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Velaglucerase alfa as therapy for Gaucher disease

Deborah Elstein, PhD Gaucher Clinic

Shaare Zedek Medical Center Jerusalem Israel

Paris, France

27-30 June 2012

Disclosure

Deborah Elstein has no current conflicts of interest; served as consultant to Shire HGT during seminal trials

Gene-Ac'vated GCB (GA-GCB)

3

Evolu'on of Protein Produc'on

Human Cell Hamster Cell

Human Cell Human Cell

Conven'onal Recombinant DNA Approach

TKTs Gene-Ac'va'on Approach

4

Gene-Ac'vated GCB (velaglucerase alfa)

GA-GCB has terminal mannose residues which target the enzyme to macrophages, the target cells in Gaucher disease

Primary amino acid sequence of GA-GCB is iden'cal to the human enzyme (and hence also to alglucerase)

GA-GCB is produced in a human cell line

Imiglucerase, Taliglucerase alfa and AbcerJn (ISU302) have a 1 amino acid difference relaJve to wild type sequence

Imiglucerase and AbcerJn are produced in CHO cells and taliglucerase alfa in plant cells

Sawkar AR, et al ACS Chem. Biol. 2006 May 23;1(4):235-51.

Poten'al Advantage of Wild Type Glucocerebrosidase

Recombinant Enzyme pH Activity (U/mg)*

Imiglucerase 5.3 9.1 + 0.4

Imiglucerase 7.0 4.0 + 0.3

WT 5.3 15.5 + 0.5

WT 7.0 8.1 + 0.4

N370S 5.3 3.0 + 0.3

N370S 7.0 1.6 + 0.2

*U = Mol of 4-methylumbelliferone released per minute

6

pH-Dependent Ac'vity of Imiglucerase, rhWT and rhN370S Glucocerebrosidase

Internaliza'on into macrophages: velaglucerase alfa versus imiglucerase

Brumshtein et al. Glycobiology 2010;20:24-32. 7

Velaglucerase alfa: Pre-clinical development

Bio-distribu'on of GA-GCB

- Immuno-histochemistry

Pharmacokine'cs of GA-GCB

- Rats, dogs, & monkeys

Toxicology summary

- Acute and long-term studies in rats & monkeys

GA-GCB Uptake into Kupffer & Endothelial Cells in Mouse Liver

8

Velaglucerase alfa: Clinical Trial Program

Clinical Trial Phase Duration Patients

(enrolled or randomized)

Dose group (EOW)

Design Splenectomy Status at BL

TKT025 I/II 9 M Nave, adult (N=12) 60 U/kg Open label No

TKT032 III 12 M Nave, 2 years old (N=25) 45 or 60 U/kg Double

blind, 1:1 randomized

No

HGT-GCB-039 III 9 M Nave, 2 years old (N=35)

60 U/kg velaglucerase

alfa or imiglucerase

Double blind, 1:1

randomized Yes or No

TKT034 II/III 12 M Transition, 2 years old (N=41) 15-60 U/kg Open label Yes or No

TKT025EXT I/II EXT 7 years (N=10) from

TKT025 30-60 U/kg Open label No

HGT-GCB-044 III EXT Ongoing (N=95) from

TKT032, TKT034 and

HGT-GCB-039

15-60 U/kg Open label Yes or No

HGT-GCB-058 EAP 65 Wks Switch, Nave (N=211) 15-60 U/kg

Open label

Yes or No

9

TKT 025: THE DREAM TEAM in a single center Phase I/II seminal trial and extension

Male : Female 5 (42%) : 7 (58%) Ashkenazi Jewish : Other 8 (67%) : 4 (33%) Mean age (years) SD (range) 41.717.3 (1970)

Mean weight (kg) SD (range) 59.6 9.1 (50-73)

Mean height (cm) SD (range) 169.48.0 (160-184)

N370S/N370S : N370S/other

6 (50%) : 6 (50%)

Osteonecrosis (hip joint) 2 (16.7%)

10

TKT 025 Phase I/II: Conclusions (9 months)

IV infusion of 60 U/kg every other week well-tolerated No hypersensitivity reactions No anti-velaglucerase alfa antibodies Mean increase hemoglobin value 2.24 g/dL (1o endpoint) Mean increase platelet counts: 67.6% Mean reduction liver volume (MRI): 18.2% Mean reduction spleen volume (MRI): 45.9%, Reduction in biomarkers chitotriosidase & CCL18 Allowed initiation of Phase III studies

11

Eligibility Criteria for TKT 025EXT Enrollment and Dosing TKT025

9-month trial TKT025EXT

Extension study TKT025

Enrollment TKT025EXT Enrollment

60 U/kg EOW velaglucerase alfa, IV infusion

604530 U/kg EOW velaglucerase alfa, IV infusion

Diagnosis of type 1 GD GD-related anemia

Thrombocytopenia Age 18 years Intact spleen No Gaucher disease-specific treatment in preceding 12 months

TKT025EXT was completed in December 2011. The maximum duration velaglucerase alfa = 79.5 months. In TKT025EXT, stepwise dose reduction was implemented after 3 months if patients met at least 2 of 4 Therapeutic Goals (1-year goals for hemoglobin / platelet counts / spleen volume / liver volume).

