A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel
Design, Prospective, 52-Week, Phase 2 Clinical Study to Evaluate the Safety and Efficacy of GV1001 Administered Subcutaneously for the Treatment of Mild to Moderate Alzheimer*s Disease

1.1.1 Alzheimer*s Disease
Alzheimer*s disease (AD) is the most common cause of dementia and the sixth
leading cause of death in adults in the United States (US) (Herbert et al,
2013; Xu et al, 2010; Burns and Iliffe, 2009). An estimated 6.07 million people
in the US had AD in 2020, and the number is expected to rise to 13.85 million
per year by 2060 (Rajan et al, 2021). Worldwide, approximately 47 million
people are affected with dementia with AD being the most common cause and
accounting for about 70% of cases (Emmady and Tadi, 2021). The average life
expectancy after diagnosis is 8 years (Alzheimer*s Association, 2021). The
economic burden of AD is substantial. Costs associated with AD ranged between
$159 and $215 billion in 2010, and are projected to be between $379 and more
than $500 billion in 2040 (Hurd et al, 2013).
The exact mechanism of AD is unknown; therefore, treatment is difficult.
According to a 2015 report by the American Pharmaceutical Association (PhRMA,
2018), between 1998 and 2014 about 123 drugs under development for AD failed.
Only 4 drugs (donepezil, galantamine, rivastigmine, and memantine) have been
approved until 2003 for use by the US Food and Drug Administration (FDA)
(PhRMA, 2018). In addition, a combination product of memantine and donepezil is
available (Alzheimer*s Association, 2021). Another product (tacrine) was
approved prior to 1998, but was discontinued in May 2012 for safety reasons.
Most recently, aducanumab (Aduhelm*) has been approved by the FDA using the
accelerated approval pathway; however, some uncertainty about the drug*s
clinical benefit remains (FDA, 2021). Available symptomatic treatments may
alleviate cognitive and behavioral symptoms and improve quality of life, but do
not impact disease progression.
Although the exact cause of AD is not known, several hypotheses are being
explored including cholinergic hypothesis (Francis et al, 1999), genetic
mutations, amyloid beta (Aβ) aggregation (Hardy and Allsop, 1991), and tau
hyperphosphorylation (Mudher and Lovestone, 2002). Among these, amyloid
hypothesis is believed to be most important. Truncated Aβ is pathologically
increased in the AD brain and its monomers start to aggregate and form
oligomers and finally plaques. The oligomers are thought to be toxic to
surrounding neurons and glial cells. Aducanumab is the first novel therapy for
AD approved since 2003 and is the first treatment directed at the underlying
pathophysiology of AD, the presence of Aβ plaques in the brain (FDA, 2021).
Tauopathy is also thought to play critical roles in the pathogenesis of AD and
is strongly correlated with cognitive decline. Tau, a protein closely related
to the microtubule associated with cell structure and transport of
intracellular substances, is hyperphosphorylated by a phosphorylating enzyme to
form a bundle and form a neurofibrillary tangle (NFT). As a result, the
axoplasmic transport of nerve cells fails to function and brain cells die
(Haass et al, 2012). Inflammation is one of the important pathogenic mechanisms
in the progression of AD. Inflammation causes functional impairment and death
of neuronal cells.
Therefore, an effective and well tolerated treatment for AD that not only
manages symptoms but prevents or improves memory loss and decline in cognition
continues to be an important unmet medical need in the long-term management of
AD. New drugs in development aim to modify the disease process itself, by
impacting one or more of the many wide-ranging brain changes that AD causes.
Drugs in development include those that target Aβ and tau protein, β secretase,
inflammation, and 5-HT2A receptor (Alzheimer*s Association, 2021).
1.1.2 GV1001
GV1001 (hTERT peptide; tertomotide hydrochloride) is a single peptide of 16
amino acids derived from telomerase reverse transcriptase (TERT). This peptide
corresponds to a fragment from the catalytic site of the enzyme telomerase.
