Clascoterone, sold under the brand name Winlevi, is an antiandrogen medication which is used topically in the treatment of acne. It is also under development in a higher concentration for the treatment of androgen-dependent

scalp hair loss Pattern hair loss (also known as androgenetic alopecia (AGA)) is a hair loss condition that primarily affects the top and front of the scalp. In male-pattern hair loss (MPHL), the hair loss typically presents itself as either a receding front ha ...

, under the brand name Breezula. The medication is used as a cream by application to the skin, for instance the face and scalp. Clascoterone is an antiandrogen, or

antagonist An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...

of the

androgen receptor The androgen receptor (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of nuclear receptor that is activated by binding any of the androgenic hormones, including testosterone and dihydrotestosterone in th ...

(AR), the biological target of androgens such as testosterone and dihydrotestosterone. It shows minimal

systemic Systemic fundamental to a predominant social, economic, or political practice. This refers to: In medicine In medicine, ''systemic'' means affecting the whole body, or at least multiple organ systems. It is in contrast with ''topical'' or ''loc ...

absorption Absorption may refer to: Chemistry and biology * Absorption (biology), digestion **Absorption (small intestine) *Absorption (chemistry), diffusion of particles of gas or liquid into liquid or solid materials *Absorption (skin), a route by which ...

when applied to skin. The medication, developed by Cassiopea and Intrepid Therapeutics, was approved by the US Food and Drug Administration (FDA) for acne in August 2020. The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.

Medical uses

Clascoterone is

indicated In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. There can be multiple indications to use a procedure or medication. An indication can commonly be confused with the term diagnosis. A diagnosis ...

for the topical treatment of

acne vulgaris 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 po ...

in females and males age 12 years and older. It is applied to the affected skin area in a dose of 1 g cream (or 10 mg clascoterone) twice per day, once in the morning and once in the evening. The medication should not be used ophthalmically, orally, or vaginally. Two large

phase 3 Phase 3, Phase III or Phase Three may refer to: Media * Marvel Cinematic Universe: Phase Three, eleven American superhero films from 2016–2019 * '' Phase 3: Thrones and Dominions'', a 1995 album by Earth * ''Phase III'' (album), a 1972 album ...

randomized controlled trials evaluated the effectiveness of clascoterone for the treatment of acne over a period of 12 weeks. Clascoterone decreased acne symptoms by about 8 to 18% more than placebo. 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. The comparative effectiveness of clascoterone between males and females was not described. 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. No active comparator was used in the phase III clinical trials of clascoterone for acne. Hence, it's unclear how clascoterone compares to other therapies used in the treatment of acne.

Available forms

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

Contraindications

Clascoterone has no contraindications.

Side effects

The incidences of local skin reactions with clascoterone were similar to placebo in two large phase 3 randomized controlled trials. Suppression of the hypothalamic–pituitary–adrenal axis (HPA axis) may occur during clascoterone therapy in some individuals due to its cortexolone

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

. 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. HPA axis function returned to normal within 4 weeks following discontinuation of clascoterone. Hyperkalemia (elevated potassium levels) occurred in 5% of clascoterone-treated individuals and 4% of placebo-treated individuals.

Pharmacology

Pharmacodynamics

Clascoterone is a

steroidal antiandrogen 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) ...

, or

of the

(AR), the biological target of androgens such as testosterone and dihydrotestosterone (DHT). In a bioassay, the topical potency of the medication was greater than that of

progesterone Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the m ...

, flutamide, and

finasteride Finasteride, sold under the brand names Proscar and Propecia among others, is a medication used to treat hair loss and benign prostatic hyperplasia (BPH) in men. It can also be used to treat excessive hair growth in women and as a part of horm ...

and was equivalent to that of cyproterone acetate. Likewise, it is significantly more

efficacious Efficacy is the ability to perform a task to a satisfactory or expected degree. The word comes from the same roots as ''effectiveness'', and it has often been used synonymously, although in pharmacology a distinction is now often made between ...

as an antiandrogen than other AR antagonists such as enzalutamide and spironolactone in scalp dermal papilla cells and sebocytes '' in vitro''.

