2nd Patient with Chronic Granulomatous Disease Successfully Treated with Prime Editing

Prime editing researchers are so excited about the technology that sponsor Prime Medicine is unable to control the newsflow on their CGD trial.  As happened 3 weeks ago at the ASGCT where news of a first patient successfully treated with PM359 leaked, Prime Medicine co-founder Dr. David Liu just dropped (23:00min mark) that a second subject has been treated…with even greater efficacy.

 

90% gene correction efficacy

As was detailed in a subsequent press release by Prime Medicine, the first patient saw a 66% correction of the GT deletion in the mutated NCF1 gene in hematopoietic stem cells that had been treated with prime editing ex vivo.  Importantly, neutrophil (day 14) and platelet (day 19) engraftment occurred extremely fast following transplantation compared to prior experiences with Cas9 nuclease (e.g. Casgevy, ~30 days) and similar to base editing (Beam Therapeutics sickle cell program).  This indicates that non-double-strand DNA cleavage methods are preferable for ex vivo HSC editing from that perspective alone.

Following a company re-organization where Prime Medicine announced it would not further pursue PM359 in favor of commercially more attractive genetic disease in the liver, the future of that program seemed in limbo.  However, with a second patient now treated, and at remarkable 90% gene correction efficacy according to David Liu, it now looks like Prime Medicine will complete the first patient cohort and seek ways to monetize the priority review voucher potential (PRV) of that program.  PRVs have recently sold for ~$150M a piece and provide a critical incentive for the development of treatments for rare pediatric diseases.

The PRV incentive was highlighted by David Liu, the intention to complete the first cohort confirmed in a fireside chat yesterday at Jefferies by the new CEO Allan Reine.  Considering the rarity of this form of CGD (~1 in 600,000 births), I would not be surprised if the new FDA granted PM359 early approval after this cohort considering that HSC gene editing is now well established.

 

Update on arbitration with Beam Therapeutics

Clinical results with CGD and preclinical data from Prime Medicine’s in vivo liver programs show that, with optimization and know-how, prime editing efficacies can be as high as with the simpler, but somewhat dirtier Cas9 nuclease and base editing.  This makes them the preferred CRISPR editing modality for virtually all indications and has led to a conflict with Beam Therapeutics as they see their lead alpha-1-antitrypsin (AATD) base editing program under threat.

Previously, I had viewed Beam Therapeutics to have the upper-hand with regard to correcting the Z allele as this, as a single transition application, would seem to fall within its exclusive field of use of prime editing under their agreement with Prime Medicine.  Allan Reine, however, hinted at Jefferies that the edit Prime Medicine is pursuing is aimed at restoring the wildtype amino acid…not necessarily wildtype DNA.  This could mean that Prime Medicine’s strategy is to replace the AAG lysine codon in the 342 Z allele to GAA glutamic acid, instead of GAG as Beam Therapeutics is doing.  This would involve two, not a single transition and thus arguably fall outside the scope of Beam’s exclusive field 😊.

Disclosure: I am long Prime Medicine with about 7% of my portfolio allocated.  Given yesterday’s bullish regulatory (FDA CBER listening session), legal, and clinical developments and the basic premise that prime editing is the preferred CRISPR modalities in the foreseeable future, I am looking to add to my position.  Hard to believe a company controlling such a monumental technology can go bankrupt as the markets seem to price in.

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.

The time for genome editing is now

Back from recent CRISPR conferences in Ireland and Denmark, I wanted to share my current thinking about the present and foreseeable future of clinical genome editing.

CRISPR is a clinically mature platform

First of all, genome editing, and in particular CRISPR Therapeutics have arrived big time.  Ignore for a moment the 90%+ declines in the share prices of Intellia, Verve, and Metagenomi, that all, with the exception of perhaps Beam Therapeutics, suggest that the industry will not survive.  Focus instead on the transformational results last week by Verve Therapeutics which will shape the management of chronic metabolic and cardiovascular disease for decades to come, Beam Therapeutics last month announcing that it  for the first time fixed a genetic disease (AATD) by reversing a point mutation, or the three ongoing phase 3 programs by Intellia Therapeutics which promise patients live unintruded by their disease.

