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.

First Commercializations of Systemic Therapies as Backstop for CRISPR Investors

There is widespread consternation about the disconnect between recent clinical breakthroughs and the performance of CRISPR-related stocks.  I am highly confident that this will correct by mid-2027 at the latest when NTLA-2002 should become the first systemically administered CRISPR therapeutic to be commercialized.  It will demonstrate the high demand by patients and physicians for this revolution in medicine and commercial viability.

 

KOL enthusiasm

In 2017 at the iconic Paris ATTR Amyloidosis Meeting where Alnylam unveiled the biggest clinical breakthrough in RNAi, the eyes of key opinion leader Dr Julian Gillmore (UCL) lit up when going another step forward into the future, talking about the promise of one-dose CRISPR genome editing for the disease.  This was notable since he is essentially involved in all the key clinical programs in ATTR amyloidosis irrespective of modality, including TTR stabilizers and RNAi silencing.    

I noticed similar genuine enthusiasm at last year’s ACAAI meeting from hereditary angioedema (HAE) KOL Dr Banerji (Harvard) regarding NTLA-2002 after experiencing NTLA-2002 in her own patients.  Another seeing-is-believing moment was recently voiced by Prof Patel of UCL, an investigator in the VERVE-102 PCSK9 base editing trial:

 “This is reality; it’s not science fiction. We’re actually doing it. I’ve had patients of mine in the trial receive this one-and-done treatment, and it’s going to change the face of cholesterol management going forward.”

I have yet to see a single trial investigator or KOL who has deeply thought about the implications of one-time therapies in clinical development for the above diseases and discarded them as freakish or irresponsible as people invested in competing therapies like to do.

 

Patient enthusiasm

The same holds true for patients, that is the people whose voice should have the most weight in the discussion on the risk/benefits and ethics of genome editing. 

In a patient preference survey commissioned by Verve Therapeutics, one third already stated that a one-time genome editing treatment would be more appealing to them than daily pills or injectible drugs.  I expect this number to further increase as VERVE-102 makes its way through the clinic and first patients get treated commercially (word of mouth will be tremendous). 

Similarly, HAE patients confronted with NTLA-2002 look to it with hopes of allowing them to forget about their disease and not having to worry about getting repeat-administered drugs covered by insurance in perpetuity.  Accordingly, enrolment in the phase 3 HAELO trial is extraordinarily swift as patients are lining up for NTLA-2002 according to Intellia Therapeutics.

 

But what about payors?

Besides public acceptance of CRISPR genome editing, cost for these one-time therapies is often brought up as an argument against CRISPR.  Surely, they will be prohibitively expensive.  Why for example would anybody pay $2M for ATTR-drug NTLA-2001 when you can get the RNAi alternative for just $500k annually.  Sure, some people will rent the child booster from the rental car company at $20 a day, instead of buying one from a Walmart around the corner for the same price.

If anything, it is CRISPR Therapeutics that have the pricing power in most settings, including for mass markets like cholesterol lowering (--> VERVE-102).  The vastly superior outcomes in terms of morbidity and mortality projected for life-long LDL cholesterol lowering, especially when initiated early on, should more than compensate the $100k or so price tag I expect it to carry initially.  There is also a noticeable shift in the new US administration towards preventing rather than treating disease.  No better modality than genome editing for that as long as the delivery and gene target is safe.

In the words of Stanford’s genome editing scientist Matt Porteus at the 2025 Copenhagen CRISPR conference, the US insurance system is 'f*cked up', but with many eyes nowadays on how the insurance and PBM industry deals with access (see United Health) and the aforementioned inherent pricing power of (non-viral) genome editing, payors will not meaningfully stand in the way of these therapies.  Similarly, the new modality should run into open doors with Medicare and Medicaid who are most vested in the long-term outcomes of covered lives.

 

Momentum building

With NTLA-2002 likely wrapping up enrolment in Q3, we should see the first commercialization of the promising crop of systemically administered CRISPR drugs in mid-2027.  NTLA-2001 for ATTR-PN, BEAM-302 for AATD, VERVE-102 for heFH and high-risk ASCVD, and finally NTLA-2001 for ATTR-CM should follow in 2028/9.  When the sales numbers finally come in, even the longest naysaying hold-outs will have to admit defeat and CRISPR stocks should rebound.  This could be greatly catalyzed if that happens in a lower interest rate environment (Powell will be replaced in 2026).

But even before that, the steady stream of recent clinical successes (VERVE-102, urea cycle N=1 base editing, NTLA-2001 ATTR-PN data at PNS, BEAM-302 initial data) have led to increased broader interest in CRISPR with large social and traditional media accounts talking about the technology once again.  If industry validation is what you are looking for, with Regeneron and Eli Lilly having to make their respective NTLA-2001 and VERVE-102 opt-in decisions soon and share prices dangerously low, we could see ‘strategics’ stepping in.  The dam could break any day, in a positive way, for long-suffering investors.

