Acne: The drought is over
After years of recycling the same ingredients, dermatologists have novel acne treatments and formulations available — with more on the horizon.
Feature
By Allison Evans, assistant managing editor, February 1, 2021
Over the past few years, an incredible amount of innovation has taken place for the treatment of acne vulgaris (acne). Since isotretinoin first came to market in 1982, few novel acne treatments had been developed. Most of the new products marketed over the past 30 years involved repurposing previously used active ingredients. While dermatologists have had many tools at their disposal, that toolbox now includes, and will continue to include, more targeted and effective drugs with potentially fewer side effects.
Pathogenesis
While there is still much to be discovered about the pathogenesis of acne, there have been a few interesting additions in the overall understanding of acne, said Linda Stein Gold, MD, director of dermatology clinical research and division head of dermatology for Henry Ford Health System. Dr. Stein Gold has served as Investigator/consultant and/or speaker for Galderma, Ortho Derm, Sun Pharmaceuticals, Almirall, Sol Gel, and Vyne.
“It used to be that dermatologists were taught that the microcomedone was the first step in the pathogenesis of acne. Over the past several years, we’ve learned that might not be true. There may be inflammation that precedes the microcomedone. If it’s true, that means that all acne is inflammatory acne,” she said. “It’s kind of a misnomer to talk about noninflammatory and inflammatory acne. It may be more correct to talk about comedonal acne and superficial inflammatory acne,” Dr. Stein Gold explained.
Another interesting development in understanding acne involves the microbiome. “When we look at the bacteria, Cutibacterium acnes (C. acnes), it’s probably not the amount of bacteria that’s important. It’s more likely the strain of bacteria. We know some strains tend to be associated with the development of acne, whereas others aren’t. Acne may be the body’s reaction to particular strains that are more inflammatory,” Dr. Stein Gold said.
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Scarring
Typically, we think of patients with nodular cystic acne as the ones most likely to develop scars, said Dr. Stein Gold. “But we know that people who have more superficial acne are also at increased risk for developing atrophic scars. Studies have looked at scar development and found that the longer a papule is present, the greater risk for scarring to develop. These studies have shown that even if the acne is flat, dermatologists should continue to treat because inflammation is still present,” she said.
A 2018 study published in the American Journal of Clinical Dermatology looked at the fixed combination of adapalene (0.3%) with benzoyl peroxide (2.5%) gel on half the face and vehicle on the other half. After six months, not only were scars prevented from forming, but the study showed, for the first time, that a topical agent had the potential to improve scars, Dr. Stein Gold added (doi: 10.1007/s40257-018-0352-y).
Isotretinoin: A few gamechangers
In 1982, isotretinoin was a breakthrough treatment for acne, and to-date it is the only drug that impacts all four of its pathogenic factors, said New York dermatologist Hilary Baldwin, MD, a founding board member and second president of the American Acne and Rosacea Society, as well as a co-author of the Academy’s acne clinical guidelines.
“The use of isotretinoin has increased in the last couple of years,” she said. “It’s the answer to a lot of our problems, including the overuse of antibiotics — 80% of people who take isotretinoin never see acne again.”
Depression and suicide risk
There are numerous reasons why patients are not willing to try or comply with the drug. Aside from some of the drug’s typical (and sometimes severe) side effects and regulatory obstacles, dermatologists are well versed in patient and parental concern regarding the perceived link between isotretinoin and depression and suicide.
Recently, however, there have been two meta- analyses published that have concluded that there is no reason to think that isotretinoin is associated with depression, Dr. Baldwin said. In fact, one August 2020 analysis found both depression and anxiety heightened in acne sufferers at an effect similar to cyberbullying on victim’s depression, anxiety, and loneliness .
“This particular group of patients have two independent risk factors for depression: The first is that they have acne. The second is the age group of most acne patients — 18 to 25-year-olds, is the peak incidence of all psychiatric problems, including depression,” Dr. Baldwin explained. The study concludes that “Given the psychiatric risk of acne itself, it is important for physicians to optimize acne management, which may include utilization of isotretinoin.”
