Clascoterone

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Clascoterone
Cortexolone 17a-propionate.svg
Clinical data
Trade names Winlevi
Other namesCB-03-01; Breezula; 11-Deoxycortisol 17α-propionate; 17α-(Propionyloxy)-
deoxycorticosterone; 21-Hydroxy-3,20-dioxopregn-4-en-17-yl propionate
AHFS/Drugs.com Monograph
License data
Pregnancy
category
Routes of
administration 		Topical
ATC code
Legal status
Legal status
Identifiers
  • [(8R,9S,10R,13S,14S,17R)-17-(2-hydroxyacetyl)-10,13-dimethyl-3-oxo-2,6,7,8,9,11,12,14,15,16-decahydro-1H-cyclopenta[a]phenanthren-17-yl] propanoate
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.210.810 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C24H34O5
Molar mass 402.531 g·mol−1
3D model (JSmol)
  • CCC(=O)O[C@@]1(CC[C@@H]2[C@@]1(CC[C@H]3[C@H]2CCC4=CC(=O)CC[C@]34C)C)C(=O)CO
  • InChI=1S/C24H34O5/c1-4-21(28)29-24(20(27)14-25)12-9-19-17-6-5-15-13-16(26)7-10-22(15,2)18(17)8-11-23(19,24)3/h13,17-19,25H,4-12,14H2,1-3H3/t17-,18+,19+,22+,23+,24+/m1/s1
  • Key:GPNHMOZDMYNCPO-PDUMRIMRSA-N

Clascoterone, sold under the brand name Winlevi, is an antiandrogen medication which is used topically in the treatment of acne. [5] [6] [7] It is also under development in a higher concentration for the treatment of androgen-dependent scalp hair loss, under the brand name Breezula. [6] The medication is used as a cream by application to the skin, for instance the face and scalp. [7]

Contents

Clascoterone is an antiandrogen, or antagonist of the androgen receptor (AR), the biological target of androgens such as testosterone and dihydrotestosterone. [8] [9] It shows minimal systemic absorption when applied to skin. [7]

The medication, developed by Cassiopea and Intrepid Therapeutics, [6] was approved by the US Food and Drug Administration (FDA) for acne in August 2020. [10] [11] The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication. [12]

Medical uses

Clascoterone is indicated for the topical treatment of acne vulgaris in people aged twelve years of age and older. [5] [13]

Two large phase III randomized controlled trials evaluated the effectiveness of clascoterone for the treatment of acne over a period of 12 weeks. [5] [13] [14] Clascoterone decreased acne symptoms by about 8 to 18% more than placebo. [5] [14] The defined treatment success endpoint was achieved in about 18 to 20% of individuals with clascoterone relative to about 7 to 9% of individuals with placebo. [5] [13] [14] The comparative effectiveness of clascoterone between males and females was not described. [5] [14]

A small pilot randomized controlled trial in 2011 found that clascoterone cream decreased acne symptoms to a similar or significantly greater extent than tretinoin 0.05% cream. [13] [15] No active comparator was used in the phase III clinical trials of clascoterone for acne. [13] Hence, it's unclear how clascoterone compares to other therapies used in the treatment of acne. [13]

Available forms

Clascoterone is available in the form of a 1% (10 mg/g) cream for topical use. [5]

Side effects

The effects of local skin reactions with clascoterone were similar to placebo in two large phase III randomized controlled trials. [5] [14] Suppression of the hypothalamic–pituitary–adrenal axis (HPA axis) may occur during clascoterone therapy in some individuals due to its cortexolone metabolite. [5] [13] HPA axis suppression as measured by the cosyntropin stimulation test was observed to occur in 3 of 42 (7%) of adolescents and adults using clascoterone for acne. [5] [13] HPA axis function returned to normal within 4 weeks following discontinuation of clascoterone. [5] [13] Hyperkalemia (elevated potassium levels) occurred in 5% of clascoterone-treated individuals and 4% of placebo-treated individuals. [5]

