Silenceurs et inhibiteurs (oligonucléotides antisens) d ARNm dans les neuropathies amyloides héréditaires à transthyrétine : c est parti!

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1 Silenceurs et inhibiteurs (oligonucléotides antisens) d ARNm dans les neuropathies amyloides héréditaires à transthyrétine : c est parti! V. Planté-Bordeneuve Service de Neurologie Réseau Amylose CHU Henri Mondor Créteil - France

2 Traitement des Neuropathies Amyloides héréditaire à Tranthyrétine Ou en est-on en 218? Les traitements actuels visent à empêcher la formation de nouveaux dépôts d amylose, donc à stabiliser la symptomatologie Ø Dans tous les cas: Il faut faire le diagnostic au plus tôt et traiter au plus vite Vyndaqel MA in Europe Liver transplantation Patisiran (Ph III) ISIS-TTR Rx + OLE TTR1 Patisiran + OLE Tafamidis No therapy Liver transplantation Diflunisal Clinical trials Early access program Patisiran / Innotersen Deux nouveaux traitements en 218.

3 Inhibiteurs (Oligonucléotides antisens) / Silenceurs d ARNm TTR: c est parti... Nuclear or Cytoplasmic action Cytoplasmic action Oligonucléotide antisens / ARNm 3 ISIS-TTR Rx binds at the 3 UTR and therefore inhibits the translation of all known TTR mutations as well as wild-type TTR L12P F33L T6A I68L E89Q V122I 5' UTR 3' UTR F64L I84S V3M T49A L111M Benson MD et al., Muscle Nerve 26, 33: Coelho T et al., NEJM 213, 369, 9:

4 Essais de phase I ASO / sirna - Réduction de l ARNm et du taux plasmatique de TTR T h e n e w e ng l a n d j o u r na l o f m e dic i n e sirna ALN-TTR-1 (N=32 patients) et ALN-TTR-2 (N=17 volontaires sains) B Activity ofionis sirna TTRrx against WT(Inotersen) and Mutant TTR A In Vitro Dual-Luciferase Reporter Assay ALN-TTR1 Dose Groups (mg/kg) T6A Placebo 3 UTR (N=8).1 (N=3) 5 UTR S77F S77Y x Empty Vector WT V3M T6A V3M V3M S77Y S77F [sirna] (nm) 4 6 S77F S77Y Multiple Dose CS1 Volontaires sains p<.5, p<.1, one-way ANOVA with Bonferroni s post-hoc test V122I The n ew 3 Geometric Mean Percent TTR Knockdown sirna dose 1 of 15 m e dic i n e 2 25 Study Day Placebo (N=4) mg/kg (N=3) TTR protein 2.5 mg/kg (N=3) 2.2 Vitamin A 2 RBP mg/kg (N=3) sirna dose Control sirna.4 mg/kg (N=6) 1.9 P<.1 R 2 = mg/kg (N=1) mg/kg (N=3) ALN-TTR2 Dose Groups 1. Efficacy in Patients with Transthyretin Amyloidosis. 3 mg will be usedfigure for the Phaseof3 ALN-TTR1 study Ackermann E et al., Amyloid 216, 23 (3): D Study Day e ng l a n d j o u r na l sirna dose 1 2 A C 1 Study Day sirna dose Percent Knockdown in TTR, Vitamin A, and RBP 8 Potent & Durable Reductions in Transthyretin Levels in Healthy Volunteers Treated with ISIS-TTR Rx. V3M V3M Mutant TTR (log) 1. Mutation Participant (N=3) 1. (N=6) Percent TTR Knockdown Normalized mrna Concentration (N=3).4 (N=3) V122I Geometric Mean Percent TTR Knockdown TTR/GAPDH (relative to control) V3M.3 (N=3).1 (N=3) sirna target site Study Day Nonmutant TTR (log) Coelho T et al., NEJM 213, 369, 9: Panel A shows the geometric mean percentbserum transthyretin (TTR) knockdown (reduction in genetic expression), as compared with