Telomerase is a reverse transcriptase that maintains telomere function in
dividing cells. GV1001 was first developed as an active immunotherapy in the
treatment of cancer forms expressing telomerase. After administration, GV1001
is processed and presented in the human leukocyte antigen (HLA) complex and
gives rise to T-cells that recognize cells expressing telomerase.
Telomerase has been proposed to possess anti-aging properties. The catalytic
subunit of telomerase, TERT, is expressed in neurons throughout the brain
during development, but is absent from neurons in the adult brain (Mattson,
2000). Telomerase reverse transcriptase has been shown to exhibit
neuroprotective properties in experimental models of neurodegenerative
disorders suggesting that restoring TERT expression in neurons in the adult
brain may protect against age related neurodegeneration (Zhu et al, 2000). The
TERT protein may offer neuronal resistance against pathological tau by reducing
production of oxidative species and improving mitochondrial function (Spilsbury
et al, 2015). The neuroprotective properties of TERT are the basis for new
treatments like GV1001 to slow or stop disease progression or to prevent
neurodegenerative diseases (GemVax Study 20140000002332-1 and Study
20140000002332-2).
GV1001 and AD
Studies using in vivo and in vitro AD models have shown that GV1001 inhibits
neurotoxicity, apoptosis, and the production of reactive oxygen species induced
by Aβ in neural stem cells (NSCs). It effectively blocks Aβ toxicity by
mimicking the extra-telomeric functions of hTERT. The findings from these in
vivo and in vitro studies, summarized below, led to the development of GV1001
as a therapeutic agent for AD.
First, GV1001 was shown to protect neural stem cells (NSCs) against Aβ (Park et
al, 2014; Park et al, 2016). Although Aβ decreased viability, proliferation,
and mobilization of NSCs, treatment with GV1001 restored the cells to wild-type
levels. These effects were mediated by mimicking the extra-telomeric functions
of hTERT. In addition, GV1001 treatment was shown to increase the expression
level of survival-related proteins, and decrease the levels of death and
inflammation-related proteins.
Second, GV1001 has been shown to have direct effects against oxidative stress.
Treatment with GV1001 rescued hydrogen peroxide (H2O2)-injured NSCs. GV1001 was
also shown to have antioxidant and neuroprotective effects, which appear to be
mediated by scavenging free radicals, increasing survival signals and
decreasing death signals (Park et al, 2014; Park et al, 2016). Third, GV1001
significantly improved memory functions when evaluated in a transgenic (Tg) AD
mice model. This was shown in both a passive avoidance test and Y-maze test. In
the mouse model, GV1001 was effective from the mild to the moderate stage (9
month to 18 month old Tg mouse) and more effective at the moderate stage
(internal report only, not published yet).
When it comes to mechanisms, GV1001 decreased the amount of Aβ, prevented
formation of NFT resulting from pathologic changes of the tau protein,
inhibited astrogliosis, and promoted neurogenesis. These results suggest that
GV1001 may play a major role in reducing cytotoxicity and enhancing
rehabilitation of brain function.
GV1001 reproduces the exact amino acid sequence from position 611 to position
626 of hTERT. Several in vitro studies have shown that GV1001 protects neural
cells against neurotoxicity, apoptosis, and reactive oxygen species (ROS)
induced by Aβ and oxidative stress inducing cell, anti-apoptotic effects,
mitochondrial stabilization, and anti-aging and antioxidant effects. Acting on
several mechanisms related to AD pathology, GV1001 may be efficacious in these
patients. In a completed Phase 2 study conducted in Korea, GV1001 showed
significant improvement in change from baseline of Severe Impairment Battery
score at Week 24 and demonstrated a c

This study has been transitioned to CTIS with ID 2024-511610-20-00 check the CTIS register for the current data.

