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?

Alnylam and ISIS Pharmaceuticals Divide Up a Small Lobe of the Liver Kingdom

For some time now, a GalNAc IP war has been brewing given that GalNAc conjugation has been used by both Alnylam and ISIS Pharmaceuticals to enable tremendous advances in targeting genes in the liver in an ever more potent and apparently safe and convenient manner.  This has suddenly opened the floodgate to numerous therapeutic targets (ApoCIII, Factor XI, HBV, TTR etc) and indications with gene knockdown likely to dominate drug innovation for cardiovascular, metabolic, plus a number of viral and rare genetic diseases in the years to come.

However, instead of escalating tensions, a partial armistice was declared this week when the companies announced that they will not get into each other’s hair for at least 4 gene targets in the liver.  According to the Agreement, Alnylam can use the two companies’ combined IP to support RNAi Therapeutics against the rare genetic disease targets antithrombin (for hemophilias) and ALAS-1 (for hepatic porphyrias) while ISIS can leverage the same for antisense therapeutics against factor XI (for anti-clotting) and Apo (a) (for cardiovascular disease). 

Interestingly, the press release talks about a reciprocal IP cross-licensing that extends to ‘RNA-targeting mechanism’ leaving open the possibility that Alnylam may use ISIS’ RNaseH antisense chemistry and ISIS in turn Alnylam’s siRNAs for these targets.  This would allow the companies to maximize the life-cycle opportunities for these targets by making available multiple routes of administrations (subQ, inhaled, oral) and pharmacodynamics (slow/rapid onset; different effects of gene/protein half-lives on required dosing frequencies).  Moreover, since some genes are easier targets for a given mechanism than others, chances are high that you can find a highly potent molecule with either RNAi or RNaseH ASO.   

By thus avoiding duplication of efforts and competition in the marketplace, the economic value of these targets is likely maximized.  I do not expect, however, that the truce will extend to all targets in the liver given the advanced stage and importance of for example the TTR amyloidosis programs of the two companies.  Moreover, there might be partner (e.g. Genzyme, GSK) pressures to go after certain targets no matter what.  For these targets, it will be interesting to see whether the companies will resort to patent litigation or whether they agree to merely compete in the marketplace. 

While the economic rationale is obvious, there is a scientific risk to the non-compete.  This is because you might end up with a late-stage failure, e.g. due to an unanticipated side effect related to sequence-specific off-targeting that is only seen in larger patient populations.

This, of course, would be welcome news to 3^rd party competitors such as Tekmira, Arrowhead, and espcially GalNAc wannabe Dicerna who could then be the last man standing.  On the other hand, the concentration and coordinated use of the IP estates of the two juggernauts in the RNA Therapeutics space will make circumventing it more difficult to the competition.

Factor XI Data by ISIS Pharmaceuticals Revolutionizes Anti-Clotting Field

Yesterday, ISIS Pharmaceuticals disclosed in-depth data from their phase II anti-clotting study in about 300 patients undergoing total knee arthroplasty (TKA).  This took place at the American Society of Hematology (ASH) meeting alongside a publication in the New England Journal of Medicine (Bueller et al. 2014).  The data for the first time provide striking evidence that it is possible to dissociate anti-clotting activity from a commensurate increase in the risk of bleeding.

Accordingly, while the 200mg per week dose (moderate 59% FXI knockdown) achieved a rate of venous thromboembolism (VTE) similar to the enoxaparin standard-of-care comparator in the trial (27% and 30%, respectively), at the 300mg per week dose (much more robust 78% FXI knockdown) the VTE rate dropped by 7-fold to just 4%.  

At the same time, bleeding risk remained the same, if not better for ISIS-FXIRx vs enoxaparin: 3% bleeding events for both FXI cohorts vs 8% for enoxaparin, albeit this was not a statistically significant difference.

In terms of safety and tolerability, ISIS-FXIRx resulted in mild local skin reactions in 6.6% of the injections, but leading to no discontinuations.  Moreoever, no flu-like symptoms were recorded.  This is a stark departure from ISIS’ legacy drug mipomersen which suffered from frequent flu-like symptoms and injection site reactions resulting in relatively frequent drug discontinuations.

Challenging the paradigm

Until now, it has been widely thought that whenever you develop a new, more powerful anticoagulant, you will pay the price of more bleeding.  This has meant not only much development money wasted, but also created important market needs such as in patients which require anticoagulants with lower bleeding risks.

It is these markets, including patients with end-stage renal disease and atrial fibrillation, that ISIS Pharmaceuticals will address first as it seeks a partner more familiar with the complexities of the anti-clotting market.

What seems to underlie the surprising results is that with Factor XI you are targeting the intrinsic branch of the clotting cascade which prevents the formation of large clots that may travel around the body often with fatal consequences, but without impeding the ability to form small clots when healing tissue damage following trauma caused by external factors. 

By contrast, conventional anticoagulants such as enoxaparin (a heparin derivative), Factor Xa and thrombin inhibitors interfere with both processes.

Challenging the establishment

The strategy of addressing niches of high unmet need in the anticlotting market first is not only explained by potentially faster orphan-type development timelines, but also by the fact that by presenting such disruptive data in a multi-billion market, ISIS can be expected to encounter stiff resistance from the anti-clotting establishment.  This refers not only to competing pharmaceutical companies, but also their associated key opinion leaders from academia that enjoy a gate-keeper function partly due to the regulators commonly seeking their advice.   

So given that the efficacy results are undoubtedly impressive, expect over the coming days, months, if not years to hear the message that the ISIS-FXIRx data ‘might’ be a proof-of-principle for dissociating clotting from bleeding for anticoagulant therapy, but that this 300-patient study needs to be replicated in a larger population and that there are ‘concerns’ around the tolerability and convenience of ISIS-FXIRx, all the while the same groups are busy catching up developing antibody- and small molecule-based versions of anti-Factor XI drugs.