Category Archives: JAK Inhibitors

JAK Inhibitors, Alopecia Areata, Androgenetic Alopecia, Angela Christiano, Brett King, Ruxolitinib, Tofacitinib

More Good News on JAK Inhibitors for AA. Mixed News for AGA

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I was 50/50 about writing an entire post on JAK inhibitors, but in the end gave in due to the fact that I usually neglect the 1-2 percent of balding people who suffer from alopecia areata (AA) or the related conditions alopecia totalis and alopecia universalis. For a majority of these people, JAK inhibitors clearly seem to be a cure assuming there are no long-term side effects.

There are also some new developments in the more controversial JAK inhibitors for androgenetic alopecia (AGA) patients discussion that are worth elaborating. As is the norm when JAK related news comes out, the discussion in the prior post was taken over by this subject, in no small part due to “nasa_rs”. I have let him run rampant in the comments section only because he came back after a lengthy break from this blog. He will be allowed to continue posting the same stuff in the comments to this post, but thereafter I will become stricter.

It should be noted that despite his often repetitive comments, over the years “nasa_rs” has sent me some highly interesting and unique scientific information. And recently, he was the first one out there to find the good news about Alcaris Therapeutics adding JAK inhibitor trials for AGA patients to their website’s pipeline page. As a side note, if I recall, “nasa_rs” really did or does work for NASA…a bit of a scary thought.

Two New Studies Show JAK Inhibitors Work for Alopecia Areata

In 2014, two groundbreaking papers discussed complete reversal of hair loss in alopecia areata patients. While this was justifiably by far the biggest news of the year in the hair loss world (and widely covered by the global media due to the spectacular before and after patient scalp photos), there was one problem: the first of these two studies only involved one patient of Dr. Brett King (on arthritis drug tofacitinib), and the second only involved three patients of Dr. Angela Christiano (all three on bone marrow cancer drug ruxolitinib).

Two weeks ago, two new larger studies were released that solidified the above findings:

  1. Dr. Angela Christiano’s team from Columbia University in New York found that 75 percent of 12 patients with alopecia areata had successful hair regrowth while on ruxolitinib for between 3-6 months followed by a 3-month follow-up period. By the end of treatment, average hair regrowth was 92 percent. Perhaps the best part of the news: “The drug was well-tolerated in all participants, with no serious adverse events.”
  2. Even more significant, a much larger joint study from Stanford University (led by Dr. Anthony Oro) and Yale University (led by Dr. Brett King) found that of 66 alopecia areata patients treated with tofacitinib, 64 percent of patients had a positive response to treatment (and 32 percent achieved an improvement of over 50 percent after only 3 months of therapy). Side effects were generally mild.

From the above studies, it seems like ruxolitinib is better than tofacitinib when it comes to treating alopecia areata. It remains to be see if results are even better when treatment is continued for a longer duration when it comes to either of the above two drugs. Note that a number of other newer JAK inhibitors will get approved and come onto the market in the US in the coming years.

Finally, for those who do suffer from alopecia areata, this is by far the best place in the internet to connect with others such as yourself.

JAK Inhibitors for Androgenetic Alopecia (AGA)

Some good news, some bad news and some in-between news here.

The Good:

  • First, from the 12 patient study article link I posted in the above section, Dr. Christiano still seems optimistic about JAK inhibitors working for AGA per the following quote:

“The CUMC research team plans to expand their studies to include testing these drugs in other conditions such as vitiligo, scarring alopecias, and androgenetic alopecia (pattern baldness) where they may also show efficacy. “We expect JAK inhibitors to have widespread utility across many forms of hair loss based on their mechanism of action in both the hair follicle and immune cells,” said Dr. Christiano.

The Bad:

  • However, Dr. King who in the past thought that it was worth testing JAK inhibitors (especially topical ones) for AGA now seems pessimistic according to this source:

“King said it is doubtful that Xeljanz (=tofacitinib) will work for the most common types of hair loss (such as male pattern baldness), which are not the result of an autoimmune disease.”

Note that both Dr. Christiano and Dr. King are listed as advisers to Alcaris Therapeutics in the conflict of interest section of the earlier linked 66 patient study summary page.

The In-Between:

  • One important bit of information on JAKs and AGA that never received the attention it should have (partly because I did not cover this subject much in recent months) happened a few months ago when Solomon interviewed Dr. Eddie Wang (who previously worked with Dr. Angela Christiano). According to Solomon, Dr. Wang “rated JAKs success chance for AGA 5 out of 10“. Dr. Wang seemed to think that JAKs could be reducing microinflammation in AGA patients and that could help hair growth. I contacted him about how he came up with this 5/10 estimate, but he never responded. I would put this development under “good news” if Dr. Wang had responded with a detailed answer.

Two (or More) Variants of AGA?

