Another Alzheimer's Failure: Recapping INmune, Alzheimer's Space, and Refocus to Later-Stage Ideas

Another Alzheimer's failure, and a bad one at that.

INmune Failure

As you’ve no doubt seen, INmune reported that its Phase 2 Alzheimer’s trial failed this morning. While yet another Alzheimer’s drug failure could never be characterized as a surprise, and while we clearly emphasized (and reemphasized) the speculative nature of betting on this readout in our thesis paper, the unilateral and complete nature of this failure was definitely somewhat surprising.

The data showed essentially no signs of XPro1595 being effective in Alzheimer’s, with the company unable really to even find a compelling post-hoc subgroup analysis to present (as companies often do in this scenario; see Annovis Bio). So, after all of the skirmishing on Twitter/X—most of which was simply my pointing out many bears’ lack of rigor, especially those just blindly following Martin Shkreli (you can search my Twitter/X profile to see some of these amusing interactions)—INmune has indeed followed in the footsteps of Alzheimer’s companies before it as a complete failure.

While it isn’t worth doing a full autopsy, you can see some of the details of the results in the company’s updated corporate slide deck. You can see below how XPro1595 failed to show any difference in cognition, and actually showed a worsening on some endpoints, in its mITT population (the closest thing to the total study population). The subgroup analysis that they focus on is patients with an amyloid bet positive test (even though every patients was supposed to be amyloid positive according to the trial protocol) and two or more biomarkers of inflammation. The results even in this sub-analysis weren’t all that compelling, with only Cohen’s d effect sizes being reported, no actual results for the placebo and treatment groups given, no p-values given…

Even if that subgroup analysis turned out to be a signal of underlying efficacy, the effect they found is modest at best, far from what we thought could be a significant disease-modifying impact. We view it as grasping at straws and, needless to say, will be moving on from this company, as many will.

In conclusion, there is still more reflection and introspection to take place, which will occur over time, but as it stands, I stand by the case laid out in my thesis paper, which argued INmune had a chance to do the seemingly impossible, while readily acknowledging the flaws and risks to the story. Ultimately, these flaws, or perhaps flaws that were never discussed or unknowable, led to a failure, which (obviously) should be considered the default outcome of these Alzheimer’s trials.

Alzheimer’s Space

While these Alzheimer’s binary events are intriguing for their potential upside, I am not currently aware of any companies/drugs that appear compelling as potential disease-modifying therapies, and certainly none that have near-term readouts.

For the rest of the year, there is Anavex Life Science’s ($AVXL) expected to report two-year data update from its Alzheimer’s patients in the 2H25, though the data thus far is uninspiring. There is Phase 1 data from Prothena ($PRTA) expected in August, though Prothena is basically just piggybacking on anti-amyloid antibodies. Beyond that, there isn’t much until 2026, and even then, nothing all that interesting until the latter half of the year.

The most interesting thing on the Alzheimer’s horizon is Novo Nordisk’s ($NVO) data from Ozempic’s (semaglutide) Phase 3 trial in Alzheimer’s expected at some point probably in Q4. I would be pretty surprised if this study failed given how large it is (~1,800 patients) and the documented anti-inflammatory actions of GLP-1s, in addition to their metabolic effects.

The other interesting implication of the INmune failure is that it means, for the meantime, there continues to be no clear disease-modifying treatment threatening the mid-term market potential of Alpha Cognition ($ACOG), which, as we discussed in our initiation/thesis report, should have a straight line to accelerating revenue growth as it launches the first differentiated symptomatic Alzheimer’s treatment in nearly two decades.

Focus Back on Late-Stage and Commercial Ideas

While the anticipation leading up to this INmune readout was all-consuming at times (again, if you missed the Twitter/X debates, they were epic), INmune was a one-off from what I believe has to be the strategy in the current biotech landscape, which is a focus on late-clinical stage and commercial stage companies. While exceptions could be considered for mid-stage companies that have unique situations, I believe the majority of time and effort should be spent on identifying opportunities in these later stage spaces.

To this end, in addition to Alpha Cognition which should be an interesting story over the next few quarters, there are a couple of interesting stories I am currently digging in to that will likely have full investment theses published in the coming weeks.