Date: 2014-09-12
Type of information: Presentation of results at a congress
phase: preclinical
Announcement: presentation of results at the American Heart Association\'s High Blood Pressure Research 2014 Scientific Sessions
Company: Alnylam Pharmaceuticals (USA - MA)
Product: ALN-AGT
Action
mechanism: ALN-AGT is a subcutaneously administered RNAi therapeutic targeting angiotensinogen (AGT) for the treatment of hypertensive disorders of pregnancy (HDP), including preeclampsia, one of the most common complications of pregnancy. AGT, which is primarily expressed in the liver, is the protein precursor for angiotensin II, a peptide hormone that promotes vasoconstriction as part of the renin-angiotensin system. Gain-of-function human mutations or variants of AGT are associated with increased risk for hypertension and preeclampsia in pregnant women. Small molecule inhibitors of the renin-angiotensin system, such as angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) are known to cross the placental barrier and are associated with fetal toxicity. Accordingly, ACE inhibitors and ARBs are contraindicated for the management of hypertension during pregnancy.
Disease: hypertensive disorders of pregnancy (HDP), including preeclampsia
Therapeutic area: Cardiovascular diseases - Women health
Country:
Trial details:
Latest
news: * On September 12, 2014, Alnylam Pharmaceuticals announced that it is broadening its pipeline with ALN-AGT, a subcutaneously administered RNAi therapeutic targeting angiotensinogen (AGT) for the treatment of hypertensive disorders of pregnancy (HDP), including preeclampsia, one of the most common complications of pregnancy. In a poster presented at the American Heart Association\'s High Blood Pressure Research 2014 Scientific Sessions, Alnylam and collaborators at the Charité - Universitätsmedizin in Berlin presented results of an ALN-AGT lead molecule in an established preeclamptic rodent model. The study showed that administration of ALN-AGT resulted in knockdown of maternal AGT in the liver without detectable evidence of fetal drug exposure, significantly improved pregnancy-related hypertension, ameliorated preeclamptic sequelae in the mother such as proteinuria, and improved fetal outcomes. Alnylam and collaborators presented results of a pre-clinical study entitled \"RNAi Therapeutics Targeting Human Angiotensinogen (hAGT) Ameliorate Preeclamptic Sequelae in an Established Transgenic Rodent Model for Preeclampsia.\" A GalNAc-siRNA conjugate targeting human AGT was designed and synthesized using Alnylam\'s ESC-GalNAc-conjugate delivery platform, which enables subcutaneous delivery of RNAi therapeutics with a wide therapeutic index. In a transgenic rat model of preeclampsia, subcutaneous administration of the lead ALN-AGT molecule resulted in silencing of human AGT in maternal liver by over 90%, reduced mean arterial blood pressure by approximately 20 mmHg, and attenuated proteinuria by greater than 80%; elevated blood pressure and proteinuria are established hallmarks of preeclampsia. ALN-AGT administration also reduced additional manifestations of the preeclamptic phenotype in the mother, including activity levels of agonistic angiotensin 1 receptor autoantibodies and maternal kidney mRNA expression of soluble fms-like tyrosine kinase-1 (sflt-1), which were reduced by approximately 90% and 75%, respectively. Preeclampsia is also known to be associated with abnormal placentation - dysfunction in the interface between mother and fetus - and reduced placental size associated with impaired fetal growth. In the pre-clinical model, administration of ALN-AGT was associated with improved uteroplacental unit weight, increased overall fetal weight, and normalized fetal brain to liver ratio. In aggregate, these results showed that ALN-AGT administration improved fetal outcomes. Finally, quantitative measurements of ALN-AGT drug levels in the maternal and fetal liver were performed. Results showed that while significant levels ( > 20 μg/g liver) of ALN-AGT could be detected in the maternal liver, levels of ALN-AGT in the fetal liver were below the lower limit of quantitation for the assay ( < 0.0013 μg/g liver). These results are consistent with published data for large macromolecules such as siRNA, in addition to current company data showing that RNAi therapeutics do not cross the placental barrier.
