Building the Foundation:Overview of Hemophilia Novel

Therapies Pipeline Steven Pipe, MD

University of MichiganAnn Arbor, MI, USA

caNEXTions05 November 2019

Disclosures

• Contract research: Siemens• Steering Committee (clinical trials): Biomarin, uniQure, Bayer• Scientific Advisory Board: Sangamo• Consultant: Shire, Pfizer, Biomarin, uniQure, Bayer, Roche/Genentech,

CSL Behring, Alnylam, Novo Nordisk, HEMA Biologics, Bioverativ, Catalyst Biosciences, DNArx, Spark Therapeutics

• Board Member: Chair – Medical and Scientific Advisory Council to the National Hemophilia Foundation

Potentialgene therapy

Hemophilia: current and future approaches to care

Pipe SW. Hematology Am Soc Hematol Educ Program. 2016;2016(1):650-656.

Pre-replacementtherapy

Replacementtherapy

Non-replacementtherapy

On demand Prophylaxis

Standardhalf-life

Extendedhalf-life

Mimetics/agonistsSubstitution therapy

AntagonistsHemostatic rebalancing

Potentialgene therapy

Hemophilia: current and future approaches to carePre-replacement

therapyReplacement

therapyNon-replacement

therapy

On demand Prophylaxis

Standardhalf-life

Extendedhalf-life

Mimetics/agonistsSubstitution therapy

AntagonistsHemostatic rebalancing

Tool

s of

our t

rade

Plasma-derivedclotting factors

Recombinantclotting factors

Unmodified Bioengineered

Supportivecare only

Bispecific antibodies

siRNA knockdown

mAb inhibitors

Bioengineered serpins

Gene addition

Gene editing

Cellular therapy

Pipe SW. Hematology Am Soc Hematol Educ Program. 2016;2016(1):650-656.

Joint Bleeding and Hemophilia Severity

• Patients with severe hemophilia (FVIII <1%) experience more joint bleeding than do those with moderate (FVIII 1-5%) or mild (FVIII >5%) disease

Adapted from: Den Uijl et al. Haemophilia. 2011;17(6):849-853.

5

Prophylaxis across the US HTC Network

Manco-Johnson MJ et al. Blood. 2017;129(17):2368-2374.

Bleed rates and range of motion across the US HTC Network

Prophylaxis in 1999

Prophylaxis in 2010

No prophylaxis in 1999

No prophylaxis in 2010

Patient treatment by year:

Manco-Johnson MJ et al. Blood. 2017;129(17):2368-2374.

The Challenge with Traditional Clotting Factor Replacement Therapy

Mahdi et al., Br J Haematol (2015)

Trends in modern hemophilia therapeutics

• Shift from “minimally effective” prophylaxis to “optimized/personalized prophylaxis”• Emphasis on higher trough levels through:

• More intensive prophylaxis• Utilization of extended half-life clotting factors

• Bioengineered molecules with enhanced properties• Steady-state prophylaxis rather than “peaks and troughs”• Subcutaneous delivery over intravenous• Cross-segment therapeutics

• Efficacy in presence and absence of inhibitors• Efficacy across a number of bleeding disorders

EHL Factors and Trough Levels• Esperoct (N8-GP)

– Prophylaxis regimen of 40 IU/kg q4d– t1/2 = 18.4 hours; mean trough of 8%– ABR (median) = 1.3

• Rebinyn– Prophylaxis regimen of 10 IU/kg or 40 IU/kg weekly– t1/2 = 110 hours, mean trough of 9.8% and 21.3%, respectively– 40 IU/kg weekly: two-thirds reported complete resolution of

target joints

• Idelvion– Prophylaxis regimen of 40 IU/kg weekly or 75 IU/kg q 2 weeks– t1/2 = 102 hours, mean trough of 20% and 12.4%, respectively– 100% resolution of target joints

10

Ehrenforth et al., Haemophilia. 2014;20(suppl 3):188. Young G et al., Thromb Res. 2016;141:69-76. Santagostino E et al., Blood. 2016;127(14):1761-1769.

