Relevant Conflicts of Interest - Untangling...

Relevant Conflicts of Interest

Consulting: Alnylam

Research Support: Prothena, Alnylam

TTR: Transporter of

thyroxine and retinol

https://www.acc.org/latest-in-cardiology/articles/2015/10/13/08/35/emerging-therapies-for-transthyretin-cardiac-amyloidosis

Wild-type

TTR

Mutant

TTR

NeuropathyCardiomyopathy

Normal liver Hereditary

TTR liver

• Amyloidotic cardiomyopathy

– Wild-type ATTR (“senile systemic amyloidosis”)

– Mutant ATTR (familial amyloid cardiomyopathy / FAC)

• Amyloidotic polyneuropathy

– Mutant ATTR (familial amyloid polyneuropathy / FAP)

TTR amyloidosis subtypes

Wild-type TTR cardiomyopathy

• 25% of autopsied hearts had TTR (n=85)

• Clinically significant deposition in ~1/3 (~8%)

• Clinically almost always occurs in men >70

• All men get it if we live long enough?

Cornwell GG, Am J Med 1983; Tanskanen M, Ann Med 2008

Rapezzi C, Eur Heart J 2013

Mutant TTR amyloidosis

Familial Amyloid

Cardiomyopathy (FAC)

• 3-5% of African-Americans are V122I carriers

• Incomplete penetrance:

– No difference in mortality over 21.5 years

– Increased evidence of early markers of CHF (sex- and

age-stratified hazard ratio 1.47 (95% CI [1.03-2.1]), but low

prevalence of overt disease

Cuarta CC, et al. New Eng J Med 2015

Adapted from Schmidt H, Muscle Nerve 2017

~1:600

Familial Amyloid

Polyneuropathy (FAP)

ATTR: Clinical Manifestations

• Cardiac:– Progressive CHF with median life expectancy 2-10 years

– Men >> women

– Variable age of onset (wtATTR age 70+, FAC age 50+)

• Neuropathic:– Progressive sensorimotor and autonomic neuropathy

– Age of onset varies, median life expectancy 10-15 years

Ruberg F, Circ 2013; Adams D, Brain 2000, Waddington-Cruz, Amyloid 2017

12

Serum TTR

Amyloid12

reducing TTR

production

TTR stabilizers

Anti-fibrillary agents

13

Serum TTR

Amyloid13

Liver transplant,

novel RNA

therapeutics

Tafamidis, diflunisal

Doxycycline, EGCG,

TUDCA

Suppressing hepatic TTR

production

• Approved agents:

– Inotersen (Ionis / Akcea)

– Patisiran (Alnylam)

• Investigational:

– TTR-LRx (Ionis / Akcea)

– TTR-SC02 (Alnylam)

– miRNA, others

Watts JK, J Path 2012

Antisense oligo siRNA*

(inotersen) (patisiran)

*siRNA = small interfering RNAWatts JK, J Path 2012

siRNA depends on

RNA-induced

silencing complex

(RISC)

The NEURO-TTR Study

Benson MD, New Eng J Med 2018


Adults with FAP

FAP stage 1-2 (less than wheelchair-bound)

Neuropathy Impairment Score (NIS) of 10-130*

KPS ≥ 50, NYHA class <3 CHF

No prior liver transplant, no concurrent diflunisal / tafamidis

*NIS scale ranges from 0-244 and is based on neurological exam. A higher score is worse.

NEURO-TTR: Eligibility

Inotersen Trial Design

Benson M, et al. N Engl J Med, 2018

ATTR-FAP

(Stage 1-2)

Inotersen (300 mg Weekly SC)

Placebo

15 months

n = 112

n = 60

OLE Trial

18 months

Stratified: +/- Val30Met, disease stage, prior tetramer stabilizer use

• Primary endpoint: Improvement at week 66 in mNIS+7 and QOL-DN* score

• Secondary endpoints: Other markers of neuro function, biomarker correlatives

• Neuro assessments were double-blinded and centrally completed

*Quality of Life – Diabetic Neuropathy assessment Benson MD, New Eng J Med 2018

Inotersen Trial design


Characteristic Placebo (n=60) Inotersen (n=112)

