泛欧制药概要：ATTR的“蛋白质扼杀”疗法——为何AZN将引领这一200亿美元的心脏市场

Pan-Euro Pharma Primer: 'protein strangling' (ATTR): why shouldAZN (O) lead in this $20bn peak cardio market? Despite the strong launch of Amvuttra (Alnylam; ALNY; O; Will Pickering; consensus peak$9bn), ‘protein strangling’ of the heart (ATTR-CM) has a 5-year survival worse than manysevere cancers as US diagnosis is just 25%. Consensus (Bloomberg throughout) projectsALNY & AZN to capture ATTR-CM peak shares of 55% and 12% respectively. But postexpert calls, we see four reasons why AZN should lead in this $20bn peak market, whichwould drive upside surprise for this stock1/AZN is the only company with all 3 validateddrug mechanisms of action2/AZN’s launches will materially expand the market as ATTR-CM is a very heterogeneous disease3/physician awareness of AZN’s Alexion (rare disease)brand is already high4/the landmark phase 3 CardioTTRansform trial (out in 2H26) should Justin Smith+44 20 7762 5899justin.smith@bernsteinsg.com Shan Mian+44 20 7676 8981shan.mian@bernsteinsg.com Maximilian Brewster+44 20 7550 2193maximilian.brewster@bernsteinsg.com be the most competitive dataset and thus make Wainua AZN’s 2ndlargest non-oncologydrug. Our new 2036e AZN ATTR of $10bn implies 10% upside to theconsensus group sales. Specialist Sales Why is ATTR relevant?Amyloidosis is the dangerous build-up of harmful proteins in vitalinternal organs which can be life-threatening. The most share price relevant amyloidosissub-type is ATTR for which the greatest unmet medical need lies in the heart (ATTR-cardiomyopathy (CM); ca 800k sufferers in the G8) as the 5-year US survival rate is<<40%. Hence, ATTR-CM is often more of a ‘death sentence’ than many severe cancers. Christian Moore+1 917 344 8555christian.moore@bernsteinsg.com Why ‘prime’ on ATTR-CM now?ALNY delivered an innovation ‘step-up’ via its 2025launch of first in class gene silencer Amvuttra. Unlike earlier, ‘lower tech’ stabilizers (egVyndaqel (Pfizer; Courtney Breen; 2025 sales $6bn), ‘higher tech’ silencers cut ATTRproduction. In 2H26 AZN will publish the landmark phase 3 cardioTTRransform data for Wainua (consensus peak $2bn; guidance >$5bn). Although the 2ndsilencer, we expectthis drug to materially expand the market as1/ATTR-CM is very heterogenous disease, sodoctors need many different mechanisms to treat it (Wainua binds to genetic code (mRNA)whereas Amvuttra degrades it)2/US diagnosis of ATTR-CM is only 25%. But in our view,there are many examples of rare disease (RD) market expansion driven by new entrants.And Key Opinion Leaders (KOLs) have told us that AZN has invested heavily pre-launch.(Whilst ALNY’s twice yearly ‘Next Gen’ silencer nucresiran may ‘step-up’ convenience, weexpect it to cannibalize Amvuttra. For nucresiran there no payaways to Sanofi (O)), whichreceives a blended mid-20’s royalty from sales of Amvuttra. Who will lead in this $20bn (10% CAGR) peak sales market?We think it’s AZN for threereasons1/ portfolio:AZN uniquely owns drugs with each of the proven mechanisms:stabilizer, silencer and depleter. Unlike silencers, depleters eradicate ATTR plaques& AZN’s cliramitug (consensus peak $2bn vs guidance $3-5bn) is first in class with aprojected 2029 launch. KOLs have opined to us that combination therapy will deliverthe best outcomes (AZN plans studies of Wainua maintenance post climaritug induction,which would imply upside to our AZN base case forecasts)2/ strongest legacy:in ourview AZN’s Alexion RD platform is a sustainable competitive advantage3/ dataset:cardioTTRransform is the largest phase 3 trial with the most rigorous endpoint and has a 4-year lead over TRITON (nucresiran phase 3). If the Vyndamax pre-treated subgroup ‘works’in cardioTTRransform there would be 34% upside to our base case 2036e Wainua of $6bn. BERNSTEIN TICKER TABLE Table Of Contents Executive Summary - why should azn lead in a $20bn peak non-oncology market?......................................................................................4Introduction to ATTR............................................................................................................................................................................................................... 6How is ATTR Treated? - conventional (symptom relief only)............................................................................................................................. 9What Are Stabilisers?...........................................................................................................................................................................................................10What are Silencers?..............................................................................................................................................................................................................11siRNA Deep Dive............................................................................................................................................................