5 Patisiran Phase 3 APOLLO Study Design Patient Population hattr amyloidosis: any TTR mutation, FAP Stage 1 or 2 Neurological impairment score (NIS) of 5-13 Prior tetramer stabilizer use permitted 2:1 RANDOMIZATION Patisiran.3 mg/kg IV q3w or Placebo IV q3w Primary Endpoint Change in mnis+7 from baseline at 18 months Secondary Endpoints Norfolk QOL-DN NIS-weakness R-ODS 1-meter walk mbmi COMPASS-31 Select Exploratory Endpoints Serum TTR levels Cardiac assessments ClinicalTrials.gov Identifier: NCT Stratification factors for randomization include: neuropathy impairment score (NIS: < 5 vs. 5), early onset V3M (< 5 years of age at onset) vs. all other mutations (including late onset V3M), and previous tetramer stabilizer use (tafamidis or diflunisal) vs. no previous tetramer stabilizer use To reduce likelihood of infusion-related reactions, patients receive following premedication or equivalent at least 6 min before each study drug infusion: dexamethasone; oral acetaminophen/paracetamol; H2 blocker (e.g., ranitidine or famotidine); and H1 blocker (e.g., diphenhydramine). Patients who completed study were eligible for patisiran treatment on Global OLE Study (NCT251261) COMPASS-31, composite autonomic symptom score-31; EQ-5D-5L, EuroQoL 5 dimensions-5l; mbmi, modified body mass index; mnis+7, modified neuropathy impairment scale +7; Norfolk QOL-DN, Norfolk quality of life-diabetic neuropathy questionnaire; OLE, open-label extension; q3w, every 3 weeks; R-ODS; Rasch-built overall disability scale Adams D, et al. BMC Neurol 217;17(1):181

6 Patisiran Phase 3 APOLLO Study Results Enrollment and Disposition 225 patients with hattr amyloidosis with polyneuropathy from 44 sites in 19 countries enrolled between December 213 and January 216 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: % Withdrawn by patient 15.6% Study Withdrawal (N=22; 28.6%) D/C Treatment (N=11; 7.4%) AE 2.% Death: 3.4% Progressive disease:.7% Physician decision: % Protocol deviation:.7% Withdrawn by patient.7% Study Withdrawal (N=1; 6.8%) 4 Completed Study Completed Study (N=55, 71.4%) (N=138, 93.2%) 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 79-8) assessments were performed; Progressive disease: patients who stopped treatment due to rapid disease progression; Rapid disease progression: patients who have 24-point increase in

7 Patisiran Phase 3 APOLLO Study Results Baseline Demographics and Disease Characteristics Demographic, n (%) Placebo (N=77) Patisiran (N=148) Median Age, years (range) 63 (34, 8) 62 (24, 83) Gender, males 58 (75.3) 19 (73.6) Race Asian 25 (32.5) 27 (18.2) Black/African or African 1 (1.3) 4 (2.7%) American White/Caucasian 5 (64.9) 113 (76.4) Region North America 1 (13.) 37 (25.) Western Europe 36 (46.8) 62 (41.9) Rest of World 31 (4.3) 49 (33.1) hattr Diagnosis Years since hattr diagnosis, mean (min, max) TTR Genotype 2.6 (., 16.5) 2.39 (., 21.) V3M 4 (51.9) 56 (37.8) nonv3m 37 (48.1) 92 (62.2) Previous tetramer stabilizer use 41 (53.2) 78 (52.7) Disease Characteristics, n (%) NIS Placebo (N=77) Patisiran (N=148) Mean (min, max) 57. (7., 125.5) 6.5 (6., 141.6) <5 35 (45.5) 62 (41.9) >5 - <1 33 (42.9) 63 (42.6) >1 9 (11.7) 23 (15.5) FAP Stage 1: unimpaired ambulation 37 (48.1) 67 (45.3) 2: assistance with ambulation 39 (5.6) 81 (54.7) required 3: wheelchair bound or bedridden 1 (1.3) PND Score I: preserved 2 (26.) 36 (24.3) walking, sensory disturbances II: impaired walking but 23 (29.9) 43 (29.1) can walk without stick or crutch IIIa: walk with 1 stick or crutch 22 (28.6) 41 (27.7) IIIb: walk with 2 sticks or crutches 11 (14.3) 28 (18.9) IV: confined to wheelchair or 1 (1.3) bedridden Cardiac Subpopulation 36 (46.8) 9 (6.8) Blue, bolded text indicated >1% difference in either group Other, patisiran N=1 (.7%); More than one race, patisiran N=2 (1.4%); missing N=1 each for placebo (1.3%) and patisiran (.7%) 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; Central & South America: MEX, ARG, BRA Represents 38 different TTR mutations Pre-specified cardiac subpopulation: patients with evidence of pre-existing cardiac amyloid involvement at baseline without confounding medical conditions (i.e., patients with baseline left ventricular [LV] wall thickneee > 1.3cm and no aortic valve disease or hypepertension in medical history

