FAMILIAL AMYLOID POLYNEUROPATHY (TTR-FAP): Genetics and Treatment

Transcription

1 FAMILIAL AMYLOID POLYNEUROPATHY (TTR-FAP): Genetics and Treatment Michelle Mezei BSc (Pharm), MDCM, FRCPC Neuromuscular Diseases Unit, VGH Division of Neurology, UBC 1

2 Learning Objectives To become familiar with Familial Amyloid Polyneuropthy hattr (Hereditary Transthyretin Amyloidosis) To review novel treatment options in hattr

3 Disclosures Principle Investigator: Alnylam Apollo and Patisiran OLE trials Honoraria: Alnylam: speaker and symposium chair Pfizer: Advisory Board Chair and speaker Genzyme: speaker

4 Patient Case Study 2008: 48 year old female with bilateral burning foot pain, numbness, progresses within 6 months to knees, and hands (predominantly ulnar distribution) Mild distal weakness, Glove-stocking deficit, absent ankle jerks Sensory>motor PN of axonal type, mild active denervation Family Hx: father died age 42 after 3 yr hx of sporadic amyloidosis (renal and PN); Confirmed V71A TTR mutation 2009: Ambulation limited by pain and imbalance, using cane hydromorphone, pregabalin gabapentin, Diflunisal Nausea/vomiting: improved with domperidone

5 Patient Case Study 2010: Ambulation limited to ½ block; loss of knee jerks; increased arm numbness Hydromorphone, duloxetine 2011: Increasing distal leg weakness, occasional walker 2014: Left followed by right visual loss: vitreous amyloid, successful vitrectomy : Apollo trial Pain improves, minimal GI sxs, improved endurance

6 Patient Case Study : Patisiran Open Label Extension study (OLE) Improved strength hands, resumed painting Dictus brace, cane, wheelchair outside Numbness stable, no dysesthesias Decreased dose of hydromorphone, duloxitine Less autonomic, no further V/D/bloating, mild Nausea Normal Echo and EKG

7 What is amyloidosis? The amyloidoses are a group of diseases that result from the abnormal deposition of amyloid protein in various tissues of the body causing clinically relevant changes 1,2 Amyloidosis Localized amyloidosis Systemic amyloidosis Primary (AL) amyloidosis Secondary (AA) amyloidosis Senile systemic amyloidosis (wild-type) Transthyretin familial amyloid polyneuropathy Affected organs: Kidney Heart Liver GI system Nervous system Affected organs: Kidneys Liver Spleen Affected organ: Heart Affected organs: Nervous system Heart 1. Kumar P, Clark M. Diabetes mellitus and other disorders of metabolism. In: Kumar P, Clark M, Kumar and Clark s Clinical Medicine; 7th Edition: Saunders, Elsevier, Merlini G et al. J Intern Med 2004;255:

8 Different precursor protein, same end result Apolipoprotein A1 Immunoglobulin light chain Lysozyme Transthyretin Β2 microglobulin Serum amyloid A Gelsolin Leukocyte chemotactic factor 2 (LECT2) Fibrinogen α- chain

9 Transthyretin is a transport protein of thyroxine and retinol-binding protein (RBP)/vitamin A 1 3 BLOOD VESSEL The transthyretin tetramer transports retinol through the RBP, vitamin A complex and thyroxine Less than 1% of transthyretin tetramers transport thyroxine in human serum The bulk of thyroxine is carried by thyroxine-binding globulin and albumin The majority of circulating transthyretin is not bound 3 TTR RBP Thyroxine 1. Benson MD, Kincaid JC. Muscle Nerve 2007;36: Sekijima Y et al. Curr Pharm Des 2008;14: Hou X et al. FEBS J 2007;274:

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11 Genetic mutations lead to variant forms of transthyretin Benson MD, Kincaid JC. Muscle Nerve 2007;36: Roberts JR et al. Amyloidosis: Transthyretin-Related. Medscape, Accessed August Zeldenrust SR. In: Gertz MA et al. eds. Amyloidosis: Diagnosis and Treatment (Contemporary Hematology). Totowa: Humana Press, Planté-Bordeneuve V et al. Neurology 2007;69:

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13 Autosomal dominant inheritance 1 4 TTR-FAP is an autosomal dominant disease Gene on chromosome 18 Affected parent has a 50% chance passing on mutated gene to their offspring Variable penetrance Affected individuals Unaffected individuals Square = male; Circle = female 1. Merlini G et al. J Intern Med 2004;255: Falk RH et al. N Engl J Med 1997;337: Stedman s Medical Dictionary. (27 th ed.) Philadelphia: Lippinocott Williams & Wilkins. 4. Benson MD, Kincaid JC. Muscle Nerve 2007;36:

14 hattr Genotype - Phenotype Genotypic-Phenotypic Correlation Late onset G47A A34T S50A A36P T49A P64L G89G V30M V41L S23A H88A C10A P33L Early onset V30M Neurologic Phenotype T60A L111M I68L V122I Cardiac 1. Based on Rapezzi et al. Eur Heart J 2013;34:520 8; 2. Coelho et al. Curr Med Res Opin 2013;29:63 76

15 Toxic amyloidogenic intermediates and amyloid deposits in peripheral and autonomic nerves 1,2 Amyloid PERIPHERAL NERVE BUNDLE Congo red-stained section of posterior tibial nerve from a patient with transthyretin amyloidosis shows hallmark green color under polarized light 2 1. Benson MD, Kincaid JC. Muscle Nerve 2007;36: Sousa MM et al. Am J Pathol 2001;159: Image courtesy M. Benson, Indiana University School of Medicine

16 Conceicao et al. J Peripher Nerv Syst 2016;21:5 9

17 Signs and Symptoms: Consider hattr Progressive, painful, predominantly small diameter PN Bilateral CTS Progressive length dependent sensory-motor PN, distal atrophy and weakness Autonomic sxs: Orthostatic hypotension Bladder symptoms: frequency, nocturia, erectile dysfunction Constipation and diarrhea, leading to unintentional weight loss Post-prandial nausea Systemic: Vitreous opacities: loss of vision Cardiac conduction defects, cardiomyopathy

18 Variable age of onset May manifest between 20 and 70 years of age 1,2 Disease course of late-onset hattr can be more severe and lead to disability more rapidly than early-onset disease 3 Progression to death within 5-15 years Don t always have Family Hx sporadic mutations family member with sporadic or primary amyloidosis Mean time to diagnosis can be up to 4 years after the onset of symptoms 4,5 1. Hou X et al. FEBS J 2007;274: Coelho T et al. CMRO 2013; 29: Adams D et al. Curr Opin Neurol 2012;25: Adams et al Amyloid 2012;19 Suppl 1: Plante-Bordeneuve et al. Neurology 2007;69:

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20 99m Tc PYP Scanning Planar whole body scan ATTR CA AL CA With SPECT Falk et al. JACC 2016;68:1323

21 Therapeutics Rate-limiting tetramer dissociation Monomer misfolding and aggregation leading to amyloid fibrils Suppression of TTR synthesis Liver transplantation 1 Investigational: Gene silencing ASOs: IONIS-TTR Rx 6 RNAi: Patisiran 7 ; ALN-TTRsc02 8 TTR stabilization Tafamidis 2,a Diflunisal 3,4,b Investigational: SOM0226 a Fibril degradation and reabsorption Investigational: Doxy + TUDCA 5,c Investigational Anti-amyloid mabs Anti-TTR mab 9 Anti-SAP mab 10 Management of disease Availability of disease-modifying therapies for hattr amyloidosis is limited Symptomatic relief is important for patients, particularly as disease progresses Genetic Counselling a Only approved in EU and select other countries; b Available off label in some geographies; c Available as a generic medication, being studied by academic institutions ASO, antisense oligonucleotides; RNAi, RNA interference; TUDCA, tauroursodeoxycholic acid 1. Ando et al. Orphanet J Rare Dis 2013;8:3; 2. Said et al. Nat Rev Drug Dis 2012;11:185 6; 3. Berk et al. JAMA 2013;310: ; 4. National Amyloidosis Centre. ATTR Amyloidosis url [accessed 18/12/2014]; 5. Ruberg & Berk. Circulation 2012;126: ; 6. Ackermann et al. Amyloid 2012;19(S1):43 4; 7. Coelho et al. N Engl J Med 2013;369:819 29; 8. Jadhav V, et al. Presentation at Oligonucleotide Therapeutics Society (OTS) meeting Higaki, et al. Amyloid 2016;23:86 97; 10. Richards, et al. N Engl J Med 2015;373:

22 Orthotopic Liver Transplantation (OLTX) Clinical Criteria: Age 60 yrs Dx duration 5 yrs PN restricted to LEs OR isolated AN No significant Renal OR Cardiac dysfunction Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; Takei et al., 1999; Adams et al., 2000 Poor Prognostic Facto BMI/nutritional status Severe PN Severe AN Urinary incontinence Marked postural hypote Fixed pulse rate

23 Domino Liver Transplantation

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25 Therapeutics Rate-limiting tetramer dissociation Monomer misfolding and aggregation leading to amyloid fibrils Suppression of TTR synthesis Liver transplantation 1 Investigational: Gene silencing ASOs: IONIS-TTR Rx 6 RNAi: Patisiran 7 ; ALN-TTRsc02 8 TTR stabilization Tafamidis 2,a Diflunisal 3,4,b Investigational: SOM0226 a Fibril degradation and reabsorption Investigational: Doxy + TUDCA 5,c Investigational Anti-amyloid mabs Anti-TTR mab 9 Anti-SAP mab 10 Management of disease Availability of disease-modifying therapies for hattr amyloidosis is limited Symptomatic relief is important for patients, particularly as disease progresses Genetic Counselling a Only approved ASO, antisense in EU and oligonucleotides; select other countries; RNAi, RNA b Available interference; off label TUDCA, in some tauroursodeoxycholic geographies; c Available acid as a generic medication, being studied by academic institutions 1. Ando et al. Orphanet J Rare Dis ;8:3; 2. Said et al. Nat Rev Drug Dis 2012;11:185 6; 3. Berk et al. JAMA 2013;310: ; 4. National Amyloidosis Centre. ATTR Amyloidosis url [accessed 18/12/2014]; 5. Ruberg & Berk. Circulation 2012;126: ; 6. Ackermann et al. Amyloid 2012;19(S1):43 4; 7. Coelho et al. N Engl J Med 2013;369:819 29; 8. Jadhav V, et al. Presentation at Oligonucleotide Therapeutics Society (OTS) meeting Higaki, et al. Amyloid 2016;23:86 97; 10. Richards, et al. N Engl J Med 2015;373:

26 Diflunisal - NSAID - Developed in mg and 500mg tablets

27 Diflunisal Take Home Points 2 year NIH sponsored Study Safe and Efficacious Reduced rate of progression of neurological impairment Reduced decline BMI Preserved quality of life Study suggests treatment benefit for FAP Off label use available in Canada Occasional lack of drug supply

28 Therapeutics Rate-limiting tetramer dissociation Monomer misfolding and aggregation leading to amyloid fibrils Suppression of TTR synthesis Liver transplantation 1 Investigational: Gene silencing ASOs: IONIS-TTR Rx 6 RNAi: Patisiran 7 ; ALN-TTRsc02 8 TTR stabilization Tafamidis 2,a Diflunisal 3,4,b Investigational: SOM0226 a Fibril degradation and reabsorption Investigational: Doxy + TUDCA 5,c Investigational Anti-amyloid mabs Anti-TTR mab 9 Anti-SAP mab 10 Management of disease Availability of disease-modifying therapies for hattr amyloidosis is limited Symptomatic relief is important for patients, particularly as disease progresses Genetic Counselling a Only approved in EU and select other countries; b Available off label in some geographies; c Available as a generic medication, being studied by academic institutions ASO, antisense oligonucleotides; RNAi, RNA interference; TUDCA, tauroursodeoxycholic acid 1. Ando et al. Orphanet J Rare Dis 2013;8:3; 2. Said et al. Nat Rev Drug Dis 2012;11:185 6; 3. Berk et al. JAMA 2013;310: ; 4. National Amyloidosis Centre. ATTR Amyloidosis url [accessed 18/12/2014]; 5. Ruberg & Berk. Circulation 2012;126: ; 6. Ackermann et al. Amyloid 2012;19(S1):43 4; 7. Coelho et al. N Engl J Med 2013;369:819 29; 8. Jadhav V, et al. Presentation at Oligonucleotide Therapeutics Society (OTS) meeting Higaki, et al. Amyloid 2016;23:86 97; 10. Richards, et al. N Engl J Med 2015;373:

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30 Tafamidis Clinical Development Program For TTR-FAP: Efficacy Data 18-mo, randomized double-blind, placebocontrolled study: Pivotal study in V30M patients with TTR-FAP 12-mo, open-label extension for Fx-005: Long-term safety and efficacy Study Fx-005 (n= 128) 1) Coelho T et al. Neurology 2012;79(8): ) Keohane D et al., Amyloid 2017;24(1):30-36 % NIS-LL responder (ITT): p= %NIS-LL responder (EE): p< ΔNIS-LL from baseline: p<0.05 1,2 ΔNQOL-DN from baseline (ITT): p= ΔNQOL-DN from baseline (EE): p< ΔNIS-LL+Σ3 from baseline: p< ΔNIS-LL+Σ7 from baseline: p< ΔmBMI from baseline (ITT): p< Study Fx-006 (n= 86) Coelho T et al. J Neurol. 2013;260(11): T-T: ΔNIS-LL (p=0.60); ΔTQOL (p=0.16) P-T: ΔNIS-LL (p<0.05); ΔTQOL (p<0.001) Earlier treatment start greater benefit Study Fx1A-201 (n= 21) Merlini G et al. J Cardiovasc. Trans. Res. 2013;6(6): mo, open-label, multicenter study: TTR stabilization in patients with non-v30m mutations TTR stabilized (6wk): 94.7% TTR stabilized (6mo): 100% TTR stabilized (12mo): 100% Open-label, ongoing, multicenter study: Long-term extension study (6+ yrs) for Fx- 006 and Fx1A-201 Study Fx1A-303 (Ongoing; n>93) Barroso F et al. Amyloid 2017; 24(3): Earlier treatment start greater benefit (continuous separation in ΔNIS-LL and ΔTQOL between T-T and P-T ) Prepared by Pfizer in response to an unsolicited request Not for further distribution

31 Therapeutics Rate-limiting tetramer dissociation Monomer misfolding and aggregation leading to amyloid fibrils Suppression of TTR synthesis Liver transplantation 1 Investigational: Gene silencing ASOs: IONIS-TTR Rx 6 RNAi: Patisiran 7 ; ALN-TTRsc02 8 TTR stabilization Tafamidis 2,a Diflunisal 3,4,b Investigational: SOM0226 a Fibril degradation and reabsorption Investigational: Doxy + TUDCA 5,c Investigational Anti-amyloid mabs Anti-TTR mab 9 Anti-SAP mab 10 Management of disease Availability of disease-modifying therapies for hattr amyloidosis is limited Symptomatic relief is important for patients, particularly as disease progresses Genetic Counselling a Only approved in EU and select other countries; b Available off label in some geographies; c Available as a generic medication, being studied by academic institutions ASO, antisense oligonucleotides; RNAi, RNA interference; TUDCA, tauroursodeoxycholic acid 1. Ando et al. Orphanet J Rare Dis 2013;8:3; 2. Said et al. Nat Rev Drug Dis 2012;11:185 6; 3. Berk et al. JAMA 2013;310: ; 4. National Amyloidosis Centre. ATTR Amyloidosis url [accessed 18/12/2014]; 5. Ruberg & Berk. Circulation 2012;126: ; 6. Ackermann et al. Amyloid 2012;19(S1):43 4; 7. Coelho et al. N Engl J Med 2013;369:819 29; 8. Jadhav V, et al. Presentation at Oligonucleotide Therapeutics Society (OTS) meeting Higaki, et al. Amyloid 2016;23:86 97; 10. Richards, et al. N Engl J Med 2015;373:

32 Therapeutics Rate-limiting tetramer dissociation Monomer misfolding and aggregation leading to amyloid fibrils Suppression of TTR synthesis Liver transplantation 1 Investigational: Gene silencing ASOs: IONIS-TTR Rx 6 RNAi: Patisiran 7 ; ALN-TTRsc02 8 TTR stabilization Tafamidis 2,a Diflunisal 3,4,b Investigational: SOM0226 a Fibril degradation and reabsorption Investigational: Doxy + TUDCA 5,c Investigational Anti-amyloid mabs Anti-TTR mab 9 Anti-SAP mab 10 Management of disease Availability of disease-modifying therapies for hattr amyloidosis is limited Symptomatic relief is important for patients, particularly as disease progresses Genetic Counselling a Only approved in EU and select other countries; b Available off label in some geographies; c Available as a generic medication, being studied by academic institutions ASO, antisense oligonucleotides; RNAi, RNA interference; TUDCA, tauroursodeoxycholic acid 1. Ando et al. Orphanet J Rare Dis 2013;8:3; 2. Said et al. Nat Rev Drug Dis 2012;11:185 6; 3. Berk et al. JAMA 2013;310: ; 4. National Amyloidosis Centre. ATTR Amyloidosis url [accessed 18/12/2014]; 5. Ruberg & Berk. Circulation 2012;126: ; 6. Ackermann et al. Amyloid 2012;19(S1):43 4; 7. Coelho et al. N Engl J Med 2013;369:819 29; 8. Jadhav V, et al. Presentation at Oligonucleotide Therapeutics Society (OTS) meeting Higaki, et al. Amyloid 2016;23:86 97; 10. Richards, et al. N Engl J Med 2015;373:

33 Investigational Disease-Modifying Therapeutics TTR-lowering Agents Antisense oligonucleotides (ASOs) m 7 G ASO ASO delivered as single strand; finds its target alone AAAA n RNA interference (RNAi) sirna RISC RISC Duplex associates with RISC Passenger strand is removed Guide strand leads RISC to target Blocking ribosomes or other factors steric block Recruiting protein factors (e.g. RNase H) Modulating splicing Serum TTR knockdown (mean maximum reduction 76%) m 7 G mrna cleavage (if perfectly complementary) RISC AAAA n Association-mediated repression (if partially mismatched) sirna, small Interfering RNA; RISC, RNA- induced silencing complex responsible for the silencing phenomenon known as RNA interference Watts & Corey. J Pathol 2012;226:365 79

34 Therapeutics Rate-limiting tetramer dissociation Monomer misfolding and aggregation leading to amyloid fibrils Suppression of TTR synthesis Liver transplantation 1 Investigational: Gene silencing ASOs: IONIS-TTR Rx 6 RNAi: Patisiran 7 ; ALN-TTRsc02 8 TTR stabilization Tafamidis 2,a Diflunisal 3,4,b Investigational: SOM0226 a Fibril degradation and reabsorption Investigational: Doxy + TUDCA 5,c Investigational Anti-amyloid mabs Anti-TTR mab 9 Anti-SAP mab 10 Management of disease Availability of disease-modifying therapies for hattr amyloidosis is limited Symptomatic relief is important for patients, particularly as disease progresses Genetic Counselling a Only approved in EU and select other countries; b Available off label in some geographies; c Available as a generic medication, being studied by academic institutions ASO, antisense oligonucleotides; RNAi, RNA interference; TUDCA, tauroursodeoxycholic acid 1. Ando et al. Orphanet J Rare Dis 2013;8:3; 2. Said et al. Nat Rev Drug Dis 2012;11:185 6; 3. Berk et al. JAMA 2013;310: ; 4. National Amyloidosis Centre. ATTR Amyloidosis url [accessed 18/12/2014]; 5. Ruberg & Berk. Circulation 2012;126: ; 6. Ackermann et al. Amyloid 2012;19(S1):43 4; 7. Coelho et al. N Engl J Med 2013;369:819 29; 8. Jadhav V, et al. Presentation at Oligonucleotide Therapeutics Society (OTS) meeting Higaki, et al. Amyloid 2016;23:86 97; 10. Richards, et al. N Engl J Med 2015;373:

35 Inotersen: Antisense oligonucleotide IONIS-TTR Rx 15 month Phase 3 randomized (2:1), double blind, placebo-controlled international NEURO-TTR study 172 Stage 1 and 2 FAP patients 300mg sc weekly Highly statistically significant improvement in primary endpoints mnis+7 and Norfolk QOL Sustained and robust TTR AE: thrombocytopenia and renal dysfunction FDA/EMA: orphan drug designation PNS Meeting, July 10, 2017

