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).