8 Patisiran Phase 3 APOLLO Study Results 56.1% of patients in the patisiran group demonstrated improvement in mnis+7 compared to 3.9% of patients on placebo (odds ratio: 39.9; p=1.82 x 1-15 ; improvement defined as < point increase from baseline to 18 months) mnis+7: Change from Baseline (2.6) Worse Better LS mean (SEM) Change in mnis+7 from Baseline (11., 153.5) 8.93 (8., 165.) (2.1) -2.4 (1.5) Difference at 18 months (Patisiran Placebo): p-value: (1.74) 7 MMRM, mixed-effects model repeated measures; mitt, modified intent to treat; mnis+7, modified neuropathy impairment score + 7; LS, least squares; SEM, standard error of the mean mnis+7 reference range: -34 points

9 Patisiran Phase 3 APOLLO Study Results mnis+7 Change by NIS Quartiles mnis+7 change at 18 months in all subgroups significantly favored patisiran Patisiran demonstrated benefit in patients with either early or advanced neuropathy at baseline Worse Worsening of Baseline Neuropathy Impairment Better mnis+7 Change from Baseline (Mean/SEM) Baseline NIS: 3 and <57 Baseline NIS: 6 and <3 Baseline NIS: 57 and <84.5 Baseline NIS: 84.5 and Placebo Patisiran APOLLO data, additional analysis mnis+7, modified neuropathy impairment score + 7; SEM, standard error of the mean

10 Patisiran Phase 3 APOLLO Study Results Secondary Endpoints: Change from Baseline (CFB) to 18 Months All secondary endpoints achieved statistical significance at 18 months 51.4% of patients in the patisiran group improved in Norfolk QOL-DN compared to 1.4% of patients on placebo (odds ratio: 1.; p=1.95 x 1-1 ; improvement defined as < point increase from baseline to 18 months) Nominal statistical significance was achieved as early as month 9 for Norfolk QOL-DN, NIS-W, R-ODS, 1-MWT and mbmi 9 Secondary endpoint; LS Mean Norfolk QOL-DN (Quality of Life) NIS-W (Muscle Weakness) R-ODS (Disability) 1-MWT, m/sec (Gait Speed) mbmi, kg/m 2 x albumin [g/dl] (Nutritional Status) COMPASS 31 (Autonomic Symptoms) Placebo Patisiran (N=77) (N=148) Baseline score, mean Treatment Diff. (Pati - PBO) P-Value CFB to 18 mos x 1-1 Baseline score, mean CFB to 18 mos x 1-13 Baseline score, mean CFB to 18 mos x 1-16 Baseline score, mean.79.8 CFB to 18 mos x 1-12 Baseline score, mean CFB to 18 mos x 1-11 Baseline score, mean CFB to 18 mos LS, least squares; Pati, patisiran; PBO, placebo; Norfolk QOL-DN, Norfolk quality of life-diabetic neuropathy questionnaire; NIS-W, neuropathy impairment score-weakness; CFB, change from baseline; R-ODS, Rasch-built overall disability scale; 1-MWT, 1 meter walk test; mbmi, modified body mass index; COMPASS 31, composite autonomic symptom score questionnaire

