Lasofoxifene

Last updated
Lasofoxifene
Lasofoxifene.png
Clinical data
Trade names Fablyn
Routes of
administration 		By mouth
Drug class Selective estrogen receptor modulator
ATC code
Identifiers
  • (5R,6S)-6-phenyl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C28H31NO2
Molar mass 413.55 g/mol
563.64 g/mol (tartrate) g·mol−1
3D model (JSmol)
  • O(c1ccc(cc1)[C@@H]4c2ccc(O)cc2CC[C@@H]4c3ccccc3)CCN5CCCC5
  • InChI=1S/C28H31NO2/c30-24-11-15-27-23(20-24)10-14-26(21-6-2-1-3-7-21)28(27)22-8-12-25(13-9-22)31-19-18-29-16-4-5-17-29/h1-3,6-9,11-13,15,20,26,28,30H,4-5,10,14,16-19H2/t26-,28+/m1/s1 Yes check.svgY
  • Key:GXESHMAMLJKROZ-IAPPQJPRSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Lasofoxifene, sold under the brand name Fablyn, is a nonsteroidal selective estrogen receptor modulator (SERM) which is marketed by Pfizer in Lithuania and Portugal for the prevention and treatment of osteoporosis and for the treatment of vaginal atrophy, [1] [2] and the result of an exclusive research collaboration with Ligand Pharmaceuticals (LGND). It also appears to have had a statistically significant effect of reducing breast cancer in women according to a study published in The Journal of the National Cancer Institute.

Contents

Medical uses

Osteoporosis

In postmenopausal women with osteoporosis, lasofoxifene at a dose of 0.5 mg per day was associated with reduced risks of nonvertebral and vertebral fractures, ER-positive breast cancer, coronary heart disease, and stroke but an increased risk of venous thromboembolic events. [3] [4]

Breast cancer

In studies of breast cancer prevention, lasofoxifene showed a 79% reduction in breast cancer incidence and an 83% reduction specific incidence of estrogen receptor-positive breast cancers, which is significantly higher than reductions found with the related SERMs tamoxifen and raloxifene. [5] In accordance, a network meta-analysis of SERMs for breast cancer prevention found the highest reduction in risk with lasofoxifene of all the drugs. [6] The reduction was even greater than that observed with aromatase inhibitors, which have generally been found to confer a greater risk reduction than SERMs. [6] It also has shown promise in ESR1 mutant patients with 'approximately 40% of patients harboring this mutation'. [7]

Pharmacology

Pharmacodynamics

Lasofoxifene selectively binds to both ERα and ERβ with high affinity. [8] Its IC50 for ERα (1.5 nM) is similar to that of estradiol (4.8 nM) and is at least 10-fold higher than those of tamoxifen and raloxifene. [3]

Tissue-specific estrogenic and antiestrogenic activity of SERMs
Medication Breast Bone Liver Uterus Vagina Brain
Lipids Coagulation SHBG IGF-1 Hot flashes Gonadotropins
Estradiol ++++++++++
"Ideal SERM"–++±±±–++±
Bazedoxifene –++++ ?–±– ?
Clomifene –++ ?++– ?–±
Lasofoxifene–+++ ? ?±±– ?
Ospemifene –+++++±±–±
Raloxifene –+++++±––±
Tamoxifen –++++++––±
Toremifene –++++++––±
Effect:+ = Estrogenic / agonistic. ± = Mixed or neutral. – = Antiestrogenic / antagonistic. Note: SERMs generally increase gonadotropin levels in hypogonadal and eugonadal men as well as premenopausal women (antiestrogenic) but decrease gonadotropin levels in postmenopausal women (estrogenic). Sources: See template.

Pharmacokinetics

Lasofoxifene has greatly improved oral bioavailability relative to tamoxifen and raloxifene, and this may also be involved in its greater potency. [9]

Chemistry

Lasofoxifene is a naphthalene derivative [8] and a desmethyl dihydro analogue of nafoxidine. [10]

History

In September 2005, Pfizer received a non-approvable letter from the U.S. Food and Drug Administration regarding lasofoxifene (trade name Oporia), a selective estrogen receptor modulator for the prevention of osteoporosis.