Pharmacokinetics

Steady-state In systems theory, a system or a process is in a steady state if the variables (called state variables) which define the behavior of the system or the process are unchanging in time. In continuous time, this means that for those properties ''p'' ...

levels of clascoterone occur within 5 days of twice daily administration. 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 In the field of pharmacokinetics, the area under the curve (AUC) is the definite integral of the concentration of a drug in blood plasma as a function of time (this can be done using liquid chromatography–mass spectrometry). In practice, the drug ...

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. In rodents, clascoterone has been found to possess strong local antiandrogenic activity, but negligible systemic antiandrogenic activity when administered via

subcutaneous injection Subcutaneous administration is the insertion of medications beneath the skin either by injection or infusion. A subcutaneous injection is administered as a bolus into the subcutis, the layer of skin directly below the dermis and epidermis, ...

. Along these lines, the medication is not

progonadotropic A progonadotropin, or hypergonadotropin, also known as a gonad stimulant, is a type of drug which increases the secretion of one or both of the major gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). This, in turn, re ...

in animals. The plasma protein binding of clascoterone is 84 to 89% regardless of concentration. Clascoterone is rapidly

hydrolyzed Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile. Biological hydrolysis ...

into cortexolone (11-deoxycortisol) and this compound is a possible primary

of clascoterone based on '' in-vitro'' studies in human

liver cell A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass. These cells are involved in: * Protein biosynthesis, Protein synthesis * Storage protein, Protein storage * Transformation of carboh ...

s. During treatment with clascoterone, cortexolone levels were detectable and generally below or near the low limit of quantification (0.5 ng/mL). Clascoterone may also produce other metabolites, including conjugates. The

elimination Elimination may refer to: Science and medicine * Elimination reaction, an organic reaction in which two functional groups split to form an organic product *Bodily waste elimination, discharging feces, urine, or foreign substances from the bo ...

of clascoterone has not been fully characterized in humans.

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 Synthetic things are composed of multiple parts, often with the implication that they are artificial. In particular, 'synthetic' may refer to: Science * Synthetic chemical or compound, produced by the process of chemical synthesis * Synthetic o ...

pregnane

steroid A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and a ...

and a derivative of

and

11-deoxycortisol 11-Deoxycortisol, also known as cortodoxone (INN), cortexolone as well as 17α,21-dihydroxyprogesterone or 17α,21-dihydroxypregn-4-ene-3,20-dione, is an endogenous glucocorticoid steroid hormone, and a metabolic intermediate towards cortisol. I ...

(cortexolone). It is specifically the C17α propionate ester of 11-deoxycortisol. An analogue of clascoterone is 9,11-dehydrocortexolone 17α-butyrate (CB-03-04).

Corticosteroid Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are involv ...

s related to clascoterone, for instance cortisone acetate and

prednisolone acetate Prednisolone acetate is a synthetic glucocorticoid corticosteroid and a corticosteroid ester. It is the 21-acetate ester of prednisolone. Safety Prednisolone acetate is acutely toxic with an LD50 of >240 mg/kg for a rat and 3500 mg ...

, show antiandrogenic activity in animals similarly to clascoterone.

History

C17α esters of 11-deoxycortisol were unexpectedly found to possess antiandrogenic activity. Clascoterone, also known as cortexolone 17α-propionate, was selected for development based on its optimal drug profile. The medication was approved by the US Food and Drug Administration (FDA) for the treatment of acne in August 2020. 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. The trials were conducted at 99 sites in the United States, Poland, Romania, Bulgaria, Ukraine, Georgia, and Serbia. Participants applied clascoterone or vehicle (placebo) cream twice daily for 12 weeks. Neither the participants nor the health care providers knew which treatment was being given until after the trial was completed. 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.

Society and culture

Names

''Clascoterone'' is the generic name of the drug and its and .

Research

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

References

External links

* * * {{Portal bar , Medicine Antiandrogen esters Diketones Pregnanes Propionate esters Steroidal antiandrogens Anti-acne preparations