individuals but also imposes a substantial economic
burden, with costs in the U.S. amounting to tens of billions of dollars annually. MDD is also a major risk factor for suicide, a leading
cause of death globally, highlighting its profound impact on public health and the urgent need for effective treatment and management
strategies. If approved by the FDA, Ketamir-2 may potentially provide antidepressant therapeutic effects.
Despite
the fact that antidepressants have been on the market for decades, with imipramine being the first FDA-approved antidepressant in 1959,
the need for a rapid-acting antidepressant that can help patients with Treatment-Resistant Depression (or TRD) using a novel mechanism
of action (e.g. not a monoamine reuptake inhibitor) has been growing. In 2019, ketamine was introduced but required by the FDA to utilize
a Risk Evaluation and Mitigation Strategy (REMS) because of its: (1) poor oral availability requiring intravenous (or IV) or intranasal
(or IN) administration, (2) ability to cause side effects including dissociation, sedation and acute hypertension, and (3) potential
abuse liability.
Ketamir-2
is a new chemical entity, an analog of ketamine that is designed to potentially preserve the same rapid antidepressant response but with
improved bioavailability. It may also have decreased side effects, and decreased abuse liability, though such conclusions are within
the sole authority of the FDA. This combination is intended to potentially facilitate safer and less cumbersome dosing requirements,
with the goal of obtaining an orally administered pill that can be taken at home.
Figure:
Chemical structures of ketamine and Ketamir-2 for comparison purposes.
The
DEA conducted a scientific review of the Ketamir-2 in 2023 in accordance with the definitions within the CSA and its implementing regulations.
Based on this review, DEA determined that” Ketamir-2 is “not a controlled substances or listed chemical under the CSA.”
Mechanism
of Action of Ketamir-2
Ketamir-2’s
mechanism of action (or MOA) as a rapid acting antidepressant is the same as ketamine’s, based on the fact that the two share a
common inhibitory effect on the N-methyl-D-aspartate (or NMDA) receptor, a type of glutamate receptor that is believed to be integral
to the antidepressant effects of both of these ketamine and Ketamir-2. In fact, Ketamir-2 and ketamine differ in less than 2% in their
antagonist activity at the GRIN1/GRIN2B receptor subunit of the NMDA receptor (based in in silico analysis, see below). This subunit
combination is prominently linked to neuroplasticity, believed to be a key factor in depression and the action of antidepressants such
as ketamine. GRIN2B-containing NMDA receptors are implicated in synaptic plasticity changes associated with depression and its treatment.
Ketamine’s
mechanism of action (or MOA) as a rapidly acting antidepressant is multifaceted and distinct from traditional antidepressants like selective
serotonin reuptake inhibitors (or SSRIs) and tricyclic antidepressants. While ketamine has shown promise as a rapid-acting antidepressant,
especially in treatment-resistant depression, its use is limited due to potential side effects and abuse potential that Ketamir-2 has
been targeted to minimize. Moreover, whereas ketamine has a poor oral bioavailability and must therefore be given IV or IN, Ketamir-2
has a much better bioavailability suggesting it may be appropriate for oral use.
The
following is a detailed synopsis of the MOAs of both Ketamir-2 and ketamine:
In
summary, while Ketamir-2’s and ketamine’s antidepressant MOA are still being studied and explored, current evidence suggests
a complex and involved synergistic action on various neural pathways, primarily through the modulation of glutamatergic neurotransmission,
enhancement of neuroplasticity, and potentially through anti-inflammatory and neuroendocrine mechanisms. Both drugs rapid onset and efficacy
in treatment-resistant cases make them potentially valuable tools in psychiatry, but the potentially improved side effect profile and
oral bioavailability are what differentiate Ketamir-2 and ketamine as described below.
