Setipiprant (

INN Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway. Before the advent of motorized transportation, they also provided accomm ...

; developmental code names ACT-129968, KYTH-105) is an investigational

drug A drug is any chemical substance other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect. Consumption of drugs can be via insufflation (medicine), inhalation, drug i ...

developed for the treatment of asthma and scalp hair loss. It was originally developed by

Actelion Actelion Pharmaceuticals Ltd. is a pharmaceuticals and biotechnology company established in December 1997, headquartered in Allschwil near Basel, Switzerland. The company is part of Johnson & Johnson Innovative Medicine business segment. Actel ...

and acts as a selective, orally available

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.prostaglandin D₂ receptor 2 (DP₂). The drug is being developed as a novel treatment for male pattern baldness by

Allergan Allergan plc is an American, Irish-domiciled pharmaceutical company that acquires, develops, manufactures and markets brand name drugs and medical devices in the areas of medical aesthetics, eye care, central nervous system, and gastroenterology. ...

Medical uses

Scalp hair loss

Acting through DP₂, PGD₂ can inhibit hair growth, suggesting that this receptor is a potential target for bald treatment. A phase 2A study to evaluate the safety, tolerability, and efficacy of oral setipiprant relative to a

placebo A placebo ( ) can be roughly defined as a sham medical treatment. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures. Placebos are used in randomized clinical trials ...

in 18- to 49-year-old males with androgenetic

alopecia Hair loss, also known as alopecia or baldness, refers to a loss of hair from part of the head or body. Typically at least the head is involved. The severity of hair loss can vary from a small area to the entire body. Inflammation or scarring ...

was completed in May 2018 and did not find statistically significant improvement.

Allergic conditions

Setipiprant proved to be well tolerated and reasonably effective in reducing allergen-induced airway responses in asthmatic patient

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

s. However, the drug, while supporting the concept that DP2 contributes to asthmatic disease, did not show sufficient advantage over existing drugs and was discontinued from further development for this application.

Adverse effects

Data from phase II and III clinical trials did not detect any severe adverse effects to setipiprant. The authors were unable to identify any pattern of adverse effects that differ from placebo, including subjective reporting of symptoms and objective laboratory monitoring.

Interactions

While setipiprant mildly induces the drug metabolizing enzyme

CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...

in vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...

'', the interaction appears to not be clinically relevant.

Pharmacology

Mechanism of action

Allergic conditions

Setipiprant binds to the DP₂ receptor with a

dissociation constant In chemistry, biochemistry, and pharmacology, a dissociation constant (''K''D) is a specific type of equilibrium constant that measures the propensity of a larger object to separate (dissociate) reversibly into smaller components, as when a complex ...

of 6 nM, representing potent antagonism of the receptor. The DP₂ receptor, also called the CRTh2 receptor, is a

G-protein-coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large protein family, group of evoluti ...

(GPCR) that is expressed on certain inflammatory cells, such as

eosinophils Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. Along wi ...

basophils Basophils are a type of white blood cell. Basophils are the least common type of granulocyte, representing about 0.5% to 1% of circulating white blood cells. They are the largest type of granulocyte. They are responsible for inflammatory reactio ...

, and certain

lymphocytes A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include T cells (for cell-mediated and cytotoxic adaptive immunity), B cells (for humoral, antibody-driven adaptive immunity), and ...

. For its mechanism of action in the treatment of allergic conditions, setipiprant's DP₂ antagonism prevents the action of prostaglandin D₂ (PGD₂) on these receptors. The DP₂ receptor mediates the activation of type 2 helper T (Th2) cells, eosinophils, and basophils in the lungs, which are

white blood cells White blood cells (scientific name leukocytes), also called immune cells or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and foreign entities. White blood cells are genera ...

implicated in producing the inflammatory response the characterizes allergic conditions. Activation of DP₂ on Th2 cells by PGD₂ induces the secretion of inflammatory

cytokines Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...

( interleukin (IL) 4, IL-5, and IL-13), which cause an increase of eosinophils in the blood, remodeling of lung tissue, and hypersensitivity of lung tissue to

allergens An allergen is an otherwise harmless substance that triggers an allergic reaction in sensitive individuals by stimulating an immune response. In technical terms, an allergen is an antigen that is capable of stimulating a type-I hypersensitivi ...

