Clascoterone

Clascoterone

(1R,3aS,3bR,9aR,9bS,11aS)-1-(2-hydroxyacetyl)-9a,11a-dimethyl-7-oxo-1H,2H,3H,3aH,3bH,4H,5H,7H,8H,9H,9aH,9bH,10H,11H,11aH-cyclopenta[a]phenanthren-1-yl propanoate

FDA APPROVED, 2020/8/26, Winlevi

Anti-acne, Androgen receptor antagonist

Clascoterone, sold under the brand name Winlevi, is an antiandrogen medication which is used topically in the treatment of acne.^[1][2][3] It is also under development for the treatment of androgen-dependent scalp hair loss.^[2] The medication is used as a cream by application to the skin, for instance the face and scalp.^[3]

Clascoterone is an antiandrogen, or antagonist of the androgen receptor (AR), the biological target of androgens such as testosterone and dihydrotestosterone.^[4][5] It shows no systemic absorption when applied to skin.^[3]

The medication, developed by Cassiopea and Intrepid Therapeutics,^[2] was approved by the US Food and Drug Administration (FDA) for acne in August 2020.^[6][7]

Medical uses

Clascoterone is indicated for the topical treatment of acne vulgaris in females and males age 12 years and older.^[1][8] It is applied to the affected skin area in a dose of 1 mg cream (or 10 mg clascoterone) twice per day, once in the morning and once in the evening.^[1] The medication should not be used ophthalmically, orally, or vaginally.^[1]

Available forms

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

Contraindications

Clascoterone has no contraindications.^[1]

Side effects

The incidences of local skin reactions with clascoterone were similar to placebo in two large phase 3 randomized controlled trials.^[1][9] Suppression of the hypothalamic–pituitary–adrenal axis (HPA axis) may occur during clascoterone therapy in some individuals due to its cortexolone metabolite.^[1][8] 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.^[1][8] HPA axis function returned to normal within 4 weeks following discontinuation of clascoterone.^[1][8] Hyperkalemia (elevated potassium levels) occurred in 5% of clascoterone-treated individuals and 4% of placebo-treated individuals.^[1]

Pharmacology

Pharmacodynamics

Clascoterone is an steroidal antiandrogen, or antagonist of the androgen receptor (AR), the biological target of androgens such as testosterone and dihydrotestosterone (DHT).^[1][4][5] 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.^[10] 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.^[5]\

Pharmacokinetics

Steady-state levels of clascoterone occur within 5 days of twice daily administration.^[1] 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.^[1] In rodents, clascoterone has been found to possess strong local antiandrogenic activity, but negligible systemic antiandrogenic activity when administered via subcutaneous injection.^[10] Along these lines, the medication is not progonadotropic in animals.^[10]

The plasma protein binding of clascoterone is 84 to 89% regardless of concentration.^[1]

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.^[1][8] During treatment with clascoterone, cortexolone levels were detectable and generally below or near the low limit of quantification (0.5 ng/mL).^[1] Clascoterone may also produce other metabolites, including conjugates.^[1]

The elimination of clascoterone has not been fully characterized in humans.^[1]

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).^[11] It is specifically the C17α propionate ester of 11-deoxycortisol.^[10]

An analogue of clascoterone is 9,11-dehydrocortexolone 17α-butyrate (CB-03-04).^[12]

History

C17α esters of 11-deoxycortisol were unexpectedly found to possess antiandrogenic activity.^[10] Clascoterone, also known as cortexolone 17α-propionate, was selected for development based on its optimal drug profile.^[10] The medication was approved by the US Food and Drug Administration (FDA) for the treatment of acne in August 2020.^[6]

Two large phase 3 randomized controlled trials evaluated the effectiveness of clascoterone for the treatment of acne over a period of 12 weeks.^[1][8][9] Clascoterone decreased acne symptoms by about 8 to 18% more than placebo.^[1][9] 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.^[1][8][9] The comparative effectiveness of clascoterone between males and females was not described.^[1][9]

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.^[8][13] No active comparator was used in the phase III clinical trials of clascoterone for acne.^[8] Hence, it’s unclear how clascoterone compares to other therapies used in the treatment of acne.^[8]

The FDA approved clascoterone based on evidence from two clinical trials (Trial 1/NCT02608450 and Trial 2/NCT02608476) of 1440 participants 9 to 58 years of age with acne vulgaris.^[14] The trials were conducted at 99 sites in the United States, Poland, Romania, Bulgaria, Ukraine, Georgia, and Serbia.^[14]

Participants applied clascoterone or vehicle (placebo) cream twice daily for 12 weeks.^[14] Neither the participants nor the health care providers knew which treatment was being given until after the trial was completed.^[14] 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.^[14]

Society and culture

Names

Clascoterone is the generic name of the drug and its INN and USAN.^[11][15]

Research

Clascoterone has been suggested as a possible treatment for hidradenitis suppurativa (acne inversa), an androgen-dependent skin condition.^[16]

