Arrowhead Reports One Injection Cut LDL and Triglycerides in 31-Patient Phase 1 Trial

On Saturday, Nov. 7, Cleveland Clinic cardiologist Luke Laffin, M.D., presented the first full clinical dataset for ARO-DIMER-PA at the American Heart Association Scientific Sessions in Chicago. The drug, from Arrowhead Pharmaceuticals (NASDAQ: ARWR), is an experimental RNA interference therapy. It is built to silence two genes, PCSK9 and APOC3, with one molecule.

PCSK9 is tied to LDL, the "bad" cholesterol. APOC3 is tied to triglyceride-rich fats. Patients with mixed hyperlipidemia have both problems, and the Cleveland Clinic says they typically need more than one medication to treat them.

What the trial found

The data come from the single-ascending-dose part of a randomized, double-blind, placebo-controlled study. Thirty-one patients received either placebo or one of five doses of ARO-DIMER-PA, ranging from 25 mg to 400 mg.

Across doses, the results rose with the dose:

• PCSK9 protein fell 50% to 89%.
• APOC3 protein fell 43% to 95%.
• LDL cholesterol fell 26% to 65%.
• Triglycerides fell 56% to 78%.

In a Sept. 15 release, Arrowhead gave the headline interim figures as mean maximal reductions. PCSK9 gene knockdown was 72% and APOC3 gene knockdown was 88%. LDL cholesterol fell 54% and triglycerides fell 73%. Non-HDL cholesterol fell 61% and ApoB fell 50%.

"These results show for the first time that one drug can successfully block two separate disease pathways in the liver at once," Laffin said. He added that the drug also lowered ApoB and remnant cholesterol, "suggesting wide-ranging benefits for heart health."

Safety and the limits of the study

The Cleveland Clinic said the drug was generally safe and well tolerated across the doses tested. The 400 mg dose produced more side effects. The most common was redness at the injection site.

This was a Phase 1/2a study enrolling up to 78 adults. Part 1, the single-dose portion, is complete. The presentation covered interim results from the single-dose cohorts. The multiple-dose portion has not been presented.

The trial measured lab values, not outcomes. No one has shown that lowering both targets at once prevents a heart attack, a stroke, or a death.

Laffin was careful on that point. "These findings support continued evaluation of dual PCSK9/APOC3 inhibition as a potential single-agent strategy for mixed hyperlipidemia," he said. Continued evaluation is a long way from approval.

The Cleveland Clinic and Arrowhead are also the main sources of the numbers. The Clinic's release is its own account of its own study, and the company's figures come from a sponsor press release. No independent review of the dataset has been published.

The company's pitch

Arrowhead CEO Chris Anzalone, Ph.D., said the drug extends the company's TRiM (Targeted RNAi Molecule) platform "by targeting two genes with a single RNAi molecule, with the goal of addressing both LDL cholesterol and triglyceride-rich lipoproteins in people with mixed hyperlipidemia."

The Cleveland Clinic says other siRNA cholesterol drugs silence only one gene, either PCSK9 or APOC3. It describes this as the first data from a dual-function siRNA that silences both.

Steven Nissen, M.D., also of the Cleveland Clinic, had said earlier that mixed hyperlipidemia "is not adequately addressed by treating LDL-C alone." He called the drug "a new approach to targeting multiple lipid abnormalities with a single therapy."

Plozasiran data at the same session

The same session included a pooled analysis of the SHASTA-3 and SHASTA-4 trials of plozasiran, presented by Christie Ballantyne, M.D., of Baylor College of Medicine and Houston Methodist. Arrowhead's already-approved RNAi drug targets APOC3 and is marketed as REDEMPLO.

Arrowhead Chief Medical Officer James Hamilton, M.D., said the analysis found plozasiran reduced acute pancreatitis event rates by 78% overall versus placebo. Among patients who had pancreatitis within five years before screening, the reduction was 91%.

Hamilton also said the PALISADE long-term extension showed sustained triglyceride and APOC3 reductions through up to three years of treatment in patients with familial chylomicronemia syndrome.

Those are company-reported figures from trial analyses presented at a medical meeting. Arrowhead frames them as evidence that looking beyond triglyceride levels alone matters for pancreatitis risk.

What comes next

The next test is the multiple-dose cohorts in Part 2 of the study. They will show whether repeat dosing holds the reductions and whether the side-effect picture at higher doses changes. Arrowhead has not announced when that data will be presented.

After that comes the harder question: whether a single injection that moves LDL and triglycerides this much can be shown to reduce cardiovascular events in a large outcomes trial.