ET-02's mechanism of action in relation to other drugs in the global hair loss pipeline.

So here are my notes regarding ET-02, its mechanism of action, and where it seems to stand in the literature. I don't think it's more effective than Minoxidil, at least the current phase 1 results don't seem to show that.

ET-02 is a pai1 inhibitor. The goal of PAI-1 inhibition is to reduce the protein PAI-1. As we age, PAI-1 increases, which leads to the production of senescent cells. Senescent cells are cells that have gone dormant in the sense that they no longer divide. However, they are also not tagged for destruction or destroyed.

https://pmc.ncbi.nlm.nih.gov/articles/PMC4439419/ A few of them are harmless. However, as they accumulate with age, their cellular secretions begin to disrupt tissues and other cells. These secretions, or "secretomes," from these cells release signals that cause oxidative stress and are very pro-inflammatory.

A poor cellular environment is eventually created, negatively impacting telomere length on the tips of chromosomes. Uh oh

https://pmc.ncbi.nlm.nih.gov/articles/PMC3370421/ Telomere length is a key marker of aging; shorter telomeres indicate older cells and higher risks of age-related diseases, while longer telomeres suggest greater cellular longevity and a potentially longer lifespan. With each cell cycle, telomeres get shorter, and the longevity of the cell, tissue, organ, and organism decreases. The story of life and death -- but you already knew this.

https://nyaspubs.onlinelibrary.wiley.com/doi/10.1196/annals.1395.051 https://www.ahajournals.org/doi/10.1161/ATVBAHA.117.309451 No other condition of aging encapsulates this better than Werner's Syndrome, also known as Adult Progeria: Rapid aging occurs after puberty, with associations of increased PAI-1 levels, increased cellular senescence, and rapid decay of telomere length.

https://pubmed.ncbi.nlm.nih.gov/29152572/ https://www.innov-research.com/blogs/news/pai-1-mutation-in-amish-community-could-lead-to-new-treatments-for-age-related-disorders https://news.northwestern.edu/stories/2017/november/amish-live-longer-healthier-internal-fountain-of-youth/ However, we can see that in populations with PAI-1 deficiency, like for instance the Amish, live 10% longer than the general population. It would be interesting to know if they also have slower/lower rates of alopecia conditions and their rate of progression.

https://www.sciencedirect.com/science/article/pii/S0022202X2032399X Studies show that in alopecia conditions, telomere length is rapidly destroyed in the dermal papilla cells or, worse yet, in the hair follicle stem cell bulge matrix, where hair follicle stem cells—the cells that are involved in regulating the anagen cycle—are housed. Should these be destroyed or suppressed, for any reason (DHT, PPAR-GAMMA dysfunction, age depletion, mechanical destruction, etc.), the follicle organ will die.

So, from this, I would assume ET-02, being this PAI-1 inhibitor, aims to slow down the aging and cellular decline in the hair follicle by reducing oxidative stress downstream of the factors that produce cellular senescence and reactive oxygen species. This slows the aging of the cell down, presumably, and allows the hair follicle organ to retain telomere length and perhaps recover a normal anagen cycle. Even so, with every anagen cycle, telomeres will still decrease. But here, the idea is to slow this rate of telomeric decline in the cells.

https://pmc.ncbi.nlm.nih.gov/articles/PMC10328083/pdf/EMBR-24-e56574.pdf https://www.semanticscholar.org/paper/Efficacy-and-Safety-of-Topical-Rapamycin-in-With-to-Koenig-Bell/9239bd2b6b746491d74a81bf2a4f63601599cdaa https://www.researchgate.net/publication/350170087_A_positive_feedback_loop_between_mTORC1_and_cathelicidin_promotes_skin_inflammation_in_rosacea/figures?lo=1 But why not topical rapamycin? It may have a benefit in reducing cellular senescence and could be just as good as ET-02.

https://www.eirionthera.com/single-post/take-five-eirion-s-jon-edelson-md https://www.tesble.com/10.1016/j.jaad.2007.04.012 Also, the comparisons with Minoxidil don't make sense because ET-02 and Minoxidil didn't go head-to-head in a clinical trial. Moreover, the full hair growth effects of Minoxidil take months to realize. So, the current data isn't robust enough for us to conclude that ET-02 is better than Minoxidil.

