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?

CRISPR Therapeutics Provides First ANGPTL3 Data

Good morning, biotech.

Yesterday, regulatory uncertainty hit fever pitch with the appointment of Dr. Vinay Prasad to head the CBER division regulating biologics, including gene therapies and genome editing at the FDA.  Instead of assuming the worst for this line of drug development, I remain a firm believer that those that matter most, very sick people, will continue to push for medicines that can be shown to be safe and effective, and that Dr Prasad keeps to his view that the FDA should not make it harder, and therefore more costly, to develop drugs for severe rare diseases which have shown promise.

With that out of the way, let’s dive into the first data snapshot provided by CRISPR Therapeutics on its first-in-human trial with CTX310 (Cas9 knockout of ANGPTL3) for disorders related to high lipds, especially triglycerides and LDL cholesterol.

 

ANGPTL3 as a genetically and pharmacologically validated target

There is strong genetic evidence that reduced ANGPTL3 activity is associated with cardiovascular benefit.  A (life-long) 50% reduction in ANGPTL3 due to heterozygous loss-of-function variants cuts the odds of developing cardiac artery disease by almost half (Dewey et al,2017).  These subjects have modestly lower triglyceride (-27%) and LDL-cholesterol (-9%) levels.

Pharmacologic inhibition is even more impactful.  The ANGPTL3-targeting monoclonal antibody evinacumab from Regeneron for example lowers TG by about -80% in hypertriglyeridemia patients (Ahmad et al, 2019).  RNAi knockdown with ARO-ANGPTL3 from Arrowhead Pharmaceuticals with an ANGPTL3 knockdown efficiency of ~-70% resulted in approximately -60% TG, -60% remnant cholesterol (known ASCVD risk factor), and a modest -10% LDL-cholesterol reduction in mixed hyperlipidemia patients (Rosenson et al, 2024).

It should be noted, however, that besides an approval in very rare homozygous familial hypercholesterolemia, approval and development in other indications has somewhat stalled with ANGPTL3 inhibitors/knockdown agents.  Indeed, a study with evinacumab in multifactorial severe hypertriglyceridemia subjects failed to show statistically significant triglyceride lowering (Rosenson et al 2023)!  This and the fact that outcomes studies using non-genome editing modalities are lacking, makes ANGPTL3 potentially the most difficult cardiovascular disease target to bring to a large patient populations among the PCSK9, Lpa, and ANGPTL3 trifecta.

 

CTX310 shows steep dose response…and a surprise

CTX310 is an LNP formulation comprising an mRNA encoding Cas9 nuclease and a guide RNA aimed at the angiopoietin-like 3 gene.  Although the company wants to develop CTX310 for homozygous familial hypercholesterolemia which is characterized by LDL-receptor deficiency, the same receptor that standard LNPs rely on for uptake in hepatocyte, I assume that CTX310 does not include ASGPR-targeting via the addition of GalNAc ligands.

CTX310 was tested at 4 doses. It should be added here that the company provided doses on the ‘basis of lean body weight’ probably in the hope that it may in fact be a better predictor of drug delivery to the liver compared to dosing based on pure body weight or fixed doses.

Anyway, the 2 lowest doses (0.1 and 0.3mg/kg) showed no desired pharmacodynamic effect.  In fact, mean LDL-cholesterol strangely increased from baseline by 35% just 30 days after drug administration (n=3).  At 0.6mg/kg (n=3) and 0.8mg/kg (n=1; ~0.48mg/kg not adjusted for lean muscle), however, there was knockdown of serum ANGPTL3 of ‘up to -75%’ with concomitant decreases of TGs and LDLc of -56% and - 29%, respectively, at 0.6mg/kg.  At 0.8mg/kg the company reported a remarkable -65% LDL-cholesterol reduction on day 30 reaching a whopping -80% on day 90 in a patient with severe hypertriglyceridemia (TG>500mg/dL).  Triglycerides were also lowered by over -80% in this subject.

Safety findings, particular in terms of changes in liver enzymes and platelets, were characterized as 'not clinically significant', and clearly need further disclosure.  

Also because of its likely non-ASGPR-targeting nature, severe hypertriglyceridemia should be the most promising indication for CTX310, for example to prevent pancreatitis. The LDL cholesterol effects, however, warrant further investigation and may justify development for ASCVD.  Given that this was seen in just one subject, the 0.1 and 0.3mg/kg LDL-cholesterol increases in LDLc indicating there may be something odd with the assay, and that it is in great contrast to the genetic and pharmacodynamic evidence presented above, further subjects dosed at 0.8mg/kg may not show such dramatic effects.  If the values are real, however, and given the near opposite findings with evinacumab in severe hypertriglyceridemia, a closer look at the genetics of this subject may lead to fresh insights into lipid biology and render ANGPTL3 a more predictable target.