Ketamir-2
Clinical Development Program
The
clinical development plan for Ketamir-2 involves a series of methodically structured phases, starting with IND-enabling studies and progressing
through Phase 1 and Phase 2 clinical trials. These trials aim to establish the safety, efficacy, and optimal use of Ketamir-2 in treating
psychiatric conditions like TRD, Major Depressive Disorder with Suicidal Ideation (MDSI), and potentially PTSD. The strategy underscores
patient safety while evaluating Ketamir-2’s therapeutic benefits and risks. The successful development of Ketamir-2 could significantly
impact the treatment landscape for depression, offering a novel approach that addresses the shortcomings of current therapies.
Initially,
the development process begins with completion of all necessary IND-enabling studies. These preclinical studies, encompassing
pharmacokinetics, pharmacodynamics, toxicology, and safety pharmacology, are crucial for ensuring that the investigational drug
meets regulatory standards. The successful completion of these studies allows for the submission of an Investigational New Drug
(IND) application to the FDA, specifically targeting TRD. We anticipate that we will submit our IND for Ketamir-2 by the end of
2024. See the section below titled “Research and Testing to Date – Ketamir-2” for more
information.
Upon
FDA acceptance of our Ketamir-2 IND, our plan progresses to Phase 1 clinical trials. These trials are designed to assess the safety and
tolerability of Ketamir-2 in healthy volunteers. They are typically randomized, double-blind, and placebo-controlled, and aim to determine
the appropriate dosing while closely monitoring for adverse effects. Key to this phase is the collection of pharmacokinetic and pharmacodynamic
data, which guides the dosing strategies for subsequent trials.
Phase
1: Safety and Dosage Determination in Healthy Volunteers
1. Study Design:
○ A randomized, double-blind, placebo-controlled trial.
○ Primary objective: Assess safety and tolerability of Ketamir-2.
○ Secondary objectives: Determine pharmacokinetics and pharmacodynamics.
2. Participant Selection:
○ Enroll healthy volunteers, ensuring a diverse demographic representation.
3. Dosing and Administration:
○ Start with a low dose, escalating gradually to higher doses.
○ Monitor participants closely for adverse effects.
4. Outcome Measures:
Following
the establishment of safety and initial dosing parameters in Phase 1, the development plan moves into Phase 2. This phase involves trials
with patients diagnosed with TRD. The primary goal here is to evaluate the optimal dose and tolerability of Ketamir-2 in this specific
patient population. Additionally, these trials provide preliminary data on the efficacy of Ketamir-2 for the treatment of TRD. Safety
remains a priority, with close monitoring for any adverse events and detailed assessments using depression rating scales.
Phase
2: Dose, Tolerability, and Early Efficacy in TRD
1. Study Design:
○ A randomized, controlled trial with TRD patients.
○ Primary objective: Evaluate the optimal dose and tolerability.
○ Secondary objective: Obtain preliminary efficacy data.
2. Participant Selection:
○ Enroll patients diagnosed with TRD.
○ Utilize standardized diagnostic criteria and severity scales.
3. Dosing Regimen:
○ Implement a dose range based on Phase 1 findings.
4. Outcome Measures:
○ Tolerability assessment: Adverse event monitoring, patient-reported outcomes.
○ Efficacy assessment: Depression rating scales (e.g., HDRS, MADRS).
As
the development of Ketamir-2 progresses, there is potential to expand its indications. One such area is MDSI, where Ketamir-2’s
application could be particularly beneficial given ketamine’s established efficacy in this domain. This would involve designing
a trial specifically targeting MDSI, with a focus on the rapid onset of action and short-term safety considerations.
Furthermore,
given the emerging research suggesting ketamine’s therapeutic potential in PTSD, a similar approach could be considered for Ketamir-2.
Developing a trial protocol for PTSD treatment requires a careful balance, considering the complexity of the disorder, potential comorbidities,
and the need for robust safety and efficacy data.
