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Natural History Study Interim Results

Anderson KE, Bloomer JR, Balwani M, Bissel DM, Rees DC, Stölzel U, Phillips JD, Kaupinnen R, Langendonk JG, Desnick RJ, Deybach JC, Bonkovsky HL, Parker C, Naik H, Badminton M, Stein P, Frank J, Gouya L, Minder E, Windyga J, Martasek P, Cappellini M, Ventura P, Sardh E, Harper P, Sandberg S, Aarsand A, Alegre M, Ivanova M, Meissner P, Marsden J, Chan A, Bettencourt B, Querbes W, Penz C, and Amy Simon on behalf of the Explore Investigators International Congress on Porphyrins and Porphyrias 15 September 2015

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Study Design Overview

Design • Observational, multinational, prospective natural

history study in up to 100 patients Key Eligibility Criteria • Males or Females ≥ 18 years old • Diagnosis of acute hepatic porphyria (AHP) by

specialist, including acute intermittent porphyria (AIP), hereditary coproporphyria (HCP) and variegate porphyria (VP), with biochemical and molecular confirmation

• Recurrent attacks ◦ 3+ attacks* within 12 months of screening ◦ Using heme or GnRH analogs prophylactically

Key Objectives Characterize natural history and current AHP management

◦ Medical history and medication usage ◦ Porphyria signs and symptoms ◦ Biomarkers ◦ Quality of life ◦ Healthcare utilization

*Attacks defined as acute porphyria symptoms requiring increase in treatment (heme, pain medications, carbohydrates) or hospitalization ClinicalTrials.gov Identifier: NCT02240784

·

Study Schedule

6 months

Clinic Visit

Clinic Visit

(Option to extend time on study to 12 months)

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Data Captured in Assessments and Labs

Screening Visit 2 Month Call 4 Month Call 6 Month Visit

Patient Questionnaires

• Symptoms and Porphyria History

• EQ-5D-5L • Healthcare Utilization

• Symptoms and interval medical course

• Symptoms and interval medical course

• Symptoms and interval medical course

• EQ-5D-5L

Lab Samples

• Chemistry and Hematology

• Urinalysis • ALA/PBG (urine and

plasma) • ALAS1 mRNA

• Urine ALA/PBG • ALAS1 mRNA

• Urine ALA/PBG ALAS1 mRNA

• Chemistry and Hematology

• Urinalysis • ALA/PBG (urine

and plasma) • ALAS1 mRNA

Questionnaires and Forms

Lab Samples

If Patients Experience an Attack (depending on treatment location)

Attack Symptom Inventory (patient) Attack Treatment Form (investigator)

ALA/PBG ALAS1 mRNA

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Participating Sites and Enrollment

Enrollment Update • Study to include 22 sites in 14 countries (USA and EU) • 68 patients enrolled • Patients enrolled to-date in USA, UK, Germany, Switzerland, Poland, Italy, Finland, Netherlands,

and Bulgaria

Data as of 14 AUG 2015

Total: N=68

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Demographics and Baseline Characteristics

Demographics Mean (median; range)

Age 37.5 (36.5; 19-68)

Weight (kg) 67.7 (62.0; 40-130)

BMI (kg/m2) 24.9 (23.3; 16-47)

*N=44, as other patients screen during a porphyria attack, LCMS Method

Percent (n)

Sex – Female Male

91 (62) 9 (6)

Race - White/Caucasian Asian Black/African American

96 (65) 3 (2) 2 (1)

AHP Disease Characteristics

Percent (n)

AIP 91 (62)

VP 4 (3)

HCP 4 (3)

Patient genotyped 87 (59)

Relatives with AHP 68 (46)

Mean (median;range)

Years with AHP Diagnosis

9.7 (7.0;0-38)

Baseline PBG* (mmol/mol Cr)

33.2 (34.5; 0.04 -88.9)

Baseline ALA* (mmol/mol Cr)