In January 2008, Ligand Pharmaceuticals, through its marketing partner, Pfizer, submitted a New Drug Application for lasofoxifene, which is expected to be marketed under the tradename Fablyn. Lasofoxifene was approved in the EU under the brand name Fablyn by the EMEA in March 2009. [11]

Research

Lasofoxifene is under development by Sermonix Pharmaceuticals for the treatment of metastatic breast cancer and dyspareunia associated with vaginal atrophy in the United States and Europe. [12] It is also being researched for the potential treatment of ovarian cancer. [12] As of December 2017, lasofoxifene is in phase III clinical trials for breast cancer and phase II clinical studies for dyspareunia. [12]

See also

Related Research Articles

<span class="mw-page-title-main">Selective estrogen receptor modulator</span> Drugs acting on the estrogen receptor

Selective estrogen receptor modulators (SERMs), also known as estrogen receptor agonist/antagonists (ERAAs), are a class of drugs that act on the estrogen receptor (ER). A characteristic that distinguishes these substances from pure ER agonists and antagonists is that their action is different in various tissues, thereby granting the possibility to selectively inhibit or stimulate estrogen-like action in various tissues.

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

Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and men. It is also being studied for other types of cancer. It has been used for Albright syndrome. Tamoxifen is typically taken daily by mouth for five years for breast cancer.

<span class="mw-page-title-main">Estrogen receptor</span> Proteins activated by the hormone estrogen

Estrogen receptors (ERs) are a group of proteins found inside cells. They are receptors that are activated by the hormone estrogen (17β-estradiol). Two classes of ER exist: nuclear estrogen receptors, which are members of the nuclear receptor family of intracellular receptors, and membrane estrogen receptors (mERs), which are mostly G protein-coupled receptors. This article refers to the former (ER).

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

Raloxifene, sold under the brand name Evista among others, is a medication used to prevent and treat osteoporosis in postmenopausal women and those on glucocorticoids. For osteoporosis it is less preferred than bisphosphonates. It is also used to reduce the risk of breast cancer in those at high risk. It is taken by mouth.

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

Bazedoxifene, used as bazedoxifene acetate, is a medication for bone problems and possibly for cancer. It is a third-generation selective estrogen receptor modulator (SERM). Since late 2013 it has had U.S. FDA approval for bazedoxifene as part of the combination drug Duavee in the prevention of postmenopausal osteoporosis. It is also being studied for possible treatment of breast cancer and pancreatic cancer.

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

Toremifene, sold under the brand name Fareston among others, is a medication which is used in the treatment of advanced breast cancer in postmenopausal women. It is taken by mouth.

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

Tibolone, sold under the brand name Livial among others, is a medication which is used in menopausal hormone therapy and in the treatment of postmenopausal osteoporosis and endometriosis. The medication is available alone and is not formulated or used in combination with other medications. It is taken by mouth.

<span class="mw-page-title-main">V. Craig Jordan</span> American/British pharmacologist (born 1947)

Virgil Craig Jordan,, is a scientist with American and British citizenship specializing in drugs for breast cancer treatment and prevention. Currently, he is Professor of Breast Medical Oncology, and Professor of Molecular and Cellular Oncology at the University of Texas MD Anderson Cancer Center, Houston, Texas. Previously, he was Scientific Director and Vice Chairman of Oncology at the Lombardi Comprehensive Cancer Center of Georgetown University. Jordan was the first to discover the breast cancer prevention properties of tamoxifen and the scientific principles for adjuvant therapy with antihormones. More recently his work has branched out into the prevention of multiple diseases in women with the discovery of the drug group, selective estrogen receptor modulator (SERMs). Currently, he plans to develop a new Hormone Replacement Therapy (HRT) for post-menopausal women that prevents breast cancer and does not increase the risk of breast cancer.