Higher Trough Levels and Bleed Prevention

•PROPEL Study (Adynovate, Shire/Takeda)– use pharmacokinetic-guided prophylaxis targeting two different FVIII trough levels in severe hemophilia A

– Low trough (1-3%) vs High trough (8-12%)– assessed proportion with annualized bleed rate = 0

– high trough (66%) vs low trough (39%)

Klamroth R et al., Presented at EAHAD, Feb 2019

Chhabra et al., Managed Care (2018)

Switches to EHL Factor VIII Associated with Increased Utilization and Expenditures

Tortella et al., J Manag Care Spec Pharm (2018)

Switches to EHL Factor IX Associated with Increased Utilization and Expenditures

What Are the Unmet Needs that Remain for Hemophilia A?

• There would still be attraction for once-weekly dosing for some patients• Particularly for moderate severity, mild severity who need prophylaxis (even if for short

courses)

• Inhibitor prevention remains highest priority• Some optimism that product-related immunogenicity may be low with these EHLs

• Inhibitor eradication may actually be higher with EHLs1-3

• Biologic rationale for improved immunomodulatory impact of Fc• Anecdotal evidence of improved ITI with rFVIIIFc• Unknown with PEGylation, but also biologic rationale for reduced immunogenicity

• Need to show improved outcomes with EHLs to justify price

1. Janbain M, Pipe S. Hematology Am Soc Hematol Educ Program. 2016;2016(1):648-649.2. Carcao M...Pipe SW. Haemophilia. 2018;24:245–252 3. Blumberg et al. Blood. 2018; in press 14

Novel approaches to hemophilia therapy

Arruda VR et al. Blood. 2017;130:2251-2256

Procoagulants Anticoagulants

More Clotting More Bleeding

Normal Hemostatic Balance

Callaghan, Sidonio and Pipe. Blood (2018)

Procoagulants Anticoagulants

More Clotting More Bleeding

Hemophilia

Callaghan, Sidonio and Pipe. Blood (2018)

Procoagulants Anticoagulants

More Clotting More Bleeding

Hemophilia plus procoagulants

aPCCrFVIIa

FVIII/FIX

Emicizumab

Callaghan, Sidonio and Pipe. Blood (2018)

Background: Emicizumab

Humanised bispecific monoclonal antibody

Bridges activated factor IX (FIXa) and FX to restore function of missing FVIIIa

No structural homology to FVIII (not expected to induce FVIII inhibitors or be affected by presence of FVIII inhibitors)

Long half-life of ~30 days

Administered subcutaneously

Approved in several countries for once-weekly prophylaxis in persons with haemophilia A with inhibitors of all ages

19

Emicizumab

Factor IXaFactor X

Shima S, et al. N Engl J Med 2016;374:2044–53.Yoneyama K, et al. Clin Pharmacokinet 2017 Epub.HEMLIBRA (emicizumab-kxwh) [prescribing information]. 2017.

HEMLIBRA (emicizumab) [summary of product characteristics]. 2018.Oldenburg J, et al. N Engl J Med 2017; 377(9):809–18.

Emicizumab clinical trials

20

ABR, annualized bleeding rate; BPA, bypassing agent; PwHA, persons with Haemophilia A; PK, pharmacokinetics; Q2W, every 2 weeks; Q4W, every 4 weeks; QW, once weekly.

Clinical trial Population

ABR, treated bleeds:emicizumab prophylaxis vs noprophylaxis

% patients with zero treated bleeds

ABR, treated bleeds: emicizumab prophylaxis vs prior prophylaxis in NIS

HAVEN 1 (NCT02622321)

PwHA ≥12 years with FVIII inhibitors

87% reduction (QW)* 63% (QW), 6% (no prophylaxis)

79% reduction with emicizumab QW vs prior BPA prophylaxis

HAVEN 2 (NCT02795767)

PwHA <12 years with FVIII inhibitors

N/A (no comparator) 87% (QW) 99% reduction with

emicizumab QW vs prior BPA prophylaxis

HAVEN 3 (NCT02847637)

PwHA ≥12 years without FVIII inhibitors

96% reduction (QW) 97% reduction (Q2W)

56% (QW), 60% (Q2W), 0% (no prophylaxis)

68% reduction with emicizumab QW vs prior FVIII prophylaxis

HAVEN 4 (NCT03020160)

PwHA ≥12 years with or without FVIII inhibitors

Primary analyses evaluating emicizumab Q4W prophylaxis on bleeding rate, safety, PK

Oldenburg J, et al. N Engl J Med 2017;377:809–18. Mancucso, ME, et al. Blood 2017;130:1071.Young G, et al. Blood 2017;130:85.