Beam Therapeutics and Prime Medicine Need to Unite

Prime Medicine disclosed this week that they were in binding arbitration with Beam Therapeutics regarding their development of prime editing for alpha-1-antitrypsin disease (ATTD).  This is one of the fall-outs from the VC-driven glut of CRISPR-related start-ups during its hype phase.  It is an opportunity to correct one mistake by uniting the two technologies under one roof for the benefit of patients and investors.

Beam gained exclusive rights for transition mutations

When Prime Medicine was set up in 2019, Beam Therapeutics (founded in 2017) gained exclusive rights to the use of prime editing for transition mutations, i.e. converting A>G, G>A, C>T, and T>C.  This way, Beam Therapeutics’ foundational base editing capabilities would be shielded from competition by a company having the same scientific founder, Dr David Liu.

2019 collaboration and license agreement

While in theory, Beam's rights appear straightforward, in practice things often become murky, especially when interests diverge.  Typical collaboration and license agreements, and this one in particular, rely on the sharing of know-how to actually enable therapeutic development.  If the parties are at war, however, this clearly is unrealistic.  

Prime editing was in its infancy in 2019 when the agreement was signed. Since then, numerous improvements to prime editing have emerged to increase the miniscule efficiency of the original invention.  Any researcher contemplating using prime editing knows what I’m talking about as he will get dizzy from the dozens of possible iterations to choose from.  Moreover, to get to the >50% in vivo prime editing efficiencies Prime Medicine is now reporting, the company will have gathered critical trade secrets.

The question that then often arises is whether related IP and know-how is within the scope of the agreement.  We also have yet to learn how long the term of the collaboration agreement was.  In any case, I expect sufficient wiggle room for Prime Editing to get something out of a hostile arbitration.

Base editing as a transition mutation in the evolution of CRISPR technology

Base editing was a tremendous invention and associated with high editing efficiencies from the get-go.  However, this high editing efficiency also comes at the cost of the bystander editing issue, meaning that bases nearby target As and Cs in the protospacer loop region also get easily edited.  This sometimes is relevant for both safety and efficacy of the editing approach.  Moreover, as the base editing enzyme hangs out in the nucleus, it similarly indiscriminately deaminates single-stranded RNAs it encounters.  This is a particular issue when the enzyme is not delivered as an RNP or mRNA and will be present in a cell for longer.  Finally, despite not introducing double-strand breaks like Cas9 nuclease, it sometimes leaves behind small indels, and in the case of cytidine deaminases surprisingly many translocations.

So as the efficiency of prime editing, which has incredible specificity, is catching up with base editing, it more and more becomes a threat to the bread-and-butter applications of base editing, including AATD.  And in theory, if Beam Therapeutics were to push alpha-1 editing upwards of 60% in competing with prime editing, the efficiency of ‘clean edits’, that is edits without concurrent bystander edits actually decreases.

And what if you had to go back in and correct the edit if you find out 10 years down the line that an edit was problematic?  With the precision of prime editing, the target site will be there as predicted and therefore targetable.  That is not the case when you have to deal with target sites containing just the on-target edit, a mix of on- and bystander edits, or just bystander edits.

A similar situation presents for sickle cell disease, although in this case Beam Therapeutics got rights to the causative sickling transversion mutation in the beta-globin gene, not 'just' reactivating fetal gamma-globin via base editing.  Base editing, it increasingly appears, is at the risk of becoming a transitory technology. 

Get David Liu in the room!

Clearly, the prime editing competition is on its heels of Beam's two lead programs (AATD and SCD) and eventually will be the preferred options for patients. 

This is where I believe the scientific founder David Liu could and should step in.  How can he watch Beam Therapeutics shelve prime editing and access to better medicines for patients just so that Beam can protect its own franchises?  Also, if not Prime Medicine, other companies working on ‘gene writers’ will eventually get there, too, so none of his companies would benefit from the opportunity prime editing presents.  With prime editing enabled in-house, Beam could further cement disease franchises in the form of follow-on products.  

Last, but certainly not least, the development of prime editing for addressing genetic disease caused by many mutations within a given gene, an application that only prime editing is fit to pursue is stalled when Prime Medicine, or their licensing partners, are prohibited from addressing basically 50% of the point mutations?  How can David Liu accept this?

So get in the room, David Liu, and talk sense into the executives.  You have the moral power to do this and investors from both companies stand to benefit from seeing the two companies united.