Twelve-month Interim Analysis of Efficacy and Safety of … · 2020-06-30 · 7.9 10.5 5.3 5.3 8.1 13.5 5.4 51.2 34.9 46.5 34.9 34.9 76.7 74.4 30.2 0 20 40 60 80 100 Traveling >1

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June 30, 2020 || Webcast

Meeting organized and funded by Alnylam Pharmaceuticals || MED-UK-AS1-2000028 || Date of Preparation: June 2020

Sardh E1, Balwani M2, Rees DC3, Stein P3, Stölzel U4, Aguilera Peiro P5, Bissell DM6, Bonkovsky HL7, Keel S8,

Parker C9, Phillips JD9, Silver S10, Windyga J11, D’Avola D12, Ross G13, Stewart P14, Ritchie B15, Oh J16, Harper

P1, Wang JD17, Langendonk JG18, Ivanova A19, Horie, Y20, Anderson KE21, Ventura P22, Cappellini MD23,

Vassiliou D1, Monroy S24, Petrides PE25, Adachi T26, Kuter D27, Scalera S28, Sweetser MT28, Hua Z28, Penz C28,

Liu S28, Ko JJ28, Simon A28, Gouya L29 on behalf of the ENVISION investigators1Porphyria Centre Sweden, Centre for Inherited Metabolic Diseases, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; 2Icahn School of Medicine at Mt. Sinai, New York, New York,

USA; 3King’s College Hospital, United Kingdom; 4Klinikum Chemnitz, Chemnitz, Germany; 5Hospital Clinic Barcelona, Barcelona, Spain; 6University of California, San Francisco, California, USA; 7Wake Forest

University NC Baptist Medical Center, Winston-Salem, North Carolina, USA; 8University of Washington, Seattle, Washington, USA; 9University of Utah, Salt Lake City, Utah, USA; 10University of Michigan, Ann

Arbor, Michigan, USA; 11Instytut Hematologii i Transfuzjologii, Warsaw, Poland; 12Clinica Universidad de Navarra, Madrid, Spain; 13Melbourne Health - Royal Melbourne Hospital, Melbourne, Australia; 14Royal

Prince Alfred Hospital, Sydney, Australia; 15University of Alberta Hospital, Edmonton, Canada; 16Konkuk University Hospital, Konkuk University Medical Center, Seoul, South Korea; 17Center for Rare Disease

and Hemophilia, Taichung Veterans General Hospital, Taichung, Taiwan; 18Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; 19St. Ivan Rilski University Hospital, Sofia,

Bulgaria; 20Tottori University School of Medicine, Tottori, Japan; 21University of Texas Medical Branch, Galveston, Texas, USA; 22Università degli Studi di Modena e Reggio Emilia, Modena, Italy; 23University

of Milan, Milan, Italy; 24Instituto Nacional de Pediatría de Mexico, Mexico City, Mexico; 25Hematology Oncology Center and LM University Munich, Munich, Germany; 26Tokyo Saiseikai Central Hospital, Tokyo,

Japan; 27Massachusetts General Hospital, Boston, Massachusetts, USA; 28Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA; 29Centre Français des Porphyries, Paris, France

Twelve-month Interim Analysis of Efficacy and Safety

of Givosiran, an Investigational RNAi Therapeutic for

AHP, in the ENVISION Open Label Extension

2

I have previously been engaged as a consultant by Alnylam Pharmaceuticals with fees paid to

Karolinska Institutet.

