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Colin Living with Porphyria

EXPLORE: A Prospective,

Multinational, Natural History Study

of Patients with Acute Hepatic

Porphyrias (AHP) with Recurrent AttacksGouya L1, Bloomer JR2, Balwani M3, Bissell DM4, Rees DC5, Stölzel U6, Phillips JD7, Kauppinen R8,

Langendonk JG9, Desnick RJ3, Deybach JC1, Bonkovsky HL10,Parker C7, Naik H3, Badminton M11, Stein P5,

Minder El12, Windyga J13, Martasek P14, Cappellini M15, Ventura P16, Sardh E17, Harper P17, Sandberg S18, Aarsand

A18, Alegre M19, Ivanova A20, Talbi1, Chan A21, Soh CH21, McCarthy K21, Querbes W21, Penz C21, Simon A21,

Anderson KE22

26 June 2017 I ICPP I Bordeaux, France

1. Centre de Référence Maladies Rares Porphyries, Colombes, FR; U Paris, Paris, FR; 2. U Alabama, Birmingham, AL; 3. Mt.

Sinai Icahn School of Medicine, NY, NY; 4. U California, San Francisco, CA; 5. King's College Hospital, UK; 6. Klinikum

Chemnitz, DE; 7. U Utah, Salt Lake City, UT; 8. U Hospital of Helsinki, FI; 9. Erasmus Medical Center, NE; 10. Wake Forest U,

Winston-Salem, NC; 11. U Hospital of Wales, UK; 12. Stadtspital Triemli, Zentrallabor, SW; 13. Instytut Hematologii i

Transfuzjologii, PO; 14. Univerzity Karlovy v Praze, CR; 15. U Milan, IT; 16. U degli Studi di Modena e Reggio Emilia, IT; 17.

Karolinska U Hospital, SE; 18. Norwegian Porphyria Centre, NO; 19. Clinica Universidad de Navarra, SP; 20. St. Ivan Rilski U

Hospital, BU; 21. Alnylam Pharmaceuticals, MA; 22. U Texas, Medical Branch, Galveston, TX

2

EXPLORE Natural History Study

Study Design Overview

^Attacks defined as acute porphyria symptoms requiring increase in treatment (hemin, pain medications,

carbohydrates) or hospitalization ClinicalTrials.gov Identifier: NCT02240784; GnRH, Gonadotropin-releasing hormone

Month 2 and 4

6 Month Visit

Screening6 Month Visit

If having an attack^ – notify site, complete attack form and collect blood/urine samples

Every 6 Month

Clinic Visit

Questionnaires

Physical Examination

Blood and Urine Samples

Phone Call

Mail Urine Samples

Questionnaires

Clinic Visit

Questionnaires

Physical Examination

Blood and Urine Samples

Study Design

• Observational, multinational, prospective on-going

natural history study

Key Eligibility Criteria

• Males or Females ≥ 18 years old

• Diagnosis of AHP by specialist, including acute

intermittent porphyria (AIP), hereditary

coproporphyria (HCP) and variegate porphyria (VP)

• Recurrent attacks

◦ 3+ attacks^ within 12 months of screening

◦ Using hemin or GnRH analog prophylactically

Key Objectives

• Characterize natural history and current

AHP management

◦ Medical history and medication usage

◦ Porphyria signs and symptoms

◦ Biomarkers

◦ Quality of life (QoL)

3

0

10

20

30

40

50

60

Pati

en

ts E

nro

lled

Enrollment (N=112)


12-Month Study Enrollment and Follow-Up

Data as of 11 April 2017

USA49 (44%)

Europe63 (56%)

Enrollment by Region

Follow-Up Time, n (%) N=112

≥6 months 107 (96%)

≥12 months 80 (71%)

4


Demographic and Baseline Clinical Characteristics

Data as of 11 April 2017†p.R173W and p.W283X were most common (n=4 each).

