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Trifarotene

Trifarotene is a topical classified as a fourth-generation receptor () , specifically selective for the RAR-γ subtype, used primarily for the treatment of vulgaris. It is formulated as a 0.005% under the brand name Aklief and is applied once daily to the affected areas of the face and trunk. Approved by the U.S. (FDA) on October 4, 2019, it is indicated for patients aged 9 years and older, marking the first new topical approved in over two decades and the first specifically studied and labeled for both facial and truncal . Developed by Laboratories, trifarotene represents a novel therapeutic option in management, addressing limitations of earlier retinoids by targeting the predominant RAR-γ receptor in the , which is overexpressed in -affected . Its is a acid derivative (C29H33NO4, molecular weight 459.58), and it exhibits minimal systemic absorption (plasma concentrations below 5–10 pg/mL), reducing the risk of systemic side effects compared to less selective retinoids. Clinical development included phase III trials (e.g., PERFECT 1 and 2) demonstrating significant reductions in inflammatory and noninflammatory lesions, with success rates in Investigator's Global Assessment (IGA) of 29.4% (PERFECT 1) and 42.3% (PERFECT 2) at 12 weeks and sustained efficacy over 52 weeks in an open-label extension study; recent phase 4 trials (2024–2025) have further shown efficacy in reducing atrophic scars and post-inflammatory hyperpigmentation. The involves binding to RAR-γ to modulate , promoting differentiation, inhibiting abnormal and comedone formation, and exerting anti-inflammatory effects by downregulating genes involved in keratinization, immune modulation, and . Trifarotene also reduces the risk of atrophic scarring by normalizing turnover. Common adverse effects are localized and mild, including application-site irritation such as , dryness, scaling, and stinging, which typically resolve with use or dose adjustment; severe reactions are rare, and no significant drug interactions have been reported. Its low photolability and stability enhance patient compliance compared to other retinoids.

Medical uses

Indications

Trifarotene is approved by the U.S. (FDA) as a topical cream (0.005%) for the treatment of acne vulgaris in patients aged 9 years and older. This approval, granted in October 2019, marks it as the first new molecule approved for acne in over two decades. The efficacy of trifarotene was established in two pivotal phase 3, randomized, double-blind, vehicle-controlled trials known as PERFECT 1 and PERFECT 2, which enrolled over 2,400 patients with moderate on the face and . In these studies, once-daily application of trifarotene resulted in significant reductions in both inflammatory and noninflammatory counts after 12 weeks, with treatment success rates (defined as at least a 2-grade improvement from baseline in Investigator's Global Assessment and clear/almost clear ) of approximately 30% on the face and 42% on the trunk, compared to 20% and 26% with vehicle, respectively. Reductions in counts were observed as early as week 1 on the face and week 2 on the trunk. A subsequent 52-week, open-label extension (SATISFY) involving from the PERFECT trials demonstrated sustained , with continued reductions in counts and treatment success rates increasing to 65% on the face and 67% on the by week 52. Trifarotene has shown effectiveness across diverse demographics, including various phototypes (Fitzpatrick I-VI) and in treating , which affects up to 50% of but is often undertreated. In addition to its approved use, trifarotene received FDA designation in 2014 for the treatment of congenital , a rare genetic skin disorder, though it has not yet been approved for this indication. Emerging from recent studies, including the 2025 Italian Acne Board review and the phase 4 START trial (published 2023), suggests potential benefits in managing sequelae such as atrophic scarring and post-inflammatory hyperpigmentation, with significant scar count reductions observed as early as week 2 in patients with moderate-to-severe facial .

