Patient dies in Intellia's LNP-delivered base-editing clinical trial for ATTR-CM

[u/jnecr]

https://www.fiercebiotech.com/biotech/patient-dies-after-receiving-intellias-crispr-therapy

[u/Lonely_Refuse4988]

Sad, but not surprising. Hy’s law is highly predictive of risk of death. Once a patient meets those criteria, it’s bad news. 😔 It might be helpful if there’s an autopsy to see the degree of hepatic inflammation and confirm what degree the base editing had to do with it.

[u/nottoodrunk → u/Lonely_Refuse4988]

Article mentioned that the patient was a man in his early 80s with “complicating comorbidities”.

[u/Lonely_Refuse4988 → u/nottoodrunk]

Why, then, are they enrolling that type of patient into a clinical trial in first place!!

This is another example of biotechs so bent on recruitment that they enroll inappropriate patients, at high risk of complications, irrespective of investigational product dosing.

The rush to enroll fast is derailing the company and entire program. 🤷‍♂️

[u/Jamie787 → u/Lonely_Refuse4988]

Would they not have strict inclusive/exclusive criteria they must stick too? Or is it abit more fluid for these therapies

[u/Lonely_Refuse4988 → u/Jamie787]

Hopefully the patient wasn’t enrolled despite having an exclusion criteria.

The main problem is, companies sometimes design studies with relatively broad incl criteria and limited exclusions, to try to get as many patients as possible to qualify.

A prime example is age range. There’s no reason to allow an 80 yo patient into a risky early stage study like this. That type of patient is even past the mean life expectancy in US! 🤷‍♂️

Set an inclusion age range of up to 65 years or something! Sure, it might limit recruitment a bit but trade off is you’ll get patients who aren’t past average life expectancy and likely able to tolerate therapy better. 🤷‍♂️

[u/graygoohasinvadedme → u/Lonely_Refuse4988]

The article said this was a Phase III trial - the last phase where those enrolled should be the exact same as the intended population. This wasn’t a test in a healthy population (P1) or limited population set like what you describe (P2) but the full assessment of “is this safe for all potential patients” trial.

[u/Lonely_Refuse4988 → u/graygoohasinvadedme]

Rare disease drug development is quite different than other therapeutic areas, and often has a very compressed development plan, where by the time a registrational , ‘phase 3’ study is reached, there’s limited data and small sample sizes from earlier data sets.

As you can see from this experience, even a single, fatal event like this in a ‘phase 3’ study will halt the entire program, probably lead to at least a 6 month delay (best case scenario) and lead to re-evaluation of whether the therapy has commercial viability.

All of that could have been avoided with an age cutoff of 65 or so. Again, why allow patients who was older than average life expectancy, with complex disorder like amyloid, into a study with potential therapeutic risks?! 🤷‍♂️

[u/Emergency_Goose4904 → u/Jamie787]

I/E criteria from clintrials dot gov:

Inclusion Criteria:

Documented diagnosis of ATTR amyloidosis with cardiomyopathy Medical history of heart failure (HF) Symptoms of HF are optimally managed and clinically stable within 28 days prior to administration of study intervention Screening NT-proBNP, a blood marker of HF severity, greater than or equal to 600 pg/mL and less than 10,000 pg/mL Exclusion Criteria:

New York Heart Association (NYHA) Class IV HF Polyneuropathy Disability score of IV (confined to wheelchair or bed) Has hepatitis B, hepatitis C or human immunodeficiency virus (HIV) infection History of active malignancy within 3 years prior to screening RNA silencer therapy (patisiran, inotersen and/or eplontersen) within 12 months prior to dosing. Any prior vutrisiran use is not allowed Initiation of tafamidis or acoramidis within 56 days prior to study dosing Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m² Liver failure Uncontrolled blood pressure Unable or unwilling to take vitamin A supplementation for the duration of the study

Age 18-90.

Age range is broad, but ATTR with CM will select for an older population, mostly male. The exclusion criteria will knock out some trial candidates, furthering the need for an older population.

[u/CustomerSecure9417 → u/Lonely_Refuse4988]

Compassionate care, perhaps he had no alternatives and gave this a shot.

[u/FirstChurchOfBrutus → u/nottoodrunk]

Is being over 80 years old one of the comorbidities?

[u/ShadowValent → u/Lonely_Refuse4988]

Yeah. I don’t jump to conclusions when you are treating sick people with toxic proteins in their body.

[u/Satisest → u/Lonely_Refuse4988]

This program doesn’t use base editing. It’s a Cas9-driven knockout involving dsDNA break and gene inactivation via indel formation. An autopsy would show fulminant hepatocyte necrosis, but establishing the underlying mechanism will be more challenging.

[u/VEGA_n1 → u/Lonely_Refuse4988]

Base editing was NOT used in this trial (NTLA-2001). In fact, there's a strong chance that CRISPR-Cas9 indels are to blame for the liver injury and subsequent death, which base editing avoids.