I am also leading an investigator-initiated study for which Karolinska Institutet receives funding from

Alnylam Pharmaceuticals

Disclosure Slide

3

AIP, acute intermittent porphyria; ALA, delta-aminolevulinic acid; ALAS1, delta-aminolevulinic acid synthase 1; CoA, coenzyme A; PBG; porphobilinogen

1. Puy et al. Am J Hum Genet 1997;60:1373–83 2. Balwani & Desnick. Blood 2012;120:4496–504 3. Bonkovsky et al. Am J Med 2014;127:1233–41; 4. Elder et al. JIMD

2013;36:849–57; 5. Bissell et al. Am J Med 2015;128:313–7; 6. Gouya et al. Hepatology 2019; DOI:10.1002/hep.30936; 7. Pischik & Kauppinen. Appl Clin Genet 2015;8:201–14;

8. Simon et al. Patient 2018;11:527–37; 9. Stewart. J Clin Pathol 2012;65:976–80; 10. Pallet et al. Kidney Int 2015;88:386–95; 11. Andersson et al. J Intern Med 1996;240:195–201

Acute Hepatic Porphyria (AHP)

ALA

PBG

Hydroxymethylbilane

Uroporphyrinogen

Coproporphyrinogen

Protoporphyrinogen

Protoporphyrin

Heme

Uroporphyrinogen cosynthase

Uroporphyrinogen decarboxylase

Fe2+Ferrochelatase

Hydroxymethylbilane synthase Acute intermittent porphyria (AIP)

ALA dehydrataseALA dehydratase-deficient

porphyria (ADP)

Coproporphyrinogen oxidaseHereditary coproporphyria

(HCP)

Protoporphyrinogen oxidaseVariegate porphyria

(VP)

ALA Synthase (ALAS1)

Enzymes Intermediates AHP Disease Types

Glycine + Succinyl CoA

ALAS1 induction

Enzyme deficiencyEnzyme unchanged

Disease Overview• Family of rare, genetic diseases due to a deficiency in one of the

enzymes in heme biosynthesis in the liver1,2

• AIP is the most common type, with mutation in hydroxymethylbilane

synthase (HMBS) gene3,4

Disease Pathophysiology• Induction of ALAS1 leads to accumulation of neurotoxic heme

intermediates ALA/PBG1,2

• Accumulation of ALA/PBG is believed to cause disease

manifestations2,5

Attacks, Chronic Manifestations, and ComorbiditiesPatients can experience:

• Acute neurovisceral attacks which commonly manifest as severe

abdominal pain and can be life-threatening6,7

• Debilitating chronic symptoms (pain, fatigue, nausea, and anxiety)6–8

• Hypertension, chronic kidney disease, and liver disease3,6,9–11

• Disability, diminished quality of life, and social isolation common6–8

4

ALA, delta-aminolevulinic acid; ALAS1, delta-aminolevulinic acid synthase 1; GalNAc, N-Acetylgalactosamine; mRNA, messenger RNA; PBG; porphobilinogen; RNAi, RNA interference; siRNA, small interfering RNA

1. GIVLAARI US Prescribing Information. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/0212194s000lbl.pdf (accessed March 19, 2020); 2. GIVLAARI EU Summary of Product Characteristics.

Available at: https://www.ema.europa.eu/en/documents/product-information/givlaari-epar-product-information_en.pdf (accessed March 19, 2020)

• Reduction of Liver ALAS1 Enzyme to Lower ALA and PBG

Therapeutic Hypothesis

Givosiran: An RNAi Therapeutic for AHP1,2

ALA/PBG induces porphyria

symptoms

Givosiran

Givosiran results in reduction

of ALAS1 mRNA and lowers

ALA/PBG accumulation to

prevent attacks and disease

symptoms

ALAS1

enzyme

ALAS1

enzyme

5

aEndpoints evaluated in genetically-confirmed AIP patients, unless otherwise noted, at 6 monthsbAll endpoints listed above were considered exploratory in OLE periodcAmendment 5 increased the dose of all patients to 2.5 mg/kg monthly

ALA, delta-aminolevulinic acid; AAR, annualized rate of composite porphyria attacks, DB, double-blind; PBG; porphobilinogen; PCS, Physical Component Summary; PPEQ, Porphyria Patient Experience Questionnaire qM, every

month; SC, subcutaneous; SF-12, Short Form (12-item) Health Survey, OLE, Open Label Extension

