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)
EXPLORE Natural History Study
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
EXPLORE Natural History Study
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
Data as of 11 April 2017
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
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
Pa
inM
oo
d
sle
ep
GI
Oth
er
EXPLORE Natural History StudyScreening Questionnaire: Patient-Reported Chronic Symptoms
Data as of 11 April 2017
8Patients (%)
0 5 10 15 20 25
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
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
Data as of 11 April 2017
9
EXPLORE Natural History StudyAttacks During Study
96 patients experienced 481 attacks*
Data as of 11 April 2017
*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
EXPLORE Natural History Study
Attack Treatment During Study Follow-Up
Data as of 11 April 2017
*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
EXPLORE Natural History Study
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
EXPLORE Natural History Study
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
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.
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
Data as of 11 April 2017
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