transthyretin familial amyloid polyneuropathy (ttr...

FAMILIAL AMYLOID

POLYNEUROPATHY

(TTR-FAP): Genetics

and Treatment

1

Michelle Mezei BSc (Pharm), MDCM, FRCPC

Neuromuscular Diseases Unit, VGH

Division of Neurology, UBC

Learning Objectives

• To become familiar with Familial Amyloid Polyneuropthy

– hATTR (Hereditary Transthyretin Amyloidosis)

• To review novel treatment options in hATTR

Disclosures

• Principle Investigator: Alnylam Apollo and Patisiran OLE

trials

• Honoraria:

– Alnylam: speaker and symposium chair

– Pfizer: Advisory Board Chair and speaker

– Genzyme: speaker

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

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

2015-2017:

• Apollo trial

• Pain improves, minimal GI sxs, improved endurance

Patient Case Study

2017-2018:

• 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

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 changes1,2

Affected organs:

• Kidney

• Heart

• Liver

• GI system

• Nervous system

Primary (AL)

amyloidosis

Affected organs:

• Kidneys

• Liver

• Spleen

Secondary (AA)

amyloidosis

Affected organ:

• Heart

Senile systemic

amyloidosis

(wild-type)

Affected organs:

• Nervous system

• Heart

Transthyretin familial

amyloid

polyneuropathy

Localized

amyloidosis

Amyloidosis

Systemic

amyloidosis

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:1072–73. Saunders, Elsevier, 2009. 2. Merlini G et al. J Intern

Med 2004;255:159–178. 7

Immuno-

globulin light

chain

Transthyretin

Serum

amyloid A

Leukocyte

chemotactic

factor 2 (LECT2)

Β2

microglobulin Fibrinogen α-

chain

Lysozyme

Apolipoprotein

A1

Gelsolin

Different precursor protein, same end result

• 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 bound3

1. Benson MD, Kincaid JC. Muscle Nerve 2007;36:411–423.

2. Sekijima Y et al. Curr Pharm Des 2008;14:3219–3230.

3. Hou X et al. FEBS J 2007;274:1637–1650.

Transthyretin is a transport protein of thyroxine

and retinol-binding protein (RBP)/vitamin A1–3

BLOOD VESSEL

TTR RBP Thyroxine

Genetic mutations lead to variant forms of

transthyretin1

1. Benson MD, Kincaid JC. Muscle Nerve 2007;36:411–423. 2. Roberts JR et al. Amyloidosis:

Transthyretin-Related. Medscape, 2009. Accessed August 2011. 3. Zeldenrust SR. In: Gertz MA et al. eds.

Amyloidosis: Diagnosis and Treatment (Contemporary Hematology). Totowa: Humana Press, 2010. 4.

Planté-Bordeneuve V et al. Neurology 2007;69:693–698.

1–3 4

Autosomal dominant inheritance1–4

• 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

13

Affected individuals

Unaffected individuals

1. Merlini G et al. J Intern Med 2004;255:159–178.

2. Falk RH et al. N Engl J Med 1997;337:898–909.

3. Stedman’s Medical Dictionary. (27th ed.). 2002. Philadelphia: Lippinocott Williams & Wilkins.


Square = male; Circle = female

hATTR Genotype - Phenotype

Genotypic-Phenotypic Correlation

Phenotype

T49A

P64L G89G

“Neurologic” “Cardiac”

