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.
