Lasofoxifene

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.

Lasofoxifene
Clinical data
Trade namesFablyn
Routes of
administration		By mouth
Drug classSelective estrogen receptor modulator
ATC code
Identifiers
IUPAC name
  • (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
FormulaC28H31NO2
Molar mass413.55 g/mol
563.64 g/mol (tartrate) g·mol−1
3D model (JSmol)
SMILES
  • O(c1ccc(cc1)[C@@H]4c2ccc(O)cc2CC[C@@H]4c3ccccc3)CCN5CCCC5
InChI
  • 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 Y
  • Key:GXESHMAMLJKROZ-IAPPQJPRSA-N Y
 NY (what is this?)  (verify)

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
MedicationBreastBoneLiverUterusVaginaBrain
LipidsCoagulationSHBGIGF-1Hot flashesGonadotropins
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

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. 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. 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. Retrieved 2019-11-12.
  8. 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. "Lasofoxifene - Sermonix Pharmaceuticals - AdisInsight".
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