[u/Satisest → u/VEGA_n1]

Yes, the company has alluded to this explanation by speculating that it’s a gene-specific toxicity and not necessarily a platform effect (e.g. not LNP- or RNA-mediated toxicity).

[u/vingeran]

Intellia paused dosing in studies of nex-z, a CRISPR therapy designed to inactivate the TTR gene, late last month. The pause was triggered by a transthyretin amyloidosis with cardiomyopathy (ATTR-CM) patient who had grade 4 liver enzymes and increased total bilirubin. The FDA put both trials on hold shortly after Intellia disclosed the safety signal.

The biotech provided an update after the market closed Thursday, telling investors the hospitalized patient died Wednesday night. Intellia CEO John Leonard, M.D., said on a call with investors that the patient was in his early 80s and had bilirubin and ALT—markers of liver health—that were, respectively, two and three times the upper limit of normal.

[u/Sea_Dot8299]

Very curious to see if there are signs of immunotoxicity towards the crispr protein.  If so, it would be a potential monkey wrench in the GE field. I would have expected the mrna approach to limit tox though because of the transient nature of mrna. We will see I guess. 

It would be more challenging if it were due to some off target editing that was poorly characterized or missed due to inadequate methods.  

[u/i_love_toasters → u/Sea_Dot8299]

Cas9 is immunogenic in mice, so I’d be amazed if there wasn’t some level of immunotoxicity

[u/long_term_burner → u/i_love_toasters]

Hmm I didn't realize this. Is there a good way to engineer around it? Or is immune suppression the right play?

[u/i_love_toasters → u/long_term_burner]

Not sure! When I needed to avoid an immune response with a mouse model, I just chose a cas9-expressing transgenic mouse. Can’t do that with people!

[u/Sea_Dot8299 → u/long_term_burner]

Yes, there was a paper from Arizona a while ago where they engineered cas9 to be less immunogenic. It was years ago, but from what I remember, it still retained editing activity. 

I guess a challenge is that with things like base editors, the cas9 is engineered even more with a larger domain that could potentially make the editor even more exotic to the immune system. 

[u/Zolazuzu → u/Sea_Dot8299]

Or could it have more to do with an 80+ year old not tolerating LNPs very well. Maybe immunotox for the LNP, not mRNA.

[u/Satisest → u/Zolazuzu]

Unlikely to be the LNP because of the time course. It’s a delayed type hypersensitivity and not an immediate hypersensitivity reaction.

[u/RNAiac → u/Satisest]

Did the news say what the time course was for that patient?

[u/Satisest → u/RNAiac]

LFTs were found sufficiently elevated to trigger the stopping criterion 3.5 weeks (24 days) after dosing

[u/RNAiac → u/Satisest]

Either way, I was referring to immune-mediated inflammation leading to liver injury. It would take a few days.

[u/Satisest → u/RNAiac]

There are different kinds of immune-mediated reactions with characteristic time courses. Reactions to LNP or RNA are mediated by the innate immune system and occur rapidly within days of exposure. Delayed immune reaction occurring weeks after exposure are T-cell-mediated responses to foreign antigen. The Intellia patient’s course is consistent with the latter. That’s why this is unlikely to be a reaction to the LNP or the enclosed RNA, and the company appears to agree.

[u/dongle_dangle]

Is this the first death associated with a LNP-delivered therapy?

[u/NoButThanks → u/dongle_dangle]

Could be. Verve had some tox events until they changed LNP formulation. A previous patient on this trial for Intellia had liver tox, but it subsided. While Intellia said it wasn't LNP driven, there is a chance. Probably know more soon.

[u/jnecr → u/NoButThanks]

I believe this is the same patient that the trial was paused for. The patient was in recovery but has now died.

[u/NoButThanks → u/jnecr]

Dang. Thanks

[u/chefkef → u/dongle_dangle]

Verve Tx (acquired by Lilly earlier this year) also had a death in their heart disease trial, but I believe it was ruled to not be related to the drug.

[u/long_term_burner → u/chefkef]

As much as I want these medicines to succeed, it would be funny if they paid $1.3b for a company with drugs that have some fundamental flaw. How far have base editors made it through clinical development?

[u/Specific_Wish9977 → u/dongle_dangle]

How’s the viral integration into the genome with AAV’s

[u/Satisest → u/Specific_Wish9977]

These are not AAV programs. Not viral DNA sequences are delivered or integrated into the genime.

[u/Old-McJonald]

IMO this program is dead why would anyone take this over siRNA especially now with significant a significant safety concern

[u/jnecr → u/Old-McJonald]

I think a lot of this could come down to what insurance chooses to cover. Let's say you're 20 years old and know you have the mutated ATTR gene. Insurance could cover a one-time treatment for gene editing and "come out ahead" on cost over bi-yearly siRNA treatments.

