UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM 10-K
(Mark One)
☒ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934
For the fiscal year ended December 31, 2024
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: 001-42403
Alpha Cognition Inc.
(Exact Name of Registrant
as Specified in its Charter)
British Columbia N/A
Vancouver, British Columbia V6C
(Address of Principal Executive Offices) (Zip Code)
(604)564-9244
(Registrant’s Telephone Number, including
Area Code)
Securities registered pursuant to Section 12(b) of the Act: None
Title of each class: Trading Symbol Name of each exchange on which registered:
Common Shares, no par value ACOG The Nasdaq Stock Market LLC
Indicate by check mark if the registrant is a
well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes ☐No☒
Indicate by check mark if the registrant is not
required to file reports pursuant to Section 13 or Section 15(d) of the Act. Yes ☐No☒
Indicate by check mark whether the registrant
(1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months
(or for such shorter period that the registrant was required to file such reports), and (2) has been subject to such filing requirements
for the past 90 days. Yes☒ No ☐
Indicate by check mark whether the registrant has submitted electronically
every Interactive Data File required to be submitted pursuant to Rule 405 of Regulation S-T (§ 232.405 of this chapter) during the
preceding 12 months (or for such shorter period that the registrant was required to submit such files). Yes☒
No ☐
Indicate by check mark whether the registrant
is a large accelerated filer, an accelerated filer, a non-accelerated filer, a smaller reporting company or an emerging growth company. See
definitions of “large accelerated filer,” “accelerated filer,” “smaller reporting company” and “emerging
growth company” in Rule 12b-2 of the Exchange Act:
Large Accelerated Filer ☐ Accelerated Filer ☐ Non-Accelerated Filer ☒
Smaller Reporting Company ☒ Emerging Growth Company ☒
If an emerging growth company, indicate by check
mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting
standards provided pursuant to Section 13(a) of the Exchange Act. ☐
Indicate by check mark whether the registrant
has filed a report on and attestation to its management’s assessment of the effectiveness of its internal control over financial
reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered public accounting firm that prepared or
issued its audit report. ☐
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 ☒
State the aggregate market value of the voting
and non-voting common equity held by non-affiliates computed by reference to the price at which the common equity was last sold, or the
average bid and asked price of such common equity, as of the last business day of the registrant’s most recently completed second
fiscal quarter: $62,829,984.
The number of shares of Registrant’s Common
Stock outstanding as of March 31, 2025 was 16,019,787.
DOCUMENTS INCORPORATED BY REFERENCE
To the extent herein specifically referenced in Part III, portions
of the Registrant’s Definitive Proxy Statement on Schedule 14A for the 2025 Annual Meeting of Stockholders are incorporated herein.
See Part III.
TABLE OF CONTENTS
Page
PART I
ITEM 1. BUSINESS 1
ITEM 1A. RISK FACTORS 32
ITEM 1B. UNRESOLVED STAFF COMMENTS 87
ITEM 1C. CYBERSECURITY 87
ITEM 2. PROPERTIES 88
ITEM 3. LEGAL PROCEEDINGS 88
ITEM 4. MINE SAFETY DISCLOSURES 88
PART II
ITEM 6. [RESERVED] 91
ITEM 7A. QUANTITATIVE AND QUALITATIVE DISCLSOURES ABOUT MARKET RISK 109
ITEM 8. FINANCIAL STATEMENTS AND SUPPLEMENTARY DATA F-1
ITEM 9A. CONTROLS AND PROCEDURES 110
ITEM 9B. OTHER INFORMATION 110
ITEM 9C. DISCLOSURE REGARDING FOREIGN JURISDICTIONS THAT PREVENT INSPECTIONS 110
PART III
ITEM 10. DIRECTORS, EXECUTIVE OFFIERS AND CORPORATE GOVERNANCE 111
ITEM 11. EXECUTIVE COMPENSATION 111
ITEM 14. PRINCIPAL ACCOUNTANT FEES AND SERVICES 111
PART IV
ITEM 15. EXHIBITS AND FINANCIAL STATEMENTS SCHEDULES 112
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SPECIAL NOTE REGARDING FORWARD-LOOKING STATEMENTS
This Annual Report on Form 10-K contains forward-looking statements
concerning our business, operations and financial performance, as well as our plans, objectives and expectations for our business operations
and financial performance and condition. All statements other than statements of historical facts included in this Annual Report are forward-looking statements.
In some cases, you can identify forward-looking statements by terminology such as “aim,” “anticipate,” “assume,”
“believe,” “contemplate,” “continue,” “could,” “design,” “due,”
“estimate,” “expect,” “goal,” “intend,” “may,” “objective,” “plan,”
“positioned,” “potential,” “predict,” “seek,” “should,” “target,”
“will,” “would” and other similar expressions that are predictions of or indicate future events and future trends,
or the negative of these terms or other comparable terminology. In addition, statements that “we believe” or similar statements
reflect our beliefs and opinions on the relevant subject.
Forward-looking statements may include, but
are not limited to, statements with respect to:
● the use of available funds;
● requirements for additional capital and future financing options;
● plans to launch new products and identify qualified distribution partners;
● expansion and acceptance of the Company’s products in different markets;
● manufacturing, license and distribution partnerships and agreements;
● plans to identify, pursue, negotiate and/or complete strategic acquisitions;
● marketing plans;
● other expectations of the Company.
