The Changing Paradigm of Amyloidosis Treatment

Jeffrey A. Zonder, MDProfessor of Oncology

Karmanos Cancer Institute

Disclosures

• Celgene (Advisory, Research Support)• BMS (Advisory)• Takeda (Advisory)• Seattle Genetics (Advisory)• Prothena (Advisory)• Pharmacyclics (Data Safety Monitoring)• Janssen (Advisory)• Array Biopharma (Advisory)

Objectives

• Provide a general overview of amyloidosis symptoms, diagnosis, and common subtypes

• Explain the importance of correct amyloidosis typing as it pertains to treatment selection

• Discuss management principles of AL and ATTR amyloidosis

• Describe emerging therapies targeting amyloid fibrils and protein production

What is Amyloidosis?

• A group of diseases characterized by misfolded proteins (classified according to protein type)

• Misfolded proteins form fibrils (“strands”) which deposit in body tissues

• Symptoms depend on which organs are affected by amyloid fibrils

Amyloid Classification

Amyloidosis Nomenclature: Examples

• AL = “Amyloid” “Light Chain”• ATTR = “Amyloid” “Transthyretin”• AA = “Amyloid” “(Apo)serum Amyloid A”

Tandem Mass Spectrometry1

1. Nelson L, et al. Blood 2012 120:3206-3213; doi:10.1182/blood-2012-03-413682

AL Amyloidosis is a Plasma Cell Disorder

κ

κ

κλ

λ

λκ

λκ

κ

κλ

λκ

λλ

λλ

λ

λλ

λ

λ λ

Polyclonal Monoclonal

Κ:λ = 1:1 Κ:λ = 1:3

Plasma cells make antibodies

Antibody Structure:2 Heavy Chains + 2 Light Chains

Light Chain (κ or λ)

Heavy Chain

“Business End”

or ??

κ

κ

κλκ

λλ

λ

λ

λλ

λ

λ λ

MisfoldedLight Chains

Toxic Soluble Oligomers

Tissue Fibrils

In AL amyloidosis, misfolded antibody light chains form amyloid fibrils

Serum Free Light Chain Testingka

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light

cha

ins

lambda light chains

Normal

λ-LC AL

www.amyloidplanet.com

Effective Treatment of AL Amyloidosis Results in Lower Light Chain Levels

kapp

a lig

ht c

hain

s

lambda light chains

www.amyloidplanet.com

κ

κ

κλ

λ

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Κ:λ = 1:3 Κ:λ = 1:1

Organ Involvement in Amyloidosis

• Widespread tissue deposition– Heart– Kidney (glomeruli)– Nerves (sensory, autonomic)– GI (tongue, gut, liver)– Vascular (bleeding)– Lung– Skin

www.amyloidplanet.com

The Heart in Amyloidosis (Staging)

IVSd(mm)

Troponin I & NT-pro-BNP NORMAL

Troponin I OR NT-pro-BNP ELEVATED

Troponin I AND NT-pro-BNP ELEVATED

I:

II:

III:

Thickness of the wall between the bottom chambers of the heart

Deepest, longest light chain reduction (“response”) possible

Multidisciplinary management of amyloid-related symptoms

Goals of Therapy

Light Chain Response Matters

Time

Complete ResponseVery Good Partial ResponsePartial ResponseNo Response

Palladini G., et al. J Clin Oncol. 2012;30:4541

Choosing Therapy

IMiDs ProteasomeInhibitors Alkylators Steroids

Thalidomide(Thalomid)

Bortezomib(Velcade)

Melphalan(Alkeran)

Dexamethasone(Decadron)

Lenalidomide(Revlimid)

Carfilzomib(Kyprolis)

Cyclophosphamide(Cytoxan) Prednisone

Pomalidomide(Pomalyst) Ixazomib Bendamustine

(Treanda)

Oprozomib

Marizomib

Treatment Algorithm

Is this AL type Amyloidosis?

Light chain remission?

Is the patient a potential candidate for stem cell transplant?

Y

ChemotherapyHigh dose

melphalan & stem cell transplant

YN

Consider additional

chemotherapy

Monitor closelyOR

NEOD001

YN

Non-chemo treatment

appropriate for the specific type of amyloidosis

N

?

Immunotherapy

11-1F4

κ

κ

κλκ

λλ

λ

λ

λλ

λ

λ λ

Anti-fibril Therapies Target the Protein Rather than the Plasma Cells

This allows the immune system to ”clean up” the organs

Anti-Fibril Therapies*

• NEOD001• Anti-SAP antibodies and CPHPC• 11-1F4• Doxycycline (yes, the antibiotic)• EGCG (green tea extract; not with Velcade!)

* all currently being evaluated in clinical studies

www.clinicaltrials.gov identifier: NCT01707264

Ongoing Phase 1/2 Study

Additional patients with cardiac, renal and/or peripheral

neuropathyinvolvement

Multiple Ascending Dose• 27 patients with AL amyloidosis• 7 cohorts; IV once every 28 days

Expansion Phase24 mg/kg*24 mg/kg*

16 mg/kg16 mg/kg

8 mg/kg8 mg/kg

4 mg/kg4 mg/kg

0.5 mg/kg0.5 mg/kg

1 mg/kg1 mg/kg

2 mg/kg2 mg/kg

Primary Objectives• Evaluate the safety and tolerability of NEOD001• Determine the NEOD001dose for future trials

Secondary Objectives

Exploratory Objectives • Evaluate organ response (NT-proBNP to assess heart and protein levels in urine to assess kidneys)

2• NEOD001 Pharmacokinetics (“how does the body

metabolize and process NEOD001?”)• NEOD001 immunogenicity (“does the body have an

immune reaction against NEO001?”)