PATENT

https://patents.google.com/patent/EP2503005B1/en

• Cortexolone derivatives in which the hydroxyl group at position C-17α is esterified with short chain aliphatic or aromatic acids and the derivatives of the corresponding 9,11-dehydro derivative, are known to have an antiandrogenic effect.
• [0002]
  EP 1421099 describes cortexolone 17α-propionate and 9,11-dehydro-cortexolone-17-α-butanoate regarding a high antiandrogenic biological activity demonstrated both “in vitro” and “in vivo” on the animal.
• [0003]
  US3530038 discloses the preparation of a crystalline form of cortexolone-17α-propionate having a melting point of 126-129 °C and an IR spectrum with bands at (cm^-1): 3500, 1732, 1713, 1655 and 1617.
• [0004]
  A method for obtaining the above mentioned derivatives is described by Gardi et al. (Gazz. Chim. It. 63, 43 1,1963) and in the United States patent US3152154 providing for the transformation of cortexolone, or transformation of 9,11-dehydrocortexolone, in the intermediate orthoester using orthoesters available in the market as a mixture of aprotic solvents such as cyclohexane and DMF, in presence of acid catalysis (ex. PTSA.H₂0). The intermediate orthoester thus obtained can be used as is or upon purification by suspension in a solvent capable of solubilising impurities, preferably in alcohols. The subsequent hydrolysis in a hydroalcoholic solution, buffered to pH 4-5 preferably in acetate buffer, provides the desired monoester.
• [0005]

  Such synthesis is indicated in the diagram 1 below
• [0006]
  However, the monoesters thus obtained were, in the reaction conditions, unstable and, consequently hard to manipulate and isolate (R. Gardi et al Tetrahedron Letters, 448, 1961). The instability is above all due to the secondary reaction of migration of the esterifying acyl group from position 17 to position 21.
• [0007]
  It is thus known that in order to obtain the above mentioned monoesters with a chemical purity in such a manner to be able to proceed to the biological tests, it is necessary to use, at the end of the synthesis, a purification process which is generally performed by means of column chromatography.
• [0008]
  Furthermore, US3152154 describes how the hydrolysis of the diester in a basic environment is not convenient due to the formation of a mixture of 17α,21-diol, of 17- and 21 -monoesters, alongside the initial non-reacted product.
• [0009]
  Now, it has been surprisingly discovered that an alcoholysis reaction using a lipase from Candida as a biocatalyst can be usefully applied during the preparation of 17α monoesters of cortexolone, or its 9,11-dehydroderivatives.
• [0010]

  As a matter of fact, it has been discovered that such enzymatic alcoholysis of the 17,21-diester of the cortexolone, or of its derivative 9,11-dehydro, selectively occurs in position 21 moving to the corresponding monoester in position 17, as shown in diagram 2 below:
• [0011]
  The chemoselectivity of the special enzymatic reaction in alcoholysis conditions, according to the present invention, opens new perspectives for preparation, at industrial level with higher yields, of 17α-monoesters with respect to the methods already indicated in literature.
• [0012]
  The diesters serving as a substrate for the reaction of the invention can be prepared according to the prior art, for example following the one described in B.Turner, (Journal of American Chemical Society, 75, 3489, 1953) which provides for the esterification of corticosteroids with a linear carboxylic acid in presence of its anhydride and PTSA monohydrate.

EXAMPLES

• Example 1

Alcoholysis with CCL of cortexolone 17α, 21-dipropionate

• • • [0055]
      Add butanol (0.4g, 5.45 mmoles) and CCL (17.4g, 3.86 U/mg, FLUKA) to a solution of cortexolone-17α,21-dipropionate (0.5g, 1.09 mmoles) in toluene (50ml). Maintain the mixture under stirring, at 30 °C, following the progress of the reaction in TLC (Toluene/ethyl acetate 6/4) until the initial material is dissolved (24h). Remove the enzyme by means of filtration using a Celite layer. Recover the cortexolone 17α-propionate (0.437, 99%) after evaporation under low pressure. Through crystallisation, from diisopropyl ether you obtain a product with a purity >99% in HPLC.
    • [0056]
      ¹H-NMR (500MHz, CDCl₃) relevant signals δ (ppm) 5.78 (br s, 1 H, H-4), 4.32 (dd, 1 H, H-21), 4.25 (dd, 1H, H-21), 1.22 (s, 3H, CH₃-19), 1.17 (t, 3H, CH₃), 0.72 (s, 3H, CH₃-18). P.f. 114 °C

Example 2 (comparative)

• • • [0057]
      According to the method described in example 1 prepare cortexolone-17α-butanoate.
    • [0058]
      ¹H-NMR relevant signals δ (ppm) 5.78 (br s, 1H, H-4), 4.32 (dd, 1H, H-21), 4.26 (dd, 1H, H-21), 1.23 (s, 3H, CH₃-19), 0.97 (t, 3H, CH₃), 0.73 (s, 3H. CH₃-18). P.F. 134-136 °C

Example 3 (comparative)

According to the method described in the example prepare cortexolone-17α-valerate.