I have mentioned in the past that it seems like a majority of balding people have significant itching and dandruff in their balding regions, while some balding people have none of those annoyances whatsoever. I always wonder if the people who have this itching and dandruff associated with their balding also have a significant inflammation (and maybe even autoimmune) component to their hair loss? If topical JAK inhibitors do end up helping people with AGA, will those with significant itching benefit more? I would not at all be surprised if researchers some day find that AGA patients can be broadly split into two main camps.

Pharmacologic Inhibition of JAK-STAT Signaling Promotes Hair Growth

Finally, while I discussed this October 2015 study on this blog before as part of a lengthy post, I keep finding new items of interest in there. I therefore thought it was worth pointing out the study again here in the hopes that some of the readers with a scientific background can give us more feedback on the contents. Dr. Angela Christiano and Dr. Claire Higgins are both co-authors of this study. Some of the more interesting quotes:

“Hair growth after JAK-STAT inhibition mimics normal anagen initiation by activating the Wnt (Note: this is what Samumed is focusing on) and Shh signaling pathways.”

“JAK-STAT inhibition causes activation of hair follicle (HF) progenitor cells.” (Note: also see this important patent filed in 2013: “Jak inhibitors for activation of epidermal stem cell populations”).

“Inhibition of JAK-STAT signaling improves skeletal muscle regeneration in aged mice.”

“Tofacitinib treatment promotes inductivity of dermal papilla (DP).”

“In human hair follicle assays, we show that JAK inhibition via tofacitinib treatment increases the growth rate of anagen hair shafts (skin grafts and organotypic culture assays) and enhances the inductivity of human DP spheres (neogenesis assays). It is surprising that ruxolitinib treatment did not improve the inductivity of human DP spheres, despite the fact that it increased the rate of growth in the organ culture model. We postulate that down-regulation of proapoptotic signals in tofacitinib-treated spheres, which did not occur in ruxolitinib-treated spheres, may promote survival of DP cells, leading to enhanced hair growth in this assay.”

JAK Inhibitors

JAK Inhibitor Updates and Miscellaneous Notes

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Update: Dr. Neal Walker just presented yet again on June 15, 2016, this time at the William Blair Conference in Chicago. Several new updates after 19:20 mins into the presentation):

  1. A more technical description of why topical JAK inhibitors work for AGA, but systemic ones do not work.
  2. He claims that some of his colleagues are using the compounded formulations of the AGA product in the initial development phase of their work and he found this to be pretty exciting.
  3. The AGA topical product will be slightly behind the vitiligo product when it comes to trials/development since the topical formulation for AGA is still being developed.

I was debating on writing this blog post, but the number of comments to the last post has become a bit insane and it is better to have some of the more intelligent discussions taking place here rather than continuing over there where it is now hard to find things. For this post, I will delete many of the one-line comments that entail repetitive whining, insults, sarcasm or totally unrelated material. In the next post more of the junk will be tolerated again.

My notes to the developments in the last post:

  • I am now raising my estimate of Janus kinase inhibitors (JAK inhibitors) being at least a partial cure for androgenic alopecia (aka androgenetic alopecia aka AGA aka male pattern baldness aka MPB) versus not being a cure from 50/50 to 60/40. I say “partial” cure because even for alopecia areata (AA) sufferers, JAK inhibitors do not seem to work for everyone per the testimonials on alopeciaworld.com (Note: they are all taking oral JAK inhibitors over there and not topical ones as will be the case for AGA). So there is a chance that we will see the same for AGA patients in the event that JAKs do work for AGA. My gut instinct is still telling me that for those who have a lot of itching and dandruff associated with their balding, JAK inhibitors are more likely to work than for those who have hair loss without any of those symptoms. However, you should not read too much into my own amateur estimates or untested theories, but I mention them here because so many commentators have asked me about my opinion, especially regarding the 50/50 estimate.
  • In the comments to the last post as well as in the various hair loss forums, a small minority of people have been very pessimistic about this news. Some have raised valid points of concern. However, some do not even seem to think that Aclaris will test JAK inhibitors on humans, even though the company clearly had two slides in their presentation saying that they will do so. Therefore, even in the most pessimistic scenario, the company will be testing these drugs on humans with AGA. In my opinion, there is a very high chance that Dr Angela Christiano (and Dr. Brett King) have already tested them on patients with AGA. After all, both doctors tested these drugs on AA patients (and vitiligo patients in the case of Dr. King) in the past without letting us know in advance. Heck Dr. King could even have tried it on himself for his own AGA. As an aside, it bears repeating Dr. King’s comment in his interview: “It’s hopeful…it’s beyond hopeful.“
  • Dr. Neal Walker talked about the two new areas in which they will be testing JAK inhibitors in humans: AGA and vitiligo. To me, that almost sounds like he is implying that he is equally hopeful about the chances for each of those conditions in humans being successfully treated with JAK inhibitors. Perhaps I am reading too much there, but in any case, we already know that JAK inhibitors work for treating vitilgo in humans, courtesy of Dr. Brett King.
  • Do not listen to Dr. George Cotsarelis when it comes to his skepticism about JAK inhibitors (see his comments in the CNN article linked in my post from 2014). For one, he has been involved with numerous competing technologies, companies and patents over the past two decades. Perhaps he has good scientific reason for his skepticism, but it is also human nature to favor your own work, especially when your work has entailed your whole career. If today someone suggested that a new car powering technology is far superior to electric, I would expect immediate skepticism from Elon Musk.
  • One funny thing that I recently noticed is that even though Dr. Cotsarelis claimed that the immune system is not involved in MPB per his 2014 CNN article quotes, in Follica’s latest presentation (courtesy of the same Jefferies Conference via PureTech’s Daphne Zohar), they clearly classify androgenic alopecia as part of an “immune system” related problem (the immune system label is on the left side written vertically). This is strange, since Dr. Cotsarelis has been involved with Follica for many years and was in fact a co-founder!
  • For that matter, do not base your decisions and optimism or pessimism on what people such as myself, commentator Matt, nasa_rs, and the many intelligent hair loss members out there state. Most people have some bias, and every single person that you listen to on the internet has no idea what Dr. Christiano, Dr. King, and now Alcaris Therapeutics’ scientists are up to in their labs. It is amazing how many times I keep getting asked whether I still think a cure will be here by 2020, whether I think JAKs will work, whether I think their are conspiracies in the hair loss world etc…I will only know for sure once I have access to insect-sized and insect-lookalike drones that I can use to spy on the various labs that are working on a cure for hair loss. Till then, my posts and comments will only give you my guesstimates and nothing more.
  • Despite my great optimism, I still see some negatives, including: JAK inhibitor treatment will remain expensive (even if prices go down significantly as I expect); clinical trials will take a few years; and once you start taking JAKs, it will be a lifelong commitment. Note that regarding clinical trials, there is a remote possibility that the companies can find ways to speed up the trial process due to the fact that JAK inhibitors already treat so many medical conditions as well as alopecia areata. At the moment, it does not seem like JAK inhibitors are causing cancer in anyone, and they have probably been used in many people for at least 10 years. Ruxolitinib was first approved for human use in 2011, and Tofacitinib was approved in 2012. Both were probably tested on humans for at least around five years prior to approval. There are many other JAK inhibitor “-tinibs” out there that may be approved soon too.

