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 June 30, 2025
OR
☐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: 001-39685
INMED
PHARMACEUTICALS INC.
(Exact
name of registrant as specified in its charter)
Suite 1445, 885 West Georgia St., Vancouver, British Columbia, Canada V6C 3E8
(Address of principal executive office) (Zip Code)
(604)669-7207
(Registrant’s
telephone number, including area code)
Securities
registered pursuant to Section 12(b) of the Exchange Act:
Title of Each Class Trading Symbol Name of Each Exchange On Which Registered
Common Stock, no par value INM 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 Exchange 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 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 emerging growth company. See the definitions of “large accelerated filer,” “accelerated filer” and
“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 fi led 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 fi rm 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
included 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 ☒
As
of December 31, 2024, the last business day of the Registrant’s most recently completed second fiscal quarter, the aggregate market
value of the Company’s voting and non-voting common equity held by non-affiliates of the Registrant was $3,316,582.
On
September 17, 2025, there were 2,384,186 shares of the registrant’s common shares, no par value, outstanding.
DOCUMENTS
INCORPORATED BY REFERENCE
Portions
of the registrant’s definitive proxy statement for the registrant’s 2024 Annual Meeting of Stockholders to be filed pursuant
to Regulation 14A within 120 days of the registrant’s fiscal year ended June 30, 2025 are incorporated herein by reference into
Part III of this Annual Report (as defined below).
InMed
Pharmaceuticals Inc.
TABLE
OF CONTENTS
Page
Part I 1
Item 1. Business 3
Item 1A. Risk Factors 27
Item 1B. Unresolved Staff Comments 66
Item 1C. Cybersecurity 66
Item 2. Properties 67
Item 3. Legal Proceedings 67
Item 4. Mine Safety Disclosures 67
Item 6. [Reserved] 68
Item 7A. Quantitative and Qualitative Disclosures About Market Risk 82
Item 8. Financial Statements and Supplementary Data F-1
Item 9A. Controls and Procedures 83
Item 9B. Other Information 84
Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevents Inspections 84
Part III 85
Item 10. Directors, Executive Officers and Corporate Governance 85
Item 11. Executive Compensation 85
Item 14. Principal Accounting Fees and Services 85
Item 15. Exhibits and Financial Statement Schedules 86
Signatures 89
i
PART
I
Special
Note Regarding Forward-Looking Statements
This
Annual Report on Form 10-K (this “Annual Report”) contains “forward-looking statements” within the meaning of
United States Private Securities Litigation Reform Act of 1995 and “forward-looking information” within the meaning of applicable
Canadian securities law, which are included but are not limited to statements with respect to InMed Pharmaceuticals Inc.’s (the
“Company” “InMed”, “we”, “our”, or “us”) anticipated results and progress
of our operations, research and development in future periods, plans related to its business strategy, and other matters that may occur
in the future. These statements relate to analyses and other information that are based on forecasts of future results, estimates of
amounts not yet determinable and assumptions of management. We may, in some cases, use words such as “anticipate”, “believe”,
“could”, “estimate”, “expect”, “intend”, “may”, “plan”, “predict”,
“project”, “will”, “would”, “budget”, “possible”, “should”, “future”,
and similar expressions that convey uncertainty of future events or outcomes to identify these forward-looking statements. These forward-looking
statements reflect our current views with respect to future events and are based on assumptions and subject to risks and uncertainties.
You should not place undue reliance on these forward-looking statements. Any statements contained herein that are not statements of historical
facts may be deemed to be forward-looking statements. Our actual results could differ materially from those anticipated in these forward-looking
statements. Among the factors that could cause actual results to differ materially are the risks and uncertainties described under “Item
1A. Risk Factors” of this Annual Report, “Item 7. Management’s Discussion and Analysis of Financial Condition
and Results of Operations” of this Annual Report, and the following:
1
● Our ability to develop our therapies through early human testing;
● Our ability to successfully file, prosecute and defend patent applications;
2
● Our ability to effectively execute our business strategy;
● Consolidation of our competitors and suppliers;
This
list is not exhaustive of the factors, events, conditions and circumstances that may affect the “forward-looking statements”
and “forward-looking information” contained in this Annual Report. Although we have attempted to identify important factors
that could cause actual results to differ materially from those described in forward-looking statements, there may be other factors that
cause results not to be as anticipated, estimated or intended. Should one or more of these risks or uncertainties materialize, or should
underlying assumptions prove incorrect, actual results may vary materially from those anticipated, believed, estimated, or expected.
