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Inotersen and Beyond A Comprehensive Antisense Therapeutic Strategy for all Forms of ATTR
Sotirios Tsimikas, MDDirector of Vascular MedicineProfessor of MedicineUniversity of California San DiegoIonis Pharmaceuticals
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Disclosures
• Dual appointment at University of California San Diego and Ionis Pharmaceuticals
InotersenAn Antisense Approach to Treat TTR-related Amyloid Diseases
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• Binds to TTR messenger RNA (mRNA) Binds to wild-type (normal)
TTR mRNA and all known mutations Results in degradation of
TTR mRNA and lowering of TTR protein production
• TEGSEDI reduces production of both mutant and wild-type TTR protein by the liver
• Self-administered as a once-weekly, at-home SC injection with no pretreatment requirements
A Generation 2.0+ Antisense Oligonucleotide (ASO)
InotersenOverview of Development Path
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CLINICAL STUDIES
Phase/Study Phase I Phase III(NEURO-TTR)
NEURO-TTROLE
Patients Healthy Volunteers (N=65)
hATTR-PN (N=172)
hATTR-PN (N=135)
Design SAD/MAD Dose-Escalation
15 mo. Placebo Control (2:1)
Patients from NEURO-TTR (Open Label) up to 5 years
Key Endpoints Safety/Tolerability TTR Reduction
mNIS+7/Norfolk QOL(coprimary) Long-Term Safety/Efficacy
Status Complete Complete Ongoing
Outcome Good Safety/Tolerability Robust TTR Reductions
Highly PositiveMarketing Approved
Long-Term Safety/Efficacy Demonstrated
InotersenPivotal Phase 3 and OLE Study In Adults with hATTR-PN
a The n values for NEURO-TTR represent the number of patients randomized and treated. b Discontinuations in the inotersen-inotersen group were due to adverse event or serious adverse event (n = 15), voluntary withdrawal (n = 6), investigator judgment (n = 3), stopped per stopping rules (n = 1), and other (n = 2). c Not all patients had completed 2 years in the OLE as of May 31, 2018. d Discontinuations in the placebo-inotersen group were due to voluntary withdrawal (n = 5), investigator judgment (n = 4), adverse event or serious adverse event (n = 3), liver transplantation (n = 1), disease progression (n = 1), and other (n = 1).Benson MD et al. N Engl J Med. 2018;379(1):22-31.
NEURO-TTRInternational, randomized, double-blind, placebo-controlled Phase 3 study
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Screen
Inotersen
Placebo
Randomization(2:1)
n = 112
n = 60
NEURO-TTRa
15 months oftreatment
Inotersen-inotersenOngoing: n = 58 (68%)
Discontinuedb: n = 27 (32%)Week 104c: n = 40 (47%)
n = 85
n = 50
Open-Label Extension
Up to 5 yearsof treatment
n = 87
n = 52
Placebo-inotersenOngoing: n = 35 (70%)
Discontinuedd: n = 15 (30%)Week 104c: n = 19 (38%)
Open-Label Enrollment
Coprimary end points: modified Neuropathy Impairment Score +7 composite score (mNIS+7) and Norfolk Quality of Life-Diabetic Neuropathy total score (QoL-DN) measured at week 66
Stratified for stage of disease, TTR mutation, and previous treatment (tafamidis or diflunisal)
139 patients (80.3%) completed the NEURO-TTR study, and >95% of patients who completed dosing participated in the OLE
-90
-80
-70
-60
-50
-40
-30
-20
-10
0
Med
ian
% C
hang
e Fr
om B
asel
ine
in S
erum
TTR
Lev
els Placebo-inotersen
Inotersen-inotersen
OLEBaselineNEURO-TTR
65350 26 52 78 104
Time From NEURO-TTR or OLE Baseline (weeks)
InotersenRapid reduction in serum TTR levels
(1) Benson MD et al. N Engl J Med. 2018;379(1):22-31.
Median serum TTR reductions in the placebo-inotersen group reached a nadir of 78% below OLE baseline from week 13 to 104
Median serum TTR reductions in the inotersen group in NEURO-TTR reached a nadir of 79% below baseline from week 13 to 651
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6
-10
0
10
20
30
Nor
folk
QoL
-DN
Cha
nge
From
NEU
RO
-TTR
Base
line
(mea
n ±
SE)
Placebo-inotersenInotersen-inotersenPlacebo-slope
InotersenhATTR PN progression slowed with greater stabilization in patients who initiated treatment with Inotersen earlier
mNIS+7, modified Neuropathy Impairment Score +7 neurophysiologic tests composite score; Norfolk QoL-DN, Norfolk Quality of Life–Diabetic Neuropathy questionnaire total score; PN, peripheral neuropathy; QoL, quality of life; SE, standard error. The minimum clinically meaningful score-change for the mNIS+7 is two-points.