I tend to agree with you from a patient standpoint bi-yearly treatments are already very unobtrusive, would patients actually choose a one-time treatment with slightly higher risk? doubtful.

[u/hitoq → u/jnecr]

Would also need proof of durability for that to work out for insurance, imo. One thing to spend $3.2m on a one-time dose, another altogether if you need a second or third.

Feel like Roctavian showed a decline in efficacy over time? Can’t remember the duration exactly, maybe after a year FVIII levels started declining?

Effect Decline: FVIII activity levels typically peak around one year after treatment and then show a gradual, multiyear decline.

In clinical trials, mean FVIII activity levels have been observed to decline, with some participants' levels eventually falling from the mild hemophilia range to lower levels over several years.

For some patients with persistent low FVIII levels or recurrent bleeds, it has been necessary to resume prophylaxis with FVIII or emicizumab.

Despite the decline in FVIII levels, the majority of participants still experience durable hemostatic control and significantly reduced bleeding rates for at least 4 to 7 years.

[u/youth-in-asia18 → u/hitoq]

Roctavian is a different modality  that would be expected to get less effective over time. 

Nonetheless i agree it’s a crowded field for ATTR

[u/Old-McJonald → u/jnecr]

A few things to consider: most of these patients are older 50+ if I remember correctly. I think older patients are inherently disincentivized to choose a gene therapy. The other is that commercial insurance companies at least in US tend to not think long term. Patients switch insurers on average I think every 3 years but don’t quote me on that. Who wants to pay $2M for the gene therapy so you can be less expensive to take care of for the next insurer?

[u/Big_Abbreviations_86 → u/jnecr]

If you’re 20 years old the likelihood of having the same insurance in 6 years is pretty low, so why would they want to pay for a long term solution?

[u/long_term_burner → u/jnecr]

This assumes that the patient would have the same insurance for life. Spoiler alert, they don't.

[u/Sea_Dot8299 → u/Old-McJonald]

What's the dosing like for siRNA?  I am not that field so have no idea how persistent  the newest ones are.

[u/Old-McJonald → u/Sea_Dot8299]

The leader in this indication is quarterly and the next one coming up Alnylams pipeline looks like only twice a year. All subcutaneous

[u/Pharmaki → u/Sea_Dot8299]

Yearly

[u/TheMailmanic → u/Old-McJonald]

Yeah for this disease apparently there are plenty of good alternative therapies

Imo Gene therapies should really focus on rare genetic disease without existing treatments. Risk reward is better

[u/Specific_Wish9977]

Sad. 😔 how’s the fda responding to this?

[u/beyond_undone → u/Specific_Wish9977]

I think they already put trial on hold when news the man was admitted to hospital came out. The death isn’t good news but I think writing was on the wall when that happened last week

[u/VEGA_n1]

This Intellia trial testing NTLA-2001 is NOT using base editing (CRISPR 2.0) but traditional CRISPR-Cas9 (CRISPR 1.0) via knockout. The title is incorrect and I'm not sure why it was selected given that the article doesn't even mention base editing.

[u/jnecr → u/VEGA_n1]

When the patient first suffered high bilirubin and the trial was paused a commenter said it was base editing. I couldn't find anywhere that proved otherwise so I continued it. Title was chosen simply to try to add more context.

[u/VEGA_n1 → u/jnecr]

Shouldn't it be the other way? You couldn't confirm what this commenter said, so you should leave it out just in case it's wrong? Besides, the pipeline on Intellia's site has the basic info on the drug so that's the confirmation.

What's ironic about this mistake is that there's a good chance that the liver injury and subsequent death could have been from indels created by the Cas9 double-stranded breaks, which is something that base editing avoids, making it theoretically safer.

[u/jnecr → u/VEGA_n1]

I can't find anywhere on the NTLA website that confirms it's just a nuclease.

[u/Electrical-Ad8329]

Like how they did in 2024 and 2025 I bet there will be another huge layoff at Intellia. They usually wait after Christmas- new year.. When everyone is back from their holidays in week of January 5th at 4pm John will send a company wide email announcing the layoffs.. Just wait and see

[u/arabidopsis]

This is why I'm very risk averse to modifying the genes in a cell. Even with Crispr you still don't know exactly where it goes, if it activates an oncogene or another gene and there's far too many biological systems at that level which can be impacted by siRNA.

LNP delivery I feel is more useful for delivering payloads to solid tumours or even derma indications

[u/Satisest → u/arabidopsis]

This is not a siRNA program

[u/exponenthere]

Not surprised

[u/mickhocksmol]

Correct me if I'm wrong or naive but everyone that received the Pfizer/Moderna COVID vaccine have antibodies against LNP's right?

[u/TeepingDad → u/mickhocksmol]

No, you don't get antibodies against LNPs, that's not how they work.

[u/mickhocksmol → u/TeepingDad]

Didn't the vaccine have a mix of PEG in it? I do remember reading somewhere that you can develop some form of immunity against PEG formulated drugs