Irosustat (, ; developmental code names STX-64, 667-coumate, BN-83495; also known as oristusane) is an orally active, irreversible,

nonsteroidal A nonsteroidal compound is a drug that is not a steroid nor a steroid derivative. Nonsteroidal anti-inflammatory drugs (NSAIDs) are distinguished from corticosteroids as a class of anti-inflammatory agents. List of nonsteroidal steroid receptor mo ...

inhibitor Inhibitor or inhibition may refer to: Biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotransmi ...

steroid sulfatase Steroid sulfatase (STS), or steryl-sulfatase (EC 3.1.6.2), formerly known as arylsulfatase C, is a sulfatase enzyme involved in the metabolism of steroids. It is encoded by the ''STS'' gene. Reactions This enzyme catalysis, catalyses the follow ...

(STS) and member of the aryl sulfamate ester class of drugs that was under development by Sterix Ltd and

Ipsen Ipsen is a French biopharmaceutical company headquartered in Paris, France, with a focus on drug development and commercialization in three therapeutic areas: oncology, rare diseases and neuroscience. Ipsen is one of the world's top 15 biopha ...

for the treatment of hormone-sensitive cancers such as

breast cancer Breast cancer is a cancer that develops from breast tissue. Signs of breast cancer may include a Breast lump, lump in the breast, a change in breast shape, dimpling of the skin, Milk-rejection sign, milk rejection, fluid coming from the nipp ...

prostate cancer Prostate cancer is the neoplasm, uncontrolled growth of cells in the prostate, a gland in the male reproductive system below the bladder. Abnormal growth of the prostate tissue is usually detected through Screening (medicine), screening tests, ...

, and

endometrial cancer Endometrial cancer is a cancer that arises from the endometrium (the epithelium, lining of the uterus or womb). It is the result of the abnormal growth of cells (biology), cells that can invade or spread to other parts of the body. The first s ...

but has not yet been marketed. The drug was first designed and synthesized in the group of Professor Barry V L Potter at the Department of Pharmacy & Pharmacology,

University of Bath The University of Bath is a public research university in Bath, England. Bath received its royal charter in 1966 as Bath University of Technology, along with a number of other institutions following the Robbins Report. Like the University ...

, working together with Professor

Michael J. Reed Michael J. Reed (30 May 1944 – 6 April 2009) was a British chemist who held the position of professor of steroid biochemistry at Imperial College, London. Scientific career Reed obtained a BSc in zoology from the University of London in 196 ...

Imperial College Imperial College London, also known as Imperial, is a public research university in London, England. Its history began with Prince Albert, husband of Queen Victoria, who envisioned a cultural district in South Kensington that included museums ...

, London and its initial development was undertaken through the university spin-out company Sterix Ltd and overseen by Cancer Research UK ( CRUK). Results of the "first-in-class"

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 ...

in breast cancer of an STS inhibitor in humans were published in 2006 and dose optimisation studies and further clinical data have been reported.

Mechanism of action

By inhibiting STS, irosustat prevents the conversion of hormonally inactive

steroid A steroid is an organic compound with four fused compound, fused rings (designated A, B, C, and D) arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes t ...

sulfate The sulfate or sulphate ion is a polyatomic anion with the empirical formula . Salts, acid derivatives, and peroxides of sulfate are widely used in industry. Sulfates occur widely in everyday life. Sulfates are salts of sulfuric acid and many ...

s such as sulfate (DHEA-S) and

estrone sulfate Estrone sulfate, also known as E1S, E1SO4 and estrone 3-sulfate, is a natural, endogenous steroid and an estrogen ester and conjugate. In addition to its role as a natural hormone, estrone sulfate is used as a medication, for instance in men ...

(E1S) into their respective active forms, and

estrone Estrone (E1), also spelled oestrone, is a steroid, a weak estrogen, and a minor female sex hormone. It is one of three major endogenous estrogens, the others being estradiol and estriol. Estrone, as well as the other estrogens, are synthesized ...

(which, in turn, can be transformed into more potent

androgen An androgen (from Greek ''andr-'', the stem of the word meaning ) is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This includes ...

s and

estrogen Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...

s, respectively). The X-ray crystal structure of the drug bound to CAII has been determined.

Pharmacokinetics

Despite Irosustat being quickly degraded in plasma ''ex vivo'', this is prevented ''in vivo'' by its sequestration almost completely inside red blood cells after oral administration, being bound to carbonic anhydrase II (CA II) like its parent steroidal sulfamate ester E2MATE and thus avoiding first pass metabolism.