Most Common Associated Medical Conditions n (%)

Renal/Vascular Disorders 43 (38%)

Hypertension

Chronic Kidney Disease

26 (23%)

9 (8%)

Nervous System Disorders 35 (31%)

Headaches/Migraine

Neuropathy/Nerve Pain

12 (11%)

10 (9%)

Psychiatric/Sleep Disorders 33 (30%)

Depression

Insomnia

Anxiety

19 (17%)

13 (12%)

9 (8%)

Gastrointestinal Disorders 25 (22%)

GERD 9 (8%)

Disease Characteristics

AHP etiology: AHP type n (%)

AIP

VP

HCP

104 (93%)

5 (4%)

3 (3%)

Genotypes represented n

AIP†

VP / HCP

56

7

Demographics N=112

Mean Age, years 39.3

Sex n (%)

Female

Male

100 (89%)

12 (11%)

Race n (%)

White/Caucasian

Hispanic or Latino

Asian

Black/African American

Not Answered

95 (85%)

5 (4%)

3 (3%)

3 (3%)

11 (10%)

5

EXPLORE Natural History StudyBaseline Diagnosis and Porphyria Manifestations

Years Since Diagnosis

19%

<2 years

19%

2-5 years61%

>5 years

2% Unknown

Patient-Reported

Symptoms/Treatment

N (%)

Known attack triggers 98 (88%)

Prodromal attack

symptoms

98 (88%)

Patient-Reported Attack

Number of attacks in last 12 months

Mean (SD)

Median (range)

9.3

6 (0, 54)

Hemin Use

Ever taken hemin prophylaxis, n (%) 61 (54%)

Current hemin prophylaxis, n (%) 52 (46%)

Frequency regular basis hemin use, n (%)

Weekly

Monthly

Other

27 (24%)

13 (12%)

20 (18%)

Time on hemin prophylaxis, years

Mean (SD)

n=48

7.3 (7.0)

Change in prophylaxis frequency, n (%)

More frequent

Less frequent

Stopped

Other

45 (40%)

23 (21%)

15 (13%)

6 (5%)

1 (1%)

Hemin side effects, n (%) 55 (49%)Data as of 11 April 2017

Patient Self-Assessment Questionnaire

6

EXPLORE Natural History StudyScreening Questionnaire: Patient-Reported Attack Symptoms


0 10 20 30 40 50 60 70 80 90 100

Abdominal painArm/leg pain

Back painMuscle pain

HeadacheSkin pain

Other painTiredness

Trouble sleepingAnxiety

Trouble concentratingFeeling sad

Feeling unmotivatedFeeling disoriented

HallucinationsOther mood/sleep

NauseaLoss of appetite

ConstipationVomiting

HeartburnFeeling thirsty

DiarrheaOther digestive

Change in urine colorWeakness

Fast heart beatSweating

NumbnessShakiness

Chills/feverOther symptoms

Blisters/rashes

Pa

inM

ood

/sle

ep

Ga

str

oin

testin

al

Oth

er

Pain

Mo

od

sle

ep

GI

Oth

er

Symptoms in > 80%: abdominal pain; nausea; change in urine color Patients (%)

7Patients (%)

0 5 10 15 20 25



HeadacheSkin pain

Other painTiredness











NumbnessShakiness


Blisters/rashes

Pa

inM

ood

/sle

ep

Ga

str

oin

testin

al

Oth

er

Pa

inM

oo

d

sle

ep

GI

Oth

er

EXPLORE Natural History StudyScreening Questionnaire: Patient-Reported Chronic Symptoms


8Patients (%)

0 5 10 15 20 25



HeadacheSkin pain

Other painTiredness











NumbnessShakiness


Blisters/rashes

Pa

inM

ood

/sle

ep

Ga

str

oin

testin

al

Oth

er

Pa

inM

oo

d

sle

ep

GI

Oth

er

EXPLORE Natural History StudyScreening Questionnaire: Patient-Reported Chronic Symptoms

In 65% patients with chronic

symptoms, most commonly

pain, tiredness, anxiety and

nausea, with 46% of patients

having daily symptoms


9

EXPLORE Natural History StudyAttacks During Study

96 patients experienced 481 attacks*


*In patients completing 12 months of follow up.