Pharmacology

Pharmacodynamics

Clascoterone is a steroidal antiandrogen, or antagonist of the androgen receptor (AR), the biological target of androgens such as testosterone and dihydrotestosterone (DHT). [5] [8] [9] In a bioassay, the topical potency of the medication was greater than that of progesterone, flutamide, and finasteride and was equivalent to that of cyproterone acetate. [16] Likewise, it is significantly more efficacious as an antiandrogen than other AR antagonists such as enzalutamide and spironolactone in scalp dermal papilla cells and sebocytes in vitro . [9]

Pharmacokinetics

Steady-state levels of clascoterone occur within 5 days of twice daily administration. [5] At a dosage of 6 g clascoterone cream applied twice daily, maximal circulating levels of clascoterone were 4.5 ± 2.9 ng/mL, area-under-the-curve levels over the dosing interval were 37.1 ± 22.3 h*ng/mL, and average circulating levels of clascoterone were 3.1 ± 1.9 ng/mL. [5] In rodents, clascoterone has been found to possess strong local antiandrogenic activity, but negligible systemic antiandrogenic activity when administered via subcutaneous injection. [16] Along these lines, the medication is not progonadotropic in animals. [16]

The plasma protein binding of clascoterone is 84 to 89% regardless of concentration. [5]

Clascoterone is rapidly hydrolyzed into cortexolone (11-deoxycortisol) and this compound is a possible primary metabolite of clascoterone based on in-vitro studies in human liver cells. [5] [13] During treatment with clascoterone, cortexolone levels were detectable and generally below or near the low limit of quantification (0.5 ng/mL). [5] Clascoterone may also produce other metabolites, including conjugates. [5]

The elimination of clascoterone has not been fully characterized in humans. [5]

Chemistry

Clascoterone, also known as cortexolone 17α-propionate or 11-deoxycortisol 17α-propionate, as well as 17α,21-dihydroxyprogesterone 17α-propionate or 17α,21-dihydroxypregn-4-en-3,20-dione 17α-propionate, is a synthetic pregnane steroid and a derivative of progesterone and 11-deoxycortisol (cortexolone). [17] It is specifically the C17α propionate ester of 11-deoxycortisol. [16]

An analogue of clascoterone is 9,11-dehydrocortexolone 17α-butyrate (CB-03-04). [18] Corticosteroids related to clascoterone, for instance cortisone acetate and prednisolone acetate, show antiandrogenic activity in animals similarly to clascoterone. [19]

History

C17α esters of 11-deoxycortisol were unexpectedly found to possess antiandrogenic activity. [16] Clascoterone, also known as cortexolone 17α-propionate, was selected for development based on its optimal drug profile. [16] The medication was approved by the US Food and Drug Administration (FDA) for the treatment of acne in August 2020. [10]

The FDA approved clascoterone based on evidence from two clinical trials (Trial 1/NCT02608450 and Trial 2/NCT02608476) of 1,440 participants 9 to 58 years of age with acne vulgaris. [20] The trials were conducted at 99 sites in the United States, Poland, Romania, Bulgaria, Ukraine, Georgia, and Serbia. [20] Participants applied clascoterone or vehicle (placebo) cream twice daily for 12 weeks. [20] Neither the participants nor the health care providers knew which treatment was being given until after the trial was completed. [20] The benefit of clascoterone in comparison to placebo was assessed after 12 weeks of treatment using the Investigator's Global Assessment (IGA) score that measures the severity of disease (on a scale from 0 to 4) and a decrease in the number of acne lesions. [20]

In October 2023, Cosmo Pharmaceuticals announced it had submitted Winlevi to the European Medicines Agency (EMA) for centralized marketing authorization in order to market Winlevi in the EU. [21]

Society and culture

Names

Clascoterone is the international nonproprietary name and the United States Adopted Name. [17] [22]