Administration

Trifarotene is available as a 0.005% topical cream for cutaneous application. The recommended dosage involves applying a thin layer to the affected areas of the face and/or once daily in the evening. For the face, one pump actuation is typically sufficient to cover the , cheeks, , and , while two pump actuations are used for the upper (upper back, shoulders, and chest), with an additional actuation if needed for the middle or lower back. Before application, the skin should be cleansed with a mild or soapless cleanser and patted dry. A fingertip unit or the appropriate pump amount should be applied as a thin layer, avoiding contact with the eyes, mouth, paranasal creases, and mucous membranes. Hands should be washed immediately after use to prevent accidental transfer to sensitive areas. Application should be avoided on cuts, abrasions, eczematous skin, or sunburned areas, and waxing is not recommended on treated skin. Treatment duration is typically 12 weeks for initial therapy, though continuation may be directed by a healthcare provider based on response. Moisturizers are recommended from the start of treatment to help manage potential skin such as , , dryness, or stinging/burning, which may peak within the first four weeks and subside with continued use. If is severe, application frequency can be reduced (e.g., to every other day) or temporarily suspended until symptoms resolve. Due to increased , patients should minimize exposure to sunlight and artificial UV sources, using broad-spectrum with 15 or higher and wearing protective clothing when outdoors. In cases of moderate to severe , trifarotene has been evaluated in combination with oral antibiotics such as in Phase 4 trials, including the study, to enhance outcomes.

Pharmacology

Mechanism of action

Trifarotene is a potent and selective agonist of the receptor-gamma (RAR-γ), with an EC50 of 7.6 nM for this receptor, demonstrating approximately 68-fold selectivity over RAR-α (EC50 = 517 nM) and 17-fold selectivity over RAR-β (EC50 = 126 nM). This selectivity arises from its targeted binding to RAR-γ, the predominant subtype in , allowing for focused modulation of retinoid-responsive pathways while minimizing activation of other isoforms. Upon binding to RAR-γ, trifarotene promotes receptor dimerization with retinoid X receptors (RXRs), enabling the complex to attach to retinoic acid response elements (RAREs) in the DNA promoter regions of target genes. This interaction regulates gene transcription, leading to alterations in cellular processes such as differentiation, proliferation, and reduction of inflammation. Specifically, trifarotene modulates genes involved in epidermal differentiation, stress response, and retinoic acid metabolism, exerting effects at concentrations significantly lower than those required for non-selective retinoids like tazarotene or tretinoin. In the skin, trifarotene normalizes follicular keratinization by reducing hyperkeratinization and promoting differentiation, which decreases and comedone formation. It also exhibits properties through downregulation of proinflammatory cytokines and modulation of immune-related genes, thereby mitigating acne-associated inflammation. As the first fourth-generation with RAR-γ specificity, trifarotene reduces off-target effects compared to non-selective retinoids such as tretinoin, which activate multiple subtypes and are associated with broader systemic or irritative responses.

Pharmacokinetics

Trifarotene demonstrates minimal systemic absorption after topical application to the skin. In pharmacokinetic studies involving adults with acne vulgaris, concentrations of trifarotene were below the lower limit of quantification (0.1 ng/mL) in the majority of subjects following single or multiple once-daily applications of up to 2 g of the 50 µg/g on the face, shoulders, chest, and upper back. Steady-state systemic was achieved after approximately 2 weeks of , with quantifiable concentrations observed in only 7 of 19 subjects; the maximum concentration (C_max) ranged from less than 5 pg/mL to 10 pg/mL, and the area under the curve ({0-24h}) ranged from 75 to 104 pg·h/mL. Similar low systemic absorption profiles were noted in pediatric patients aged 9 to 17 years, with C_max values ranging from less than 5 pg/mL to 9 pg/mL and {0-24h} from 89 to 106 pg·h/mL after 2 weeks of application. No drug accumulation occurs with repeated dosing due to the short . Distribution of trifarotene is primarily localized to layers following topical , with limited systemic circulation attributable to the low . In vitro studies indicate that trifarotene is highly bound to proteins, approximately 99.9%, though the clinical relevance of this binding is minimal given the negligible levels achieved. Trifarotene undergoes hepatic primarily via enzymes, including (contributing approximately 67% to ), (17%), and CYP2C8 (16%), with a minor role for CYP2B6. involves ring opening, , ketone formation, and subsequent conjugation, resulting in multiple metabolites; the major circulating metabolite is CD06530 (4'-hydroxy-trifarotene), which accounts for about 40% of identified metabolites and retains pharmacological activity, though its levels remain below the limit of quantification (10 pg/mL) under maximal use conditions. Additional active metabolites include CD06700 and CD09986, each comprising around 7% of the profile. Excretion of trifarotene and its metabolites occurs predominantly via the fecal route, with (rats and ) showing 63-67% recovery in and 18-22% in over 48 hours, and negligible biliary clearance (less than 1%). The terminal elimination of the parent compound ranges from 2 to 9 hours following topical application. Due to the minimal systemic exposure, no dosage adjustments are necessary for patients with renal or hepatic impairment, and appear consistent across age groups, sexes, and races based on available data.

