Introduction
For years, the scientific focus may have been too focused on targeting amyloid, while inflammation and modulation of glial activity has been overlooked. Inflammation and the correlated glial cell activity is a major target; glial cells outnumber nerve cells in the brain by a ratio of perhaps 3 to 1.
Biomarkers—biological indicators that provide critical insights into disease progression and treatment response—have become indispensable tools in the fight against Alzheimer’s. In this post, we’ll explore how XPro’s unique mechanism of action is reshaping the biomarker landscape, offering a potential breakthrough in the quest to slow, halt, or even reverse the course of the debilitating disease that is Alzheimer’s disease.
As Alzheimer’s disease progresses, the relevant biomarkers continue to deteriorate. Stabilizing them should therefore already be indicative of disease modification.
As previously discussed, the key biomarkers here are NfL and ptau-217. Reportings on those biomarkers should be the reference for all competitors of Biogen/Eisai and Eli Lilly.
Outperformance of one or more of these biomarkers, whether or not through a different mechanism of action, could indicate disease modification, be prognostic of cognitive efficacy, and may pave the way for accelerated (see blog post “Is the FDA openly suggesting accelerated approval based on NfL?” and full approval). The other biomarkers serve to corroborate these, and allow insight in the overall picture of change in patients.
Biomarkers reported by anti-amyloid antibodies
As we know, anti-amyloid antibodies lead to about a 30% slowing of cognitive decline in amyloid-positive Alzheimer’s patients. Both are unsafe, as they come with amyloid-related imaging abnormalities, referred to ARIA.
Biomarkers such as p-tau, neurogranin, GFAP and NfL generally precede cognitive deterioration as shown by Eli Lilly:
Eisai/Biogen and Eli Lilly have enrolled patients with MCI and mild AD. I will focus on biomarkers reported by Eli Lilly. Those for Biogen/Eisai’s lecanemab are mostly similar.
NfL – neurofilament light: no significant difference
Neurofilament Light is a biomarker of neurodegeneration across neurodegenerative diseases. Neurofilaments are structural elements. When NfL is detected, it indicates loss of cellular structure.
Similar to Biogen/Eisai’s lecanemab, donanemab did not have a significant effect on NfL values.
P-tau217: estimated 13% reduction at three months
Tau is a structural element within the cell. Tangles of phosphorylated tau are a hallmark of Alzheimer’s disease.
Ptau-217 is now considered the prognostic biomarker with the most accuracy for diagnosis and progression of Alzheimer’s disease.
Donanemab reported about a 35% decrease of ptau-217 from baseline at 52 and 76 weeks for the combined population. At 3 months, the decrease was approximately on third of that value, namely about ~13%. At 6 months, the decrease was approximately ~30%.
Neurogranin: estimated 12.5% reduction at three months
Neurogranin is a measure of synaptic function. Unless mistaken, Eli Lilly did not include it in their trial protocol, but Biogen/Eisai did. Neurogranin levels in the lecanemab trial were lowered by 75% at 18 months compared to a rise of more than 20% in the placebo group. At three months the reduction may be estimated at 12.5%twelve months, and at six months it may be estimated at 25%.
GFAP: estimated 7% reduction at three months
GFAP is a measure of glial activity, which are considered majorly implicated in Alzheimer’s disease and other neurodegenerative diseases (see blog post ‘It’s the (micro)glia, stupid.). That ‘stupidity’, so to speak – a word play more than reality - is explained in more detail in the blog post ‘How not to study a disease’, and in Charles Piller’s recent book which I plan to cover soon, although he also implicates intent.
Donanemab led to a 19% decrease from baseline of GFAP in the combined study population over the course of 72 weeks. The reduction at three months was by about one third of that value, estimated at 7%.
INmune Bio’s reporting for XPro
Introduction
XPro has been tested in a three-month Phase 1 trial in patients with mild, moderate and severe Alzheimer’s disease.
Not only did XPro reduce the entire biomarker panel of inflammation using the Olink target 48 cytokine assay.