36 Therapeutics Rate-limiting tetramer dissociation Monomer misfolding and aggregation leading to amyloid fibrils Suppression of TTR synthesis Liver transplantation 1 Investigational: Gene silencing ASOs: IONIS-TTR Rx 6 RNAi: Patisiran 7 ; ALN-TTRsc02 8 TTR stabilization Tafamidis 2,a Diflunisal 3,4,b Investigational: SOM0226 a Fibril degradation and reabsorption Investigational: Doxy + TUDCA 5,c Investigational Anti-amyloid mabs Anti-TTR mab 9 Anti-SAP mab 10 Management of disease Availability of disease-modifying therapies for hattr amyloidosis is limited Symptomatic relief is important for patients, particularly as disease progresses Genetic Counselling a Only approved in EU and select other countries; b Available off label in some geographies; c Available as a generic medication, being studied by academic institutions ASO, antisense oligonucleotides; RNAi, RNA interference; TUDCA, tauroursodeoxycholic acid 1. Ando et al. Orphanet J Rare Dis 2013;8:3; 2. Said et al. Nat Rev Drug Dis 2012;11:185 6; 3. Berk et al. JAMA 2013;310: ; 4. National Amyloidosis Centre. ATTR Amyloidosis url [accessed 18/12/2014]; 5. Ruberg & Berk. Circulation 2012;126: ; 6. Ackermann et al. Amyloid 2012;19(S1):43 4; 7. Coelho et al. N Engl J Med 2013;369:819 29; 8. Jadhav V, et al. Presentation at Oligonucleotide Therapeutics Society (OTS) meeting Higaki, et al. Amyloid 2016;23:86 97; 10. Richards, et al. N Engl J Med 2015;373:

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39 Patisiran: Investigational RNAi Therapeutic for hattr Amyloidosis Therapeutic Hypothesis Lipid nanoparticle formulated RNAi, administered by IV infusion, targeting hepatic production of mutant and wild-type TTR Patisiran Therapeutic Hypothesis Production of mutant and wild type TTR Patisiran Unstable circulating TTR tetramers reduced Organ deposition of monomers, amyloid (β-pleated) fibril prevented, clearance promoted Neuropathy, cardiomyopathy stabilization or improvement 39

40 Patisiran Phase 3 APOLLO Study Results Study Enrollment D.Adams EU ATTR meeting, Nov patients with hattr amyloidosis with polyneuropathy from 44 sites in 19 countries enrolled between Dec 2013 and Jan % 2% 2% <1% <1% 1% <1% North America: 21% Western Europe: 44% 4% 4% 4% 19% USA 4% 4% Mexico 7% Germany 7% Japan 7% Spain 8% 16% France Taiwan 8% Rest of World: 36% 40 *North America: USA, CAN; Western Europe: DEU, ESP, FRA, GBR, ITA, NLD, PRT, SWE; Rest of world: Asia: JPN, KOR, TWN, Eastern Europe: BGR, CYP, TUR; Asia: JPN, KOR, TWN; Central & South America: MEX, ARG, BRA

41 Mean [± SEM] Serum TTR Knockdown, % Patisiran Phase 3 APOLLO Study Results Serum TTR Reduction 87.8% mean max serum TTR reduction from baseline for patisiran over 18 months Placebo (N=77) Patisiran (N=148) Weeks -100 TTR Change Change from baseline at 9 months Change from baseline at 18 months Placebo (N=77) Patisiran (N=148) Placebo (N=77) Patisiran (N=148) Mean (SEM) Serum TTR Knockdown 1.5% (4.47) 82.6% (1.36) 4.8% (3.38) 84.3% (1.48) 41

42 LS mean (SEM) change in mnis+7 from baseline Patisiran Phase 3 APOLLO Study Results mnis+7: Change from Baseline (2.60) (2.10) (11.0, 153.5) Difference at 18 mos (Pati PBO): p-value: Worse Better (8.0, 165.0) (1.50) (1.74) 42 MMRM, mixed-effects model repeated measures; mitt, modified intent to treat; Pati, patisiran; PBO, placebo; CFB, change from baseline mnis+7 reference range: points