• • • [0059]
      ¹H-NMR relevant signals δ (ppm) 5.77 (br s, 1H, H-4), 4.32 (dd, 1H, H-21), 4.26 (dd, 1H, H-21), 1.22 (s, 3H, CH₃-19), 0.95 (t, 3H, CH₃), 0.72 (s, 3H, CH₃-18). P.f. 114 °C (diisopropyl ether).

Example 4 (comparative)

According to the method described in the example prepare 9, 11-dehydro-cortexolone-17α-butanoate.

• • • [0060]
      ¹H-NMR relevant signals δ (ppm) 5.77 (br s, 1H, H-4), 5.54 (m, 1H, H-9), 4.29 (dd, 1H, H-21), 4.24 (dd, 1H, H-21), 1.32 (s, 3H, CH₃-19), 0.94(t, 3H, CH₃), 0.68 (s, 3H, CH₃-18). P.f. 135-136 °C (acetone/hexane).

Example 5

Alcoholysis with CALB of cartexolone-17α, 21-dipropionate

• • • [0061]
      Dissolve cortexolone, 17α, 2-dipropionate (0.5g, 1.09 mmoles) in acetonitrile (40ml), add CALB (2.3g, 2.5 U/mg Fluka) and octanol (0.875ml). Leave the mixture under stirring, at 30 °C, for 76 hrs. Remove the enzyme by means of filtration using a paper filter. Once the solvents evaporate, recover a solid (0.4758) which upon analysis ¹H-NMR shall appear made up of cortexolone-17α-propionate at 91%.

Example 6

Crystallisation

• • • [0062]
      Add the solvent (t-butylmethylether or diisopropylether) to the sample according to the ratios indicated in Table 3. Heat the mixture to the boiling temperature of the solvent, under stirring, until the sample dissolves completely. Cool to room temperature and leave it at this temperature, under stirring, for 6 hours. Filter using a buchner funnel and maintain the solid obtained, under low pressure, at a room temperature for 15 hours and then, at 40°C, for 5 hours.

Example 7 (comparative)

Precipitation

• • • [0063]
      Disslove the sample in the suitable solvent (dichloromethane, acetone, ethyl acetate or ethanol) according to the ratios indicated in table 3 and then add the solvent, hexane or water, according to the ratios indicated in table 3, maintaining the mixture, under stirring, at room temperature. Recover the precipitate by filtration using a buchner funnel and desiccate as in example 6.

Example 8.

Obtaining a pharmaceutical form containing the medication in a defined crystalline form.

• [0064]
  Prepare a fluid cream containing 2 % cetylic alcohol, 16% glyceryl monostearate, 10% vaseline oil, 13 % propylene glycol, 10% polyethylenglycol with low polymerization 1.5% polysorbate 80 and 47.5 % purified water. Add 1 g of cortexolone 17α-propionate of crystalline form III to 100 g of this cream and subject the mixture to homogenisation by means of a turbine agitator until you obtain homogeneity. You obtain a cream containing a fraction of an active ingredient dissolved in the formulation vehicle and a non-dissolved fraction of an active ingredient, present as a crystal of crystalline form III. This preparation is suitable for use as a formulation vehicle for skin penetration tests on Franz cells, where a coefficient of penetration in the range of 0.04 to 0.03 cm/h is observed on the preparation.

References

External links

• “Clascoterone”. Drug Information Portal. U.S. National Library of Medicine.
• Clinical trial number NCT02608450 for “A Study to Evaluate the Safety and Efficacy of CB-03-01 Cream, 1% in Subjects With Facial Acne Vulgaris (25)” at ClinicalTrials.gov
• Clinical trial number NCT02608476 for “A Study to Evaluate the Safety and Efficacy of CB-03-01 Cream, 1% in Subjects With Facial Acne Vulgaris (26)” at ClinicalTrials.gov

Clascoterone

Clinical data
Trade names	Winlevi
Other names	CB-03-01; Breezula; 11-Deoxycortisol 17α-propionate; 17α-(Propionyloxy)- deoxycorticosterone; 21-Hydroxy-3,20-dioxopregn-4-en-17-yl propionate
License data	US DailyMed: Clascoterone
Routes of administration	Topical (cream)
ATC code	None
Legal status
Legal status	US: ℞-only
Identifiers
IUPAC name[show]
CAS Number	19608-29-8
PubChem CID	11750009
DrugBank	DB12499
ChemSpider	9924713
UNII	XN7MM8XG2M
KEGG	D11451
ChEMBL	ChEMBL3590187
CompTox Dashboard (EPA)	DTXSID10471883
ECHA InfoCard	100.210.810
Chemical and physical data
Formula	C24H34O5
Molar mass	402.531 g·mol−1
3D model (JSmol)	Interactive image
SMILES[hide] 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[hide] 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, クラスコステロン , FDA 2020, 2020 APPROVALS, ANTI ACNE

[H][C@@]12CC[C@](OC(=O)CC)(C(=O)CO)[C@@]1(C)CC[C@@]1([H])[C@@]2([H])CCC2=CC(=O)CC[C@]12C