ACW Bioshares presentation, strong cortisol rationale
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Actinogen Medical Limited ACN 086 778 476
Suite 901, Level 9, 109 Pitt Street, Sydney NSW 2000
+61 2 8964 7401 | actinogen.com.au
1
ASX ANNOUNCEMENT
Actinogen presentsa brief corporate presentationhighlightingthe Company, Xanamem
and its strong scientific rationale in Alzheimer’s disease based on human cortisol
literature
Sydney, 06 August 2026. Actinogen Medical ASX: ACW (“ACW” or “the Company”) is pleased to
announce the 12-minute podium presentation entitled “Advancing Oral Xanamem in Alzheimer’s disease”
presented at the annual Bioshares Biotech Summit in Queenstown, NZ, today.
Highlights from the presentation are:
1. Xanamem® (emestedastat) is a promising, oral enzyme inhibitor designed to control elevated levels
of the “stress hormone”, cortisol, in the brain
2. Cortisol is synthesized from inactive cortisonein brain tissueby Xanamem’s target enzyme, 11β-HSD1
3. The rationale for controlling cortisol in Alzheimer’s disease (AD) via inhibition of its production by 11β-
HSD1 is strong:
a. The adverse effects in the brain of therapeutic cortisol or excess cortisol seen in diseases
such as Cushing’s syndrome include impairment of memory, learning and problem-solving, as
well as psychiatric symptoms and shrinkage of brain tissue
b. Elevated cortisol levels in brain fluid are associated with AD
c. Elevated cortisol levels in brain fluid are also associated with the major genetic risk factor for
AD, ApoE4
d. Genetic alterations of 11β-HSD1 affect risk of cognitive decline: overexpression leads to
decline while absence of expression is protective
e. Xanamem has shown preliminary activity in a trial of patients with mild AD and positive effects
on attention and working memory in older volunteers.
4. The Company’s first pivotal trial in 247 participants with AD will report topline, final results in November
this year.
A copy of the presentation is attached to this announcement.
View this announcement on our InvestorHub: https://investors.actinogen.com.au/link/eW1apP
ENDS
®
Xanamem is a registered trademark of Actinogen Medical Limited
Actinogen Medical Limited ACN 086 778 476
Suite 901, Level 9, 109 Pitt Street, Sydney NSW 2000
+61 2 8964 7401 | actinogen.com.au
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Investors Media
Dr Steven Gourlay Michael Roberts George Hazim
CEO & Managing Director Communications Media & Public Affairs Australia
P: +61 2 8964 7401 M: +61 423 866 231 M: +61 417 516 262
E. steven.gourlay@actinogen.com.au E. michael.roberts@actinogen.com.au E: georgehazim@mediaaffairs.com.au
Announcement authorised by the Disclosure Committee of Actinogen Medical Limited
About Actinogen Medical
Actinogen Medical (ACW) is an ASX-listed, biotechnology company developing a novel therapy for neurological and
neuropsychiatric diseases associated with dysregulated brain cortisol.There is a strong association between cortisol and
detrimental changes in the brain, affecting cognitive function, harm to brain cells and long-term cognitive health.
Cognitive function means how a person understands,remembers and thinks clearly.Cognitive functions include memory,
attention, reasoning, awareness and decision-making.
Actinogen is currently developing its lead compound, Xanamem, as a promising new therapy for Alzheimer’s Disease. It
has also conducted a phase 2 trial in patients with cognitive impairmentand depression andmay study Fragile X Syndrome
and other neurological and psychiatric diseases in the future. Reducing cortisol inside brain cells could have a positive
impactin these and many other diseases.The cognitive dysfunction,behavioural abnormalities,and neuropsychological
burden associated with these conditions is debilitating for patients,and there is a substantial unmetmedical need for new
and improved treatments.
