The Cb (breezula [clascoterone]) Community Thread

[Dimitri001]

We don't know how much of an effect the CB in the blood should have. Cassiopea DID do a large and long study with phase III and found no sexual sides. There's also all the winlevi studies that, AFAIK, found no AA related sides.

There WAS the HPTA axis finding, so maybe that can account for the member's unfortunate sides. It COULD also be nocebo.

 

[Dimitri001]

Why would you assume this is upregulation rather then the difference of 20-30% more DHT in your system? I would assume you are just shocking your follicles with levels of hormones they havn't experienced in years.

The idea of upregulation from CB though is complete non-sense. If that were the case, kids using winlevi for acne would get subtle relief then destroy their skin. It feels like an idea thought up by people who know nothing about drug interactions or body chemistry but saw a chart that looks like a sine wave and thought there is no possible other reasonable explanation then hairloss getting worse (while ironically still being above baseline 1 year in).

Do you have an alternative explanation of the Breezula 6 month cliff?

 

[Dimitri001]

The data doesn't indicate it loses it's effectiveness after 7 months, it's still above baseline and well above vehicle after 12 months. The only thing that we can infer from the data is that it wasn't able to maintain growth or potentially fully stabilize loss within 12 months. There is absolutely 0 evidence for AR upregulation, just uneducated guesses because the gains disappeared. This drug also wasn't developed as a growth product, so the only thing we should care about is being above vehicle and baseline longer then 1 year, which, of course we don't know because the study ended.

If it lost effectiveness or sped up hair loss (AR upregulation), then the 12 month results would be equal to or less then vehicle. Instead, it was 9% (or whatever) above vehicle while still being above baseline.

I may be wrong about this and I'm too lazy to look at the data, but I believe that after 6 months the CB group is losing ground faster than control, so that's the evidence for upregulation. Not conclusive, certainly, maybe not even strong evidence, but it supports the idea - again, if I'm correct on my facts here, been a while since I looked at the chart.

 

[trialAcc]

Do you have an alternative explanation of the Breezula 6 month cliff?

Loss of effectiveness? We already know it's not a very strong AA. It's not even as strong as RU and RU doesn't work miracles for many people who use it.

 

[Dimitri001]

@pegasus2

Damn that's a shame I was hoping to see whether they recorded TAHW (target area hair width) to baseline comparison at 6 and 12 months in that presentation. If we were able to see whether TAHW followed the same drop of TAHC (target area hair count) between 6-12 months then maybe we would be able to say for certain that androgen receptor upregulation is occurring.

All we have is the comparison to vehicle at 12 months:

View attachment 155489

What do you mean, how would that say something about whether upregulation is occurring?

Hey all,

I found the original presentation here: https://www.jefferies.com/CMSFiles/Jefferies.com/files/Cassiopea SpA V2.pdf

I'm also going to attach it just incase the link goes down in the future.

@pegasus2

Since it seems you looked through Cassiopea's documentation, did you per chance come across the papers for the phase I and II Breezula studies? I've tried looking for those, but been unable to find them. Only a paper briefly summarizing both.

Loss of effectiveness? We already know it's not a very strong AA.

Well, loss of effectiveness is what we are seeing, the question is what is the mechanism if not upregulation.

 

[trialAcc]

What do you mean, how would that say something about whether upregulation is occurring?



Since it seems you looked through Cassiopea's documentation, did you per chance come across the papers for the phase I and II Breezula studies? I've tried looking for those, but been unable to find them. Only a paper briefly summarizing both.



Well, loss of effectiveness is what we are seeing, the question is what is the mechanism if not upregulation.

The mechanism is called androgenic alopecia lol. The same reason why some people continue to lose hair on finasteride, because they're loss is too aggressive.

With breezula, it's probably the opposite. The AA is not strong enough to stave off much loss at all.

 

[pegasus2]

The mechanism is called androgenic alopecia lol. The same reason why some people continue to lose hair on finasteride, because they're loss is too aggressive.

With breezula, it's probably the opposite. The AA is not strong enough to stave off much loss at all.