● risks related to early stage of development and significant history of losses;
● risks related to our ability to generate revenue and achieve profitability;
● risks related to our lack of history in commercializing products;
● risks related to our need for substantial additional capital;
● risks related to fluctuations in currency exchange rates;
ii
● risks related to our focus on treatments for Alzheimer’s disease;
● risks related to substantial delays in our preclinical and clinical trials;
● risks related to our reliance on third-parties to conduct our clinical trials;
● risks related to product liability;
● risks related to our information systems;
● risks related to disruptions at the FDA;
● risks related to our failure to comply with health and data protection laws;
● risks related to approval in foreign jurisdictions;
● risks related to competition in our industry;
● risks related to commercialization and manufacturing;
● risks related to our market opportunity being smaller than we anticipate;
● risks related to our reliance on third-party suppliers;
● risks related to supply chain risks;
● risks related to the complexity of manufacturing drugs;
● risks related to our lack of a sales organization;
● risks related to obtaining protection under Hatch-Waxman Amendments;
● risks related to maintaining our patent protections;
● risks related to our need to license intellectual property from third parties;
iii
● risks related to third party claims of infringement;
● risks related to lawsuits to protect and enforce our patents;
● risks related to unfavorable publicity;
● risks related to changes in U.S. patent law;
● risks related to sharing our trade secrets;
● risks related to claims we wrongfully hired employees;
● risks related to claims challenging inventorship;
● risks related to trademarks;
● risks related to our products remaining subject to regulatory scrutiny;
● risks related to using accelerated pathways to FDA approval;
● risks related to healthcare legislation including unfavorable pricing;
● risks related to our business exposing us to regulatory penalties;
● risks related to U.S. foreign export and import laws;
● risks related to our need to increase the size of our organization;
● risks related to establishing sales and marketing personnel;
● risks related to exploring strategic collaborations;
● risks related to acquisitions and related integrations; and
● risks related to our common shares.
We have based these forward-looking statements
largely on our current expectations, estimates, forecasts and projections about future events and financial trends that we believe may
affect our financial condition, results of operations, business strategy and financial needs. In light of the significant uncertainties
in these forward-looking statements, you should not rely upon forward-looking statements as predictions of future events. Although
we believe that we have a reasonable basis for each forward-looking statement contained in this Annual Report, we cannot guarantee
that the future results, levels of activity, performance or events and circumstances reflected in the forward-looking statements
will be achieved or occur at all. You should refer to the section entitled “Risk Factors” and elsewhere in this Annual Report
for a discussion of important factors that may cause our actual results to differ materially from those expressed or implied by our forward-looking statements.
Furthermore, if our forward-looking statements prove to be inaccurate, the inaccuracy may be material. Except as required by law,
including applicable Canadian laws, we undertake no obligation to publicly update any forward-looking statements, whether as a result
of new information, future events or otherwise.
You should read this Annual Report and the documents
that we reference in this Annual Report and have filed as exhibits to the registration statement, of which this Annual Report is a part,
completely and with the understanding that our actual future results may be materially different from what we expect. We qualify all of
the forward-looking statements in this Annual Report by these cautionary statements.
iv
PART I
ITEM 1. BUSINESS
Business Overview
Alpha Cognition Inc. (the “Company,”
“Alpha Cognition,” “we,” or us”) is a biopharmaceutical company dedicated to developing treatments for patients
suffering from neurodegenerative diseases, such as Alzheimer’s disease (“Alzheimer’s disease” or “AD”),
for which there are limited or no treatment options. On July 26, 2024, the Company received approval by the FDA of the Company’s
New Drug Application (the “NDA”) for ZUNVEYLTM (benzgalantamine) previously known as ALPHA-1062 (“ZUNVEYL”
or “ALPHA-1062”) a delayed release oral tablet formulation indicated for the treatment mild to moderate dementia of the Alzheimer’s
type in adults (Alzheimer’s disease). The Company’s current focus is on the commercial manufacturing and sales of ZUNVEYL
oral tablet formulation. The Company’s commercial development program for ZUNVEYL is primarily focused on building a long term care
(“LTC”) commercial team that can focus on providing key points of differentiation, exploiting key issues with existing Acetylcholinesterase
inhibitors (“AChEI”) treatments, and seeking potential licensing partners for other additional indications and new formulations.
The Company intends to target large volume nursing homes specializing in Alzheimer’s, to leverage an account based sales team with
demonstrated success in LTC, in order to position ZUNVEYL with Medicare payors, and to work with strategic and clinical partnerships with
consultant pharmacists and long term care pharmacies. The Company has six additional pre-clinical development programs: (1) ZUNVEYL in
combination with memantine for the treatment of moderate-to-severe Alzheimer’s disease, (2) ALPHA-1062 sublingual formulation, (3)
ALPHA-1062 intranasal (“ALPHA-1062IN”) formulation for the treatment of cognitive impairment with mild traumatic brain injury
(mTBI; otherwise known as concussion), (4) ALPHA-0602, and (5) ALPHA-0702 & ALPHA-0802, the latter two programs also referred to as
‘Progranulin’ and ‘Progranulin GEM’s’, respectively, for the treatment of neurodegenerative diseases including
amyotrophic lateral sclerosis (ALS) or Lou Gehrig’s disease and spinal muscular atrophy (SMA) , and (6) ALPHA-1062 for the treatment
of acute pancreatitis.
ZUNVEYL, is a patented next generation acetylcholinesterase
inhibitor indicated for the treatment of mild to moderate dementia of the Alzheimer’s type in adults. ZUNVEYL’s active metabolite
is differentiated from donepezil and rivastigmine in that it binds neuronal nicotinic receptors, most notably the alpha-7 subtype, which
is known to have a positive effect on cognition. In addition to our approved oral formulation, ZUNVEYL is also in pre-clinical development
(1) in combination with memantine to treat moderate to severe Alzheimer’s disease, (2) alone as a with sublingual formulation for
patients suffering from dysphagia, and (3) alone and referred to herein as “ALPHA-1062IN” that is intended to be out-licensed
for pre-clinical development to study an intranasal formulation for cognitive impairment with mTBI.
