Patisiran
Details
Patisiran (Onpattro; Alnylam Pharmaceuticals) is a lipid nanoparticle (LNP)-formulated siRNA targeting the 3' untranslated region of TTR mRNA in hepatocytes, reducing production of both wild-type and mutant transthyretin protein. It achieves ~87% serum TTR knockdown. Patisiran is approved for ATTRv polyneuropathy (based on APOLLO, NEJM 2018). It was investigated for ATTR-CM in the APOLLO-B Phase 3 trial (NEJM 2023), which demonstrated preserved functional capacity over 12 months but failed hard composite endpoints due to insufficient duration and power; patisiran was not approved for ATTR-CM on this basis. Its successor vutrisiran (GalNAc-conjugated siRNA, SC Q12W) demonstrated all-cause mortality benefit in ATTR-CM in HELIOS-B 2025.
Key Facts
Mechanism and Delivery
- LNP-mediated hepatic delivery of siRNA complementary to the 3' UTR of TTR mRNA (shared between WT and variant transcripts)
- Silences TTR mRNA → markedly reduces hepatic TTR protein secretion → 86.8% reduction in circulating TTR at 12 months (sources/patisiran-attrcm-apollob-nejm-2023, rating: high)
- Requires IV infusion Q3W (0.3 mg/kg; max 30 mg) with premedication (corticosteroids, antihistamines, acetaminophen) to reduce infusion-related reactions
- Compared with vutrisiran (GalNAc-SC Q12W), patisiran has higher knockdown (87% vs 81%) but requires IV infusion and premedication — inferior delivery for long-term use
APOLLO-B Trial (ATTR-CM, NEJM 2023)
- Phase 3, double-blind RCT; n=360; 12 months; 69 sites, 21 countries; funded by Alnylam; led by Maurer and Gillmore (sources/patisiran-attrcm-apollob-nejm-2023, rating: high)
- Population: ~80% ATTRwt; 25% on background tafamidis; median age 76; mostly male; excluded NYHA III + NAC Stage 3 and NYHA IV
- Primary endpoint (6MWT): median difference +14.69 m (95% CI 0.69–28.69; P=0.02) ✓ — statistically significant but below 30 m MCID
- 1st secondary (KCCQ-OS): LS mean difference +3.7 pts (95% CI 0.2–7.2; P=0.04) ✓ — below 5-pt MCID
- 2nd secondary (composite death/CV events/6MWT): win ratio 1.27 (0.99–1.61); NS ✗
- 3rd secondary (composite death/hospitalisation/urgent HF): HR 0.88 (0.58–1.34); NS ✗
- Deaths: 4 (2.2%) vs 10 (5.6%); HR 0.36 (0.11–1.14); NS — trial underpowered for mortality
- TTR knockdown: 86.8±13.6% at 12 months; consistent on and off background tafamidis
- Exploratory echo/biomarkers: LV mass −9.45 g difference; GLS −0.54 pp; stroke volume +3.00 mL; NT-proBNP ratio 0.80; troponin I ratio 0.87 — all favoring patisiran (hypothesis-generating only)
- Safety: AEs 91% vs 94%; infusion-related reactions/arthralgia/muscle spasms more common; SAEs similar frequency
- Conclusion: 12-month RCT demonstrates preserved functional capacity but insufficient for mortality/hospitalization conclusions; authors concluded longer trials needed
Regulatory Status
- Approved for ATTRv polyneuropathy (US, EU — Onpattro; LNP formulation)
- Not approved for ATTR-CM based on APOLLO-B alone
- Successor vutrisiran (GalNAc-SC): FDA-approved for both ATTRv-PN and ATTR-CM (HELIOS-B 2025 mortality benefit)
Patisiran vs Vutrisiran
| Feature | Patisiran | Vutrisiran |
|---|---|---|
| Delivery | LNP, IV Q3W | GalNAc, SC Q12W |
| TTR knockdown | ~87% | ~81% |
| Premedication | Required (steroids, antihistamine, APAP) | Not required |
| ATTR-CM trial | APOLLO-B (12 months) | HELIOS-B (up to 42 months) |
| Hard composite endpoint | NS | HR 0.72 (P=0.01) |
| All-cause mortality | HR 0.36 NS (underpowered) | HR 0.65 (P=0.01) |
| ATTR-CM approval | No | Yes |
| ATTRv-PN approval | Yes | Yes |
Contradictions / Open Questions
- APOLLO-B was underpowered for mortality: The HR for death (0.36) is numerically impressive but statistically NS (4 vs 10 deaths); does the directional signal represent a real effect that HELIOS-B (vutrisiran) confirmed, or is it a chance finding? The successor agent's mortality benefit supports the RNAi class mechanism, but patisiran itself was not tested in a sufficiently powered ATTR-CM mortality trial (sources/patisiran-attrcm-apollob-nejm-2023, rating: high)
- Clinical significance of primary endpoint: 14.69 m 6MWT improvement is statistically significant but below the 30 m MCID. Whether this represents a clinically meaningful functional benefit or merely proof-of-mechanism is debated (sources/patisiran-attrcm-apollob-nejm-2023, rating: high)
- Patisiran vs vutrisiran — is TTR knockdown the key or is delivery the key? Patisiran achieves higher knockdown (87% vs 81%) but vutrisiran demonstrated mortality benefit while patisiran did not. This may reflect trial duration (36+ months vs 12 months) rather than drug potency; impossible to disentangle with current data (sources/patisiran-attrcm-apollob-nejm-2023)
Connections
- Related to entities/ATTR-Amyloidosis — disease entity; APOLLO-B trial target
- Related to entities/Vutrisiran — successor GalNAc-SC siRNA; HELIOS-B 2025 mortality benefit in ATTR-CM
- Related to concepts/TTR-Stabilizer-Therapy — stabilizer class vs RNAi class comparison