Clinical Trials
The XanaMIA Phase 2b/3 Alzheimer’s disease trial is a double-blind, 36-week treatment, placebo-controlled, parallel
group design trial in 247 patients with mild to moderate AD and progressive disease, determined by clinical criteria and
confirmed by an elevated level of the pTau181 protein biomarker in blood.Patients receive Xanamem 10 mg or placebo,
once daily,and its ability to slow progression of Alzheimer’s disease is assessed with a variety of endpoints.The primary
endpointof the trial is the internationally-recognized CDR-SB (Clinical Dementia Rating scale – Sum of Boxes). The trial
is being conducted in Australia and the US and is now closed to participant recruitment. It has passed an independent
Data Monitoring Committee safety and efficacy futility review and final topline results are expected in November 2026.
The XanaMIA-OLE Alzheimer’s disease open-label extension is an open-label phase of up to 25 months treatment
where all participants will receive active Xanamem 10 mg once daily. The trial evaluates safety and a limited number of
efficacy endpoints such as the CDR-SB. The trial commenced in March 2026 and is open to all former and current
participants in the XanaMIA Phase 2b/3 trial.
The XanaCIDD Phase 2a depression trial was a double-blind, six-week proof-of-concept, placebo-controlled, parallel
group design trial in 167 patients with moderate, treatment-resistant depression and a degree of baseline cognitive
impairment. Participants were evenly randomized to receive Xanamem 10 mg once daily or placebo, in most cases in
addition to their existing antidepressanttherapy,and effects on cognition and depressionwere assessed.Trial results were
reported in August 2024 and showed clinically and statistically significantbenefits on depression symptoms with positive
effects on the MADRS scale (a validated scale of depression symptom measurement) and the PGI-S (a valid patient
reported assessmentof depression severity). Cognition improved markedly and to a similar extent in both Xanamem and
placebo groups. The peer-reviewed publication relating to this trial can be accessed for free via this link:
https://tinyurl.com/ckm63z63.
About Xanamem (emestedastat)
Xanamem’s novel mechanism is to control elevated levels of cortisol (aka the “stress hormone”) in the brain through the
inhibition of the cortisol synthesis enzyme,11β-HSD1,withoutaffecting production of cortisol by the adrenal glands which
is essential for the body’s normal functioning.Xanamem is a first-in-class,once-a-day pill designed to deliver high levels
of cortisol control in key areas of the brain related to Alzheimer’s and other diseases such as the hippocampus and frontal
cortex. To view Xanamem’s two-minute Mechanism of Action animation, click here.
Actinogen Medical Limited ACN 086 778 476
Suite 901, Level 9, 109 Pitt Street, Sydney NSW 2000
+61 2 8964 7401 | actinogen.com.au
3
Chronically elevated cortisol is associated with progression in Alzheimer’s Disease and excess cortisol is known to be
toxic to brain cells. Cortisol itself is also associated with depressive symptoms and when targeted via other mechanisms
has shown some promise in prior clinical trials. The recent XanaCIDD trial demonstrated clinically and sometimes
statistically significant benefits on depressive symptoms, further validating the cortisol control mechanism for the
Xanamem 10 mg oral daily dose.
The Company has studied 11β-HSD1 inhibition by Xanamem in more than 500 volunteers and patients in eight clinical
trials. Xanamem has a promising safety profile and has demonstrated clinical activity in patients with depression,patients
with biomarker-positive Alzheimer’s disease and cognitively normal volunteers. High levels of target engagement in the
brain with doses as low as 5 mg daily have been demonstrated in a human PET imaging study.
Xanamem is an investigational productand is not approved for use outside of a clinical trial by the FDA or by any global
regulatory authority. Xanamem® is a trademark of Actinogen Medical.
Disclaimer
This announcement and attachments may contain certain "forward-looking statements" that are not historical facts; are
based on subjective estimates,assumptions andqualifications;and relate to circumstances and events thathave nottaken
place and may nottake place.Such forward looking statements should be considered “at-risk statements” - notto be relied
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and uncertainties) that may lead to actual results being materially different from any forward looking statement or the
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obligation to revise such statements to reflect events or any change in circumstances arising after the date hereof, or to
reflect the occurrence of or non-occurrence of any future events. Past performance is not a reliable indicator of future
performance. Actinogen Medical does not make any guarantee, representation or warranty as to the likelihood of
achievementor reasonableness of any forward-looking statements and there can be no assurance or guarantee that any
forward-looking statements will be realised.
