Grade 4 Liver Enzyme Elevation in Intellia’s Phase 3 ATTR Amyloidosis Trial

 Last night, Intellia filed a material event report (8-k) with the SEC.  In there, they revealed a case of very high, grade 4 liver enzyme elevations in a single subject treated with NTLA-2001 (nex-z) in the ongoing MAGNITUDE phase 3 ATTR-CM trial.  This case appears to be resolving without any hospitalization or medical intervention.

For context, Intellia has now dosed around 400 subjects with its particular LNP-mRNA formulation across the ATTR and HAE trials.  This is the first such case to be reported.  Earlier cases of liver enzyme elevations were rare.  There were 2 milder, but significant AST elevations in the first month following dosing among the 36 subjects in the phase I/II portion of ATTR-CM development of nex-z (Fontana etal, 2024).  These cases similarly resolved within days.

Liver safety is a key consideration in the development of systemically administered LNP-delivered nucleic acids.  Following delivery, the liver soaks up these LNPs containing non-natural lipids that could insert themselves into normal lipid biology.  It is therefore important that they degrade and get removed from the body- the sooner the better.

There has for example been a case of so called Hy’s Law with Alnylam’s LNP-formulated Patisiran (RNAi) in its phase 3 trial in ATTR-CM (APOLLO-B), meaning that bilirubin was concurrently elevated (excerpt from the APOLLO-B Briefing Docs):

  

Clearly, more context, including the temporal association with nex-z administration, any changes in bilirubin, and the general health and behavior of the subject involved, need to be eventually provided by Intellia for better judgement of the event (it is a blinded study).  It needs to be remembered, too, that nex-z (or most other CRISPR-LNPs) is administered only once which allows for close monitoring in clinical practice.  The fact that the trial is allowed to continue is a positive sign.

Update (5 June, 2025): Since the initial 8-k came out, the company had meetings with analysts during which it emerged that the liver enzyme elevations occured and waned in week 4-5 following administration.  This is inconsistent with acute LNP toxicity as I speculated.  For example, VERVE-101 triggered such an acute response with ALT peaking in the first week.  

This leaves a rare adaptive immune response to the CRISPR editing enzyme (Cas9) or a delayed response to the editing mechanism (double-strand breaks) as the two main other plausible mechanisms.  Pre-existing immunity to various Cas9 enzymes is quite common, so that might be a line of investigation and lead to future adaptations of use.  If hepatocytes that highly express Cas9 for a prolonged period of time got preferentially attacked by cytotoxic T-cells, there should be a decrease in editing levels following the immune attack.

There was also the disclosure that the subject had taken 3g paracetamol for 8 days prior to receiving therapy, a medicine known for occasional severe hepatotoxicity (yes, even common, over-the-counter medicines can cause grade 4 and higher liver enzyme elevations).  Keeping your liver happy around systemic LNP-RNA administration, for example by abstaining from alcohol should be good practice in any case.

1 1/2 weeks following the hepatotoxicity disclosure, no clinical halt has been placed on NTLA-2001 by any of the global regulatory bodies involved in the phase 3 trial, giving extra comfort around its overall safety profile.