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.

Beam Therapeutics and Prime Medicine Need to Unite

Prime Medicine disclosed this week that they were in binding arbitration with Beam Therapeutics regarding their development of prime editing for alpha-1-antitrypsin disease (ATTD).  This is one of the fall-outs from the VC-driven glut of CRISPR-related start-ups during its hype phase.  It is an opportunity to correct one mistake by uniting the two technologies under one roof for the benefit of patients and investors.

Beam gained exclusive rights for transition mutations

When Prime Medicine was set up in 2019, Beam Therapeutics (founded in 2017) gained exclusive rights to the use of prime editing for transition mutations, i.e. converting A>G, G>A, C>T, and T>C.  This way, Beam Therapeutics’ foundational base editing capabilities would be shielded from competition by a company having the same scientific founder, Dr David Liu.

2019 collaboration and license agreement

While in theory, Beam's rights appear straightforward, in practice things often become murky, especially when interests diverge.  Typical collaboration and license agreements, and this one in particular, rely on the sharing of know-how to actually enable therapeutic development.  If the parties are at war, however, this clearly is unrealistic.  

Prime editing was in its infancy in 2019 when the agreement was signed. Since then, numerous improvements to prime editing have emerged to increase the miniscule efficiency of the original invention.  Any researcher contemplating using prime editing knows what I’m talking about as he will get dizzy from the dozens of possible iterations to choose from.  Moreover, to get to the >50% in vivo prime editing efficiencies Prime Medicine is now reporting, the company will have gathered critical trade secrets.

The question that then often arises is whether related IP and know-how is within the scope of the agreement.  We also have yet to learn how long the term of the collaboration agreement was.  In any case, I expect sufficient wiggle room for Prime Editing to get something out of a hostile arbitration.

Base editing as a transition mutation in the evolution of CRISPR technology

Base editing was a tremendous invention and associated with high editing efficiencies from the get-go.  However, this high editing efficiency also comes at the cost of the bystander editing issue, meaning that bases nearby target As and Cs in the protospacer loop region also get easily edited.  This sometimes is relevant for both safety and efficacy of the editing approach.  Moreover, as the base editing enzyme hangs out in the nucleus, it similarly indiscriminately deaminates single-stranded RNAs it encounters.  This is a particular issue when the enzyme is not delivered as an RNP or mRNA and will be present in a cell for longer.  Finally, despite not introducing double-strand breaks like Cas9 nuclease, it sometimes leaves behind small indels, and in the case of cytidine deaminases surprisingly many translocations.

So as the efficiency of prime editing, which has incredible specificity, is catching up with base editing, it more and more becomes a threat to the bread-and-butter applications of base editing, including AATD.  And in theory, if Beam Therapeutics were to push alpha-1 editing upwards of 60% in competing with prime editing, the efficiency of ‘clean edits’, that is edits without concurrent bystander edits actually decreases.

And what if you had to go back in and correct the edit if you find out 10 years down the line that an edit was problematic?  With the precision of prime editing, the target site will be there as predicted and therefore targetable.  That is not the case when you have to deal with target sites containing just the on-target edit, a mix of on- and bystander edits, or just bystander edits.

A similar situation presents for sickle cell disease, although in this case Beam Therapeutics got rights to the causative sickling transversion mutation in the beta-globin gene, not 'just' reactivating fetal gamma-globin via base editing.  Base editing, it increasingly appears, is at the risk of becoming a transitory technology. 

Get David Liu in the room!

Clearly, the prime editing competition is on its heels of Beam's two lead programs (AATD and SCD) and eventually will be the preferred options for patients. 

This is where I believe the scientific founder David Liu could and should step in.  How can he watch Beam Therapeutics shelve prime editing and access to better medicines for patients just so that Beam can protect its own franchises?  Also, if not Prime Medicine, other companies working on ‘gene writers’ will eventually get there, too, so none of his companies would benefit from the opportunity prime editing presents.  With prime editing enabled in-house, Beam could further cement disease franchises in the form of follow-on products.  

Last, but certainly not least, the development of prime editing for addressing genetic disease caused by many mutations within a given gene, an application that only prime editing is fit to pursue is stalled when Prime Medicine, or their licensing partners, are prohibited from addressing basically 50% of the point mutations?  How can David Liu accept this?

So get in the room, David Liu, and talk sense into the executives.  You have the moral power to do this and investors from both companies stand to benefit from seeing the two companies united.