That doesn't make sense. I'm not saying it's AR upregulation, but it's not the same as minoxidil and finasteride. Finasteride and minoxidil results both peak and then begin to drop, but they don't drop faster than placebo. Between months 6 and 12 CB gets outperformed by placebo, meaning the drop off is greater in the treatment group than in the control group. That's not simply Androgenetic Alopecia being too strong for the drug, it's the drug making it worse than no drug at all.

 

[tgfbeta]

We don't know how much of an effect the CB in the blood should have. Cassiopea DID do a large and long study with phase III and found no sexual sides. There's also all the winlevi studies that, AFAIK, found no AA related sides.

There WAS the HPTA axis finding, so maybe that can account for the member's unfortunate sides. It COULD also be nocebo.

It's not nocebo, I promise you. 0%

 

[tgfbeta]

That doesn't make sense. I'm not saying it's AR upregulation, but it's not the same as minoxidil and finasteride. Finasteride and minoxidil results both peak and then begin to drop, but they don't drop faster than placebo. Between months 6 and 12 CB gets outperformed by placebo, meaning the drop off is greater in the treatment group than in the control group. That's not simply Androgenetic Alopecia being too strong for the drug, it's the drug making it worse than no drug at all.

My personal theory, like others have said above, is HPTA suppresion causing strong negative feedback on the hormone profile, which can theoretically explain hair loss. Honestly, from what I've read so far regarding upregulation of AR, AA can downregulate AR expression; conversely, it's been shown that DHT analogues upregulate AR expression.

 

[tgfbeta]

If anybody is familar with the cortisol synthesis pathway please let me know. I have not studied it enough to make any connections yet; however, I've come across a possible culprit: 17 alpha-hydroxylase/17,20-lyase deficiency. It could be possible that the HPTA suppression caused by excessive cortisol and its downstream metabolites, which are steroids after all (since CB is steroidal), are far more dangerous and damaging than the direct systemic AA effects caused by low levels of un-metabolized CB.

Edit: After doing a quick search, I've put two and two together, but I still don't have the full picture, I'm sure. Take a look at the attached image.

We know from the Winlevi trials that ~10% of patients acquired HPA axis suppression, which was measure by abnormal ACTH (Adrenocorticotropic hormone), which is secreted by the pituitary gland. ACTH acts as a regulator for hormone production. My proposal is that in the case of the patients with HPA axis suppression, abnormally high levels of ACTH indicate an underlying issue, namely a short-circuiting of the cortisol synthesis pathway, where the 17 alpha-hydroxylase enzyme is underexpressed, severely reducing the normal conversion of pregnenelone and progesterone to cortisol and androgens like testosterone.

According to the pharmacokinetics of clascoterone, it breaks down into Cortexolone 17alpha-propionate, which is the direct precursor to cortisol. When CB rapidly hydrolyzes into Cortexolone 17alpha-propionate, it raises the baseline conversion rate of cortexolone, leading to elevated levels of cortisol, which will shut off the the normal production cortisol. Now, here is my leap of faith. My very, very unscientific intuition is that the body will shut off natural cortisol production by downregulating expression of 17 alpha-hydroxylase. The major downside is that the conversion into sex steroids will also decrease in proportion to the decrease of natural cortisol production, since cortisol and sex steroids both utilize 17 alpha-hydroxylase at some point in the their respective synthesis pathways. Overtime, ACTH will rise significantly because of the lack of negative feedback of sex steroids.

One issue with my theory is that elevated cortisol caused by exogenous CB - > Cortexolone 17alpha-propionate, should act as negative feedback, therefore reducing ACTH and opening up the pathway into sex steroids via upregulation of 17 alpha-hydroxylase. I am unsure about this contradiction. Moreover, I'm unsure how this has an effect on synthesis of testosterone in the testes, as the picture I've described related to adrenal production of sex steroids, which accounts for a significantly smaller % of overall androgen production in the body. My guess then would be GnRH, but according to my labs, FSH and LH were similar to baselines. Please let me know if you see any major errors in my analysis. I will continue studying in the meantime.