Chemistry

Structure and properties

Trifarotene has the molecular formula C₂₉H₃₃NO₄ and a molecular weight of 459.58 g/mol. Its CAS number is 895542-09-3. The chemical name is 3''-tert-butyl-4'-(2-hydroxyethoxy)-4''-(pyrrolidin-1-yl)-[1,1':3',1''-terphenyl]-4-carboxylic acid. Trifarotene is a terphenyl acid derivative featuring a [1,1':3',1''-terphenyl] core, which consists of a central 1,3-diphenylbenzene skeleton substituted with a tert-butyl group at the 3'' position, a 2-hydroxyethoxy group at the 4' position, a pyrrolidin-1-yl group at the 4'' position, and a carboxylic acid group at the 4 position. The molecule is achiral and contains no stereocenters. As a solid, trifarotene appears as a white to off-white to slightly yellow powder with a of 245°C. It is practically insoluble in but slightly soluble in organic solvents such as acetone, , and . In its therapeutic formulation, trifarotene is present at a concentration of 0.005% w/w (50 mcg/g) in a and is chemically stable within this vehicle. The is designed for topical application with a compatible with .

Development synthesis

Trifarotene, developed by Laboratories under the code name CD5789, emerged from a structure-based design approach that leveraged of the receptor gamma (RAR-γ) bound to the known CD437 to guide the creation of a novel triaryl series with enhanced selectivity. This methodology allowed researchers to optimize the for potent binding to RAR-γ while minimizing interactions with RAR-α and RAR-β subtypes. The key synthetic route centers on constructing the characteristic core through palladium-catalyzed reactions between appropriately substituted phenylboronic acids or esters and brominated intermediates, enabling the assembly of the extended aromatic system essential for receptor affinity. Subsequent steps involve the attachment of the ring via or of a or precursor, followed by esterification and base-mediated to introduce the functionality. The overall synthesis proceeds in approximately 10-12 steps from commercially available starting materials, achieving high yields in critical transformations such as the (up to 57%) and final (up to 94%). Preclinical optimization entailed iterative structural modifications, including variations in the substituents and side-chain appendages, to further reduce off-target RAR-α/β activation by over 65-fold relative to RAR-γ potency while improving metabolic stability compared to earlier non-selective retinoids. These efforts culminated in the patenting of the compound and related analogs, notably US 7,807,708 issued in , which covers the core chemical entity and emphasizes improvements in RAR subtype specificity. The resulting molecule, with the formula C₂₉H₃₃NO₄, demonstrated superior preclinical profiles for topical application.

