Alnylam adds HDP treatment ALN-AGT to strengthen pipeline

Preeclampsia is one of the most common complications of pregnancy and it leads to increased risk of maternal mortality, perinatal fetal mortality, fetal pre-maturity, or even the need for late-term abortion to save the mother’s life.

AGT is the protein precursor for angiotensin II, a peptide hormone that promotes vasoconstriction as part of the renin-angiotensin system and it is primarily expressed in the liver.

Recently, the company and collaborators at the Charité – Universitätsmedizin in Berlin have reported results of an ALN-AGT lead molecule in an established preeclamptic rodent model.

According to the results, 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 vice president of Research and RNAi Lead Development (RLD) Rachel Meyers said ALN-AGT, the company’s new cardio-metabolic program targeting angiotensinogen, exemplifies this strategy since human gain-of-function AGT variants are associated with preeclampsia and also more broadly with hypertension.

"New therapies are clearly needed to prevent or treat HDP, including preeclampsia, since existing small molecule anti-hypertensive drugs readily cross the placental barrier and can cause fetal toxicity," Meyers said.

"The new pre-clinical data demonstrate that an RNAi therapeutic targeting AGT ameliorates the clinical sequelae of preeclampsia and improves outcomes for the fetus in an established transgenic rat model.

"This treatment approach has the potential for selective delivery to the pregnant mother without fetal drug exposure, as our study has confirmed undetectable siRNA levels in the fetus.

"We look forward to advancing ALN-AGT as a highly innovative approach for the management of HDP and preeclampsia."