Balwani et al. International Liver Congress 2019. Oral

• 94 patients with AHP enrolled in ENVISION at 36 sites in 18 countries

• All patients completed 6-month double-blind (DB) period; all eligible patients (n=93) entered 30-month open

label extension (OLE) period

ENVISION Phase 3 Study Design

Givosiran

SC qM

2.5 mg/kg

Placebo

SC qM

or

1:1

RA

ND

OM

IZA

TIO

NKey Inclusion Criteria

• Age ≥12 years

• Diagnosis of AHP

• ≥2 attacks within prior 6

months

• Willing to discontinue and/or

not initiate hemin prophylaxis

Primary Endpoint • Composite annualized attacks (AAR)

requiring hospitalization, urgent

healthcare visit, or hemin

administration at home in AIP patients

Secondary Endpointsa

• ALA and PBG

• Hemin use

• AAR in AHP over 6 months

• Pain

• Fatigue

• Nausea

• PCS of SF-12

Selected Exploratory Endpoints• PPEQ

• Analgesic use

6-Month DB Period 30-Month OLE Periodb

Givosiran

SC qM

2.5 mg/kg

Givosiran

SC qM

1.25 mg/kg

Givosiranc

SC qM

2.5 mg/kg

Assig

nm

en

t

Assig

nm

en

t

6

aComposite porphyria attacks are attacks requiring hospitalization, an urgent healthcare visit, or IV hemin treatment at homebOne patient in the placebo group did not meet inclusion criterion of ≥2 attacks requiring hospitalization, urgent healthcare visit or intravenous hemin at home within 6 months prior to screening (patient had 2 attacks that were

treated at home without intravenous hemin). This was identified as a protocol deviation

AAR, annualized rate of composite porphyria attacks; IV, intravenous

• Baseline characteristics were generally balanced between groups

Demographics and Baseline Characteristics of AHP Patients

Baseline Disease Characteristic

Characteristic

Placebo

Crossover

Patients

(n=46)

Givosiran

Patients

(n=48)

Age at screening, years, median (range) 36 (20, 60) 42 (19, 65)

Female, n (%) 41 (89) 43 (90)

Years since diagnosis, median (range) 6.46 (0.1, 38.5) 6.98 (0.2, 43.3)

Prior hemin prophylaxis, n (%) 18 (39) 20 (42)

Historical AARa, median (range) 7.0 (0b, 46) 8.0 (4, 34)

Chronic symptoms daily or most days between attacks, n (%) 26 (57) 23 (48)

Opioid use daily or most days between attacks, n (%) 13 (28) 14 (29)

Baseline urinary ALA (mmol/mol), median (range) 16.4 (1.4, 41.5) 16.4 (1.8, 88.9)

Baseline urinary PBG (mmol/mol), median (range) 39.3 (3.6, 87.7) 39.6 (0.4, 150.0)

7

aDescriptive analysisbPlacebo cross over patients receiving 2.5mg/kg (n=29) cPlacebo cross over patient receiving 1.25mg/kg (n=17)

OLE, open label extension; AAR, annualized rate of composite porphyria attacks

Balwani et al. International Liver Congress 2019. Oral

• Continued givosiran treatment led to sustained AAR reduction during the OLE

• Placebo crossover patients had similar AAR reduction in OLE period as givosiran patients in DB perioda

– Trend towards increased efficacy in placebo crossover patients for 2.5 mg/kgb dose compared to 1.25 mg/kgc dose

(Intra-patient AAR reduction of 79% vs 67%, respectively)

Sustained AAR Reduction with Long-Term Dosing

Placebo

treatment

Givosiran

treatment

10.7

1.8

0

2

4

6

8

10

12

Me

dia

n A

AR

AAR

Placebo Crossover Patients

DB period

(0−6 months)

OLE period

(6−12 months)

83%

1.0

00.0

2.0

4.0

6.0

8.0

10.0

12.0

Givosiran

treatment

Givosiran

treatment

Me

dia

n A

AR

AAR

Givosiran Patients

DB period

(0−6 months)

OLE period

(6−12 months)

8

aMonth = 28 days bOLE Data for 1.25mg/kg and 2.5mg/kg are pooled

DB, double-blind; OLE, open label extension

Balwani et al. International Liver Congress 2019. Oral

• Patients who continued givosiran treatment had sustained or enhanced reduction in attacks over time