Genentech Press Release. Nov 19, 2017.Mahlangu J, et al. Presented at WFH 2018. Abstract 854.

*Improved bleeding rate observed in subsequent 24-week periods beyond initial 24-weeks.

HAVEN 1–4 long-term efficacy: treated bleeds over time• Across HAVEN 1─4, the model-based ABR* for treated bleeds was 1.5 (95% CI, 1.20; 1.84)

over the median 83-week duration of exposure

*Calculated using negative binomial regression; †based on calculated ABRs. ABR, annualized bleed rate.Callaghan M et al. Presented at ISTH; July 6‒10, 2019; Melbourne, Australia.

Treated bleed ABRs† over consecutive24-week treatment intervals (N=400)

Proportion of participants with 0 or 1–3 treated bleeds over time (N=400)

0

1

2

3

4

5

6

7

1–24 weeks 25–48 weeks 49–72 weeks 73–96 weeks

Calc

ulat

ed A

BR

n 391 354 284 114

1.9

0.8 0.80.30 0 0 0

Mean ABR (95% CI) Median ABR (IQR)

70.879.4 82.7

88.622.5

18.6 14.4 11.4

0102030405060708090

100

1–24 weeks 25–48 weeks 49–72 weeks 73–96 weeks

Perc

enta

ge o

f par

ticip

ants

0 bleeds 1–3 bleeds

n 391 354 284 114

PK and efficacy modelling for different emicizumab dosing regimens

1.5 mg/kg QW

Mod

elle

d AB

R

3 mg/kg Q2W 6 mg/kg Q4W

PK m

odel

ling

All 3 regimens were expected to achieve clinically efficacious concentrations and provide similar efficacy

All dosing regimens begin with loading period of 3 mg/kg/week for 4 weeks, followed by maintenance dose as indicated

5

Yoneyama K, et al. Clin Pharmacokinet 2017 Epub.

120

90

Plas

ma

emic

izum

abco

ncen

tratio

n (µ

g/m

L)

60

30

0

0 4 8 12 16 20 24

60

40

50

Prop

ortio

n of

pat

ient

s w

ith e

ach

annu

al b

leed

ing

rate

(%)

30

20

10

00 1 32 4 5 76 8

60

40

50

Prop

ortio

n of

pat

ient

s w

ith e

ach

annu

al b

leed

ing

rate

(%)

30

20

10

00 1 32 4 5 76 8

60

40

50

Prop

ortio

n of

pat

ient

s w

ith e

ach

annu

al b

leed

ing

rate

(%)

Annual bleeding rate

30

20

10

00 1 32 4 5 76 8

120

90

Plas

ma

emic

izum

abco

ncen

tratio

n (µ

g/m

L)

60

30

0

0 4 8 12 16 20 24

120

90

Plas

ma

emic

izum

abco

ncen

tratio

n (µ

g/m

L)

Time after starting emicizumab (week)

60

30

0

0 4 8 12 16 20 24

Annual bleeding rate

Time after starting emicizumab (week)

Annual bleeding rate

Time after starting emicizumab (week)

Procoagulants Anticoagulants

More Clotting More Bleeding

Hemophilia

Callaghan, Sidonio and Pipe. Blood (2018)

Procoagulants Anticoagulants

More Clotting More Bleeding

Hemophilia minus anticoagulants

Callaghan, Sidonio and Pipe. Blood (2018)

New Targets

Achneck et al Circulation 2010;122:2068–2077

TF VIIa

X Xa

IXa IX

XVa

thrombin

XIa XI

fibrinformation

XIIaExtrinsic pathway

Intrinsic pathway

Common pathway

VIIIa VIIITFPI

Anti-thrombin

PF-06741086 Concizumab

Fitusiran

Emicizumab

APCSerpinPC

26Machin and Ragni (2018)

Potential advantages of RNAi technology for the treatment of haemophilia

Therapeutic hypothesis

Individuals with haemophilia who have co-inherited thrombophilia mutations – such as AT deficiency –have milder bleeding phenotypes: thus AT lowering represents a rational therapeutic strategy for bleed control in haemophilia

