Item 1A. Risk Factors 25
Item 1B. Unresolved Staff Comments 65
Item 1C. Cybersecurity 65
Item 2. Properties 66
Item 3. Legal Proceedings 66
Item 4. Mine Safety Disclosures 66
Item 6. [Reserved] 67
Item 7A. Quantitative and Qualitative Disclosures About Market Risk 78
Item 8. Financial Statements and Supplementary Data F-1
Item 9A. Controls and Procedures 79
Item 9B. Other Information 80
Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevents Inspections 80
Part III 81
Item 10. Directors, Executive Officers and Corporate Governance 81
Item 11. Executive Compensation 81
Item 14. Principal Accounting Fees and Services 81
Item 15. Exhibits and Financial Statement Schedules 82
Signatures 84
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 the Company’s 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;
3
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. 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.
Overview
We are a pharmaceutical company developing a pipeline
of proprietary small molecule drug candidates that are preferential signaling ligands of the endogenous cannabinoid 1 (“CB1”)
and cannabinoid 2 (“CB2”) receptors as well as other receptor targets linked to human diseases. 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, we also have garnered significant know-how in developing proprietary manufacturing approaches to produce and sell
bulk rare cannabinoids as ingredients for various market sectors (“Products”).
InMed has sought to focus on the research and
development of preferential signaling ligands of CB1 and CB2 and has produced a library of novel, proprietary drug candidates (“Product
Candidates’). These Product Candidates are patentable NCEs for pharmaceutical drug development, aimed at targeting diverse clinical
indications. Our current pharmaceutical pipeline consists of three programs, with drug candidates targeting Alzheimer’s disease,
dry age-related macular degeneration (“AMD”), and Epidermolysis Bullosa (“EB”).
InMed’s INM-901 is a proprietary small
molecule, disease modifying drug candidate that is 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
PPAR signaling pathway. Combined, these mechanisms of action may offer a unique treatment approach targeting several biological pathways
associated with Alzheimer’s disease.
Outcome from our ocular research, based on the
proprietary small molecule INM-089, indicates potentially promising neuroprotective effects in the back of the eye, which may lead to
the preservation of the retinal function. Neuroprotection in dry Aged-related Macular Degeneration (“dry AMD”) remains an
unmet medical need and a new treatment option may help solve this multifactorial disease.
InMed has 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 conducted during 2022
and 2023 showed a positive indication of enhanced anti-itch activity for INM-755 (cannabinol) cream versus the control cream alone in
an exploratory clinical evaluation. The Company is also pursuing strategic partnership opportunities for INM-755 in EB and other itch-related
skin conditions.
Together with our wholly owned subsidiary BayMedica,
our manufacturing capabilities include traditional approaches such as chemical synthesis and biosynthesis, as well as a proprietary,
integrated manufacturing approach called IntegraSyn. With several manufacturing approaches, InMed has 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
use. BayMedica’s commercial business specializes in the business-to-business (“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.
4
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, V6C3E8 and our telephone number is +1-604-669-7207. Our website is https://www.inmedpharma.com/.
The contents of our website are not incorporated, in whole or in part, into this Annual Report in any respect.
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 by individuals with significant experience in
the pharmaceutical and biotechnology industries. As of September 20, 2024, 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.
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.
5
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, we are actively seeking development and commercial partnerships. The optimal commercial strategy for the INM-901 and INM-089 compounds
will be evaluated in due course.
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 the company. 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, InMed has 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 the combined
manufacturing technologies from InMed and BayMedica 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 rare
cannabinoids to the health and wellness sector.
As demonstrated by the launch of several 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.
BayMedica’s chemical synthesis and biosynthesis
technologies for the development and production of cannabinoids, their variants and analogs
BayMedica continues to develop manufacturing techniques
that are ‘method agnostic’, utilizing the most practicable, expeditious and cost-effective means to produce any particular
Product or novel Product Candidate.
6
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.
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, reduced 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 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
Current treatments in Neurodegenerative Diseases
Brand Company Mechanism of Action Status
Semorinemab Genentech Anti-tau Phase 2 Failed
Currently approved medications for AD 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.
Over the past three decades, only four drugs have received approval
for AD treatment, and while they can manage certain symptoms, they do not address the prevention or progression of the disease. These
drugs, known as cholinesterase inhibitors and glutamate regulators, primarily target cognitive symptoms.
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.
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.
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 B (“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.
8
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. 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 2. 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.
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Key Results:
Preclinical studies in AD models demonstrated
the following:
● reduces neuroinflammation;
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 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 the Company’s 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.