So you say that this is only half the truth and many of them will develop cancer?  With hundreds of subjects having been given CRISPR therapeutics, we still have yet to hear about such cases, including for the hematopoietic stem cell applications, probably the most stringent test in that regard given the history of retroviral gene therapy.  This is supported by ample detailed genomic analyses demonstrating that many CRISPR modalities, in particular prime editing, often do not have any detectable off-targeting (!) and therefore are safer than going out in the sun or eating grilled meat.  And don’t get me started with analysts and investors pretending that small molecule drugs, 'dirty drugs' by design, are much safer in that regard when many of them like methotrexate and hydroxyurea are known to cause cancer which barely gets a mention or is routinely accepted as part of the risk-benefit of a drug.  Similarly, the currently more widely embraced antisense and RNAi technologies exhibit considerably more off-targeting, which in theory could result in cancer development with chronic use, than the average CRISPR therapeutic candidate today. 

Prime editing is the ultimate CRISPR manifestation

Prime editing is the foreseeable endgame for genome editing involving edits up to 50 nucleotides.  This is because in addition to being able to knock out genes like (Cas9) nuclease or base editing, it allows the developer to change nucleotides at will and with incredible specificity, and for gain-of-function.  It has therefore surprised me to see that prime editing is still such a niche part in these conferences and barely used in industry and even academia where IP is less of an issue.  This can likely be explained with it requiring a good deal of mental gymnastics when devising a prime editing strategy and subsequent tinkering to optimize efficacy.  Prime editing will likely also be part of strategies for achieving even larger edits, including whole gene replacements that are often desirable.

In some ways this is reminiscent of zinc fingers which make for poor screening and quick molecular biology tools and were quickly forgotten when CRISPR came along with the promise of simple sgRNA design.  However, a panel at the Copenhagen CRISPR meeting by genome editing veterans made it clear that when optimized, zinc fingers can be every bit as powerful as CRISPR and currently have a leg up where delivery is going to be viral for some time to come.  

This is particularly true for the CNS, the fourth major tissue/organ target for genome editing applications after the liver, hematopoietic stem cell, and immune cells.  Not only is it impossible to fit in prime and base editors in single AAV vectors, expressing a CRISPR effector nuclease of bacterial origin for years may be tricky (but not unsolvable) in terms of immunogenicity.  There is also some unease about having nucleases loiter around in cells for years after their job has been done.  Self-targeting/inactivation strategies may here be called for.  Zinc fingers by being small and mimicking human proteins by contrast are ready for clinical use, a fact, as the deal flow by Sangamo Therapeutics illustrates, is increasingly being recognized by the wider industry.

Genome editing versus non-permanent modalities

Another popular argument against CRISPR Therapeutics questions why one should take a ‘risk’ with permanently altering the genome when you have oligonucleotide therapeutics options that need to be administered as infrequently as every quarter, half annually, or even annually.  

While there is some application overlap between genome editing and oligonucleotide therapeutics, especially when it comes to knocking down genes, a closer look shows that the overlap is limited.  Where there is clear genetic evidence that a gene can be disabled for life without safety risks, then genome editing is the endgame, or at least capture a good portion of the market, and transient modalities may serve to de-risk the targets first.  

When it comes to bringing pathways back into finely tuned balance and/or the disease is not chronic and likely requires only temporary treatment (e.g. some cases of hypertension), transient options are preferable.  Still in other cases such as prion or Huntington’s disease where it is not clear whether it is the overall level or distribution of gene knockdown that is more important for efficacy, the preferred modality has yet to emerge from clinical studies. 

Part of the Wall Street fashion show

Wall Street is a fashion show when it comes to biotech platforms.  A little less than 10 years ago, it predicted that CRISPR would kill off the RNAi Therapeutics industry. Today, Alnylam sports a $30B market cap, about 4x that of the entire CRISPR industry combined (much of it in cash).  Of course, investing in technologies ahead of their time is fatal. The electric vehicle industry is just one example.  As I have laid out above, genome editing, however, is now and here to stay.  Having the potential to save the healthcare system money (e.g. $2M for a one-and-done HAE/ATTR treatment as opposed to $500k annually) or to lead to drastically improved outcomes (as can be predicted from chronic LDLc lowering) got to be embraced by patients, their caregivers, docs, regulators, and insurers alike.  

It's been a rough couple of years investing in development-stage, cutting-edge biotechs and current politics does not seem helpful, but if this is when it is darkest, then generational wealth awaits the survivors with the guts to hold on during a volatile comeback.  One of my two conviction bets that I look up to in this regard is therefore CRISPR therapeutic biotech Verve Therapeutics.  Uniqure, which works in the similarly unloved gene therapy arena and has a promising DNA-directed RNAi candidate for Huntington’s disease, is the other in case you were wondering.  