Happy Gene Therapy Talk Presaged Market Correction

In January, many biotech stocks went parabolic shattering all-time-highs.  Now they have started crashing back down to earth.

The run-up was partly driven by real fundamentals.  These include corporate tax reform in the US, a new FDA commissioner (Scott Gottlieb) who makes all the right decisions (speeding access to innovative medicines, fostering generic competition, amenable to rational discussion etc), and a voracious appetite for innovative pipelines in the pharmaceutical industry which has manifested itself in a number of chunky, multibillion dollar acquisitions. 

At the same time, ever-increasing valuations in a deceptively low-volatility stock market environment has emboldened analysts, investors, and managements alike to proclaim that the golden era of curative medicines is upon us.  Gene therapy and genome editing in particular got hyped beyond reason as if all of a sudden critical bottlenecks in tech development had been solved.  CRISPR companies Editas Medicines and CRISPR Therapeutics, without a single drug candidate in the clinic, were bid up to $2B valuations although access to genome editing tools have become a commodity and cannot be considered gate-keeping tech any more.

Not much changed technology-wise

I understand that gene therapies have made tremendous inroads into the pharmaceutical marketplace with the first 3 gene therapy approvals in the US over the last year, one for an eye disease by Spark Therapeutics and two CAR-T cell cancer therapies going after the same target.

While I acknowledge these successes, what is really surprising here is that it took that long to get there given that the related delivery and genetic technologies (AAV, gene insertion, immune cell transfer) have been in existence for a decade or two already.  In that light, the recent Happy Talk around gene therapy seemed overdone.

The CEO of one genome editing company, Sangamo Therapeutics, is a great example of this divergence between scientific progress and clinical reality.  

Having come on board only a year ago, the good Dr. Macrae looks as if he is having a steep learning curve ahead of himself.  The reason I got the impression is that he likes to grandiosely talk about how the company's AAV capsid shuffling will enable them to cure all these CNS disorders while making great progress with LNPs to address the rest of humanity's afflictions.

Well, LNPs have gotten 10x more potent every year for the last 15 years so we must have reached homeopathic doses by now; and looking at the literature, AAV shuffling hasn't changed all that much since I completed my post-doc in an AAV lab in Stanford.  Or maybe Jim Wilson has grown exceedingly gun-shy when he resigns from his well-paying function at AAV company Solid Biosciences over concerns of toxicity from high systemic AAV doses and possibly also his finding that delivery to a certain tissue in the mouse does not predict same delivery in humans.

Certainly, there are also tailwinds supporting gene therapy that had not been around a decade ago.  As alluded to above, society and regulators have finally warmed up to a very sensible approach to medicines in the genomic era.  Moreover, there are established paths now to effectively develop such therapies and the challenge of producing large quantities of viral vectors is gradually being addressed.

Still, amid the hype and stock market giddiness, valuations in many of these companies have run ahead of themselves and were ripe for a pull-back.

Next time you hear so much Happy Talk around a biotech subsector leader as has been the case for gene therapy, watch out for a correction.   

What about RNAi stocks?

RNAi stocks have also benefited from the overall bullishness in the biotech sector with ARWR and DRNA having run up by 300% or so in a matter of months.  While I still hold shares in these companies, I have written calls (largely in-the-money) on essentially all of them meaning that I am fairly insulated should they fall another 10% or so.   

Since I still like ARWR and DRNA ahead of their first clinical GalNAc knockdown data, and in the case of Dicerna the potential removal of the overhang from the Alnylam litigation, I am eyeing (and have been) selling out-of-the money puts on these for 10+% premiums or so.

If the market turns back up, you pocket the premium. 10% or so in a matter of 2 months is not bad in my mind.  If, however, the stocks decline and the puts are in-the-money at expiration, you get handed a stock that you like anyway.  Say Arrowhead for a price of $4.5 instead of $5.45 yesterday.  

But before you place any such options bets, consult with your investment advisor first to familiarize you with the risks of writing options!

On the simple, naked long side, I like Ionis Pharmaceuticals which, as a biotech stock that has essentially missed out on the post-Trump rally and with the upcoming Huntington’s data catalyst, has the potential to become a new biotech bellwether following subsector rotations that usually occur following corrections (remember the 2015 correction following which oligonucleotide stocks turned from sector leaders to laggards?).  Alnylam, meanwhile, looks tired here with a lot of the upside priced in, at least regarding the TTR story.

Happy trading and be mindful.