rna therapeutics for cardiovascular diseases · u.s. companies developing rna-targeted therapies* *...
TRANSCRIPT
RNA therapeutics for cardiovascular diseases
Sotirios Tsimikas, MD
Director of Vascular Medicine
Professor of Medicine
University of California San Diego
39th Panhellenic Congress of Cardiology
Oct 19, 2018
1
2
Disclosures
Named as co-inventor and receives royalties from patents
owned by the University of California San Diego on oxidation-
specific antibodies
Co-Founder of Oxitope, Inc
Dual appointment at UCSD and Ionis Pharmaceuticals
2
Unmet need – Beyond LDL-CFOURIER Trial Demonstrated 2% Absolute reduction n CVD events and no Effect of CVD Mortality
Sabatine et al. NEJM 2017 3
Lipoprotein Targets in Preventing and Treating Cardiovascular Disease
TG
ApoC-III
Lp(a)
Apo(a)
Genetically Validated Lipoprotein Targets
TG-LDL
ANGPTL3
LDL-C
apoB
4
FDA Approvals for RNA Therapeutics6 drug approvals to date
▪ 1998 - Vitravene (fomivirsen, Ionis) – CMV retinitis
▪ 2004 - Mucagen (pegaptanib, OSI Pharma)—VEGF
▪ 2013 - Kynamro® (mipomersen, Ionis)- HoFH
▪ 2016- Spinraza (nusinersen, Ionis) - SMA
▪ 2018- Tegsedi (inotersen-Ionis/Akcea) – TTR amyloidosis
▪ 2018- Patisiran (Onpattro- Alnylum)- TTR amyloidosis
▪ ?2018- Waylivra (volanesorsen, Ionis/Akcea)
5
U.S. Companies Developing RNA-targeted Therapies*
* As of April 2017
Antisense Technology Companies
Ionis Pharmaceuticals
Bio-Path Holdings
Enzo Biochem
Idera Pharmaceuticals
Rexahn
Sarepta Therapeutics
Wave Therapeutics
RNAi Technology Companies
Alnylam
Arrowhead Research Corp.
Dicerna Pharmaceuticals
Galenta Biopharma (previously RXi Pharmaceuticals)
Marina Biotech (f.k.a mdRNA)
Merck (Sirna)
Opko (f.k.a cuRNA)
PhaseRx
Rxi Pharmaceuticals
Quark Pharma
Sirnaomics
Solstice Biologics
SomaGenics
Additional RNA-targeting Technology
Companies
Company Platform Technology
Arcturus
Therapeutics LNP oligomers
Avidity
NanoMedicines Antibody-siRNA complexes (ARCs™)
Bioneer
SAMiRNA (Self-Assembled-Micelle-inhibitory-
RNA)
Halo-Bio, RNAi
TherapeuticsMultivalent RNAi
miragen miRNA
miRNA (subsidiary
of Asuragen)miRNA
Moderna
synthetic mRNA to upregulate protein
expression
Voyager
Therapeutics AAV-directed RNAi therapeutics
Ziopharm DNA therapeutics
◼ 24 non-U.S. companies developing
RNA-targeted therapies*
6
RNA Therapeutics to “Silence” GenesFundamentally Novel Therapy Compared to Small Molecules and Antibodies
Gene mRNA
Transcription
Translation
DISEASE
Traditional Small Molecule Drugs
Inhibitors or Agonists of proteins
Biologics
Inhibitors or Mimics of proteins
DISEASE
Disease-Causing
Protein
DISEASEX XTranslation
Disease-Causing
Protein
Antisense
OligonucleotideInhibition of RNA function
(no production of disease
causing protein) 7
AntisenseSingle-Strand
Multiple Mechanisms
DNAPhosphorothioate (PS)
2’-MOE, 2’-OMe, cEt, LNA
siRNADouble-strandRISC Mechanism
RNAPhosphodiester
2’-OMe, 2’-F
Aliphatic substituents
AptamerStructured
DNA or RNA Mixed modifications
Pegylation(REG1 anticoagulation system)
