Arrowhead Pharmaceuticals is mulling what’s next for a pair of RNA interference therapies after reporting positive data from separate mid-stage trials in mixed hyperlipidemia.
As RNAi treatments, both candidates target the cell’s RNAi mechanism to knock down specific genes responsible for producing certain proteins. But the first treatment, dubbed plozasiran, targets apolipoprotein C-III, while the other, named zodasiran, zeroes in on angiopoietin-like proteins.
The biotech has conducted an “exhaustive analysis internally and with external advisors” on a potential path forward for both treatments and has proposed this to regulators, with plans to finalize and disclose its strategy later this year, a spokesperson said in an emailed statement.
With different targets, the RNAi therapeutics have slightly different effects on various lipids and atherogenic lipoproteins, meaning they could be advanced for different patient populations, the spokesperson said.
Arrowhead’s separate Phase 2b data for both candidates, presented at the European Atherosclerosis Society’s annual meeting this week, could warrant further investigation into cardiovascular outcomes in mixed hyperlipidemia, the spokesperson added.
In its Phase 2b ARCHES-2 trial, the highest 200 mg dose of zodasiran achieved a 63% placebo-adjusted reduction in triglyceride levels at 24 weeks (p<0.001), according to a Wednesday release. It was also linked with a 20% reduction in LDL-C or “bad” cholesterol, a 22% reduction in apolipoprotein B (ApoB) and a 36% reduction in non-HDL-C.
Apolipoprotein B plays a key role in the breakdown of lipids into cholesterol in the liver. Non-HDL-C is a measure of all the cholesterol in the body minus the “good” cholesterol known as HDL-C.
Separately, in the Phase 2b MUIR study, the highest 50 mg dose of plozasiran attained a 62% placebo-adjusted reduction in triglyceride levels at 24 weeks (p<0.001), according to a Tuesday release. It also led to a 19% reduction in ApoB and a 24% reduction in non-HDL-C.
The biotech has already completed a Phase 3 trial of plozasiran in patients with a rare fat metabolism disorder known as familial chylomicronemia syndrome (FCS), with topline data due to be released within the next month before a planned NDA filing at the end of the year. Patients with FCS have extremely high triglyceride levels of more than 750 mg/dL. The ideal level of triglycerides is less than 150 mg/dL.
Plozasiran is also currently under study in the registrational SHASTA-3 and SHASTA-4 trials in patients with severe hypertriglyceridemia, who have triglyceride levels of at least 500 mg/dL.
Further Phase 3 tests of both therapies are planned for later this year, including one for zodasiran in the genetic disorders homozygous and heterozygous familial hypercholesterolemia (HoFH/HeFH). HoFH patients have bad cholesterol levels of between 400 and 1,000 mg/dL while HeFH patients’ levels sit at the 190 mg/dL range. The ideal level of LDL-C for adults is less than 100 mg/dL.
Both zodasiran and plozasiran have a “favorable safety profile” in the Phase 2b mixed hyperlipidemia trials, according to Arrowhead.