of Patients with Acute Hepatic Colin Living with Porphyria - - PowerPoint PPT Presentation

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EXPLORE: A Prospective, Multinational, Natural History Study of Patients with Acute Hepatic Colin Living with Porphyria Porphyrias (AHP) with Recurrent Attacks Gouya L 1 , Bloomer JR 2 , Balwani M 3 , Bissell DM 4 , Rees DC 5 , Stlzel U 6 ,

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Colin

Living with Porphyria

EXPLORE: A Prospective, Multinational, Natural History Study

  • f Patients with Acute Hepatic

Porphyrias (AHP) with Recurrent Attacks

Gouya 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

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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

Screening 6 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)
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10 20 30 40 50 60 Patients Enrolled Enrollment (N=112)

EXPLORE Natural History Study 12-Month Study Enrollment and Follow-Up

Data as of 11 April 2017

USA 49 (44%) Europe 63 (56%) Enrollment by Region Follow-Up Time, n (%) N=112 ≥6 months 107 (96%) ≥12 months 80 (71%)

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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%)

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EXPLORE Natural History Study Baseline Diagnosis and Porphyria Manifestations

Years Since Diagnosis

19% <2 years 19% 2-5 years 61% >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

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EXPLORE Natural History Study

Screening Questionnaire: Patient-Reported Attack Symptoms

Data as of 11 April 2017

10 20 30 40 50 60 70 80 90 100

Abdominal pain Arm/leg pain Back pain Muscle pain Headache Skin pain Other pain Tiredness Trouble sleeping Anxiety Trouble concentrating Feeling sad Feeling unmotivated Feeling disoriented Hallucinations Other mood/sleep Nausea Loss of appetite Constipation Vomiting Heartburn Feeling thirsty Diarrhea Other digestive Change in urine color Weakness Fast heart beat Sweating Numbness Shakiness Chills/fever Other symptoms Blisters/rashes Pain Mood/sleep Gastrointestinal Other

Pain Mood sleep GI Other

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

Patients (%)

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Patients (%)

5 10 15 20 25

Abdominal pain Arm/leg pain Back pain Muscle pain Headache Skin pain Other pain Tiredness Trouble sleeping Anxiety Trouble concentrating Feeling sad Feeling unmotivated Feeling disoriented Hallucinations Other mood/sleep Nausea Loss of appetite Constipation Vomiting Heartburn Feeling thirsty Diarrhea Other digestive Change in urine color Weakness Fast heart beat Sweating Numbness Shakiness Chills/fever Other symptoms Blisters/rashes Pain Mood/sleep Gastrointestinal Other

Pain Mood sleep GI Other

EXPLORE Natural History Study

Screening Questionnaire: Patient-Reported Chronic Symptoms

Data as of 11 April 2017

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Patients (%)

5 10 15 20 25

Abdominal pain Arm/leg pain Back pain Muscle pain Headache Skin pain Other pain Tiredness Trouble sleeping Anxiety Trouble concentrating Feeling sad Feeling unmotivated Feeling disoriented Hallucinations Other mood/sleep Nausea Loss of appetite Constipation Vomiting Heartburn Feeling thirsty Diarrhea Other digestive Change in urine color Weakness Fast heart beat Sweating Numbness Shakiness Chills/fever Other symptoms Blisters/rashes Pain Mood/sleep Gastrointestinal Other

Pain Mood sleep GI Other

EXPLORE Natural History Study

Screening 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

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EXPLORE Natural History Study Attacks 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

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

Patients, n Attacks per patient (n)

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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 facility 77% 76% 77%

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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

  • rigin

 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 Study Disease 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)

% ALAS1 mRNA relative to NH Mean 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

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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

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

  • r 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.
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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

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

  • r 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.
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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
  • 5.5 attacks/person if not on hemin prophylactically; 4.0 attacks/person if on hemin

prophylactically

  • 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

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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

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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