Longtime JAK Inhibitor Superfan “nasa_rs” and his Blast from the Past

About one week ago, nasa_rs asked me to find an important link to a relatively old study that he had posted in one of his past comments on this blog. I found the link (it was in my Elon Musk post and I even replied to it at the time) and was excited to read the contents of the study, which was published back in 1994. Not sure why I never mentioned that great find before. In any case here it is. The key quote:

The hair growth stimulating effect of CsA is observed not only in normal but also in pathological conditions of hair growth, i.e. in patients with alopecia areata and also in some patients with male-pattern alopecia.

Clear evidence that immune system suppressants help hair. However, I am not sure how closely cyclosporin A and FK506 are linked to JAK inhibitors. Also, later on in the abstract they mention that topical application of FK506 induces hair growth in mice, but oral ingestion does not. A similar situation as with JAK inhibitors so more good news. However, in the abstract they do suggest that this means that the hair growth effects of FK506 may not be related to immune suppression, since oral ingestion does not help hair growth. Topical application might be impacting some other mechanism that is not well elucidated as yet per the study authors.

FYI — This was supposed to be my big blog post last week, but I first postponed it because I had delayed discussing the Dr. Rendl presentation for too long and needed to do that, and then of course I had to postpone it again due to the excellent new development discussed in the last post. Matt and nasa_rs had some discussion about the above study in the comments to the last post, but perhaps they can do that in this post now.

“Matt” (aka “matt”)

When I first started this blog, I was hoping there would be at least a few very intelligent (at least when it comes to biology and chemistry) people who post accurate highly technical comments on here every so often so as to overcome my own shortcoming as well as laziness in reading up in that area. I think user “Matt” is now the go to guy for that purpose, and we are all grateful to have him on board as can be inferred from the numerous appreciative comments that he has received in the comments to the last post. I find it funny that so many people who are appreciative of him (including myself) probably do not even understand half of what he writes. However, my intuition tells me that what he is writing is accurate and grounded in legitimate science. I would encourage people to go through all his comments in the last post (you can search via ctrl-f to find his name on each page of comments). Matt, you can repeat (i.e. paste) some of your most useful comments to the last post within this post’s comments if you want since most people will not want to search through those 500 comments. One of these days, I hope I will have time to go through your most important comments in extreme detail. FYI — “Matt” also goes by “matt”, and there was another commentator who briefly used the same name before my asking him to change it.

One of the interesting things that Matt wrote caught my eye:

“It sure looks like jak/stat signaling has a ton to do with all of hair biology (really, all of biology in general) not just AA.”

This is clear, just based on the number of conditions that the -inib drugs are already approved to treat or pending approval to treat. Moreover, there are many studies out there that suggest totally unexpected benefits of JAK inhibitors and the JAK-STAT signaling pathway (e.g., white-to-brown fat cell conversion).