Hormonal therapy in oncology is hormone therapy for cancer and is one of the major modalities of medical oncology, others being cytotoxic chemotherapy and targeted therapy (biotherapeutics). It involves the manipulation of the endocrine system through exogenous or external administration of specific hormones, particularly steroid hormones, or drugs which inhibit the production or activity of such hormones. Because steroid hormones are powerful drivers of gene expression in certain cancer cells, changing the levels or activity of certain hormones can cause certain cancers to cease growing, or even undergo cell death. Surgical removal of endocrine organs, such as orchiectomy and oophorectomy can also be employed as a form of hormonal therapy.

Antiestrogens, also known as estrogen antagonists or estrogen blockers, are a class of drugs which prevent estrogens like estradiol from mediating their biological effects in the body. They act by blocking the estrogen receptor (ER) and/or inhibiting or suppressing estrogen production. Antiestrogens are one of three types of sex hormone antagonists, the others being antiandrogens and antiprogestogens. Antiestrogens are commonly used to stop steroid hormones, estrogen, from binding to the estrogen receptors leading to the decrease of estrogen levels. Decreased levels of estrogen can lead to complications in sexual development. Antiandrogens are sex hormone antagonists which are able to lower the production and the effects that testosterone can have on female bodies.

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

Arzoxifene is a selective estrogen receptor modulator (SERM) of the benzothiophene group which was never marketed. It is a potent estrogen antagonist in mammary and uterine tissue while acting as an estrogen agonist to maintain bone density and lower serum cholesterol. Arzoxifene is a highly effective agent for prevention of mammary cancer induced in the rat by the carcinogen nitrosomethylurea and is significantly more potent than raloxifene in this regard. Arzoxifene is devoid of the uterotrophic effects of tamoxifen, suggesting that, in contrast to tamoxifen, it is unlikely that the clinical use of arzoxifene will increase the risk of developing endometrial carcinoma.

Antihormone therapy is a type of hormone therapy that suppresses selected hormones or their effects, in contrast with hormone replacement therapy, which encourages hormone activity.

A hormone-receptor-positive (HR+) tumor is a tumor which consists of cells that express receptors for certain hormones. The term most commonly refers to estrogen receptor positive tumors, but can also include progesterone receptor positive tumors. Estrogen-receptor-positive tumors depend on the presence of estrogen for ongoing proliferation.

<span class="mw-page-title-main">Bionovo</span> Biotechnology company

Bionovo was an American biotechnology company focused on the discovery and development of botanically derived treatments for women's health and cancer based in Emeryville, California. The company had multiple drug candidates in U.S. Food and Drug Administration (FDA) clinical trials- Menerba a selective estrogen receptor beta agonist for hot flashes associated with menopause Seala a selective estrogen receptor beta agonist for menopausal vaginal dryness and Bezielle for advanced breast cancer. The company has ceased activity after filing for Chapter 7 bankruptcy protection in California. Bionovo's stock is no longer listed.

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

Ospemifene is an oral medication indicated for the treatment of dyspareunia – pain during sexual intercourse – encountered by some women, more often in those who are post-menopausal. Ospemifene is a selective estrogen receptor modulator (SERM) acting similarly to an estrogen on the vaginal epithelium, building vaginal wall thickness which in turn reduces the pain associated with dyspareunia. Dyspareunia is most commonly caused by "vulvar and vaginal atrophy."

<span class="mw-page-title-main">Nonsteroidal estrogen</span> Class of drugs

A nonsteroidal estrogen is an estrogen with a nonsteroidal chemical structure. The most well-known example is the stilbestrol estrogen diethylstilbestrol (DES). Although nonsteroidal estrogens formerly had an important place in medicine, they have gradually fallen out of favor following the discovery of toxicities associated with high-dose DES starting in the early 1970s, and are now almost never used. On the other hand, virtually all selective estrogen receptor modulators (SERMs) are nonsteroidal, with triphenylethylenes like tamoxifen and clomifene having been derived from DES, and these drugs remain widely used in medicine for the treatment of breast cancer among other indications. In addition to pharmaceutical drugs, many xenoestrogens, including phytoestrogens, mycoestrogens, and synthetic endocrine disruptors like bisphenol A, are nonsteroidal substances with estrogenic activity.

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

Elacestrant, sold under the brand name Orserdu, is an anticancer medication which is used in the treatment of breast cancer. It is taken by mouth.

