If LDL⬇️for a long time, really hard to get heart attack

Cool new evidence

Some lucky people born with DNA variation that naturally lowers LDL

~50 mg/dl⬇️LDL, lifelong
&
risk for heart attack/death is ~50%⬇️!

So, for every 1 mg/dl⬇️LDL lifelong,
~1%⬇️risk heart attack/death @jsdron looked at sequence data from 2 different datasets

Dataset 1:

5 US cohorts, ~19K ppl,

~ 1 in 140 won genetic lottery,

carried DNA variant that
turned off
either PCSK9 gene
or APOB gene

49 mg/dl lower LDL (L)

49% reduction in risk for coronary heart disease (R)

Excited to announce today:

development candidate for 2nd program

(VERVE-201 targeting the ANGPTL3 gene)

to treat homozygous FH as well as ASCVD

data to be presented by @amitvkhera @escardio 2022

Press release: ir.vervetx.com/news-releases/…

Data: ir.vervetx.com/static-files/3…

$VERV @VerveTx first program VERVE-101 (targeting PCSK9) is designed to permanently lower LDL cholesterol after a single treatment and is intended to treat FH and ASCVD

What's the unmet need beyond this?

Two patient populations👇🏽

Now, you thought @VerveTx was just a CVD product Co.

No, we invent delivery tech as well

New data today in wild-type NHPs:

our proprietary GalNAc-LNP *more potent & consistent* than standard LNP

with 98% reduction in plasma ANGPTL3!!

(editing of basically every hepatocyte) We developed proprietary GalNAc-LNP last year in order to better treat patients with homozygous FH who completely lack LDLR

Now, the new NHP data suggests that GalNAc-LNP might become

best-in-class technology

to deliver genetic medicines to the liver

A thread on LNPs...

New NHP data from @ambellinger & team @VerveTx to address:

how durable & potent will VERVE-101 be?

*20 months & going for precursor

*68% lower LDL-C for VERVE-101 clinical formulation (n=22 NHPs)!

To be presented at TIDES meeting on Wed.

See here: ir.vervetx.com/static-files/e… One-time treatment with VERVE-101

Permanently switch off PCSK9 gene in liver

Blood PCSK9 down 89% a year later

Today, @harijay from @VerveTx presenting

comprehensive off-target analyses for VERVE-101

@KeystoneSymp Precision Genome Engineering

ir.vervetx.com/static-files/d…

Some highlights: Before we get to off-target, let's look at on-target site in PCSK9 gene

Single base pair change at canonical splice site between exon 1 & intron 1

Precise, stereotypical A to G change after treatment in 98.7% alleles (key advantage base editing)

No edits of bystander adenines!

Some patients with very high LDL-C who have already suffered a heart attack:

*may need both the PCSK9 and the ANGTPL3 pathways inactivated

*can we accomplish this with gene editing -

the switching off of two genes in the liver in the same individual?

#ACC22 @VerveTx $VERV NHPs treated:
*day 0 with VERVE-101 targeting PCSK9 (one-time IV infusion)
*day 30 with ANGPTL3 base editor (one-time IV infusion)

*necropsy at day 90 -->
high level editing of each gene!!

69% editing PCSK9
61% editing ANGTPL3

Each edit designed to switch off respective gene

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

New pre-clinical studies with clinical formulation of VERVE-101
1. large NHP study (L)
2. liver regeneration model
3. absence germline editing
4. absence off-target at 244 sites

+

15-month durability with precursor (R)

=

On track for IND 2022

globenewswire.com/news-release/2…

$VERV New large NHP study (n=36) with clinical formulation VERVE-101

2 dose levels 0.75 mg/kg and 1.5 mg/kg

Mean liver PCSK9 editing 70%! (L)

Potent, durable reduction plasma PCSK9 (R)

Dr. Braunwald, arguably world's leading cardiologist, on:

How to live to 100 (free of a heart attack)?

Get LDL as low as possible for as long as possible.

(mission of @VerveTx)

academic.oup.com/eurheartj/adva… 1. "general agreement that LDL-C is the most important risk factor for atherosclerosis & causal role in the development of ASCVD."

2. "atherogenic effect of LDL-C appears to be dependent on both the level of circulating LDL-C and the *duration* of this level."

A home run!

@intelliatweets shows for first time in humans that in vivo liver gene editing (CRISPR-Cas9 mRNA + guide RNA packaged in a lipid nanoparticle)

is going to work (REALLY WELL)

At dose of just 0.3 mg/kg in 3 humans,
plasma TTR reductions:

80%, 84%, & 96%

No AEs

😳 A most surprising finding:

@intelliatweets reveals effective dose in non-human primates had been 3 mg/kg (L)

Effective dose humans 0.3 mg/kg (R)

From monkey to human, a full 10-fold lowering effective dose

Incredible. Can only imagine J. Leonard’s reaction after 1st 3 pts

😳

Does chronic disease need to equal chronic care? No

👇in @Nature from @VerveTx

One-time base editing Rx (in vivo liver),
durable⬇️LDL-C

In monkeys:

*⬇️90% PCSK9,⬇️60% LDL-C, now out to 10 mos

* VERVE-101: efficacy at LNP doses as low as 0.5 mg/kg

nature.com/articles/s4158… What's happening with this treatment to lead to potent, durable LDL lowering?