. Setipiprant does not antagonize the

thromboxane receptor The thromboxane receptor (TP) also known as the prostanoid TP receptor is a protein that in humans is encoded by the ''TBXA2R'' gene, The thromboxane receptor is one among the five classes of prostaglandin receptor, prostanoid receptors and was ...

(TP). The bronchoconstricting properties of PGD₂ are not inhibited by setipiprant, since these are mediated by the TP receptor. As a point of contrast, ramatroban is a selective TP antagonist and DP₂ receptor antagonist. Setipiprant does not appreciably inhibit the activity of the enzyme

cyclooxygenase 1 Cyclooxygenase 1 (COX-1), also known as prostaglandin-endoperoxide synthase 1 ( HUGO PTGS1), is an enzyme that in humans is encoded by the ''PTGS1'' gene. In humans it is one of three cyclooxygenases. History Cyclooxygenase (COX) is the cent ...

(COX-1), which is responsible for the synthesis of prostaglandins (including PGD₂).

Scalp hair loss

Prostaglandin D2 synthase Prostaglandin-H2 D-isomerase (PTGDS) is an enzyme that in humans is encoded by the ''PTGDS'' gene. Function The protein encoded by this gene is a glutathione-independent prostaglandin D synthase that catalyzes the conversion of prostaglandin ...

(PTGDS) is an enzyme that produces PGD₂. In men with

androgenic alopecia 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 ...

, the enzyme PTGDS is elevated in the bald scalp tissue, as well as its product PGD₂. PGD₂ inhibits the growth of hair follicles through its activity on the DP₂ receptor, but not the DP₁ receptor. Theoretically, setipiprant's DP₂ receptor antagonism may counteract the activity of PGD₂ in hair follicles, thereby stimulating hair growth.

Pharmacokinetics

The oral

bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...

of setipiprant is 44% in rats and 55% in dogs, which suggests that it should be orally bioavailable in humans. The

half-life Half-life is a mathematical and scientific description of exponential or gradual decay. Half-life, half life or halflife may also refer to: Film * Half-Life (film), ''Half-Life'' (film), a 2008 independent film by Jennifer Phang * ''Half Life: ...

of setipiprant in humans is about 11 hours. The maximum concentration in plasma (C_max) is 6.04 and 6.44 mcg/mL for setipiprant tablets and capsules respectively, with an area under the curve of 31.88 and 31.50 mcg×hours/mL for setipiprant tablets and capsules respectively. C_max was reached between 1.8–4 hours after oral administration. The tablet and capsule formulations are bioequivalent.

Chemistry

Setipiprant appears as a light yellow to yellow colored solid. Based on general guidelines, the powder form is considered stable for 2 years at 4 degrees C, and for 3 years as -20 degrees C. When dissolved in a solvent, setipiprant is stable for 1 month at -20 degrees C, and 6 months at -80 degrees C. It is considered soluble in

DMSO Dimethyl sulfoxide (DMSO) is an organosulfur compound with the formula . This colorless liquid is the sulfoxide most widely used commercially. It is an important polar aprotic solvent that dissolves both polar and nonpolar compounds and is ...

at concentrations ≥ 36 mg/mL.

History

Setipiprant was initially researched by

as a treatment for allergies and inflammatory disorders, particularly

asthma Asthma is a common long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wh ...

, but despite being well tolerated in

s and showing reasonable efficacy against allergen-induced airway responses in asthmatic patients, it failed to show sufficient advantages over existing drugs and was discontinued from further development in this application. However, following the discovery in 2012 that the prostaglandin D₂ receptor (DP/PGD₂) is expressed at high levels in the scalp of men affected by

male pattern baldness 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 ...

, the rights to setipiprant were acquired by Kythera to develop the drug as a novel treatment for baldness. The favorable pharmacokinetics and relative lack of side effects seen in earlier clinical trials mean that fresh clinical trials for this new application can be conducted fairly quickly. , setipiprant is currently under development by

for the prevention of androgenic alopecia after their successful acquisition of Kythera.

References

External links

Setipiprant - AdisInsight
{{Prostanoid signaling modulators Prostaglandins Receptor antagonists 1-Naphthyl compounds

Medical uses

Scalp hair loss

Allergic conditions

Adverse effects

Interactions

Pharmacology

Mechanism of action

Allergic conditions

Scalp hair loss

Pharmacokinetics

Chemistry

History

See also

References

External links