Title of Invention	A PHARMACEUTICAL COMPOSITION OF 2.5 MG OF THE PENTASACCHARIDE METHYL O-(2, 3, A-TRI-O-METHYL-6-O- SULFO- α-D-GLUCOPYRANOSYL)-(1→4)-O-(2, 3-DI-O-METHYL-β-D- GLUCOPYRANOSYL URONIC ACID)- (1→4)-O-(2, 3, 6-TRI-O- SULFO-α-D- GLUCOPYRANOSYL)- (1→4)-O-(2, 3-DI-O-METHYL-α-2, 3, 6-TRI-O-SULFO- α-D-GLUCOPYRANOSIDE) OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF .
Abstract	The invention relates to a dose of 2.5 mg of the pentasaccharide methyl O-(2,3,4-tri-O- methyl-6-O-sulfo-a-D-glucopyranosyl)-(1→4)-O-(2,3-di-0-methyl-β-D-glucopyranosyl uronic acid)-(l→4)-O-(2,3,6-tri-0-sulfo-α-D-glucopyranosyl)-(1→4)-O-(2,3-di-O-methyl-α-L- idopyranosyl uronic acid)-(l→4)-0-2,3,6-tri-O-sulfo-α-D-glucopyranoside or a pharmaceutically acceptable salt thereof for once a week administration, in particular for the treatment and/or secondary prophylaxis of venous thromboembolic events in patients with deep venous thrombosis.

Title of Invention

A PHARMACEUTICAL COMPOSITION OF 2.5 MG OF THE PENTASACCHARIDE METHYL O-(2, 3, A-TRI-O-METHYL-6-O- SULFO- α-D-GLUCOPYRANOSYL)-(1→4)-O-(2, 3-DI-O-METHYL-β-D- GLUCOPYRANOSYL URONIC ACID)- (1→4)-O-(2, 3, 6-TRI-O- SULFO-α-D- GLUCOPYRANOSYL)- (1→4)-O-(2, 3-DI-O-METHYL-α-2, 3, 6-TRI-O-SULFO- α-D-GLUCOPYRANOSIDE) OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF .

Abstract

The invention relates to a dose of 2.5 mg of the pentasaccharide methyl O-(2,3,4-tri-O- methyl-6-O-sulfo-a-D-glucopyranosyl)-(1→4)-O-(2,3-di-0-methyl-β-D-glucopyranosyl uronic acid)-(l→4)-O-(2,3,6-tri-0-sulfo-α-D-glucopyranosyl)-(1→4)-O-(2,3-di-O-methyl-α-L- idopyranosyl uronic acid)-(l→4)-0-2,3,6-tri-O-sulfo-α-D-glucopyranoside or a pharmaceutically acceptable salt thereof for once a week administration, in particular for the treatment and/or secondary prophylaxis of venous thromboembolic events in patients with deep venous thrombosis.