Our other pre-clinical assets include ALPHA-0602
and ALPHA-0702 & ALPHA-0802 (Progranulin and Progranulin GEM’s), which are expressed in several cell types in the central nervous
system and in peripheral tissues, promotes cell survival, regulates certain inflammatory processes, and play a significant role in regulating
lysosomal function and microglial responses to disease. Its intended use for the treatment of neurodegenerative diseases has been patented
by the Company and ALPHA-0602 has been granted an Orphan Drug Designation for the treatment of ALS by the FDA. Orphan Drug Designation
was provided for ALPHA-0602 by the Office of Orphan Drug Products, FDA on February 2020 based on the Federal Food Drug, and Cosmetic Act,
whereby the ALPHA-0602 met the criteria designated in Section 526 of such Act. For a further description see the section entitled “——
Orphan Drug Designation”. The Orphan Drug Designation allows for exclusivity provisions provided the drug is approved first for
indication: treatment of amyotrophic lateral sclerosis ALPHA-0702 and ALPHA-0802 are Granulin Epithelin Motifs, (“GEMs”),
derived from full length progranulin which have therapeutic potential across multiple neurodegenerative diseases. GEMs have been shown
to be important in regulating cell growth, survival, repair, and inflammation. ALPHA-0702 and ALPHA-0802 are designed to deliver this
result with potentially lower toxicity, and greater therapeutic effect than full length progranulin. As the assets are pre-clinical and
do not add material value to the Company, the Company will not develop these assets further and instead will seek to out-license the assets
to interested third parties. Given the early stage of discussion with third parties, the Company cannot assess value to a license agreement.
The Company exercised a reversion of rights for
ALPHA-1062 for TBI, pancreatitis, and related conditions in January and has brought ALPHA-1062 Intranasal for mTBI and related conditions,
ALPHA-1062 for Acute pancreatitis back to the Company to develop both compounds for said conditions.
1
Our Strategy
The Company’s principal business objectives
are to:
In order to meet these business objectives, the
Company plans to initiate or complete the following milestones over the coming year:
Alzheimer’s Disease Mild-to-Moderate
Stage Program
Disease and Market Overview
An estimated 6.7 million Americans age 65 and
older were living with Alzheimer’s dementia in 2023(1). This often causes burdensome effects on their families and caregivers.
It is by far the most common form of dementia, estimated to be 60% to 80% of all diagnosed cases(1). Treatment options for
Alzheimer’s disease are limited, and health care professionals along with patients/caregivers are generally dissatisfied with the
currently available treatments due to limited efficacy and unmanageable tolerability from adverse events.
Of the patients with Alzheimer’s disease,
the vast majority, approximately 2.5 million(1), have been diagnosed with mild Alzheimer’s disease. Mild Alzheimer’s
disease is expected to grow over the next decade, signaling a continued need for symptomatic drugs with greater efficacy and fewer side
effects.
Current acetylcholinesterase inhibitor medications
are absorbed in the gastrointestinal system and bind to locally present acetylcholinesterase, the enzyme responsible for breaking down
the neurotransmitter, acetylcholine. The local acetylcholine levels are then increased, and the neurons associated with the gastrointestinal
system become overstimulated. The result is an increase of gastrointestinal side effects (nausea, vomiting, diarrhea).
2
Alzheimer’s disease symptomatic treatments
are currently limited and perceived to provide limited symptom improvement and cause difficult to manage tolerability side effects. Symptomatic
treatments are designed to improve the ability to learn, remember data, and function normally with daily tasks like toileting, cooking,
or home care. Each year more than 2 million patients are on medication for the disease, which makes up half of the estimated number of
people with Alzheimer’s disease in the US. Approximately 70% of patients with mild Alzheimer’s disease, 80% with moderate,
and 75% with severe Alzheimer’s disease are on drug-treatment. On average, it can take up to 2.5 months from diagnosis to treatment,
but can take up to 2 years, and roughly 32% will never go on treatment. Patients are treated primarily with symptomatic medications to
help the cognitive and functional symptoms of Alzheimer’s disease. In addition to symptomatic treatments, patients are often prescribed
behavioral and psychiatric medications for depression, hallucinations, aggression and agitation.
The current and forecasted prevalence of Alzheimer’s
disease is a large societal and public health care crisis. More than 1 in 9 elderly people have Alzheimer’s disease (age 65 or older),
and of that group, 73% are actually 75+ years old with a majority (61%) being women.Alzheimer’s disease was
officially listed as the sixth-leading cause of death in the United States in 2019. In 2020 and 2021, when COVID-19 became
the third-leading cause of death, Alzheimer’s disease was the seventh-leading cause of death; official counts for 2022
are still being compiled.Though the length of time varies for each person, on average patients 65+ years will live for
average four to eight years after their Alzheimer’s disease diagnosis. With the large baby boomer generation advancing in age
and longer life expectancies, by 2025 Alzheimer’s disease prevalence is forecasted to rise 7% to 7.2 million people, and the
number will jump to 13.8 million in the United Sates by 2060. Alzheimer’s disease is a significant societal and healthcare
burden due to the large and growing at-risk patient population, physician perceived limited effectiveness of current treatments and
a shortage of drug innovation.