Fitusiran is a nonbiologic therapy with an N-acetylgalactosamine(GalNAc) ligand for targeted delivery to the liver, site of antithrombin (AT) synthesis

0

20

40

60

80

100

120

0 3 6 9 12 15 18 21 24 27 30 33 36

Antit

hrom

bin

(%)

Months since first dose

AT lowering with monthly fitusiran1,*

Fitusiran Phase 2 OLE Interim Results:Antithrombin Levels and Thrombin Generation

Fitusiran is an investigational medicine. Its safety and efficacy have not been established by any health authorities.Data cutoff: May 2, 2019. *Data indicate mean AT or mean TG peak height ± SE. Data include period of dosing resumption after the clinical hold and exclude period during the clinical hold. Month 0 indicates baseline values. †HVs with AT lowering <25%.2‡n=12 for month 1 and n=11 for month 2 (50 mg); n=21 for month 1 and n=19 for month 2 (80 mg). §n=10 for months 1 and 2 (50 mg); n=20 for month 1 and n=19 for month 2 (80 mg).AT, antithrombin; HV, healthy volunteer; OLE, open-label extension; SE, standard error; TG, thrombin generation.1. Sanofi Genzyme. Data on file. 2019. 2. Pasi KJ et al. N Engl J Med 2017;377:819–828. 27

Fitusiran 50 mg monthly (n=12)Fitusiran 80 mg monthly (n=22)

n‡= 12 11 11 10 7 7 2 1 2 3 7 5 5n‡= 22 18 14 12 11 5 5 3 4 12 11 8 4

HVrange†

n§= 12 11 10 9 6 5 1 1 2 2 7 5 5n§= 22 17 14 10 9 3 5 3 4 10 11 9 4

0

20

40

60

80

100

120

140

0 3 6 9 12 15 18 21 24 27 30 33 36Thro

mbi

n ge

nera

tion

peak

hei

ght,

nmol

/L

Months since first dose

TG with monthly fitusiran1,*

Fitusiran 50 mg monthly (n=12)Fitusiran 80 mg monthly (n=22)

0

4

8

12

16

28

Fitusiran is an investigational medicine. Its safety and efficacy have not been established by any health authorities.Data transfer: May 2, 2019. ABR and duration represent pooled data from Phase 1 and Phase 2 OLE studies. Phase 1 data are included if gap between studies was ≤56 days. Only subjects with 28 days of follow-up during the observation period are included in this analysis.

Fitusiran Phase 2 OLE Interim Results:Exploratory Analysis of Bleeding Events

ABR in subjects with inhibitors

Median duration in observation period: 25 months (range: 5–33 months)

Median duration in observation period: 18 months (range: 7–25 months)

Med

ian

ABR

2.0

12.0

1.08

Pre-study

Prophylaxis (n=7)

On demand(n=12) Observation

period (n=19)

05

101520253035404550

Med

ian

ABR

42.0

1.04

Observation period (n=14)

Pre-study(n=14)

ABR in subjects without inhibitors

Overall median ABR of 1.08

29

These data are from an ongoing clinical program and results may be subject to change.Fitusiran is an investigational medicine. Its safety and efficacy have not been established by any health authorities.Data cutoff: May 2, 2019. AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; HCV, hepatitis C virus; OLE, open-label extension; ULN, upper limit of normal.

Fitusiran Phase 2 OLE Interim Results: Overview of Safety and Tolerability• AEs were reported in 33 of 34 subjects

‒ The majority of AEs were mild or moderate in severity and unrelated to the study drug‒ The most common AEs (occurring in ≥15% of subjects overall) were: ALT increased (32% of subjects); headache

(24%); injection-site erythema (21%); arthralgia (18%)

• Increases in ALT >3× ULN were observed in 14 subjects (all confirmed HCV antibody positive at baseline)

‒ All asymptomatic and resolving, with no elevations of bilirubin >2x ULN

• No instances of anti-drug antibody formation• A total of 14 serious adverse events (SAEs) were reported in 8 of 34 subjects

‒ 3 with SAEs considered possibly related to study drug ‒ Asymptomatic ALT and AST elevation in subject with chronic HCV infection; led to discontinuation

‒ Seizures in subject with history of seizure disorder (CT and MRI negative for bleed and thrombosis)

‒ Fatal cerebral venous sinus thrombosis (CVST)

