Verve Therapeutics Gene editing to treat coronary heart disease - Sekar Kathiresan, MD Chief Executive Officer - Verve ...
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Verve Therapeutics
Gene editing to treat
coronary heart disease
Sekar Kathiresan, MD
Chief Executive Officer
38th Annual JP Morgan Healthcare Conference
January 12, 2021
1
Imagine if…
there was a …safely and permanently Such a medicine has
“once-and-done” lowered blood LDL cholesterol potential to treat and
treatment that… and/or triglycerides. ultimately eradicate
coronary heart disease.
2
Pioneering a pipeline of “once-and-done” gene editing
medicines to treat coronary heart disease
DEVELOPMENT STATUS
PROGRAM INDICATION
Research Lead optimization IND-Enabling Phase 1 Phase 2/3
Low-density lipoprotein (LDL)
VERVE-101 Heterozygous familial
ABE-PCSK9 hypercholesterolemia
Triglyceride-rich lipoprotein (TRL)
ANGPTL3 Undisclosed
Lipoprotein(a) Lp(a)
LPA Undisclosed
3
Significant opportunity to transform care of coronary heart disease
Coronary heart disease (CHD) is a leading health problem worldwide,
with blood LDL cholesterol (LDL-C) clogging heart arteries
Atherosclerotic Plaque
Caused by LDL-C
#1 cause of death globally
24 million with CHD in US/Europe
1.6 million with monogenic subtype:
familial hypercholesterolemia
Site of Blockage
5
Familial hypercholesterolemia is a life-threatening genetic disease
with high cumulative exposure to LDL-C causing early CHD and stroke
High genetic risk:
• Familial hypercholesterolemia (FH)
• Genetic disease, high blood LDL-C
• Early coronary disease, stroke, death
• 1.6 million people in U.S & Europe
6
Targets to treat FH and CHD: genes that harbor resistance
mutations which lower LDL-C lifelong
Low genetic risk:
• Resistance mutation lowers LDL-C
• Turns off any of 8 genes
• All expressed in liver
• Include ANGPTL3 and PCSK9
7
Individuals who naturally lack ANGPTL3 gene have lifelong
low blood lipids, are healthy and resistant to heart attack
Target gene de-risked
by human genetics
Human knockout:
Extremely low blood lipids, healthy
mg/dl
Triglycerides: 19
LDL-C: 37 mg/dl
By Gina Kolata
May 24, 2017
Anna Feurer learned
she had unusually low
triglyceride levels after
having bloodwork at a Heterozygous deficiency:
corporate health fair.
The discovery prompted
researchers to recruit
Low lipids
her and her family for a
research study of their
Resistant to heart attack
genetic makeup.
Credit. Jess T. Dugan
for The New York Times
Musunuru et al., N Engl J Med 2010 8
Individuals who naturally lack PCSK9 gene have lifelong
low blood LDL-C, are healthy and resistant to heart attack
Low genetic
Target gene de-risked Human knockout:
risk population
by human genetics
Extremely low LDL-C, healthy
14 mg/dl
By Gina Kolata July 9, 2013
Heterozygous deficiency:
Low LDL-C
Her cholesterol was
Resistant to heart attack
astoundingly low. Her
low-density lipoprotein,
or LDL, the form that
promotes heart disease,
was 14, a level unheard-
of in healthy adults,
whose normal level is
over 100.
The reason was a rare
gene mutation she had
inherited from both her
mother and her father.
Cohen et al., N Engl J Med 2006;
354:1264-1272
9
Can we transform care of coronary heart disease from daily pills/intermittent injections to “once-and-done?”
Gene editing technologies to permanently turn off either
PCSK9 or ANGPTL3 in the liver: Cas9 vs base editing
editing domain
A
DNA PAM DNA PAM
≈20 nucleotides ≈20 nucleotides
guide RNA guide RNA
Cas protein catalytically impaired
Cas9
Cas protein
Cpf1/Cas12a base editors
C2c1/Cas12b double-strand break
(modified from
gene deamination of CRISPR systems)
cytidine to uridine
or adenosine
to inosine
non-homologous end-joining repair process
(error-prone)
G
disruption of gene introduction of CàT or AàG change
11Prioritized DNA adenine base editing (ABE) technology to
precisely & permanently turn off PCSK9 or ANGPTL3 in liver
More potent
Better safety profile due to
absence of double-strand breaks
Base editing of liver cells Exclusive IP access from Beam
turns off a gene and
lowers LDL-C in the blood
12VERVE-101 is a lipid nanoparticle (LNP) containing
mRNA for ABE & a guide RNA targeting PCSK9
1. mRNA for ABE
2. guide RNA targeting PCSK9 Electron
3. Amino lipid micrograph of
4. Cholesterol Lipid VERVE-101
5. DSPC components
6. PEG-lipid
60 nm
• Single course treatment
• Intravenous infusion over ~60 min
13Testing adenine base editing (ABE) in non-human primates
Non-human primate study design: in vivo ABE
GROUP 1*
Primary endpoints at 2 weeks
mRNA: ABE
Guide RNA: PCSK9 1. Whole liver DNA editing
2. Blood protein level
Lipid nanoparticle
3. Blood lipid level
Intravenous
infusion T=0 T = 2 weeks