Pursuing
Additional INDs:
1. Major Depressive Disorder with Suicidal Ideation (MDSI):
2. Post-Traumatic Stress Disorder (PTSD):
In
summary, the clinical development plan for Ketamir-2 is a meticulous, multi-phase strategy that prioritizes patient safety while exploring
the drug’s potential in treating complex psychiatric conditions. Each phase is carefully designed to address specific research
questions and regulatory requirements, ensuring a thorough evaluation of Ketamir-2’s therapeutic benefits and risks.
Manufacture
of Product for Pre-Clinical and Clinical Development Activities
Recipharm
Israel LTD, a leading global contract development and manufacturing organization (or CMDO), is currently developing a large-scale
synthesis protocol for us and will be supplying quantities of Ketamir-2 and MIRA-55 needed for our pre-clinical and clinical
development activities. We previously utilized Curia Global as our CMDO and are currently in discussions with other partners to have
Ketamir-2 and MIRA-55 formulated into solid oral dosage forms for clinical trials.
We also utilize Frontage Laboratories and Pharmaseed LTD to conduct preclinical
studies on Ketamir-2.
MIRA1A
In
early February 2024, we made a significant discovery during the manufacturing and scale-up process of our patented molecule known as
“MIRA1a,” which we believed was the molecule used in our pre-clinical trials and had been synthesized by contract manufacturer.
Through this process, we identified a novel and improved version of the molecule, which we call MIRA-55.
As
part of our due diligence and subsequent testing, which began in late 2023, we discovered that the pre-clinical studies we conducted,
previously attributed to MIRA1a, were in fact performed on MIRA-55. Following this revelation, in early March 2024, we promptly filed
a provisional patent for MIRA-55, which encompasses all pre-clinical studies disclosed in our two registration statements on Form S-1,
declared effective on August 2, 2023, and December 27, 2023 (File Nos. 333-273024 and 333-276118, respectively). If such patent is issued,
we would own the patent rights to both MIRA1a and MIRA-55.
Moreover,
based on our pre-clinical analyses to date, we believe that MIRA-55 is an improvement over MIRA1a in that it displays enhanced potency
and potential for efficacy.
Based on our discoveries to date, we decided to advance MIRA-55 as our
lead compound for our oral pharmaceutical marijuana drug candidate while still retaining our rights to MIRA1a. As such, we do not intend
to move MIRA1a forward as of the date of this Report.
MIRA-55
Our
objective is to develop and commercialize new treatment options for neuropsychiatric, inflammatory, and neurologic diseases and disorders.
Cannabinoids are a class of chemical compounds that are naturally occurring and are primarily found in cannabis plant extracts. The two
major cannabinoids found in cannabis plant extracts include tetrahydrocannabinol, a compound that is the main psychoactive ingredient
of cannabis (or THC) and cannabidiol, the second most prevalent active ingredient in cannabis which does not have psychoactive properties
(or CBD). These compounds bind to CB1 and CB2 cannabinoid receptors, which are found throughout the body. Specifically, CB1 receptors
are concentrated in the central nervous system (or CNS), while CB2 receptors are found mostly in peripheral organs and are associated
with the immune system. When the chemical compounds bind to these cannabinoid receptors, the process elicits certain physiological responses.
Physiological responses to cannabinoids may vary among individuals. Some of the effects of cannabinoids have been shown to impact nervous
system functions, immune responses, muscular motor functions, gastrointestinal maintenance, blood sugar management, and the integrity
of ocular functions. Based on pre-clinical testing, our product candidate, MIRA-55, appears to have a strong selectivity for CB2 versus
CB1, and is designed to minimize the risk of psychoactive adverse events associated with CB1 activation.
Mechanism
of Action of MIRA-55
We
believe that the effects of MIRA-55 at the cannabinoid receptors CB1 and CB2 is predicted to account for the majority of its
potential therapeutic effects, especially as it relates to its anti-anxiety, anti-pain and anti-inflammatory properties. For
example, the difference in the dose-response effects of MIRA-55 compared with THC on CB1 receptors appears to coincide with its
improved therapeutic profile. If approved by the FDA, MIRA-55 may potentially provide therapeutic effects and enhanced cognition for
anxiety, pain and inflammation.