• Since implementation of the new bleed management guidelines, developed to mitigate the risk of thrombosis, there have been no related thrombotic events

Protocol Factor VIII Factor IX (SHL) Factor IX (EHL) aPCC rFVIIaRecommended single dose 10 IU/kg 20 IU/kg 20 IU/kg 30 U/kg ≤45 μg/kg

Single dose should not exceed 20 IU/kg 30 IU/kg 30 IU/kg 50 U/kg 45 μg/kg

Repeat dosing

Must call clinical study center before second dose*; evaluation and treatment at clinical study center should be considered

Must call clinical study center

before third dose†

Should not repeat in <24 hours Should not repeat in <5–7 days

Should not repeat in <24 hours

Should not repeat in <2 hours

For situations requiring higher doses, more frequent administration, or multiple repeat doses, discussion with study medical monitor and clinical advisor is recommended, and AT replacement should be considered

Antifibrinolytics should not be used in combination with replacement factor or bypassing agent

Fitusiran is an investigational medicine. Its safety and efficacy have not been established by any health authorities.These bleed management recommendations were implemented after the lift of the Phase 2 OLE clinical hold.*Should be seen at site within 48–72 hours if >2 doses are required. †Should be seen at site within 48–72 hours if >3 doses are required.aPCC, activated prothrombin complex concentrate; AT, antithrombin; EHL, extended half-life; OLE, open-label extension; rFVIIa, recombinant activated factor VII; SHL, standard half-life. Sanofi Genzyme. ALN-AT3SC-002 Clinical Study Protocol Amendment 5. May 31, 2018.

Recommendations for Bleed Management During Fitusiran Prophylaxis

30

Management of Bleeds in Phase 2 OLE with New Recommendations15 subjects had ≥ 1 bleed, and 12 of these subjects (80%) were compliant with the recommendationsa

Treatment of Bleeds

Factor VIII(n=6)

Factor IX(n=2)

aPCC(n=2)

rFVIIa(n=4)

Total treated bleeds 26 4 25 54

Administrations per bleed, mean (range) 1.3 (1-4) 2.0 (1-3) 1.2 (1-2) 2.0 (1-5)

Mean dose per injection (range)

13.5 IU/kg(5 - 25 IU/kg)

11.5 IU/kg(8 - 21 IU/kg)

32.5 U/kg(27 - 57 IU/kg)

70.9 μg/kg(34 – 105

IU/Kg)

Bleed Causality1

Spontaneous, %Traumatic, %

4654

0100

7228

6731

Bleed Location2

Joint, %Muscle, %Other, %

9280

502525

9280

9622

a3 subjects considered non-compliant: 1 subject had higher than recommended doses of BPA to control multiple bleeds; 1 subject had repeat doses of BPA prior to the recommended 24-hour interval; and 1 subject had a higher than recommended dose of BPA to control a single bleed. Additional training was provided for the personnel and subjects at these centers.OLE, open-label extension; aPCC, activated prothrombin complex concentrate; BPA, bypassing agentPasi J et al., ISTH 2019 Poster Presentation (PB0324)

11 other cause of bleed was an operation (1 bleed, rFVIIa)2Other bleed locations included skin/mucosa (1 bleed, factor IX) and operative site (1 bleed, rFVIIa).

*Of 109 treated bleeds, 2 were not accessed at time of data transfer (November 19, 2018) Note: of the 13 bleeds that required repeat dosing and were treated non-compliantly: 9 occurred in 1 subject, and 4 in a second subject

Conclusions• Monthly fitusiran dosing demonstrated a durable therapeutic effect,

including sustained AT lowering, increased TG, and low ABR• Effect of fitusiran on AT lowering is reversible upon dose interruption and can be

restored with resumption of dosing• Lower doses of factor or BPA may provide adequate haemostatic

protection against bleeds for people receiving fitusiran prophylaxis • Promising investigational approach for rebalancing hemostasis in patients with

hemophilia A or B, with or without inhibitors• The safety and efficacy of fitusiran is now being evaluated in the ongoing

global Phase 3 ATLAS program*

32

*ATLAS trials: NCT03417102, NCT03417245, NCT03549871.Fitusiran is an investigational medicine. Its safety and efficacy have not been established by any health authorities