Timing of procedures
The notion that isotretinoin taken within 6 to 12 months of cutaneous procedures contributes to abnormal scarring or delayed wound healing is widely taught and practiced. In August 2017, a panel of experts in pediatric dermatology, procedural/cosmetic dermatology, plastic surgery, scars, wound healing, acne, and isotretinoin convened. The group published consensus recommendations based on an expert survey showing insufficient evidence to support delaying procedures including manual dermabrasion, superficial chemical peels, cutaneous surgery, laser hair removal, and fractional ablative and nonablative laser procedures for patients who are currently taking or have recently completed isotretinoin therapy (doi:10.1001/jamadermatol.2017.2077).
“For patients, for instance, who have acne scarring, they certainly could get started on their treatments concurrently with isotretinoin or immediately after, and not have to wait six months,” Dr. Berson said. “You would still want to avoid ablative laser resurfacing and mechanical dermabrasion right after treatment because you would be concerned about healing and the potential development of scar tissue.”
Topical retinoids
Over the past year, three new topical retinoid formulations have come to market — all approved for ages nine and above. There is a micronized tretinoin (0.05%) that launched in 2018 that uses a unique vehicle called polymeric emulsion technology, which is a mesh-like emulsion that allows the active ingredient to penetrate into the sebaceous follicle, said Diane S. Berson, MD, associate professor of dermatology at Weill Cornell Medical College and co-author of the Academy’s acne clinical guidelines. Dr. Berson has also served on advisory boards for Ortho, Allergan, Sun Pharma, P&G, La Roche Posay, L’Oreal, Revance, Evolus, Galderma, Almirall, TopMD, Sonoma, and Cassiopea. “It’s the first tretinoin product to be available in lotion form. It’s less irritating than the original retinoids and cosmetically a nice alternative because it has hydrating agents, including glycerin and hyaluronic acid.”
There is also a new tazarotene (0.045%) lotion that uses the same polymeric emulsion technology. It is the first tazarotene acne treatment available in lotion form. “Traditionally, tazarotene was used with a moisturizer due to potential irritation. This new technology and the hydrating agents make the tazarotene formulation better tolerated cosmetically,” Dr. Berson said. In a phase 2 comparative study, tazarotene (0.045%) lotion showed similar efficacy as tazarotene (0.1%) cream with fewer side effects.
In 2019, a new topical, fourth generation retinoid came to market: trifarotene (0.005%) cream. This is the first new retinoid molecule approved by the U.S. Food and Drug Administration (FDA) for the treatment of acne in more than 20 years. “What makes trifarotene unique is that it has selective binding for the retinoic acid receptor gamma (RAR-ɣ). It is also very well tolerated,” Dr. Berson explained. Additionally, this is the first retinoid to receive FDA approval for truncal acne, she added.
The selectivity of trifarotene for RAR-ɣ distinguishes it from the existing topical retinoids, which target both retinoic acid receptors beta and gamma. This may help reduce the risk of potential side effects mediated by the other receptors.
Antibiotics and a new chemical entity
“You can’t eradicate C. acnes from the hair follicles. It lives there and it’s supposed to live there. The best you can do is restrict its growth and pull off a couple of its buddies,” said New York dermatologist Hilary Baldwin, MD, a founding board member and second president of the American Acne and Rosacea Society, as well as a co-author of the Academy’s acne clinical guidelines. Dr. Baldwin also serves as advisor and investigator, and is on the speakers’ bureaus, for Almirall, Cassiopea, Vyne, Galderma, Ortho Dermatologics, Sol Gel, and Sun Pharmaceuticals.
Ultimately, this supports antibiotic stewardship, which is outlined in the Academy’s clinical guidelines of care for the management of acne vulgaris, and the desire to avoid the use of antibiotics when possible, Dr. Baldwin said. “This is not to say oral antibiotics are not important in the treatment of acne; they clearly are. There are patients that really require them — we just do our best to avoid them.”
While prescribing practices may be shifting away from antibiotics, a new oral antibiotic and third generation tetracycline drug, sarecycline, launched in January 2019. “Sarecycline was formulated to be anti-inflammatory and also have a narrower spectrum of activity,” Dr. Stein Gold said. “It specifically targets C. acnes in the skin and avoids killing other bacteria that our bodies need.” Sarecycline is also the only oral antibiotic approved for truncal acne, and it can be taken with or without food. Additionally, it’s approved down to the age of 9 — the other tetracycline drugs are only approved for age 12 and above, Dr. Baldwin noted.
