Post on 14-May-2022
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
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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 ??
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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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lambda light chains
Normal
λ-LC AL
www.amyloidplanet.com
Effective Treatment of AL Amyloidosis Results in Lower Light Chain Levels
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lambda light chains
www.amyloidplanet.com
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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
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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?