Thread by @Ron_Witteles

(1/14) 🚨I had the privilege of providing commentary on the Phase 2 #coramitug trial at #AHA25. The headline was that patients who received high-dose (60 mg/kg) coramitug had significant reductions in NT-proBNP at 1 year compared with placebo. So it’s an unequivocal win, right? The full story is a bit more complicated…🤔

(2/14) For background, coramitug (previously known as NI006 and ALXN2220) is a monoclonal antibody designed to remove amyloid deposits from tissue. This is an attractive concept, as it offers hope for true reversal of disease. Is this the holy grail of amyloidosis treatments?

(3/14) The reality is that the story of antibody trials in #amyloidosis is a mixed bag… and that’s being generous. Let’s take a quick walk down memory lane... 🧠

(4/14) Dezamizumab was an anti-SAP antibody. (SAP is present in all amyloid deposits). Not only did the trial not show any hint of efficacy, but it was stopped after 7 patients enrolled due to 2 cases of new vasculitis. 😱

(5/14) Birtamimab was an antibody targeting AL amyloid deposits, and was trialed with much hope in 260 patients in the VITAL trial. The results? No hint of benefit in either all cause mortality or cardiac hospitalization.

(6/14): A post-hoc analysis in the most advanced (Mayo Stage 4) patients seemed to show a mortality benefit with birtamimab in VITAL. But keep in mind – the choice of endpoint, the Mayo Stage, and the timing of the assessment was all made post-hoc. Danger, Will Robinson!

(7/14) This post-hoc data led to another Phase 3 trial of birtamimab, this time only in Mayo Stage 4 patients. The results were announced in May 2025: No hint of benefit in the primary endpoint or either secondary endpoint. The company has since continued the birtamimab program.😢

(8/14) Another antibody, anselamimab, was tested in advanced AL amyloidosis patients, in the CARES trial. The results? Another disappointment. The company announced in July 2025 that the trial failed to meet its primary endpoint.😢 (They also noted a benefit in a “prespecified subgroup of patients”, but no further details so far.)

(9/14) The Phase 1 ATTR amyloid trial with cliramitug (formerly NI 006 – not to be confused with coramitug!) was published 2 years ago. In 40 patients treated with cliramitug or placebo, there were encouraging trends in imaging and biomarkers, rightly leading to the ongoing Phase 3 trial DepleTTR-CM. Nothing definitive here, but finally some good news!

(10/14): So what about the new data presented with coramitug at #AHA25? The positives were the NTBNP data shown above, and some seeming improvements in exploratory echo parameters. But there were some real negatives as well…

(11/14): The other primary endpoint, 6-minute walk distance, didn’t show any significant difference vs. placebo (P=0.54). None of the secondary endpoints were positive, including GLS by echo or ECV by MRI.

(12/14): If you’re a glass-half-empty kind of person, consider this: There were 7 prespecified primary and secondary efficacy endpoints, and only a single one (NTBNP in the 60 mg/kg group) was positive.👀😲

(13/14): One other note of caution: a potential imbalance in arrhythmias. This is scientifically plausible & was seen in 43% of high-dose coramitug patients compared with 23% of placebo patients. Not definitively a problem, but not reassuring either.

(14/14) I leave you with my take-home slide from #AHA25. There are some reasons for optimism with coramitug and the ATTR antibody depleters – but this is hardly an unequivocal win or the “holy grail”. Let’s see what we learn with time – and more data.

@KMAlexanderMD @Paul_P_Cheng @MarthaGrogan1 @MasriAhmadMD @BrettSperryMD @MargotDavisMD @maz_hanna @DorbalaSharmila @MGKhouri_md @JLGrodin @JLRosenthal @SumeetMitter @UreyTony @LilySternMD @frederickruberg @sarahcud @MKIttlesonMD

@KMAlexanderMD @Paul_P_Cheng @MarthaGrogan1 @MasriAhmadMD @BrettSperryMD @MargotDavisMD @maz_hanna @DorbalaSharmila @MGKhouri_md @JLGrodin @JLRosenthal @SumeetMitter @UreyTony @LilySternMD @frederickruberg @sarahcud @MKIttlesonMD One small edit to 2/14: Coramitug is the former NNC6019 & PRX004. Cliramitug is the former NI006, as noted in 9/13. Why do the names have to be so similar???😠