Evolving trends with modern therapeutics for haemophilia A

Factor replacement therapy• Breaking the VWF ceiling – FVIII divorced

from VWF

• Once weekly dosing now possible

• SQ vs IV

• PK-directed therapy

• Flexibility – “normalize” hemostasis as needed

• Routine monitoring available

• Prophylaxis and breakthrough bleeding may be treated

Non-factor replacement therapy• Fixed dosing – weekly to monthly

• Subnormal to “normalized” hemostasis

• No routine monitoring

• Limited to no personalization for optimization of prophylaxis

• Liberation from routinely “having to think about their hemophilia”

• Advantage of steady-state correction

• Continued reliance on factor replacement therapy

Drivers for choice/preference of current therapeutics

Factor replacement therapy• Physician-driven

• Familiarity and flexibility

• Addresses the physiologic defect

• Concern regarding potential FVIII functions not corrected with non-replacement therapies

• Monitoring for clinical management

• Patient-driven• Inertia related to legacy treatment

• Comfort with peak correction as needed

• No perceived medical need to change

• Concern with observed or unknown AEs

Non-replacement therapy• Physician-driven

• Medically-driven necessity• Better bleed control, adherence

• Venous access challenges

• Experience suggesting a new standard for prophylaxis

• Opportunity for inhibitor avoidance?

• Patient-driven• Lower frequency of treatment

• Route of administration easier

• Worry about bleeds less

• Satisfaction with improved bleed control

Current FVIII Treatments Are Subject to a VWF-Imposed t1/2 Ceiling1

Increasing the half-life of rFVIII is ultimately dependentupon decoupling FVIII and endogenous VWF

35

EHL, extended half-life; FVIII, factor VIII; PEG, polyethylene glycol; rFVIIIFc, recombinant factor VIII Fc fusion protein; t1/2, elimination half-life; VWF, von Willebrand factor.1. Pipe SW. Am J Hematol. 2012;87(Suppl 1):S33-S39. 2. Mahlangu J, et al. Blood. 2014;123(3):317-325. 3. Tiede A, et al. J Thromb Haemost. 2013;11(4):670-678. 4. Coyle TE, et al. J Thromb Haemost. 2014;12(4):488-496. 5. Konkle BA, et al. Blood. 2015;126(9):1078-1085.

Technology for FVIII EHL t1/2Conventional FVIII

comparator t1/2

Fc fusion (rFVIIIFc) 19.0 h2 12.4 h

Glyco-PEGylation (N8-GP) 19.0 h3 11.7 h

Cys variant-PEGylation (BAY 94-9027) 18.7 h4 13.0 h

Amino group-PEGylation (BAX 855) 14.3 h5 10.4 h

VWF binding to FVIII

VWF monomer

VWF

mul

timer

BIVV001: The First FVIII Therapy Designed to Break the VWF-Imposed t1/2 Ceiling

36BIVV001 is an investigational product that has not been proven to be safe or effective; XTEN technology in-licensed from Amunix Operating, Inc. FVIII, factor VIII; rFVIIIFc, recombinant factor VIII Fc fusion protein; t1/2, elimination half-life; VWF, von Willebrand factor.

C1 C2

D’D3

Fc

A1

A2

A3

C1 C2

D’D3

Fc

Fc

rFVIIIFc-VWF-XTEN

BIVV001

VWF D’D3 domain to decouple FVIII from

VWF

XTEN insertionsto increase t1/2

C1 C2

D’D3

Fc

A1

A2

A3

C1 C2

D’D3

Fc

Fc C1 C2

D’D3

Fc

A1

A2

A3

C1 C2

Fc

Fc

Activated rFVIIIFc

Activated BIVV001 EqualsEffects of Activated Thrombin

rFVIIIFc VWF XTEN

Single 65 IU/kg Dose of BIVV001 Extends FVIII t1/2 to 43 Hours

37AUC0–inf, total area under the curve from time zero to infinity; CL, clearance; Cmax, maximum concentration; FVIII, factor VIII; IR, incremental recovery; MRT, mean residence time; PK, pharmacokinetic; rFVIII, recombinant factor VIII; SD, standard deviation; t1/2, elimination half-life.