Adapted from Alzheimer’s Facts and Figures,
2023, page 30
3
Symptoms
There are 5 main stages of severity on the Alzheimer’s
disease continuum, which are defined by brain changes and the resulting symptoms that affect a patient’s daily life. These stages
are preclinical Alzheimer’s disease, mild cognitive impairment (MCI) caused by Alzheimer’s disease, dementia due to mild Alzheimer’s
disease, dementia due to moderate Alzheimer’s disease, and dementia due to severe Alzheimer’s disease. Alzheimer’s disease
isbelieved to start causing changes in the brain upwards to 20 years prior to symptoms becoming noticeable.Within
the brain, nerve cells become damaged and/or destroyed due to accumulation of beta-amyloid plaque clumps outside neurons, and the
abnormal formation of tau tangles inside the neurons. As these brain changes become more prominent over the years, symptoms begin
to occur and become noticeable. Common cognitive symptoms are memory loss, learning decline, challenges planning or solving problems,
forming words/speaking and confusion with places or time. As symptoms become more severe, they affect daily activities, such as the ability
going to the bathroom, eating and swallowing, drinking, and overall mobility. Alzheimer’s disease progresses within each person
differently. Depending on the individual risk factors, time of diagnosis, and other factors, the length of time a patient is within each
stage of the continuum will vary greatly.
Alzheimer’s disease symptoms affect the
whole patient: mind, body and behavior/personality. The five main areas of symptoms are cognitive, psychological, physical, behavior,
and other, which would include sleep disorder and rapid eye movement disorder.
Adapted from Porsteinsson 2021
An Alzheimer’s disease patient’s diagnosis
journey usually begins with their primary care physicians, as they are the first to detect cognitive impairment. Once detected, 99% of
primary care physicians will refer the patient to a dementia specialist. Neurologists/Psychiatrists prescribe 27% of all Alzheimer’s
disease Rxs and due to the large Alzheimer’s disease afflicted population within LTC facilities, these physicians prescribe 36%
of the total Rxs.
4
Alzheimer’s disease caregivers carry
a heavy burden
People suffering from Alzheimer’s disease
are not relegated only to the patients. Family members and caregivers are affected greatly and carry a huge burden due to this progressive
disease. The vast majority (83%) of the 11 million unpaid Americans that provide care for Alzheimer’s disease patients are
doing so for a family member, usually a parent or parent-in-law. Two-thirds are women and the majority are under the age of 65 years
old. These caregivers provide upwards to 18 billion hours of unpaid care, which equates to $339.5 billion a year. While
many believe they don’t have the information or resources necessary to do their job as a caregiver well, they feel they have no
choice but to take on this role, as cited in a 2014 Alzheimer’s Association poll. In addition to providing help with daily activities,
caregivers are also providing emotional, physical, communication, and financial support.As the disease progresses and
the patient exhibits behavioral and functional changes that are more severe, the burden becomes larger and the overall stress increases.
According to the Alzheimer’s Association, caregivers report feeling high emotional stress, and experience financial and physical
difficulties while caring for their loved one.
Adapted from Alzheimer’s Association Facts &
Figures 2023, Page 50
Long-term care homes and death rates
LTC facilities carry a substantial burden in the
care of Alzheimer’s disease patients. The costs of health care and long-term care for individuals with Alzheimer’s disease
or other dementias are substantial, and dementia is one of the costliest conditions to society. Researchers have estimated that approximately
75% of surviving Alzheimer’s disease patients diagnosed at age 70 will reside in a nursing home by age 80, compared with only
4% of the general population. 36% of short-stay (less than 100 days) nursing home residents have Alzheimer’s disease or
other dementias, and 58% of long-stay (100 days or longer) residents have this condition. Due to this large and growing population,
15% of nursing homes have a special dementia care unit, which the Company anticipates will become more common place over the coming years
as more baby boomers are admitted. When a patient has been admitted into a long-term care facility, their Alzheimer’s disease
symptoms are affecting daily activities and have caused general disability and overall decline in their health. The mental, emotional
and physical stress on the caregiver and family members is extremely high. Some studies state distress remains unchanged or even increases
after a relative is admitted to a residential care facility.
5
Alzheimer’s disease was officially listed
as the sixth-leading cause of death in the United States in 2019. In 2020 and 2021, when COVID-19 became the third-leading cause
of death, Alzheimer’s disease was the seventh-leading cause of death; official counts for 2022 are still being compiled. Alarmingly,
deaths from Alzheimer’s disease have more than doubled from 2000 to 2019, to 145.2%, while all other major causes of deaths have
declined or remained the same, such as cancer, heart disease or stroke. Alzheimer’s disease accounts for two-thirds of deaths
in a nursing home, which is greater than cancer and any other condition. Due to the stress associated with caring for a loved one suffering
from Alzheimer’s disease, 72% of family caregivers experienced relief when the person with Alzheimer’s disease or another
dementia died.
ALPHA-1062 (now known as ZUNVEYL) Clinical
Development
The original nasal formulation of ALPHA-1062 was
used to conduct Phase I human studies, initially by Neurodyn Life Sciences Inc. (“NLS”) a former related party through
common shareholders, and subsequently, on completion of the ALPHA-1062 license agreement, by the Company. The Phase I human
studies included a SAD Study followed by a MAD Study. These Phase I studies were designed to determine the safety of the drug, which
was administered to healthy subjects, including elderly, at increasing doses of ALPHA-1062, initially one time in the SAD Study, and subsequently
multiple times over a seven-day period in the MAD Study. These studies indicated that ALPHA-1062 formulations may have reduced
gastrointestinal side effects (nausea, diarrhea, vomiting) as compared to one of the existing treatments; Razadyne (galantamine is the
generic name).