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

Droloxifene, also known as 3-hydroxytamoxifen, is a nonsteroidal selective estrogen receptor modulator (SERM) of the triphenylethylene group that was developed originally in Germany and later in Japan for the treatment of breast cancer, osteoporosis in men and postmenopausal women, and cardiovascular disorders but was abandoned and never marketed. It reached phase II and phase III clinical trials for these indications before development was discontinued in 2000. The drug was found to be significantly less effective than tamoxifen in the treatment of breast cancer in two phase III clinical trials.

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

Nitromifene (INN; also as the citrate salt nitromifene citrate (USAN), developmental code names CI-628, CN-5518, CN-55945) is a nonsteroidal selective estrogen receptor modulator (SERM) related to triphenylethylenes like tamoxifen that was never marketed. It is a mixture of (E)- and (Z)-isomers that possess similar antiestrogenic activity. The drug was described in 1966. Along with tamoxifen, nafoxidine, and clomifene, it was one of the earliest SERMs.

References

  1. ↑ Gennari L, Merlotti D, Martini G, Nuti R (September 2006). "Lasofoxifene: a third-generation selective estrogen receptor modulator for the prevention and treatment of osteoporosis". Expert Opinion on Investigational Drugs. 15 (9): 1091–103. doi:10.1517/13543784.15.9.1091. PMID   16916275. S2CID   20693299.
  2. ↑ "Fablyn (Lasofoxifene tartrate) FDA Approval Status".
  3. 1 2 Gennari L, Merlotti D, Nuti R (2010). "Selective estrogen receptor modulator (SERM) for the treatment of osteoporosis in postmenopausal women: focus on lasofoxifene". Clinical Interventions in Aging. 5: 19–29. doi: 10.2147/cia.s6083 . PMC   2817938 . PMID   20169039.
  4. ↑ Cummings SR, Ensrud K, Delmas PD, LaCroix AZ, Vukicevic S, Reid DM, Goldstein S, Sriram U, Lee A, Thompson J, Armstrong RA, Thompson DD, Powles T, Zanchetta J, Kendler D, Neven P, Eastell R (February 2010). "Lasofoxifene in postmenopausal women with osteoporosis". The New England Journal of Medicine. 362 (8): 686–96. doi:10.1056/NEJMoa0808692. PMID   20181970.
  5. ↑ I. Craig Henderson (27 October 2015). Breast Cancer. Oxford University Press, Incorporated. pp. 31–. ISBN   978-0-19-991998-7.
  6. 1 2 Mocellin S, Pilati P, Briarava M, Nitti D (February 2016). "Breast Cancer Chemoprevention: A Network Meta-Analysis of Randomized Controlled Trials". Journal of the National Cancer Institute. 108 (2). doi: 10.1093/jnci/djv318 . PMID   26582062.
  7. ↑ "Cristofanilli Calls for More Effective Options in ESR1-Mutant Breast Cancer". OncLive. 4 November 2019. Retrieved 2019-11-12.
  8. 1 2 Gennari L (June 2006). "Lasofoxifene: a new type of selective estrogen receptor modulator for the treatment of osteoporosis". Drugs of Today. 42 (6): 355–67. doi:10.1358/dot.2006.42.6.973583. PMID   16845439.
  9. ↑ Gennari L (September 2009). "Lasofoxifene, a new selective estrogen receptor modulator for the treatment of osteoporosis and vaginal atrophy". Expert Opinion on Pharmacotherapy. 10 (13): 2209–20. doi:10.1517/14656560903127241. PMID   19640205. S2CID   21020484.
  10. ↑ Lednicer D, Emmert DE, Lyster SC, Duncan GW (September 1969). "Mammalian antifertility agents. VI. A novel sequence for the preparation of 1,2-disubstituted 3,4-dihydronaphthalenes". Journal of Medicinal Chemistry. 12 (5): 881–5. doi:10.1021/jm00305a038. PMID   5812203.
  11. ↑ "Fablyn - lasofoxifene". European Medicines Agency. 7 August 2009. Archived from the original on 13 April 2010.
  12. 1 2 3 "Lasofoxifene - Sermonix Pharmaceuticals - AdisInsight".
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