ACTINOGEN MEDICAL ENCOURAGES ALL CURRENT INVESTORS TO GO PAPERLESS BY REGISTERING THEIR DETAILS
WITH THE DESIGNATED REGISTRY SERVICE PROVIDER, AUTOMIC GROUP.
Advancing oral Xanamem® in Alzheimer’s Disease
Topline data from phase 2b/3 pivotal trial in November (n=247)
Potentially game-changing product profile
Strong scientific rationale for brain cortisol as a therapeutic target
Corporate Presentation, Bioshares 2026
August 6, 2026
® Xanamem is a registered trademark of Actinogen Medical Limited
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This presentation is dated June 2026 and has been prepared by Actinogen Medical Limited. (“Actinogen” or the “Company”) based on information available to it as at the date of this presentation. The information in this presentation is
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Disclaimer
Corporate Presentation Bioshares August 2026
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Corporate and Xanamem highlights
Validated 11β-HSD1 mechanism with differentiated oral profile
• Xanamem is a novel oral therapy targeting elevated brain cortisol, a well-
established risk factor for Alzheimer’s disease and depression
• Oral administration and favorable safety profile support broad use
Biomarker-enriched pivotal trial with independent validation
• XanaMIA phase 2b/3 pivotal trial (n=247) fully enrolled; open-label extension commenced;
topline results November 2026
• January 2026 independent Data Monitoring Committee recommended the trial continue
unchanged following unblinded interim review of safety and efficacy futility
Regulatory clarity in the US and EU
• Current pivotal trial expected to form part of registrational package for Alzheimer’s disease
• FDA and EMA guidance support a streamlined marketing approval path requiring only one
additional pivotal trial following positive XanaMIA results
Corporate Presentation Bioshares August 2026
Potentially game-changing oral therapy in late-stage trials for Alzheimer’s disease
Strong capital position
• Company funded through mid 2027
• Resources focused on execution of the XanaMIA trial and its extension phase
NEXT MAJOR VALUE INFLECTION
Pivotal trial topline results
November 2026
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Why do we believe brain cortisol
control with Xanamem can slow
Alzheimer’s disease (AD)?
Corporate Presentation Bioshares August 2026 4
Cortisol and the Alzheimer’s brain
“Stress” and/or genetic factors may drive multiple AD mechanisms via cortisol
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Corporate Presentation Bioshares August 2026
Seckl J 2024 (left panel); Milligan Armstrong et al. 2021 https://doi.org/10.1111/brv.12750
Xanamem’s target:
Genetic alternations are
both protective (down)
and a risk factor (up) for
cognitive decline
Elevated human brain cortisol levels linked to AD
Brain fluid cortisol measurements best reflect the tissue cortisol environment
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Corporate Presentation Bioshares August 2026
Popp et al, 2015
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
Cognitive Normal MCI Other MCI AD AD dementia
CSF
cortisol
(μg/dl)
p<0.001
Popp et al., 2015, Neurobiol. Aging 36:601–607
German Dementia Competency Network study
Major AD genetic risk factor of ApoE4 associated with
elevated brain cortisol levels
~67% of patients in AD trials have one or two copies of the ApoE4 gene
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Corporate Presentation Bioshares August 2026
Gil-Bea et al. 2010
a) CSF cortisol level by disease classification (SCI:
subjective cognitive impairment; SMCI stable mild
cognitive impairment: progressive mild cognitive
impairment; AD Alzheimer’s disease
b) As above by known ApoE4 genetic status (0 vs. 1-2
copies)
Therapeutic cortisol worsened AD over 12 months
Historical trial of 10mg prednisolone in patients with mild to moderate disease (n=138)
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Corporate Presentation Bioshares August 2026
