Fall 2020: An Innovative Topical Retinoid for Acne (AKLIEF)

Speaker: Dr. Katie Beleznay is a practitioner at Humphrey Cosmetic Dermatology and Seymour Dermatology, and a clinical instructor at the University of British Columbia, Department of Dermatology.

Dr. Beleznay: Thank you to Derm Update and Galderma for inviting me here today. It’s nice to do a talk in person for a change. I’m really excited about this.

I’m speaking about AKLIEF today, which is a new topical retinoid for the treatment of acne for the face and the trunk.

Let’s start with the impact of acne on patients. It is associated with lower self-esteem, anxiety, and depression. In addition, acne can produce emotions like embarrassment, humiliation, and self-consciousness. Acne also influences how patients are perceived by others, even affecting employment if the acne is severe. Lastly, acne can lead to scarring, which also has a negative impact on quality of life.

  • Over 50% of people have skipped a social event because of acne
  • 42% of professionals say that acne has had a negative impact on their career
  • 50% of people in their 20s have given up on dating until they have clear skin
  • 74% of acne sufferers have seen a health care provider about their acne
  • 94% believe their health care provider needs to do more to improve their acne

A large multinational online survey suggested that acne has a large impact on perception. The first thing that viewers notice on a person’s face is usually the eyes, but they notice the skin first in people with acne scars. Acne influences perceptions of unrelated skills such as sports and public speaking, and are perceived as less confident, and less healthy. Acne has a big impact not only on their own self-esteem but on how others perceive them. We want to treat acne to prevent scarring as it’s difficult to treat once it’s already there.

Truncal Acne and its Pathogenic Features

Truncal acne is hidden and often under-recognized as patients often feel embarrassed to mention it to their healthcare provider. However, 52% of patients with facial acne also have truncal acne, and 78% of patients wanted their truncal acne treated too. I often ask a patient about truncal acne, especially if they are teenagers who may be reluctant to mention their truncal acne.

  • Truncal acne can also scar, and it’s important to recognize and treat it as well
  • Hypertrophic and keloid scarring is common on the trunk because the skin is thicker in the area
  • Perifollicular elastolysis scars usually appear as small skin-colored lesions
  • Truncal acne is more common in males
  • Asian and black patients are more prone to hypertrophic and keloid scarring, which are hard to treat

The four main pathogenic features:

  • Altered follicular growth and differentiation – clogging of the pores
  • The proliferation of C. Acnes
  • Sebum overproduction and ductal blockage
  • Inflammation

Treatments aim to target as many of these features as possible. I take some extra time to explain the pathogenesis to my patients so that they understand why they are using the topicals. They know that spot treatments will be less effective because they aren’t preventing future acne down the road by applying it to areas where the pathogenesis may have started but are still not visible. They understand why it takes time for acne medications to work and are more compliant for those reasons. I also explain the irritation that is common when starting topical treatments so they know what to expect.

Topical Retinoids

Retinoids play an essential role as first-line therapy for both mild and severe acne. Evidence-based guidelines agree that topical retinoids should be considered as the foundation of acne therapy. They have multiple targets of pathogenesis:

  • Comedolytic (inhibits the formation of comedones)
  • Resolve the precursor microcomedone lesion
  • Anti-inflammatory

We also use topical retinoids in other contexts such as photoaging and fine lines to improve skin texture, acne scarring and manage pigmentation problems. In addition to acne, we use retinoids for various issues in dermatology.

Let’s talk a bit about some basic science as it goes well in explaining AKLIEF. RAR Gamma is the most prevalent of the three subtypes in the skin. Targeting RAR Gamma with retinoids serves several vital interests.

  • Inflammation is modulated with AP-1
  • Epidermal turnover and normalizing cell growth, keratinization, desquamation

We’re now on the fourth generation of retinoids.

  1. Tretinoin (1st generation – 1978)
  2. Acitretin (2nd generation – 1994)
  3. Tazarotene and Adapalene (3rd generation – 1997)
  4. Trifarotene (4th generation – 2020)

The newer generations can target better. Trifarotene targets RAR-y, the most relevant retinoic acid receptor in the skin, and allows for use on large surfaces. It’s effective at lower doses and has low systemic exposure from use and is rapidly removed from the body.

Trifarotene: Basic Science

Some key facts about trifarotene (AKLIEF):

  • Trifarotene showed dose-dependent comedolytic activity and achieved 98% reduction of comedones at 0.01%, a ten-fold lower concentration than Tazarotene. (Mouse model)
  • 77% reduction of comedones with Trifarotene 0.005% compared to 61% reduction with Tretinoin 0.05%.
  • Trifarotene 0.005% increased epidermal thickness by 223%.
  • Trifarotene showed potent anti-inflammatory effects.
  • Trifarotene 0.01% along with tretinoin 0.01% showed significant depigmenting properties compared to Adapalene.

What about the gene pathway?

Gene expression showed known retinoid pathways such as epidermal differentiation and proliferation. Three new pathways were identified with Trifarotene: Cell Adhesion, Transport, and Skin Hydration (less TEWL). Proteolysis – MME downregulation – potential effect on skin aging.

