retosiban (GSK-221,149-A) / GSK - LARVOL DELTA

New medicines for spontaneous preterm birth prevention and preterm labour management: landscape analysis of the medicine development pipeline. (PubMed, BMC Pregnancy Childbirth) - "This analysis provides a drug-agnostic approach to assessing the potential of candidate medicines for spontaneous preterm birth. Research should be prioritised for high-potential candidates that are most likely to meet the real world needs of women, babies, and health care professionals."

Journal

Identification of potential therapeutic intervening targets by in-silico analysis of nsSNPs in preterm birth-related genes. (PubMed, PLoS One) - "Blind docking approach were used to search the binding cavities and molecular interactions with progesterone, ranked with energetic estimations. Further, molecular docking experimentation of CNN1 showed the significant interactions at S102, L105, A106, K123, Y124 with five selected PTB-drugs, Allylestrenol (-7.56 kcal/mol), Hydroxyprogesterone caproate (-8.19 kcal/mol), Retosiban (-9.43 kcal/mol), Ritodrine (-7.39 kcal/mol) and Terbutaline (-6.87 kcal/mol). Calponin-1 gene and its molecular interaction analysis could serve as an intervention target for the prevention of PTB."

Journal • CNN1 • Collagen Type IV • SLIT2

Oxytocin antagonists for assisted reproduction. (PubMed, Cochrane Database Syst Rev) - "We are uncertain whether intravenous atosiban improves pregnancy outcomes for women undergoing assisted reproductive technology. This conclusion is based on currently available data from seven RCTs, which provided very low- to low-certainty evidence across studies. We could draw no clear conclusions about subcutaneous barusiban, based on limited data from one RCT. Further large well-designed RCTs reporting on live births and adverse clinical outcomes are still required to clarify the exact role of atosiban and barusiban before ET. Oral nolasiban appears to improve clinical pregnancy rate but not live birth rate, with an uncertain effect on miscarriage and adverse events. This conclusion is based on a phased study comprising three trials that provided low- to high-certainty evidence. Further large, well-designed RCTs, reporting on live births and adverse clinical outcomes, should focus on identifying the subgroups of women who are likely to benefit from this intervention."

Journal • Review • Gynecology

Safety and Outcomes in Infants Born to Mothers Participating in Retosiban Treatment Trials: ARIOS Follow-Up Study. (PubMed, Am J Perinatol) - "· There is a need for an effective and safe treatment for sPTL. · ARIOS was a follow-up study of two Phase 3 trials in sPTL. · There were no safety concerns with retosiban treatment. · Slow recruitment led to termination of the Phase 3 trials."

Clinical • Journal • Autism Spectrum Disorder • Developmental Disorders • Genetic Disorders • Infectious Disease

Erratum: Randomized Trials of Retosiban versus Placebo or Atosiban in Spontaneous Preterm Labor. (PubMed, Am J Perinatol) - No abstract available

Clinical • Journal

Novel oxytocin receptor antagonists for tocolysis: a systematic review and meta-analysis of the available data on the efficacy, safety, and tolerability of retosiban. (PubMed, Curr Med Res Opin) - "With the limited high quality evidence available, retosiban demonstrates no clear benefit over placebo in the management of preterm labor. Nevertheless, its favorable safety profile, oral bioavailability, and novel mechanism of action and the limited number of studies available for review warrant further analysis."

Clinical • Journal • Retrospective data • Review • Constipation • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Hepatology • Infectious Disease • Nephrology • Pain

Crystal structure of the human oxytocin receptor. (PubMed, Sci Adv) - "Here, we report the crystal structure of human OTR in complex with retosiban, a nonpeptidic antagonist developed as an oral drug for the prevention of preterm labor...Furthermore, our structure in combination with experimental data allows the identification of a conserved neurohypophyseal receptor-specific coordination site for Mg that acts as potent, positive allosteric modulator for agonist binding. Together, these results further our molecular understanding of the oxytocin/vasopressin receptor family and will facilitate structure-guided development of new therapeutics."

Journal

Functionally selective inhibition of the oxytocin receptor by retosiban in human myometrial smooth muscle. (PubMed, Endocrinology) - "Retosiban and epelsiban demonstrate distinct pharmacology when compared to atosiban in human myometrial smooth muscle. Atosiban displays agonist activity at micromolar concentrations leading to stimulation of prostaglandin production."

Journal • Infectious Disease

A Phase III Efficacy and Safety Study of Intravenous Retosiban Versus Placebo for Women in Spontaneous Preterm Labor (clinicaltrials.gov) - P3; N=900; Not yet recruiting; Sponsor: GlaxoSmithKline; Initiation date: Apr 2015 ->Jul 2015

Trial initiation date • Biosimilar

Follow up Study to Assess Long Term Safety and Outcomes in Infants Born to Mothers Participating in Retosiban Treatment Studies (clinicaltrials.gov) - P=N/A; N=2100; Recruiting; Sponsor: GlaxoSmithKline; Not yet recruiting -> Recruiting

Enrollment open • Biosimilar

Randomized Trials of Retosiban Versus Placebo or Atosiban in Spontaneous Preterm Labor. (PubMed, Am J Perinatol) - " Despite considerable efforts to conduct two adequate and well-controlled studies in patients with sPTL, both studies were unable to recruit effectively and consequently terminated prematurely. Key factors negatively affecting participation were patient and physician resistance to use of a placebo comparator, lack of investigator consensus on diagnostic criteria and acceptance of protocol procedures, and ethics committee decisions. Meaningful cooperation between pharmaceutical companies, regulatory authorities, and the obstetric community is essential for future development of drugs to treat sPTL."

Clinical • Journal

ARIOS: Follow up Study to Assess Long Term Safety and Outcomes in Infants and Children Born to Mothers Participating in Retosiban Treatment Studies (clinicaltrials.gov) - P3; N=99; Completed; Sponsor: GlaxoSmithKline; Active, not recruiting ➔ Completed; N=2100 ➔ 99

Clinical • Enrollment change • Trial completion

ARIOS: Follow up Study to Assess Long Term Safety and Outcomes in Infants and Children Born to Mothers Participating in Retosiban Treatment Studies (clinicaltrials.gov) - P3; N=2100; Active, not recruiting; Sponsor: GlaxoSmithKline; Phase classification: P2/3 ➔ P3; Trial completion date: Jul 2022 ➔ Jul 2019; Trial primary completion date: Jul 2022 ➔ Jul 2019

Clinical • Phase classification • Trial completion date • Trial primary completion date

Production and characterization of 2,5-diketopiperazines produced by the cyclodipeptide synthase SNC-109 (ACS-Sp 2019) - "DKPs serve as precursors to common pharmaceuticals, such as the oxytocin receptor antagonist Retosiban and the vasodilator Cialis (Tadalafil). One major product is preliminarily identified as cyclo (Pro-Tyr). There are approximately 2 other compounds produced that further chemical analysis will aim to identify."