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Frontline Forum Part 3: A Discussion of the Pathophysiology of Acne and Available Treatment Strategies

Dermatology TimesDermatology Times, Acne Supplement, March 2023 (Vol. 44, Supp. 01)
Volume 44
Issue 03

In part 3 of this Frontline Forum series, Joshua Zeichner, MD, FAAD; Hilary Baldwin, MD; Zoe Diana Draelos, MD; Aaron S. Farberg, MD, FAAD; and Leon H. Kircik, MD, discuss the main pillars of acne and topical treatments available for patients with acne.

Continued from part 2

Zeichner: Let’s just talk a little bit about the role of androgens and the development of acne when androgens start to increase in levels in the bloodstream and the effects of that.

Kircik: So no puberty, no acne. No androgens, no acne. These are well known.

Zeichner: Adrenarche is the first stage of puberty, when the adrenal glands start to mature and produce androgen hormones. This is the time where prepubertal children start to develop acne, particularly comedones, in the T-zone of the face, which is the forehead, the nose, and the chin, which are the parts of the face that have the largest and most active
sebaceous glands.

Zeichner: What about androgens in men vs women? People typically think of testosterone as a male hormone, but this is not completely true.

Baldwin: In some cases, plasma levels of androgens are far less important than we think they are in terms of the sebaceous gland function and acne. So what does that mean? Are we saying that spironolactone [is] helping acne because it’s suppressing the levels in the bloodstream? Or is it doing something to the follicle as well?

Zeichner: I would think it’s a roadblock at the level of the skin.

Baldwin: The place to act when you’re trying to suppress sebum is at the sebaceous gland level, and that’s what clascoterone does. It’sprobably what spironolactone does too, but we don’t know.

Zeichner: Why do kids get acne during puberty and then in many of them, it goes away? Is there that acclimation to the new level of hormones? Something that you’re not actually seeing in transgender patients? When giving hormones to patients transitioning from female to male, they’re not going through that pubertal adjustment period. And even though they have a sustained higher level of exogenous testosterone, the sebaceous glands aren’t adjusting, and they continue to have severe acne.

Baldwin: How long do you think they will, though? We don’t really know the end point yet, do we?

Zeichner: I think many of these patients have been on exogenous testosterone at this point for many years.

Baldwin: You’re right. How many years is the maximum? Is it 10 years old? It’s longer than a boy would have been going through puberty.

Zeichner: There’s a lot we don’t know, but I think that the most important take-home is what you said, is that there’s an interaction between testosterone and the sebaceous glands at the end organ level and the skin, which is completely separate from drug levels in the bloodstream.

Baldwin: Which is also probably why spironolactone works in adult women with acne, even if they have normal androgen levels in their bloodstream.

Zeichner: I think there’s a sensitivity.

Baldwin: Yes, end organ hypersensitivity. Therefore, it seems that Winlevi would be an appropriate drug for the treatment of adult acne patients. Adult acne is commonly referred to as hormonal acne, a term that we use to describe the cyclical breakouts that we see in adult women. But this is
a misnomer.

Kircik: As Julie Harper says, “All acne is hormonal.”

Zeichner: Traditionally, hormonal therapies have been limited to women. How is topical clascoterone different?

Baldwin: Clascoterone is metabolized within the epidermis into cortexolone, which is not an antiandrogen. So before it even reaches the bloodstream, it has been metabolized into an agent, which is no longer an antiandrogen, making it safe in men. And during the pivotal phase 3 trials, they were not even required to check clascoterone levels because in the pharmacokinetic studies it was demonstrated to be nonexistent in the systemic circulation.

Zeichner: When we’re talking about the role of androgen hormones and the sebaceous glands, sebaceous glands are much more than just oil factories. And while they produce sebum, we also know that they have endocrine and immune roles. If sebaceous gland production is dampened, how might this lead to a decrease in acne proliferation?

Draelos: No sebum, no acne.

Kircik: Less sebum, less acne. More sebum, more acne.

Baldwin: I say the follicle is like the Ritz Carlton to C. acnes because it has all the food it needs, a nice place to sleep, and no oxygen.

Kircik: The antiandrogen blocks either the receptor or the enzyme itself. By blocking that, you are decreasing your sebum production. But it’s not only decreasing the serum production but also decreasing the proinflammatory cytokine release, which plays a role in acne pathogenesis such as IL-1β, IL-6, and IL-8. The drug binds to the androgen receptor by inhibiting the binding of the dihydrotestosterone to the androgen receptor on the sebaceous glands.

Zeichner: All new drugs coming to the market need to go through phase 1, 2, and 3 three studies. Phase 3 studies are the pivotal studies that the FDA evaluates, looking at statistical superiority of an active drug compared to its vehicle comparator. If someone would like to briefly comment on the study protocol or design?

Kircik: The study protocol was a typical classical acne study protocol. We included patients with moderate to severe acne on the IGA scale of 3 or 4. The patient population was 9 years of age and above. However, the drug is indicated for 12 years of age and above. There are two coprimary end points; success was defined as clear or almost clear, with two-grade improvement on the IGA scale as well as absolute number reduction in inflammatory and non-inflammatory lesion count at week 12. And all acne studies are in week 12. Patients were randomized 1:1 to receive clascoterone cream vs its vehicle, and it was applied twice daily for 12 weeks. Then there was an open-label extension study, where the patients who choose to go on that open-label study were included. That ended for 9 months, which totaled up to 12 months for safety. However, we also looked at the efficacy anyway.