Cognitive and functional abilities will be evaluated using psychometric scales
(ie, cognitive subscale of the Alzheimer*s Disease Assessment Scale [ADAS
cog11]), assessment of activities of daily living (ie, Amsterdam Instrumental
Activities of Daily Living Questionnaire [A-IADL-Q]), and global ratings of
dementia (ie, Clinical Dementia Rating-Sum of Boxes [CDR SB], Neuropsychiatric
Inventory [NPI], Mini Mental State Examination [MMSE],Alzheimer*s Disease
Cooperative Study-Clinical Global Impression of Change [ADCS-CGIC], Clinician*s
Interview-Based Impression of Change - Plus Family Input [CIBIC-Plus], and
Quality of Life in Alzheimer*s Disease [QoL-AD]). Efficacy evaluations will be
performed at baseline, Week 12, Week 26, Week 38, and Week 52 (the primary
endpoint [PE]). Structural changes in the brain will be evaluated using
volumetric magnetic resonance imaging (vMRI) at baseline and Week 52. The
safety of GV1001 will be assessed throughout the study.

This is a multicenter, randomized, double-blind, placebo-controlled, parallel
group Phase 2 study in participants with mild to moderate AD. The study
population will include male and female participants between 55 and 85 years of
age (inclusive), with a diagnosis of probable AD as demonstrated by meeting
National Institute of Neurological and Communicative Disorders and
Stroke-Alzheimer*s Disease and Related Disorders Association (NINCDS ADRDA)
criteria. Participants should have a magnetic resonance imaging (MRI) or
computed tomography (CT) scan performed within the 2 years prior to screening
with findings consistent with a diagnosis of AD. Results from Aβ positron
emission tomography (PET) scan or cerebrospinal fluid (CSF) examination
performed within the 2 years prior to screening will be used to confirm
eligibility. If no Aβ PET scan or CSF examination results are available,
participants will undergo an Aβ PET scan at screening. Participants or their
legal representative, as well as the participant*s caregiver, must be able to
provide written informed consent.
The study will consist of a screening period (up to 60 days prior to the first
dose), a 52 week double blind treatment period, and an end-of-study (EOS)
visit. Eligible participants will be randomized in a 1:1:1 ratio to receive
treatment with GV1001 0.56 mg, GV1001 1.12 mg, or placebo (normal saline) every
week for 4 weeks beginning on Day 1 (of Week 1) followed by every 2 weeks
through Week 50.
An independent Data and Safety Monitoring Board (DSMB) review will be planned
when 90 participants (50%) have either completed Week 26 or have discontinued
the study to evaluate safety data. The DSMB may recommend early stopping of the
study for safety reasons.
If a participant discontinues treatment prematurely, the participant will be
asked to continue with the scheduled study visits until the EOS visit. If a
participant discontinues the study prematurely (except for those who withdraw
consent), the participant will be asked to come for an early termination (ET)
visit for efficacy scale and safety assessments. These assessments are the same
as those scheduled at the PE visit at Week 52. If the ET visit takes place
within 4 weeks after a completed protocol scheduled visit with efficacy
assessments, efficacy scale assessments are not required at the ET visit.
Prior to randomization, eligibility of potential participants will be confirmed
through an adjudication process in which screening data (eg, MMSE, MRI/CT
scans) obtained to evaluate AD status are reviewed by a central independent
adjudicator. The central independent adjudicator will review the scoring sheet
completed by the Investigator prior to randomization and provide an independent
assessment of the participant*s eligibility and may request exclusion of a
participant from entry into the study. A central independent reader will review
magnetic resonance imaging (MRI) and/or computed tomography (CT) scans to
confirm eligibility. Investigators must not randomize a participant prior to
receipt of this independent confirmation of the participant*s eligibility.