-10
0
10
20
30
40
50
60
mN
IS+7
Cha
nge
From
NEU
RO
-TTR
Base
line
(mea
n ±
SE)
Placebo-inotersenInotersen-inotersenPlacebo-slope
NEURO-TTR
Placebo-inotersen, nInotersen-inotersen, n
66350 26 52 78 104
Time From NEURO-TTR or OLE Baseline (weeks)
4980
5079
4980
4778
3470
2253
1939
Placebo-inotersen, nInotersen-inotersen, n
350 78 104
Time From NEURO-TTR or OLE Baseline (weeks)
NEURO-TTR
5079
5078
4978
4678
3876
2253
1941
−17.1 −11.9
66 26 52
-11.3
OLEBaseline
OLEBaseline
-21.0
42% of placebo-inotersen patients had a <0-point score change from OLE baselinec to
week 104
46% of inotersen-inotersen patients had a <0-point score
change from NEURO-TTR baselined to OLE week 104
47% of placebo-inotersen patients had a <0-point score change from OLE baselinea to
week 104
24% of inotersen-inotersen patients had a <0-point score
change from NEURO-TTR baselineb to OLE week 104a
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InotersenSummary of Clinical Study Results• NEURO-TTR
• Inotersen demonstrated significant, sustained improvements in measures of both neuropathy and quality of life in the pivotal randomized, double-blind, placebo-controlled phase 3 trial
• Serious side effects, included thrombocytopenia and glomerulonephritis
• NEURO-TTR OLE• Data from the long-term extension study showed benefits of early
therapy with inotersen based on measures of objective neuropathic progression and neuropathy-related quality of life
• No new safety signals identified• No new cases of grade 4 platelet count decrease or acute
glomerulonephritis
InotersenConclusions
*Inotersen is authorised for the treatment of stage 1 or stage 2 PN in adult patients with hATTR. DN, diabetic neuropathy; hATTR, hereditary transthyretin amyloidosis; mNIS+7, modified neuropathy impairment score +7; QoL, quality of life; SC, subcutaneous.
Both primary endpoints, mNIS+7 and Norfolk QoL–DN, favoured inotersen vs placebo
SC injections were successfully administered at home outside pre-specified clinical visits
Enhanced safety monitoring enabled early detection and management of thrombocytopenia and glomerulonephritis
Inotersen modified the course of neuropathy and improved the QoL of patients with hATTR
Inotersen is a novel, convenient and effective treatment for hATTR*
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AKCEA-TTR-LRx
Patients with Hereditary and Wildtype ATTR
AKCEA-TTR-LRxIn Development to Treat Patients with All Forms of TTR Amyloidosis
• Utilizes our most advanced LICA chemistry, providing high potency with potential forimproved convenience and tolerability
• In partnership with Akcea Therapeutics, a rapid and comprehensive development strategy is underway to treat all forms of TTR amyloidosis
*Co-developing with Akcea
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LICA (Ligand Conjugated Antisense)Game Changing Advance in Potency
• Enhanced tissue-specific potency
• Low dose volume• Monthly dosing
regimen
(1) Crooke ST, Baker BF, Xia S, et al. Nucleic Acid Ther. 2019;29:16-32. (2) Alexander VJ, Xia S, Hurh E, et al. Eur Heart J 2019 Apr 24. (3) Graham MJ, Lee RG, Brandt TA, et al. N Engl J Med 2017;377:222-32; (4) Viney NJ, van Capelleveen JC, Geary RS, et al. Lancet 2016;388:2239-53; (5) Yu RZ, Gunawan R, Post N, et al. Nucleic Acid Ther 2016;26:372-80; (6) Kinberger GA, Prakash TP, Yu J, et al. Bioorg Med Chem Lett 2016;26:3690-3; (7) Tsimikas S, Viney NJ, Hughes SG, et al. Lancet 2015;386:1472-83; (8) Ostergaard ME, Yu J, Kinberger GA, et al. Bioconjug Chem 2015;26:1451-5; (9) Prakash TP, Graham MJ, Yu J, et al. Nucleic Acids Res 2014;42:8796-807.