Moreover, new risks regularly emerge, and it is not possible for our management to predict or articulate all risks we face, nor can we
assess the impact of all risks on our business or the extent to which any risk, or combination of risks, may cause actual results to
differ from those contained in any forward-looking statements, which differences could be material. We caution readers not to place undue
reliance on any such forward-looking statements, which speak only as of the date made and are based only on the information available
to us at that time. Except as required by law, we disclaim any obligation to subsequently revise any forward-looking statements to reflect
events or circumstances after the date of such statements or to reflect the occurrence of anticipated or unanticipated events. We qualify
all of our forward-looking statements by these cautionary statements.
ITEM
1. BUSINESS
All
dollar amounts stated herein are in U.S. dollars unless specified otherwise.
Overview
We
are a pharmaceutical company developing a pipeline of proprietary small molecule drug candidates that are preferential signaling ligands
of the endogenous CB1 and CB2 receptors as well as other receptor targets linked to human disease. CB1 and CB2 receptors are each part
of the endocannabinoid system that is found throughout the human body and is responsible for many homeostatic functions. CB1 receptors
are primarily located in the brain and central nervous system, while CB2 receptors are involved in modulating neuroinflammation and immune
responses. Our research efforts target the treatment of diseases with high unmet medical needs. Together with our wholly owned subsidiary,
BayMedica, LLC, or BayMedica, we also have significant know-how in developing proprietary manufacturing approaches to produce and sell
bulk rare cannabinoids as ingredients for various market sectors.
We
have sought to focus on the research and development of preferential signaling ligands of CB1 and CB2, and have produced a library of
novel, proprietary drug candidates, or Product Candidates. These Product Candidates are patentable new chemical entities, or NCEs, for
pharmaceutical development, aimed at targeting diverse clinical indications. Our current potential pharmaceutical pipeline consists of
three programs, with drug candidates targeting Alzheimer’s disease, dry Age-Related Macular Degeneration, or dry AMD, and Epidermolysis
Bullosa, or EB.
3
Our
INM-901 is a proprietary small molecule, disease modifying drug candidate being developed as a potential treatment for Alzheimer’s
disease. INM-901 has multiple potential mechanisms of action as a preferential signaling agonist for both CB1 and CB2 receptors, as well
as impacting the peroxisome proliferator-activated receptor, or PPAR, signaling pathway. Combined, these mechanisms of action may offer
a unique treatment approach targeting several biological pathways associated with Alzheimer’s disease.
Outcomes
from our ocular research, based on the proprietary small molecule INM-089, indicate potentially promising neuroprotective effects in
the back of the eye, which may lead to the preservation of retinal function. Neuroprotection in dry AMD remains an unmet medical need
and a new treatment option may help solve this multifactorial disease.
We
have completed a Phase 2 clinical trial of INM-755 (cannabinol) cream studying its safety and efficacy in treating symptoms related to
EB. Results from the Phase 2 clinical trial showed a positive indication of enhanced anti-itch activity for INM-755 cream versus the
control cream alone in an exploratory clinical evaluation. We are also pursuing strategic partnership opportunities for INM-755 in EB
and other itch-related skin conditions.
Together
with BayMedica, our manufacturing capabilities include traditional approaches such as chemical synthesis and biosynthesis, as well as
a proprietary, integrated manufacturing approach called IntegraSyn. With multiple manufacturing approaches, we have sought to maintain
enhanced flexibility to select the most cost-effective method to deliver high quality, high purity Products and Product Candidates fit
for their intended uses. BayMedica’s commercial business specializes in the B2B commercialization of bulk rare, non-intoxicating
cannabinoids as raw materials for the Health and Wellness sector that are bioidentical to those found in nature.
Corporate
Information
We
were originally incorporated in the Province of British Columbia, under the Business Corporations Act (British Columbia) (the
“BCBCA”), on May 19, 1981 (the “Incorporation Date”), and we have undergone a number of executive management,
corporate name and business sector changes since such Incorporation Date, ultimately changing our name to “InMed Pharmaceuticals
Inc.” on October 6, 2014. Our principal executive offices are located at Suite 1445, 885 West Georgia Street, Vancouver, BC, V6C
3E8 and our telephone number is +1-604-669-7207. Our website is https://www.inmedpharma.com/. The information that is contained on, or
that may be linked to or accessed through our website, is not incorporated, in whole or in part, into this Annual Report in any respect.
We have included our website address in this Annual Report solely as an inactive textual reference.
