Blackstone Group Inc. / Alnylam Pharmaceuticals Inc.

Hypercholesterolemia / ASCVD prevention (inclisiran) and adjacent cardiometabolic disease (vutrisiran ATTR amyloidosis, ALN-AGT hypertension)

38M US cases/yr · $22.0B Global lipid-lowering therapy sales 2020 (USD MM, statins + PCSK9i + ezetimibe) · 696000 US cardiovascular disease deaths 2020

Disease Overview

Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of death in the United States, with the AHA estimating ~127 million US adults (>50% of adults) having some form of CVD and 696,000 CVD deaths in 2020. Elevated LDL-cholesterol is a primary modifiable risk factor; an estimated 38 million Americans have LDL-C >190 mg/dL or established ASCVD requiring intensive lipid-lowering. Statins reduce LDL-C by 30-55% and represent first-line therapy, but ~10-20% of patients are statin-intolerant or fail to reach LDL-C goals on maximum tolerated statin therapy. PCSK9 monoclonal antibodies (Repatha/evolocumab, Praluent/alirocumab) reduce LDL-C an additional 50-60% and have outcomes data (FOURIER, ODYSSEY OUTCOMES) but are administered every 2 weeks, limiting adherence. Inclisiran is an siRNA targeting hepatic PCSK9 mRNA — administered subcutaneously twice yearly after a loading regimen — addressing the adherence/persistence gap inherent in mAb dosing. The ORION Phase 3 program (~3,500 patients, primary endpoints LDL-C reduction at day 510) had read out positively when this deal was struck. Adjacent assets in the financing: vutrisiran (subcutaneous TTR siRNA, hereditary ATTR amyloidosis, Phase 3) and ALN-AGT (angiotensinogen siRNA, treatment-resistant hypertension, Phase 1/2). Inclisiran was central to Alnylam's revenue model and to The Medicines Company's $9.7B Novartis acquisition Jan 2020.

Competitive Landscape

At deal date (April 2020), the lipid-lowering competitive landscape was dominated by generic statins (atorvastatin, rosuvastatin, simvastatin, pravastatin, lovastatin) accounting for >90% of prescriptions, with branded add-ons including Merck Zetia/Vytorin (ezetimibe / simvastatin-ezetimibe), Esperion Bempedoic acid/Nexletol (ATP-citrate lyase inhibitor, FDA-approved Feb 2020), and the PCSK9 monoclonal antibody class — Amgen Repatha/evolocumab (FDA-approved Aug 2015, FOURIER outcomes 2017) and Sanofi/Regeneron Praluent/alirocumab (FDA-approved July 2015, ODYSSEY OUTCOMES 2018) — both Q2W subcutaneous, with combined 2019 sales ~$1.3B held back by step-edits and adherence challenges. Inclisiran's first-in-class siRNA mechanism, twice-yearly subcutaneous dosing and PCSK9 silencing differentiated it on persistence. RNA interference platform competition was thin — the GalNAc-conjugated siRNA platform was largely Alnylam's, with Arrowhead Pharmaceuticals (TRiM platform — ARO-AAT, ARO-APOC3, ARO-ANG3) as the principal independent competitor and Dicerna Pharmaceuticals (Novo Nordisk-partnered nedosiran for primary hyperoxaluria, later acquired by Novo for $3.3B in late 2021) as a secondary entrant. Antisense oligonucleotide alternatives included Ionis Pharmaceuticals (Tegsedi, Waylivra) and Akcea/Ionis vupanorsen (apoC-III antisense, later discontinued by Pfizer in 2022). Adjacent ATTR amyloidosis competition for vutrisiran included Pfizer Vyndaqel/Vyndamax (tafamidis, FDA-approved May 2019) and BridgeBio acoramidis (Phase 3 ATTRibute-CM ongoing). Treatment-resistant hypertension (ALN-AGT) competitors at deal date included Idorsia aprocitentan (Phase 3 PRECISION, later approved as Tryvio Mar 2024) and renal denervation devices (Medtronic Symplicity, ReCor Paradise).