[PPT] - Dis clo sures O utline Background RNAi Mec hanisms and delivery PowerPoint Presentation

SLIDE 1

Dis clo sures

SLIDE 2

O utline

Background
RNAi
Mec hanisms and delivery
ATTR: Clinical results
AL: In vivo models
Monoc lonal antibodies
Spec trum of clinical ac tivity
Anti-amyloid
D ual monoclonal antibody therapy
ATTR: O n-going trial
AL: In vivo model
Conc lusions and Perspec tives

SLIDE 3

Amyloidosis

Culprit proteins
Transthyretin
Immunoglobulin light chains
Cellular Phase
Production
Trafficking
Sec retion
Extracellular Phase
D issoc iate
Circulate
Misfold
Fibrillate (β-structure]
Deposit
D isplace

SLIDE 4

TTR

16 16 to to 40 40 mg mg/dL /dL Re Retinol tinol-bind binding ing pr protei

tein

n + re + reti tinol nol

Th Thyrox

xine

ine

PNAS 2012;109:9629

SLIDE 5

FLC

In133 AL patients at diagnosis, 84% λ Median edian iFLC FLC 13 135mg/L 5mg/L (2 (29.4 9.4-9780) 9780) Medi edian an dF dFLC LC 12 123m 3mg/L g/L (4 (4-9770) 9770)

SLIDE 6

RNA Interferenc e

Com
mplementary

plementary to to ta target rget mRNA NA

Degradat

gradation ion of ta f targ rget et mRNA NA --

- sto

topping pping tr translation anslation

An

Anti tisen sense se oligo igonu nucleotid cleotides es (AS ASO) O)

Synth

ntheti etic c shor

rt

t sin ingle le-str stran and RNA/DNA hybrid rids s

Modif

ifie ied d suga gar groups ups

Secondary

condary structure cture and d bin inding ding energy ergy li limi mitations ions

Inhibit

ibit mRNA spli licin ing and nd activate ivate RNase e H1 to cle leave ve the e dup uple lex

Small

all inte terf rfering ering RNA (siRN iRNA) A)

Shor
rt

t dsRNA wit ith mo modif ifica icati tions,

ns, cle

leave ved d by DICER

Activa

ivati ting ng the RNA-in induced duced sil ilenc ncing ing compl plex ex (RISC)

Sense strand

and becomes s part of RISC

Seeking

eking targe get mRNA

SLIDE 7

RNA Interferenc e

Cha

hallen enge ges s of

f Effec

ecti tive ve Del eliver ery

Prot
tec

ectio tion n from

m ser

erum um nu nuclea eases es in c n circul ulat atio ion

Man

any veh ehicles: es: virus uses es, , pr prot

tei

eins, ns, pa particle les

Li

Lipi pid d en encap apsul ulat atio ion n (na nano nopa particl icles es)

ion

ioniz izabl able e li lipid id+ and sugar ar-phos phosphate phate nucleic cleic acid id- back ckbone bone

Hom
ming

ng to t

tar

arge get t cel ells or

r or
rga

gan n syste tem

Clea

earan ance ce by by li liver er = Del eliver ery y to

liver

er

Ent

ntry an and u d unl nloa

adi

ding ng of

f car

argo go

Int

ntrac acel ellu lular ar traf affi fickin cking

SLIDE 8

ATTR Inotersen (ASO)

ATTRm / PN
Phase III RCT
2:1 randomization
2/2013 - 11/2017
N = 172
~50% V30M
Δ NIS+7
2o cardiac endpoints
22% withdrawal rate
3% thrombocytopenia

NEJM 2018;379:23

SLIDE 9

ATTR Patisiran (siRNA)

ATTRm / PN
Phase III RCT
2:1 randomization
12/2013 - 1/2016
N = 225
V30M
38% / 52%
Δ NIS+7
2o cardiac endpoints
5% withdrawal rate

NEJM 2018;379:11

SLIDE 10

ATTR Patisiran (siRNA)