Employees
and Human Capital
Our
management team is comprised of highly experienced pharmaceutical and biotechnology executives with successful track records in researching,
developing, gaining approval for and commercializing novel medicines to treat serious diseases. Each member of our management team has
20 to 30+ years of industry experience, including our Chief Executive Officer (“CEO”), Chief Operating Officer (“COO”),
Chief Financial Officer (“CFO”), General Manager and VPs of Preclinical Drug Development, Discovery Research, Chemistry,
Synthetic Biology and of Sales & Marketing. Together, this management team has covered the spectrum of pharmaceutical drug discovery,
preclinical research, formulation development, manufacturing, human clinical trials, regulatory submissions and approval, and global
commercialization of pharmaceutical and wellness products. Additionally, the management team has significant experience in company formation,
capital raises, mergers and acquisitions, business development, and sales and marketing in the pharmaceutical and other industries. Our
Board is constituted of individuals with significant experience in the pharmaceutical and biotechnology industries. As of September 12,
2025, inclusive of our management team, we had 13 full-time employees, and we also utilize the services of several consultants. None
of our employees are represented by a collective bargaining agreement, nor have we experienced any work stoppage. We believe that we
maintain strong relations with our employees.
4
We
are committed to growing our business over the long-term. As a result of the competitive nature of the industry in which we operate,
employees have significant career mobility and opportunity, and as a result, the competition for experienced employees is great. The
existence of this competition, and the need for talented and experienced employees to realize our business objectives, underlies the
design and implementation of our compensation programs. At the same time, we seek to keep our approach to compensation simple and streamlined
to reflect the still relatively moderate size of the Company. We have, therefore, implemented compensation, leave and benefits programs
necessary to attract and retain the talented and experienced employees necessary to develop our business, including what we believe to
be competitive salaries, stock options awards to permanent employees (both upon initial hiring and on an annual basis thereafter), and
pay annual bonuses to permanent employees contingent on the achievement of corporate and/or personal objectives. We have developed an
Employee Handbook that contains all corporate policies and guidelines for professional behavior. Our policies and practices apply to
all employees, regardless of title. These guidelines include, among others, our Code of Business Conduct as well as our policies for
corporate disclosure, insider trading and whistle blower, all of which are posted on our website.
For
all current and future pharmaceutical Product Candidates we intend to submit new drug applications (“NDAs”) (or their international
equivalents) in most major jurisdictions, including the United States, either alone or with development/commercial partners.
Our
Business Strategy
Our
goal is to develop a pipeline of prescription-based Product Candidates targeting treatments for diseases with high unmet medical needs.
These
activities are at various stages of development, including, with INM-901 (for the treatment of Alzheimer’s disease), INM-089 (for
the treatment of dry AMD) and INM-755 (for the treatment of symptoms related to EB). We have the internal capabilities to design and
execute, together with multiple external vendors, the preclinical experimentation and clinical studies required to advance pharmaceutical
drug candidates towards commercialization.
We
do not currently have an internal organization for the sales, marketing and distribution of pharmaceutical products. With respect to
the commercialization of each Product Candidate, we may therefore rely on (i) a “go-it-alone” commercialization effort; (ii)
out-licensing to third parties; or, (iii) co-promotion agreements with strategic collaborators for our Product Candidates. The decision
to pursue a “go-it-alone” commercialization effort versus out-licensing to third parties will depend on various factors including,
but not limited to, the complexity of the Product Candidate and process, the expertise required and related cost of building any such
infrastructure for our Product Candidates. For INM-755 in EB, further advancement is contingent on identifying drug development and commercial
partnerships. The optimal commercial strategy for the INM-901 and INM-089 compounds will be evaluated in due course.
5
Our
Strengths
We
are a pharmaceutical drug development company as well as a developer and supplier of rare, naturally occurring cannabinoids that is focused
on commercializing important medicines to treat diseases with high unmet medical needs. Our key strengths include the following:
Experienced
executive team and board of directors with proven track records.
One
key critical success factor in the field of pharmaceutical drug development is the experience and skill set of the individuals leading
us. We have been successful in attracting and retaining executive and directors with extensive experience in all facets of the pharmaceutical
industry, including fundamental research and development, multiple manufacturing techniques, drug formulation, clinical trial execution,
regulatory approvals, pharmaceutical commercialization, company and capital formation, business development, legal, and corporate governance.
Our leadership team is well-poised to lead us through all facets of drug development and product commercialization, either internally
or externally via partnerships. It is this group of individuals that will help optimize our chances for success.