The mean (SD) FVIII activity post-infusion at 5 days was 38% (10) and at 7 days was 17% (5)

1

1 0 0

D a y s a fte r e n d o f in fu s io n

Me

an

pla

sma

FV

III

act

ivity

(IU

/dL

)

10 2 3 4 5 7 1 0

5 %

3 %

1 %

1 2 1 4

1 01 0 %

6 5 IU /k g rF V III (n = 9 )

6 5 IU /k g B IV V 0 0 1 (n = 8 )

2 0 %1 7 %

3 8 %

PK parameter 65 IU/kg BIVV001 (n=8)a

65 IU/kg rFVIII(n=9)a Mean ratiob

t1/2, h42.85

(38.28–48.55)13.15

(9.96–18.23)3.24 (2.76–3.79)

P<0.001

Cmax, IU/dL 159(117–198)

138(93–173)

1.17 (1.09–1.25)P<0.001

AUC0–inf, h × IU/dL 12,800(9440–17,100)

1960(1440–2550)

6.54 (5.89–7.27)P<0.001

MRT, h 68.1(56.9–75.7)

15.7(13.2–19.2)

4.32 (3.96–4.72)P<0.001

CL, mL/h/kg 0.51(0.38–0.69)

3.31(2.56–4.49)

0.15 (0.14–0.17)P<0.001

IR, IU/dL per IU/kg 2.45(1.80–3.04)

2.11(1.42–2.66)

1.18 (1.10–1.26)P<0.001

FVIII activity determined by the one-stage activated partial thromboplastin clotting assay.aValues are geometric means (range).bValues are mean ratio (95% confidence interval).

Novel approaches to hemophilia therapy

Arruda VR et al. Blood. 2017;130:2251-2256

P. ClementPEN May 2017L.A. Kelly Communications Inc.

Pre-clinicalDevelopment

First Waveof Clinical Trials

Proof of Conceptin Hemophilia B

Current Waveof

Clinical Trials

Pre-2000’s 1996-2006 2010-2014 2014-present

More Pre-clinical Studies

Overview of adeno-associate virus (AAV)-mediated liver-directed gene therapy

Doshi and Arruda, Ther Adv Hematol (2018)

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1 11 21 31 41 51 61 71 81 91 101 111 121 131 141 151 161 171 181

FIX

activ

ity (I

U/d

L)

1 (7.2) 2 (5.3) 3 (1.5) 4 (8.2) 5 (3.5)

0

10

20

30

40

50

0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150

FIX

activ

ity (I

U/d

L)

6 (11.2) 7 (7.1) 8 (8.4) 9 (3.9) 10 (6.7)

Sustained dose-dependent increases in FIX activity

Values in parentheses represent mean FIX activity over time. Only values at least 10 days after last FIX concentrate administration are included. FIX prophylaxis was continued after AMT-060 and tapered between Weeks 6 and 12 *Patient retrospectively tested positive for AAV5 neutralizing antibodies using the luciferase-based assay. 3 patients were presumed cross-reactive matter positive. FIX, factor IX; CI, confidence interval; IU, international units 42

Cohort 1Steady state mean FIX activity (95%CI):

5.1 (1.7 – 8.5)

Cohort 2Steady state mean FIX activity (95%CI):

7.5 (4.1 – 10.8)

Weeks following AMT-060 treatment

FIX activity levels correlated approximately 1:1 with FIX protein expression

* * *

Reductions in FIX use and bleeds sustained over long term follow up (Cohort 1)

Mean FIX consumption excludes surgical procedures 43

4.0

1.50.5 0.8

0

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8

10

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16

Cohort 2

Mea

n an

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tota

l ble

eds

(n)

Pretreatment Year 1 Year 2

Annualized Bleed Rate (Cohort 2)Annualized Bleed Rate (Cohort 2)

14.4

7.6

2.8

6.2

1.7

0

2

4

6

8

10

12

14

16

Cohort 1

Mea

n an

nual

ized

tota

l ble

eds

(n)

Annualized Bleed Rate (Cohort 1)

Pretreatment Year 1 Year 2 Year 3

354,800

64,00031,700

60,84223,817

0

50,000

100,000

150,000

200,000

250,000

300,000

350,000

400,000

Mea

n to

tal a

nnua

lized

FIX

repl

acem

ent (

IU)

Mean FIX consumption (Cohort 1)