And in my opinion, ET-02 won't be better than Minoxidil.

But it's way too early to say so, and I could be wrong; in fact, I would genuinely be happy to be proven wrong.

And just some thoughts here: it seems that a lot of these new treatments, like PP405 and AMP-303, are playing on mechanisms that involve mitochondrial metabolism and cellular senescence.

https://onlinelibrary.wiley.com/doi/10.1111/exd.14307

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0303742

PP405, via MPC inhibition, creates the internal survival response. This response is created when an environmental stressor of some kind (perhaps in this case MPC protein not being able to deliver pyruvate as often to mitochondria) causes ATF4 activation and upregulation.

https://www.nature.com/articles/ncb3575 Here, energy is created using the enzyme lactate dehydrogenase in order to break down the buildup of pyruvate that couldn't reach mitochondria. This makes a backdoor path using anaerobic respiration.

https://www.jidonline.org/article/S0022-202X(24)01672-5/fulltext Now, I have some thoughts: could this be an advantage? Mitochondrial metabolism (getting ATP and releasing it) involves the use of reactive oxygen species to create energy. Sure, this is beneficial, and usually, we have buffers to keep those reactive oxygen species in check, but what if they are too plentiful? Maybe, at least in the hair follicle, there could be an advantage to using this internal survival response to create energy that's good enough for hair follicle cellular growth while not requiring as much oxidation from aerobic factors in mitochondrial metabolism because of MPC inhibition. Maybe this also protects hair follicle stem cells and their telomeres? Would this make PP405 the fountain of youth for our hair?

https://pubmed.ncbi.nlm.nih.gov/19169664/ https://pmc.ncbi.nlm.nih.gov/articles/PMC6992882/

I find it interesting that AMP-K drugs like metformin are used with some success in treating conditions like CCCA and LPP—autoimmune hair loss disorders. I find this interesting because by activating AMPK, drugs like metformin can shift the cell's metabolism away from oxidative phosphorylation (mitochondrial ATP production), which generates high levels of ROS, toward alternative, lower-energy pathways like glycolysis. Surely, though, it also has a factor in regulating lipotoxicity that's typically seen in conditions like LPP and CCCA.

https://www.sciencedirect.com/science/article/abs/pii/S0306987723001512 Some research even shows a potential intreating alopecia areata as well due to its ability to reduce inflammatory pathways.

This reduction in oxidative stress might protect hair follicle stem cells and dermal papilla cells, preserving telomere length and cellular function. AMPK activation reduces inflammation by inhibiting NF-κB and other pro-inflammatory pathways. This could mitigate the inflammatory environment in autoimmune conditions like LPP and CCCA, slowing follicle destruction.

https://onlinelibrary.wiley.com/doi/10.1155/2017/2501248 https://pubmed.ncbi.nlm.nih.gov/19169664/ Other drugs like Pioglitazone, aside from improving lipid metabolism in conditions like LPP and thus reducing lipotoxicity (essentially secretomes from sebocytes and other cells that have lost functions of lipolysis-metabolism due to PPAR-GAMMA dysfunction and downregulation), also improve AMP-activated protein kinase signaling. This could be another reason why it is protective in autoimmune hair loss conditions that are due to lipid dysregulation—primarily LPP and its derivative conditions, which all share histological similarities.

https://www.nature.com/articles/s41419-018-0391-6.pdf https://www.wired.com/story/a-hair-loss-study-raises-new-questions-about-aging-cells/ On the other hand, AMP-303 is a derivative of Osteopontin, which is a secretome from senescent cells in hair nevi (moles). Osteopontin could be beneficial as a hair growth stimulant, but it may have issues, as Osteopontin is related to many age-related diseases.

https://www.nature.com/articles/s41586-023-06172-8.pdf https://amplificabio.com/amplificas-amp-303-study-unveils-new-hope-for-hair-loss-treatments/

AMP-303, being a derivative of it, could also have the same drawbacks. Sure, we may grow hair with it, but we don't know how safe it is to use Osteopontin or a derivative of it: Osteopontin is implicated in pro-inflammatory diseases and cancers. More research will prove if this is safe or not.

Madison Howard

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ET-02's mechanism of action in relation to other drugs in the global hair loss pipeline.