11 Patisiran Phase 3 APOLLO Study Results Exploratory Analysis: Cardiac Subpopulation Patisiran treatment resulted in favorable improvement in mean LV wall thickness, global longitudinal strain, and NT-proBNP compared to placebo at 18 months Improvement was seen in additional echocardiographic parameters at 18 months: LV end-diastolic volume, interventricular septum thickness, posterior wall thickness, LV relative wall thickness, cardiac output, and LV mass LS Mean (SEM) Change from Baseline at 18 Months Mean LV Wall Thickness (mm) (p-value =.17) -1. (.19) Patisiran -.1 (.33) Placebo LS Mean (SEM) Change from Baseline at 18 Months Global Longitudinal Strain (%) (p-value =.15).8 (.28) 1.46 (.48) Patisiran Placebo Adjusted Geometric Mean Fold-Change (95% CI) from Baseline to 18 Months -1 NT-proBNP (ng/l) (ratio of patisiran/placebo =.45; p-value = 7.74 x 1-8 ).89 (.78, 1.1) Patisiran 1.97 (1.55, 2.5) Placebo Pre-specified cardiac subpopulation: patients with evidence of pre-existing cardiac amyloid involvement at baseline without confounding medical conditions (i.e., patients with baseline left ventricular [LV] wall thickness 1.3 cm and no aortic valve disease or hypertension in medical history) Ratio is the adjusted geometric mean fold-change of patisiran/placebo 95% CI, 95% confidence interval; LS, least squares; LV, left ventricular, SEM, standard error of the mean

12 Patisiran Phase 3 APOLLO Study Results Safety and Tolerability Type of Adverse Event, number of Placebo Patisiran patients (%) (N=77) (N=148) Adverse event (AE) 75 (97.4) 143 (96.6) Severe AE 28 (36.4) 42 (28.4) Serious adverse event (SAE) 31 (4.3) 54 (36.5) AE leading to treatment discontinuation 11 (14.3) 7 (4.7) AE leading to study withdrawal 9 (11.7) 7 (4.7) Death 6 (7.8) 7 (4.7) Overall, 13 deaths in APOLLO study; no deaths considered related to study drug Causes of death (e.g., cardiovascular, infection) consistent with natural history; frequency of death trended lower in the patisiran group compared with placebo group Majority of AEs were mild or moderate in severity Peripheral edema Did not result in any treatment discontinuations and decreased over time Infusion-related reactions (IRRs) Majority mild in severity that decreased over time; led to treatment discontinuation in 1 patient No severe, life-threatening or serious IRRs No safety signals regarding cataracts, hyperglycemia, infection, or osteopenia/ osteoporosis No safety signals regarding liver function tests, hematology including thrombocytopenia, or renal dysfunction related to patisiran Safety in cardiac subpopulation comparable to overall study population Adverse Events Occurring in 1% in Either Group Preferred AE Term, number of patients (%) Placebo (N=77) Patisi ran (N=1 48) Diarrhea 29 (37.7) 55 (37.2) Edema, peripheral 17 (22.1) 44 (29.7) Infusion related reaction (IRR) 7 (9.1) 28 (18.9) Fall 22 (28.6) 25 (16.9) Constipation 13 (16.9) 22 (14.9) Nausea 16 (2.8) 22 (14.9) Dizziness 11 (14.3) 19 (12.8) Urinary tract infection 14 (18.2) 19 (12.8) Fatigue 8 (1.4) 18 (12.2) Headache 9 (11.7) 16 (1.8) Cough 9 (11.7) 15 (1.1) Insomnia 7 (9.1) 15 (1.1) Nasopharyngitis 6 (7.8) 15 (1.1) Vomiting 8 (1.4) 15 (1.1) Asthenia 9 (11.7) 14 (9.5) Pain in Extremity 8 (1.4) 1 (6.8) Muscular Weakness 11 (14.3) 5 (3.4) Anemia 8 (1.4) 3 (2.) Syncope 8 (1.4) 3 (2.) Blue, bolded text: Indicates 5 percentage point difference in either group

13 Essai de phase III: ASO (Neuro-TTR / Inotersen) Design de l étude Screen Stratification Stage 1 / 2 ATTR-V3M / Non V3M Stabilizers / No treatment Randomisation (2/1) 2 1 NEURO-TTR Inotersen Placebo Traitement 15 mois 3mg / semaine (ss cutanée) + vitamine A IONIS-TTR Rx Primary endpoints Change from baseline to week 66 in the mnis+7 and Norfolk QOL-DN (total score) OLE Traitement 3 ans Norfolk QoL-DN 5 Domains/138 Points (pt) Total Higher Score = Poorer QoL Physical Function / Large fiber 58pt, 42% Symptoms 32 pt, 23% n Main Cardiological endpoints Global longitudinal strain (GLS) by echocardiography n Echocardiography parameters 1 n NT-proBNP Autonomic neuropathy 12pt, 9% Activities of daily living 2pt, 14% Small fiber neuropathy 16pt, 12% QoL endpoints SF36 questionnaire