Attack characteristics (N=94)

Mean (range) attack duration, days 7.05 (1.3–33.2)

Attack rate per person-year

Overall 4.9

Chronic symptoms

Yes (n=52)

No (n=57)

5.1

4.8

Current hemin prophylaxis

Yes (n=52)

No/unknown (n=60)

4.0

5.5

0

5

10

15

20

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37

Pa

tien

ts, n

Attacks per patient (n)

10


Attack Treatment During Study Follow-Up


*Non-steroidal Anti-inflammatory drugs.

Attack Treatment

% of Attacks

Total EU US

Treatment location

Home 31% 33% 27%

Healthcare facility 69% 68% 72%

Unknown 0.2% 0% 0.6%

Treatment type

Included hemin 69% 68% 71%

Included narcotics 55% 58% 50%

Included carbohydrates, NSAIDs*, or other 45% 44% 46%

Treatment with hemin or at healthcare

facility77% 76% 77%

11

Liver ALAS1 mRNA via Circulating Extracellular RNA

Detection (cERD)

Exosomes shed into bodily fluids from different cells

contain mRNA derived from non-human tissue of

origin

Correlation of liver and serum ALAS1 mRNA shown

in preclinical studies1

Exosomes may enable monitoring of porphyria

disease activity through changes in circulating

ALAS1 mRNA in urine/serum

EXPLORE Natural History StudyDisease Biomarkers

Data as of 11 April 2017†Upper Limit of Normal: PBG < 1.2 mmol/mol Cr; ALA < 3.1 mmol/mol Cr); *paired urinary samples; 1. Chan A, et al. Mol Ther—Nuc Acids. 2015;4:1-9.

Paired Urinary ALA/PBG Samples

Urinary ALAS1 mRNA by cERD *

Biomarkers†

(N=65 ALA, N=66 PBG)

Non-Attack

Mean (range)

Attack Maximum

Mean (range)

Attack Maximum Fold

Above Non-Attack

PBG (mmol/mol Cr) 31.2 (0.5-87.3) 57.6 (0.3-843.9) 3.5 (0.1-31.9)

ALA (mmol/mol Cr) 29.8 (1.7-109.6) 64.1 (2.2-1019.6) 3.4 (0.4-39.0)

% A

LA

S1

mR

NA

rela

tive

to

NH

Me

an

100

200

300

400

500

600

700

800

900

1000

1100

1200

1300

1400

'Baseline

ALAS1 Levels

'Peak Attack

ALAS1 Levels

*Normal Healthy (NH) derived from healthy individuals not in study

12


Quality of Life: EQ-5D-5L at 12 Months (Non-attack)

Mobility/Walking

Self-Care

Usual Activities

Pain/Discomfort

Anxiety/Depression

N=74

0 50 100

Extremely anxious or depressed

Severely anxious or depressed

Moderately anxious or depressed

Slightly anxious or depressed

Not anxious or depressed

Extreme pain

Severe pain

Moderate pain

Slight pain

No pain

Unable to do my usual activities

Severe Problems

Moderate problems

Slight problems

No problems

Unable to wash or dress myself

Severe Problems

Moderate problems

Slight problems

No problems

Unable to walk

Severe Problems

Moderate problems

Slight problems

No problems

Moderate

or Greater

Problems

Reported

16%

30%

4%

43%

28%

Patients (%)Data as of 11 April 2017

1.Nordenfelt A, et al. Allergy Asthma Proc. 2014;35(2):185-90.; 2.Lin F, et al. BMC Med Res

Method. 2014;14:78. 3.Lubetkin E, et al. Qual Life Res. 2005;14(10):2187-96.

