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?

First Curative Correction of a Deletion Mutation by Prime Editing

Another week, another disease cured by CRISPR technology.  

Today, Prime Medicine revealed that a young man with autosomal recessive chronic granulomatous disease (CGD) successfully received his own hematopoietic stem cells after ex vivo correction of a 2 nucleotide deletion in the NCF1 gene.  This is the first time a deletion mutation has been corrected and was achieved by prime editing, the most versatile of CRISPR technologies.  Cells, in particular the critical neutrophils engrafted in record time, supporting the ‘gentle’ nature of prime editing which does not involve double-strand breaks.  This can be problematic in the hematopoietic stem cell setting (p53 response).

CGD is an ultra-rare (~6000 patients in the US and EU) severe immunodeficiency caused by insufficient NADPH oxidase activity in phagocytic cells.  This activity is needed to kill off pathogens via reactive oxygen species (ROS).  The disease carries a high morbidity from recurrent and chronic infections with life expectancies in developed countries typically ranging from 30-60 years.  20% restoration of NADPH activity is thought to be curative.  Prime Medicine exceeded that easily with activity rising to 66% by day 28 following transplant.

  

NCF1 accounts for ~20% of CGD, most of which due to the deltaGT mutation.  This translates into a market opportunity of ~2000 patients in developed countries.  Considering that PM359 represents a most compelling treatment option despite of pre-conditioning concerns, de-prioritizing a  ca. $10B TAM is not an obvious decision as this trial could rapidly be expanded into pivotal trial phase.

I suspect Prime Medicine did not want to invest in the infrastructure involved in commercializing such an ex vivo cell therapy.  Instead, it is seeking a partner for the asset and is now concentrating its resources on in vivo LNP-delivered prime editing treatments for Wilson’s and alpha-1-antitrypsin diseases.  Vertex Pharmaceuticals, the commercial entity behind sickle cell CRISPR medicine Casgevy, would be a possible option and the prospect of PM359 receiving a priority review voucher (which recently have been selling for ~$150M a piece) should be a nice incentive.

Unfortunately, as part of the re-organization of the company, Prime Medicine is also dropping the program for X-linked CGD which is 3-4x more common than NCF1 CGD, but is caused by a plethora of mutations throughout the CYBB gene.  The company had pursued a gene drop-in approach with which it had hoped to address the entire CYBB market.  Considering the progress in ‘N=1’ drug development, X-linked CGD could have been a great showcase of conducting a basket-trial (possibly including them in the NCF1 pivotal trial phase) involving various mutation-specific prime editors.  Because whether CGD is caused by a mutation in the NCF1 or CYBB gene, the end goal would be the same: restoration of NADPH1 oxidase activity (as measured by DHR).

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.

Biotech Should Give Vinay Prasad Benefit of Doubt

The uncertainty stemming from the unpredictability and lack of evidence-based policies of the Trump administration has frozen many investment decisions.  Nevertheless, the new healthcare appointments such as Martin Makary as the FDA commissioner are turning out to not be all that bad for innovative biotech companies- unless, of course, you are in the vaccines space.  The appointment this week of Vinay Prasad as the new Director of CBER regulating, amongst others, gene and cell therapies, has caused renewed panic by expecting him to demand placebo-controlled outcomes trials that enrol thousands of patients in (ultra-)orphan diseases.  That indeed would be the end of the industry.

Here, I will lay out why I believe that many in the biotech industry are probably making false assumptions about Dr Prasad based on caricatured takes on comments he has made on social media and that he may, after all, turn out to be good for evidence-based drug approval processes, but at the same time allowing for speedy access to innovative therapies for underserved patient communities.

 

The Skeptic

Dr Prasad has made a name for himself on Twitter for spotting poorly run clinical trials or trials showing results of questionable medical value that have still led to FDA approvals.  As a hematologist-oncologist, his focus has been on oncology and the issue of having drugs on the market for which drug makers have failed to show benefit in terms of overall survival and quality of life following surrogate-based (typically PFS) accelerated approval.   

I agree that there is substantial money wasted in oncology on prescribing expensive drug regimens without providing actual patient benefit.  Neglecting to conduct confirmatory outcome trials to get at the question of patient benefit has been a routine game played by many in the pharmaceutical industry, including some in the orphan disease space.  