14 Patients Disposition 173 patients randomized 2:1 1 patient randomized in error in inotersen group and did not 172 Patients treated with initiate study drug inotersen or placebo arms 6 Treated with placebo 112 Treated with inotersen 8 (13.3%) Discontinued treatment with placebo 26 (23.%) Discontinued treatment with inotersen 52 (86.7%) Completed treatment 87 (77.%) Completed treatment 135 Patients participated in OLE (data lock point Oct 217) Over 8% of patients completed the 15-month NEURO-TTR study Participation rate in OLE 96% One early termination patient in NEURO-TTR allowed to participate in OLE 5 patients declined to participate in OLE

15 Baseline Demographics Represent a Diverse hattr-pn Patient Population Demographic characteristics were well balanced between the treatment groups % S u b j e c t s Baseline Disease Characteristics (strata recorded from CRF) S t a g e S t a g e 2 Non-V3M: 26 mutations V 3 M N o n - V 3 M P r e v i o u s T x t T x t N a i v e Mean Age (yr) Demographics (Total) 59.2+/ % with 65 of age Male 118 (68.6%) Mean mnis+7 (SD) (37.63) Cardiomyopathy phenotype defined by Clinical Dx or Echo, n (%) Prior Stabilizer with tafamidis or diflunisal Region, n (%) 18 (62.4%) 99 (57.6%) Europe: 6 (34.9%) (FR: 15 pts) North America: 82 (47.7%) South America / Australasia: 3 (17.4%) 15

16 Substantial and Highly Statistically Significant Benefit in Neuropathy Disease Progression - mnis+7 Primary Endpoint Statistically significant difference was observed at both 8 months and 15 months 3 P l a c e b o 2 5 I n o t e r s e n m N I S + 7 C h a n g e f r o m B a s e l i n e ( L S M ± S E M ) ( p =. 5 ) ( p =. 4 ) LSM = Least Squares Method S t u d y W e e k 36.5% of Inotersen patients had no disease progression or improved (change from baseline was or negative by month 15) All 12 Pre-specified Sensitivity Analyses for mnis+7 Maintained Statistical Significance at Both Timepoints (Month 8 and Month 15)

17 Substantial and Highly Statistically Significant Benefit in Quality of Life Norfolk QoL-DN Primary Endpoint Statistically significant difference was observed at both 8 months and 15 months 1 6 P la c e b o N o rfo lk Q o L -D N T o ta l S c o re C h a n g e fr o m B a s e lin e (L S M ± S E ) In o te rs e n p = p = LSM = Least Squares Method S tu d y W e e k 5.% of Inotersen patients had no disease progression or improved (change from baseline was or negative by month 15) All 9 Pre-Specified Sensitivity Analyses for Norfolk QoL-DN Maintained Statistical Significance at Month 15 17

18 Cardiac Benefit Compared to Placebo Observed Across Multiple Endpoints in Patients with Significant Cardiac Disease at Baseline (IVS 1.5 cm) Left Ventricle Mass Interventricular Septum Thickness (IVS) Posterior Wall Thickness Global Longitudinal Strain LV Mass (g) Change from Baseline (LSM±SE) 2 p= Interventricular Wall Thickness (cm) Change from Baseline (LSM±SE) p=.15 Posterior Wall Thickness (cm) Change from Baseline (LSM ±SE) p=.425 Global Longitudinal Strain (%) Change from Baseline (LSM ±SE) p=.5753 Inotersen (n=35) Placebo (n=16) Inotersen (n=35) Placebo (n=16) Inotersen (n=35) Placebo (n=16) Inotersen (n=35) Placebo (n=16) High variability in NT-proBNP in both treatment groups