43 Patisiran : Safety and Adverse Events 13 deaths in APOLLO study; no deaths considered related to study drug Similar frequency of deaths in patisiran and placebo Causes of death (e.g., cardiovascular, infection) consistent with natural history Similar % AE in Patisiran vs Placebo group Majority of AEs Were mild or moderate in severity Decreased over time Peripheral edema Infusion-related reactions (IRRs) No liver, hematological, or renal toxicity

44 Red-flag Symptom Cluster for hattr-pn Family history Early autonomic dysfunction Progressive symmetric sensory-motor neuropathy 1 of Gastrointestinal complaints Unexplained weight loss Cardiac hypertrophy, arrhythmias, ventricular blocks, or cardiomyopathy Renal abnormalities Vitreous opacities 44 Based on Conceicao et al. J Periph Nerv Syst 2016;21:5 9

45 Familial Amyloid Polyneuropathy (hattr Amyloidosis) SummaryanTreatment Rare and fatal neurodegenerative disease Mutation results in Tetramer destabilization, protein misfolding and amyloid deposits AD with variable penetrance Wide range age of onset Painful sensory > motor, autonomic peripheral neuropathy, CTS Often cardiac conduction/cardiomyopathy Need to think of it to dx and find it! Limited current Tx options available but novel ones on horizon

46 Acknowledgements Dr. Kristin Jack, UBC Dr. Margot Davis, UBC Dr. Diego Delgado, U of T Dr. Nowell Fine, U of C Pfizer Alnylam

47 The Differential Diagnosis Challenge for hattr- PN Symptoms may be common to other disorders, confounding diagnosis Patient phenotype Potential diagnoses Ataxia and foot numbness Motor involvement Upper limb neuropathy Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) ALS Motor polyradiculoneuropathy Carpal tunnel syndrome Idiopathic polyneuropathy Paraneoplastic neuropathy CIDP Motor neurone diseases Weakness in feet, ankles, legs Charcot Marie tooth disease Pain and tingling with alcohol abuse Alcoholic neuropathy Polyneuropathy with diabetes Diabetic neuropathy Polyneuropathy with evidence of amyloid deposition AL amyloidosis AA amyloidosis AA, amyloid A; AL, light-chain, ALS, amyotrophic lateral sclerosis Based on Adams et al. Curr Neurol Neurosci Rep 2014;14:435 & Adams et al. Curr Opin Neurol 2012;25:564 72

48 Surveillance/Other Considerations Multidisciplinary Approach Blood work Serial EDX Serial Cardiac Investigations (EKG, echo) Monitoring nutritional status Genetic Counseling Offer at-risk relatives molecular genetics testing Referrals

49 Inclusion Criteria: Age yrs Bx proven amyloid deposition and/or + TTR molecular genetics testing Assessed by Neurologist w proven Sensorimotor PN spending 50% time out of chair/bed Exclusion Criteria: Alternate cause for PN Survival 2 years Severe CHF Renal insufficiency Anticoagulation

50 1. Higaki et al. Amyloid 2016;23:86 97; 2. ClinicalTrials.gov: NCT Investigational Disease-Modifying Therapeutics Monoclonal Antibodies (mabs) mabs have been designed to bind to non-native, misfolded forms of TTR Promote clearance of non-native TTR by phagocytosis Preclinical data 1 mabs generated were selective for monomeric, misfolded and amyloidogenic forms of TTR no binding to the native tetramer Immunolabeling of cardiac tissue from patients with ATTR amyloidosis mabs inhibited TTR fibril formation in vitro, and induced antibody-dependent phagocytosis of amyloidogenic TTR A clinical trial of an anti-serum amyloid P component (SAP) monoclonal antibody has been completed in systemic amyloidosis 2