Distinct Chemical Classes of RNA-Based
Technologies & Therapeutics
Aptamer
Target
Protein
Sense
Strand
Antisense
Strand
Antisense
Strand
8
Isis Pharmaceuticals Confidential
RNaseH1 and siRNA Antisense Mechanisms
◼ siRNA Mechanism ◼ RNase H1 Mechanism
Antisense Strand
mRNA-Antisense Duplex
RNase H1
DNA
mRNA
Nucleus
Cytoplasm
Cell Membrane
Cell Membrane
CytoplasmNucleus
Antisense Strand
RNase H like nuclease
DNA
mRNA
RISCSense Strand
siRNA Duplex
9
9
Antisense
Oligonucleotide RNA Target
The Antisense Drug-Receptor Interaction
~15-20 base pairs required for specificity and bindingNatural DNA and RNA do not make good drugs due to insufficient stability and distribution in animalsThis can be addressed with appropriate chemical modification
10
10
Examples of Chemical Modifications Used in RNA Therapeutic Agents
2ʹ-O-methoxyethyl (MOE)
OB
O
O
B
O
O
B
O
O
O
B
O
O
OP
O
O
OP
O
B
O
OP
O
OP
O
OP
OMe
OO
Me
OO
Me
OO
Me
OO
MeX = S, O
-X
-X
-X
-X
-X
11
11
RNAse H1 ASO Design and Ionis Clinical Experience
Clinical Experience with 2nd Generation ASOs
• >6000 subjects treated by IV and/or SC administration
• >60 clinical studies
• Multiple therapeutic indications
• >100 patients dosed for >1 year
• Some patients dosed for > 4 years
• Doses up to 1200 mg/wk tolerated
MOEMOE
↑ affinity
↑ stability
↑ tolerability
↑ affinity
↑ stability
↑ tolerability
RNase H1
Substrate
DNA
Chimeric RNase H1 ASO Design
• Specific sequence not repeated throughout genome, reducing potential for off-target binding
12
RNase H1 Terminating Mechanism
12
12
Composition of Lp(a) and Relationship to Plasminogen
1
3
Tsimikas J Am Coll Cardiol 2017;69:692-711 13
Continental Differences in the Prevalence of Elevated Lp(a)Lp(a) level gradient (high to low): Africa, South Asia, Europe, North America, South America, East Asia
14
Baseline Lp(a) Quartile vs. MACE ODYSSEY OUTCOMES
*Adj. for age, sex, race, geographic region, time since index event, BMI, smoking history,
diabetes, baseline LDL-C, and treatment assignment. Quartile interaction P-value in
adjusted model: p=0.44 with treatment, p=0.67 with baseline LDL-C
Quartile 1(<6.7 mg/dL)
Quartile 2(6.7 to <21.2 mg/dL)
Quartile 3(21.2 to <59.6 mg/dL)
Quartile 4(≥ 59.6 mg/dL)
0.0
2.5
5.0
7.5
10.0
12.5
MA
CE
Incid
ence (
%)
9.7%9.3%
12.2%
10.2%
Unadjusted Adjusted*
HR (95% CI)
Q2 vs Q1:
Q3 vs Q1:
Q4 vs Q1:
1.06 (0.93-1.21) 1.05 (0.92-1.20)
1.12 (0.99-1.28) 1.08 (0.95-1.23)
1.37 (1.21-1.55) 1.28 (1.13-1.46)
Quartile p-value: <0.0001 0.0005
15
What are the mechanisms through which Lpa) mediates CVD and CAVS?
Tsimikas JACC 2017;69:692-71116
OxPL-apoB and CVD Outcomes
Byun et al JACC 2015;65:1286-95 17
Lp(a)-OxPL and Aortic Stenosis
18
Unifying Hypothesis of Lp(a)-OxPL-ATX axis in CAVS
Torzewski et all JACC BTS 201719
2016 ESC/EAS Guidelines for the Management of Dyslipidemias
Catapano et al Eur Heart J 2016;37:2999-3058
Also endorsed by the 2016
Canadian Lipid Guidelines
20
Lp(a) – The Sword of Damocles?Lp(a) – The Sword of Damocles?