GROUP 2
Necropsy or liver
DPBS Control biopsy at 2 weeks
*Lipid nanoparticle
in collaboration with
Acuitas Therapeutics
15We achieved substantial base editing of PCSK9 in NHPs:
67% whole liver editing
PCSK9 editing
% whole liver adenine editing
DPBS ABE-PCSK9
control
67%
16In vivo base editing to turn off PCSK9 gene in NHP liver leads to
89% lower blood PCSK9 protein levels
PCSK9 editing Reduction of blood PCSK9
protein at 2 weeks
% whole liver adenine editing
% change from baseline
DPBS ABE-PCSK9 DPBS ABE-PCSK9
control control
67% -- 89%
17In vivo base editing to turn off PCSK9 gene in NHP liver leads to
89% lower blood PCSK9 protein & 59% lower blood LDL-C
PCSK9 editing Reduction of blood PCSK9 Reduction of blood LDL-C
protein at 2 weeks at 2 weeks
% whole liver adenine editing
% change from baseline
% change from baseline
DPBS ABE-PCSK9 DPBS ABE-PCSK9 DPBS ABE-PCSK9
control control control
67% -- 89% -- 59%
18Durable lowering of blood PCSK9 protein & blood LDL-C
out to 6 months in NHPs
Blood PCSK9 protein reduction Blood LDL-C reduction
120 120
100 100
PCSK9 % of baseline
LDL-C % of baseline
80
-- 89%
80
-- 61%
60 60
40 40
20 20
0 0
0 20 40 60 80 100 120 140 160 180 200 0 20 40 60 80 100 120 140 160 180 200
Days Days
Each data point represents a consecutive measurement from n = 4 cynomolgus monkeys
19No evidence of off-target base editing in human hepatocytes
Primary human hepatocytes treated with
LNP formulated with ABE8.8 mRNA + PCSK9 gRNA
80
net adenine editing % 60
(treated samples
minus control 40
PCSK9 on-target site
samples) 20
0
141 putative off-target sites
20VERVE-101 advancing into IND-enabling (2021)
followed by first-in-human (2022) studies
2020 2021 2022
Selected VERVE-101 as Commence IND-enabling studies Initiate first-in-human
development candidate trials for lead program
21VERVE-101 clinical development: start with genetic disease of FH
Step 1. Initial focus on patients with FH; ~1.6 million patients in US and Europe
22VERVE-101 clinical development: expand to atherosclerotic CVD
Step 2. Expand to those with established atherosclerotic cardiovascular disease
and a high risk for future events; ~24 million patients in US and Europe
23VERVE-101 clinical development: ultimately, prevention
Step 3. Offer as preventive therapy to all at risk of coronary heart disease
24Verve’s pipeline: targeting three distinct pathways each with
compelling human genetics validation
DEVELOPMENT STATUS
PROGRAM INDICATION
Research Lead optimization IND-Enabling Phase 1 Phase 2/3
Low-density lipoprotein (LDL)
VERVE-101 Heterozygous
ABE-PCSK9 FH
Triglyceride-rich lipoprotein (TRL)
ANGPTL3 Undisclosed
Lipoprotein(a) Lp(a)
LPA Undisclosed
25In vivo base editing to turn off ANGPTL3 gene in NHP liver leads to
95% lower blood ANGPTL3 protein, 64% lower blood triglycerides
Reduction of blood Reduction of blood
ANGPTL3 whole-liver editing ANGPTL3 protein at 2 weeks triglycerides at 2 weeks
% whole-liver adenine editing
% change
% change
Study 1 Study 2 Study 1 Study 2 Study 1 Study 2
60% -- 95% -- 64%
26Why a “once-and-done” medicine when there is a standard of care for cholesterol lowering?
FH: high cumulative exposure to blood LDL-C is the problem
200
Patient with
150 heterozygous FH:
LDL-C
LDL-C in 200s
mg/dl starting at birth
100
50
40 45 50 55 60 65 70
Age
28Current care model:
cumulative LDL-C exposure remains high over life-course
Stent
Fatal heart attack
200
Standard of care:
lifestyle +
statin
Patient with heterozygous FH &
150
first heart attack at age 44:
LDL-C
standard of care
mg/dl
100 in the real world
Add PCSK9i mAb or siRNA
Lost job,
lost health insurance
50 ”Feeling well”:
self-stopped all medicines Missed MD appointment,
failed to re-fill prescription for 1y
40 45 50 55 60 65 70
Age
29Verve model:
curative, lifelong lowering of LDL-C
200
150
VERVE-101:
LDL-C
mg/dl
value of curative
100 lowering of LDL-C
50
40 45 50 55 60 65 70
Age
30World-leading experts in gene editing and drug development
31Transforming the future of coronary heart disease treatment
Pioneering a pipeline of “once-and-done” gene editing medicines to treat coronary heart
disease, world’s leading cause of death
Stepwise development strategy with initial focus on patients with genetic coronary heart
disease – heterozygous familial hypercholesterolemia
Lead candidate VERVE-101 with best-in-class in vivo liver editing efficacy and safety data
in non-human primates; plan for IND-enabling studies in 2021 & first-in-human in 2022
Worldwide experts in cardiology, genetics, gene editing/safety, and drug development
Top-tier investor syndicate supporting the company
Partners
Innovation Fund
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