INM-901 Next Steps
Research & Development
● Assess long-term (7-month dosing) study in 5xFAD mice (on-going)
● Plan/execute study in PS19 Tau model
● Plan to execute IND enabling toxicology studies
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Key Milestones
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INM-089 for the Treatment of 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”) formulation.
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 geographic atrophy (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.
12
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 (late-stage 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
Role of CB1 and CB2 agonists in ocular disease
Mounting scientific research 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 effects of naturally occurring CB1 and
CB2 agonists and their analogs in well-recognized study models.
In was during this research of INM-088 when InMed scientists observed
the ability of a novel CB1 and CB2 agonist, now called INM-089, to proactively protect the nerve cells in the back of the eye. As a result
of this discovery, InMed launched the INM-089 drug development program for the potential treatment of AMD.
INM-089: Small molecule compound acting as
a selective dual CB1 / CB2 agonist
CB1 and CB2 receptors are both part of the endocannabinoid
system and are found throughout the body and are 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. Activation of
CB1 and CB2 receptors has been shown to have neuroprotective effects and protect cells from damage and death.
INM-089 is a small molecule compound, one of several proprietary CB1and
CB2 agonists discovered and developed by the Company’s team of scientists.
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INM-089 in vitro and in vivo studies to date
Preclinical studies of INM-089 demonstrate significant
functional and pathological improvements in an AMD disease study model. Results from several in vitro and in vivo studies
demonstrate INM-089’s pharmacological effects in the potential treatment of dry AMD:
● INM-089 provides neuroprotection of retinal cells
● INM-089 improves the integrity of the retinal pigment epithelium (“RPE”)
Based on widely accepted ocular research, the
thickness of the outer nuclear layer is strongly correlated with photoreceptor preservation and visual acuity.
INM-089 Study: Neuroprotective effects
INM-089 demonstrates neuroprotective effects
in pressure-induced toxicity in vitro model in retinal ganglion cells in a dose-dependent manner.
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INM-089 Study: Photoreceptor Function Preservation
In a light-induced toxicity in vivo AMD
model, a single intravitreal injection was performed at the back of the eye to deliver either INM-089, INM-088 or vehicle control. INM-089
outperforms INM-088 (‘CBN’ in the graph below) and vehicle control in preserving photo-receptor function.
INM-089 Study: Autofluorescent Extracellular
Deposit Level
In a light-induced
toxicity in vivo AMD model, a single intravitreal injection was performed at the back of the eye to deliver either INM-089
or vehicle control. INM-089 reduced build-up of autofluorescent extracellular deposits, which causes damage
to the macular. The build-up of autofluorescent deposits such as drusen is a hallmark of dry AMD.
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INM-089 Next Steps
Research & Development
● Additional Protein and RNA analysis results are pending
● Continuing CMC activities for drug substance and drug product
● On-going studies of receptor interactions (MoA) and DMPK
● GLP studies to follow
INM-755 for the Treatment of Epidermolysis
Bullosa (‘EB’)
Introduction
INM-755 (cannabinol, or ‘CBN’) cream
is a proprietary, topical product candidate intended as a therapy in dermatological diseases. The first clinical indication under development
is treatment of symptoms related to EB. EB is a collective name for a group of genetic disorders of connective tissues characterized by
skin fragility leading to extensive blistering and wounding. It affects skin and mucous membranes, particularly of the gastrointestinal
tract, genitourinary and respiratory systems. EB is a debilitating disease affecting a small proportion of people in the United States,
thus earning it an orphan-disease status. The disease has no definitive cure, and all current treatments are directed towards symptom
relief. There are, however, a number of products, mainly gene therapies, currently in clinical trials, in which a cure is being explored,
according to several recent scientific publications. Our preclinical research has identified a specific Product Candidate, CBN, that may
prove beneficial to patients: first, by addressing certain key disease hallmarks (which may include wound healing, infection, pain, inflammation,
and itch); and second, by regulating the expression of various proteins (keratins) that may compensate for reduced expression of others.
The active ingredient in
INM-755, CBN, is an agonist for both CB 1 and CB2 receptors, with a higher affinity for CB2, which means it should have a greater effect
on the immune system than on the central nervous system. The distribution of CB1 and CB2 receptors in sensory nerves and inflammatory
cells in the skin make it an attractive pharmaceutical agent for dermal treatments in medical conditions characterized by inflammation
and pain.