• Placebo crossover patients had similar attack reduction during OLE period as givosiran patients in DB period

Givosiran Treatment Led to Sustained and Rapid Reduction of

Attacks Over Time

Average Number of Attacks Over Time

No. of patients:

Placebo Crossover

Givosiran

46

48

42

47

44

47

42

48

46

47

39

45

45

44

41

46

45

44

44

43

44

46

42

46

43

45

44

45

42

45

35

32

25

25

19

21

13

15

9

9

OLE periodDB period

Placebo Crossover Patients

Givosiran Patients1.2

0.9

0.6

0.3

17161514131211109876543210

Visit (montha)

Ave

rag

e N

um

be

r o

f A

tta

ck

s p

er

Pa

tie

nt

pe

r M

on

thb

1.5

0.0

9

DB, double-blind; OLE, open label extension

Attacks are composite

• Proportion of patients with zero attacks (61.7%) increased with continued givosiran treatment

• Proportion of placebo crossover patients with zero attacks (42.2%) increased with givosiran treatment in OLE

period

Increased Number of Patients With Zero Attacks with Long-Term

Dosing

Placebo treatment Givosiran treatment

17.4

42.2

0

20

40

60

80

100

Pa

tie

nts

wit

h 0

att

ac

ks

(%

)

Patients with 0 Attacks

Placebo Crossover Patients

DB period

(0−6 months)

OLE period

(6−12 months)

50.0

61.7

0

20

40

60

80

100

Givosiran treatment Givosiran treatment

Patients with 0 Attacks

Givosiran Patients

Pa

tie

nts

wit

h 0

att

ac

ks

(%

)

DB period

(0−6 months)

OLE period

(6−12 months)

10

Placebo Crossover Patients

Givosiran Patients

50

40

30

20

10

0

aOLE Data for 1.25mg/kg and 2.5mg/kg are pooled

ALA, delta-aminolevulinic acid; DB, double-blind period; Cr, creatinine; No., number; OLE, open label extension; PBG; porphobilinogen; PBO, Placebo

1. Balwani et al. International Liver Congress 2019. Oral

• Continued givosiran treatment led to sustained ALA and PBG reduction during OLE period

• Placebo crossover patients had >75% reduction in median ALA and PBG levels compared to baseline,

consistent with data in givosiran patients during DB period1

Rapid and Sustained Lowering of ALA and PBG Levels with

Long-Term Dosing

Urinary PBG Levels Over TimeUrinary ALA Levels Over Time

22

2018

161412

1086420

17161514131211109876543210

Visit (month)

Me

dia

n o

f u

rin

ary

AL

A (

mm

ol/m

ol

Cr)

a

17161514131211109876543210

Visit (month)

Me

dia

n o

f u

rin

ary

PB

G (

mm

ol/

mo

l C

r)a

No. of patients:

PBO Crossover

Givosiran

46

48

42

47

44

47

42

48

46

47

39

45

45

44

41

46

45

44

44

43

44

46

42

46

43

45

44

45

42

45

35

32

25

25

19

21

13

15

9

9

No. of patients:

PBO Crossover

Givosiran

46

48

42

47

44

47

42

48

46

47

39

45

45

44

41

46

45

44

44

43

44

46

42

46

43

45

44

45

42

45

35

32

25

25

19

21

13

15

9

9

OLE periodDB period OLE periodDB period

Placebo Crossover Patients

Givosiran Patients

11

DB, double-blind; OLE, open label extension

1. Balwani et al. International Liver Congress 2019. Oral

• Continued givosiran treatment led to sustained reductions in hemin use in OLE period, with 70% of patients

requiring zero days of hemin

• Placebo crossover patients had 100% reduction in median annualized days of hemin use during OLE period,

consistent with data in givosiran patients during DB period1

• Proportion of patients with 0 days of hemin use increased in OLE compared with DB period