Scope
of research and robust pharmaceutical pipeline
Over
several years of dedicated research, we have built a robust pipeline of drug development candidates, including two preclinical programs
targeting Alzheimer’s (INM-901) and ocular diseases (INM-088 for glaucoma and INM-089 for AMD), as well as a completed Phase 2
study in dermatology (INM-755). The INM-089 and INM-901 preclinical programs offer a differentiated treatment approach using proprietary,
disease-modifying small molecules that target the CB1 and CB2 receptors, which management believes is a key strength of the Company.
Multiple
manufacturing approaches.
Our
management team believes that our combined manufacturing technologies provide us with a competitive advantage to utilize the most cost-efficient
methodology (i.e. chemical synthesis, biosynthesis and IntegraSyn) for the development and commercialization of new Products and Product
Candidates to a wide spectrum of market opportunities.
Early
mover status as a B2B supplier of non-intoxicating rare cannabinoids to the health and wellness sector.
As
demonstrated by the launch of several non-intoxicating rare cannabinoids into the health and wellness sector, the team at BayMedica has
substantial expertise in the commercial manufacturing scale-up to produce rare cannabinoids at large scale as well as extensive sales
and marketing expertise. This know-how is important to establishing an early-mover status and to maintain cost leadership with regards
to specific rare cannabinoids.
Diverse
portfolio of patent applications covering a spectrum of commercial opportunities.
Success
in pharmaceutical markets often rests with the strength of intellectual property, including patents, to protect our commercialization
interests. We have filed several patents on our novel findings and expect to continue to do so. The acquisition of BayMedica brought
several additional new patent families to bolster our manufacturing as well as drug development opportunities.
Research
and Development Pipeline of Therapeutic Drug Candidates
INM-901
for the Treatment of Alzheimer’s Disease (“AD”)
Traditionally,
Alzheimer’s disease has been defined by the buildup of amyloid beta (“Aβ”) plaques and neurofibrillary, also referred
to as tau protein, tangles within the brain, making it a central focus of neurological research for many years. However, more recently,
other factors such as neuroprotection and synaptic dysfunction are being recognized as contributors to disease progression.
6
Our
early research demonstrating the neuroprotective capabilities of CB1 and CB2 agonists in the eye led us to investigate how such molecules
might play a role in protecting other neurons in the human body, potentially, impacting different diseases. To this end, we initiated
research on the neurons that are associated with the brain and how our proprietary CB1 and CB2 agonist drug candidates could affect neurodegenerative
diseases such as Alzheimer’s, Parkinson’s, and Huntington’s. In October 2023, InMed announced it had selected and would
be advancing a lead AD drug candidate, named INM-901, following positive results from several proof-of-concept studies. INM-901 is a
proprietary small molecule drug candidate. which, based on preclinical studies in well-characterized AD study models, may address multiple
pathologies related to AD progression. In these preclinical study models, INM-901 demonstrated neuroprotective effects, statistically
significant reduction in neuroinflammation, the ability to extend the length of neurites signifying enhanced neuronal function, and improvement
in behavior, cognitive function and memory. These early studies show the potential of INM-901 to reverse neuronal damage from AD and
potentially provide disease-modifying effects.
As
a small molecule compound, INM-901 may offer various modes of administration including oral delivery, which could overcome several limitations
associated with currently approved antibody therapies for AD, such as the high drug expenses, complicated and inconvenient drug administration
and its associated compliance and accessibility challenges.
INM-901’s
innate ability to safely cross the blood-brain barrier, promising preclinical studies, multifactorial mechanism of action and small molecule
profile offer a potentially attractive treatment option for AD.
Alzheimer’s
Disease Prevalence and Impact – A Major Medical and Societal Burden
Alzheimer’s
disease is a progressive neurodegenerative condition that predominantly afflicts the elderly, resulting in severe cognitive impairments.
It is a subset of dementia that impacts the part of the brain that controls memory and language and leads to increased morbidity and
mortality.
According
to the U.S. Alzheimer’s Disease Association, AD accounts for 60-80% of dementia cases and is the fifth leading cause of death for
people aged 65 and older. It’s estimated that 6.9 million Americans are living with AD, and it’s expected to grow to 12.7
million by 2050. About 1 in 9 people aged 65 and older has AD (10.7%), affecting 1 in 5 women and 1 in 10 men in their lifetime.
The
disease has a major medical and societal burden with health and long-term care costs valued at $360 billion. In addition to the cost
to the healthcare system, it’s estimated 11 million Americans are providing 18.4 billion hours of unpaid care valued at $350 billion
for people living with AD or other dementias, making it one of the costliest diseases to society.
Additionally,
the emotional and mental health burden on patients and their caregivers cannot be overstated.