THC
has been demonstrated to have biphasic physiological effects (meaning effects in two phases), which have been described for over 40 years:
at low levels THC has positive effects while high doses cause the opposite, undesirable symptoms. Examples of biphasic effects at low
versus high levels of THC include the anti-anxiety versus pro-anxiety effects, respectively. Through pre-clinical test, we obtained the
following dose-response effects for MIRA-55 and THC at the CB1 receptor (see below). In contrast to THC, which displays an initial maximally
stimulatory and then inhibitory response at CB1, MIRA-55 appears to act as a monophasic partial agonist (meaning it has a lower intrinsic
activity than full agonists) in that it creates a stimulation throughout its dose range, achieving a moderate activation of the CB1 even
at high doses. We believe that this accounts for the potential broad therapeutic efficacy of MIRA-55 and the observed absence of negative
symptoms even at maximal doses of the drug.
Figure:
Compound activity with the selected GPCR Biosensor Assays: THC vs MIRA-55 agonist activity at the CB1 Receptor.
In
pharmacology, “efficacy” or “Emax” refers to the maximum response that can be achieved with a drug or agent.
It represents the extent or magnitude of the response produced by the drug once it has bound to its target, typically referred to as
a receptor. The binding between a drug and its receptor is characterized by affinity, which quantifies the strength of their interaction.
Efficacy, however, assesses the action or effect of the drug following binding to the receptor.
The
dose-response curve is a commonly used graph in pharmacology that depicts the relationship between the effect of a drug and its dosage.
The X-axis represents the increasing doses of the drug, while the Y-axis represents the response produced by the drug. In the case of
the figure above, the term “% Efficacy” on the Y-axis refers to the maximum response that can be achieved with the agonist
(MIRA-55 or THC) in relation to its ability to activate GPCR receptors (specifically CB1 receptors). GPCRs are G-protein-coupled receptors
that form a large group of proteins which are expressed on the cell surface of eukaryotic cells to detect molecules outside the cell
and activate cellular response.
The
data presented in the figure above has been normalized to the maximal and minimal responses observed in the presence of a control compound
and vehicle, respectively. This normalization allows for a standardized comparison of the agonist’s efficacy.
MIRA-55
Pre-clinical Developments and Studies
As
of the date of this Report, we completed several pre-clinical studies of MIRA-55, including, but not limited to, radio-ligand binding
assay, elevated plus maze (or EPM) model of anxiety and hot plate model thermal sensitivity testing.
We
have studied the effects of acute administration of MIRA-55 on anxiety-related phenotypes in mice to model human conditions. An intraperitoneal
injection of Placebo [PBO] (e.g. saline) or MIRA-55 (e.g. 50mg/kg = Treatment) was administered to C57Bl/6 mice (n=5/group) that were
8-12 weeks old. Thirty minutes following injection, mice were tested in anxiety related measures using the Elevated Plus Maze (EPM).
The EPM is a widely used pre-clinical behavioral assay for rodents and it has been validated to assess the anti-anxiety effects of pharmacological
agents. If determined and approved by the FDA or other regulatory agencies, MIRA-55 appears to have anti-anxiety effects at doses that
lacked side effects of sedation or intoxication in mice. The EPM is a test measuring anxiety in rodents as a screening test for putative
anxiolytic compounds and as a general research tool in neurobiological anxiety research such as Generalized Anxiety Disorder (or GAD)
or Post-Traumatic Stress Disorder (or PTSD). The model is based on the animal’s aversion to open spaces which are present in the
open arms (Open Arm) of the maze. Anti-anxiety effects of test agents are demonstrated by an increase in the percentage of time spent
in the Open Arm with treatment compared to placebo. The total distance traveled is a measure of the overall level of arousal and mobility
of the mice undergoing testing on the EPM and is used to rule out any sedating or intoxicating effects of the test agent.
