Actinogen are now ramping up their phase 2/3 XanaMIA Alzheimer's trial, with interim data expected in Q3 CY2025, following the interesting results from the depression trial. This year has a lot of potential catalysts, that may be enough to bring in a partner to take it to the next level.

Here's an IR presentation where the CEO lays out the state of play, and why it might be a step up from the current Alzheimer's drugs, which are a bit controversial. The more I hear from him, the more I feel it's a good bet (I do have a small stake).

They are going for the holy grail - a safe, once a day pill for the modification of Alzheimer's and then also depression. It's a pill that might be able to be safely paired with other medication. It's a novel mechanism of action - reducing cortisol in the brain (while not affecting the normal hormonal function). It hasn't shown the kind of side-effects associated with SSRIs and other established anti-depressants.

They have evidence that it improves cognition, even in healthy adults. If the trial results prove consistent, it's the kind of thing I think anyone who's interested in maintaining good mental health might take a look at in the long run.

Currently available treatments and most of the competitor trials appear to be focused on reducing brain plaque buildup. I asked Perplexity why these treatments were considered controversial, and why Actinogen could improve the situation.

Discussion of the amyloid-beta treatment controversies

Aducanumab (Aduhelm) is a monoclonal antibody targeting amyloid-beta (Aβ) plaques in Alzheimer’s disease (AD), controversially approved by the FDA in 2021 under accelerated approval pathways. Here’s an analysis of its trajectory and Actinogen Medical’s potential role:

Aducanumab: Current Status

What Works

13. Amyloid Plaque Reduction

• Demonstrated 59%-71% amyloid plaque clearance on PET scans in phase 3 trials (EMERGE/ENGAGE), with dose-dependent effects.

• Biomarker data showed reductions in plasma p-tau181, a downstream tau pathology marker.

14. Regulatory Precedent

• First amyloid-targeting drug approved since 2003, paving the way for newer anti-amyloid therapies like lecanemab and donanemab.

15. Subgroup Benefits

• In EMERGE, high-dose aducanumab showed a 22% relative reduction in cognitive decline (CDR-SB score) over 18 months vs. placebo.

Challenges

Issue Impact

Divergent Trial Results EMERGE (positive) vs. ENGAGE (neutral) raised validity concerns; post-hoc analyses deemed statistically fragile.

Safety Risks 35%-41% incidence of amyloid-related imaging abnormalities (ARIA-E/ARIA-H).

Cost & Access Priced at $56,000/year, with Medicare restricting coverage to clinical trials due to uncertain benefit.

Clinical Relevance Amyloid reduction ≠ cognitive improvement: CDR-SB difference of 0.39 points (vs. ~1.5-2.0 MCID).

Actinogen’s Position

Actinogen’s emestedastat (Xanamem) represents a paradigm shift from amyloid-centric approaches:

16. Mechanistic Advantage

• Targets brain cortisol via 11β-HSD1 inhibition, addressing neuroinflammation and synaptic dysfunction linked to Aβ/tau pathology.

• Phase 2 trials showed cognitive improvements in AD patients without amyloid-related safety signals.

17. Strategic Differentiation

• Oral administration vs. aducanumab’s IV infusions.

• Targets broader neurological conditions (e.g., depression, Fragile X) beyond AD.

18. Clinical Progress

• XanaMIA phase 2b/3 trial (n=220) uses pTau181 biomarker stratification, with interim results expected Q4 2025.

Key Debates

• Amyloid Hypothesis Validity: Aducanumab’s approval reignited skepticism about Aβ’s causal role in AD.

• Regulatory Trust: FDA’s accelerated approval faced criticism for prioritizing biomarkers over clinical outcomes.

• Market Dynamics: Lecanemab/donanemab now dominate amyloid-targeting pipelines, while Xanamem offers a cortisol-focused alternative.

Conclusion

Aducanumab’s legacy lies in accelerating AD drug development despite its commercial and scientific setbacks. Actinogen aims to supersede it by addressing cortisol dysregulation—a mechanism orthogonal to amyloid—with a safer oral therapy. While amyloid remains a therapeutic pillar, the field increasingly recognizes multifactorial approaches as essential for meaningful disease modification.

In case anyone wants to dive in to the pharmacology. I also asked Perplexity to summarise it!

https://pmc.ncbi.nlm.nih.gov/articles/PMC11788964/

Perplexity summary:

This publication discusses the clinical development of emestedastat (also known as Xanamem), a drug being developed by Actinogen Medical for potential treatment of Alzheimer's disease and other neurological conditions. Here's a summary of the key points in plain English:

Background

• Emestedastat inhibits an enzyme called 11β-HSD1, which is involved in producing cortisol in the brain.