Research

Clascoterone has been suggested as a possible treatment for hidradenitis suppurativa (acne inversa), an androgen-dependent skin condition. [23]

Related Research Articles

<span class="mw-page-title-main">Acne</span> Skin condition characterized by pimples

Acne also known as acne vulgaris, is a long-term skin condition that occurs when dead skin cells and oil from the skin clog hair follicles. Typical features of the condition include blackheads or whiteheads, pimples, oily skin, and possible scarring. It primarily affects skin with a relatively high number of oil glands, including the face, upper part of the chest, and back. The resulting appearance can lead to lack of confidence, anxiety, reduced self-esteem, and, in extreme cases, depression or thoughts of suicide.

<span class="mw-page-title-main">Antiandrogen</span> Class of pharmaceutical drugs

Antiandrogens, also known as androgen antagonists or testosterone blockers, are a class of drugs that prevent androgens like testosterone and dihydrotestosterone (DHT) from mediating their biological effects in the body. They act by blocking the androgen receptor (AR) and/or inhibiting or suppressing androgen production. They can be thought of as the functional opposites of AR agonists, for instance androgens and anabolic steroids (AAS) like testosterone, DHT, and nandrolone and selective androgen receptor modulators (SARMs) like enobosarm. Antiandrogens are one of three types of sex hormone antagonists, the others being antiestrogens and antiprogestogens.

<span class="mw-page-title-main">Spironolactone</span> Steroidal antiandrogen and antimineralocorticoid

Spironolactone, sold under the brand name Aldactone among others, is a diuretic medication primarily used to treat fluid build-up due to heart failure, liver scarring, or kidney disease. It is also used in the treatment of high blood pressure, and low blood potassium that does not improve with supplementation, early puberty in boys, acne and excessive hair growth in women. Spironolactone is taken by mouth.

<span class="mw-page-title-main">Ketoconazole</span> Antifungal chemical compound

Ketoconazole, sold under the brand name Nizoral among others, is an antiandrogen, antifungal, and antiglucocorticoid medication used to treat a number of fungal infections. Applied to the skin it is used for fungal skin infections such as tinea, cutaneous candidiasis, pityriasis versicolor, dandruff, and seborrheic dermatitis. Taken by mouth it is a less preferred option and only recommended for severe infections when other agents cannot be used. Other uses include treatment of excessive male-patterned hair growth in women and Cushing's syndrome.

<span class="mw-page-title-main">Cimetidine</span> Medication

Cimetidine, sold under the brand name Tagamet among others, is a histamine H2 receptor antagonist that inhibits stomach acid production. It is mainly used in the treatment of heartburn and peptic ulcers.

<span class="mw-page-title-main">Tazarotene</span> Topical retinoid medication

Tazarotene, sold under the brand name Tazorac, among others, is a third-generation prescription topical retinoid. It is primarily used for the treatment of plaque psoriasis and acne. Tazarotene is also used as a therapeutic for photoaged and photodamaged skin. It is a member of the acetylenic class of retinoids.

<span class="mw-page-title-main">Cyproterone</span> Chemical compound

Cyproterone, also known by its developmental code name SH-80881, is a steroidal antiandrogen which was studied in the 1960s and 1970s but was never introduced for medical use. It is a precursor of cyproterone acetate (CPA), an antiandrogen, progestin, and antigonadotropin which was introduced instead of cyproterone and is widely used as a medication. Cyproterone and CPA were among the first antiandrogens to be developed.

<span class="mw-page-title-main">Benorterone</span> Chemical compound

Benorterone, also known by its developmental code name SKF-7690 and as 17α-methyl-B-nortestosterone, is a steroidal antiandrogen which was studied for potential medical use but was never marketed. It was the first known antiandrogen to be studied in humans. It is taken by mouth or by application to skin.