Baldwin: The inclusion criteria were a minimum of 30 inflammatory and 30 non-inflammatory lesion count, which is very high. I like to ask the reader or the people sitting in the room to think about what they would look like with a minimum of 60 acne lesions on their face. Because that’s an awful lot of acne.

Farberg: And patients were well balanced between the active and vehicle arms and well balanced across the 2 clinical trials.

Baldwin: In the open-label extension study [Open-label, long-term extension study to evaluate the safety of clascoterone (CB-03-01) cream, 1% twice daily, in patients with acne vulgaris]2…609 people were enrolled for the phase 3 trial. Approximately half of them had been in the clascoterone arm, and half had been in the vehicle arm. All patients spent 1 month taking clascoterone twice a day on their face, and they were also allowed to place it on their trunk. After that, they were evaluated at month 1, 3, 6, and 9. And if they were doing well, that is to say, an IGA of 0 or 1 or clear or near clear, they were taken off drug. If they were mild, moderate, or severe, they were placed on drug or continued on drug until the next evaluation. So at the end of the study, you had people who had been on drug for a full 12 months and with a minimum of 9 months and all permutations in between.

Zeichner: Is clascoterone an appropriate option for truncal acne, irritation, and bleaching?

Baldwin: In the open-label study, patients were also allowed to place the medication on their trunk, which of course is helpful because this is basically a safety study, so we do want maximum use during a safety study. So they applied it on a daily basis to the trunk if they had acne there, obviously. And there was efficacy data captured, which demonstrated a nice improvement in truncal acne, which actually was numerically superior to the results on the face, although the numbers were quite a bit lower. This suggests that we have yet another medication that’s appropriate for use on the trunk, which is an area that’s often very difficult to treat. We have medications that stain, medications that bleach, and medications that irritate, and this drug does none of those.

Kircik: The drug was safe and well-tolerated throughout the study.

Draelos: With an excellent safety profile.

Zeichner: Regarding the indication for isotretinoin, who do you use it for? When do you use it? And are you using it differently now compared to 10 years ago?

Farberg: Primarily when I’m considering utilizing isotretinoin or when treating patients with acne, I tend to discuss all treatment options, including a high-quality skincare regimen, topical treatments, various oral treatments which include isotretinoin, because I want my patients to understand the breadth of treatment options. And then we discuss personalizing this treatment, and it goes back to this understanding of what’s the impact that this acne is having on the patient. For example, I have some patients with what I might consider mild acne, but it’s having a significant impact on their social life. And of course, I see the contrary, patients with very severe acne that would prefer just to use a topical medication. And so I’ll discuss isotretinoin almost with every acne patient and then come to a group decision as to whether or not it’s appropriate
for them.

Zeichner: Isotretinoin is indicated for patients with severe nodular cystic acne or in patients with acne resistant to traditional treatment as well as patients with physical or emotional scarring. There are some patients who have more severe acne but are not emotionally affected by it and are not interested in isotretinoin. And there are some patients who have less objectively severe acne but are more emotionally affected. And all of these patients are potential candidates.

Zeichner: I think we all have seen those patients who have objectively mild pimples, but they’re leaving scars behind.

Kircik: Exactly. So we cannot ignore the mild disease not knowing what will be the scarring.

Zeichner: And I think that many of us have seen patients on oral antibiotics for 2 years. Patients have been mismanaged, and I think that, in our expert opinion in treating acne patients, we’re reaching to isotretinoin much earlier now than we did 10 years ago because of our current understanding of both the safety of the drug as well as the
effectiveness of the drug.

Kircik: But also, our understanding of the antibiotic resistance contributed to us using isotretinoin earlier and using less antibiotics.

Draelos: And the ability of the patient to make matrix metalloproteinases in response to the free fatty acids. So that’s where the immune system comes in, and that’s why mild people can have very severe scarring.

Zeichner: I think it’s really important as to the mechanism by which some patients scar out of proportion to what we would expect based on their acne severity.

Baldwin: I think in the last 10 years we’ve really taken to heart the concept of being better stewards of antibiotics. And part of that is recognizing that our European colleagues turn to isotretinoin much sooner than we do, after 1 or only 2 courses of failed antibiotics. And we have a study that shows that the average person who goes on isotretinoin has already been on antibiotics for a year. And if they’ve visited more than one institution, they’ve been on antibiotics for something like 350 days before they finally go on the isotretinoin that they probably needed to begin with. So I think we’ve turned a corner in the last 10 years. We’re not afraid of isotretinoin anymore, there was a period…when we were. There was a…time when we weren’t using it because iPLEDGE was so difficult to utilize. And I think we’ve come past that now, we recognize it for the wonderful drug that it is. And we celebrate its 40th birthday with it still being the best medication that we have to treat our severe acne patients. One of the benefits of using Winlevi in the treatment of acne, of course, [is that] this is not an antibiotic.


This Frontline Forum is supported by Sun Pharmaceutical Industries Ltd.

Continued in part 4 coming soon.

[Edited for space and clarity].


2. An open-label, long-term extension study to evaluate the safety of CB-03-01 cream, 1% in participants with acne vulgaris. Accessed December 5, 2022. https://clinicaltrials.gov/ct2/show/NCT02682264

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