Pathology
of Alzheimer’s disease
Alzheimer’s
disease is a complex neurodegenerative disease with multiple pathologies leading to its development and progression. Hallmarks of the
disease point to the toxicity and disruption of proteostasis caused by misfolded amyloid beta protein and neurofibrillary tangles or
tau tangles. Amyloid-beta is a naturally occurring protein in the brain, but when abnormal levels of amyloid-beta clump together to form
plaques, it causes damage to neuronal cell function resulting in AD.
The
focus of Alzheimer’s research has been traditionally centered around amyloid-beta plaques and tau protein, which play a crucial
role in stabilizing microtubules within neurons, supporting their structure and function. Increased activity of enzymes called tau kinase
causes the tau protein to misfold and clump, creating neurofibrillary tangles which disrupt the normal functioning of neurons. The stage
and severity of AD is associated with an abundance of tau tangles.
In
addition to these two aspects of Alzheimer’s disease, neuroinflammation and synaptic dysfunction are also recognized as contributors
to AD progression. Microglia, the brain’s immune cells, are involved in the removal of amyloid-beta and has been a focus of research
in neuroinflammation. Therapies targeting the modulation of microglial activity aim to reduce inflammation and protect neurons.
7
Examples
of Current treatments in Neurodegenerative Diseases
Brand Company Mechanism of Action Status
Remternetug (LY3372993) Eli Lilly Anti-tau, O-GlcNAcase Inhibitor Phase 3
BIIB080 Biogen Anti-Tau, antisense oligonucleotide (ASO) Phase 2
Semorinemab Genentech Anti-tau Phase 2 Failed
Currently
approved medications for AD generally fall into two main categories. The first category comprises drugs designed to address symptoms
related to memory and cognitive function. While these medications cannot halt the damage that AD inflicts on brain cells, they can help
alleviate or stabilize symptoms for a limited duration by influencing specific chemicals responsible for transmitting messages between
nerve cells in the brain. Essentially, these medications are aimed at preserving neurotransmitters. However, they do not replace the
deteriorating ones and thus do not impede the disease’s progression.
Until
recently, cholinesterase inhibitors and glutamate regulators were the only treatments available to people living with AD. These drugs
are intended to improve cognitive and behavioral symptoms and do not address the prevention or progression of the disease.
In
recent years, there has been a growing emphasis on developing disease-modifying treatments that target the underlying biology of AD.
One major focus of these research and development endeavors has centered on addressing the accumulation of amyloid plaques and the removal
of both these plaques and tau proteins. This approach aligns with the long-standing amyloid hypothesis, which posits that AD is triggered
by the buildup of (Aβ) in the brain. This accumulation leads to neuronal toxicity within the central nervous system, disrupting
neuronal and synaptic function, ultimately culminating in neuronal degeneration and cell death.
Since
2021, three disease-modifying treatments have been approved for the treatment of mild cognitive impairment due to Alzheimer’s disease.
All three treatments primarily address symptoms related to memory and cognitive function via the reduction of beta-amyloid plaques. AduhelmTM,
the first of these drugs to be approved by the FDA has since been discontinued by Biogen. These disease-modifying medications are aimed
at removing amyloid plaque build-up between the neurons in the brain; however, they do not restore or rebuild deteriorating neurons and
thus do not reverse Alzheimer’s disease progression. In addition, these treatments are related to some significant side effects,
including amyloid-related imaging abnormalities (“ARIA”) with edema (brain swelling), requiring brain scans once or twice
a year. The administration of these treatments, which include an intravenous infusion every 2-4 weeks, also presents a challenge.
Role
of CB1 and CB2 Agonists in Alzheimer’s disease:
Numerous
studies have indicated dysregulation of the Endocannabinoid System (“ECS”), which encompasses receptors, endocannabinoids,
and synthesizing/metabolizing enzymes, in various neurodegenerative conditions, notably AD. These investigations have unveiled the potential
of CB1 and CB2 agonists, both endogenous and synthetic, in mitigating the harmful effects of AD pathology. These CB1 and CB2 agonists
have been suggested to diminish Aβ toxicity, reduce tau hyper-phosphorylation, and suppress neuroinflammatory responses while curbing
the production of reactive oxygen species (“ROS”). As a result, they may enhance the survival of neurons in the aftermath
of Aβ aggregation.
8
CB1
and CB2 agonists exert their biological effects through two primary membrane receptors, endogenous CB1 and CB2 receptors, which are widely
distributed in the central nervous system and peripheral tissues. Activation of CB1 has demonstrated its ability to alleviate neurotoxicity
in various AD models. Conversely, CB2 agonism and increased expression have been associated with the removal of Aβ by macrophages.