 

[trialAcc]

That doesn't make sense. I'm not saying it's AR upregulation, but it's not the same as minoxidil and finasteride. Finasteride and minoxidil results both peak and then begin to drop, but they don't drop faster than placebo. Between months 6 and 12 CB gets outperformed by placebo, meaning the drop off is greater in the treatment group than in the control group. That's not simply Androgenetic Alopecia being too strong for the drug, it's the drug making it worse than no drug at all.

I would agree if it fell below baseline, but it's not the case. Again, the idea of upregulation is complete non-sense, otherwise the acne trials would have yielded the exact same results but with acne rather then hairloss.

 

[pegasus2]

I would agree if it fell below baseline, but it's not the case. Again, the idea of upregulation is complete non-sense, otherwise the acne trials would have yielded the exact same results but with acne rather then hairloss.

Assuming that's accurate, a lack of AR upregulation in the sebaceous gland doesn't prove a lack of AR upregulation in the DP anymore than AR upregulation in the prostate proves AR upregulation in the DP. You're comparing apples to oranges, which is fine for forming a hypothesis, but it doesn't prove anything.

 

[tgfbeta]

Assuming that's accurate, a lack of AR upregulation in the sebaceous gland doesn't prove a lack of AR upregulation in the DP anymore than AR upregulation in the prostate proves AR upregulation in the DP. You're comparing apples to oranges, which is fine for forming a hypothesis, but it doesn't prove anything.

This provides grounds for further independent research - using antibodies for AR and measuring them in DP over time.

 

[trialAcc]

Assuming that's accurate, a lack of AR upregulation in the sebaceous gland doesn't prove a lack of AR upregulation in the DP anymore than AR upregulation in the prostate proves AR upregulation in the DP. You're comparing apples to oranges, which is fine for forming a hypothesis, but it doesn't prove anything.

Fair enough, you clearly have better understanding of this then I do. Are you also convinced that AR upregulation through finasteride is possible (RHA)?

 

[pegasus2]

Fair enough, you clearly have better understanding of this then I do. Are you also convinced that AR upregulation through finasteride is possible (RHA)?

I'm not even convinced of AR upregulation from AR antagonists like CB. It's just one theory for what's happening from CB. Another is some type of negative feedback on estrogen receptor expression. I think AR upregulation is more likely from AR antagonists, and I don't see any reason to believe it happens with 5-ARIs.

 

[trialAcc]

I'm not even convinced of AR upregulation from AR antagonists like CB. It's just one theory for what's happening from CB. Another is some type of negative feedback on estrogen receptor expression. I think AR upregulation is more likely from AR antagonists, and I don't see any reason to believe it happens with 5-ARIs.

So what would you think is happening to people who get greasy and inflamed scalps while using finasteride that are accompanied with heavy shedding?

 

[pegasus2]

So what would you think is happening to people who get greasy and inflamed scalps while using finasteride that are accompanied with heavy shedding?

I really haven't seen that complaint. I don't put much stock in anecdotal experiences of forum users anyway when I know many are neurotic hypochondriacs. It's not really worth considering until a clinical trial shows something like that.

 

[trialAcc]

I really haven't seen that complaint. I don't put much stock in anecdotal experiences of forum users anyway when I know many are neurotic hypochondriacs. It's not really worth considering until a clinical trial shows something like that.

Oh, I'm experiencing it right now haha.

 

[pegasus2]

Oh, I'm experiencing it right now haha.

Are you on anything else? How long have you been on finasteride?

 

[trialAcc]

Are you on anything else? How long have you been on finasteride?

I was on it for 6 years and got maintenance. Ran out during covid for 2-3 months and started again in October. Since then I've got all the symptoms mentioned; insane scalp itch with scalp acne, greasy like never before and shedding unlike any finasteride shed I've ever had. At any point during the day I can run my hands through my hair and get 5-10 hairs.

Also on minoxidil since last March which has done absolutely nothing, no sheds or anything.