Aklief Mechanism of Action

Pharmacotherapeutic group: Retinoids for topical use in acne. ATC code: D10AD06.
Pharmacology: Pharmacodynamics: Mechanism of action: Aklief cream contains 50 micrograms (mcg/g) (w/w) trifarotene, which is a chemically stable, terphenyl acid derivative with retinoid-like activity. It is a potent RARγ agonist (retinoid acid receptor γ agonist), characterized by its high specificity to this receptor over RAR_α & RAR_β (50- and 8-fold, respectively, with no Retinoid X Receptor (RXR) activity).
In addition, trifarotene modulates retinoid target genes (differentiation and inflammatory processes) in immortalized keratinocytes and reconstructed epidermis.
Pharmacodynamic effects: Trifarotene has demonstrated, in the Rhino-mouse model, marked comedolytic activity with the reduction in the comedone count and marked increased epidermis thickness. In this model, trifarotene produced the same comedolytic effect as other known retinoids, at about 10 times lower dose.
Trifarotene has also shown anti-inflammatory and depigmenting activities.
Clinical efficacy and safety: Aklief cream applied once daily in the evening was evaluated for 12 weeks in 2 randomized, multi-center, parallel group, double-blind, vehicle-controlled studies of identical design. They were conducted in a total of 2420 patients aged, 9 years and older, with moderate facial and truncal acne vulgaris.
Acne severity was evaluated using the 5-point Investigator's Global Assessment (IGA) scale for the face and Physician's Global Assessment (PGA) for the trunk, with moderate acne vulgaris defined as a score of Grade 3-Moderate (see Table 1).

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There were three identical co-primary efficacy endpoints in both pivotal studies 1) the success rate based on the IGA and PGA outcome (percentage of subjects "clear" and "almost clear" and with at least a 2-grade change from baseline) and absolute and percentage change from baseline in 2) inflammatory and 3) non-inflammatory lesion counts at Week 12.
Overall, 87% of subjects were Caucasian and 55% were female. Thirty four (1.4%) subjects were 9 to 11 years of age, 1128 (47%) subjects were 12 to 17 years and 1258 (52%) subjects were 18 years and older. All patients had moderate acne vulgaris on the face and 99% on the trunk. At baseline subjects had between 7 and 200 (average 36) inflammatory lesions on the face and between 0 and 220 (average 38) on the trunk. Additionally subjects had 21 to 305 (average 52) non-inflammatory lesions on the face and 0 to 260 (average 46) on the trunk.
The IGA and PGA success rates, mean absolute, and percent reduction in acne lesion counts from baseline after 12 weeks of treatment are presented in the following tables: See Tables 2 and 3.

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Paediatric population: Age group 9 to 11 years: In the phase 3 studies a total of only 34 children of this age group were included - 19 of them in study 18251 and 15 in study 18252. In this age group, patient number was low and efficacy could not be demonstrated.
Age group 12 to 17 years: In the phase 3 studies a total of 1128 children aged 12 to 17 years with moderate acne vulgaris were included: 573 of them in study 18251 and 555 children in study 18252.
The IGA and PGA success rates, mean absolute, and percent reduction in acne lesion counts from baseline after 12 weeks of treatment are presented in the following tables: See Tables 4 and 5.

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Long-term efficacy: In Study 3, a one-year open label safety study of 453 patients, 9 years and older, with moderate facial and truncal acne vulgaris, Aklief cream demonstrated a clinically meaningful improvement with IGA and PGA success rates increasing: from 26.6% at Week 12 visit to 65.1% at Week 52 visit for the face and from 38.6% at Week 12 visit to 66.9% at Week 52 visit for the trunk, respectively.
IGA and PGA success experienced by the same subject increased from 22.0% at Week 12 to 57.9% at Week 52.
Pharmacokinetics: Absorption: The absorption of trifarotene from Aklief cream was evaluated in adult and paediatric (10-17 y.o.) subjects with acne vulgaris. Subjects were treated once daily for 30 days with 2 grams/day of Aklief applied on the face, shoulders, chest, and upper back.
Overall, systemic exposure levels were low and similar between adults and paediatric populations. After 4 weeks treatment, seven of nineteen (37%) adult subjects had quantifiable Trifarotene plasma levels. Cmax ranged from below the limit of quantification (LOQ <5 pg/mL) to 10 pg/mL and AUC _0-24h ranged from 75 to 104 pg.hr/mL.
Three of the seventeen (18%) of paediatric subjects presented quantifiable systemic exposure. Cmax ranged from below the limit of quantification (LOQ <5 pg/mL) to 9 pg/mL and AUC _0-24h ranged from 89 to 106 pg.hr/mL.
Steady state conditions were achieved in both adult and paediatric subjects following 2 weeks of topical administration. No drug accumulation is expected with long-term use.
Distribution: Trifarotene penetrates into the skin with an exponential distribution from the stratum corneum to the epidermis and dermis.
An in vitro study demonstrated that Trifarotene is greater than 99.9% bound to plasma proteins. No significant binding of Trifarotene to erythrocytes was observed.
Biotransformation: In vitro studies using human hepatic microsomes and recombinant CYP450 enzymes have shown that Trifarotene is primarily metabolized by CYP2C9, CYP3A4, CYP2C8 and at lesser extent by CYP2B6.
Pharmacokinetic drug interaction potential: In vitro studies show that Aklief cream at the concentrations achieved systemically after topical administration did not inhibit the CYP450 isoenzymes CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4, and did not induce CYP1A2, 2B6, or 3A4.
In vitro studies have shown that Aklief cream at the concentrations achieved systemically after topical administration did not inhibit either MATE, OATP, OAT or OCT uptake transporters or BCRP, PgP, BSEP or MPR efflux transporters.
Toxicology: Preclinical safety data: Note: the animal multiples of human systemic exposure calculations were based on Area Under the Curve (AUC) comparisons for a topical human dose of 2 g of Aklief Cream, applied once daily.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated oral dose toxicity, genotoxicity, or carcinogenic potential.
In dermal repeat-dose toxicity studies in minipigs for up to 9 months, systemic exposure to trifarotene was very low, generally below the limit of quantification. There were no systemic effects and the only noteworthy finding consisted of reversible skin irritation at the application sites.
In animal reproduction studies, oral administration of trifarotene in pregnant rats and rabbits during organogenesis was teratogenic and embryotoxic at exposures (AUC) that were 1614 to 18245-times and 800 to 4622-times those observed in humans at the maximum recommended human dose (MRHD) of 2 g.
Trifarotene was not teratogenic in rats and rabbits at systemic exposures corresponding to 534 and 98-times respectively those observed in humans.
Trifarotene had no effects on pre- and post-natal development in rats, up to the highest oral doses tested which corresponded to systemic exposures (AUC) 595 to 1877-times higher than those observed in humans.
Trifarotene showed no adverse effects on fertility in rats administered orally at exposures of approximately 1754 (males) and 1877 (females) times the 2 g dose in humans. However, after oral administration to dogs, Germ cell degeneration with pyknotic/apoptotic germ cells was evident from the lowest dose tested of 0.2 mg/kg/day corresponding to a systemic exposure 1170 times higher than those observed in humans. All animals with this finding also showed hypospermatogenesis and debris in the epididymides. The findings did not completely recover after 8 weeks, suggesting an extended and possibly chronic effect. As these effects were noted also at the lowest dose tested, the relevance of the findings for lower doses is unknown.
Oral study in rats have shown trifarotene and/or related metabolites are excreted into maternal milk.