VenkatLiving with Hemophilia

Development of a Pharmacokinetic-Pharmacodynamic (PK-PD) Model of Fitusiran, an Investigational RNAi Therapeutic Targeting Antithrombin for the Treatment of Hemophilia in Patients With and Without InhibitorsHusain Attarwala, Varun Goel, Kate Madigan, Akin Akinc, and Gabriel J. Robbie

10 July 2017 | ISTH | Berlin, Germany

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Background

• Hemophilia A and B are bleeding disorders characterized by ineffective clot formation due to insufficient TG

• Fitusiran is a subcutaneously (SC) administered investigational RNA interference (RNAi) therapeutic targeting antithrombin (AT) with goal of promoting sufficient thrombin generation (TG) to restore hemostasis and prevent bleeding in patients with hemophilia

• Fitusiran is targeted to hepatocytes –where AT is produced – through trivalent N-acetyl galactosamine(GalNAc) ligand via the asialoglycoprotein receptor (ASGPR)

• After internalization, fitusiran binds to RNA Induced Silencing Complex (RISC), and mediates cleavage of AT mRNA and consequently lowers AT production

Fitusiran Therapeutic Hypothesis Hepatocyte Targeted siRNA Delivery and RNAi Mechanism

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ObjectivesTo quantify the relationship between fitusiran dose, predicted fitusiran liver concentrations and serum anti-thrombin (AT) lowering in hemophilia patients

To quantify the relationship between serum AT levels and thrombin generation (TG) in hemophilia patients

To quantify the effects of patient covariates that describe inter-individual variability on AT lowering and TG

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0 7 1 4 2 1 2 8 3 5 4 2

0 .1

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Fit

us

ira

n C

on

ce

ntr

ati

on

(ng

/mL

or

ng

/g)

Pla

sm

a A

T P

rote

in (%

of B

as

elin

e)

T im e p o s t-d o s e (D a y )

F itu s ira n in P la s m a (n g /m L )

F itu s ira n in L iv e r (n g /g )

F itu s ira n in R IS C (n g /g )

A T P ro te in (% o f B a s e lin e )

Background

Following fitusiran administration, plasma concentrations decline rapidly and are below lower limit of quantitation within 1 day; fitusiran concentrations in liver and RISC are sustained for several weeks after a single dose

• Lag time is observed between peak liver concentration and maximum AT lowering

• RISC concentrations of fitusiran correlate well with onset, peak and durability of AT lowering

PK-PD of Fitusiran in Mice after a Single SC Dose of 2.5 mg/kg

AT, antithrombin; RISC, RNA induced silencing complex

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Fitusiran Phase 1 and Phase 2 Open-Label ExtensionStudy Design

OLE, open-label extension; SC, subcutaneous *ClinicalTrials.gov Identifier:NCT02035605; EudraCT: 2013-003135-29; Pasi KJ, et al. N Engl J Med. 2017; epub ahead of print.; Pasi KJ et al. Blood. 2016, 128: 1397^ClinicalTrials.gov Identifier: NCT02554773; EudraCT: 2015-001395-21†5 patients participating in Part C previously participated in Part B‡3 patients started Phase 2 OLE at their original Phase 1 dose; later they were converted to 50 mg or 80 mg

Phase 1, Part B (N=12 patients with HA or HB)

Phase 1, Part C (N=18 patients with HA or HB)†

15, 45, 75 mcg/kg weekly x 3 SC

225, 450, 900, 1800 mcg/kg, or 80 mg monthly x 3 SC

Phase 1, Part D (N=16 patients with HA or HB with inhibitors)

50, 80 mg monthly x 3 SC

Phase 2 OLE‡ (n= 33)

• Individual patient dose adjustment may be allowed (per SRC)

50 mg monthly SC

80 mg monthly SC

Phase 1, Part A (N=4 healthy volunteers)

0.03 mg/kg or placebo x 1 SC

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Patient Demographics and Disease Status

Observed Time Course of AT Lowering after Monthly Dosing (Study ALN-AT3SC-001)

