I repost here 2 posters about ATH434 and again the "Standford...

I repost here 2 posters about ATH434 and again the "Standford paper discussion" we had here. IMO these results give the best theoretical understanding of why I am also expecting positive results in the phase 2 studies and how we already got positive results in both PD and MSA animal models.



Dr.Pall: https://alteritytherapeutics.com/wp-content/uploads/Biophysical-Characteristics-of-ATH434_Unique-iron-targeting-drug-for-treating-Friedreichs-Ataxia.pdf

The unique iron binding properties of ATH434 suggests
this drug could be suited to assist in intracellular iron
targeting and delivery. These novel properties include:
• Low micromolar binding affinity for intracellular Fe2+
,similar to endogenous iron chaperones including
FXN and PCBP [1-3]
• Sub-micromolar affinity for Fe3+
, significantly weaker
than that of traditional chelators DFX and DFP [5-6],
allowing for selective targeting of pathogenic Fe2+
• 1:1 Fe2+ stoichiometry, a coordination architecture
that would allow for the recognition and drug-protein
exchange of Fe2+ bound ATH434

So, Dr. Pall says that ATH434 acts similarly to normal, physiological iron chelators in our body.

Prof. Kosman: https://alteritytherapeutics.com/wp-content/uploads/Society-for-Neuroscience-2023_poster.pdf
434 vs Dfp: 434 possesses potent antioxidant activity that Dfp does not. This antioxidant
activity supports and protects the mitochondria...

434 vs 434-met: 434 is a more potent antioxidant than 434-met, likely due to its electron
transfer capacity.

Standford scientists: https://hotcopper.com.au/threads/stanford-scientists-iron-calcium-in-mitochondrion-as-target-in-pd-treatment.7754348/

This paper brings the role of calcium into the picture and that iron causes Ca overload.

" Fe2+ elicits mitochondrial Ca2+ overload through acting on IMM (inner mitochondrial membrane) Ca2+ channels and transporters. The relatively low affinity of MCU (mitochondrial calcium uniporter) to Fe2+ in vitro (Figure 2B) is consistent with its low affinity to other divalent metals such as Mg2+. These data suggest that MCU may not be predominantly occupied by these divalent ions under physiological conditions. By contrast, under pathological conditions with elevated Fe2+, MCU binds to more Fe2+ and cellular detriment ensues. This finding agrees with prior evidence showing that inhibiting MCU prevents Fe2+-induced cell death and Parkinsonian neurodegeneration".