Safety and tolerability

Adverse effects

The most common adverse effects of trifarotene are local skin reactions at the application site, occurring primarily during the initial weeks of treatment and typically resolving with continued use. In two randomized, double-blind, vehicle-controlled 12-week phase 3 clinical trials involving 2420 patients with , the incidence of application site was 7.5%, pruritus 2.4%, and sunburn 2.6%, compared to 0.3%, 0.8%, and 0.5% with vehicle, respectively. Specific local tolerability assessments showed in up to 64.4% of facial applications (mostly mild to moderate), scaling/dryness in up to 69.1%, and stinging/burning in up to 62.1%, with peak severity at week 1 for the face and weeks 2-4 for the trunk, followed by a decline. These reactions are consistent with the class and can be managed with emollients and gradual introduction of the medication. Less common adverse effects include manifesting as increased sunburn risk, as well as application site pain, dryness, discoloration (including or ), , swelling, erosion, exacerbation, allergic , and , each reported in less than 1% of patients in the phase 3 trials. Allergic occurred in less than 1% of cases. Systemic of trifarotene is minimal, with concentrations often unquantifiable at the therapeutic dose of 50 μg/g, contributing to a low incidence of systemic effects such as or (less than 1%). In a 52-week open-label extension with 453 patients, trifarotene demonstrated sustained tolerability, with treatment-emergent adverse events related to the drug in 12.6% (mostly mild cutaneous reactions like pruritus at 4.6%, at 4.2%, and sunburn at 1.8%), and discontinuation due to adverse events in 2.9%. A 2025 review by the Italian Acne Board, citing data from multicenter clinical such as the START study, reported treatment-emergent adverse events in 5.8% of trifarotene-treated areas (none severe, primarily mild to moderate ), with high compliance and no increased risk of scarring. Overall, discontinuation rates due to adverse effects remain low at under 3% in long-term use.

Contraindications and precautions

The FDA labeling lists no specific contraindications for trifarotene. However, it should not be used by individuals with a known to the active ingredient or any excipients, such as in the cream formulation. Use of trifarotene during is not recommended, as animal studies have demonstrated adverse developmental outcomes at oral doses resulting in systemic exposures approximately 800 times higher than those estimated in humans following topical application of the maximum recommended human dose. Although there is limited human data and the topical route results in minimal systemic absorption, women of childbearing potential should be advised to use effective contraception during treatment due to the potential risks associated with retinoids. For breastfeeding individuals, there are no available data on the presence of trifarotene in human , the effects on the breastfed , or the impact on production; however, the was detected in the of lactating rats. Caution is advised, and the smallest effective amount should be applied to the smallest area necessary, with application avoided in the area of the breast that may contact the 's mouth. Additional precautions include avoiding application to areas of broken, abraded, eczematous, or sunburned , as this may increase the risk of or adverse reactions. In pediatric patients aged 9 years and older, where trifarotene is approved for use, close monitoring for is recommended, particularly during the initial treatment phase. Patients should minimize exposure to , light, and environmental sources of UV ; when sun exposure cannot be avoided, broad-spectrum with 30 or higher and protective clothing should be used over treated areas.

History

Research and development

Trifarotene's preclinical development began in the early , with in vitro studies confirming its high selectivity for the receptor gamma (RAR-γ), demonstrating over 20-fold selectivity compared to RAR-α and RAR-β subtypes. This selectivity was key to targeting skin-specific receptors while minimizing systemic effects. In animal models, topical trifarotene at 0.01% concentration exhibited strong comedolytic activity, anti-inflammatory properties, and antipigmenting effects, effectively modulating epidermal differentiation, proliferation, and stress responses in ex vivo and in vivo skin models. These studies also highlighted low toxicity, attributed to its stability in and rapid metabolism in hepatocytes, supporting its potential for topical use in acne-like conditions. In 2014, the U.S. Food and Drug Administration granted designation to trifarotene for the treatment of congenital , recognizing its promise for rare skin disorders. The followed with orphan designation in 2020 for autosomal recessive congenital . Early clinical development included Phase 1 trials in the , which assessed safety and tolerability in healthy volunteers, confirming that trifarotene was well tolerated even under maximized application conditions in both adults and pediatric populations. Phase 2 dose-ranging studies evaluated concentrations from 0.001% to 0.005% in patients with mild to moderate vulgaris, identifying the 0.005% formulation as optimal for balancing efficacy and safety while showing early reductions in lesions. Pivotal Phase 3 trials, PERFECT 1 and PERFECT 2, conducted between 2017 and 2019, were randomized, double-blind, vehicle-controlled studies enrolling over 2,400 patients with moderate facial and truncal acne. These trials demonstrated trifarotene 50 μg/g cream's efficacy in reducing both inflammatory and noninflammatory lesions on the face and trunk, with rapid onset of action observed within 1-2 weeks. A subsequent 52-week open-label extension study further evaluated long-term safety, involving patients from the pivotal trials who continued trifarotene treatment, confirming sustained efficacy and a favorable tolerability profile with no new safety signals over the extended period. Post-approval, the Phase 4 (NCT04451330), a randomized, double-blind , investigated trifarotene cream combined with oral in patients with severe vulgaris, showing improved lesion clearance compared to doxycycline monotherapy and supporting its role in . As of 2025, an ongoing (NCT07186413) is comparing trifarotene 50 mcg/g cream against in subjects with vulgaris to further assess , , and . Real-world evidence from observational and case series has indicated trifarotene's potential in preventing atrophic acne scarring, with reductions in scar counts observed alongside acne improvement in diverse patient populations.