Age 60 59

Val30Met 55% 50%

mNIS+7 score 74.8 79.2

Stage 2 (walks with

assistance)70% 66%

Prior stabilizer 60% 56%

Norfolk QOL-DN score 48.7 48.4

Presence of

cardiomyopathy55% 67% Benson MD, New

Eng J Med 2018

Inotersen Trial: Patients

mNIS+7 and Norfolk QoL-DN

mNIS+7 Norfolk QoL-DN

• “a 2-point mNIS+7 change is the minimal clinically meaningful change detectable”

• Benefit independent of stage, mutation, prior TTR stabilizer, or presence of cardiomyopathy

• No change in cardiac markers after 15 months (longitudinal strain, other measures)Benson MD, New Eng J Med 2018

Inotersen: Safety

• Thrombocytopenia (54% on inotersen vs. 13% on placebo had PLT

<140K)

– One fatal intracranial hemorrhage (PLT < 10K)

• Glomerulonephritis (n = 3)

• No further severe episodes with intensive CBC, renal monitoring

• Mild GI, fever, fatigue, skin reactions

• 22% dropout for inotersen vs. 13% for placebo

• 5 deaths on inotersen arm, 0 in placebo (4 progressive ATTR, 1 bleed)


Inotersen Trial


Adams D, New Eng J Med 2018

The APOLLO Study

Adults with FAP

Polyneuropathy disability score ≤IIIB (less than wheelchair-bound)

Neuropathy Impairment Score (NIS) of 5-130

NYHA class <3 CHF

No prior liver transplant, no concurrent diflunisal / tafamidis


APOLLO: Eligibility


APOLLO Trial Design

ATTR-FAP

(Stage 1-2)

Patisiran (0.3 mg/kg IV q 3 wk)

Placebo

18 months

n = 148

n = 77

OLE Trial

Stratified by NIS, Val30Met, disease stage, prior tetramer stabilizer

APOLLO trial endpoints

• Primary endpoint: mNIS+7 improvement at 18 mos

• Secondary endpoints: QoL-DN score, other

markers of neuro function, biomarker correlatives

• mNIS+7 assessments were double-blinded and

centrally completed


Characteristic Placebo (n=77) Patisiran (n=148)

Age 63 62

Val30Met 52% 38%

Stage 2 (walks with assistance) 51% 55%

Prior stabilizer 53% 53%

NYHA class 2 47% 52%


APOLLO Trial: Patients


• Benefit independent of stage, mutation, prior TTR stabilizer, or presence of cardiomyopathy

• Suggestion of cardiac improvement by NT-proBNP and echo findings

APOLLO: mNIS+7 &

Norfolk QoL-DN

• Mortality: 5% patisiran and 8% placebo

– primarily cardiac for patisiran, various causes for placebo

– BUT fewer “any” cardiac events in patisiran group (28% vs 36%)

• Mild peripheral edema, infusion reactions with patisiran

• 7% dropout for patisiran vs. 38% for placebo

Patisiran Safety



APOLLO Trial

Concluding Thoughts:

The Present

• Inotersen or Patisiran?

– No head-to-head data

• Best to combine with tafamidis, doxy, etc.?

• What about amyloid cardiomyopathy?

– Not a no-brainer: revusiran FAC trial halted due to excess mortality

• If and when to start treatment in asymptomatic carriers?

• Optimal duration of therapy not known ($$$)

• Next gen RNA therapeutics – focus on durability/convenience:

– TTR-SC02 (Alnylam) – SC injection q3m

– TTR-LRx (Ionis)

• New stabilizers: AG10 (Eidos)

• Fibril disruptors: PRX-004 anti-ATTR moAb (Prothena)

• The future: CRISPR?


Concluding Thoughts:

The Future

CRISPR: The Future?

Adapted from https://www.slideshare.net/jamiehworkman/dna-replication-transcription-and-translation

CRISPR

RNA drugs

http://ir.intelliatx.com/static-files/b15d1bdf-9109-4add-8bf5-c1d123f9425d

CRISPR delivery via lipid

nanoparticles


CRISPR: Durable TTR suppression

in non-human primates

Thank You!

Relevant Conflicts of Interest - Untangling...

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