21
IONIS-APO(a)-LRx Produced Dose-dependent Significant Reductions in Lp(a)
Up to 99% Reduction in Lp(a),
with Mean Reduction of 92%
Multiple Ascending Dose
▪ Well tolerated with no safety
concerns
Lp
(a)
(nm
ol/
L)
Mean
% C
ha
ng
e F
rom
Baseli
ne
(+
/-S
EM
)
Study Day
20 mgPlacebo 10 mg 40 mg
Viney et al. Lancet 2016
Mean Lp(a) reductions:
10 mg= ↓ 68%
20 mg= ↓ 80%
40 mg= ↓ 92%
22
Phase 2ISIS 681257-CS6 STUDY
(AKCEA APO(a)-LRx)
A Randomized, Double-Blind, Placebo-Controlled, Dose Ranging Phase 2
Study of ISIS 681257 Administered Subcutaneously to Patients with
Hyperlipoproteinemia(a) and Established Cardiovascular Disease (CVD)
Accepted as a Late Breaking Clinical Trial at AHA
Nov 12 2018
23
Potential Design of CVOT Targeting Lp(a)
Lp(a) Cardiovascular Outcomes Trial
Inclusion Criteria:
Lp(a) >70 mg/dL, guideline recommended
LDL-lowering therapy, prior hx CVD
Lp(a) lowering therapy vs. Placebo
Primary Endpoint: MACE+ (CV Death, MI, Revascularization)
4 yr median f/u
Randomize to:
24
Potential RCT of Mild-Mod Aortic Stenosis
Lp(a) AS Trial (n=600)
Lipoprotein(a) Directed Antisense Therapy to Reduce
Progression of Aortic Stenosis Trial
Inclusion Criteria:
Lp(a) >60 mg/dl, AVA 1.3-1.7 mm2, EF >50%
ASO to apo(a) (sc monthly) vs. Placebo
Primary Endpoint: 3 Year change in AVA or mean AV gradient by echocardiography
Secondary Endpoints: 1- Rate of AVR
2- Progression of AV calcification measured by
AoV calcium and Na18F uptake
25
Potential RCT of Aortic Stenosis
OxPL AS Trial (n=600)
OxPL Directed Therapy to Reduce
Progression of Aortic Stenosis Trial
Inclusion Criteria:
OxPL-apoB in upper tertile, AVA 1.3-1.7 mm2, EF >50%
OxPL-ATX directed Rx vs. Placebo
Primary Endpoint: 3 Year change in AVA or mean AV gradient by
echocardiography
Secondary endpoints: 1- Rate of AVR
2- Progression of AV calcification measured by
AoV calcium and Na18F uptake26
We did it Jenkins!
We found the Higgs
boson!
Now let’s search for a
medical cure for
aortic valve stenosis
The future?…
27
APOC3 as a Target for CHD Risk Reduction
40% Reduction in apoC-III
40% Reduction in TG
40% Reduction in CHD Risk
28
FCS (Familial Chylomicronemia Syndrome)A Rare Genetic Disease Due to Mutations in LPL
European and FDA Orphan Drug Designation
29
30
Familial Chylomicronemia Syndrome (FCS): A Severe and Rare Genetic Disorder
▪ Background:▪ Rare autosomal recessive disorder (orphan disease)
▪ Caused by null loss-of-function LPL, GPIHPB1, APOC2, APOA5, LMF1 gene mutations
▪ Clinical expression/risk:▪ TG most often > 1000 mg/dl (11,1 mmol/L)
▪ Signs and symptoms:
▪ Abdominal pain (recurrent, often severe)
▪ Plasma lactescence and viscosity
▪ Lipemia retinalis
▪ Hepatosplenomegaly
▪ Eruptive xanthomas
▪ Acute pancreatitis
▪ Pancreatic insufficiency
▪ Diabetes, other complications30
APPROACH TrialPrimary Endpoint
Patients had an average 77% reduction in triglycerides at 3 months on volanesorsen, as compared to an average of 18% increase on placebo, p<0.001, for an absolute difference in average percent change of -94%
-100
-80
-60
-40
-20
0
20
40 Volanesorsen
(n=33)
Placebo
(n=33)
94% Treatment Effect
(-121.7, -66.6)
p-value < 0.001
LSM (95% CI) %
Change from
Baseline in TG
(mg/dL)
Placebo (N=33)
Baseline TG* 2152 (1153)
Month 3 TG* 2367 (1315)
Volanesorsen (N=33)
Baseline TG* 2267 (1259)
Month 3 TG* 590 (497)
-77
+18
31
Relationship of TG levels and CVD in dal-OutcomesPotential Effect of IONIS-APOCIII-LRx (now in Phase I)
32
Adjusted for age, sex, smoking, diabetes, HDL-C, BMI
0.0
0.5
1.0
1.5
2.0
≤80 >80-103 >103-130 >130-175 >175
Ris
k o
f p
rim
ary
en
dp
oin
t ev
en
t(Q
1=r
efe
ren
t)
Quintiles of triglycerides (mg/dL)
PlaceboIONIS-APOCIII-LRx
Schwartz et al., J Am Coll Cardiol 2015;65:2267-75
Risk reduction
32
Acknowledgments
UCSD
Calvin YeangXiaohong Yang
Phuong MiuJoseph Witztum
Ionis
Nick VineyVickie Alexander
Mark GrahamRosanne CrookeMichelle Fugett
Joseph TamiLynnetta WattsSteve HughesRichard GearyStanley Crooke
Ionis/Akcea
Ewa ProkopczukBoyan Litchev
Karren WilliamsPhil Piscitelli
Jonathan GuerrieroLouis O’Dea
Collaborators
Santica MarcovinaPatrick Moriarty
F. M. Van der WalkJ. C. van CapelleveenRaimund Pechlaner
Erik StroesJohn Kastelein
Romain CapouladePatrick Mathieu
Phil PibarotPia Kamstrup
Borge NordestgaardPeter WilleitManuel Mayr
Stephan Kiechl
33