1All Patients are now treated at 24 mg/kg

Cardiac Responses after NEOD001 (NT-pro-BNP reduction of > 30%)

53% responders (30%+ reduction)86% improved (any reduction)

Renal responses (urine protein reduction) also seen in about ½ of pts

No correlation with hematologic responses (none expected)

www.clinicaltrials.gov identifier: NCT01707264

ATTR (Transthyretin) Amyloidosis

Switching Gears:

ATTR amyloidosis is NOT a plasma cell disease

The liver makes misfolded transthyretin protein – there are

over 120 different mutations known to cause ATTR amyloidosis

Normal and Abnormal Transthyretin

Tetramer Normal Monomers

MisfoldedMonomers

Amyloid Pre-Fibrils

ATTR Amyloid Fibrils

Image source: http://www.biovoicenews.com/wp-content/uploads/2016/05/Liver-fibrosis.jpg

Retinol Binding Protein

Thyroxine Transport

Transthyretin Amyloidosis: Overview

• Three major forms of ATTR:

Familial AmyloidPolyneuropathy (FAP)

Familial AmyloidCardiomyopathy (FAC)

Wild-Type AmyloidCardiomyopathy (wt-TTR)*

Mixed deposits of mutant & wild-type TTR

Deposits of wild-type TTR

ATTR Treatment Overview

MisfoldedMonomers

Amyloid Protofilaments(“pre-fibrils”)

AmyloidFibrils

DiflunisalTafamidis*

XXXX

Liver Transplant

Doxycycline Anti-SAPmAbs**

* Tafamidis available in EU and Japan** Experimental only

ATTR Treatment Overview

MisfoldedMonomers

Amyloid Protofilaments(“pre-fibrils”)

AmyloidFibrils

XXXX

Liver Transplant

DiflunisalTafamidis*

Doxycycline Anti-SAPmAbs**

* Tafamidis available in EU and Japan** Experimental only

Liver Transplant in ATTR Amyloidosis

• First disease-modifying therapy for ATTR• Reduces misfolded TTR production by 90%• Generally utilized in younger patients with

earlier-stage disease• Some pts have continued disease progression

even after transplant (normal transthyretin incorporated)

• Variable post-transplant quality-of-life• Limited by organ availability

Hypothesis: a targeted reduction of misfolded protein production could

be of benefit in many types of amyloidosis

How would this best be accomplished?

Protein SynthesisNucleus Cytoplasm

DNA mRNA mRNAProtein Chain (Polypeptide)

Mature Protein

Transcription Translation Post-TranslationalModification and Protein Folding

DNA mRNA mRNA

+siRNA RISC

RISC/siRNAcomplex

siRNA“unwinds”

mRNAcleaved

Small Interfering RNA (siRNA) or antisense RNA (asRNA) can block production of a specific protein

Patisiran – Phase I, Healthy Volunteers

Coelho T, et al. N Engl J Med 2013;369:819–829

IONIS-TTRrx (Antisense Oligonucleotide)

• Single-dose Phase I trial in healthy volunteers

Placebo (n=4)50 mg (n=3)100 mg (n=3)200 mg (n=3)400 mg (n=3)

Ackermann EJ, et al. Amyloid 2012;19(S1):43–44

APOLLO Phase III Trial (FAP)

ATTR-FAP(Stage 1-2)

Patisiran (IV q 3 wk)

Placebo

18 months

n = 133

n = 67

OLE Trial

• 1° endpoint: Δ mNIS+7 (neuro score) at 18 mos• 2° endpoints: various Quality-of-Life scales • Accrual complete

Endeavour Ph III Trial (FAC)

ATTR-FAC(not wt-ATTR)

Revusiran

Placebo

18 months

• 1° endpoint: Δ 6-minute walk time at 18 months• 2° endpoints: CV deaths & hospitalizations, others• Trial terminated early

• Neuropathy signal in open-label Phase II trial• Safety committee recommended closure

2:1

Ionis-TTRrx – Phase III Trial in FAP

Benson M, et al. American Academy Neurology, Apr 2015

ATTR-FAP(Stage 1-2)

Ionis-TTRrx (Weekly SC)

Placebo

15 months

n = 130

n = 65

OLE Trial18 months

• Trial placed on hold by FDA• Low platelet counts

• Planned ATTR-cardiomyopathy trial cancelled

RNAi Therapies for Amyloidosis

• ATTR Amyloidosis• Revusiran and Patisiran siRNA agents (Alnylam)• LUNAR-101 and -102 mRNA agents (Arcturus)• IONIS-TTRx antisense drug (Ionis Pharmaceuticals)

• AL Amyloidosis• siRNA targeting immunoglobulin LC production

(?)

Doxycycline slows AL progression*

* In laboratory mice… Ward JE, et al. Blood. 2011;118(25):6610-6617

69%

23%

0

50

100

0

50

100

% of mice with gastric amyloid

EGCG and AL Amyloidosis

© Stefan Kresin

Dr. Werner Hunstein

1. Hunstein W. Blood.2007;110(6):2216 2. Mereles D, et al. Clin Res Cardiol. 2008;97(5):341 3. http://www.hunstein-egcg.de

VGPR

Key Points

• Tissue deposits made up of misfolded protein fibrils damage organs

• Current AL therapy targets the abnormal plasma cells which make the light chains

• Lowering light chain levels is important!• Clinical trials are the means to new drugs• Newer drugs targeting the fibrils and

proteins are being studied in AL and ATTR

Key Questions

• Newer chemotherapy regimens increase hematologic response rates, but will they overcome initial (cardiac) risk?

• Will investigational fibril-directed therapy (alone or together with chemotherapy) improve clinical outcomes in AL amyloidosis?

• Will RNA-interference (RNAi) therapy be developed for ATTR amyloidosis?• If yes, are other types next?