Unsurprisingly, Sarepta has caught his attention here with the approvals of both exon skipper eteplirsen and the more recent gene therapy Elevidys for Duchenne Muscular Dystrophy.  Like him, I have also been very vocal about the shenanigans around eteplirsen, including dubious molecular biology presentations on exon skipping efficiencies and their trial conduct.  It has also struck me, and actually many in the science-minded biotech community and FDA staffers, as wrong how FDA politics in the end overruled FDA staffers in approving eteplirsen.

Aducanumab by Biogen for Alzheimer’s was a similar situation drawing his ire, and although I could never understand how a risk/benefit analysis could favor aducanumab, I am able to see some value in Elevidys.

On the other hand, it would be nice if he would also talk more about what type of pharmaceutical innovations, if any, Prasad is open to.  As a medical hematologist-oncologist, however, I have no doubt that he understands the need for better medicines and that there more than enough people out there advocating for drugs.  Ever been to a big annual medical gathering?  I have been to a few of those and we all know how central pharmaceutical companies are in shaping the agendas. 

Let us be clear: these are big sales shows and unfortunately these are the meetings that Prasad will have attended.  In his new role, I hope he will also attend more patient-centered and sciencey meetings to get a more balanced view of the community and motivation behind drug innovation.

 

Covid19

Vinay Prasad rose to broader prominence during Covid19.  He criticized (mainly on Twitter and Youtube) social distancing measures, masking 2-year olds, indiscriminate vaccine recommendations and the US government showering Pfizer with billions in taxpayer money in the form of vaccine contracts and doing the sales and marketing job for its Covid19 treatment pill PAXLOVID of dubious benefit.

As a father of a daughter who had close to zero risk from Covid19, but had to basically self-teach herself basic language and mathematics skills at home, and then in fourth grade with a mask in school (oh the hot summer), and as somebody who has closely followed the science and politics around covid19 vaccine development, I wholeheartedly agree with his criticism.  Remember when (non-mRNA) Novavax was disadvantaged and delayed at every turn?  Or when it was clear that the risk/benefit would not justify not only giving, but mandating (!) young men to get covid19 boosters, yet many colleges and universities followed ACIP recommendations to do it anyway?

If having been critical of covid19 policies is a problem for the biotech community, then maybe they are indeed ‘woke’ beyond repair.  It is too easy to paint people black or white depending on one’s political views. It is more fruitful to engage in a nuanced, open-minded discussion.  It should be said that Vinay Prasad is beyond the point of emphasizing the value of vaccines, and amply uses them in his practice while considering anti-vaxxers to be weirdos.   

 

Rare disease and ‘gene therapy’

Most of the concern of the gene and cell therapy investor community related to the appointment of Dr Prasad stems him emphasizing the importance of drugs meet clinically meaningful endpoints in randomized controlled trials, not some biomarker endpoint in an uncontrolled trial.  

Clearly, this can be show-stopping criteria in the development of orphan disease drugs and drugs aimed at slow, progressing chronic diseases like Alzheimer’s and a number of metabolic and cardiovascular disorders underlying the ‘chronic health epidemic’.

Fortunately, Dr Prasad seems to acknowledge that this causes a quandary for the rare disease space and has shown openess to the idea of speeding up the approval of ‘gene therapies’ that have shown promise.  For example, in 2021 he noted:

“Uncontrolled data from Israel might be acceptable for an accelerated approval in a rare disease setting with dire outcomes, pending confirmatory study. It is not appropriate for a regulatory decision affecting 50 million healthy people.”

In fact, last year, a small biotech company in the rare disease space, Amylyx Pharmaceuticals, did exactly this: pull a drug for ALS from the market the moment the confirmatory study failed to achieve its goals.  As we know, the real problem with accelerated approvals has been in enforcing that the confirmatory studies get finished in a timely manner.  Fortunately this is being addressed by demanding that a confirmatory trial is underway at the time an accelerated approval is granted.  There is good reason to expect that the current framework can work and bad players like Sarepta (eteplirsen confirmatory trial that never reported results) should frankly be penalized for their conduct.

One concern dug up by those concerned about genome editing and CRISPR were posts on X ridiculing ‘the woke media’ (me paraphrasing here) for celebrating the results by Verve Therapeutics with its 1st generation PCSK9 CRISPR medicine VERVE-101.  This despite of concerning safety signals in a small trial, including cardiac events, liver enzyme elevations, and low platelet counts.  He called for halting the development of VERVE-101 and questioned why people would ever take this 'particular gene therapy’ when pills against the same target exist.

With regard to halting the development of VERVE-101, I had to agree with him.