ASGR mediates productive uptake of GalNAc3-Conjugated ASOs by hepatocytes
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Increased Potency Observed with GalNAc3-Conjugated PS 2’MOE ASOs across Phase 1 Healthy Volunteer StudiesGalNAc3-conjugated ASOs have demonstrated a 20 to 30-fold increase in potency and an improved safety and tolerability profile compared to parent ASOs in human clinical trials
(1) Crooke ST, Baker BF, Xia S, et al. Nucleic Acid Ther. 2019;29:16-32. (2) Alexander VJ, Xia S, Hurh E, et al. Eur Heart J 2019 Apr 24. (3) Graham MJ, Lee RG, Brandt TA, et al. N Engl J Med 2017;377:222-32; (4) Viney NJ, van Capelleveen JC, Geary RS, et al. Lancet 2016;388:2239-53.
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AKCEA-TTR-LRxAnticipated Profile
• High Potency• ≥ 90% reduction in TTR levels at low doses
• Convenience• Once monthly low volume self-administered SC injection
• Improved safety & tolerability profile• No unusual monitoring (including platelets/renal)
• Combination with stabilizers not contraindicated
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AKCEA-TTR-LRxPhase 1/2 Study Objectives
• Primary Objective: Evaluate the safety and tolerability of single and
multiple subcutaneous doses of AKCEA-TTR-LRx in healthy volunteers and patients with ATTR
• Secondary and Exploratory Objectives: Evaluate the pharmacokinetics and
pharmacodynamics following single and multiple subcutaneous doses of AKCEA-TTR-LRx in healthy volunteers and patients with ATTR
AKCEA-TTR-LRxPhase 1 Study Design in Healthy Volunteers
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A randomized, blinded, placebo-controlled, dose-escalation study
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AKCEA-TTR-LRxDose-dependent Reductions in TTR Levels in Healthy Volunteers
Nadir-86%
-86%-94%
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AKCEA-TTR-LRxSummary Phase 1 Results in Healthy VolunteersRobust PD Profile• TTR reductions maintained between monthly doses as predicted by PK
properties of these drugs• Maximum mean reductions of 86% and 94%, from baseline two weeks
after the 4th dose of 45 and 90 mg, respectively
No Safety Issue Identified• No SAEs• No treatment-related safety signals
• No effect on platelets• No hepatic or renal safety signals• No dose discontinuations
AKCEA-TTR-LRxDevelopment Path
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Healthy Volunteers
----------------------------
ATTR
ATTR-CM
hATTR-PN
Phase 1/2 Phase 3 / Registration
InotersenInvestigator Initiated Phase 2 ATTR-CM Studies
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CLINICAL STUDIES
Phase/StudyPhase II
Investigator Study (M. Benson, MD)
Phase II Investigator Study*
(R. Falk, MD)
Patients ATTR-CM (n=33)
ATTR-CM (n~50)
Design Open-Label up to 5 years
Open-Label up to 3 years
Key Endpoints Safety/Tolerability Efficacy vs Natural History Data
Safety/Tolerability Efficacy vs Patient Hx & Disease Nat Hx
Status Ongoing Ongoing
Outcome Long-Term Safety demonstrated w/ Evidence of Efficacy Just initiated
* See abstract, this meeting
Phase 2 Open-Label Investigator Initiated StudyBenson & Dasgupta, Indiana University School of Medicine
Single center, investigator trial in patients with TTR cardiomyopathy
Objective is to evaluate long-term safety and clinical efficacy of inotersen in patients with ATTR cardiomyopathy (vs natural history data)
• Biopsy-proven ATTR cardiomyopathy with clinical CHF symptoms (hereditary or wild type)
• LVW thickness ≥ 1.3 cm on transthoracic echocardiography
Main inclusion criteria:
Inotersen 300 mg SC weekly
• Wild-type and hereditary ATTR-CM• Open-label design• Up to 5 years of treatment
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Phase 2 Open-Label ATTR-CM StudyPatient Disposition and Baseline Characteristics
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Dasgupta, et al. (2019, manuscript submitted). Inotersen Therapy of Transthyretin Amyloid Cardiomyopathy
Baseline Hereditary Wild-Type
n 10 23
Age, mean, y 63.4 76.2
MutationsT60A (7) V30M (1)P24S (2)
—
Pacemaker 1 (10%) 8 (35%)
Atrial fibrillation/flutter 2 (20%) 16 (70%)
CAD 0 9 (39%)
HTN 2 (20%) 9/23 (39%)
