Detroit, USA

Disclosures

• Celgene (Advisory, Research Support)

• BMS (Advisory, Research Support)

• Takeda (Advisory)

• Alnylam (Advisory)

• Prothena (Advisory)

• Janssen (Advisory)

• Caelum (Advisory)

• Amgen (Advisory)

• Oncopeptide (Advisory)

solu

ble

aggre

gate

sOrgan Injury Mediated by Aggregated

Misfolded Light Chains

Renz M, et al. Amyloid 2016; Tam SJ, et al. ISA XVI Kumamoto, 2018

Cont FLCa FLCm FLCa

Hmox-1i

FLCa

p38i

FLCa

Hmox-1i

p38i

FLCaCont

monom

ers

~20 nm

~30 nm

~40 nm

~100 nm

NEOD001

NEOD/2A4

Binding Site

VL

Dolan P, et al. ISA XVI Kumamoto, 2018

Additional patients

with cardiac, renal

and/or peripheral

neuropathy

Expansion

Phase

Secondary Objectives 2• NEOD001 pharmacokinetics

• NEOD001 immunogenicity

• Cardiac, Renal Responses (exploratory)

Primary Objectives• Evaluate the safety and tolerability of NEOD001

• Determine the NEOD001dose for future trials 1

Multiple Ascending Dose27 patients with AL amyloidosis

7 cohorts; IV once every 28 days

24 mg/kg*

16 mg/kg

8 mg/kg

4 mg/kg

0.5 mg/kg

1 mg/kg

2 mg/kgAll Patients are now treated at 24 mg/kg

NEOD001 Phase 1/2

(n=3)

(n=6)

(n=3)

(n=3)(n=3)

(n=3)(n=6)

Proteinuria (% Change from Baseline)

(N=23)

Kidney

No Correlation with Hematologic Parameters

www.clinicaltrials.gov identifier: NCT01707264

NT-proBNP (% Change from Baseline)

(N=27)

Heart

Gertz MA, et al. J Clin Oncol. 2016 Apr 1;34(10):1097-103

Organ Responses on NEOD001 Phase 1/2 Trial

• PRONTO: NEOD001 vs Placebo Cardiac AL

• VITAL: CyBorD +/- NEOD001 Newly Dx AL

• RAIN: NEOD001 vs Placebo Renal AL

• OLE: Open Label Extension Trial

• Others planned (imaging, post-ASCT, etc)

NEOD001 Trials

Previously treated AL

(cardiac, >PR last Rx)

NEOD001 24 mg/kg q 4 wks

Placebo

12 months Extension Therapy

NEOD001 Trials

Randomized Phase 2b

(n=66)

• 1º endpoint: Cardiac best response (NT-pro-BNP) BL to 12 mos

• 2º endpoints: SF-36 PCS, 6MWT, NIS-LL, Renal best response, NT-pro-BNP slope

(n=63)

PRONTO Results

(Public Domain)

Primary Endpoint NEOD001 Placebo

Cardiac Response (NT-pro BNP by 12 months) 39% 47%

Secondary Endpoints

SF-36v2 Physical Component Summary (@ 12 mos) 0.19 0.97

Change in 6-minute walk test (meters, @ 12 mos) 19.25 8.00

Renal Response (proteinuria and GFR) 54% 33%

Change in NIS-LL score (@ 12 mos) -1.20 -0.60

ALL CAUSE MORTALITY (% DEATHS) 4.5% 9.5%

NEOD001 Trials

Newly-diagnosed AL

(cardiac, non-ASCT)

CyBorD + NEOD001 24 mg/kg q 4 wks

CyBorD + Placebo

varied duration, varied 2nd line Rx Extension Therapy

n=260

• 1º endpoint: Time to composite of all-cause mortality & cardiac hospitalizations

• 2º endpoints: SF-36 PCS, 6MWT, best cardiac NT-pro-BNP response, others

Randomized Phase 3

Early futility analysis: HR 0.84 favoring NEOD001 (p=NS): TRIAL HALTED

• Hypothesis re: pathophysiology may be wrong

– Doubt this is the problem

• Statistical assumptions may have been wrong

– Therapeutic effect of NEOD001 overestimated?

– Clinical course of placebo-treated pts underestimated?

– Endpoints of amyloidosis trials are a challenge

NEOD001: What Happened?