15.2 (15.3; 0.6-35.8)

ULN: ALA <3.1 m/mol Cr; PBG <1.2 mmol/mol Cr

Data as of 14 AUG 2015

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Patient-reported Attack Number Porphyria Screening Questionnaire

0

5

10

15

Number of Attacks Past Year (per patient)

Cou

nt

Mean: 10.6 Median: 6 Min, Max: 0, 52

Attack Treatment Location

Percent (mean; range)

Home 36 (4; 0-50)

Outpatient 36 (4; 0-40)

Hospital 27 (3; 0-18)

0 20 40 60

Porphyria Type

AIP

HCP

VP

Data as of 14 AUG 2015

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Patient-reported Attack Symptoms Screening Questionnaire

0

10

20

30

40

50

60

70

80

90

100

Abd

omin

al p

ain

Bac

k pa

inA

rm/L

eg p

ain

Mus

cle

pain

Hea

dach

eN

umbn

ess

Ski

n pa

inO

ther

pai

nB

liste

rs/R

ashe

sTi

redn

ess

Trou

ble

slee

ping

Anx

iety

Trou

ble

conc

entra

ting

Feel

ing

sad

Feel

ing

unm

otiv

ated

Feel

ing

diso

rient

edH

allu

cina

tions

Nau

sea

Loss

of a

ppet

iteV

omiti

ngC

onst

ipat

ion

Hea

rtbur

nFe

elin

g th

irsty

Dia

rrhe

aO

ther

dig

estiv

eW

eakn

ess

Cha

nge

in u

rine

colo

rFa

st h

eart

beat

Sw

eatin

gS

haki

ness

Chi

lls/F

ever

Pain Mood/Sleep GI Other

Sym

ptom

Ass

ocia

ted

with

Atta

ck (%

of p

atie

nts)

In addition, some attack symptoms present chronically (i.e. all the time) in 49% of patients • Most common chronic symptoms: pain, tiredness, N/V, constipation, and anxiety

Data as of 14 AUG 2015

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Patient-reported Attack Characteristics Porphyria Screening Questionnaire

Data as of 14 AUG 2015

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Quality of Life: EQ-5D-5L at Screen

Nordenfelt et al., Allergy Asthma Proc 2014 Lin et al., BMC Med Res Method 2014 Lubetkin et al., Qual Life Res 2005 Millward et al., J Inherit Metab 2001 Data as of 14 AUG 2015

0 10 20 30 40 50 60 70 80 90

Extremely anxious or depressedSeverely anxious or depressed

Moderately anxious or depressedSlightly anxious or depressed

Not anxious or depressedExtreme pain

Severe painModerate pain

Slight painNo pain

Unable to do my usual activitiesSevere Problems

Moderate problemsSlight problems

No problemsUnable to wash or dress myself

Severe ProblemsModerate problems

Slight problemsNo problems

Unable to walkSevere Problems

Moderate problemsSlight problems

No problems

Motility/Walking

Self-Care

Usual Activities

Pain/Discomfort

Anxiety/Depression 37%

46%

29%

7%

24%

N=68 EQ-5D Mean Summary Index = 0.74 • 0.79 in patients with diabetes mellitus • 0.78 in patients with heart disease • 0.82 in patients with hereditary angioedema

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Attack Data: Site Treatment Log

• 101 attacks total with mean duration of 7.9 days • 41/68 (60%) patients reported 1+ attack during study

Data as of 14 AUG 2015

Attack Number

Current Heme Prophylaxis

No (60%, n=41) Yes (40%, n=27)

Mean (SD) Days on Study 137.7 (102.9) 180.5 (80.2)

# of Attacks* , total= 101 63 38

Annualized Attack Rate 4 attacks/per person 3 attacks/per person

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Individual Patient ALA and PBG Changes Relative to Baseline