Pre-clinical
studies also have shown the potential of MIRA-55 for relieving pain. A number of clinically approved pharmacological agents used to treat
pain, including opioids, have been demonstrated to delay or ameliorate the onset of heat sensitivity upon paw exposure of mice to heat.
Thirty minutes after treatment with either a placebo (control) or MIRA-55, mice were placed on a heated plate to measure the time it
took for each mouse to lift its paw in response to the mild pain they felt from the heat. Mice treated with pain alleviating drugs took
significantly longer to become bothered by the heat and to lift their paws. Similarly, mice treated with MIRA-55 statistically took significantly
more time to lift their legs, indicating MIRA-55’s potential effectiveness as a possible treatment for pain in this model. If approved
by the FDA, MIRA-55 may potentially provide therapeutic effects for pain control.
MIRA-55
is a CB2 agonist which may also be an optimal treatment for neurodegenerative diseases associated with neuroinflammation caused by microglial
activation. CB2 agonism has been shown in pre-clinical studies to regulate neuroinflammatory processes, reducing the neuronal damage
characteristic of degeneration. We believe there may be a strong rationale for CB2 agonism in neurodegenerative diseases, given increased
CB2 expression in patients with these diseases as well as preliminary results from animal models. We see potential for a potent CB2 agonist
to treat a range of neurodegenerative diseases. MIRA-55, through its robust activity at CB2 compared to CB1, was designed to minimize
the risk of psychotropic adverse events associated with CB1 activation. If approved by the FDA, MIRA-55 may potentially provide therapeutic
effects for neurodegenerative and neuroinflammatory illnesses.
Our
pre-clinical development program for MIRA-55 has included a variety of testing. Summarized below are the tests we have completed. Our
interpretation of results derived from pre-clinical data or our conclusions based on our pre-clinical data may prove inaccurate and are
not necessarily predictive indicators of future results. See the section below titled “Research and Testing to Date –
MIRA-55” for more information.
Our
MIRA-55 Clinical Development Program
Following
the pre-clinical development plan outlined above, we plan to submit to the FDA an Investigational New Drug application (or IND) focused
on investigating MIRA-55 for the treatment of anxiety and cognitive decline in elderly patients.
We
expect that our first IND application submission relating to MIRA-55 for the treatment of elderly patients suffering from anxiety with
some cognitive decline is currently planned for the end of the second quarter of 2025, as we believe this is a patient population with
unmet needs. If allowed to proceed by the FDA, a Phase I trial will be initiated 30 days post-IND submission. We expect that our second
IND for MIRA-55 will focus on investigating MIRA-55 for the treatment of neuropathic pain.
All
development plans depend on FDA acceptance of our IND applications. As appropriate and pursuant to discussions with the FDA, we may periodically
adjust the timeline for certain filings and associated clinical trials. It is important to note that the process for conducting clinical
trials is uncertain and there is no assurance that our clinical development activities will meet the planned timelines set forth above.
Our
Market Opportunity and Market Advantage
Ketamir-2
Ketamir-2’s
market opportunity and market advantage was analyzed by IQVIA who were contracted to perform an independent Market Characterization and
Drug Valuation Analysis. TRD and MDSI indications represent areas of high unmet medical need, with significant disease burden and limited
effective treatments available. Ketamir-2’s formulation as a once-daily oral medication addresses shortcomings in existing treatments,
such as route of administration (RoA) and time to effectiveness.
The
market opportunity for Ketamir-2 is substantial. Based on the IQVIA analysis, the U.S. has a large patient pool looking for effective
treatments, with diagnosed prevalence rates of 3.1% for MDSI and 2.4% for TRD, translating to total addressable populations of 4.9 million
and 3.8 million patients respectively. Based on total estimates of MDSI and TRD together, this represents a Total Diagnosed Prevalence
rate of 12.3 million patients and, assuming a Treatment Rate of 65%, the Total Addressable Population is 8.7 million patients This represents
a significant market, especially considering the current limitations and side effects associated with existing treatments.
Figure:
Estimates by IQVIA of the total addressable populations affected with MDSI and TRD.