Sustained Reductions in Hemin Use with Long-Term Dosing

Placebo

treatment

Givosiran

treatment

15.0

00.0

2.0

4.0

6.0

8.0

10.0

12.0

14.0

16.0

Annualized Days of Hemin Use

Placebo Crossover Patients

Me

dia

n a

nn

uali

ze

d

da

ys

of

he

min

us

e

DB period

(0−6 months)

OLE period

(6−12 months)

0 00

2

4

6

8

10

12

14

16

Givosiran

treatment

Annualized Days of Hemin Use

Givosiran Patients

Me

dia

n a

nn

uali

ze

d

da

ys

of

he

min

us

e

DB period

(0−6 months)

OLE period

(6−12 months)

Givosiran

treatment

100%

12

NRS, numerical rating scale for assessing pain intensity; OLE, open label extension

1. Balwani et al. International Liver Congress 2019. Oral

• Continued givosiran treatment led to a further decrease in pain during the OLE period

• Placebo crossover patients had a decrease in pain and proportion of days with analgesics use, consistent

with data in givosiran patients during DB period1

Daily Worst Pain Decreased with Long-Term Dosing

Period

Placebo Crossover

Patients

(N=46)

Givosiran Patients

(N=48)

Baseline Pain score (NRS), median 3.50 2.29

DB period (0−6 months), median change from baseline +0.10 −0.34

OLE period (6−12 months), median change from baseline −0.54 −0.77

13

aHigher scores represent an improvement in that summary or domain

DB, double-bind; MCS, mental component summary; OLE, open label extension; PCS, physical component summary; SF-12, Short Form (12-item) Health Survey

1. Sardh et al. International Congress on Porphyrins and Porphyrias 2019. Oral; 2. Clement et al. Knee Surg Sports Traumatol Arthrosc 2014;22:1933–9; 3. Parker et al. J Neurosurg Spine 2012;16:471–8

• Continued givosiran treatment

resulted in improvements in SF-

12 scores, with most impact on

role physical, bodily pain,

general health and social

functioninga

• Placebo crossover patients had

improvement in SF-12 scoresa,

consistent with givosiran treated

patients during DB period1

• Research from chronic diseases

suggests a 2–5 point increase

in PCS scores represents a

clinically meaningful difference2,3

Improvement in Physical Health (SF-12) with Long-Term Dosing

5.13.6

2.1

6.17.3

5.7

1.7

5.9

4.1 3.9

6.4

4.12.6

5.2

9.0 8.6

3.4

7.3

3.24.6

-3

0

3

6

9

12

15

PCS MCS Physicalfunctioning

Rolephysical

Bodilypain

Generalhealth

Vitality Socialfunctioning

Roleemotional

Mentalhealth

Givosiran Patients

Me

an

ch

an

ge f

rom

ba

se

lin

e

DB period (0−6 months)

OLE period (6−12 months)

1.70.4 1.2 1.9 2.2 2.2

0.2

-1.0

3.1

0.3

7.8

2.0

5.16.3

11.1

5.03.5

2.54.1 4.1

-3

0

3

6

9

12

15

PCS MCS Physicalfunctioning

Rolephysical

Bodilypain

Generalhealth

Vitality Socialfunctioning

Roleemotional

Mentalhealth

Placebo Crossover Patients

Me

an

ch

an

ge f

rom

ba

se

lin

e

DB period (0−6 months)

OLE period (6−12 months)

14

aHigher scores represent an improvement in that category

DB, double-blind; OLE, open label extension; PPEQ, Porphyria Patient Experience Questionnaire