12

Completed TKT025

TKT 025 & 025EXT Clinical Trial Results

Change from Baseline statistically significant at 9 months (P

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

%

Hb Plts Hep SplGoal

Percent of Patients with Suboptimal Goals who Achieve each Goal with ERT

Cd (B&G)(mean)Cz (G)VA

1. Barton et al. N Engl J Med. 1991;324:1464-1470. 2. Grabowski et al. Ann Intern Med. 1995;122:33-39. 3. Zimran et al Blood 2010;115:4651-4656.

Anemia & thrombocytopenia at 9 months Hepatomegaly &splenomegaly at 6 months

Percent patients achieving 4 clinical Therapeutic Goals

Alglucerase Imiglucerase velaglucerase

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

%

Hb Plts Hep SplGoal

Percent of Patients with Suboptimal Goals who Achieve each Goal with ERT

Cd (B&G)(mean)Cz (G)VA

Time to Therapeu'c Goal response with velaglucerase alfa

0 20 40 60 80 100 120 140 160

Weeks

Hb

Plts

Hep

Spleen

Goal

Weeks to Completer Response Per Goal (Vela)

Hb Plts

Hep Spleen

1 2 3 YEAR

Anemia may be a risk factor for osteonecrosis in Gaucher disease (Khan et al, 2012)

15

Early achievement and maintenance of clinical Therapeu'c Goals despite dose reduc'on

Elstein et al. Blood Cells Mol Dis 2011;46:119-23. 16

Mean dose & percentage pa'ents achieving all therapeu'c goals 4 goals un'l 36 months; 5 goals including BMD therea_er

0

20

40

60

80

100

0

20

40

60

80

100

Velaglucerase alfamean dose (U/kg)Achievement oftherapeutic goals (%)

9 24 36 48 57

Time (months)

Achi

evem

ent o

f th

erap

eutic

goa

ls (%

) Velaglucerase alfam

ean dose (U/kg)

Lumbar Spine (n=6) Femoral Neck (n=6)

BMD Status (based on T-scores) at Baseline and 69 Months of velaglucerase alfa without bisphosphonates

All 4 pa'ents on bisphosphonates had no change in WHO Category Low BMD at LS may be a risk factor for fractures in Gaucher disease (Khan et al, 2012)

18

Conclusions: Improvement in BMD with velaglucerase

In paJents with baseline osteopenia/osteoporosis (and osteonecrosis) treated with velaglucerase alfa, BMD improved in both lumbar spine (Month 24) and femoral neck (Month 36)

Improvement in bone pathology was not dependent upon con'nuous high-dose therapy (paJents were dose-reduced to 30u/kg/EOW)

19

Impact of velaglucerase alfa on Bone Marrow Burden (BMB) score

Improvements (2 point reduc'ons) began at 9 months in some pa'ents

Con'nual improvements in BMB scores at LS & FN with most achieving normal values at LS and at least 2 point reduc'on in others

Improvements in BMB parallel changes in bone density BMB data was evaluable earlier than other radiological indices (but later than hematology/viscera)

20

21

TKT 032: Randomized, Double-Blind, Global, Phase III Study of treatment-nave patients at two doses

(45 and 60units/kg/EOW) 12 months

Ari Zimran1, MD; Derlis Emilio Gonzalez Rodriguez2 MD; Elena A. Lukina3, MD; Marie-Franoise Ben Dridi, 4 MD; Isaac Kisinovsky 5, MD; Eric Crombez 6, MD and Kiran Bhirangi 6, MD.

1Shaare Zedek Medical Center, Jerusalem, Israel; 2Sanatorio Espaol, Asuncin, Paraguay; 3National Research Center for Haematology, Moscow, Russia; 4La Rabta Hospital, Tunis, Tunisia; 5Your Health S.A., Buenos Aires, Argentina; 6Shire Human Genetic Therapies, Cambridge, USA

Mean % change (+SEM) from Baseline: hemoglobin & platelet counts

22

0 530

1

2

3velaglucerase alfa 45 U/kg (n=13)velaglucerase alfa 60 U/kg (n=12)

Study week

Hem

oglo

bin

conc

entra

tion

(cha

nge

from

bas

elin

e, g

/dL)

0 530

10

20

30

Study week

Hem

oglo

bin

conc

entra

tion

(cha

nge

from

Bas

elin

e, %

)

53-20

0

20

40

60

80

100

Study week

Plat

elet

cou

nt(c

hang

e fro

m B

asel

ine,

%)

TKT032 Clinical Trial: 12 month results

Mean % change (+SEM) from Baseline: spleen and liver volumes

TKT 032: Results a_er 2 years velaglucerase alfa

Clinical

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