Ketamir-2’s
market advantage lies in its novel profile and potential to address these unmet needs. As a synthetic ketamine derivative, we believe
it potentially offers an improved mechanism to treat disease, building on the success of existing marketed therapeutics but with differences
to the base molecules that potentially reduce unwanted side effects. Ketamir-2’s oral formulation is being developed to potentially
not require health care professional supervision, potentially improving patient compliance and ease of use.
Figure:
Summary of assessment by IQVIA of valuation of Ketamir-2, including the background, commercial opportunity, and drivers of valuation
assessment.
The
projected addressable market for Ketamir-2 are promising. If approved by the FDA and deemed safe, peak annual net sales in the U.S. are
estimated to potentially reach approximately $3 billion across both MDSI and TRD, with a base case eNPV (expected net present value)
of around $92 million. In the high case scenario, the unadjusted peak revenue opportunity could go up to about $7.8 billion by 2035,
with the eNPV potentially reaching $324 million. The estimated patient pool for Ketamir-2 treatment may reach approximately 0.2 million
patients in the U.S. by 2036. The NPV (net present value) ranges from approximately $270 million to $4.6 billion, with the base case
being around $1.4 billion.
Figure:
Actual valuation of Ketamir-2 over time, including base and peak revenue opportunities in the US.
These
estimates are based on several key assumptions, including the market share Ketamir-2 might achieve, the years to peak sales, gross price
per dose, and the Probability of Technical & Regulatory Success (PTRS). Feedback from key opinion leaders (KOLs) and payors suggests
that there is a significant unmet need in behavioral health, particularly for treatments like Ketamir-2 with fewer adverse effects and
more consistent outcomes. However, issues such as pricing, insurance coverage, and potential DEA scheduling are important considerations
that could affect Ketamir-2’s market penetration.
As
such, we believe Ketamir-2 presents a significant market opportunity in the treatment of TRD and MDSI, with the potential in the PTSD
market, offering a novel approach with potential advantages over existing therapies in terms of efficacy, safety, and patient compliance.
The financial outlook is positive, contingent upon successful market penetration and realization of its therapeutic potential.
MIRA-55
MIRA-55,
if approved, will compete in three key overlapping growth markets: the anxiety, cognitive decline (CNS/dementia), and neuropathic pain
markets where multiple products with varying safety and efficacy profiles are already on the market. MIRA-55 competes at the intersection
of these three markets given the target patient profile for MIRA-55.
MIRA-55
will compete primarily within the CNS market that encapsulates anxiety, dementia, other pain, Alzheimer’s, migraines and related
conditions. Based on the market size of the CNS opportunity as set forth in IQVIA’s Global Use of Medicines 2023 analysis (the
“IQVIA Report”), we estimate that by 2027, the U.S. CNS market will be worth $48 billion, growing between two and five percent
during the period from 2023 to 2027. Within that market opportunity, anxiety is worth between approximately $10 billion and $15 billion
in annual sales. If approved by the FDA, MIRA-55 may potentially provide therapeutic effects for anxiety, dementia and pain.
Anxiety
and pain are expected to grow approximately five percent over the same period according to the IQVIA Report, while Alzheimer’s
is expected to grow approximately twelve percent. This is critical given MIRA-55’s focus on early-stage patients with dementia,
as according to the Alzheimer’s Association 2023 Alzheimer’s Disease Facts and Figures analysis (the “Alzheimer
Association”), 500,000 new Alzheimer cases emerge in the U.S. each year. According to the Alzheimer Association, about 60 to 80
percent of Alzheimer cases evolve into dementia. Thus, Alzheimer case directions are an important signal and gateway for MIRA-55-related
opportunities in dementia. Based on that epidemiology, the U.S. Center for Disease Control (“CDC”) estimates that approximately
5.8 million Americans are living with Alzheimer’s, with that number expected to grow to 14 million by 2060 (“CDC Alzheimer”).