Dose Dependent Maximum AT Lowering is Observed that Appears to be Sigmoidal

Rel

ativ

e N

adir

AT L

evel

(%)

0

10

20

30

40

50

60

70

80

90

100

.015 mg/kg .045 mg/kg .075 mg/kg .225 mg/kg .45 mg/kg .9 mg/mg 1.8 mg/kg 50 mg 80 mg

AT, antithrombin

Covariate Result (N=41)

Age, median (range), years 36 (19-65)

Weight, median (range), kg 75.5 (52-116)

Baseline peak thrombin, median (range), nM 16 (5-47)

Hemophilia sub-type N (%)

Hemophilia A 34 (83)

Hemophilia B 7 (17)

Inhibitor status N (%)

Positive 16 (39)

Negative 25 (61)

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PK-PD Model for AT Lowering: In Liver, Fitusiran is Loaded into RISC Complex and Inhibits AT Synthesis

Modeling Strategy• Rat liver PK concentrations were described by a 2-compartment PK model• Human liver PK was predicted based on allometric scaling of liver PK parameters from

rats• Within liver, fitusiran gets loaded onto RISC complex• Fitusiran loaded RISC concentrations inhibit the synthesis rate of AT thus leading to

lowering of AT activity• Lowering of AT activity led to increase in thrombin generation and this relationship was

best described using a quadratic function

Q = Rate of uptake into RISC compartment, RV = Volume of RISC compartment, CLRISC = Clearance from RISC compartment, Ksyn = Synthesis rate of AT Protein, Kdeg = Degradation rate of AT Protein, IC50 = Concentration producing 50% of the maximal effect, Imax = Maximum inhibition of KsynCovariate effects were tested on IC50 parameter

Liver (V, C)

Liver (V2, C2)

RISC(RV, R)

AntithrombinKsyn Kdeg

Ka

CL

CL2

CLR

(-) IC50, Imax

Q

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Associated PK Parameters

in Human Liver

Parameter Estimate

Ka (1/h) 0.157

V (g) 3300

V2 (g) 6075

CL (g/h) 39.6

CL2 (g/h) 27.2

0 7 1 4 2 1 2 8 3 5 4 20 .1

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1 0

Pre

dic

ted

Hu

ma

n L

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r C

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ntr

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(µ

g/g

)T im e (D a y )

Allometric

Scaling

Human Liver PK was Predicted Based on Allometric Scaling of Rat Liver PK

Human liver PK was predicted based on allometric scaling of PK parameters in rats with exponents of 1 for volume and 0.75 for clearance parameters

• Predicted half-life of fitusiran in human liver is 12 days

0 2 4 6 8 1 0 1 2 1 40 .1

1

1 0

1 0 0

T im e (D a y s )

Ob

se

rve

d a

nd

Fit

ted

Ra

t L

ive

r C

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ntr

ati

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(µ

g/g

)

O b se rv ed

F itted

Rats – 3 mg/kg Humans – 80 mg

PK, Pharmacokinetic

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Model Adequately Describes the Kinetics and Interpatient Variability of AT Activity

PK-PD model adequately describes AT response during onset, steady-state and recovery phases

• The estimated degradation half-life of AT was similar to that reported in literature1, at ~2 days

• Predicted half-life of RISC loaded fitusiran in human liver is 20.5 days

AT, antithrombin; RISC, RNA induced silencing complex1. Menache, D., et al. Blood 75.1 (1990): 33-39

0 5 6 1 1 2 1 6 8 2 2 4

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T im e (D a y )

AT

Ac

tiv

ity

(%

)

80 mg QMx3

Solid blue line: MedianShaded blue area: 90% Prediction Interval Symbols = Observations

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Predicted Dose-Response for Steady State AT Lowering

Dose response curve shows an asymptote at doses >80 mg

0 2 0 4 0 6 0 8 0 1 0 0 1 2 0 1 4 0

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M o n t h y D o s e (m g )

Pre

dic

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Ste

ad

y-S

tate

AT

Ac

tiv

ity

(%

)

