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).