MIRA-55’s
other key market will be the neuropathic pain market. Developing targeted and efficient therapies for neuropathic pain stands as a priority
to address this common source of suffering and morbidity. Innovative strategies are under exploration to tackle the distinctive challenges
posed by this type of pain. According to the International Association for The Study of Pain, neuropathic pain affects approximately
7-10% of the world’s population. Examples include diabetic peripheral neuropathy, postherpetic neuralgia, and multiple sclerosis
related neuropathy.
Our
initial focus will be a dual path: potentially winning in traditional markets as well as the marijuana analog markets using a safe, effective
and, if determined by the FDA, an FDA-approved treatment option since safety and efficacy determinations are in the exclusive purview
of the FDA. According to Grandview Research, today, legal medical marijuana is a $11.6 billion industry whereas legal recreational marijuana is a $26.9
billion industry. Both are sub-sets of the traditional pain and anxiety markets. However, in many patient populations, non-U.S. legal,
and cultural settings, marijuana may not be the first or a viable option for treatment of neurological disorders. As a result, these
patients will typically use non-steroidal anti-inflammatory drugs (NSAIDs) or various mood management drugs, opening them up to a range
of non-ideal outcomes. The objective of MIRA-55 is to offer physicians and patients an approved, viable synthetic option. Thus, if approved
by the FDA, we believe that MIRA-55 may potentially provide a preferred alternative in such patient populations, as it is not derived
from the marijuana plant.
MIRA-55
is being developed as the first manufactured prescription drug to potentially target the CB1 and CB2 receptors for neuropathic pain and
anxiety without the impurities of marijuana or its side effects, such as increased appetite and paranoia. MIRA-55 has demonstrated the
ability to rapidly and significantly improve cognitive performance with acute use—i.e. doubling cognitive performance after a single
dose in normal mice MIRA-55 is a novel synthetic cannabinoid analog directed at potentially treating patients with dementia associated
cognitive decline and anxiety diagnoses. Unlike other cannabinoids in the market, MIRA-55 is not derived from plants. Plants generate
alkaloids as a defense mechanism, and it has been speculated that plant-derived cannabinoids have adverse side effects in humans.
Furthermore,
in animal studies conducted by us, MIRA-55 has preliminarily demonstrated more than 30-fold increased CB2 activation compared to CBD.
Our
Strategy
Ketamir-2
The
goal is to continue develop Ketamir-2 as an orally administered medication with potentially fewer side effects, free from the restrictions
such as those imposed by ketamine’s REMS, to fill the current clinical need for a rapid acting antidepressant to manage TRD and
MDSI in patients who are able to take Ketamir-2 at home. The strategic plan for Ketamir-2’s development encompasses several critical
stages, from scaling up manufacturing to exploring effective exit strategies.
Additionally,
the potential for an acquisition from a larger pharmaceutical company remains a viable exit strategy, especially if Ketamir-2 demonstrates
substantial promise.
Throughout
this process, it is crucial for us to maintain a robust intellectual property strategy, regularly assess the antidepressant market landscape,
especially for TRD, and engage with key stakeholders. Implementing a risk management plan is also essential to navigate potential development
and commercialization challenges. This strategic plan must be adaptable, capable of responding to new data, regulatory feedback, and
changes in the market. Regular assessments and checkpoints will ensure the project aligns with our strategic goals and the evolving landscape
of pharmaceutical development.
MIRA-55
Our
goal is to develop therapeutics targeting well-characterized CB1 and CB2 receptors with optimized pharmacological properties to transform
the lives of patients with neurological diseases. Key elements of our strategy to achieve this goal include:
Competition
Ketamir-2
The
principle competitor of Ketamir-2 is ketamine or ketamine analogs. Ketamine, originally known as a dissociative anesthetic, has emerged
as a significant breakthrough in the treatment of depression, particularly due to its rapid-acting antidepressant properties. The FDA
approved in 2019 esketamine delivered intranasal, developed by Janssen with the brand name Spravato. This has opened new avenues in psychiatric
treatment, especially for patients who do not respond to traditional antidepressants, have depression with suicidal ideation, or require
rapid antidepressant responses.
