Thread by @skathire

A single IV infusion -->
96% lower plasma ANGPTL3 nearly 2y later in non-human primates!!

Coming era of "molecular surgery":
* one time Rx
* permanent switch off disease-causing gene in liver
* lifelong benefit

#ACC22

@ACCinTouch $VERV @VerveTx

newsfilter.io/a/45db4c967cb4…

some ASCVD patients start with very-high LDL

and

still do not reach LDL goal
despite oral standard-of-care and PCSK9i

In these patients,

ANGPTL3 inhibition with mAb (Evkeeza) proven to work,

to lower LDL-C by ~50% on top of oral SOC and PCSK9i

Complete lack of ANGPTL3 well-tolerated in humans:

human ANGPTL3 knockouts:
very low LDL-C, no liver fat

Key to LDL-C lowering with ANGPTL3 inhibition:

NEED NEAR-COMPLETE INHIBITION

this is clear from the human genetics:

compared with wild-type,

het deficiency (50% deficiency) led to minimal lower LDL-C

with 100% deficiency (human knockouts), 50% lower LDL-C

Can we achieve near-complete inactivation of ANGPTL3 with a once-and-done?

One-time IV infusion of ANGPTL3 base editor,

96% lower ANGPTL3 20 months later in NHPs

Well-tolerated out to 20 months

Stable LFTs, no change in T Bili

Grateful to @ambellinger and @VerveTx team

who over the last 3 years

have moved ANGPTL3 program from concept
to
proof-of-concept in NHPs!

👏👏

Full #ACC22 presentation here: ir.vervetx.com/static-files/6…

These developments raise the prospect of

sequential editing of two genes (PCSK9 followed by ANGPTL3)

for inactivation of two LDL-raising pathways in the same individual

Stay tuned for that thread.