 

The key question: How Open-Minded is Dr Prasad?

The fact that Dr Prasad repeatedly called genome editing drugs ‘gene therapy’ and did not point out that the short-term tox signals seen with VERVE-101 had to do with drug delivery and not the long-term effect of genome (here base) editing, strongly indicate that he is not a genome editing expert.  It is also important to recognize that Prasad's comment was not against gene therapy per se, but directed at this 'particular' one.  

A key question therefore is whether Dr Prasad is open-minded enough to take advantage of having immediate access to the world’s experts on all types of medical specialties and technologies and adjust his views accordingly.  They would not only tell him about the delivery problem with VERVE-101, but also that many CRISPR genome editing candidates are amongst the safest drugs from a genotox point of view in the universe of drug development.  No ‘swelling up’ of side effects over time, but cleansing, healing genetics.

I would love to hear from him in the coming months about what he thinks of the fact that Verve not only paused (voluntarily, not by mandate) the development of VERVE-101, but has since come up with VERVE-102 based on excellent science and impressive clinical results.  This is how drug development is supposed to work and he should be excited by that.

Or what does he make of the observation that while bluebird's 'gene therapy' was associated with cancer based on lentiviral vector integration, CRISPR Therapeutics' Casgevy has so far escaped that?

Also, if he or his buddies (for example his boss at the FDA Makary and his love for life-long hormone replacement therapy for women starting with menopause) believe that people will stick to taking daily pills starting in their 30s and 40s until death, so be it and good luck with that.  

I would take the opposite view that a one-time, early genome editing intervention would lead to much better outcomes if the target is chosen wisely.  So will Prasad, Makary and all those others in the new administration who are pro-choice in medicine use his powers at the FDA to prevent a potentially revolutionary drug and technology from coming to the market, instead of having patients and docs decide about its adoption?  That would be ironic indeed for pro-choice libertarians and deprive the fight against the chronic disease epidemic in the US an invaluable tool in the form of genome editing.

Investors do not like uncertainty and biotech is no different.  We are all holding our breath for when Vinay Prasad will provide a first insight into how he would change CBER processes to align with his view of evidence-based, patient outcome-focused drug approval without depriving patients of new promising treatments they are in dire need of.  My hope is that it will reflect his recognition of the great responsibility laid upon him and show a willingness to listen to and learn from the interaction with all stakeholders, including the top experts he will be exposed day in, day out.

I must say that Dr Prasad strikes me as somebody who is willing to look at the evidence and listen. Biotech companies who embrace good science and aim at truly changing the lives of patients for the better should not be afraid of the leadership change.  In the end, healthcare dollars are limited and should go to those that provide the most value, also in terms of pushing the boundaries of medicine, and not to those trying to game the system by keeping ineffective drugs on the market indefinitely or by preventing generic competition through monopolistic practices.

Update (9 May, 2025)

Subsequent to this entry, the FDA posted an ad hoc conversation with FDA commissioner Makary and CBER Director Prasad.  Clearly, the tumultuous reaction to Prasad's appointments, also in the gene and cell therapy stock market, forced their hand to be more transparent.  Congrats and thank you for coming out like that to the public and not just some select audiences.

In comments consistent with remarks made in a first address to FDA staffers by Prasad the day before, Prasad emphasized that he does not intend to be disruptive and continue CBER policy of being flexible depending on need, severity, and size of a patient population.  Change will largely be 'at the edges' of current operations.  'Nuance' and 'open-mindedness' are also terms that were repeatedly used in these dialogues.   

Importantly, Prasad reiterated his belief in the importance of vaccines and that he was amply using them also in the care post allogeneic transplantation.  This familiarity with blood stem cell transplantation is also positive for CRISPR-based HSC approaches like Casgevy which do away with the need for burdensome post-transplant immune suppression. 

nuance, open minded

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.

PTC Therapeutics Full-Length Huntingtin-Targeting Pill Comes Up Short, Setting Stage for Exon 1-targeting ddRNAi by UniQure

Today, PTC Therapeutics reported full results from a 52-week trial with PTC518 for Huntington’s Disease.  The data failed to support an intriguing early data cut last year that prompted Novartis to pay $1B for shared US profits and majority rights outside the US.  Unlike the previous n=32 data hinting at dose-dependent full-length huntingtin lowering (up to -43% in the CSF at the high dose) and corresponding improvements in functional outcome measures, the company had to dig deep to find hints of functional efficacy in today’s n=159 dataset.  In other words, an accelerated approval based on the PIVOT-HD trial is now highly unlikely.  Even huntingtin knockdown came down from -43% reported last year to the -20-25% range in the CSF and was not dose dependent.