Clinical development

In 2004 Sterix Ltd was acquired by Ipsen and Irosustat continued in development through formal academic-industry partnerships by Ipsen with the University of Bath and Imperial College. The drug reached phase II

s in women with hormone-dependent breast cancer and endometrial cancer prior to the discontinuation of its initial development by Ipsen as a monotherapy for endometrial cancer in women with advanced/metastatic or recurrent estrogen-receptor positive endometrial cancer after a futility analysis of trial data. Results published in 2017 showed clinical activity and a good safety profile for Irosustat, with 36% of patients on Irosustat alive without progression at 6 months; 11% showed responses and there was more stable disease noted (47%) compared to the current therapy (32%), the progestin

megestrol acetate Megestrol acetate (MGA), sold under the brand name Megace among others, is a progestin medication which is used mainly as an appetite stimulant to treat wasting syndromes such as cachexia. It is also used to treat breast cancer and endometrial ...

(MA). However, overall there were no statistically significant differences between Irosustat and the current standard of care MA in response and survival rates. It also reached a phase I trial in the US for prostate cancer, being safe and well tolerated in male patients with castration-resistant prostate cancer and ongoing androgen deprivation therapy. Pharmacodynamic proof of concept was demonstrated with Irosustat effecting nearly complete STS inhibition at three doses, and in all patients there was notable suppression of endocrine parameters. The development of Irosustat has continued with clinical trials overseen by CRUK designed to explore its activity in early breast cancer (IPET trial) and also in combination with an aromatase inhibitor (AI) (IRIS trial). The multicentre IRIS trial, an open-label phase II clinical study, explored the clinical value of adding an STS inhibitor in addition to a first-line AI in patients with advanced breast cancer and enrolled postmenopausal women with ER+ locally advanced or metastatic breast cancer who had benefited from a first-line AI but were subsequently progressing. The IPET trial was a pre-surgical window-of-opportunity study, assessing Irosustat for the first time in ER+ early breast cancer and recruiting postmenopausal women with untreated early disease. Importantly, these data are the first to demonstrate clinical activity of Irosustat in early breast cancer, albeit in a small patient population. The results of both trials were published in 2017, showing evidence of clinical benefit and underpinning the scientific concept of STS inhibition. Larger studies are now required. Irosustat was also evaluated as a combination therapy with an oral

epidermal growth factor receptor The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is a transmembrane protein that is a receptor (biochemistry), receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligand (biochemistry ...

tyrosine kinase inhibitor A tyrosine kinase inhibitor (TKI) is a pharmaceutical drug that inhibits tyrosine kinases. Tyrosine kinases are enzymes responsible for the activation of many proteins by signal transduction cascades. The proteins are activated by adding a phosph ...

for the treatment of

Non-Small Cell Lung Cancer Non-small-cell lung cancer (NSCLC), or non-small-cell lung carcinoma, is any type of epithelial lung cancer other than small-cell lung cancer (SCLC). NSCLC accounts for about 85% of all lung cancers. As a class, NSCLCs are relatively insensitiv ...

Patients. Clinical development continues and the current status was reviewed in 2018. Administration of 5 mg/day irosustat to women with breast cancer for 5 days inhibited STS activity by 98 to 99% in

breast The breasts are two prominences located on the upper ventral region of the torso among humans and other primates. Both sexes develop breasts from the same embryology, embryological tissues. The relative size and development of the breasts is ...

tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

tissue and significantly decreased serum levels of estrone (by 76%), estradiol (by 39%), DHEA (by 41%),

androstenediol Androstenediol, or 5-androstenediol (abbreviated as A5 or Δ5-diol), also known as androst-5-ene-3β,17β-diol, is an endogenous weak androgen and estrogen steroid hormone and intermediate in the biosynthesis of testosterone from dehydroepiand ...

(by 70%),

androstenedione Androstenedione, or 4-androstenedione (abbreviated as A4 or Δ4-dione), also known as androst-4-ene-3,17-dione, is an endogenous weak androgen steroid hormone and intermediate in the biosynthesis of estrone and of testosterone from dehydroe ...

(by 62%), and

testosterone Testosterone is the primary male sex hormone and androgen in Male, males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testicles and prostate, as well as promoting se ...

(by 30%), whereas levels of DHEA-S and E1S increased slightly (by 1.1% and 7.4%, respectively).

Animal studies

Importantly, it was demonstrated that oral treatment with Irosustat alleviates the symptoms of

Alzheimer’s Disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

in a murine model, indicating that the drug passes the

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...

. STS inhibitors could therefore potentially be employed to treat aging and aging-associated diseases.

References

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External links