With two cardiovascular disease candidates in or near phase 3, RNAi specialist Arrowhead Pharmaceuticals has dropped one prospect and thrown its weight behind the other to manage its spending.
Arrowhead’s cardiometabolic disease pipeline is led by plozasiran and zodasiran, RNAi molecules that hit different targets: APOC3 and ANGPTL3, respectively, but have similar uses. Both molecules are designed to boost cardiovascular health by reducing levels of molecules such as triglycerides and lipoproteins that drive disease.
The biotech took both assets through midphase development. But, with a big cardiovascular outcome study next on the agenda, management has decided it can no longer back both horses. The end result is that plozasiran is in, while zodasiran is out.
On a call with investors, Vincent Anzalone, head of investor relations at Arrowhead, framed the decision as being more about what’s right about plozasiran than what’s wrong with zodasiran. Plozasiran has generated compelling data in three settings, Anzalone said, and funding all of them could position Arrowhead to launch in progressively larger indications and stagger its commercial expansion.
The fact plozasiran acts on triglycerides, while zodasiran is a LDL cholesterol drug, was another factor. Bruce Given, M.D., chief medical scientist at Arrowhead, said the cardiovascular disease drug market was different when the company was choosing whether to focus on APOC3, ANGPTL3 or both targets.
“In the 2016, 2017 time frame, we didn’t have PCSK9s. We didn’t have the Regeneron antibody against ANGPTL3. We didn’t have bempedoic acid. We really were pretty much having statins,” Given said. “Now there’s actually a lot of drug availability over on the LDL side, a lot of competition for these patients.”
In contrast, there is “still a relative desert with respect to the ability to really treat high triglycerides,” the Arrowhead executive said. Given sees plozasiran as a drug that can address unmet needs in a range of people, from symptomatic patients with pancreatitis through asymptomatic atherosclerotic individuals with mixed hyperlipidemia or severe hypertriglyceridemia.
While Arrowhead is putting its own money behind plozasiran, the company hopes to find a partner for the now-deprioritized zodasiran. Given wants to see “somebody with the deep enough resources and large enough commercial apparatus that they could actually go compete in that LDL space” pick up the candidate and take it to market.
“There are a lot of drugs over there, but they’re not perfect. We do believe zodasiran in a perfect world, if you could snap your fingers and make it available, would be a big contribution in that space. But it’s really beyond our capabilities at this time to prosecute it,” the executive said.
The decision frees up Arrowhead to bet big on plozasiran. With a pivotal win in one setting positioning Arrowhead to bring plozasiran to market in 2025, the biotech is pushing ahead with other trials including a phase 3 cardiovascular outcomes study. The outcomes trial will mainly enroll people who have already had a cardiovascular event in the past but will also include a smaller primary prevention cohort.