Notes: ALA and PBG normalized to urinary creatinine Data as of 14 AUG 2015

•Curated list of 16 patients with ≥ 1 asymptomatic measure and ≥1 attack measure •Graph in Ln scale; arrows show mean and (median) fold change in actual scale •BIORAD assay results; similar trends seen with LC-MS assay

Attack-post-Rx Attack-post-Rx Attack-post-Rx

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p<0.0001+

p<0.0001+

ALAS1 mRNA Data

p< 0.001^

^ P value from unpaired t test + P values from pairwise comparisons under repeated measures mixed mode with Subject as random and Visit Type as fixed effects

•Mean ALAS1 mRNA is increased >4-fold in asymptomatic AIP patient compared to normal healthy volunteers (NHV)

•ALAS1 mRNA further increased in AIP patients during acute attack

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Interim Study Summary and Next Steps

General AHP Disease Findings • Approximately 50% of patients experience chronic porphyria symptoms even

when not having an attack • Patients have diminished quality of life even when not having an acute attack Porphyria Attack Findings • Current mean attack rate on study ~ 4 /per person/ per year • Patients on heme prophylaxis are still experiencing attacks • Early urinary ALA/PBG data suggest it may be useful attack biomarker Exploratory circulating ALAS1 mRNA assay (cERD) • Mean ALAS1 mRNA 4-fold higher in asymptomatic AHP patients than NHVs • ALAS1 mRNA further induced in AHP patients during acute attacks and may have

utility as attack biomarker Explore Study is ongoing • Study completion and publication of full study data planned in 2016

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Acknowledgements ALN-AS1 Core Team • Bill Querbes (PL) • Tanya Sengupta (PM) • Amy Simon • Craig Penz • Amy Chan • Scott Barros • Lauri Binne • Jason Costigan • Satya Kuchimanchi • Anshul Gupta • Rena Denoncourt

• Nate Taneja • Jon O’Shea • Sarfraz Shaikh • Mano Manoharan • Rajeev Kallanthottathil • Jeff Rollins • Lubo Nechev • John Frenz • Jolly Bhatia • Patrick Igwenagu • Husain Attarwala • Renta Hutabarat • Ju Liu • Krishna Aluri • Chris Tran • Yongli Gu • Minggeng Gao • Qianfan Wang • Xuemei Zhang • Mary Carioto • Julia Hettinger • Garvin Warner • Mike Placke • Matt Algarin • Dave Mosher • Svetlana Shulga Morskaya • Meghan Collins • Tim Mooney

EXPLORE Investigators • Karl Anderson • Herb Bonkovsky • Montgomery Bissel • John Phillips • Charles Parker • Manisha Balwani • Joseph Bloomer • Pauline Harper • Eliane Sardh • David Rees • Mike Badminton • Penny Stein • Raili Kauppinen • Ulrich Stölzel • Jorge Frank • Elisabeth Minder • Jean Charles Deybach • Laurent Gouya • Pavel Martesek • Janne Langendonk • Sverre Sandberg • Felix Alegre • Aneta Ivanova • Paolo Ventura • Maria Cappellini • Jerzy Wingyga • Joanne Marsden • Peter Meissner

ALN-AS1 Advisors and Extended Team • Abigail Liebow • Tim Racie • Brian Bettencourt • Kirsten McCarthy • Siddharth Jain • Don Foster • Stu Milstein • Rick Duncan • Jared Gollob • Martin Maier • Klaus Charisse • Matthias Kretschmer • Lauren Melton • Akshay Vaishnaw • Jeff Cehelsky • Kevin Fitzgerald • Rachel Meyers • Dave Watkins • Oved Amitay • Sara Nochur • Carol Pitcher Towner • Donna Mackey • Ligang Zhang • Lubomir Tchangov • Karen Dobson • Jeff Kopacz • Jennifer Pena • Kelley Hanson

Most importantly,

we thank the patients for participating

APF • Desiree Lyon • Jessica Hungate • Natalia Sturza Mount Sinai • Hetanshi Naik • Robert Desnick