Summary of Completed Clinical Trials
Phase 1 Clinical Trials (Studies 755-101-HV
and 755-102-HV)
A regulatory application to support our first Phase 1 clinical trial in healthy volunteers with INM-755 (755-101-HV)
was submitted November 4, 2019 and approved December 6, 2019 in the Netherlands. The initial Phase 1 clinical trial evaluated the safety,
tolerability, and pharmacokinetics of INM-755 cream in 22 healthy volunteers with normal, intact skin; the volunteers had cream applied
once daily for a period of 14 days. All subjects in this first clinical trial completed treatment and evaluations by March 27, 2020.
Database completion and data analyses were delayed by pandemic restrictions. Study results were reported November 25, 2020. A blinded
interim safety review from the first 16 subjects in this Phase 1 clinical trial were included in a regulatory application that was approved
April 17, 2020, for a second Phase 1 clinical trial of 8 healthy volunteers to test the local safety and tolerability of applying sterile
INM-755 cream to small wounds once daily for 14 days. As with the initial Phase 1 trial, the second clinical trial (755-102-HV) was conducted
with two different drug concentrations and a vehicle control. Enrollment began in early July 2020 and the clinical trial completed treatment
and evaluations at the end of September 2020. Study results were reported January 8, 2021.
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Phase 2 Clinical Trial (Study 755-201-EB)
Regulatory applications to support this global
trial were filed for review by the National Competent Authorities and Ethics Committees in 8 countries for 13 clinical sites. Approvals
were obtained in all countries (Austria, France, Germany, Greece, Israel, Italy, Serbia, and Spain) as of March 2022. Enrollment and
patient treatment began in December 2021 and completed in April 2023.
The goal of the Phase 2 study was to obtain safety
and preliminary efficacy of INM-755 cream in treating symptoms and wound healing in patients with EB, using a within-patient design in
which matched index areas were randomized to INM-755 cream or vehicle (no drug) cream in a blinded manner. A target of up to 20 patients
were to be enrolled with treatment for 28 days, the longest period supported by nonclinical toxicology studies.
No single primary endpoint was set for
the trial to allow for possible variations in presenting symptoms in each patient. These include the presence of open wounds, wound pain
associated with dressing changes, background wound pain, wound itch, and itch in non-wound areas. To this end, InMed’s goal was
to harvest data from the trial to evaluate the ability of INM-755 to treat chronic non-wound itch and to heal wounds and treat associated
pain and itch.
The Phase 2 Trial enrolled a total of 19 patients.
Data from one patient were excluded from efficacy analyses due to a significant protocol deviation. Of the 18 remaining patients whose
data were considered reliable for clinical review, 17 were treated for chronic non-wound itch and one patient was treated for wound-related
itch. The remaining endpoints (pain, wound healing) could not be analyzed due to too few enrollees with such symptoms.
Of the 18 participants assessed, chronic itch
improved by a clinically meaningful amount in 12 patients (66.7%), of whom:
● 1 patient (5.6%) showed better itch reduction with the control cream.
In summary, 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. The results for non-wound itch were not statistically significant in this small trial due, in part, to the clinically important
anti-itch effect of the underlying control cream. We are, nevertheless, encouraged by and satisfied with the INM-755 clinical data
for non-wound itch treatment. That the majority of the assessed patients in the trial showed clinically meaningful improvement in non-wound
itch from the application of INM-755, be it with similar outcomes to the control cream or better than the control cream, can be considered
impressive.
Based on the safety and efficacy data for treating
non-wound itch in this EB study, as well as previous safety data from Phase 1 trials, we are now seeking R&D and commercial partnership
opportunities for any continued development of INM-755 cream. Continued development of INM-755 cream will likely move beyond EB into broader
indications involving chronic itch, with potentially much larger target populations and commercial opportunities than offered solely by
the EB indication.
On average, it takes at least ten years to complete
the development of an investigational drug from its initial discovery to the marketplace, with clinical trials alone taking six to seven
years on average. It is not possible with any degree of certainty to estimate how long it will take to complete clinical trials and potentially
obtain marketing approval for INM-755. To the extent that INM-755 may potentially be designated as either a Fast Track drug, a Breakthrough
Therapy, or eligible for Priority/Accelerated Review, the timeline to any potential marketing approval may be shorter than might otherwise
be the case.
Additional Indications for INM-755
Once a company has gone to the significant investments
of bringing a new chemical entity into human clinical trials, the traditional approach is to investigate as many therapeutic uses as
possible of that product in different indications, or specific diseases. We intend to pursue this strategy with a co-development partner
as a way to leverage our knowledge of CBN and investment in the development of INM-755 as a topical skin cream. Under the assumption
that we would use the same formulation for other dermatological indications, there should be no need for further Phase 1 safety studies
allowing us to proceed directly to Phase 2 safety and preliminary efficacy studies in humans, since the toxicology and initial human
safety studies have been completed; however, the adequacy of the nonclinical and human safety data to support new dermatologic indications
will be determined by the appropriate health authority.