1. Sardh et al. Presented at International Congress on Porphyrins and Porphyrias 2019. Oral

• Custom questionnaire that

used global rating of change

scale, with questions asked

at month 6 and month 12,

looking back at entire study

period

• Continued givosiran

treatment led to further

improvements in every PPEQ

category at Month 12a

• Placebo crossover patients

had improvement in all PPEQ

categories, consistent with

data in givosiran patients

during the DB perioda,1

Improvement in PPEQ with Long-Term Dosing

35.1 35.1 35.1 35.1 32.4

72.2 72.2

41.7

65.2

52.2 54.347.8 50.0

80.084.4

55.6

0

20

40

60

80

100

Traveling >1day for work or

pleasure

Participating insocial

activities

Planning forfuture events

Doinghousehold

chores

Exercisingmoderately

Convenienceof treatment

Overallstatisfaction

with treatment

Study drughelping return

to morenormal life

Givosiran Patients

Perc

en

t o

f p

ati

en

ts w

ith

resp

on

ses

“M

uch

Bett

er”

or

“A

lways”

DB period (Month 6)

OLE period (Month 12)

13.27.9 10.5

5.3 5.3 8.113.5

5.4

51.2

34.9

46.5

34.9 34.9

76.7 74.4

30.2

0

20

40

60

80

100

Traveling >1day for work or

pleasure

Participating insocial

activities

Planning forfuture events

Doinghousehold

chores

Exercisingmoderately

Convenienceof treatment

Overallsatisfaction

with treatment

Study drughelping return

to morenormal life

Placebo Crossover PatientsP

erc

en

t o

f p

ati

en

ts w

ith

resp

on

ses

“M

uch

Bett

er”

or

“A

lways”

DB period (Month 6)

OLE period (Month 12)

15

aFor calculating exposure: 1 Month=30.44 days

AE, adverse event; ALT, alanine aminotransaminase; CKD, chronic kidney disease; ISR, injection site reaction; LFT, liver function test; SAE, serious adverse event

Safety Profile of Givosiran Remained Acceptable with No New Safety Concerns

Safety in AHP Patients with Ongoing Dosing

Patients with at least 1 event, n (%)

Placebo

Crossover

Patients

(N=46)

Givosiran

Patients

(N=48)

All

Patients

(N=94)

AEs 42 (91) 46 (96) 88 (94)

SAEs 6 (13) 14 (29) 20 (21)

Severe AEs 9 (20) 11 (23) 20 (21)

AE leading to treatment

discontinuation

0 1 (2) 1 (1)

AE leading to study

withdrawal

0 1 (2) 1 (1)

Deaths 0 0 0

Safety data from first dose of givosiran to data cut-off date (23 July 2019)

• Overall exposure: 11.22 months (median; range 1.8 to 19.5 months); cumulative exposure of 84.5 person-yearsa

• 87 patients treated for ≥6 months, 36 patients treated for ≥12 months and 3 patients ≥18 months

Majority of AEs were mild or moderate in severity

• Most common related AEs (≥ 10%) were ISRs,

nausea and fatigue

• ISRs in 33% of patients; 7.4% of injections• Erythema, pruritus, rash, pain, and swelling most

common

• SAEs in ≥ 2% were CKD and urinary tract infection

(2 patients each)• SAEs of CKD reported during the DB period

• 1 patient with SAE of LFT abnormal discontinued

treatment during the DB period per protocol-

specified rules

• No other treatment discontinuations due to AEs; no

deaths

• Safety profile was acceptable at both 2.5 mg/kg and

1.25 mg/kg doses

16

aHepatic AEs included any AEs within the Drug-related hepatic disorders Standardized MedDRA query

AE, adverse events; ALT, alanine aminotransaminase; BL, baseline; M, median; ULN, upper limit of normal; W, week

• Hepatic AEs were reported in 16 patients (17%)a, all were mild or moderate in severity

– Majority were elevations of serum aminotransferases

• ALT >3×ULN in 10 patients (10.6%), of whom 3 (3.2%) had ALT >5×ULN

– 1 patient with ALT >8×ULN, discontinued treatment due to protocol-defined stopping rule in DB period

– 2 patients with ALT of >5×ULN:

◦ 1 patient on 2.5 mg/kg had dose interruption during DB period with resumption at 1.25 mg/kg

◦ 1 patient on 1.25 mg/kg during OLE period had resolution during ongoing dosing

– 7 patients with ALT >3×ULN: 6 patients with resolution during ongoing dosing and 1 patient with transient interruption