Efficacy evaluations will be performed at baseline, Week 12, Week 26, Week 38,
and Week 52 using the ADAS-cog11, A-IADL-Q, CDR-SB, NPI, MMSE, CIBIC-Plus, and
QoL AD scales. The ADAS-cog11 scale will be evaluated by a central independent
reader for each visit. At the visits where several efficacy assessments are
administered, every effort should be made to perform the efficacy evaluations
in the same order at each visit (ADAS-cog11, A-IADL-Q, CDR SB, NPI,
MMSE,ADCS-CGIC, CIBIC-Plus, and QoL AD). To ensure the objectivity and accuracy
of the study results, efficacy evaluations must be performed by adequately
trained and experienced raters. The raters must be certified for this study to
administer the ADAS-cog11, A IADL Q, CDR-SB, NPI, MMSE, CIBIC-Plus, QoL-AD, and
C-SSRS scales. Training, certification, and materials for rating will be
provided by a rater training group. To mitigate the risk of breaking the blind,
the efficacy evaluator is not to be involved in the participant*s treatment or
have access to the record of reported AEs.
Safety will be assessed throughout the study by monitoring for AEs, laboratory
evaluations, electrocardiogram (ECG) findings, vital signs measurements,
physical examination, and suicidal ideation and behavior (C-SSRS). Blood and
CSF samples will be collected to evaluate the effect of GV1001 on analysis of
biomarkers of AD. Blood samples will also be collected for and immunogenicity
analysis (antibodies to GV1001).

The study will consist of a screening period (up to 60 days prior to the first
dose), a 52-week double-blind treatment period, and an EOS visit. For an
individual participant, the maximum duration of study participation is
approximately 14.5 months, including an up to 60-day screening period.
GV1001 (0.56 mg or 1.12 mg) or placebo (normal saline) will be administered by
a SC injection once weekly for 4 weeks (4 times) beginning on Day 1 (of Week 1)
followed by a SC injection every 2 weeks through Week 50 (23 times) for a total
of 27 SC injections.

1.3 Benefit/Risk Assessment
Although there have been numerous clinical studies evaluating treatments for
AD, most treatments currently approved for use are symptomatic treatments (ie,
donepezil, galantamine, rivastigmine, memantine, or memantine/donepezil
combination product). To date, treatments with a single mechanism of action
have been developed based on the pathophysiology of AD. However, these are not
disease modifying agents, and their effect is unsatisfactory. Recently,
aducanumab has been approved as the first treatment directed at the underlying
pathophysiology of AD, the presence of Aβ plaques in the brain (FDA, 2021). As
AD is thought to be a complex disease caused by a variety of mechanisms,
therapeutic agents with various mechanisms of actions may be more successful in
clinical practice than a single mechanism-based therapy.
Unlike conventional therapeutic drugs with single mechanism of action, GV1001
with its multiple mechanisms of action is expected to be effective as a
therapeutic agent for AD as it has anti inflammatory and anti oxidative
properties and blocks the accumulation of Aβ and inhibits tau protein
condensation. Therapeutic agents, such as GV1001, with various mechanisms
rather than single mechanism-based agents may be successful in the treatment of
AD patients in clinical practice. The current study is expected to further
demonstrate the potential of GV1001 as a new class of medication for the
treatment of AD.
In this study, participants may continue to take their prior medications for AD
available per local regulations, as long as they were taking a stable dose for
at least 12 weeks prior to the screening visit. Participants may continue to
take over-the-counter (OTC) cognition supplement during the study if they were
not exceeding the recommended dose for at least 12 weeks prior to the screening
visit.
Treatment with GV1001 has been well tolerated in clinical studies in multiple
cancer indications and BPH. Therefore, the potential adverse effects or risks
associated with GV1001 in the current study are expected to be small and
manageable, while the expected benefits may be substantial. However, the
experience with GV1001 as treatment for AD is limited. Further information on
the safety of GV1001 will be obtained in the current study.
The available information suggests that the present study may have a favorable
risk-benefit ratio. However, the potential benefits of GV1001 as treatment for
AD have not been fully explored. The GV1001 clinical development program will
continue to evaluate the risk-benefit of GV1001 in specific clinical
circumstances with high medical need, including AD.
Refer to Section 3 for details of study procedures, dose, and study design
justification. Detailed information about the known and expected benefits and
risks and reasonably expected AEs of GV1001 is available in the Investigator*s
Brochure.