Aisen et al. Neurology 54:Feb 2000; dropouts were more common in the prednisolone group
0
1
2
3
4
5
6
7
8
9
Cognition Dementia Depression
Placebo Prednisolone (cortisol)
Worsening
Point
Change
In
Score
ADAS-cog
P=0.16
CDR-SB
P=0.07
Ham-D
P=0.25
Cortisol excess is toxic to the brain
Literature from clinical use as a therapeutic and excess cortisol in
Cushing’s syndrome
Symptom or sign of brain toxicity
Trends to worsening Alzheimer’s disease
Shrinkage to hippocampus
General brain shrinkage
Memory impairment
Executive function impairment
Difficulty learning
Poor concentration
Anxiety
Depression
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Corporate Presentation Bioshares August 2026
Data reported for Cushing’s syndrome of endogenous excess cortisol and/or therapeutic corticosteroids
Dekkers et al. 2022; Liu et al. 2022; De Alcubierre et al. 2023; Katragadda et al. 2025
Xanamem achieves high brain target occupancy
Distribution of cortisol synthesis enzyme 11β-HSD1 shown in left panel
SUVRcarotid
5 mg Xanamem
Baseline After 7 days of daily dosing
10 mg Xanamem 20 mg Xanamem
Journal of Alzheimer’s Disease 97 (2024) 1463–1475
Brain 11-Hydroxysteroid Dehydrogenase Type 1 Occupancy by Xanamem Assessed by PET in Alzheimer’s Disease and Cognitively Normal Individuals
Victor L. Villemagne, Vincent Dor, Lee Chong, Michael Kassiou, Rachel Mulligan, Azadeh Feizpour, Jack Taylor, Miriam Roesner, Tamara Miller and Christopher C. Rowe
Corporate Presentation Bioshares August 2026
Reduction in tracer signal (loss of color) indicates high 11β-HSD1 occupancy -
Strong occupancy observed across evaluated clinical doses
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Xanamem data in patients with mild Alzheimer’s
Phase 2a data showed slowing of decline over 12 weeks (n=34 with high pTau181)
Corporate Presentation Bioshares August 2026
0.36
0.98
0
0.2
0.4
0.6
0.8
1
1.2
1.4
Baseline Week 12
Xanamem Placebo
0.6-point benefit @12 weeks
Xanamem vs. Placebo
• Mean 0.6 units
• Median 0.8 units
• p = 0.09
• Cohen’s d = 0.4
CDR-SB* units
Change from
Baseline (SE)
Worse
performance
Journal of Alzheimer’s Disease 100 (2024) 139–150 * Clinical Dementia Rating scale – Sum of Boxes
Plasma pTau181 Predicts Clinical Progression in a Phase 2 Randomized Controlled Trial of the 11-HSD1 Inhibitor Xanamem® for Mild Alzheimer’s Disease
Jack Taylor, Mark Jaros, Christopher Chen, John Harrison and Dana Hilt
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Durable activity in phase 2 depression trial
Separation from placebo overall and on background SSRI therapy
Corporate Presentation Bioshares August 2026
EOT 2.6-point difference
Cohen’s d = 0.38
p = 0.15
PT 4.2-point difference
Cohen’s d = 0.64
p = 0.03
Abbreviations: SSRI, selective serotonin reuptake inhibitor.
*Planned phase 3 population
MADRS
LS
mean
change
from
baseline
(±
SE)
Xanamem (n=37) Placebo (n=39)
ON TREATMENT AND BACKGROUND SSRI THERAPY (n=76)* FOLLOW
UP
-12
-10
-8
-6
-4
-2
0
Baseline Week 2 Week 4 Week 6 Week 10
12
Better
Depression
-3
-2.5
-2
-1.5
-1
-0.5
0
0.5
donanemab all placebo all
What we hope to see in November: much greater
ability to slow disease than existing treatments
Xanamem phase 2a p-
tau–positive patients
showed near-
stabilization
Worsening of
CDR-SB
over 18 months
Worse
performance
Modest benefit
of donanemab
(Kisunla) over
18 months1
1. Sims et al. JAMA 2023 336(6):512-527 Corporate Presentation Bioshares August 2026
Xanamem may stabilize or slow CDR-SB progression more than other therapies
SIMULATED PHASE 2B/3 DATA
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Contacts
Will Souter
CFO & Investor Relations
M: +61 402 035 716
E. will.souter@actinogen.com.au
Steven Gourlay
CEO & Managing Director
P: +61 2 8964 7401
E. steven.gourlay@actinogen.com.au
Join the Actinogen Investor Hub:
https://investors.actinogen.com.au/
Corporate Presentation Bioshares August 2026 14
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