• ALT elevations generally occurred ~3 to 6 months after givosiran started and resolved

Hepatic Events in AHP Patients

6

5

4

3

2

1

0

BL W2 M1 M2 M3 M4 M5 M6 M6.5 M7 M8 M9 M10 M11 M12 M13 M14 M15 M16 M17

94 92 93 93 90 89 90 91 43 80 69 65 59 55 48 34 30 23 14 9No. of patients:

Visit

Givosiran (N=94)

ALT

re

lati

ve

to

UL

N

ALT Relative to ULN During Treatment with Givosiran

17

aRenal AEs included custom search for any AEs of blood creatinine increased, glomerular filtration rate decreased, chronic kidney disease, nephropathy, renal impairment, renal failure

eGFR, estimated glomerular filtration rate

• 10 patients (11%) had renal AEsa, characterized by increased serum creatinine and/or decreased eGFR

– Majority of AEs mild or moderate in severity

– None led to discontinuation of study treatment

• Small increases in serum creatinine were observed at Month 6 and 12

– Median change 0.09 mg/dL at Month 6 and 0.11 mg/dL at Month 12

• Mean eGFR was generally stable over time

• A decrease in eGFR has been observed in some patients with pre-existing renal disease

Renal Events in AHP Patients

BL W2 M1 M2 M3 M4 M5 M6 M6.5 M7 M8 M9 M10 M11 M12 M13 M14 M15 M16 M17

180

150

120

90

60

30

0

Visit

eG

FR

(m

L/m

in/1

.73

m2

)

eGFR During Treatment with Givosiran

Givosiran (N=94)

94 92 93 93 88 89 89 90 43 80 69 65 59 55 48 34 30 23 14 9No. of patients:

18AHP, acute hepatic porphyria; ALA, delta-aminolevulinic acid; OLE, open label extension; PBG; porphobilinogen; PCS, physical component score; PPEQ, Porphyria Patient Experience Questionnaire; QOL, quality of life; SF-12,

Short Form (12-item) Health Survey

• Reductions in annualized rate of composite porphyria attacks in patients with AHP were sustained or

enhanced during the OLE

– 61.7% of patients who continued on givosiran had zero attacks during the OLE period

• Givosiran treatment led to sustained lowering of ALA and PBG levels through month 12 in the OLE

• Reductions in the annualized days of hemin use in patients with AHP were sustained during the OLE

– 70% of patients who continued on givosiran reported no hemin use during the OLE period

• Givosiran treatment led to reductions in daily worst pain and analgesic use, and improvements in quality of

life compared to placebo according to PCS of the SF-12 and PPEQ measurements

• Safety profile of givosiran remained acceptable with no new safety findings identified

ENVISION 12-Month OLE Summary

19

• Tomohide Adachi

• Paula Aguilera Peiro

• Karl Anderson

• Manisha Balwani

• Montgomery Bissell

• Herb Bonkovsky

• Maria Cappellini

• David Cassiman

• David Coman

• Delia D’Avola

• Yoshie Goto

• Laurent Gouya

• Encarna Guillén Navarro

• Pauline Harper

• Yutaka Horie

• Ole Hother-Nielsen

• Aneta Ivanova

• David Kuter

• Raili Kauppinen

• Sioban Keel

• Hung-Chou Kuo

• Janneke Langendonk

• Ming-Jen Lee

• Cynthia Levy

• Elisabeth Minder

• Susana Monroy

• Jeeyoung Oh

• Charles Parker

• Petro E Petrides

• John Phillips

• David Rees

• Bruce Ritchie

• Gayle Ross

• Eliane Sardh

• Appalanaidu Sasapu

• Samuel Silver

• Penny Stein

• Peter Stewart

• Ulrich Stölzel

• Kei-ichiro Takase

• Manish Thapar

• Daphne Vassiliou

• Paolo Ventura

• Jiaan-Der Wang

• Bruce Wang

• Jerzy Windyga

We also wish to thank the study site staff, the patient organizations, and most importantly the patients for participating

ENVISION Investigators

Acknowledgements