Landmark ATTR-Polyneuropathy Data by Intellia Caps Off Momentous Week in CRISPR Therapeutics

This has been a most remarkable week in CRISPR Therapeutics as momentum continues to build. 

Bespoke therapeutic in 6 months

First, the drug development world and beyond was captivated by the story of how a baby born with life-threatening point mutations in the CPS1 gene was able to receive a bespoke base editing therapy in just 6 months by harnessing the platform potential of nucleic acid-targeted therapeutics and regulators getting out of the way (Musunuru et al 2025). 

Every pharma CEO will be asking her business development underlings about recent underinvestment in the technology when the report shows how development timelines and expenses can be slashed by a factor of 10 when everybody applies ‘common sense’.

I purposely make use of new US administration lingo, because while the CPS1 deficiency story happened under the watch of Peter Marks who was fired as CBER chief because of his involvement in Covid19 mRNA vaccines, there is every reason to believe that drug development will continue to be streamlined by cutting out time-consuming bureaucratic hurdles and applying AI-based document reviews.  Accordingly, Trump's HHS and FDA has repeatedly called for accelerated drug development based on common sense, including biological plausibility.  As further evidence of that, it is phasing out certain lengthy animal toxicology studies.

The most immediate beneficiaries of the story are nucleic acid-targeted therapeutics addressing severe, underserved diseases by harnessing proven delivery and which have a clean off-target profile.  Besides CRISPR-based therapeutics, this also includes oligo-mediated RNA editing which has exquisite on-target specificity and where Rett Syndrome could serve as a template when addressing disease populations segmented by numerous mutations.   

 

First patient treated with prime editing medicine

Though behind a paywall, STAT reported last week that the first patient had been treated with a CRISPR prime editing agent.  The timing is fitting, as prime editing, by virtue of it being able to address any small mutation, including non-transition mutations and small deletions, is the most universal iteration of CRISPR.  It is also the safest of them all with Prime Medicine claiming no detectable off-targeting for any of its development candidates.

The CPS1 urea cycle story could have been even better if they had used the safer and more effective delivery of VERVE-102 instead of VERVE-101 used by former Verve employee and co-founder Kiran Musunuru.  Also, the base editor in question had not been tested before in the clinic and was selected by comparing a number of adenine base editors in cell lines which also differed in terms of PAM sites and bystander editing.  A prime editing approach by contrast is not subject to PAM constraints as the edit can happen well within a 50 nucleotide window of a given PAM without losing much efficacy.  There is also no bystander editing to worry about.  This way, the same (proven) prime editor mRNA could be used in the same LNP formulation.

The key to quickly applying prime editing in such circumstances would be (AI/machine) learning from the growing dataset of prime editing experiments to find guide RNAs of high efficacy.

Prime Medicine has made great strides towards getting editing efficiencies up to standard Cas9 and base editing levels.  With the first patient dosed, we can expect data in support of that well before the end of the year (2 months for engraftment in the CGD setting).

 

CRISPR Therapy sets new standard in ATTR-Polyneuropathy

And as if all this was not enough, Intellia today reported 2-year data from their phase I/II study of its Cas9 CRISPR agent NTLA-2001.  Unlike prior TTR knockdown agents by Alnylam (RNAi) and Ionis (RNaseH antisense), key mNIS+7 and Norfolk quality of life measures show that after 2 years of sustained -90% TTR reductions, NTLA-2001 not only stabilizes patients, but the majority of patients improve.  In the dose expansion cohort, there was a clinically highly impactful -8.5 point improvement in mNIS+7. 

Clinically meaningful >4 point improvements were also seen in 5 out of the 6 patients that had been on an RNAi treatment (Patisiran) before.  It is also an improvement over what had been observed at the 12-month timepoint before with NTLA-2001 and sends a strong message:

A one-course treatment permanently changing genetics for the better leads to superior outcomes as the body itself becomes the healing agent. 

I look forward to seeing histology data looking at TTR deposition and whether they start to disappear as the balance shifts towards clearance.

The superior outcome may not come as a surprise when considering that with a 90% gene knockout efficacy, NTLA-2001 halves the amount of TTR being produced following therapy compared to what knockdown agents have been able to achieve.  Still, the fact that improvements seem to accelerate over time is remarkable.

Concordantly, there were no new adverse events and illustrates that acute infusion reactions and possibly transient liver damage around LNP administration is the main safety and arguably only concern of liver-directed CRISPR therapeutics.  Safety challenges arising from having to maintain a certain level of drug concentration, which may e.g. lead to low chronic inflammation and associated transcriptionopathies, do not apply to RNA-/oligo-based CRISPR therapeutics.

With this data, NTLA-2001 should own the ATTR-polyneuropathy market, not just because of its superior efficacy and safety, but also because it is a genetically defined disease and could be given earlier, perhaps even before symptoms manifest.  This would be a hard sell from a health economics point of view for drugs that need to be taken chronically for life.  In the same vein, Intellia reported just yesterday that NTLA-2001 similarly improves the lives of people with genetic ATTR-cardiomyopathy, leading to never seen before increases in the 6 minute-walk-distance measure, not with vutrisiran and not with acoramidis.

Phase 3 studies of NTLA-2001 in ATTR-PN and ATTR-CM are ongoing and should gather steam with the new data.

It is possible that together with the recent PCSK9 data by Verve Therapeutics, last week’s developments and increased signs that regulatory flexibility will continue to be applied if not greatly accelerated by the new administration could mean that the worst for CRISPR investors could be behind.