Bioavailability and Bioequivalence Pivotal Trials: The
Company completed two studies (fed and fasted) in Q2 2022 (from April to June) and a third in Q3 2022 (from July to August). All studies
were completed in India with Vimta Labs, Inc., a clinical research organization with significant experience in running bioanalytical and
bioequivalence studies. The studies were designed to demonstrate pharmacokinetic equivalence in healthy subjects compared to the reference
listed drug galantamine hydrobromide immediate release (fed and fasted) and galantamine hydrobromide extended release, which are standard
of care treatments for patients with mild to moderate Alzheimer’s disease. The studies were designed in accordance with FDA 505(b)(2)
guidance for industry. Primary endpoints of all studies were to evaluate bioavailability and bioequivalence by comparative measurements
of peak plasma concentration (Cmax), and area under the plasma concentration-time curve from time zero to infinity (AUC0-inf.). Secondary
endpoints were to measure adverse events and safety outcomes. Topline results from the bioequivalence studies suggested that ALPHA-1062 achieved
bioequivalent area-under-the-curve (fed and fasted) and peak exposures (fed) relative to galantamine hydrobromide immediate release
and galantamine hydrobromide extended release. There were minimal adverse events (<2%) reported for ALPHA-1062 delayed release
oral tablet formulation during these studies. With these bioavailability and bioequivalence pivotal study results, the Company filed an
NDA for ALPHA-1062 delayed release oral tablet formulation for the treatment of mild to moderate dementia of the Alzheimer’s
type in adults during Q3 2023, with FDA approval for the U.S. market on July 26, 2024.
6
The following table summarizes the results of
each of the two ZUNVEYL, formerly known as ALPHA-1062 delayed release oral tablet formulation, Pivotal Studies (fed and fasted) — Bioequivalence/Bioavailability
(“BABE”) Study vs. Immediate Release (“IR”) (completed in June 2022) and an additional BABE Study vs. Extended
Release (“ER”) (completed in August 2022).
BABE Study vs. Immediate Release
The primary objective of both the fed and fasted
studies was to evaluate the relative bioavailability of a single-dose of ALPHA-1062 (or benzgalantamine) 5mg delayed release oral tablet
formulation compared to galantamine hydrobromide tablet 4mg immediate release — the reference drug. Primary endpoints of these studies
were to evaluate bioavailability and bioequivalence by comparative measurements of peak plasma concentration (Cmax), and area under the
plasma concentration-time curve from time zero to infinity (AUC0-inf.). Secondary endpoints were to measure adverse events and safety
outcomes. Thirty-six healthy subjects were enrolled in each trial.
Two drug products are recognized to be bioequivalent
if the 90% confidence interval of the ratio of geometric means of the primary pharmacokinetic (PK) responses (after log-transformation)
is within the bioequivalence limits of 80% and 125%.
A secondary objective of the studies was to evaluate
the safety and tolerability of single-dose administration of ALPHA-1062 5mg delayed release oral tablet formulation. The primary pharmacokinetic
outcomes were AUC0-inf or area under the curve, and Cmax, the highest concentration of drug in the blood. The area under the curve represents
the total exposure to the active drug galantamine over time after a single administration, and the Cmax represents the highest peak exposure
to galantamine.
Bioequivalence of ALPHA-1062 delayed release oral
tablet formulation to galantamine hydrobromide appeared to be established in both the fed and fasted studies with the 90% confidence intervals
for area under the curve falling within the 80%-125% bioequivalence range. The mean area under the curve ratio to reference drug for ALPHA-1062
delayed release oral tablet formulation was 95% (306.8) in the fasted study and 87% (286.7) in the fed study.
The average Cmax ratio to reference drug for ALPHA-1062
delayed release oral tablet formulation was 76% (30.7) in the fasted study and 91% (27.6) in the fed study both Cmax results being higher
than the published Cmax data for galantamine hydrobromide 8 mg extended release capsule. Bioequivalence of ALPHA-1062 delayed release
oral tablet formulation appeared to be demonstrated based on overall drug exposure in both the fed and fasted states, and the Cmax with
ALPHA-1062’s delayed release oral tablet formulation is expectedly lower than that of the immediate release formulation of galantamine,
yet higher than the published data with galantamine extended release capsule. Bioequivalence of ALPHA-1062 delayed release oral tablet
formulation appeared to be established on Cmax compared to galantamine hydrobromide in the fed state. When the Cmax of a proposed drug
product falls between the reported Cmax of two formulations of an approved reference product (immediate and extended release), this should
allow for a scientific bridge to both formulations of the reference standard galantamine hydrobromide.
Single-dose administration of ALPHA-1062 delayed
release oral tablet formulation was well tolerated with no adverse events reported.
7
BABE Study vs. Extended Release
During August 2022, the Company announced results
from an additional bioequivalence study with ALPHA-1062. The Company elected to conduct this additional study which was designed to demonstrate
pharmacokinetic (PK) equivalence between ALPHA-1062 5mg delayed release oral tablets and 8 mg galantamine hydrobromide extended release
capsules, when dosed to steady state. Bioequivalence appeared to be established based on total drug exposure (AUC) and the Cmax was expectedly
higher than that of the extended release reference. These data, coupled with the bioavailability and bioequivalence pivotal data released
in June, establishes bioequivalence to both formulations of galantamine hydrobromide, based on the approval of the FDA on July 26, 2024.
The study was a two-treatment, two-period, crossover
study wherein 40 subjects were randomly assigned 1:1 to either treatment with ALPHA-1062 5mg delayed release oral tablet formulation twice
daily, or galantamine hydrobromide 8mg ER capsules once daily, for 7 days. After a one-week washout period, subjects were then crossed
over to the other treatment arm and dosed for 7 days. Primary endpoints of all studies were to evaluate at day seven bioavailability and
bioequivalence by comparative measurements of peak plasma concentration of test and reference (Cmax), and area under the plasma concentration-time
curve from time zero to infinity (AUC0-24.). Secondary endpoints were to measure adverse events and safety outcomes.
