R NA Interferenc e and Mo no c lo nal A ntibo dies Raymond Comenzo, - - PowerPoint PPT Presentation

No vel C las s es of A gents fo r A m ylo ido s is : R NA Interferenc e and Mo no c lo nal A ntibo dies

Raymond Comenzo, MD Director, The John C. Davis Myeloma and Amyloid Program Tufts Medical Center Boston, Massachusetts, USA

Disclosures

Outline

• Background
• RNAi
• Mechanisms and delivery
• AT T R: C linical results
• AL : In vivo models
• Monoclonal antibodies
• Spectrum of clinical activity
• Anti-amyloid
• Dual monoclonal antibody therapy
• AT T R: On-going trial
• AL : In vivo model
• C onclusions and Perspectives

Amyloidosis

• C ulprit proteins
• Transthyretin
• Immunoglobulin light chains
• C ellular Phase
• Production
• T rafficking
• Secretion
• Extracellular Phase
• Dissociate
• Circulate
• Misfold
• Fibrillate (β-structure]
• Deposit
• Displace

T T R

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

FL C

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)

RNA Interference

• 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

RNA Interference

• 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

AT T R 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

AT T R 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

AT T R Patisiran (siRNA)

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

AL T MC 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

Monoclonal 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

PRX004 (anti-T T R)

• 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

C AEL -101 (anti-amyloid)

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

NEOD001 (anti-amyloid)

PLOS One 2012 Amyloid 2016 Prothena April 18, 2019

No longer in development

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

Dual MoAb T herapy

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

BC MA-based T herapies for AL

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

Gene Ther 2019;26:187

AL M1 - If Ebola can be cleared . . .

• Anti-λ light chain monoclonal 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 MAINT ENANC E to achieve iFL C <10mg/L?

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

• 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

C onclusions & Perspectives

Acknowledgements

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