CARDIO-TTTransform Fallout: NT Impact Slight Pos, Big LT Overhang *SLIDES*

Research evidence excerpt

CARDIO-TTTransform Fallout: NT Impact Slight Pos, Big LT Overhang *SLIDES*

Faisal Khurshid | 212-707-6341 | FaisalTeam@jefferies.com

While the CARDIO-TTRansform failure may be a near-term incremental pos

Amvuttra growth 2027–31, outlook post-2031 is challenging given q’s on

silencer positioning post-generic taf entry + risk on nucresiran’s TRITON-CM

Key debates JEF Findings

What happens to ALNY’s TTR franchise We see some NT upside to Amvuttra ATTR-CM revenue as the only marketed silencer,, though

financially, now that eplontersen will generic tafamidis could pressure ALNY’s TTR franchise beyond 2031 as the incremental benefit

not be on the market? of silencers vs stabilizers is a major question and we model declining sales 2031 onwards

To what extent was CARDIO-

Eplontersen’s nominal monotherapy statistical significance in a healthier/contemporary ATTR-CM

TTRansform’s miss driven by

population supports drug activity, suggesting the miss was likely driven by background stabilizer

background stabilizer use versus

use >> this reads through negatively to the role of silencers vs stabilizers and to TRITON-CM

healthier patient enrollment?

TRITON-CM is better positioned than CARDIO-TTRansform given its larger size, event-driven

What design advantages does TRITON-

design, and targeted patient selection, with further upside from design updates (e.g., tafamidis

CM have versus prior ATTR-CM trials?

cap, endpoint optimization), although risk remains most notably to timing of events

How much incremental benefit could

Nucresiran’s ~90% placebo-adjusted TTR reduction outperforms prior silencers, and the ATTR-PN

nucresiran provide, and would it

correlation between lower serum TTR and improved outcomes suggests deeper knockdown

translate into meaningful clinical