Topline results suggested that in healthy adult
volunteers treated to steady state, ALPHA-1062 delayed release oral tablet formulation was bioequivalent to galantamine hydrobromide extended
release. In the pre-specified primary analysis, ALPHA-1062 delayed release oral tablet formulation achieved area-under-the-curve and peak
exposures
(Cmax) of approximately 107% and 127%, respectively,
compared to those generated by galantamine hydrobromide extended release. As expected, Cmax results for ALPHA-1062 delayed release oral
tablet formulation is bracketed between galantamine hydrobromide immediate release and galantamine hydrobromide extended release (lower
than immediate release, higher than extended release) providing the data set for the NDA filing. These data further describe the delayed
release profile of ALPHA-1062 delayed release oral tablet formulation and supplements the NDA data set by characterizing the therapeutic
and acceptable exposures compared to both the immediate release and extended release products.
Multiple dose administration of ALPHA-1062 delayed
release oral tablet formulation was well tolerated with two adverse events reported, both of which were mild and transitory. No serious
safety issues were observed in the study. During the second quarter of 2022, the Company met with FDA regarding the ALPHA-1062 program
for mild-to-moderate Alzheimer’s disease. The Company received feedback regarding the ALPHA-1062 RESOLVE trial, labeling, and manufacturing.
Labeling and manufacturing guidance for stability of ALPHA-1062 delayed release oral tablet formulation was provided by FDA to support
commercial strengths in commercially marketed product. The Company believes it has demonstrated the required stability endpoints for twelve
months of long-term stability data in the three potential strengths of ALPHA-1062 delayed release oral tablet formulation. The RESOLVE
trial was a trial designed to measure adverse events in an Alzheimer’s population and provide label enabling data for ALPHA-1062
delayed release oral tablet formulation. It was not a required trial to complete in order to submit an NDA application for approval. Post
second quarter meeting with FDA, the Company determined this trial would not be implemented and informed the FDA on this matter. As a
result of the agency’s feedback that the ALPHA-1062 RESOLVE trial was not required for the submission of an NDA, the Company filed
its NDA for ALPHA-1062 delayed release oral tablet formulation in mild-to-moderate Alzheimer’s disease in Q3 2023, allowing the
Company to include additional CMC stability data in the NDA filing. See the section entitled “Risk Factors — Risks Related
to Government Regulation — The regulatory approval processes of the FDA and other comparable foreign regulatory authorities are
lengthy, time consuming and inherently unpredictable”.
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Commercialization
ZUNVEYL Alzheimer’s Disease Commercialization
During the second half of 2023 the Company started,
in parallel with the Company’s regulatory activities, taking steps to develop a commercialization team to launch ZUNVEYL in the
U.S. The Company has completed sufficient planning and launched ZUNVEYL on March 19th, 2025 using a specialty sales force that
focuses on LTC physicians in the U.S. LTC physicians who treat elderly patients that reside in nursing homes also make pharmacologic decisions
in concert with the LTC treatment team. Our research has indicated that the acetylcholinesterase inhibitor (AChEI) prescription market
in the U.S. from the LTC market is large, representing 36% of the over 11 million prescriptions filled in pharmacies each year. The AChEI
class includes Aricept, Exelon, Exelon Patch, Razadyne, Adlarity, Namzaric, and generic versions of the AChEIs. Prescription data suggests
that there is currently high turnover of patients treated with currently approved AChEI medications, with 30% of patients discontinuing
treatment by month 4 and 55% discontinuing treatment within one year. The Company believes that patients who discontinue a first therapy
will try a 2nd and 3rd line therapy. Patient willingness to try multiple therapeutics provides an opportunity for ZUNVEYL to take market
share in the overall AChEI market. The sales force will message potential key points of label differentiation and exploit key issues with
existing AChEI medications. The Company will attempt to secure product coverage with U.S. payors. Market research indicates that payors
are likely to cover ZUNVEYL if the product is competitively priced.
Additionally, the Company intends to seek strategic
partnerships to expand promotional efforts and physician promotional coverage. Since ZUNVEYL received FDA regulatory approval, the Company
expects to seek distribution partners for major territories, identified as Europe, LATAM (Mexico, Central and South America), and Asia.
Distributors often have a deep understanding of local market dynamics, including regulatory requirements, distribution channels, and consumer
preferences. Partnering with a local distributor should allow the Company to leverage this expertise and navigate the complexities of
entering a new market more effectively. FDA regulatory approval does not guarantee regulatory approval for distribution in other territories.
We will need to seek and obtain regulatory approval through the processes in each of the above mentioned jurisdictions, which will take
additional time and resource. Please see the section entitled “Risk Factors — We have conducted, and in the future plan to
conduct, clinical trials for product candidates outside the United States, and the FDA and comparable foreign regulatory authorities may
not accept data from such trials”. Additionally, the Company intends to seek approval for potential additional indications and product
line extensions.
On January 8, 2025, the Company announced an exclusive
licensing agreement with China Medical System Holdings Limited (CMS) for the development, manufacturing and commercialization of ZUNVEYL
(benzgalantamine) in Asia (excluding Japan), Australia and New Zealand. ZUNVEYL is a next generation acetylcholinesterase inhibitor approved
in the US for the treatment of mild-to-moderate Alzheimer’s disease. Terms of the agreement total $44 million, which includes $6
million in total upfront payments split into tranches and development and commercial milestone payments. Additionally, ACI is eligible
to receive royalties on net sales of ZUNVEYL in Asia (excluding Japan), Australia and New Zealand. CMS will be responsible for the regulatory,
development, manufacturing, and commercialization of ZUNVEYL in the licensed territories.
On January 14, 2025, the Company announced the
strategic appointments of Jen Pesa, Vice President of Commercial; Jack Kelly, Head of Market Access; Rommel Fernandez, Vice President
of Corporate Strategy and Operations; and Kurt Grady, Vice President of Medical Affairs. These hires mark significant milestones in building
Alpha Cognition’s commercial and medical teams.
On March 19, 2024, the Company announced the
official commercial launch of ZUNVEYL.
