WFH Bangkok 2004

Nanotiv – Factor IX Concentrate

Plasma-derived, Very High Purity Factor IX Concentrate

WFH Bangkok 2004

Nanotiv – Factor IX Concentrate

Nanotiv is a highly pure factor IX concentrate derived from carefully selected donors and extensively tested plasma

The Nanotiv manufacturing process is designed to fulfil the highest modern requirements for virus safety by combining two reliable and validated methods of virus elimination

The Nanotiv manufacturing process is gentle, in order to preserve biological function of the factor IX, reduce the risk of thrombogenicity and lead to good clinical tolerance

WFH Bangkok 2004

Nanotiv – Rigorously Controlled Plasma

Carefully selected donors Controlled donation centres Extensive donation testing

– HBsAg – Anti-HCV – Anti-HIV – ALT – Syphilis

PCR tests on – Mini pools and – Production pools

Inventory holding

WFH Bangkok 2004

Nanotiv Manufacturing Process

Cryoprecipitate supernatant plasma

Anion exchange chromatography

S/D Virus inactivation

Affinity chromatography

Cation exchange chromatography

Virus removal: Nanofiltration

Diafiltration

Ultrafiltration

Sterile filtration

Lyophilisation

NANOTIV

WFH Bangkok 2004

Nanotiv – Nanofiltration

WFH Bangkok 2004

Nanotiv – Viral Safety: Conclusion

Nanotiv factor IX fulfils all current requirements for virus safety set out by regulatory bodies such as the Committee for Proprietary Medicinal Products*

Two effective steps against lipid enveloped viruses

One effective step against non enveloped viruses

A combination of methods based on different principles of action

Inactivation/removal with a high safety margin

Rapid virus inactivation

Robustness in the event of process variations

Validation of each step with a wide variety of viruses

An individual step efficacy equivalent to 4 log10

*CPMP/BWP/268/95, 1996. CPMP/BWP/269/95 rev 3., 2001

WFH Bangkok 2004

Nanotiv Purity

Nanotiv is among the purest factor IX preparations available

Prothrombin complex factors are removed to trace amounts

The high purity of Nanotiv is the prerequisite for its excellent clinical tolerability and efficacy

WFH Bangkok 2004

High purity factor IX preparations, like Nanotiv are almost devoid of other vitamin K-dependent factors, as well as phospholipids

They are less likely to be thrombogenic, compared with products of low purity

Even at very high dose (200 IU/kg BW), Nanotiv still does not have an elevated thrombogenic effect

Nanotiv – In Vivo Thrombogenicity

WFH Bangkok 2004

Nanotiv – Clinical Efficacy, Pharmacokinetics

0

0.1

0.2

0.3

0.4

0.5

0.6

0 12 24 36 48 60 72 84

Nanotiv

MAB-purifiedcompetitor

Mean plasma concentration (IU/ml) vs. time (h), n = 12

WFH Bangkok 2004

Nanotiv – Clinical Efficacy

Half-life (t½, hours) 22.6

In vivo recovery (%) 58.3

Incremental recovery (IU/dl per IU/kg) 1.2

Clearance (ml x kg x h-1) 4.84

Pharmacokinetic Parameters

WFH Bangkok 2004

Nanotiv – 6 Months Follow Up Study

1009690

80

0

20

40

60

80

100

120

1 2 3 >4Number of injections

Per

cen

t o

f b

leed

s

Most bleeding episodes were managed using a single dose of (mean) 29 IU/kg BW

Number of injections per bleed vs. Cumulative % of bleeds managed

% o

f b

leed

s

WFH Bangkok 2004

Nanotiv – Clinical Efficacy Summary

In comparative pharmacokinetic studies, Nanotiv half-life and recovery values were within the normal range

After 6 months, the same cohort of patients showed similar values for half-life and recovery as at the beginning

Nanotiv gave no inhibitors

Most bleeding episodes were managed using a single dose of Nanotiv with a mean of 29 IU/kg BW

Nanotiv was well-tolerated

WFH Bangkok 2004

Nanotiv – Clinical Efficacy in Surgery

Nanotiv was well-tolerated in surgery At high bolus doses and in continuous infusion The haemostatic effect always rated as good or excellent No signs of thrombosis or pulmonary embolism observed No adverse events observed No inhibitors detected 14 days after conclusion of

continuous infusion

WFH Bangkok 2004

Nanotiv – Convenience: All You Need

Water for Injections Alcohol swab x 3 Transfer needle Filter needle Syringe Infusion line (Butterfly) Gauze Plaster

WFH Bangkok 2004

Nanotiv at a Glance – Key Features

Highly purified factor IX

Triple chromatography process Specific activity ~ 200 IU/mg Gentle purification Non denatured

Heparin-free formulation

Reduced risk of thrombocytopenia Minimal interference with diagnostic tests

Complementary virus safety concept

High quality starting plasma Double virus elimination procedures Solvent / Detergent (S/D) treatment Nanofiltration Chromatographic steps provide additional safety

WFH Bangkok 2004

Nanotiv at a Glance – In Daily Clinical Use

Extensive clinical experience

Excellent general safety proven over more than 10 y Effective Well-tolerated

Convenient handling

Small injection volume Easy documentation Pull-off labels Dissolves rapidly

Presentation

Storage and shelf-life

36 months shelf-life at + 4 °C to + 8 °C

1 month storage at elevated temperature up to 25 °C

Package Size (IU) Injection Volume

Nanotiv 500 5 ml

Nanotiv 1000 10 ml