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Key Milestones for the EB Program:
Rare Cannabinoid Products in the Health and
Wellness Sector
BayMedica has a revenue-generating commercial
business unit that leverages our significant expertise in synthetic biology and chemistry to develop efficient, scalable, and proprietary
manufacturing approaches to produce high quality, regulatory-compliant, non-intoxicating rare cannabinoids (“Products”) for
consumer applications. BayMedica is currently commercializing Products as a B2B supplier to distributors and manufacturers in the health
and wellness sector, including nutraceuticals, cosmetics, functional foods and beverages, as well as animal health markets. BayMedica
currently has a robust portfolio of four different non-intoxicating Products including: cannabichromene (“CBC”), cannabidivarin
(“CBDV”) tetrahydrocannabivarin (“THCV”) and cannabicitran (“CBT”).
Following
the acquisition of BayMedica in 2021, a key priority in 2022 was accelerating commercial activities and building out a robust product
portfolio as a supplier of Products to the health and wellness sector. While there was slower than expected revenue growth in 2022, we
have seen increased demand through 2023 and the first half of 2024 due to better research of rare cannabinoids, companies and brands
looking for product innovation and effects-based outcomes, and the ability of companies like ours to reliably supply high quality and
consistent Products. During the financial year ended June 30, 2024, BayMedica had sales of approximately $4.6 million.
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The increased sales in part resulted from expanded
marketing efforts and increased demand for certain Products. BayMedica will continue to evaluate opportunities for potential structured
supply arrangements and collaborations for the commercial business. Sales and marketing efforts will remain focused on Products that
contribute highest margins where BayMedica continues to hold a strong competitive position.
Chemical Synthesis-Derived Cannabinoids Commercialized
by BayMedica
Cannabichromene (CBC)
The high cost of goods for rare / minor cannabinoids (e.g. CBC) extracted
and purified from the plant made adoption of these more difficult due to the cost of manufacture and cost to include in the final marketed
product(s). Chemical synthesis has provided a consistent, scalable approach to produce CBC and other minor cannabinoids at a highly competitive
cost of goods with consistent batch to batch variability and high purity of the cannabinoid. BayMedica has successfully manufactured and
commercialized the rare cannabinoid CBC, for sale to distributors into the health and wellness industry. The development of a scalable
process for the manufacturing of CBC began in 2018 using well established chemical synthesis protocols.
In 2019, a Material Services Agreement was
completed with a multinational contract research, development and manufacturing organization (“Chemistry CDMO”) to facilitate
the optimization and scale-up of BayMedica’s proprietary CBC manufacturing process using commercially available starting materials
sourced from various manufacturers. We scaled to a batch size of greater than 1kg by calendar 2019 at which time we contracted a leading
U.S. manufacturer to provide the final purification of CBC to greater than 95% purity. This manufacturer also operates a North American
based toll-processing facility with the capability to process from 10kg to metric ton quantities of our crude CBC material
under food-grade GMP conditions. By late 2019, our Chemistry CDMO had scaled the process to greater than 10kg, and by year end 2019 to
almost 30kg with final purification at the NA contractor. We commenced commercial sales of CBC in November 2019.
Large scale manufacturing of crude CBC began at our Chemistry CDMO
in 2020 at >40kg. The emergence of the Covid-19 pandemic significantly impacted sales beginning in calendar 2020. Large scale production
continues with current batch sizes exceeding 100kg.
Cannabicitran (CBT)
We have developed a process for the efficient chemical synthesis of
CBT through both in-house R&D efforts and via our CDMO. We began scaling this process and conducted downstream processing and purification
trials in late calendar 2021. We received initial purchase orders and commenced commercial sales of CBT in calendar 2022.
Cannabidivarin (CBDV)
Beginning in early 2021, BayMedica worked
internally and with external parties to access and develop manufacturing technologies for the chemical synthesis of the rare,
non-intoxicating “varin” cannabinoid, CBDV. In calendar 2021, via a Chemistry CDMO, we successfully scaled CBDV
synthesis to commercial quantities. In April 2022, we commenced B2B sales of CBDV to the health and wellness sector. As of fiscal
2023, a new source of CBDV was developed to provide a lower cost of goods replacement to the previously produced CBDV. Sales of this
CBDV were initiated in the second quarter of calendar 2024.
Tetrahydrocannabivarin (THCV)
As part of the R&D into manufacturing techniques