Solid blue line: MedianShaded blue area: 90% Prediction Interval

Monthly Dose (mg)

AT, antithrombin

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80 mg QM Results in Larger Proportion of Patients Maintaining Greater AT Lowering During Dosing Interval

% of Patients with >80% AT Lowering at Steady-State 50 mg QM 80 mg QM

Peak 72 92

Trough 66 88

AT, antithrombin

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Simulation of Dosing Regimen

Greater AT lowering with minimal difference between peaks and troughs is expected with monthly regimen compared to bimonthly regimen

Red = Bimonthly RegimenBlue = Monthly Regimen

AT, antithrombin

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Impact of Covariates on AT Lowering

Similar AT lowering is expected in hemophilia A or B patients, with or without inhibitors, across range of observed baseline weights and age in the trial

AT, antithrombin

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0 2 5 5 0 7 5 1 0 00

2 5

5 0

7 5

1 0 0

1 2 5

1 5 0

A T L o w e rin g (% )

TG

(n

M)

O b s e rv a t io n s

O b s e rv e d 5 thO b s e rv e d M e d ia nO b s e rv e d 9 5 th

P re d ic te d 5 thP re d ic te d M e d ia nP re d ic te d 9 5 th

More than Proportional (Non-Linear) Increase in TG is Observed with Increase in AT Lowering

There is generally good agreement between the observed TG values and model predictions, thus, confirming the predictability of the final model and its utility in predicting TG across different doses

• AT-TG relationship is described by the equation

Observed and Model Predicted AT-TG Relationship across 41 Patients

𝑇𝐺 = 16.1 + 0.0065 ∗ 𝐴𝑇 𝐿𝑜𝑤𝑒𝑟𝑖𝑛𝑔 2

AT, antithrombin; TG, thrombin generation

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Predicted Fitusiran Dose-Response of Thrombin Generation

Dose response curve shows greater TG at 80 mg compared to lower doses

• Doses greater than 80 mg are not anticipated to cause substantial additional increase in TG, suggesting that near maximal PD effect is anticipated at 80 mg QM dose

0 2 0 4 0 6 0 8 0 1 0 0 1 2 0 1 4 0

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D o s e (m g )

TG

Pe

ak

He

igh

t (n

M)

Solid blue line: Median TG at steady stateShaded blue area: 90% Prediction Interval steady state TG responseSymbols = Observed mean TG after >1 monthly doses

TG, thrombin generation

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Continued monthly dosing of fitusiran at 80 mg results in an increased TG with minimal difference between peaks and troughs throughout the dosing interval

Predicted Time-Course of Thrombin Generation in Hemophilia Patients Following Fitusiran 80 mg Monthly Regimen

0 1 2 3 4 5 6 7

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T im e (M o n t h s )

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igh

t (n

M) N o n - In h ib ito rs

In h ib ito rs

80 mg Monthly

Simulation performed at baseline TG of 16 nMSolid blue line = Median; Shaded blue area = 90% Prediction Interval; Symbols = Observations (ALN-AT3SC-001)

TG, thrombin generation

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Impact of Covariates on Thrombin Generation

TG is similar across patients with hemophilia A or B, with or without inhibitors, across range of observed baseline weights, age, baseline TG in the trial

• Patients with higher baseline TG have greater absolute increase in thrombin generation from baseline

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Summary

PK-PD model was developed that adequately described the time course and inter-individual variability in observed AT lowering and TG in hemophilia patientsThere was no significant covariate effect of age, weight, hemophilia subtype, or inhibitor status on AT lowering and thrombin generation, suggesting fitusiran is similarly effective in these sub-populationsBased on population PK-PD modeling, recommended Phase 3 dose is 80 mg administered monthly

• Data suggest that 80 mg is adequate for maximizing PD effect• Higher doses are not anticipated to yield substantial additional increase in AT

lowering and TG• 80 mg results in larger proportion of patients maintaining >80% AT lowering

during dosing interval compared to 50 mg• Monthly regimen results in minimal variation between peak and trough

compared to bimonthly regimen