ARWR Completes YOSEMITE Zodasiran Enrollment in HoFH

Arrowhead Pharmaceuticals (ARWR) announced on July 27, 2026 that it has completed patient enrollment in the global Phase 3 YOSEMITE trial of zodasiran, an investigational RNA interference (RNAi) therapy for homozygous familial hypercholesterolemia (HoFH). The study enrolled 70 patients, exceeding its original 60-participant target. Study completion is anticipated in mid-2027.

What the trial is testing

YOSEMITE (NCT07037771) is a global, multicenter, randomized, double-blind, placebo-controlled Phase 3 study. Patients age 12 and older with genetically or clinically diagnosed HoFH were randomized 2:1 to receive 200 mg zodasiran or placebo as a subcutaneous injection once every three months for four doses. After month 12, eligible participants can continue in an optional open-label extension.

HoFH is a rare genetic disorder causing severely elevated low-density lipoprotein cholesterol (LDL-C) from birth, affecting roughly 1 in 300,000 people. The condition drives early-onset atherosclerotic cardiovascular disease, often before age 20. Current treatments include high-intensity statins, PCSK9 inhibitors, evinacumab (Regeneron), and lomitapide, but many patients still fail to reach LDL-C targets.

Zodasiran uses RNAi to silence the gene producing ANGPTL3, a protein that inhibits triglyceride and cholesterol clearance. The approach is similar to Ionis’ population-level targeting of the same pathway with olezarsiran, though zodasiran is specific to Arrowhead’s TRiM RNAi platform.

Why this matters

Zodasiran is the second RNAi candidate in Arrowhead’s cardiometabolic pipeline to reach Phase 3, following plozasiran, which reported positive Phase 3 SHASTA-3/4 results on July 22. Plozasiran targets severe hypertriglyceridemia and is already approved as REDEMPLO for familial chylomicronemia syndrome. Arrowhead plans to file an sNDA for broader sHTG before year-end 2026.

The two drugs address different lipid abnormalities. Plozasiran targets triglycerides; zodasiran targets LDL cholesterol in a rare, high-unmet-need population. A successful YOSEMITE readout would expand Arrowhead’s cardiometabolic franchise from one drug to two, each addressing a distinct patient population.

Risk factors

The HoFH population is small, which limits the commercial opportunity even if zodasiran is approved. Orphan Drug designation is likely but does not guarantee commercial success. Evinacumab and lomitapide are already FDA-approved for HoFH, and both have significant limitations: lomitapide carries a black box warning for hepatotoxicity, and evinacumab requires IV infusion every four weeks. Zodasiran’s subcutaneous dosing could differentiate, but the data must show meaningful LDL-C reduction on top of maximally tolerated lipid-lowering therapy.

What to watch next

YOSEMITE study completion in mid-2027 is the next catalyst. Arrowhead must demonstrate that zodasiran produces a clinically meaningful LDL-C reduction in this difficult-to-treat population, with a clean safety profile. The open-label extension data will also inform durability.

ARWR closed at $85.53 on July 25, 2026.

What It Means for the Trade

Enrollment completion is a timeline catalyst, not a data catalyst — it converts a vague “Phase 3 ongoing” line into a dated binary: study completion mid-2027, data shortly after. Topping the 60-patient target at 70 patients matters for a different reason than optics: in a disease with roughly 1-in-300,000 prevalence, 70 genetically or clinically diagnosed HoFH patients across global sites is a meaningful share of the identifiable worldwide trial-eligible population. That has two implications. First, the dataset will be among the more complete pictures of this population ever assembled — good for regulators and label claims. Second, and less comfortable, HoFH is so small that competitors building their own HoFH programs will face a genuinely constricted recruitment pool; the company that reads out first effectively sets the standard-of-care question for the whole field.

For ARWR the near-term valuation driver is not zodasiran anyway. Plozasiran’s sNDA for broader severe hypertriglyceridemia before year-end 2026 is the nearer catalyst, and YOSEMITE is the 2027 story. The read-through between them is platform-level: two TRiM-platform RNAi drugs in Phase 3 in cardiometabolic disease is the proof-of-platform argument that distinguishes Arrowhead from single-asset RNAi stories, and enrollment completion on schedule is a quiet operational signal that the platform’s trial-execution machinery works.

Mechanism and Competitive Context

Zodasiran’s target choice is the strategically interesting part. ANGPTL3 inhibition is a genetically validated lipid pathway — humans with loss-of-function ANGPTL3 variants carry low LDL and triglycerides and reduced cardiovascular risk, which is the kind of human genetics evidence that de-risks a target more than any mouse model. RNAi silencing of ANGPTL3 with a once-quarterly subcutaneous injection is a convenient way to pharmacologically mimic that loss-of-function state, and it addresses both LDL-C and triglycerides — a dual-lipid profile that is unusual among LDL-lowering agents.

The competitive positioning against existing HoFH therapy is where the commercial case will be argued. Evinacumab works but is an every-four-week IV infusion; lomitapide is oral but carries a hepatotoxicity black box and demanding GI tolerability. Zodasiran’s pitch is subcutaneous once-every-three-months dosing with, so far, none of those constraints — in a pediatric-onset population where treatment burden across a lifetime is a real driver of adherence. The unanswered question is magnitude: HoFH patients have dramatically impaired LDL clearance, and ANGPTL3 inhibition does not touch the underlying receptor deficiency, so the additive LDL reduction on top of maximally tolerated therapy must be clinically meaningful — not a 10-15% cosmetic effect — for the drug to earn a place in a regimen that already includes statins, PCSK9 inhibitors, and possibly evinacumab.

Risks and What Could Go Wrong

1. Efficacy magnitude risk is the big one: if the placebo-adjusted LDL-C reduction lands in the high-teens or low-20s percent range on top of background therapy, zodasiran is a niche addition in a niche disease, and the commercial model gets written down hard.
2. The population is small enough that a modest number of hepatic or injection-related safety events carries outsized statistical weight; RNAi class-wide hepatic monitoring is routine, and any signal forces the standard workup.
3. Competitive timing: other ANGPTL3-directed assets (Ionis’ olezarsiran targets the same pathway in a different population) could complicate the narrative if a readout in a nearby indication muddies the class’s perceived efficacy.
4. Commercial ceiling: even a best-case approval targets a population measured in low thousands of patients worldwide. Orphan economics can work, but this is a franchise-expansion story for Arrowhead, not a needle-mover alone.

The position read: YOSEMITE is a 2027 binary that supports the platform thesis; the 2026 catalysts (plozasiran sNDA, launch execution) are what move ARWR in the meantime. Size zodasiran as optionality, not as the thesis.

Source: Arrowhead Pharmaceuticals press release | ClinicalTrials.gov YOSEMITE