“It’s more specific for gram positive bacteria, and it’s highly effective against C. acnes. It’s not very effective against gram negative bacteria, which means it’s less likely to have an impact on the GI tract. It was also developed to have less resistance to C. acnes,” she added.
Sarecycline was effective on both inflammatory lesions as well as comedones, which you don’t necessarily expect with oral antibiotics, Dr. Stein Gold remarked.
“The drug has what’s called a C7 moiety. This structural alteration prevents the development of resistance by affecting the messenger RNA and ribosomes, which are involved in the development of resistances,” Dr. Berson said.
In addition to reduced GI side effects, sarecycline doesn’t have a lot of the side effects that are typical of other tetracycline drugs. In clinical trials, photosensitivity was very rare, vaginal yeast infections were rare, and participants experienced less dizziness, Dr. Stein Gold said. “An animal study found that sarecycline does not penetrate the blood-brain barrier like minocycline does, which means patients are less likely to experience central nervous system side effects as well.”
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Minocycline foam
In 2019, the FDA approved a topical minocycline foam (4%), which is the first time minocycline has been formulated to be applied directly to the skin.
“The foam absorbs well because of micronized particles and a triglyceride-based vehicle. It’s lipophilic, which means it likes fat, so it gets into the sebaceous follicle. The foam spreads very easily and can cover a large surface area,” Dr. Berson said. “It also doesn’t feel greasy or heavy,” she added.
The other advantage of the foam is that dermatologists can be less concerned about drug resistance because there’s no systemic absorption — it’s all localized in the sebaceous follicle.
The amount of the minocycline deposited in the skin from the foam is very, very high — about 850 times more than what we see in the amount of drug that is deposited if taken orally. When we look at the amount of drug in the plasma, it’s very, very low, Dr. Stein Gold explained. “When we have drug levels that are that high, we’ve found that the probability of resistance is significantly less than with other agents.”
“The reason we’ve never formulated minocycline topically is because it’s a large molecule, and it’s challenging to deliver it topically in a stable formulation in something that’s also cosmetically elegant,” Dr. Stein Gold said. “The drug is very well tolerated, and in the clinical trials we didn’t see hyperpigmentation.”
Caring for iPLEDGE patients during the pandemic
In March 2020, the FDA indicated that “for drugs subject to REMS with laboratory testing or imaging requirements,” which includes isotretinoin under the iPLEDGE program, physicians “prescribing and/or dispensing these drugs should consider whether there are compelling reasons not to complete these tests or studies during this public health emergency and use their best medical judgment in weighing the benefits and risks of continuing treatment in the absence of laboratory testing and imaging studies. They should also communicate with their patients regarding these judgments including their benefits and risks.”
The iPLEDGE contractor has indicated to the Academy that at-home pregnancy tests and telemedicine visits are acceptable for complying with the iPLEDGE requirements during the COVID-19 outbreak. Dermatologists still must enter pregnancy test information for prescriptions to be filled. The list below describes what has changed. Note that the updated requirements are only in effect during an emergency declaration.
Requirements and changes due to COVID-19:
Telemedicine: Prescriber to use best medical judgement to manage their patients. Please refer to the March 17, 2020 notice from The Department of Health and Human Services Office for Civil Rights (“Notification of Enforcement Discretion for telehealth remote communications during the COVID-19 nationwide public health emergency”) for guidance.
Pregnancy testing: Pregnancy test can be “at-home.” The tests can be obtained at drug store, grocery store, or online retailer. The test results and date performed must be communicated to prescriber. Prescriber or designee would enter the date performed (specimen collection date) and test results per usual iPLEDGE program process.
Prescription window: This requirement will not change.
Two forms of birth control or abstinence: This requirement will not change.
For clinical guidance about practicing during the COVID-19 pandemic, visit the Academy’s Coronavirus Resource Center.
A new molecule
In August 2020, the FDA approved a new molecule — clascoterone cream 1%, a selective androgen antagonist that inhibits sebum production. The last FDA approval of an acne drug with a new mechanism of action occurred nearly 40 years ago. At the time of publication, clascoterone is not yet available.