• High cortisol levels in the brain are thought to be harmful and may contribute to cognitive decline and Alzheimer's disease.

Study Approach

The researchers used several methods to determine the best dose of emestedastat for future clinical trials:

1. Traditional pharmacokinetic studies to see how the drug moves through the body

2. Brain imaging (PET scans) to see how much of the drug reaches its target in the brain

3. Cognitive tests to measure any improvements in thinking and memory

4. Hormone measurements to check for effects on the body's stress response system

Key Findings

• Earlier studies suggested 20 mg daily might be needed, but newer data showed lower doses of 5-10 mg may be sufficient.

• Brain scans showed the drug reaches its target in the brain at these lower doses.

• Cognitive tests in healthy older adults showed improvements in attention and working memory with emestedastat treatment.

• The drug was well-tolerated with no major safety concerns identified so far.

Conclusions

• Using multiple types of evidence helped refine the dosing strategy for emestedastat.

• A dose of 10 mg daily appears promising for future clinical trials in Alzheimer's disease.

• While no single study was definitive, the combined results support further development of emestedastat.

The researchers believe this approach of using various biomarkers and tests can help improve drug development for complex brain disorders like Alzheimer's disease, where many potential treatments have failed in the past.

A couple of introduction pieces:

• 10 min Spotify podcast on the upcoming Alzheimer's trial and science overview. October 2024.
• Stockhead article from September (before the depression trial result which was not a home run). Some good colour on the twists and turns the company has already taken, and the depression and Alzheimer's landscape.

The very basics: Chronic cortisol is toxic to nerve cells. This drug inhibits an enzyme that something something reduces cortisol in the brain.

Why was the depression trial result not a home-run?

The drug has a good safety and side-effect profile so far in hundreds of patients.

They did see clinically and statistically significant improvements in 'depression symptoms'.

But, because the placebo group also improved over the 10 weeks of the trial in the cognition tests, they cannot make any claims about cognitive improvements in depression. In case this is confusing, 'cognitive impairment' is apparently a different aspect of depression than 'depression symptoms' and they are tested independently.

I think they want to circle back for a longer depression trial with a funding partner after the Alzheimer's trial, but they would have immediately been in a better bargaining position had they hit a home-run. They want to prove out the cognition side because that would broaden the market...a lot.

Regardless, they are focused on Alzheimer's now, and if they stick to the schedule, the trial is fully funded as an independent pivotal trial (one of 2 that would be required for FDA approval).

• 220 patients, 9 months, Aust and US sites
• Interim results expected in mid-2025
• Final results mid-2026

' The patients are assessed on both cognition and Alzheimer’s progression.

“We believe we have already validated the target by showing improved cognition in healthy older volunteers and potentially a big clinical benefit in biomarker-positive patients with Alzheimer’s,” Dr Gourlay says. '

CEO Dr Steven Gourlay put $1m into an $11m capital raising. From what I can gather, he now owns at least $2m in shares of a 75m market cap.

They state this should fund trials until late CY2026.

From what I can gather Dr Gourlay has worked in biomedical research for 30 years, including at the FDA and the European equivalent. He may have already done rather well if he had skin in the game at prior ventures, but he seems to have good experience anyway.

Actinogen is entering a Stage 2b/3 trial to test their compound Xaneman over 36 weeks targeting an inhibition of brain cortisol for Alzheimer's (as well as in depression).

I got interested here after hearing him chat with Alan Kohler and seeing the volatile share price after a recent depression trial. The market decided it didn't like the trial results. Results were somewhat promising in early weeks against 'depression' and the signal strength improved between 4 and 10 weeks. But they lucked out in a test of 'cognition' because the placebo control group also saw a positive result there. Not an expert but apparently placebo groups doing well in depression trials can be a thing, because taking action of any kind tends to help (including entering a trial).

They wheeled out the chief science officer who did a series of talks and then the price recovered (only to tank again at the announcement of the raise).

I am not a Doctor but: I am tempted to believe them, the theory makes sense that reducing brain cortisol would help a lot of people (and it doesn't interfere with non-brain cortisol). I imagine (guessing) that they can't go back to test depression for a longer period since the money is spent. So they are moving forward with Alzeimer's in a longer test (36 weeks).