V122I V30M

A34T

S50A

G47A

S23A

I68L

P33L

C10A

A36P

L111M

H88A V41L

T60A

V30M

Early onset

Late onset

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

Congo red-stained section of posterior tibial nerve

from a patient with transthyretin amyloidosis shows

hallmark green color under polarized light2


2. Sousa MM et al. Am J Pathol 2001;159:1993–2000.

PERIPHERAL NERVE BUNDLE

Amyloid

Toxic amyloidogenic intermediates and amyloid

deposits in peripheral and autonomic nerves1,2

Image courtesy M. Benson, Indiana University School of Medicine

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

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

Variable age of onset

• May manifest between 20 and 70 years of age1,2

• Disease course of late-onset hATTR can be more

severe and lead to disability more rapidly than

early-onset disease3

• 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 symptoms4,5

1. Hou X et al. FEBS J 2007;274:1637–1650.

2. Coelho T et al. CMRO 2013; 29:63–76.

3. Adams D et al. Curr Opin Neurol 2012;25:564–572

4. Adams et al Amyloid 2012;19 Suppl 1:61–64

5. Plante-Bordeneuve et al. Neurology 2007;69:893–99.

Diagnosis

99mTc PYP Scanning

Falk et al. JACC 2016;68:1323

ATTR CA AL CA

Planar whole body scan

With SPECT

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

Suppression of TTR synthesis

• Liver transplantation1

• Investigational: Gene silencing

• ASOs: IONIS-TTRRx6

• RNAi: Patisiran7; ALN-TTRsc028

TTR stabilization

• Tafamidis2,a

• Diflunisal3,4,b

• Investigational: SOM0226a

Fibril degradation and reabsorption

• Investigational: Doxy + TUDCA5,c

• Investigational Anti-amyloid mAbs

• Anti-TTR mAb9

• Anti-SAP mAb10

Rate-limiting

tetramer

dissociation

Monomer

misfolding and

aggregation

leading to amyloid

fibrils

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;310:2658–67; 4. National Amyloidosis Centre. ATTR Amyloidosis. 2014. url –http://www.amyloidosis.org.uk/introduction-to-attr-amyloidosis/ [accessed 18/12/2014]; 5. Ruberg & Berk. Circulation 2012;126:1286–300; 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 2016 9. Higaki, et al. Amyloid 2016;23:86–97; 10. Richards, et al. N Engl J Med 2015;373:1106–14

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

Therapeutics

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

• Takei et al., 1999; Adams et al., 2000

Poor Prognostic Factors: • BMI/nutritional status

• Severe PN

• Severe AN

• Urinary incontinence

• Marked postural hypotension

• Fixed pulse rate

• Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews®

[Internet]. Seattle (WA): University of Washington, Seattle; 1993-

2016.

Treatment Options

Domino Liver Transplantation










TTR stabilization

• Tafamidis2,a

• Diflunisal3,4,b





• Anti-TTR mAb9

• Anti-SAP mAb10

Rate-limiting

tetramer

dissociation

Monomer

misfolding and

aggregation

leading to amyloid

fibrils

ASO, antisense oligonucleotides; RNAi, RNA interference; TUDCA, tauroursodeoxycholic acid 1. Ando et al. Orphanet J Rare Dis 2. 2013;8:3; 2. Said et al. Nat Rev Drug Dis 2012;11:185–6; 3. Berk et al. JAMA 2013;310:2658–67; 4. National Amyloidosis Centre. ATTR Amyloidosis. 2014. url –

http://www.amyloidosis.org.uk/introduction-to-attr-amyloidosis/ [accessed 18/12/2014]; 5. Ruberg & Berk. Circulation 2012;126:1286–300; 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 2016 9. Higaki, et al. Amyloid 2016;23:86–97; 10. Richards, et al. N Engl J Med 2015;373:1106–14


Therapeutics

Diflunisal

- NSAID

- Developed in 1971

- 250mg and 500mg

tablets

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










TTR stabilization

• Tafamidis2,a

• Diflunisal3,4,b





• Anti-TTR mAb9

• Anti-SAP mAb10

Rate-limiting

tetramer

dissociation

Monomer

misfolding and

aggregation

leading to amyloid

fibrils



Therapeutics

Tafamidis Clinical Development Program

For TTR-FAP: Efficacy Data

Prepared by Pfizer in response to an unsolicited request – Not for further distribution

Study Fx-005 (n= 128) 1) Coelho T et al. Neurology 2012;79(8):785-92 2) Keohane D et al., Amyloid 2017;24(1):30-36

18-mo, randomized double-blind, placebo-controlled study: Pivotal study in V30M patients with TTR-FAP

% NIS-LL responder (ITT): p=0.0681

%NIS-LL responder (EE): p<0.051

ΔNIS-LL from baseline: p<0.051,2

ΔNQOL-DN from baseline (ITT):

p=0.1161

ΔNQOL-DN from baseline (EE): p<0.051

ΔNIS-LL+Σ3 from baseline: p<0.052

ΔNIS-LL+Σ7 from baseline: p<0.052

ΔmBMI from baseline (ITT): p<0.00011

Study Fx-006 (n= 86) Coelho T et al. J Neurol. 2013;260(11):2802-14

12-mo, open-label extension for Fx-005: Long-term safety and efficacy

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):1011-20

12-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%

Study Fx1A-303 (Ongoing; n>93) Barroso F et al. Amyloid 2017; 24(3): 194-204

Open-label, ongoing, multicenter study: Long-term extension study (6+ yrs) for Fx-006 and Fx1A-201