Prealbumin 25 to 8.9 mg/dL
BNP (pg/mL)
Vitamin A (mcg/dL)

SLIDE 11

AL TMC 534 (siRNA)

Blood 2014;123:3440 Gene Ther 2016;23:727 Gene Ther 2019;26:187

κ and λ constant region
Preclinical
In vitro
Patient CD138+ cells
NSG mice xenografts
12 day models
JJN3, MM1.S
IP delivery
Lipidoid nanoparticles
FLC, Flux
sBCMA

SLIDE 12

Monoclo nal Antibodies

MoA
Ab Tar

arge gets

Ce

Cells lls

Cir

Circulating ulating proteins teins

Ebola

la virus irus core re receptor ceptor bind inding ing domain main

Co

Compl plex exity ity of

f de

design gn an and de d devel elop

pment

ent

Hu

Human anizati ation

n
Hu

Human anized ed mou

use
Mod
dificat

cations ions an and I d Int ntel ellect lectua ual l Prop

per

erty

Ch

Chal allen enge ges s of

f de

deliver ery

Prot
tei

eins? ns? Agg ggreg egat ates? es? Fibr brils? s? Ch Chap aper eron

nes

es?

Nat Rev 2019;18:585

SLIDE 13

PRX004 (anti-TTR)

Anti-TTR monomer
Electrophoresis
Coomassie blue
Partially denatured
Δ Charge
Δ Size
Δ Glycosylation
Phase I clinical trial
CT03336580
Accruing
radhika.tripuraneni@prothena.com

PNAS 2012;109:9629 BBA 1998;1407:185

SLIDE 14

CAEL-101 (anti-amyloid)

Blood 2010;116:2241 Blood 2018;132:958 Blood 2018;132:1003

SLIDE 15

NEO D001 (anti-amyloid)

PLOS One 2012 Amyloid 2016 Prothena April 18, 2019

No longer in development

Stage IV: Cardiac stage 3 dFLC>180mg/L

SLIDE 16

D ual MoAb Therapy

Ant nti-CD3 CD38, 8, an anti-FLC LC ag aggr greg egat ates es

EHA 2019

JCO 2019;37:8009a Cl Lymph Myelom Leuk in press

SLIDE 17

BCMA-based Therapies for AL

Poster 4409 – Amandeep Godara, MD Monday, December 9, 2019: 6:00 PM-8:00 PM, Hall B

Gene Ther 2019;26:187

SLIDE 18

ALM1 - If Ebola c an be cle ared . . .

Anti-λ light chain monoclo nal antibody
In vitro activity
SPR, IP/IB
Epitope mapping
Humanization underway
In vivo activity in NSG mouse xenograft model
Testing in vitro against patient samples
Use in MAINTENANCE to achieve iFLC <10mg/L?

Poster 4369 – Amandeep Godara, MD Monday, December 9, 2019: 6:00 PM-8:00 PM, Hall B

SLIDE 19

Broad interest in amyloidosis, ATTR and AL (and ALect2 . . .)
Mature and evolving technologies
Next-generation RNAi for ATTR
Monoclonal antibodies against the culprit cells and proteins
Cryo-EM, CRISPR, NGS
Patient advocacy
Amyloidosis Patient Forum with the FDA (https://arci.org)
Support groups around the globe
Investigator and travel grants
Focus in cardiology
American Society of Nuclear Cardiology
Continue to drive for early diagnosis and novel clinical research

Conclu sions & Perspec tives

SLIDE 20

Ac knowledgements

Demarest Lloyd Jr Foundation The Amyloidosis Foundation Werner and Elaine Dannheiser Fund for Research on the Biology of Aging

f the Lymphoma Foundation

The Amyloidosis and Myeloma Research Fund MMRF The Cam Neely and John Davis Myeloma Research Fund Janssen Neely Center for Clinical Cancer Research Cindy Varga, MD Terry Fogaren, NP

Laboratory

Ping Zhou Xun Ma Adin Kugelmass Denis Toskic Amandeep Godara