The 26 biomarkers of neuronal function and injury, dendritic spine morphogenesis and synaptic plasticity that were subsequently tested also saw meaningful reductions, with 20 of such 26 targets being significant.
NfL – Neurofilament Light: - 84% reduction
INmune Bio reported a 84% reduction of NfL values at three months. No other drug candidate a value that comes even close. I had already covered some comparative reportings here.
Denali’s corporate presentation contains a slide linking reduction of NfL values to FDA approval in different neurodegenerative indications, and comparing its own drug candidat DNL310 for MPSII with these values, as shown below. The time to the reduction shown logically always needs to be taken into account.
Denali’s slide underscores that even a lesser reduction than 84% could allow either accelerated or full approval. Recently, the FDA is seemingly pushing drug developers to file for accelerated approval based on NfL values. Examples given were the companies Clene and UniQure.
As a reminder, anti-amyloid antibodies Leqembi and Kisunla did not show considerable change in NfL values.
Ptau-217: -46% reduction
INmune Bio reported a 46% decrease in ptau-217 values, with improvements continued throughout the 12-month extension trial.
In comparison, donanemab reported a ptau-217 decrease from baseline of about 13%, and about ~30% at 6 months. The 46% decrease at 3 months for XPro therefore radically outperforms this reporting.
Neurogranin: -56% reduction
XPro reduced levels of neurogranin by 56% at three months. This compares favorably to the estimated 12.5% reduction at the same time point by Biogen/Eisai’s Leqembi.
No results for GFAP
INmune Bio has not yet reported values of GFAP yet.
Further biomarkers
The following biomarkers from the Phase 1 trial were also reported.
While focusing on one of these may not bear much relevance if one were to prognose efficacy, the overall picture painted by the above, to me, is that of a fast-onset disease-modifying biologic for Alzheimer’s disease.
INmune Bio has repeatedly stated that stabilization of cognition is the goal. If the overall picture of the biomarkers of anti-amyloid antibodies leads to about a 30% slowing of cognitive decline, then XPro's reported biomarkers' clear outperformance appears to justify that ambition.
Conclusion
For years, the scientific focus may have been too focused on targeting amyloid, while inflammation and modulation of glial activity has been overlooked. Inflammation and the correlated glial cell activity is a major target; glial cells outnumber nerve cells in the brain by a ratio of perhaps 3 to 1.
With XPro, INmune Bio tries to bring a disease-modifying biologic that selectively inhibits soluble TNF to the market for Alzheimer’s disease. The selective anti-inflammatory mechanism of action of XPro, allowing for fast-onset remyelination and modulation of glial cells, is entirely different from that of approved anti-amyloid antibodies.
Anti-amyloid antibodies reduce cognitive decline by about 30%. They do not reduce NfL values. They do reduce biomarker levels of tau, GFAP and neurogranin. At the three month timepoint, these reductions can be estimated at 13% (donanemab, ptau-217), 7% (donanemab, GFAP) and 12.5 (lecanemab, neurogranin).
Xpro outperforms these estimated values at three months for the biomarkers NfL, GFAP and neurogranin. At that time point, XPro reduced NfL levels by 84%, ptau-217 levels by 46%, and neurogranin levels by 56%. Relatively speaking, this outperformance is massive. While values for patients with progressing disease move the other way, the following values can be used for comparison:
a 84% reduction of NfL values for XPro, versus an insignificant difference for anti-amyloid antibodies;
a 46% reduction of ptau-217 values for XPro, versus an estimated 13% reduction for Kisunla;
a 56% reduction of neurogranin values for XPro, versus an estimated 12.5 reduction for Leqembi.
Apart from the overall dose-dependent reduction of inflammation, INmune Bio has additionally reported several other biomarker results that align with the afore-mentioned data. These biomarkers also continue to improve over a twelve-month timeframe.
Taken together, the extensively reported biomarkers values are consistent and indicate that, at least on a biomarker level, XPro may significanty and robustly outperform anti-amyloid antibodies. Particularly in light of reporting of NfL and ptau-217 values, it is reasonable to consider that biomarker efficacy will translate into cognitive efficacy.
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