Ann: Positive ATH434 Phase 2 Results Led By Clinical Efficacy, page-440

On 20 Jan 2025, at 11:04 am, Ana Luiza Graça Harrop wrote:
Hi David,
Apologies for the late response and thank you for your questions. I reached out to the Alterity team to get some info. See below their response: "Thank you for sharing the article. It in fact highlights some of the important differences in the mechanism of action between ATH434 and deferiprone that we believe positions ATH434 to be successful in diseases with iron-driven oxidative damage.As noted in the article, the form of iron that catalyzes the oxidative stress depicted in Figure 2 is Fe2+. Our recent publication attached, Pall et al 2024, confirms that ATH434 has an affinity for Fe2+ that is similar to that of endogenous cellular Fe2+ chaperones such as glutathione or poly-C-binding proteins. These proteins manage the Fe2+ pool, providing the Fe2+ to enzymes, shuttling it into safe storage, or sending it for normal export. By augmenting the buffering capacity of these proteins, we believe that ATH434 is limiting Fe2+’s potential to trigger oxidative stress.By contrast, under normal cellular conditions, we found that deferiprone is unlikely to bind Fe2+ in a meaningful manner. Deferiprone has an enormously greater affinity for Fe3+ than Fe2+. As noted for other such chelators, we demonstrated that before deferiprone molecules can “trap” or bind one Fe2+ molecule, an electron in Fe2+ is ejected from the complex. This has two consequences:•     Fe2+ is converted into Fe3+. Table 1 in the article you shared lists deferiprone as having a positive result in Friedreich’s ataxia (Pandolfo, ref 63). However, the discussion in Pandolfo 2013 notes that in a 6-mon trial, high doses of deferiprone actually exacerbated ataxia, similar to the worsening of symptoms in PD patients described in Devos 2024 (reference 55). In the case of Friedreich’s ataxia, neurons that control motor activities are already starved for Fe2+; converting it to Fe3+ accelerates their disease. Similarly for PD, as the article you shared indicates, neuromelanin is one way aged primates can keep Fe2+ at bay. However, the conversion of Fe3+ to Fe2+ is a necessary step in the synthesis of dopamine which is essential for proper motor control. In Devos 2024, hormonal biomarker data showed that deferiprone depleted central dopamine in a manner consistent with worsening motor function. Deferiprone’s detrimental effect on endogenous dopamine likely reflects unnecessary removal of Fe3+ from the dopamine synthetic enzymes, some of which arises from this conversion of Fe2+ to Fe3+.•     Generation of “free radicals”. The electron that is ejected when Fe2+ is converted into Fe3+ is itself a source of oxidative stress. This free electron will combine with oxygen, leading to the formation of hydroxyl radicals discussed in the paper you shared (i.e., the reaction at the top of Figure 1). These free radicals can damage intracellular structures such as DNA and lipids and contribute to cellular injury.ATH434 is distinguished from deferiprone in several key ways:•     ATH434 does not have the properties to be a chelator. ATH434’s affinity for Fe3+ is very mild compared to deferiprone. While it still has the sufficient affinity to compete for iron in misfolded alpha synuclein in neurons, it will not remove Fe3+ from enzymes. Although deferiprone forms a cage around Fe3+ allowing it to pass freely through membranes and into the urine, ATH434 cannot. This is why deferiprone removes excess iron from the body (i.e., a chelator). In contrast, when ATH434 binds Fe2+ or Fe3+, it will not cross out of the cell like deferiprone. Instead, the iron will be handed off to other proteins in the body and redistributed for use in normal cellular functions.•     ATH434 is less potent at converting Fe2+ to Fe3+. In Pall et al, we demonstrated that the rate of conversion of Fe2+ to Fe3+ by ATH434 was dramatically slower than that of deferiprone. Thus, more beneficial Fe2+ will stay in its form safely bound to ATH434 or endogenous chaperones, and fewer oxygen radials will be formed.•     ATH434 has direct anti-oxidant properties while deferiprone does not. This may help manage oxygen radicals in diseased tissues."I hope this was helpful. Let us know if there's any further questions.



Now guys
Be man enough to apologise
Every shareholder has the right to ask Management for an answer to a question re a drug…

Now please stop the bullying ..