In summary, AKLIEF is a 4th generation selective RARy agonist and has greater efficacy with decreased skin irritation. It is rapidly metabolized by human hepatic microsomes; and therefore has a theoretically better systemic safety profile. In vivo studies show significant comedolytic, anti-inflammatory, and anti pigment activities. Gene expression shows potent activation of retinoid modulated processes (epidermal differentiation, proliferation) & novel pathways (proteolysis, hydration, adhesion) A reduction in pigmentation, may expand its use in acne-related PIH and scarring as well.

The Clinical Data

AKLIEF is the first new retinoid molecule in more than 20 years. It’s the first to be indicated for the treatment of truncal acne as well as facial acne.

  • In the PIVOTAL 1 study, less than 50% fewer inflammatory lesions on the face and trunk at week 12. The results are from 2 large clinical trials studied in treating moderate truncal and facial acne vulgaris.
  • Patient population: 119 sites, 81 sites in Europe, moderate acne (IGA 3). Population – AKLIEF vs. Vehicle Only.
  • Moderate acne patients (IGA 3 Investigator’s Global Assessment Scale) with face and trunk involvement. A 2 level improvement was the criteria for treatment success.
  • Adverse events were at 1.5% and 2%.
  • At week 12 AKLIEF, there are improved IGA success rates at week 4 and 8, as well as a continued improvement into week 12.
  • Mean % reduction – over 50% by week 8, non-inflammatory at week 12.
  • PGA success rate was statistically significant at week 8 – 12 vs. vehicle.
  • Tolerability is good with less than 2% discontinuing (the common side-effects were irritation, itch, and redness). Similar to most retinoids, the irritation peaked at week 2 and continued to taper into week 12.

Looking at a Long-Term Study of AKLIEF

We looked at long-term studies extending beyond 12 weeks. This study was for 52 weeks, focused on safety, but also efficacy.

  • Both IGA and PGA assessments were taken – and show a similar treatment curve with success rates sharply increasing until week 12 but continuing to improve to 65% by week 52.
  • I tell patients not to stop at 12 weeks. The longer you use it, the more likely you are to see complete improvement.
  • Side effects were mild. Irritation, redness, and itch were the common adverse events.
  • Some patients won’t make the 2-grade improvement at 12 weeks but do better after 52 weeks.
  • Off-label, I notice it has excellent tolerability. Mask-induced acne, keratosis pilaris, post-isotretinoin follow-up, photoaging, texture, skin pigmentation are some uses. I’m finding success in this group, with people who don’t like the irritation.
  • We don’t have all the data available today for off-label (it’s for truncal acne), but we’ll get more information soon.

How to Use AKLIEF (On Label)

On label – AKLIEF topical cream is indicated for acne in the face or the trunk for patients 12 years or older. A thin layer should be applied to the trunk. Sun protection is recommended when using these topicals. One pump should cover the face with a thin layer, and two pumps should cover the upper trunk, including the upper back, shoulders, and chest. Moisturizer use is also recommended before or after application. A 75g pump should last an average of 5-6 months. If used on the face and trunk, it should last approximately 2-4 months. As AKLIEF is new, it currently does not have public coverage. However, it has outstanding private coverage (around 85% or more are covering). On average, most pharmacies tend to price AKLIEF at $185 + dispensing fee but varies depending on the region in Canada. AKLIEF also has a patient assistance program – up to 100% of the prescription cost (dispensing fees not included) which expires Nov. 30, 2020. Samples are also available.

Adverse events include:

  • Dryness
  • Redness
  • Burning
  • Irritation
  • Peeling

Compliance is the big issue with topical retinoids, particularly in the first couple of weeks. I give all my patients handouts that outline expectations and strategies for handling some of these adverse events.

Some strategies I recommend to mitigate irritation:

  • Use a small amount of the medication and start with less frequent applications
  • Wait 30 minutes after washing the face, for those who are sensitive
  • Moisturize
  • Wash the medication off after a few hours
  • Avoid harsh cleansers, astringents

In summary, trifarotene is the first new retinoid in 20 years, indicated for facial and truncal acne. It has proven efficacy, visible results, and strong tolerability. I’m using it for both the face and the trunk, and it doesn’t have benzoyl peroxide which is an advantage for treating truncal acne, as BP can bleach the clothes.

Q&A

Dr. Lynde: I was involved in the clinical trials. Sometimes, drugs that work in clinical trials don’t pan out the same in the real world, but so far, I found it highly effective, much gentler than some of the other retinoids, but it’s still a retinoid. So I go slow and educate the patient. I use it for post-isotretinoin. I notice that some of my darker-skinned patients who have PIH have also improved on the dark spots.

Dr. Beleznay: I was pulling the science data. It does seem to be working on pigment. The data is reassuring. It was nice to see the tolerability.

Dr. Kraft: Thoughts on combination therapy?

Dr. Beleznay: I try to keep it simple with just one topical for face and truncal acne. For those who already use oral treatments, I add it. Patients can use AKLIEF long-term, so we keep using it.

Dr. Lynde: More and more people have maskne – I wear them all day. I’d rather get patients to use a more tolerable drug. It can erode trust when acne breaks out.

Dr. Beleznay: We are lucky to have a novel mechanism of action. Tolerability is very important. It’s also nice to have something for keratosis pilaris.