In
contrast to most novel antidepressants, which are multi-billion dollar drugs annually, for 2023 Janssen reported $683 million in revenue
from Spravato. We believe the primary reason for Spravato’s revenue performance versus other antidepressants is because Spravato’s
REMS requires Spravato to be patient administered but clinician observed for 2 hours, with the patient unable to drive for the rest of
the day. As described further below, we believe this presents challenges for both patients and clinicians, which has restricted the use
of this form of ketamine from patients who would benefit from this treatment (e.g. those with TRD and MDSI). Ketamir-2, if ultimately
FDA approved without the requirement of a REMS, could potentially avoid these challenges.
Niche
Filled by ketamine
Limitations
of ketamine Due to Side Effects
Requirements
of ketamine under the REMS (Risk Evaluation and Mitigation Strategy)
The
use of ketamine, especially Esketamine (a nasal spray form of ketamine approved for treatment-resistant depression), is regulated under
the Risk Evaluation and Mitigation Strategy (REMS) program to ensure safe use:
Ketamine’s
possible role as a rapid-acting antidepressant could fill a crucial niche in the management of treatment-resistant depression and acute
suicidality. However, its potential use is tempered by significant side effects and the stringent requirements of the REMS program, which
necessitate careful patient selection and monitoring to optimize safety and efficacy.
The
finding of up to 80% oral bioavailability with the potential for decreased abuse liability (e.g. because of the lack of opiate agonist
activity) and potentially decreased side effects (e.g. fewer dissociative experiences and less hypertension) puts Ketamir-2 in a situation
to potentially offer the same antidepressant effects but with fewer restrictions, perhaps even permitting patients to take it orally
at home.
MIRA-55
We
are subject to competition from pharmaceutical and biotechnology companies and academic and research institutions. We believe our future
success will depend, in large part, on our ability to maintain a first mover advantage and competitive lead in our industry.
Competition
arises mainly from two sources, traditional cell-based in vitro culture approaches and traditional in vivo animal models and testing.
We also face future competition from companies developing cannabinoid therapies, as summarized in the table below:
Sativex
(delta-9-tetrahydrocannibinol and cannabidiol in the EU) is an oromucosal spray indicated as treatment for symptom improvement in adult
patients with moderate to severe spasticity due to multiple sclerosis (MS) who have not responded adequately to other anti-spasticity
medication and who demonstrate clinically significant improvement in spasticity related symptoms during an initial trial of therapy.
Sativex is not assigned a schedule in the U.S. by the DEA as it is not approved but is a Class B controlled drug under the Misuse of
Drugs Act 1971 and is placed in Schedule 4 to the Misuse of Drug Regulations 2001 in the United Kingdom.
Marinol
(dronabinol) is an oral cannabinoid indicated in adults for the treatment of: Anorexia associated with weight loss in patients with AIDS
and nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic
treatments. Marinol is a Schedule III controlled substance.
Cesamet
(Nabilone) is a synthetic cannabinoid for oral administration that are indicated for the treatment of the nausea and vomiting associated
with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments. Cesamet contains nabilone,
which is a controlled in Schedule II of the Controlled Substances Act (CSA).
Research
and Testing to Date
Ketamir-2
Preclinical
Research Findings
In
Silico Analysis of Targets of Ketamir-2 vs ketamine
In
silico analysis, referring to computer-based techniques, has become an integral part of pharmaceutical research and development.7
This approach utilizes computational methods to analyze and predict the properties and behaviors of pharmaceutical compounds. The
use of in silico analysis is especially crucial in the early stages of drug development, as it aids in identifying potential drug targets
and elucidating differences between a new drug and its parent compound. By analyzing large datasets, such as genomic, proteomic, and
metabolomic data, researchers can predict how different compounds might interact with various biological targets. This approach helps