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Executive Summary

First-in-class RNAi therapeutic achieving 80% triglyceride reduction with quarterly dosing

Plozasiran

APOC3 · RNAi (siRNA)

Approved (FCS) / Phase 3 (sHTG) Partnered with Amgen

Target: APOC3

Full NameApolipoprotein C-III

PathwayTriglyceride metabolism

See Target Biology →

Mechanism of Action

TypeRNAi (siRNA) via TRiM platform

DescriptionPlozasiran is a GalNAc-conjugated siRNA that is taken up specifically by hepatocytes via the asialoglycoprotein receptor. Once inside, it engages the RISC machinery to catalytically degrade APOC3 mRNA, reducing APOC3 protein production by >90%.

DifferentiationEach siRNA molecule can degrade multiple mRNA transcripts, enabling potent and durable knockdown with quarterly dosing

Indications: Familial Chylomicronemia Syndrome (FCS)Severe Hypertriglyceridemia (sHTG)Mixed Hyperlipidemia

Target Biology

APOC3 is a protein that inhibits lipoprotein lipase (LPL), the enzyme that clears triglycerides from the blood. By silencing APOC3 with RNAi, plozasiran unleashes LPL activity, dramatically accelerating clearance of triglyceride-rich lipoproteins.

Human Genetic Evidence: APOC3 LoF carriers have lower TG, lower coronary heart disease

Clinical Data

SHASTA-3

Phase 3 Active, not recruiting Target n=

Indication: Severe Hypertriglyceridemia

Design:

Population:

Primary Endpoint:

Data Expected: 2026

SHASTA-4

Phase 3 Active, not recruiting Target n=

Indication: Severe Hypertriglyceridemia

Design:

Population:

Primary Endpoint:

Data Expected: 2026

SHASTA-5

Phase 3 Recruiting Target n=

Indication: Severe Hypertriglyceridemia

Design:

Population:

Primary Endpoint:

Data Expected: 2026

SHASTA-10

Phase 3 Recruiting Target n=

Indication: Severe Hypertriglyceridemia

Design:

Population:

Primary Endpoint:

Data Expected:

MUIR-3

Phase 3 Active, not recruiting Target n=

Indication: Mixed Hyperlipidemia

Design:

Population:

Primary Endpoint:

Data Expected:

PALISADE

n=?

Design: Randomized, double-blind, placebo-controlled

Population: FCS patients

SHASTA-2

n=?

Design: Randomized, double-blind, placebo-controlled, dose-ranging

Population: Patients with severe hypertriglyceridemia

Investment Analysis

Satya Bio Analysis — estimates based on public data and analyst judgment, not sourced from company materials

Bull Case

Thesis Point	Supporting Evidence	Confidence
First-in-class RNAi for APOC3 with best-in-class 80% TG reduction	PALISADE Phase 3: -80% TG, 83% pancreatitis risk reduction	High - Fda Approved
sHTG represents 10x larger market opportunity	~500K US patients vs ~3K for FCS	High - If Trials Succeed
Amgen partnership provides experienced CV sales force	Amgen has established cardiometabolic commercial infrastructure	High
Durable quarterly dosing improves compliance	Q12W dosing vs weekly for volanesorsen	High

Bear Case

Risk	Evidence	Mitigating Factors
FCS is a tiny orphan market	~3,000 US patients limits near-term revenue	sHTG is the real commercial opportunity
Competition from olezarsen (Ionis)	Tryngolza approved Dec 2024 for FCS	Plozasiran has higher TG reduction (80% vs 60%)
Amgen controls commercialization	Majority economics flow to partner	Royalties still meaningful on multi-billion market
No CV outcomes data yet	TG reduction is surrogate, not hard endpoint	Genetic validation of APOC3 LoF and CV risk

Key Debates

Question	Bull View	Bear View	Resolution Catalyst
Will Phase 3 sHTG trials succeed?	Phase 2 data strong (-77%), mechanism validated	Larger trials may show safety signals or less efficacy	SHASTA-3/4/5 data in 2026

Market Opportunity

Competitive Advantage
Best-in-class TG reduction (80% vs ~60% for olezarsen), favorable safety vs volanesorsen

Catalysts & Upcoming Events

Event	Timing	Importance	Key Metrics to Watch	Consensus
sHTG PDUFA decision	H1 2026	Critical	Approval for larger sHTG market	—
SHASTA-3 topline data	2026	High	TG reduction in sHTG population	—
SHASTA-4 topline data	2026	High	TG reduction in sHTG population	—
Plozasiran sHTG PDUFA decision	H1 2026	critical	—	—
SHASTA-3/4 Phase 3 sHTG data	2026	high	—	—

Data sourced exclusively from public filings, corporate presentations, and published clinical data. For informational purposes only. Not investment advice. Satya Bio does not provide recommendations to buy or sell securities. Terms · Privacy