CRISPR Therapeutics Goes RNAi in Major Embarrassment to Field

 Just when we thought there could not be more frustration at the lack of appreciation for CRISPR genome editing, CRISPR Therapeutics announced this week that it was licensing in an RNAi agent from US-Chinese biotech Sirius Therapeutics.  For a company that billed itself a CRISPR platform company to do such a thing so early in the game, raises a number of questions, both for the company and the CRISPR field in general.

Opportunistic deal

With a healthy cash balance of almost $2B, but an emerging valuation air pocket as the ex vivo sickle cell therapy Casgevy is proving hard to commercialize and early-stage CRISPR assets are essentially valued at zero, CRISPR Therapeutics is taking advantage of currently depressed prices in the biotech market.  Valuations for China-based assets that can take advantage of the quick translational data generation opportunity there, are particularly attractive and en vogue in pharma.  Accordingly, Factor XI-targeted SRSD107 has shown robust and long-lived >90% knockdown following a single dose out to 6 months, just what we have come to expect from RNAi.

SRSD107 will be developed for anti-thrombotic purposes, hoping it will cut thrombosis risk without an undue increase in bleeding risk.  It won’t be an easy task as the history of Ionis and Bayer for a related antisense compound (fesomersen) has shown.  But for $25M upfront and a $70M equity investment in Sirius, it was worth the flier for CRISPR Therapeutics.  The hope is that the company can rapidly take SRSD107 through phase II and get investors to attribute some value.

CRISPR Therapeutics should have enough to chew on

I get it: CRISPR Therapeutics is engaged in cardiovascular disease and permanent genome editing for managing risk factors like blood clotting and pressure is probably not always ideal.  On the other hand, if the company felt that life-long lowering of cardiovascular risk factors following a one-time CRISPR treatment was attractive and that the company was at the top of the CRISPR game, it should have more than enough targets to chew on in a capital-efficient manner before expanding into other modalities.

Let’s not forget, in addition to CTX310 (ANGPTL3) and CTX320 (Lpa) which are in the clinic for lipid-driven cardiovascular disease, CRISPR Therapeutics entertains an obscenely broad pipeline already from immune-oncology, diabetes, sickle cell and other genetic diseases.

One interpretation could be that CRISPR Therapeutics views cardiovascular disease to be most attractive in the pipeline and therefore wants to expand it. There is indeed considerable interest and investment from small biotech to Big Pharma alike into genetic approaches for this area of drug development.  CAR-Ts on the other hand remain overcrowded and at risk from new types of antibody formats.

Platform development failure

It is also likely that CRISPR Therapeutics is concerned about not having the competitive edge needed to compete in the sickle cell and cardiovascular CRISPR arena long-term. 

For sickle cell, more reliable outcomes via prime or base editing instead of first-generation Cas9 nuclease combined with milder pre-conditioning or systemic LNP delivery is clearly the future.  Beam, Editas, and a few others are working on it and I believe getting close to an attractive product profile following a course of maybe 2 or 3 administrations in the case of LNPs.

And with prime editing, it must have crossed drug developers’ minds that instead of aiming to upregulate fetal hemoglobin, the most obvious, elegant, and likely effective approach is to correct the famous sickling A>T transversion in the sixth coding of the (adult) beta-globin gene in the first place- with prime editing, of course.

While CRISPR Therapeutics, too, works on gentle preconditioning and systemic LNP delivery along with the field, I believe they have lost the edge as it comes to CRISPR next-generation editing systems.  Especially for hematopoetic stem cells, non-cleaving methods should be preferred.

I am also curious to learn more about the safety profile of CTX310 and CTX320.  With GalNAc-enabled VERVE-102 setting a new standard in the safety of CRISPR all-RNA LNP delivery to the liver and Prime Medicine following suit, we still need to find out whether the safety of CTX310 and CTX320 are commercially acceptable, and if so, competitive.

Multi-modality

Building franchises around certain genetically highly validated targets using different modalities is obvious.  It is being practiced by cardiovascular disease leaders Eli Lilly and Novo Nordisk (e.g. Lpa, PCSK9) and caters to different audiences:

oral pills for those that value the daily breakfast ritual...to less frequent antibodies and especially RNAi Therapeutics for those that like to see their healthcare professionals occasionally and feel confident about their access to health insurance in perpetuity...and finally one-course-and-done genome editing for those that simply want to go on with their life and achieve the best medical outcomes through life-long lowering of validated risk factors. 

Why RNAi powerhouse Alnylam, unlike Ionis (via Metagenomi) is not thinking about fortifying their current TTR and rare disease franchises by taking advantage of their $30B+ market cap is beyond me.  As you can see, my current frustration at the disconnect between what CRISPR technology has achieved clinically (almost all the biotech highlights of 2025 so far have been CRISPR related) and market valuations is approaching madness.  CRISPR-Sirius, seriously?