13


Quality of Life: EQ-5D-5L at 12 Months (Non-attack)

Mobility/Walking

Self-Care

Usual Activities

Pain/Discomfort

Anxiety/Depression

N=74

0 50 100

Extremely anxious or depressed

Severely anxious or depressed

Moderately anxious or depressed

Slightly anxious or depressed

Not anxious or depressed

Extreme pain

Severe pain

Moderate pain

Slight pain

No pain

Unable to do my usual activities

Severe Problems

Moderate problems

Slight problems

No problems

Unable to wash or dress myself

Severe Problems

Moderate problems

Slight problems

No problems

Unable to walk

Severe Problems

Moderate problems

Slight problems

No problems

Moderate

or Greater

Problems

Reported

16%

30%

4%

43%

28%

Patients (%)

EQ-5D-5L Mean Summary Index= 0.80 • 0.79 patients with diabetes mellitus1

• 0.78 patients with heart disease2

• 0.82 patients with hereditary angioedema3


1.Nordenfelt A, et al. Allergy Asthma Proc. 2014;35(2):185-90.; 2.Lin F, et al. BMC Med Res

Method. 2014;14:78. 3.Lubetkin E, et al. Qual Life Res. 2005;14(10):2187-96.

14

EXPLORE Natural History Summary: AHP Disease Findings and Unmet Need

Baseline Demographics and Disease Characteristics• Patients had a mean of 9.3 attacks in prior year, with severe pain cardinal feature in 99% of

attacks

• Approximately 65% of patients experience chronic porphyria symptoms (most commonly

pain), with 46% overall experiencing symptoms daily

Biomarkers• Non-invasive cERD assay enables monitoring of disease activity via changes in circulating

ALAS1 mRNA

• Asymptomatic patients have induced ALAS1 and high ALA/PBG compared to normal

healthy individuals, that increase further during attacks

Disease Activity and Study Management• Annualized attack rate on study of 4.9 attacks/person with mean duration of 7 days

o 5.5 attacks/person if not on hemin prophylactically; 4.0 attacks/person if on hemin

prophylactically

o Lower attack rate on study may relate to underreporting by patients of home attacks

• ~77% of attacks required treatment with hemin or at healthcare facility

• Patients report diminished QOL, most often in domains of pain, usual activities and

anxiety/depression

• Novel therapies are needed to prevent attacks and decrease chronic symptoms

Please see posters PO15 and PO19 for further information on health care utilization and

qualitative research on AHP from the patient perspective


15

Acknowledgements

• Karl Anderson

• Herb Bonkovsky

• Montgomery Bissell

• John Phillips

• Charles Parker

• Manisha Balwani

• Joseph Bloomer

• Pauline Harper

• Eliane Sardh

• David Rees

• Mike Badminton

• Penny Stein

• Raili Kauppinen

• Jerzy Windgyga

APF

• Desiree Lyon

• Jessica Hungate

• Natalia Sturza

Mount Sinai

• Hetanshi Naik

• Ulrich Stölzel

• Jorge Frank

• Elisabeth Minder

• Jean Charles Deybach

• Laurent Gouya

• Neila Talbi

• Pavel Martasek

• Janneke Langendonk

• Sverre Sandberg

• Felix Alegre

• Aneta Ivanova

• Paolo Ventura

• Maria Cappellini

• Joanne Marsden

EXPLORE Investigators and Contributors

16

Acknowledgements

• Karl Anderson

• Herb Bonkovsky

• Montgomery Bissell

• John Phillips

• Charles Parker

• Manisha Balwani

• Joseph Bloomer

• Pauline Harper

• Eliane Sardh

• David Rees

• Mike Badminton

• Penny Stein

• Raili Kauppinen

• Jerzy Windgyga

APF

• Desiree Lyon

• Jessica Hungate

• Natalia Sturza

Mount Sinai

• Hetanshi Naik

• Ulrich Stölzel

• Jorge Frank

• Elisabeth Minder

• Jean Charles Deybach

• Laurent Gouya

• Neila Talbi

• Pavel Martasek

• Janneke Langendonk

• Sverre Sandberg

• Felix Alegre

• Aneta Ivanova

• Paolo Ventura

• Maria Cappellini

• Joanne Marsden

Most importantly, we thank the patients for participating

EXPLORE Investigators and Contributors

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