ACC 2022 – full vupanorsen data shed light on Pfizer’s split

Ionis’s anti-ANGPTL3 antisense vupanorsen already looked dead in the water after Pfizer abandoned it in January after ostensibly positive topline results last year. Now full data from the phase 2b Translate Timi 70 dose-ranging trial, presented at ACC yesterday, show why the big pharma walked away. While the study met its primary endpoint, non-HDL cholesterol lowering at week 24, even the most effective dose of vupanorsen produced an unimpressive 28% placebo-adjusted reduction. LDL cholesterol lowering was even more lacklustre, and a cross-trial comparison against Regeneron’s approved ANGPTL3 inhibitor Evkeeza and marketed anti-PCSK9 products show just how uncompetitive vupanorsen looks. It is worth noting that the Elipse study of Evkeeza only included patients with homozygous familial hypercholesterolaemia, the most serious form of FH, while Translate Timi 70 enrolled a broad dyslipidaemia population. But vupanorsen has also been hit by previously disclosed liver toxicity concerns, and ACC heard that 39% of patients in the highest dose, 160mg every two weeks, had ALT or AST increases over three-times the upper limit of normal. Other groups involved in ANGPTL3 include Arrowhead, Lilly/Novo Nordisk – via Dicerna – and Verve Therapeutics. They will hope that these issues are unique to vupanorsen.

How vupanorsen stacks up against approved cholesterol lowerers
Product/project Company Description Non-HDL lowering LDL lowering
Vupanorsen Ionis SC anti-ANGPTL3 antisense 28%* 16%*
Evkeeza Regeneron IV anti-ANGPTL3 MAb 52%** 49%**
Leqvio (inclisiran) Novartis SC anti-PCSK9 RNAi 44-47%^ 50-52%^
Repatha Amgen SC anti-PCSK9 MAb 46%^^ 55%^^
Praluent Sanofi/Regeneron SC anti-PCSK9 MAb 50%~ 58%~
All on top of background statins; all data placebo-adjusted; SC=subcutaneous; IV=intravenous; *best result from dose-ranging Translate Timi 70; **Elipse-HoFH (homozygous familial hypercholesteraemia pts only); ^Orion-10 & 11; ^^Descartes; ~Odyssey Long Term. Source: product labels & ACC 2022.

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