That Novartis licensed the PCT molecule was surprising to me in the face of overwhelming evidence that protein derived from exon 1 huntingtin mRNA is the toxic molecule and increases in production as the CAG triplett somatically expands during the disease course (see this blog entry).  To me at least it seems that full-length huntingtin has fairly little to do with contributing to the disease.  Indeed, some had started to worry that targeting (full-length) huntingtin may even be harmful based on striatal atrophy caused by an antisense compound by Roche and Ionis (which I and others think can be attributed to the problematic phosphorothioate backbone chemistry of tominersen).  So at least in that sense, comfort can be taken from the PIVOT-HD results that there was no apparent worsening of disease caused by full-length huntingtin-lowering by the PTC518 splice modulator pill.

I can see that taking a once daily oral pill instead of drilling a hole in your skull may be preferable and an enticing prospect for a Big Pharma, but what good is that when the pill aims at the wrong target and will not work?  Of course, UniQure’s AAV-based DNA-directed RNAi therapy capable of targeting exon 1 mRNA will eventually be challenged and complemented by similar, but less invasive exon 1-targeting oligonucleotides or the nascent class of triplett expansion inhibitors, but a lot has to be said about the virtues of a drug that is not only targeted at the right transcript, but also where the exposure is limited to the main affected structure in the CNS.  

So while I understand that PIVOT-HD will cause some disappointment in the Huntington’s community, the data is making much more sense again from a mechanistic point of view following the confusion caused by the earlier data cut.  This should also give regulators further impetus to fast-track AMT-130 towards accelerated approval based on an upcoming 3-year comparison with propensity-matched natural history data.

China Fast-Follower Competition Reaches Clinical CRISPR

There is panic among Western biotech that Chinese competitors will eat their lunch with their capital-efficient fast-follower strategy which typically involves rapid clinical translation via investigator-initiated trials.  This issue has now reached the CRISPR space in the form of first clinical data announced by YolTech regarding a PCSK9 base editing trial for the treatment of hypercholesterolemia.

Almost identical to pioneer Verve Therapeutics which reported stellar data earlier this month (discussed here), YolTech’s YOLT-101 formulation involved a GalNAc-LNP encapsulating an adenine base editor mRNA and guide RNA targeting a splice site of the PCSK9 pre-mRNA for gene knockout.  The more detailed nature of the LNP formulation was not disclosed in the accompanying medRXiv publication.   

The trial tested 3 dose levels of YOLT-101: 0.2mg/kg (n=1), 0.4mg/kg (n=2), and 0.6mg/kg (n=3) indicating an unusually rapid move up in the dose level by international standards.  Efficacy was only reported for one subject treated with 0.4mg/kg and the three 0.6mg/kg subjects with heterozygous familial hypercholesterolemia.

Similar to Verve Therapeutics, LDL-cholesterol lowering was roughly -50% for 0.6mg/kg.  Unfortunately, the information provided did not allow for an analysis of the relationship of total dose of YOLT-101 and LDLc reduction.  On the PCSK9 front, YolTech seemingly did better than Verve Therapeutics reaching a mean of -76% versus the -60% for VERVE-102 both at 0.6mg/kg.

This, however, is where the similarities ended.  In terms of the critical safety of a potentially very widely applicable therapy, 3 out of the 6 subjects treated with YOLT-101 exhibited ‘transient elevations in ALT and AST’ that ‘almost’ returned to normal within one month.  Furthermore, 5 of 6 subjects experienced infusion-related reactions involving fever, myalgia, and vomiting. And similar to Verve’s ill-fated VERVE-101 formulation, one subject at the 0.4mg/kg dose experienced chest pain shortly after LNP infusion.

Nevertheless, the authors noted that the trial remains ongoing to ‘validate the therapeutic durability and safety profile’.  Considering the ALT/AST elevations for which more detailed values were not disclosed, it seems questionable whether this is an ethical decision.  Add to this the rapid dose escalation and selective data disclosures, it provides fodder to those criticizing China for allowing human experimentation and Big Pharma taking advantage of it by licensing therapeutic candidates built on such strategies on the cheap, not even mentioning the intellectual property issues of ‘Chinese Beam Therapeutics’