Twelve-month Interim Analysis of Efficacy and Safety of … · 2020-06-30 · 7.9 10.5 5.3 5.3 8.1...
Transcript of Twelve-month Interim Analysis of Efficacy and Safety of … · 2020-06-30 · 7.9 10.5 5.3 5.3 8.1...
1
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