The
precise molecular mechanisms responsible for safeguarding specific neuronal populations remain elusive. However, several observations
support this concept:
a)
CB1 and CB2 agonists possess a capacity to exert broad effects on multiple molecular targets, including critical brain structures and
behavior;
b)
CB1 and CB2 agonists act not only through ECS receptors but also interact with other non-ECS receptors such as transient receptor potential
vanilloid 1, peroxisome proliferator-activated receptors (“PPARs”), and transcription factors such as nuclear factor kappa-light-chain-enhancer
of activated B cells (“NFkB”); and
c)
CB1 and CB2 agonists exhibit anti-inflammatory properties, modulate neurotransmitter release, and limit oxidative stress, collectively
contributing to the enhancement of neuronal viability.
AD
is a progressive neurodegenerative condition primarily driven by the toxicity and disruption of proteostasis caused by misfolded Aβ
protein. CB1 and CB2 agonists have emerged as promising agents capable of preserving neuronal integrity and functionality, offering a
potential strategy to slow down disease progression and enhance the quality of life for affected individuals. Furthermore, CB1 and CB2
agonists exhibit the capacity to mitigate neuroinflammation, shield against beta-amyloid-induced neurotoxicity, and mitigate neurodegeneration
in animal models of AD. Additionally, research has unveiled dysregulation of the ECS in the brains of AD patients, which could contribute
to the cognitive and behavioral symptoms associated with the disease.
INM-901
is highly lipophilic (dissolves in fats, oils and lipids) and can easily cross the blood-brain barrier, a capability that renders it
a promising candidate for pharmaceutical use in the treatment of neurological disorders.
The
use of CB1 and CB2 agonists in AD treatment holds great promise; however, further research is needed to fully understand the mechanisms
to develop safe and effective CB1 and CB2 agonists-based therapeutics.
INM-901:
A Multi-factorial Approach to Treating Alzheimer’s disease
While
progress has been made recently in the development of new treatments for AD, there are no treatments addressing the multiple aspects
of this complex disease such as neuroinflammation, neuroprotection, synaptic dysfunction or the restoration of the damaged neurons –
factors that may help to restore brain function loss or reverse the damage caused by AD.
Preclinical
studies indicate that INM-901 may target multiple biological pathways. InMed has conducted several in vitro and in vivo
studies to test the pharmacological effects of INM-901 in well-characterized AD preclinical models.
Figure
1. Multiple Mechanisms of Action
9
Figure
2. Neuroprotection of human neuronal cells
Phyto-cannabinoids
(“pCBx”) promote neuroprotection. (A) Amyloid peptide (Aβ, 5μM) induces cytotoxicity in SHSY5Y
cells. Aβ1-42 insult induced approximately ~45% cytotoxicity of the SH-SY5Y cells. (B) Concurrent exposure of Aβ
with pCBx at 5 μM and 10 μM concentrations protected cells from Aβ induced toxicity in a dose-dependent manner. Cell
viability was determined by MTT assay.
Figure
3. Neurogenesis of human neuronal cells
Cannabinoid
pCBx promotes neuritogenesis. Tuj1 Tubulins are building blocks of microtubules. As such, Tuj1 expression can reveal the fine
details of axonal structures and dendrites. Therefore, changes in Tuj1 expression can be directly correlated with neuronal health and
communication. (A) Photomicrographs illustrating Tuj1 expression in control and pCBx (5 and 10μM) treated cells. The formation
of extended neurites and arborization is evident upon pCBx treatment.
INM-901
demonstrates anti-inflammatory effects
Neuroinflammation
plays a key role in the progression of Alzheimer’s disease and is a hallmark of neurodegenerative disorders. INM-901 has demonstrated
the ability to reduce neuroinflammation in both in vivo and ex vivo models, reinforcing its potential as a disease-modifying
therapeutic candidate.
10
In
a long-term (seven-month dosing) in vivo study, INM-901 demonstrated statistically significant, dose-dependent reductions in several
pro-inflammatory cytokines in plasma, including tumor necrosis factor alpha (“TNF-α”), interleukin-1 beta (“IL-1β”),
and interferon gamma (“IFN-γ”). In addition, INM-901-treated groups showed reduced plasma levels of neurofilament light
chain (“NfL”), a biomarker associated with neurodegeneration. mRNA analysis from brain tissue revealed reduced expression
of glial fibrillary acidic protein (“GFAP”), CD-33, and Toll-like receptor 2 (“TLR-2”), all of which are associated
with neuroinflammatory responses in Alzheimer’s disease.