<span class="mw-page-title-main">Oxendolone</span> Chemical compound

Oxendolone, sold under the brand names Prostetin and Roxenone, is an antiandrogen and progestin medication which is used in Japan in the treatment of enlarged prostate. However, this use is controversial due to concerns about its clinical efficacy. Oxendolone is not effective by mouth and must be given by injection into muscle.

<span class="mw-page-title-main">Rosterolone</span> Chemical compound

Rosterolone, also known as 17α-propylmesterolone or 1α-methyl-17α-propyl-5α-androstan-17β-ol-3-one, is a steroidal antiandrogen which was first described in 1984 and was developed for topical administration but was never marketed. It has shown some efficacy in the treatment of acne, and lacks systemic effects with either topical or systemic administration. Rosterolone is a derivative of mesterolone, which, in contrast, is an androgen and anabolic steroid.

<span class="mw-page-title-main">Nonsteroidal antiandrogen</span> Antiandrogen with a nonsteroidal chemical structure

A nonsteroidal antiandrogen (NSAA) is an antiandrogen with a nonsteroidal chemical structure. They are typically selective and full or silent antagonists of the androgen receptor (AR) and act by directly blocking the effects of androgens like testosterone and dihydrotestosterone (DHT). NSAAs are used in the treatment of androgen-dependent conditions in men and women. They are the converse of steroidal antiandrogens (SAAs), which are antiandrogens that are steroids and are structurally related to testosterone.

Darolutamide, sold under the brand name Nubeqa, is an antiandrogen medication which is used in the treatment of non-metastatic castration-resistant prostate cancer in men. It is specifically approved to treat non-metastatic castration-resistant prostate cancer (nmCRPC) in conjunction with surgical or medical castration. The medication is taken by mouth twice per day with food.

<span class="mw-page-title-main">Apalutamide</span> Chemical compound

Apalutamide, sold under the brand name Erleada among others, is a nonsteroidal antiandrogen (NSAA) medication used for the treatment of prostate cancer. It is an androgen receptor inhibitor. It is taken by mouth.

<span class="mw-page-title-main">Inocoterone acetate</span> Chemical compound

Inocoterone acetate is a steroid-like nonsteroidal antiandrogen (NSAA) that was developed for topical administration to treat acne but was never marketed. It is the acetate ester of inocoterone, which is less potent in comparison. Inocoterone acetate is actually not a silent antagonist of the androgen receptor but rather a weak partial agonist, similarly to steroidal antiandrogens like cyproterone acetate.

<span class="mw-page-title-main">BOMT</span> Chemical compound

BOMT, also known by its developmental code name Ro 7-2340 and as 6α-bromo-4-oxa-17α-methyl-5α-dihydrotestosterone, is a synthetic steroidal antiandrogen which was first produced in 1970 and was never marketed for medical use. It is the 6α-brominated, 4-oxygenated, and 17α-methylated derivative of the androgen dihydrotestosterone (DHT). Along with benorterone, cyproterone, and flutamide, BOMT was among the earliest antiandrogens to be developed and extensively studied, although it is less well-documented in comparison to the others. BOMT has been investigated clinically in the treatment of benign prostatic hyperplasia, though development for this use did not continue. There was also interest in BOMT for the potential applications of acne, pattern hair loss, and possibly prostate cancer, but it was not developed for these indications either.

<span class="mw-page-title-main">Trimethyltrienolone</span> Chemical compound

Trimethyltrienolone (TMT), also known by its developmental code name R-2956 or RU-2956, is an antiandrogen medication which was never introduced for medical use but has been used in scientific research.

<span class="mw-page-title-main">Steroidal antiandrogen</span> Class of compounds

A steroidal antiandrogen (SAA) is an antiandrogen with a steroidal chemical structure. They are typically antagonists of the androgen receptor (AR) and act both by blocking the effects of androgens like testosterone and dihydrotestosterone (DHT) and by suppressing gonadal androgen production. SAAs lower concentrations of testosterone through simulation of the negative feedback inhibition of the hypothalamus. SAAs are used in the treatment of androgen-dependent conditions in men and women, and are also used in veterinary medicine for the same purpose. They are the converse of nonsteroidal antiandrogens (NSAAs), which are antiandrogens that are not steroids and are structurally unrelated to testosterone.

