JAK inhibitors, the lost cure for Androgenetic Alopecia? (Incredible mistake by Aclaris)

[FollicleGuardian]

After looking at JAK stat inhibitors incredible success in regrowing hair in mice I started looking into what really happened to their use in Androgenetic Alopecia/male pattern baldness. Yes it’s in mice, but it performed as rapidly and effective as the dangerous hair growth promoter Smoothened Agonist (SAG). The results are seriously impressive.

ATI-502, a JAK inhibitor were tested by Aclaris. It failed for Androgenetic Alopecia. Results were mediocre. But most of the participants had some hair growth. Meanwhile Hope Medicine has shown the most impressive results we’ve ever seen. In the gold standard macaque model.

Why am I bringing up a PRLR silencer when we are talking about JAK inhibitors? Well most of the PRLR signalling happens when PRL (prolactin) attaches to the PRLR (prolactin receptor), and then activates JAK.

«PRL signaling activate Janus kinase 2 (JAK2) [21], mitogen activated protein kinase (MAPK) [7], Phosphoinositide 3-kinase (PI3- kinase) [22], Src kinase [23] and serine/threonine kinase Nek3-vav2-Rac1 pathways [24] through the long isoform of the receptor.
The prolactin signaling through short isoform can activate different downstream cascades except JAK/STAT pathway [25]. JAK2 phosphorylates multiple tyrosine residues of the receptor PRLR [26, 27] and enables the binding of downstream signaling molecules mainly signal transducer and activator of transcription (STAT) proteins.

PRLR signalling also:

-activates MAP kinase pathways
-stimulates PI-3K pathway and is reported that activation of PI-3K/AKT pathway initiates cell survival of lymphoid cells.
-activates the Rac pathway [31]. The Prolactin receptor dependent interactions of serine/threonine kinases NEK3 with guanine nucleotide exchange factors VAV1 and VAV2 and Tec with VAV1 regulate cytoskeleton remodeling»

TLDR; most of PRLR is all about JAK signalling, and JAK2 is especially essential.

Why did Aclaris fail their trial then? BAY/HMI-115 and ATI-502 almost totally overlaps. It regulates most of the same pathways. On paper they should have comparable results

The idea behind using JAK inhibitors for Androgenetic Alopecia from the research of Dr. Angela Christiano:

«Hair growth can be induced from resting mouse hair follicles by topical application of JAK inhibitors, suggesting that JAK-STAT signaling is required for maintaining hair follicle stem cells (HFSCs) in a quiescent state. Here, we show that Oncostatin M (OSM), an IL-6 family cytokine, negatively regulates hair growth by signaling through JAK-STAT5 to maintain HFSC quiescence. Genetic deletion of the OSM receptor or STAT5 can induce premature HFSC activation»

So Oncostatin M (OM) and STAT-5 is the essential here. ATI-502 was used in the Androgenetic Alopecia trial. Here is where it all went wrong. Oncostatin M signalling is regulated by JAK 1, 2 and 3. The oncostatin M receptor interacts directly with JAK-1 and JAK-2. So these two are the most important for OM signalling. Downstream STAT5 signalling is especially important too.

ATI-502 is a selective JAK-1 and JAK-3 inhibitor. Aclaris chose to completely ignore JAK-2 signalling. They also speculated that their dose of approx 0.5 % was too low.

Our faith could have been a lot different had they completely inhibited JAK signalling as happens with BAY/HMI. By for example combining two JAK inhibitors to cover the full spectrum. Or together with a STAT5 SH2 site inhibitor. To my knowledge no other company than Aclaris have tried out a JAK inhibitor for Androgenetic Alopecia.

Again the researchers for Androgenetic Alopecia underperform…

A pathway map of prolactin signaling

www.ncbi.nlm.nih.gov

NetSlim

A Subset of TREM2+ Dermal Macrophages Secretes Oncostatin M to Maintain Hair Follicle Stem Cell Quiescence and Inhibit Hair Growth - PubMed

Hair growth can be induced from resting mouse hair follicles by topical application of JAK inhibitors, suggesting that JAK-STAT signaling is required for maintaining hair follicle stem cells (HFSCs) in a quiescent state. Here, we show that Oncostatin M (OSM), an IL-6 family cytokine, negatively...

pubmed.ncbi.nlm.nih.gov

NetSlim

 

[Redgate]

This is an interesting list: https://en.wikipedia.org/wiki/Janus_kinase_inhibitor
There's a topical JAK1/2/3 inhibitor called Delgocitinib (brand name Corectim), approved in Japan and phase 3 in the US for eczema.
It's actually surprising to me how many JAK inhibitors there are in the market, and there are quite a lot of companies pursuing topical solutions for them.