CAEL-101 (11-1F4)

• Chimeric IgG1 MoAb derived from Bence Jones kappa

Soluble LC LC in fibril:

11-1F4

reactive

Congo red 11-1F4

λ1

λ8

κ4 AL

Am

ylo

id t

ype

κ-AL

λ-AL

O’Nuallain B, et al. Biochemistry 2007;46:13049

O’Nuallain B, et al. Biochemistry 2007;46:1240

Wall, JS et al, Tijdschr Nucl Geneeskd. 2011;33:807

CAEL-101: Phase 1a/1b trial

Phase 1a Phase 1b

• 1º endpoint: MTD of CAEL-101 (up/down; max 500 mg/m2)

• 2º endpoints: organ responses, PK, safetyClinical trial Identifier: NCT02245867

CAEL-101: Ph 1a/1b results

• 27 pts with treated AL

• Six pts each 1b cohorts 6 and 7

• Median 6 mos since last therapy

• 85% with > VGPR with last Rx

• OrR @ wk 8 (1a) or wks 5,8,12 (1b)

NO DLTsNO TRDs*

*therapy-

related deaths

Rash Response

(n=8)

Cardiac (n=12)

Response

(n=5)

Renal (n=10)

CAEL-101: Cardiac Response

GLS: - 9.58

NTproBNP 2549 pg/mL

GLS: -13.39

NTproBNP 1485 pg/mL

Mean GLS

improvement

1.69 points

Pre-targeting with p66

AL ATTR AA p66 peptope

Source of fibril image: Jimenez, JL, et al (2002) Proc. Natl. Acad. Sci. USA 99, 196-201; Wall JS, et al. PNAS 2018; 115(46): E10839-48

GGGYS KAQKA QAKQA KQAQK AQKAQ AKQAK QAQKA QKAQA KQAKQ SVTVV TKHYA AFPEN LLI

p5+14 11-1F4 epitope

AA

ATTR

AL

Congo Red p66+11-1F4 11-1F4

11-

1F4

P66 Enhances AL Clearance

11-1F4 only

11-1F4 + p66

Wall JS, et al. PNAS 2018; 115(46): E10839-48

Targeting SAP

AL ATTR AA

Source of fibril image: Jimenez, JL, et al (2002) Proc. Natl. Acad. Sci. USA 99, 196-201; Comenzo R, N Engl J Med 2015;373:1167-69

• Serum Amyloid P component

• Member of pentraxins family

• 51% sequence homology with CRP

• Associates with all amyloid types

• Accounts for >10% dry wt of deposits

• Stabilizes fibrils, prevents proteolysis

Miridesap (CPHPC)

Dezimizumab

Clinical Development

of Anti-SAP Therapy

Trial halted, program discontinued: “Change in risk-benefit ratio”

Cardiac AL with > VGPR (prior Rx)

Cardiac ATTR

Cardiac AL with < VGPR (on Rx)

(n=30; 10 in each cohort)

Miridesap 20 mg/hr IV x 72 hrs, then 60 mg TID SC x 11d

Dezimizumab up to 1200 mg IV, divided doses on d1,3

6 cycles

NCT03044353

Phase I single-dose escalation trial: 16 pts

Pre-Rx Post-Rx

Serum C3

SAA level

CRP

DB Richards, et al. N Engl J Med 2015;373:1106-14

SAP Scan

PRX004: misTTR Specificity

TTR Tetramer TTR Monomer TTR Ab mPRX004

Dimer

Tetramer

Aggregated

TTR Species

Heart

V122I

wtATTR

Normal

Higaki, et al. Amyloid 2016;23:86-97

PRX004: MoA

Higaki, et al. Amyloid 2016;23:86-97; Higaki, et al. ISA XVI Kumamoto, 2018

Dose-dependent V30M ATTR

mPRX004-induced ADCP Control Ab mPRX004

Promotes Phagocytosis

V122I Aggregation

Inhibits Fibril Formation

PRX004: Clinical Trial

0.1 mg/kg (n=3)

0.3 mg/kg (n=3)

1 mg/kg (n=3)

3 mg/kg (n=3)

10 mg/kg (n=3)

30 mg/kg (n=3)

• Max: 36 pts with hATTR (5 US, 2 EU ctrs)

• 3 IV infusions (BL, wk 4, wk 8)

• 1ᴼ endpoints: safety, PK/PD, MTD or RP2D

• 2ᴼ endpoint: immunogenicity, mBMI

Clinicaltrials.gov trial # NCT03336580

• misTTR elevated in hATTR and AS

• Established for hATTR (not wtATTR)

• May be useful for PD assessment

- absolute misTTR reduction?

- misTTR:TTR reduction?

- other?

misTTR Assay

Salmans J, et al. ISA XVI Kumamoto, 2018

• Targeting toxic, misfolded protein aggregates

hypothesized to improve outcomes in amyloidosis

• NEOD001 and anti-SAP therapies led the way, but

development of each halted after failed trials

• CAEL101 and PRX004 in early clinical stages in

AL and ATTR amyloidosis, respectively

Summary (I)

• Lessons learned from prior failures will guide the

design of future trials

• Strategies to enhance (or broaden) therapeutic

effects of anti-fibril MoAbs in development

Summary (II)

Thank You!

Questions?