<span class="mw-page-title-main">9,11-Dehydrocortexolone 17α-butyrate</span> Chemical compound

9,11-Dehydrocortexolone 17α-butyrate is a synthetic steroidal antiandrogen that was developed for use as a topical medication but was never marketed. It is the C17α butyrate (butanoate) ester of the 9,11-dehydrogenated analogue of 11-deoxycortisol (cortexolone). C17α esters of 11-deoxycortisol were unexpectedly found to possess antiandrogen activity, and 9,11-dehydrocortexolone 17α-butyrate was selected for development based on its optimum drug profile. In rats, the drug has been found to possess strong local antiandrogen activity and to also be active systemically upon subcutaneous injection. In addition, it has been found to possess antigonadotropic activity. In terms of topical antiandrogen potency, 9,11-dehydrocortexolone 17α-butyrate was found to be more potent than flutamide and finasteride and less than or equal to cyproterone acetate in potency. The drug has been suggested for possible development and medical use for the treatment of prostate cancer and benign prostatic hyperplasia.

Dimethylcurcumin is a nonsteroidal antiandrogen and a synthetic curcuminoid which is under development by AndroScience Corporation as a topical medication for the treatment of acne vulgaris. It has also been under investigation for the treatment of male pattern hair loss, spinal muscular atrophy, and wounds, but no development has been reported for these indications. There has been interest in the drug for the potential treatment of prostate cancer as well. As of 2017, it is in phase II clinical trials for acne vulgaris.

<span class="mw-page-title-main">EM-5854</span> Chemical compound

EM-5854 is a steroidal antiandrogen which was under development by Endoceutics, Inc. for the treatment of prostate cancer. It was first described in a patent in 2008, and was further characterized in 2012. EM-5854 reached phase I/II clinical trials for the treatment of prostate cancer but development was discontinued in March 2019.