51 Patisiran: Investigational RNAi Therapeutic for hattr Amyloidosis Clinical Development Program Phase 1 1 Phase 2 2 Phase 2 OLE 3 Phase 3 4 APOLLO Global OLE 5 Completed Completed Completed Completed Ongoing Healthy Volunteers hattr hattr hattr hattr Positive results in human healthy volunteers (N=17) Single dose mg/kg by IV infusion Positive multi-dose results in adult patients with hattr amyloidosis (N=29) Multiple doses Multiple schedules Positive results in adult patients with hattr amyloidosis with polyneuropathy who participated in the Phase 2 study (N=27) 0.3 mg/kg every 3 weeks by IV infusion for up to 2 years Adults with hattr amyloidosis with polyneuropathy (N=225) 0.3 mg/kg every 3 weeks by IV infusion for 18 months Randomized, doubleblind, placebocontrolled Adults with hattr amyloidosis with polyneuropathy who participated in the Ph 2 OLE or Ph 3 study (N=211 enrolled) 0.3 mg/kg every 3 weeks by IV infusion Includes some patients with over 3 years treatment Coelho T, et al. N Engl J Med. 2013;369:819-29; 2. Suhr OB, et al. Orphanet J Rare Dis. 2015;10:109; 3. Adams D, et al. Neurology (2017); 88:16 Supplement S (Clinicaltrials.gov: NCT );4. Clinicaltrials.gov: NCT ; 5. Clinicaltrials.gov: NCT

52 Patisiran Phase 3 APOLLO Study Results Enrollment and Disposition Randomized (1:2) (N=225) Placebo (N=77)* Patisiran (N=148)* D/C Treatment (N=29; 37.7%) AE 9.1% Death: 5.2% Progressive disease: 5.2% Physician decision: 2.6% Protocol deviation: 0% Withdrawn by patient 15.6% Study Withdrawal (N=22; 28.6%) D/C Treatment (N=11; 7.4%) AE 2.0% Death: 3.4% Progressive disease: 0.7% Physician decision: 0% Protocol deviation: 0.7% Withdrawn by patient 0.7% Study Withdrawal (N=10; 6.8%) Completed Study (N=55, 71.4%) Completed Study (N=138, 93.2%) 52 *Study populations: modified intent-to-treat (mitt) population: All patients who were randomized and received at least 1 dose of patisiran or placebo (placebo, N=77; patisiran, N=148) Discontinued (d/c) treatment: patients who permanently stopped treatment prior to the last scheduled dose (Week 78 visit); Discontinued (d/c) study: patients who stopped the study before any Month 18 (Week 79-80) assessments were performed Progressive disease: patients who stopped treatment due to rapid disease progression Rapid disease progression: patients who have 24-point increase in mnis+7 from baseline [based on an average of 2 measurements] and FAP Stage progression relative to baseline at 9 months and had no major protocol deviations

53 LS mean (SEM) change in Norfolk QOL-DN from baseline Patisiran Phase 3 APOLLO Study Results Norfolk QOL-DN: Change from Baseline 14.4 (2.73) 7.5 (2.15) Worse 55.5 (8, 111) Difference at 18mos (Pati PBO): p-value: Better 59.6 (5, 119) -7.5 (1.52) -6.7 (1.77) 53 MMRM, mixed-effects model repeated measures; mitt, modified intent to treat; Pati, patisiran; PBO, placebo; CFB, change from baseline Norfolk QOL-DN reference range: -4 to 136

54 Patisiran Phase 3 APOLLO Study Results Additional Secondary Endpoints: Change from Baseline (CFB) to 18 Months All secondary endpoints achieved statistical significance at 18 months Nominal statistical significance was achieved as early as month 9 for NIS-W, R-ODS, 10-MWT and mbmi Secondary endpoint; LS Mean Placebo (N=77) Patisiran (N=148) Treatment Difference (Pati - PBO) P-Value NIS-W R-ODS 10-MWT, m/sec Baseline score, mean CFB to 18 mos Baseline score, mean CFB to 18 mos Baseline score, mean CFB to 18 mos mbmi, kg/m2 x albumin [g/dl] Baseline score, mean CFB to 18 mos COMPASS-31 Baseline score, mean CFB to 18 mos Pati, patisiran; PBO, placebo; NIS-W, neuropathy impairment score-weakness; CFB, change from baseline; R-ODS, Rasch-built Overall Disability Scale; 10-MWT, 10 meter walk test; mbmi, modified body mass index; COMPASS-31, Composite Autonomic Symptom Score questionnaire