CAD, coronary artery disease; HTN, hypertension
9 Study Withdrawals: 6 Voluntary; 2 Non-compliance; 1 Death, Non-related.
1 year n = 20
2 years n = 16
3 years n = 14
EnrollmentN = 33
Completed 1 year n = 11
Completed 2 years n = 8
Completed 3 years n = 6
Completed 3 years n = 8
Completed2 years n = 8
Hereditaryn=10
Wild-typen=23
Completed 1 year n = 9
5 Withdrawals
October 2018
< 1 yearn = 8
2 Withdrawal
2 Withdrawals
Phase 2 ATTR-CM: Case Presentation63-year-old Caucasian male with threonine-60-alanine mutation
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• LVEF remained in the normal range
• LV longitudinal strain remained stable
• BNP decreased from 161 to 22 pg/ml without the use of diuretics
• 6MWD increased 97.2 meters
Benson M. (2017). Safety and Efficacy of inotersen in Patients with Hereditary Transthyretin Amyloidosis with Polyneuropathy. Presented at the 1st European ATTR Amyloidosis Meeting, Paris, France.
2/9/15: IVS 1.7 cm 2/3/17: IVS 1.5 cm
2/20/15: LVM 231 g 12/28/16: LVM 173 g Cardiac Improvement seen with 2 yrs of inotersen treatment
Phase 2 Investigator Study of Inotersen Demonstrates Stabilization or Improvements of TTR Cardiomyopathy
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1. Benson MD, et. al., (2011) Am J Cardiol 108(2) 285-9. Benson, M.D., AAN.2. Ruberg et al. (2012) Am Heart J. 64:222-228.e1. Benson, M.D., AAN.
Patients treated for more than 3 years
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InotersenDemonstrates Stabilization and Improvements in TTR Cardiomyopathy Investigator Study
• No severe thrombocytopenia or drug-related renal adverse events
• Mild injection site reactions in 25% patients, with a few patients experiencing mild flu-like symptoms
• One non-drug related death after surgery due to cardiac arrest
• Strong evidence of efficacy at 2 and 3 years of therapy compared to natural history• Improved 6 minute walk distance
• Reduced left ventricular mass
• Decrease in mean BNP compared to baseline
AKCEA-TTR-LRxATTR-CM Phase 3 Study Schema and Key Information
A Phase 3 Global, Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Efficacy and Safety of AKCEA-TTR-LRx in Patients with Transthyretin-Mediated Amyloid Cardiomyopathy (ATTR-CM)
• Sample size: ~750• Primary composite endpoint:
CV death and CV clinical events• Secondary endpoints:
6MWT, KCCQ, CV clinical events• Exploratory endpoints:
Echo, biomarkers, PROs, (potential CMRI sub-study)
Patients with hATTR-CM or wtATTR-CM on available
SoC
AKCEA-TTR-LRx
PlaceboScre
enin
g
Ran
dom
izat
ion
1:1
Post
-trea
tmen
t Ev
alua
tion
Perio
d
D1 W4 W8 W12 W60 W120W24 W36 W48 W72 W84 W96 W108
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AKCEA-TTR-LRxATTR-PN Phase 3 Study Schema and Key Information
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Adults with hATTR-PN meeting all 3 of the following criteria:
• Stage 1 or Stage 2• Documented TTR genetic mutation• Symptoms and signs consistent with polyneuropathy (NIS ≥ 10 and ≤ 130)
Post Tx / OLE
Patients with hATTR-PN
Scre
enin
g AKCEA-TTR-LRx~120 patients
Inotersen~20 patients
Baseline
AKCEA-TTR-LRx
Ran
dom
izat
ion
6:1
AKCEA-TTR-LRx
NEURO-TTR Historical Placebo (60 patients)
Week 35 Week 66 Week 85
A Comprehensive Therapeutic Franchise to Treat All Forms of Transthyretin Amyloidosis
• First-approved RNA-targeted therapeutic for hATTR-PN• Published in New England Journal of Medicine (Benson, M.D. et al. 2018; 379: 22-31)• Approved in the US, Canada and European Union for the treatment of polyneuropathy
in adult patients with hATTR
• Patients previously on placebo experiencing disease stabilization• Disease improvement achieved in many patients• Earlier treatment results in better outcomes
• Phase I study in healthy volunteer nearly complete• Phase III pivotal studies in hATTR-PN & ATTR-CM to initiate in 2H 2019
Inotersen demonstrated substantial benefit with manageable safety in Phase 3 NEURO-TTR study
NEURO-TTR OLE demonstrating long-term benefit with no new safety concerns with long-term treatment
Long-term safety with strong evidence of clinical efficacy in patients with wild type and hereditary TTR cardiomyopathy (Benson & Dasgupta, Open-label Phase 2 Investigator Initiated Study)
Development of LICA follow-on medicine (AKCEA-TTR-LRx) for all forms of ATTR underway
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Thank you