References

  1. 1 2 "Winlevi APMDS". Therapeutic Goods Administration (TGA). 17 May 2024. Retrieved 10 June 2024.
  2. ↑ "Details for: Winlevi". Health Canada . 8 September 2023. Retrieved 3 March 2024.
  3. ↑ "Summary Basis of Decision for Winlevi". Health Canada . 30 August 2023. Retrieved 4 October 2023.
  4. ↑ "Details for: Winlevi". Health Canada . 8 September 2023. Retrieved 4 October 2023.
  5. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 "Winlevi (clascoterone) cream, for topical use" (PDF). Cassiopea. Retrieved 9 September 2020.
  6. 1 2 3 "Clascoterone - Cassiopea - AdisInsight".
  7. 1 2 3 Kircik LH (July 2019). "What's new in the management of acne vulgaris". Cutis. 104 (1): 48–52. PMID   31487336.
  8. 1 2 Rosette C, Rosette N, Mazzetti A, Moro L, Gerloni M (February 2019). "Cortexolone 17α-Propionate (Clascoterone) is an Androgen Receptor Antagonist in Dermal Papilla Cells In Vitro". J Drugs Dermatol. 18 (2): 197–201. PMID   30811143.
  9. 1 2 3 Rosette C, Agan FJ, Mazzetti A, Moro L, Gerloni M (May 2019). "Cortexolone 17α-propionate (Clascoterone) Is a Novel Androgen Receptor Antagonist that Inhibits Production of Lipids and Inflammatory Cytokines from Sebocytes In Vitro". J Drugs Dermatol. 18 (5): 412–418. PMID   31141847.
  10. 1 2 "Cassiopea Receives FDA Approval for Winlevi (clascoterone cream 1%), First-in-Class Topical Acne Treatment Targeting the Androgen Receptor". Cassiopea (Press release). Archived from the original on 28 August 2020. Retrieved 30 August 2020.
  11. ↑ "Winlevi: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Retrieved 9 September 2020.
  12. ↑ "New Drug Therapy Approvals 2020". U.S. Food and Drug Administration (FDA). 31 December 2020. Retrieved 17 January 2021.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  13. 1 2 3 4 5 6 7 8 9 10 Barbieri JS (2020). "A New Class of Topical Acne Treatment Addressing the Hormonal Pathogenesis of Acne". JAMA Dermatology. 156 (6): 619–620. doi:10.1001/jamadermatol.2020.0464. ISSN   2168-6068. PMID   32320045. S2CID   216075268.
  14. 1 2 3 4 5 Hebert A, Thiboutot D, Stein Gold L, Cartwright M, Gerloni M, Fragasso E, et al. (April 2020). "Efficacy and Safety of Topical Clascoterone Cream, 1%, for Treatment in Patients With Facial Acne: Two Phase 3 Randomized Clinical Trials". JAMA Dermatol. 156 (6): 621–630. doi:10.1001/jamadermatol.2020.0465. PMC   7177662 . PMID   32320027.
  15. ↑ Trifu V, Tiplica GS, Naumescu E, Zalupca L, Moro L, Celasco G (2011). "Cortexolone 17α-propionate 1% cream, a new potent antiandrogen for topical treatment of acne vulgaris. A pilot randomized, double-blind comparative study vs. placebo and tretinoin 0·05% cream". Br. J. Dermatol. 165 (1): 177–83. doi:10.1111/j.1365-2133.2011.10332.x. PMID   21428978. S2CID   38404925.
  16. 1 2 3 4 5 6 Celasco G, Moro L, Bozzella R, Ferraboschi P, Bartorelli L, Quattrocchi C, et al. (2004). "Biological profile of cortexolone 17alpha-propionate (CB-03-01), a new topical and peripherally selective androgen antagonist". Arzneimittelforschung. 54 (12): 881–6. doi:10.1055/s-0031-1297043. PMID   15646372. S2CID   36709725.
  17. 1 2 "ChemIDplus - 19608-29-8 - GPNHMOZDMYNCPO-PDUMRIMRSA-N - Clascoterone [USAN] - Similar structures search, synonyms, formulas, resource links, and other chemical information".
  18. ↑ Celasco G, Moroa L, Bozzella R, Ferraboschi P, Bartorelli L, Di Marco R, et al. (2005). "Pharmacological profile of 9,11-dehydrocortexolone 17alpha-butyrate (CB-03-04), a new androgen antagonist with antigonadotropic activity". Arzneimittelforschung. 55 (10): 581–7. doi:10.1055/s-0031-1296908. PMID   16294504. S2CID   35386850.
  19. ↑ Lerner LJ (1975). "Androgen antagonists". Pharmacol Ther B. 1 (2): 217–31. doi:10.1016/0306-039x(75)90006-9. PMID   772705.
  20. 1 2 3 4 5 "Drug Trial Snapshot: Winlevi". U.S. Food and Drug Administration (FDA). 26 August 2020. Retrieved 10 September 2020.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  21. ↑ "Cosmo Announces Submission of Winlevi® to the European Medicines Agency (EMA)". Cosmo Pharmaceuticals NV. Retrieved 21 October 2024.
  22. ↑ World Health Organization (2019). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 82". WHO Drug Information. 33 (3): 106. hdl: 10665/330879 .
  23. ↑ Der Sarkissian SA, Sun HY, Sebaratnam DF (August 2020). "Cortexolone 17 α-proprionate for hidradenitis suppurativa". Dermatol Ther. 33 (6): e14142. doi: 10.1111/dth.14142 . PMID   32761708. S2CID   221036602.
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