Potential ZUNVEYL coverage and reimbursement
in the United States
The Company believes ZUNVEYL will have limited
payor barriers based on current US access and reimbursement data of generic Alzheimer’s disease symptomatic medications (e.g., acetylcholinesterase
inhibitors, memantine) and branded Namzaric® which are widely accessible to most MA-covered lives. Donepezil and Namzaric® are
mostly covered by health care plans.
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Third party market research with pharmacy and
medical directors, indicates that coverage of ZUNVEYL would be similar to Namzaric®. They forecast ZUNVEYL to be managed at a preferred
or non-preferred branded tier, without Prior Authorization or step edits, depending on rebates, as long as it is competitively priced
and differentiated from other products via its improved tolerability. Importantly, caregiver market research highlights cost is not an
issue. They are willing to pay a premium for a product that is more efficacious with less side effects. This provides additional confidence
to the Company that family members will request branded ZUNVEYL for their mild-to-moderate Alzheimer’s disease patients, even at
a higher cost than current generics.
The Wholesale Acquisition Cost (WAC) for ZUNVEYL
has been set at $749 per month. This pricing reflects the company’s commitment to ensuring affordability and access while supporting the
commercialization strategy in the $2 billion U.S. Alzheimer’s long-term care market. The WAC price serves as the benchmark for negotiations
with payers and channel partners, influencing reimbursement dynamics and market access strategy. Alpha Cognition remains focused on optimizing
patient access and formulary positioning to drive adoption and long-term revenue growth
Competitive Conditions and ZUNVEYL Positioning
Alzheimer’s disease symptomatic treatments
are currently limited and perceived to provide limited symptom improvement and cause difficult to manage tolerability side effects. Symptomatic
treatments are designed to improve the ability to learn, remember key events and loved ones, and function normally with daily tasks like
toileting, cooking, or home care. Each year greater than 2 million patients are on medication for the disease, which makes up half of
the estimated number of people with Alzheimer’s disease in the US. Approximately 70% of patients with mild Alzheimer’s disease,
80% with moderate, and 75% with severe Alzheimer’s disease are on drug-treatment. On average, it can take up to 2.5 months from
diagnosis to treatment, but can take up to 2 years, and roughly 32% will never go on treatment. Patients are treated primarily with symptomatic
medications to help the cognitive and functional symptoms of Alzheimer’s disease. In addition to symptomatic treatments, patients
will also be prescribed behavioral and psychiatric medications for depression, hallucinations, aggression and agitation.
There are five symptomatic drug treatments that
have been approved by the FDA to date for mild to moderate dementia of the Alzheimer’s type in adults, including ZUNVEYL.
1) Donepezil (marketed under the brand name, Aricept by Eisai and Pfizer)
a. First-to-market, approved in 1996; generic
b. Acetylcholinesterase inhibitor drug class, oral QD medication
b. Acetylcholinesterase inhibitor drug class, oral BID medication
c. Indicated for mild-to-moderate stage of Alzheimer’s disease
a. Approved in 2022, branded transdermal patch
b. Acetylcholinesterase inhibitor drug class, once-weekly transdermal system
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5) Benzgalantamine (marketed under the brand name ZUNVEYL by Alpha Cognition)
a. Approved in 2024, commercially available in Q1 2025
b. Acetylcholinesterase inhibitor drug class, oral BID medication
c. Indicated for mild-to-moderate stage of Alzheimer’s disease
The FDA approved Aducanumab (marketed under the
branded name Adulhelm by Biogen) in 2021 and lecanemab (marketed under the branded name Leqembi by Easai) for mild-to-moderate Alzheimer’s
disease. Adulhelm was the first disease modifying treatment (DMT), but due to several issues associated with the drug, including CMS restricting
overage, it was not easily accessible and was only covered for qualified clinical trial patients. Biogen has announced that it is discontinuing
sale of Adulhelm by the end of 2024. Leqembi is indicated for the treatment of Alzheimer’s disease. It is expected that coverage
and utilization may be better for Leqembi than Adulhelm, but this will only be apparent after several quarters of commercialization. It
is important to note that DMT agents will not be a competitor to the current standard of care, the AChEI class. DMTs will be used in combination
with these medications, as they do not address the symptoms of the disease.
Alzheimer’s disease is a highly genericized
market with limited drug development innovation. As noted above, three out of the five approved symptomatic medications are generic and
many have been in the market up to two decades. The acetylcholinesterase inhibitors drug class (i.e.: donepezil 70% market share, rivastigmine
4.86% market share, and galantamine 2.27% market share) are largely prescribed, with approximately 80% of the total Rx market share. N-methyl-D
(NMDA) receptor agonists (memantine and branded Namzaric) are indicated for moderate-to-severe Alzheimer’s disease and as such are
used in later stages, and as combination therapy with acetylcholinesterase inhibitors. Due to the perceived limited efficacy and side
effects of the acetylcholinesterase inhibitor medications, patients are often taking multiple therapies, ultimately increasing their drug
burden. ~60% of patients are on combination therapy in hopes of increasing efficacy outcomes and mitigating side effects. Of note, 55%
of patients progress to second line therapy, and 60% will progress further to a third line therapy. This further illustrates the unmet
needs of current treatment options, but also the patient’s willingness to keep trying medication until something works.
Source: Decision Resources Group, 2021
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The perceived limited efficacy or not enough efficacy
improvement, and tolerability side effects, including gastrointestinal issues (nausea, diarrhea, and vomiting), insomnia, cause a substantial
rate of treatment discontinuation. Some data and studies suggest that patients on acetylcholinesterase inhibitor medications, will discontinue
treatment approximately 30% of the time within 4 months and 55% discontinue therapy within 12 months. Gastrointestinal issues are cited
as a leading reason for discontinuing treatment, as reported in both physicians and caregiver market research. The high rates of gastrointestinal
adverse effects are also included in the prescribing information for each approved drug. The most common adverse events that are reported
to lead to discontinuation of therapy were diarrhea, nausea, vomiting, dizziness and decreased appetite among acetylcholinesterase inhibitors.