Further
supporting these findings, an ex vivo study using lipopolysaccaride (“LPS”)-induced inflammation in animal brain tissue
demonstrated that INM-901 significantly reduced the expression of NLRP3, a key inflammasome marker, as well as the cytokines IL-6, IL-1β,
IL-2 and KC/GRO. These anti-inflammatory effects were observed in a dose-dependent manner and were statistically significant. The data
support INM-901’s direct anti-inflammatory activity independent of amyloid-beta or tau-related pathology.
INM-901
shows behavioral improvements in in vivo models
INM-901
treatment in the well-established 5xFAD AD mouse model led to improvement in cognitive function and memory, locomotor activity, anxiety-based
behavior, and sound awareness. InMed’s most recent study evaluated INM-901 using a longer treatment duration and subjects with
more advanced disease to validate and expand upon previous findings, which have demonstrated improvements in cognitive function, anxiety-related
behavior, and sensory responsiveness.
Summary
of INM-901 Iong-term 5xFAD study:
INM-901
Interacts with Specific Receptors in the Brain
Studies
of INM-901 demonstrate activity as a preferential signaling ligand for CB1 and CB2 and impacts the peroxisome proliferator-activated
receptors (“PPAR”) signaling pathway. Research indicates that activating CB1 and CB2 receptors may induce neuroprotective
effects and may help to protect brain cells from damage and death. Enhancing the activity of these receptors may help to slow down the
progression of the AD, in which neuronal cell death is a hallmark. Moreover, the activation of these receptors, along with other cellular
receptors, has also been shown to have an impact on neuroinflammation. As neuroinflammation is believed to contribute to the progression
of AD, targeting these receptors could help alleviate this inflammatory response.
INM-901
is a Proprietary Small Molecule Compound
INM-901
is a small molecule compound, one of several cannabinoid analogs developed by our scientists. Cannabinoids are small molecules known
to be highly lipophilic and can safely cross the blood-brain barrier, enabling the potential therapeutic modulation of brain signaling
and making them promising pharmaceutical targets for neurological diseases such as AD.
Small
molecule drugs have several advantages that contribute to their widespread use. Those advantages include oral administration (making
it convenient for patients to comply), good bioavailability (allowing these compounds to be efficiently absorbed), ability to cross the
blood-brain barrier (enabling therapeutic modulation in brain signaling), stability in storage and transport (ease of drug handling and
dose adjustment) and low-cost manufacturing.
Key
Outcomes from INM-901 Studies
In
Vitro Studies
● Treated groups demonstrated dose- dependent cell survival and proliferation
11
In
Vivo Studies
● Showed a reduction in neurofilament light chain, marker of cellular damage
Ex
Vivo Studies
INM-901
Next Steps
Research
& Development
● Dose Ranging and other non-GLP studies, with GLP studies to follow
● Seeking business development partnerships
Key
Milestones
12
INM-089
for the Treatment of Age-related Macular Degeneration (“AMD”)
Introduction
While
conducting the preclinical studies of a previous drug candidate, INM-088 in glaucoma, which involved comparing various naturally occurring
compounds including InMed’s proprietary small molecule candidates, it was discovered that one of InMed’s candidates was demonstrating
interesting pharmacological effects in the back of the eye. Further preclinical studies of this compound using AMD study models demonstrated
significant functional and pathological improvements. InMed has selected drug candidate INM-089, a proprietary small molecule analog
of INM-088, for further preclinical development in the potential treatment of dry AMD.
AMD
is a progressive eye disease that causes damage to the macula which affects a person’s central vision. AMD is common amongst the
elderly and is a leading cause of vision loss. Dry AMD is the most common form of AMD, accounting for 80% of AMD cases according to the
American Academy of Ophthalmology.
Until
recently, there were no approved pharmaceutical treatments for people with dry age-related macular degeneration. In 2023, the FDA approved
two new treatments which are complement inhibitors for advanced stages of dry AMD (called geographic atrophy (“GA”)).
In
vitro and in vivo studies of INM-089 have demonstrated neuroprotection of photoreceptors, improvement of the integrity of
the retinal pigment epithelium, a reduction in extracellular autofluorescent deposits (a hallmark of AMD), preservation of the retinal
function in the back of the eye and improvement in the thickness of the outer nuclear layer of the retina.
As
a small molecule, INM-089 is likely deliverable via various modes of administration, such as a topical eye drop or intravitreal injection
(“IVT”) formulations.
13
Pathology
of Age-related Macular Degeneration
AMD
is a progressive eye disease that causes damage to the macula which is part of the retina at the back of the eye. The macula controls
the sharp vision straight ahead of you, and damage to the macular affects a person’s central vision.