Regulatory history

Trifarotene received orphan drug designation from the U.S. (FDA) on June 6, 2014, for the treatment of congenital . The (EMA) granted orphan drug designation for trifarotene in the treatment of autosomal recessive congenital on March 24, 2020, though this designation was later withdrawn. In December 2019, received a positive outcome through the European decentralized procedure for Aklief, paving the way for national marketing authorizations in participating EU member states. The FDA approved trifarotene cream 0.005% (branded as Aklief) on October 4, 2019, for the topical treatment of vulgaris in patients 9 years of age and older, marking the first new molecule approved for in over 20 years. approved Aklief (trifarotene 50 mcg/g) on November 28, 2019, for the topical treatment of vulgaris on the face and/or in patients 12 years of age and older. The (TGA) in approved Aklief (trifarotene 50 /g) on January 18, 2021, for the topical treatment of vulgaris on the face and/or . As of November 2025, trifarotene has not received centralized marketing authorization from the , though it may be available through national authorizations in some EU member states. A 2025 periodic safety update report references nationally authorised products. Post-approval, trifarotene's patents became eligible for Paragraph IV challenges starting October 5, 2023, with at least one such filing noted by manufacturers between 2023 and 2025; no versions have been approved by the FDA as of 2025.

Society and culture

Brand names

Trifarotene is commercially available under the brand name Aklief, developed and marketed by Laboratories as a 0.005% . , it is supplied in pump dispensers containing 30 g, 45 g, or 75 g of cream. The cream features a base incorporating emollients such as medium-chain triglycerides and to enhance tolerability during application. Internationally, Aklief remains the primary brand name, with in markets including and following approvals in 2019 and 2021, respectively; no alternative brand names have been introduced as of 2025 due to the drug's relatively recent market entry. In these regions, pack sizes may include tubes of 5 g or pumps of 15 g, 30 g, or 75 g, though not all variants are universally marketed. No generic equivalents of trifarotene have been approved worldwide to date. Aklief is available by prescription only in approved jurisdictions. offers patient assistance through the CAREConnect program, which provides cost-reduction options such as savings cards for eligible commercially insured or uninsured patients . Trifarotene, marketed under the brand name Aklief, is not classified as a and is available exclusively by prescription under the oversight of the (FDA), which approved it in October 2019 for the topical treatment of in patients aged 9 years and older. Most commercial plans cover trifarotene for treatment, often subject to criteria to ensure clinical necessity. In Canada, trifarotene received approval from in November 2019 and is classified as a prescription-only for the topical treatment of facial and truncal vulgaris. Similarly, in Australia, it was approved by the () in January 2021 as a prescription-only product indicated for vulgaris on the face and trunk in patients aged 12 years and older, and it is listed on the () for subsidized access to eligible patients. Trifarotene has not received centralized marketing authorization from the () as of 2025 but obtained decentralized procedure approval in December 2019 for use as a prescription-only treatment in 16 member states, including for patients aged 12 years and older. In other EU countries without national approval, it may be available through import under specific regulatory provisions. Elsewhere, approval in remains pending as of 2025, with the Ministry of Health, Labour and Welfare identifying it as a high-priority unapproved requiring a for further . Trifarotene holds no over-the-counter status in any country due to its classification as a , which carries risks of irritation, photosensitivity, and teratogenicity necessitating medical supervision.

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