Reduction relative to pre-AMT-060 FIX use Bleeds

Year 1 82% 47%Year 2 91% 81%Year 3 83% 57%Year 4 93% 88%

Year 4 Pretreatment Year 1 Year 2 Year 3 Year 4

Reductions in FIX use and bleeds sustained over long term follow up (Cohort 2)

44

4.0

1.50.5 0.8

0

2

4

6

8

10

12

14

16

Cohort 2

Mea

n an

nual

ized

tota

l ble

eds

(n)

Pretreatment Year 1 Year 2 Year 3

Annualized Bleed Rate (Cohort 2)Annualized Bleed Rate (Cohort 2)

4.0

1.40.6 0.7

0

2

4

6

8

10

12

14

16

Cohort 2

Mea

n an

nual

ized

tota

l ble

eds

(n)

Pretreatment Year 1 Year 2 Year 3

Annualized Bleed Rate (Cohort 2)

173,200

38,60014,600 7,278

0

50,000

100,000

150,000

200,000

250,000

300,000

350,000

400,000

Mea

n to

tal a

nnua

lized

FIX

repl

acem

ent (

IU)

Pretreatment Year 1 Year 2 Year 3

Mean FIX consumption (Cohort 2)

Reduction relative to pre-AMT-060

FIX use Bleeds

Year 1 78% 65%Year 2 92% 85%

Year 3 96% 83%

Mean FIX consumption excludes surgical procedures

Introduction: gene therapy for hemophilia B: AMT-060/AMT-061

AAV5 capsid Liver-specific promoter & human FIX gene

AMT-060 – wildtypeClinically demonstrated safe and durable3 increases in FIX

activity with meaningful improvements in clinical outcomes36,7

AMT-061 – Padua variant (expected 6- to 7-fold increase in activity)

• Low prevalence of pre-existing neutralizing antibodies able to impact clinical outcomes1,4

• Previously tested in humans without sign of cellular immune activation2

AMT-061AGG to CTG in gene resulting in R338L in protein

1. Boutin et al, Human Gen Ther 2010; 21(6):704-12. 2. D’Avola et al, Journal of Hepatology 2016; doi: http://dx.doi.org/10.1016/j.jhep.2016.05.012. 3. Nathwani et al. NEJM 2014; 371:1994-2004. 4. Majowicz et al, ASGCT 2018

54.1

30.1

50.9

0

10

20

30

40

50

60

70

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

FIX

activ

ity o

ne-s

tage

aPT

T (%

of n

orm

al)

Week

Participant 1Participant 2Participant 3

AMT-061 Efficacy: FIX activity at 36 weeks post-treatment

46

Mean FIX activity at 36 weeks: 45.0%

*

aPTT, FIX, Factor IX. No immunosuppression required. *May include activity from exogenous FIX replacement. activated partial thromboplastin time;

*

AMT-061 Phase 2b: Conclusions and next steps

AE, adverse event; FIX, Factor IX; NAbs, neutralizing antibodies. 47

AMT-061 was generally well-tolerated with no serious AEs related to treatment All participants achieved clinically meaningful FIX activity:

FIX activity increased by week 1-2 Mean 45% of normal at week 36 FIX activity in the normal range for two of the three participants

No bleeds or associated use of factor replacement therapy No clinically significant liver enzyme elevations No loss of FIX activity or requirement for immunosuppression

The Phase 3 HOPE-B AMT-061 study (NCT03569891) is enrolling First patient treated early 2019 Expected to enroll approximately 55 participants with severe hemophilia B Those with pre-existing AAV5 NAbs will not be excluded

85% reduction in mean ABR from baseline where all patients were on standard of care prophylaxis

95% reduction in mean FVIII usage annualized after week 5

New paradigm of current and potential treatmentsSubstitution & hemostatic rebalancing therapies

Pros• SQ delivery, low burden• Steady state hemostasis• Pediatric and adult application• Inhibitor/non-inhibitor efficacy

Cons• Likely not achieving “normal”

but may be “curative”• Thrombotic risk• Assay issues• Managing peak bleeding risk events• Annual expense

Investigational gene therapy

Pros• “One and done”• Steady state hemostasis• “curative” levels if not even “normal”• Annual cost savings

Cons• Eligibility

• Not for pediatric or inhibitors (yet)• Pre-existing immunity

• Known/unknown risks• Immunologic, cellular stress, integration risk?

• Uncertain durability, ability for redosing• High initial costs