Prescribing habits within long-term care physicians, seem to be well entrenched, and overall, physicians report feeling dissatisfied and/or
apathetic about their symptomatic treatment options. Caregivers also expresses dissatisfaction with the currently approved symptomatic
treatments options.
Our solution: ZUNVEYL
There is a significant unmet need for better treatment
options for patients suffering from Alzheimer’s disease. The Company believes that ZUNVEYL is poised to be a next-generation treatment
option. The Company believes that we can differentiate ZUNVEYL based on several potential advantages to Alzheimer’s disease patients:
● No incidence of insomnia in the FDA approved label for ZUNVEYL
According to primary market research conducted
by and for the Company, including a report prepared by a third-party paid for by the Company in October 2021, we believe the market research
confirms that based on the product attributes listed above, 88% of LTC prescribers are likely to prescribe ZUNVEYL, with a 29% preference
share.
Alzheimer’s Disease Moderate-To-Severe
Stage Program
Disease and Market Overview
Our second program is a combination oral product
of benzgalantamine and memantime for moderate-to-severe Alzheimer’s disease. The product is in formulation and pre-clinical development.
The Company believes combining ALPHA-1062 with previous FDA approved NMDA receptor memantine would provide differentiating efficacy and
an attractive tolerability profile to patients within these advance stages. Moderate Alzheimer’s disease and severe Alzheimer’s
disease affects a total of ~1.4M patients in the United States. In 2020, over 7 million Rx’s were written for memantine-containing
product. In the moderate stage of Alzheimer’s disease symptoms becomes more intense, significantly affecting patients’ everyday
life. They have difficulties with communication and personality and behavioral changes present. The caregiver burden also increases during
this stage, as many activities (dressing, bathing, bathroom) require assistance and management. In the severe stage of the disease, patients
will experience more robust and debilitating symptoms. The complete deterioration of cognition and functional abilities require round-the-clock
care, eating and drinking prove difficult, and they usually become bed bound. On average 40% of the final years of an Alzheimer’s
disease patients (ages 70 to 80 years old) will be spent in the severe stage and the nature of the symptoms leads to the vast majority
being admitted into a LTC facility.
Increasing caregiver burden
The caregiver burden rises to new heights during
these stages, and many describe it as “extremely stressful”. The last 12 months of life, people with dementia relied on more
hours of family care (64.5 hours per week), 59% of caregivers felt they were “on duty” 24 hours a day, and financial care
costs increase. Once a decision is made to place the patient into a LTC facility, the stress of the caregiver isn’t alleviated.
In fact, many say the distress is unchanged or even increases.
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Our Product and Approach to Treatment
The Company plans to develop ALPHA-1062+ memantine,
to simplify the co-administration of these drugs by a patient or caregiver with the goal of increasing compliance and adherence to
the prescribed regimen. We believe that ALPHA-1062 + memantine has the potential to be adopted by patients already taking Namzaric® or
generic combination therapy as well as moderate to severely affected patients currently taking donepezil or memantine alone.
Following the launch of ALPHA-1062 now known
as ZUNVEYL for the treatment of mild-to-moderate dementia of the Alzheimer’s type in adults (Alzheimer’s disease), we
plan to progress the development of ALPHA-1062 + memantine through a streamlined 505(b)2 regulatory path. The product combination
is currently in a pre-clinical stage of development and will require additional product development and pre-clinical studies
to advance to an IND. Should the product advance ultimately to FDA approval, the Company believes ALPHA-1062 + memantine would have
the potential to provide differentiating product characteristics including, 3 mechanisms of action and a minimal side effect profile for
the treatment of moderate-to-severe dementia associated with Alzheimer’s disease. The Company believes ALPHA-1062 &
memantine will be absorbed through the gastrointestinal tract; ALPHA-1062 inertly with minimal gastrointestinal side effects and
memantine with acceptable side effects when up-titrated. The combination therapy will act via 3 distinct mechanisms of action acetylcholinesterase
inhibition, enhanced nicotinic receptor activity and sensitivity, and NMDA receptor antagonism. The Company believes ALPHA-1062 +
memantine could capture a substantial market share due to physicians’ established practice of prescribing combination therapies
in later stages of Alzheimer’s disease and patients’ acceptance of multiple medications.
As long-term care settings predominate in
the provision of care to moderately-to-severely affected patients, the Company will also raise awareness of the compelling results
from the Swedish Dementia Registry that demonstrated that galantamine had the strongest effect on cognitive improvement and was the only
drug to demonstrate a significant reduction in the risk of developing severe dementia, and a lower risk of death as compared to other
evaluated acetylcholinesterase inhibitors.
Should both ALPHA-1062 and the combination
therapy (ALPHA-1062+memantine) ultimately be approved for commercialization, the Company would be able to offer a solution that treats
all the stages of Alzheimer’s disease. The Company will plan to leverage the existing sales forces being established for the mild-to-moderate indication
targeting LTC providers. These groups make up 36% of all Rx within the Alzheimer’s disease market.The Company will
promote awareness and educate on differentiating features of its marketed treatments The sales force approach will consist of long-term care
home materials, peer-to-peer learning programs, partnerships with Alzheimer’s disease and long-term care societies and
associations.
For caregivers, we plan to deploy a targeted multi-channel market
campaign with the goal of motivating requests for ALPHA-1062 + memantine from their physician. Channels utilized will be focused
on long-term care home, partnership with patient advocacy groups, public relation efforts, website education, and a focused media
strategy.
Potential ALPHA-1062 coverage and reimbursement
in the United States