There
are two principal forms of AMD, atrophic (non-exudative) dry AMD and neovascular (exudative) wet AMD. Wet AMD constitutes about 10%-20%
of all cases of AMD and occurs when an abnormal blood vessel grows in or under the retina leading to central vision loss. Dry AMD is
the most common form affecting nearly 80%-90% of all patients with AMD. It is associated with the gradual loss of the outer nuclear layer
(“ONL”) photoreceptors and the retinal pigment epithelium (“RPE”) thinning, formation of drusen deposits, and
loss of the vessels in the retinal choriocapillaris. Advanced stage of dry AMD is characterized by GA at the center of the macula extending
through the outer neuroretina, RPE and choroid. GA is characterized by the atrophy of RPE, photoreceptors, choriocapillaris, and ONL.
The loss of functional RPE and photoreceptors in GA is not endogenously replaced and can result in complete sight loss.
AMD
is a leading cause of vision loss in adults
According
to the World Health Organization, 196 million people worldwide live with age-related macular degeneration. An estimated 19.8M Americans
aged 40+, about 12.6% of the population, suffer from AMD. While AMD does not cause complete vision loss, it affects central vision and
impairs one’s ability to perform daily tasks such as cooking, reading and driving.
As
the name suggests, aging is a strong risk factor for developing AMD. Adults aged 50 or older, smoke, have a diet of high saturated fat,
have cardiovascular disease or have a family history of AMD are more at risk of developing AMD. People of European ancestry are more
likely to develop AMD than Blacks, Hispanics or Asians. In addition, people with blue eyes have higher incidence rates of AMD than someone
with brown eyes.
Early
detection is key to slowing the progression of AMD. A sign of whether you might have AMD is when straight lines look wavy.
A
Major Unmet Medical Need for New AMD Treatments
Until
recently, there were no approved pharmaceutical treatments for people with dry age-related macular degeneration, which accounts for about
80%-90% of AMD cases.
In
2023, the FDA approved two new treatments which are complement inhibitors for advanced stages of dry AMD (or geographic atrophy). These
complement inhibitors are injected directly into the eye every one to two months.
Syforvre®
(pegcetacoplan), developed by Apellis Pharmaceuticals, was approved by the FDA in February of 2023 for the treatment of geography atrophy,
the late stage of dry AMD. Syforvre®, a C3 complement inhibitor, is injected into each eye every 25-60 days and reduces
the rate of lesion growth in the eye.
In
August 2023, the FDA approved Iveric’s Izervay® (avacincaptad pegol), a complement C5 inhibitor, which aims to reduce
an immune response that damages retinal cells. Similar to Syforvre®, the drug is approved for geographic atrophy and is
administered via intravitreal injection every month. According to the Alzheimer’s Association, these new complement inhibitor drugs
slow the development of GA by about 14%-20%, but do not improve eyesight, nor restore lost vision. Side effects of these new treatments
include inflammation, bleeding beneath the clear lining of the eye, blurred vision and fluid pressure, and some patients develop wet
AMD.
In
addition to the new complement inhibitors, there are surgical implants and ongoing clinical drug trials. An ophthalmologist may recommend
specific vitamins to slow the progression of AMD in its intermediate stage.
The
approval of complement inhibitors offers hope to people living with dry AMD, however, the modest effect, inconvenient drug delivery and
the increased risk of developing wet AMD may outweigh the benefit for some patients and their physicians. There remains a large unmet
medical need for more effective and convenient treatments for the large patient population affected by dry AMD.
Treatments
approved or in late-stage development for Geographic Atrophy (advanced dry AMD)
Brand Company Mechanism of Action Status
Syforvre® Apellis Pharmaceuticals Complement C3 inhibitor Approved February 2023
Izervay® Iveric Complement C5 inhibitor Approved August 2023
Tinlarebant Belite Bio Targets retinol binding protein 4 (RBP4) Phase 3
ANX007 Annexon Biosciences Anti-C1q antibody Initiating Phase 3
Danicopan (ALXN2040) Alexion Complement Factor D inhibitor Phase 2
14
Role
of CB1 and CB2 agonists in ocular disease
Mounting
scientific e is pointing to the neuroprotective effects of CB1 and CB2 agonists, supporting their therapeutic potential in ocular diseases
such as AMD and glaucoma, in which neuroprotection is key to preserving the nerve cells in the eyes and potentially slowing or reversing
eye damage. Several preclinical studies conducted by InMed in three of its drug development programs have consistently shown the neuroprotective