In addition to being a new molecule, clascoterone provides a new option for male patients. Female patients can be prescribed oral contraceptives and spironolactone to help with sebum inhibition. However, the only option to suppress sebum for male patients has been isotretinoin, Dr. Baldwin added.
“When we look at the topical medications available for acne, we’ve been able to do three out of the four things,” Dr. Stein Gold said. “We can decrease inflammation. We can kill C. acnes. We can normalize abnormal keratinization. But we’ve never been able to decrease sebum production topically. In addition to sebum inhibition, the drug also has anti-inflammatory properties, she added. “It worked on comedones as well as inflammatory lesions.”
“This anti-androgen blocks the androgen receptors on the sebaceous glands that interact with hormones such as dihydrotestosterone, leading to decreased production of oil and sebum by sebocytes,” Dr. Berson explained. The studies have shown no systemic side effects and no evidence of adrenal suppression.
Improving isotretinoin
As a lipophilic drug, the absorption of isotretinoin is significantly improved if taken with a high-fat meal. When studied in clinical trials, patients were given the drug with 800 to 1,000 calories, half of which was comprised of fat. When taken without food, fasting plasma levels of the drug were 60% lower than when taken with the high-calorie, high-fat meal. For those who typically opt out of breakfast or who engage in specific diets, including the increasingly popular trend of intermittent fasting, isotretinoin may not be as efficacious, explained Dr. Stein Gold. “We know if you don’t take it with a fatty meal, the absorption goes down. The amount of drug that is realized is less and a patient’s likelihood of relapse increases because they’re not getting a full course.”
In 2012, a new formulation of isotretinoin was released. “It utilized Lidose® technology, which is a lipid encapsulation that, in pharmacokinetic studies, showed increased drug exposure (83% difference) in fasted states compared to generic isotretinoin. It was subsequently taken for a clinical spin and shown to be effective in the fasted state. Since 2019, we have had a new micronized formulation that increases the bioavailability by an additional 50% compared to the already superior lidose formulation,” Dr Baldwin said. “It is dosed at 20% below what is normally given with generic isotretinoin,” Dr. Stein Gold said. “If you take the micronized low-dose isotretinoin on a fasting stomach, you get double the absorption of the Lidose isotretinoin.”
What’s ahead?
Even with all the recent developments in acne treatment, there are more exciting things in the pipeline, including new fixed combination treatments, said Dr. Stein Gold. “In the past, we have not been able to prescribe tretinoin and benzoyl peroxide together because tretinoin inactivated the benzoyl peroxide. There is a new formulation in clinical trials that’s silica-based that allows these two drugs to be combined in the same formulation while remaining stable,” she said.
Another combination that completed phase 2 trials in early 2020 is a combination minocycline (3%) and adapalene (0.3%) foam. Also, for the first time, Dr. Stein Gold added, “There is a triple combination in phase 3 clinical trials: adapalene, benzoyl peroxide, and clindamycin that looks promising.”
Further down the road, there may be a topical cannabidiol (CBD) formulation for the management of acne. In early phase testing, a topical gel formulation of CBD has been shown to be well tolerated in patients with moderate to severe acne (doi:10.1016/j.jid.2018.03.1074). There is a CBD formulation (BTX 1503) that recently completed phase 2 trials and is preparing for phase 3 trials. The group getting a once-daily dose of 5% BTX 1503 saw the highest efficacy with an average reduction in lesions of 40.54%. The drug, however, did not beat placebo, which saw a 40.15% reduction in lesions.
The past few years have seen some exciting developments for the treatment of acne. “We have all the tools in our toolbox to make patients better,” Dr. Berson said. “But patients won’t improve if they’re not compliant. It’s spending enough time with each patient to go over the entire regimen — from soup to nuts including skin care — that will help patients not only get the best benefit from their medications, but learn how and when to use them correctly to optimize both efficacy and tolerability.”
“It’s important to have options; it’s important to really strive to get our patients as clear as possible,” Dr. Stein Gold said. “Nobody is going to be satisfied having 50% less acne on their face.”