Earlier treatment start →greater benefit (continuous

separation in ΔNIS-LL and ΔTQOL between T-T and P-T )










TTR stabilization

• Tafamidis2,a

• Diflunisal3,4,b





• Anti-TTR mAb9

• Anti-SAP mAb10

Rate-limiting

tetramer

dissociation

Monomer

misfolding and

aggregation

leading to amyloid

fibrils



Therapeutics

Investigational Disease-Modifying Therapeutics

• Antisense oligonucleotides (ASOs)

• TTR-lowering Agents

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

RNA interference (RNAi)

• Serum TTR knockdown (mean

maximum reduction 76%)

ASO

m7G AAAAn

• ASO delivered

as single strand;

finds its target alone

Blocking ribosomes

or other factors

“steric block” Recruiting

protein factors

(e.g. RNase H)

Modulating

splicing

RISC

mRNA cleavage

(if perfectly complementary)

RISC

RISC

siRNA

Association-mediated

repression

(if partially mismatched)

m7G

AAAAn

• Duplex associates with RISC

• Passenger strand is removed

• Guide strand leads RISC to target










TTR stabilization

• Tafamidis2,a

• Diflunisal3,4,b





• Anti-TTR mAb9

• Anti-SAP mAb10

Rate-limiting

tetramer

dissociation

Monomer

misfolding and

aggregation

leading to amyloid

fibrils



Therapeutics

Inotersen: Antisense oligonucleotide

• IONIS-TTRRx

• 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










TTR stabilization

• Tafamidis2,a

• Diflunisal3,4,b





• Anti-TTR mAb9

• Anti-SAP mAb10

Rate-limiting

tetramer

dissociation

Monomer

misfolding and

aggregation

leading to amyloid

fibrils



Therapeutics

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 Production of mutant and wild type

TTR

Patisiran Therapeutic Hypothesis

Neuropathy, cardiomyopathy

stabilization or improvement

Organ deposition of monomers,

amyloid (β-pleated) fibril prevented,

clearance promoted

Unstable circulating TTR tetramers

reduced

40

Patisiran Phase 3 APOLLO Study Results

Study Enrollment

225 patients with hATTR amyloidosis with polyneuropathy from 44 sites in

19 countries enrolled between Dec 2013 and Jan 2016

*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

North America: 21% Western Europe: 44%

Rest of World: 36%

19%

16%

8%

8% 7%

7%

7%

4%

4%

4%

4%

4%

2%

2%

2%

1%

<1% <1%

<1%

USA

France

Taiwan

Spain

Mexico

Germany

Japan

D.Adams EU ATTR meeting, Nov 2017

41


Serum TTR Reduction

87.8% mean max serum TTR reduction from baseline for patisiran over 18 months

Me

an

[± S

EM

] S

eru

m T

TR

Kn

oc

kd

ow

n, %

100

90

80

70

60

50

40

30

20

10

0

-10

Weeks

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 75 78 81

-100

-90

-80

-70

-60

-50

-40

-30

-20

-10

0

10

Placebo (N=77)

Patisiran (N=148)

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)

42


MMRM, mixed-effects model repeated measures; mITT, modified intent to treat; Pati, patisiran; PBO, placebo; CFB, change from baseline

mNIS+7 reference range: 0-304 points

mNIS+7: Change from Baseline

Better

Worse

LS

me

an

(S

EM

) c

han

ge

in

mN

IS+

7 f

rom

ba

se

lin

e

Difference at 18 mos

(Pati – PBO): -33.99

p-value: 9.26 10-24

-6.03 (1.74)

-2.04 (1.50)

27.96 (2.60)

13.95 (2.10)

80.93

(8.0, 165.0)

74.61

(11.0, 153.5)