1. One-time infusion intravenous

2. Drug product: mRNA for adenine base editor + guide RNA targeting PCSK9 gene with both packaged in a lipid nanoparticle

2 powerful relationships in medicine:

(L) For every 39 mg/dL pharmacologic LDL lowering ~5y,
⬇️21% in CV events
(regardless starting LDL)

Now, we have:

(R) For every 5 mmHg pharmacologic BP lowering ~4y,
⬇️10% in CV events
(regardless starting BP) (LDL, 2005) thelancet.com/action/showPdf…

BP, 2021) thelancet.com/action/showPdf…

Amazing.

Once weekly injection, 30lbs average weight loss

Phenomenal results for a medicine to treat obesity

Once-Weekly Semaglutide in Adults with Overweight or Obesity | NEJM nejm.org/doi/full/10.10… And look at all the metabolic benefits of the weight loss:

lower glucose,
lower DBP,
lower TG,
lower CRP

(L) 2010, human genetics:
1st suggestion ANGPTL3 inactivation can lower LDL

(R) 2020, pharmacology:
RCT proving pharmacologic inactivation ANGPTL3 substantially lowers LDL (in homozygous familial hypercholesterolemia)

Lessons:
human genetic validation👌🏽
Rx development=time evinacumab targeting ANGPTL3, IV infusion q4 wks

65 patients homozygous FH
*placebo controlled* trial
90% pts with established CAD
Majority pts on statin, ezetimibe, *and* PCSK9i

Baseline LDL still 255 mg/dl

ANGPTL3i lowered LDL by 49%!!

👏🏽@Regeneron

nejm.org/doi/full/10.10…

11yo: Dad, what did you do this past decade?

As the sun sets on 2010s,

thread reflecting on our scientific contributions this past decade to understanding 2 simple questions:

1. why do some get a heart attack at a young age?
2. why are some protected from heart attack? @broadinstitute @MassGeneralNews @MGHHeartHealth @VerveTx 2010 👇🏽

(L) family with LDL 20, triglycerides 20: reason was complete deficiency of gene ANGPTL3; now target for LDL lowering

(R) in many, very high LDL (>190) due to the additive effect of multiple variants (polygenic model)

After being told of BRCA1 mutation,
up to 50% women opt for prophylactic mastectomy

Should this be so?

For "monogenic" forms breast ca, colorectal ca, & heart attack, we find polygenic background powerfully modifies risk

New on @medrxivpreprint

medrxiv.org/content/medrxi… @medrxivpreprint @amitvkhera @Color @broadinstitute @MassGeneralNews For breast cancer, polygenic background:
1. has main effect +
2. modifies penetrance of BRCA1/2 mutation

For BRCA1/2 mutation carrier, probability of breast ca by age 75 can vary from 13% to 76% based on polygenic background

A reason why ID of young people at risk for heart attack is
challenging:

A large fraction of early heart attack patients are abnormal
in a risk factor
that
we *don’t* currently measure:

polygenic background

https://twitter.com/JACCJournals/status/1183012877235609600

Recently studied 2,081 pts (66%♀️) who had suffered a heart attack age <= 55 yo

Of these, 17% had high polygenic score as key risk factor. A risk factor we don't currently measure.

Only 1.7% had a familial hypercholesterolemia mutation.

Both conferred similar degree risk

News:

After 22y @MassGeneralNews @broadinstitute understanding risk & resistance to heart attack,

I am moving to new role as CEO @VerveTx - a biotech we have founded

to develop gene editing Rx that permanently reduce risk of coronary disease in adults

vervetx.com @VerveTx has been built to address one problem - heart attack

*the world’s leading killer
*is rising in prevalence worldwide
*present day, chronic care medicines and lifestyle recommendations not adequately changing that reality

vervetx.com/why-heart-dise…

Astounding fact I learned today:

Weight of average adult US male

1960: 166 pounds
2002: 191 pounds

😬 Weight of average adult US female

1960: 140 pounds
2002: 164 pounds

👇🏽 what I hope will be our most impactful discovery to date

An enzyme whose loss of function lowers blood cholesterol & *protects* against fatty liver & cirrhosis

Kudos to @connoremdin whose clever analysis of public data (@ukbiobank) led to observation

biorxiv.org/content/10.110… Here's the story of the discovery:

@connoremdin noticed that gene variants affect cirrhosis in same direction, similar effect size regardless of underlying etiology (fatty liver, alcohol, viral)

Excited about real-world data (ie, electronic health records) for causal inference? a cautionary tale👇🏾

in @uk_biobank analysis LDL extremes & risk for future coronary disease (one of surest causal relationships in medicine) by @jpirruccello yields:
WRONG ANSWER

What happened? Answer: confounding based on LDL-lowering treatment at entry into @uk_biobank

(L) plot without accounting for lipid-lowering therapy

(R) plot after accounting for lipid-lowering therapy at baseline (about 17% of participants on lipid-lowering Rx at entry)