 

[trialAcc]

This is an interesting list: https://en.wikipedia.org/wiki/Janus_kinase_inhibitor
There's a topical JAK1/2/3 inhibitor called Delgocitinib (brand name Corectim), approved in Japan and phase 3 in the US for eczema.
It's actually surprising to me how many JAK inhibitors there are in the market, and there are quite a lot of companies pursuing topical solutions for them.

If they have approved inhibitors, would they not have already noted an impact on hair if they noticed it in the trials?

 

[Redgate]

If they have approved inhibitors, would they not have already noted an impact on hair if they noticed it in the trials?

It's hard to say. If you really need complete inhibition of JAK for hair then Delgocitinib is the only drug in that list that seems to do it, and since it's a topical for eczema I doubt they would test/notice anything about hair growth. Unless there are patients with eczema on the scalp.
There are a few success stories about tofacitinib and others working for other types of alopecia. I think Aclaris was pursuing areata just before they closed and it had decent result IIRC.

 

[FollicleGuardian]

If they have approved inhibitors, would they not have already noted an impact on hair if they noticed it in the trials?

No one has tried a combo of jak inhibitors for total jak inhibition, topically. Aclaris said oral won’t work. We can’t dose jak inhibitors so high orally that it will acheive total inhibition in the scalp.

 

[fashy]

So is there a way we can experiment with this? Would buying Delgocitinib and applying it topically achieve the desired inhibition?

 

[fashy]

https://pubmed.ncbi.nlm.nih.gov/32166597/

"Delgocitinib inhibits all members of the JAK family [JAK1, JAK2, JAK3 and tyrosine kinase 2]. Topical delgocitinib (Corectim®) is approved in Japan for the treatment of atopic dermatitis. This article summarizes the milestones in the development of delgocitinib leading to this first approval for the treatment of adults with atopic dermatitis. Clinical development of the topical formulation is also underway for alopecia areata, chronic hand eczema, discoid lupus erythematosus, inverse psoriasis and atopic dermatitis in several countries worldwide."

It seems like they are aware it may have positive effect on alopecia areata if they are pursuing it, but no word on androgenetic alopecia.

 

[FollicleGuardian]

if oral doesn't work for scalp, how do you explain Baricitinib and areata?
also 1% etc topically would start getting $$ vs 2-4mg oral...

Alopecia areata doesn’t need full inhibition of JAK to work. It’s even sufficient to only inhibit one of the JAK’s. Androgenic alopecia needs full blockade of STAT signalling. Therefore full blockade of JAK. Areata is not about STAT signalling.

 

[Zon Ama]

So FollicleGuardian what do you suggest? You wouldnt post a theory without an idea how to execute

 

[FollicleGuardian]

Scratch that. Tyrosine kinase cannot be lowered too much. It will cause hair loss. @fashy

Theoretically what I would research with for this theory is Toficitinib+Ruxolitinib+Pimozide. @Zon Ama

 

[pegasus2]

This is what happens when you give someone with both AA and Androgenetic Alopecia tofacitinib.

 

[FollicleGuardian]

This is what happens when you give someone with both AA and Androgenetic Alopecia tofacitinib. View attachment 171314

Orally I assume. Doesn’t work for Androgenetic Alopecia because it doesn’t inhibit fully the STAT signalling. And Tofacitinib has modest inhibition of JAK 2.

 

[pegasus2]

I think the better option over JAK inhibitors is to use a direct STAT3/5 inhibitor such as SH-4-54. While JAK inhibitors are sufficient for AA, they appear unable to override Prl-induced STAT3/5 signaling in Androgenetic Alopecia. Even better might be to go further downstream and use one of the recently developed Twist1 inhibitors if you can get them.

 

[Zon Ama]

I dont want to spread negativity, but what could be the possible side effects?

 

[pegasus2]

I dont want to spread negativity, but what could be the possible side effects?

Of systemic JAK inhibition? It's not feasible long term. Topical might be fine.

 

[Oppenheimer]

Topical Delgocitinib seems very interesting.

 

[Redgate]

I dont want to spread negativity, but what could be the possible side effects?

JAK inhibitors cause immunosuppression. Some papers I read say that topical use doesn't have this risk but speculate that you need to "observe the application area for local infections"