erb-041 and Endometriosis

The drug research and development (R&D) for endometriosis/adenomyosis has been painfully slow. Most completed clinical trials on endometriosis did not publish their results, and presumably failed. While few published trials did report how they foundered, the reasons why they failed are often completely unclear. Surprisingly, there has been no open discussion on why these trials failed. If the causes for these failed trials remain unelucidated, mistakes made in these failed trials may be repeated in the future. Since failure can be infinitely more instructive and educational than success, elucidating the causes for failed clinical trials may yield a treasure trove for future drug R&D. Given our growing understanding of the natural history of ectopic endometrium, it is also important to make an inventory of biologicals/compounds that are currently under development to see where we stand and whether they would stand a better chance of gaining regulatory approval than their predecessors.. We provide an overview of all compounds under clinical investigation and in development in order to assess the evolution of R&D since the last inventory, reported in 2013. We also have attempted to analyse selected failed clinical trials in the context of published translational/preclinical research and our growing understanding of the natural history of endometriotic/adenomyotic lesions, in the hope that the lessons learned will steer investigators toward the right track in future drug R&D.. We searched ClinicalTrials.gov and a database containing information on drugs gathered daily by Thomson Reuters from a wide range of sources (e.g. patent offices, biomedical literature, congresses, symposia, meetings, company information, regulatory information) for all therapeutic compounds that have undergone or are under clinical trials, or in the developmental stage, and then searched PubMed and Google to determine their publication status using trial identifiers. For trials that were completed at least 2 years ago and have, or have not, published their results, a PubMed search was performed using the name of the therapeutic that has been tested and 'endometriosis' or 'adenomyosis' to identify published preclinical studies prior to the launch of the trial. For those published trials, the cited preclinical studies were also retrieved and scrutinized.. Despite repeated calls for more transparency, only a small fraction of completed trials on endometriosis has been published. A large number of 'novel' compounds under development are simply repurposed drugs, which seem to be ill-prepared to combat the fibroproliferative nature of endometriosis/adenomyosis. This sobering picture indicates an alarming innovation 'drought' in the drug R&D front, resulting in trickling drug pipelines. Some trials foundered owing to unanticipated serious side-effects, or because attempts were made to suppress a target that can be compensated for by redundant pathways, but many failed in efficacy, indicating that the translational value of the current models is seriously questionable. All existing animal models of endometriosis do not recapitulate the key features of human conditions.. The glaring innovation drought in drug R&D for endometriosis/adenomyosis should sound alarms to all stake-holders. The failed clinical trials in endometriosis also indicate that some past research had serious deficiencies. In light of the recent understanding of the natural history of ectopic endometrium, it is perhaps time to shift the research paradigm and revamp our research focus and priorities.

Topics: Adenomyosis; Clinical Trials as Topic; Drug Development; Endometriosis; Female; Hormone Antagonists; Humans; Infliximab; Oxazoles; Progesterone; Raloxifene Hydrochloride; Treatment Outcome

The aim of the present study was to assess the anti-inflammatory effects of selective ER beta (ER beta) agonist on lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS) production in peritoneal macrophages (PMs) of endometriosis (EMS).. ER alpha (ER alpha) and ER beta expressions in PMs were analyzed by RT-PCR and immunoblot. The PMs of endometriosis were exposed to increasing concentrations of ER beta agonist ERB-041 over a period from 0.5 to 8h before stimulation with LPS and the levels of iNOS protein were evaluated by immunoblot. Subsequently, the PMs were pretreated with vehicle, ERB-041 or ER alpha agonist PPT before exposing to LPS. iNOS expression, p65 protein and active extracellular signal-regulated kinases (ERKs) level accumulated in the nuclear were detected by immunoblot. For experiment investigating the role of ERKs in LPS-induced iNOS expression, the PMs were pretreated with U0126, a specific ERK inhibitor, for 60 min before LPS treatment and iNOS expression was detected by immunoblot.. The PMs of EMS expressed ER beta to a greater extent compared with normal women. Pretreatment the PMs with ERB-041 resulted in a significant inhibition of LPS-induced iNOS expression and NF-kappaB activation by preventing its nuclear translocation. The ERKs pathway was involved in the LPS-induced iNOS production and was not repressed by the activation of ERs.. The inhibitory effect of ER beta agonist on LPS-induced iNOS production in PMs of EMS is likely mediated via repressing of nuclear factor-kappa B (NF-kappaB) but not ERKs signaling pathways.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Cells, Cultured; Endometriosis; Estrogen Receptor beta; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Lipopolysaccharides; Macrophage Activation; Macrophages, Peritoneal; NF-kappa B; Nitric Oxide Synthase Type II; Oxazoles; Signal Transduction

Endometriosis is a common gynaecological problem of uncertain aetiology. It affects primarily young, reproductive-aged women and can result in chronic pelvic pain and infertility. Current approved therapies have significant side-effects and hysterectomy is employed as a final solution. ERB-041 is a selective estrogen receptor-beta (ERbeta) agonist that has anti-inflammatory activity in preclinical models of arthritis and inflammatory bowel disease, but is inactive in many preclinical models of classic estrogen activity. Because endometriosis is now thought to be, at least in part, an inflammatory disease, we evaluated ERB-041's activity in an experimentally induced model of endometriosis.. Athymic nude mice (ovariectomized or intact) were implanted with tissue fragments of normal human endometrium. After establishment of lesions for 11-14 days, mice were treated with ERB-041 for 15-17 days. Upon euthanasia, the number of lesions, their size and location were noted. Five lesions were recovered for RNA analysis.. Across six studies, ERB-041 caused complete lesion regression in 40-75% of the mice studied. The compound appeared to be equally effective in gonad-intact as in ovariectomized mice, and analysed recovered lesions expressed ERalpha but not ERbeta mRNA.. ERB-041 and possibly other ERbeta selective agonists may be a useful new approach to treating endometriosis.

Topics: Adolescent; Adult; Animals; Biopsy; Disease Models, Animal; Endometriosis; Endometrium; Estrogen Receptor beta; Female; Humans; Mice; Mice, Nude; Middle Aged; Organ Culture Techniques; Ovariectomy; Oxazoles; RNA, Messenger