Silicon Valley Bank Failure is Warning Against More RNA Editing Start-Ups

As the collapse of Silicon Valley Bank (SVB) is making the rounds, let's take a step back and ponder what it means for the RNA Editing space.

SVB has been a prominent banking partner for start-ups in tech and biotech, willing to do business where traditional banks did not feel comfortable with the unique risk profiles and needs of such businesses.  Short-term, the failure means that some jobs are at risk as small companies for which SVB was the only banking partner may not be able to make this month’s payroll in time, and 10-20% of uninsured deposits above the $250k FDIC limit may be lost forever. 

SVB’s failure is a crack in the system resulting from rampant inflation and the dramatic rise of interest rates in response.  It’s quite possible that other cracks, also among the more traditional banking sector, emerge soon due to an imbalance of short-term cash demands of bank customers and banking treasuries overweighted in bonds with long maturities that can now only be sold at a loss.   

Too many biotechs!

That SVB, along with a smaller crypto-catering bank (Silvergate), is among the first victims is largely due to biotechnology’s voracious appetite for capital, but an inability to raise more of it in the current environment.  Having too many companies developing the same platforms and targeting the same diseases in parallel, especially in the gene therapy, genome editing, and immune oncology spaces, has only exacerbated the interest rate problem. 

SVB is thus symbolic for the (bio)tech excesses in recent years, culminating with the Covid19 crisis where every little idea was transformed into a start-up with $100M of funding from the get-go housed in glitzy labs and offices in the most expensive hubs, run by entitled executives more focused on ESG issues than bringing their technologies to fruition.   Contrast this to 15 years ago when little biotechs like LNP pioneer Tekmira (Protiva then) did better science, developed platforms more rapidly while fighting off larger rivals, yet spending just $3-4M a quarter.

Take CRISPR genome editing.  It seems like every new Cas enzyme, every new enzyme tethered to Cas9 doing something, anything with DNA or the epigenetics around it needs a new cash-burning start-up.  Instead of for example licensing prime editing to Beam Therapeutics, founded on more advanced base editing technology from the same academic laboratory, the movers and shakers in the VC scene sought to exploit David Liu’s star scientist status to found yet another immature biotech company many years away from a potential product and with even more inexperienced management.  To add insult to injury, this has been taken to the extreme of selling Liu’s* genius to suggest that he has solved nucleic acid delivery where thousands of humble scientists have worked over decades on similar concepts.  Enter Aera Therapeutics with- hold your breath- $193M in start-up funding.  

* correction: the scientific founder behind Aera Therapeutics is another CRISPR researcher from MIT, Feng Zhang, not David Liu.  The message, however, is the same.

Every paper a new biotech it seems. Sorry, and with all due respect to those involved: this type of behavior is unacceptable and comes across as greed and hubris.

 

Not too late for RNA Editing

One of the reasons I like ADAR RNA Editing also as an area of investment is that it is a differentiated technology platform allowing for unique therapeutic approaches and, equally important, where there has not been this hype leading to an overproliferation of companies and inefficient use of capital.

It is also not surprising that the two most advanced companies in the space, ProQR and Wave Life Sciences, are not pure-play startups.  By contrast, the refinement of editing oligonucleotides here happens within companies with a decade of experience in oligonucleotide drug development, and at least in the case of Leiden-based ProQR, at a fraction of the cost of its start-up rivals KorroBio and ADARx based in the Boston and San Diego hubs, respectively.

I am highlighting KorroBio and ADARx because they are the two most prominent start-ups around synthetic oligo-based ADAR RNA Editing that have significantly benefited from the Covid19 boom in biotech financing, but where I fail to understand what they are bringing to the table and thus the point of their existence.  For example, I wrote about my surprise at Korro Bio going with LNP delivery for liver-targeted AATD.  This most likely comes down to their inexperience in oligonucleotide chemistry.

So here is my plea to the ADAR RNA Editing industry: we do not need to repeat the mistakes made in other areas of biotechnology.  Competition, such as the rivalry between Alnylam and Sirna Therapeutics in RNAi, is a good thing as it focuses the mind, but 2 or 3 strong ADAR Editing-based pure-plays are really enough, plus some platform adoptions by larger oligonucleotide therapeutics companies like Ionis, Arrowhead, or Alnylam and disease-specific licensing activities of Big Pharma; and if there are important advances in academia relevant for the space, tech licensing the old style is appropriate.