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

Progressive

symmetric

sensory-motor

neuropathy

Based on Conceicao et al. J Periph Nerv Syst 2016;21:5–9

Family history

Early autonomic dysfunction

Gastrointestinal complaints

Unexplained weight loss

Cardiac hypertrophy, arrhythmias,

ventricular blocks, or cardiomyopathy

Renal abnormalities

Vitreous opacities

≥1 of

• 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

Familial Amyloid Polyneuropathy

(hATTR Amyloidosis)

SummaryanTreatment

Acknowledgements

Dr. Kristin Jack, UBC

Dr. Margot Davis, UBC

Dr. Diego Delgado, U of T

Dr. Nowell Fine, U of C

Pfizer

Alnylam

The Differential Diagnosis Challenge for hATTR-

PN

• Symptoms may be common to other disorders, confounding diagnosis

Patient phenotype Potential diagnoses

Ataxia and foot numbness • Chronic inflammatory demyelinating

polyradiculoneuropathy (CIDP)

Motor involvement • ALS

• Motor polyradiculoneuropathy

Upper limb neuropathy

• 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

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

• Inclusion Criteria: – Age 18-75 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

Investigational Disease-Modifying Therapeutics

• mAbs have been designed to bind to non-native, misfolded forms of TTR

• Monoclonal Antibodies (mAbs)

1. Higaki et al. Amyloid 2016;23:86–97;

2. ClinicalTrials.gov: NCT01777243

• mAbs generated were selective for monomeric,

misfolded and amyloidogenic forms of TTR –

no binding to the native tetramer

• mAbs inhibited TTR fibril formation in vitro, and

induced antibody-dependent phagocytosis of

amyloidogenic TTR

Preclinical data1 Immunolabeling of cardiac tissue from

patients with ATTR amyloidosis

Promote clearance of

non-native TTR by

phagocytosis

A clinical trial of an anti-serum amyloid P component (SAP) monoclonal antibody has been completed in systemic amyloidosis2

51

Patisiran: Investigational RNAi Therapeutic for hATTR Amyloidosis

Clinical Development Program

1. 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 S27.004 (Clinicaltrials.gov: NCT01961921);4. Clinicaltrials.gov: NCT01960348;

5. Clinicaltrials.gov: NCT02510261

Positive results in

human healthy

volunteers (N=17)

• Single dose

• 0.01−0.5 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)



for 18 months

• Randomized, double-

blind, placebo-

controlled

hATTR hATTR hATTR hATTR

Adults with hATTR

amyloidosis with

polyneuropathy who

participated in the

Ph 2 OLE or Ph 3 study

(N=211 enrolled)



• Includes some patients

with over 3 years

treatment

Healthy Volunteers

Global OLE5 Phase 34

APOLLO Phase 22 Phase 11 Phase 2 OLE3

Completed Completed Completed Ongoing Completed

52


Enrollment and Disposition

*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

Randomized (1:2)

(N=225)

Patisiran (N=148)*

Placebo (N=77)*

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%)

53


Norfolk QOL-DN: Change from Baseline

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

Worse

Better

Difference at 18mos

(Pati – PBO): -21.1

p-value: 1.10 10-10

LS

me

an

(S

EM

) c

han

ge

in

No

rfo

lk Q

OL

-DN

fro

m b

as

eli

ne

-6.7 (1.77) -7.5 (1.52)

14.4 (2.73)

7.5 (2.15)

59.6

(5, 119)

55.5

(8, 111)

54


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

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

Secondary endpoint; LS Mean

Placebo

(N=77)

Patisiran

(N=148)

Treatment Difference

(Pati - PBO) P-Value

NIS-W Baseline score, mean 29.03 32.69

CFB to 18 mos 17.93 0.05 -17.87 1.40 10-13

R-ODS Baseline score, mean 29.8 29.7

CFB to 18 mos -8.9 0.0 9.0 4.07 10-16

10-MWT, m/sec Baseline score, mean 0.79 0.80

CFB to 18 mos -0.24 0.08 0.311 1.88 10-12

mBMI, kg/m2 x albumin [g/dL]

Baseline score, mean 990 970

CFB to 18 mos -119.4 -3.7 115.7 8.83 10-11

COMPASS-31 Baseline score, mean 30.31 30.61

CFB to 18 mos 2.24 -5.29 -7.53 0.0008

transthyretin familial amyloid polyneuropathy (ttr...

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