19 Patient disposition at the end of Phase III Study Patient Disposition at End of Phase III Study Placebo (n=6) Inotersen (n=112) Total (n=172) Completed 52 (86.7%) 87 (77.7%) 139 (8.8%) Discontinued 8 (13.3%) 25 (22.3%) 33 (19.2%) Adverse Event 1 (1.7%) 16 (14.3%) 17 (9.9%) Stopping Rule Met^ 1 (1.7%) 2 (1.8%) 3 (1.7%) Disease Progression 3 (5.%) 2 (1.8%) 5 (2.9%) Voluntary Withdrawal 3 (5.%) 2 (1.8%) 5 (2.9%) Liver Transplant 1 (.9%) 1 (.6%) Other 2 (1.8%) 2 (1.2%) () Further details in Treatment Discontinuations section (^) All three subjects discontinued due to an adverse event that met a stopping rule so when reporting how many subjects discontinued due to an AE, these subjects should be included (ie. 2 subjects discontinued due to AE)

20 Safety Observations - Key Adverse Event Profile Very common adverse reactions Deaths Thrombocytopenia Anaemia Platelet Count Decreased Headache Vomiting Nausea Pyrexia Chills Injection site reactions Peripheral oedema Common adverse reaction Eosinophilia Decreased appetite Orthostatic hypotension Hypotension Haematoma Transaminases increased Pruritus Rash Glomerulonephritis Renal failure Acute kidney injury Renal impairment Proteinuria Influenza like illness Peripheral swelling Injection site discoloration Contusion n n n n 5 Deaths in CS2 and 2 in CS3 All deaths but one disease related In CS2 all deaths in inotersen treated subjects Death rate (4.7%) in inotersen treated subjects in CS2 is similar or less than that observed in placebo arms of randomized controlled phase 3 studies in similar populations

21 Identified Safety Concern: 3 Cases of Grade Thrombocytopenia Occurred prior to the implementation of enhanced monitoring 2 cases recovered completely following discontinuation of dosing and initiation of corticosteroids 1 case presented with intracranial hemorrhage, which was fatal Received inotersen for 9 weeks prior without a platelet count 1 additional recent SAE of Grade 3 thrombocytopenia detected with enhanced monitoring Platelet Levels in NEURO-TTR Study Platelets Platelets (1 (1 9 /L) 9 /L) Level Level Treatment Analysis Visit (weeks) placebo inotersen

22 Creatine clearance: subjects appeared to stabilize at a new level with a mean decrease from Baseline in the range of 5 to 1 ml/min/1.73 m 2 during treatment particularly in V3M patients egfr variation in NEURO-TTR Study placebo Treatment Identified Safety Concern: Three Cases of Glomerulonephritis 2 cases prior to frequent monitoring of serum creatinine and urine protein 1 diagnosed late and ended up on dialysis 1 successfully treated with steroids and recovered significant renal function 1 case recently detected early through urine protein monitoring resolved with steroid treatment, no decline in renal function (egfr) All 3 cases showed glomerulonephritis by renal biopsy with complex pathology, features consistent with crescentic GN superimposed on background of amyloidosis and in two cases interstitial fibrosis All cases V3M / showed significant increase in urine protein

23 Patisiran Phase 3 APOLLO Study Inotersen Phase 3 study Conclusions Patisiran treatment resulted in significant improvement in polyneuropathy from baseline relative to placebo Benefits in motor, sensory and autonomic neuropathy Positive effects across wide range of disease severity, TTR genotypes, and in patients with cardiac involvement Significant improvement in quality of life, reduction in disease symptoms and disability, and improvement in nutritional status, strength, and ambulation seen with patisiran relative to placebo Favorable changes in exploratory cardiac measures in patisiran treated patients within cardiac subpopulation Improvement in NT-proBNP, longitudinal strain, and LV wall thickness relative to placebo Patisiran showed an encouraging safety and tolerability profile Frequency of deaths trended lower in the patisiran group vs placebo group Key patisiran safety findings include mild to moderate peripheral edema and IRRs; only one treatment discontinuation due to these event The randomized, placebo-controlled, Phase 3 study evaluating inotersen in hattr patients with polyneuropathy, met both primary endpoints Inotersen-treated patients achieved early, significant and increasing benefit compared to placebo in Norfolk QoL-DN and mnis+7 endpoints Benefit achieved independent of disease stage, presence of cardiomyopathy and types of mutation compared to placebo Attractive patient convenience as a once weekly, self-administered at-home subcutaneous injection The important identified risks of thrombocytopenia and glomerulonephritis are monitorable and managable

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