Full Text	The invention relates to a specific dose of SanOrg 34006 for use in the treatment and secondary prophylaxis of venous thromboembolic events (VTE) in patients with deep venous thrombosis (DVT). Recurrence of VTE after treatment of acute DVT is a common clinical feature after the acute treatment of the disease with antithrombotic therapy has been completed. Therefore, to decrease the long-term recurrence rates long-term antithrombotic therapy is required. Usually, unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), thrombolytic agents, and warfarin are used to treat VTE. The currently accepted approach of acute treatment of DVT followed by long-term therapy is to begin heparin and oral anticoagulant therapy (warfarin or another coumarin) together at the time of diagnosis and to discontinue the heparin therapy between the fourth and seventh day. Several randomized trials in patients with VTE have shown that 5 to 7 days of initial heparin therapy coupled with early warfarin initiation and treatment for at least 3 months is effective and safe [Hyers, et al., ACCP 2001, CHEST 2001; 119:180S]. For effective treatment, both animal and human studies have shown that a plasma heparin level in the range of 0.2 - 0.4 IU/mL inhibits thrombus propagation [Hyers, et al., ACCP 2001, CHEST 2001; 119-.178S]. Surprisingly and contrary to common practice in the art, it has now been found that a dose of as low as of 2.5 mg of the pentasaccharide methyl O-(2,3,4-tri-O-methyl-6-O-sulfo-a-D- ^ glucopyranosyl)-(l?4)-O-(2,3-di-O-methyl-ß-D-glucopyranosyl uronic acid)-(l?4)-O-(2,3,6- tri-O-sulfo-a-D-glucopyranosyl)-(l?4)-O-(2,3-di-O-methyl-a-L-idopyranosyl uronic acid)- (l?4)-2,3,6-tri-0-sulfo-a-D-glucopyranoside or a pharmaceutically acceptable salt thereof (in particular its nonasodium salt SanOrg34006, see e.g. US 5,378,829) is effective and safe for the treatment and secondary prophylaxis of VTE in patients with DVT when adrninistered once a week. After administration of the dose of 2.5 mg of SanOrg34006 the plasma through levels (Cmin = 126 ± 63 ng/mL) correspond with 0.09 - 0.26 anti-Xa U/mL, whereas 0.2 - 0.4 IU/mL D-GLUCOPYRANOSIDE OR A PHARMACEUTICALY ACCEPTABLE SALT THEREOF" UFH plus additional anti-IIa activity is generally considered effective in VTE-treatment (vide supra). Since therapeutic regimens for the treatment and secondary prophylaxis of VTE in patients with DVT may be associated with increased bleeding risk, the lowest dose of an anticoagulant which is effective and safe is the most preferred dose. The once-a-week administration of the low dose of SanOrg34006 according to the present invention results in very low plasma levels which unexpectedly are still effective in the prophylaxis and treatment of VTE. The therapeutic regimen of the present invention does not require subsequent monitoring and dose adjustment. The term "pharmaceutically acceptable salt" means a salt with counter-ions like alkali or earth- alkali metal ions, like sodium, calcium, or magnesium. The dose of the pentasaccharide of this invention is administered as a subcutaneous injection to the patient undergoing treatment. Preferably, the patient is a human. The pentasaccharide may be used as a pharmaceutical composition comprising said pentasaccharide together with pharmaceutically acceptable auxiliaries and optionally other therapeutic agents. The term "acceptable" means being compatible with the other ingredients of the composition and not deleterious to the recipients thereof. The pharmaceutical composition for parenteral administration of the dose of the pentasaccharide of this invention may be presented in unit-dose or multi-dose containers, e.g. injection liquids in predetermined amounts, for example in sealed vials and ampoules, and may also be stored in a freeze dried (lyophilized) condition requiring only the addition of sterile liquid carrier, e.g. water, prior to use. Mixed with such pharmaceutically acceptable auxiliaries and liquids, e.g. as described in the standard reference, Gennaro et al., Remington's Pharmaceutical Sciences, (18th ed Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical Preparations and Their Manufacture), the pentasaccharide can be applied as a fluid composition, an injection preparation, in the form of a solution, suspension or emulsion. Aqueous suspensions, isotone saline solutions and sterile injectable solutions may be used, containing pharmaceutically acceptable dispersing agents and/or wetting agents, such as propylene glycol or butylene glycol. The preferred pharmaceutical composition is an isotone saline solution of the pentasaccharide. The pharmaceutical composition according to the invention may also be presented in the form of a veterinary composition, such compositions may be prepared by methods conventional in the art. The invention is further illustrated by the following example. EXAMPLE Clinical data demonstrating both efficacy and safety of the (use of the) dose of 2.5 mg of SanOrg34006 in the treatment and secondary prophylaxis of venous thromboembolic events (VTE) in patients with deep venous thrombosis (DVT) when compared to warfarin. Overall study design The study was a phase n, multicenter, randomized study in five parallel groups, double blind for the dose of SanOrg34006, and open label, assessor blind for oral warfarin (comparator group). The study design is illustrated in Figure 1. After an initial treatment of 9-14 injections (corresponding to 6 ± 1 days) with enoxaparin (representing the LMWHs) for all patients, a total of 650 patients with confirmed symptomatic proximal DVT were to be randomly assigned to one of the treatment groups (2.5 mg, 5 mg, 7.5 mg, or 10 mg SC SanOrg34006, or oral warfarin). Each treatment group was to consist of 130 patients, of which at least 100 patients eligible for inclusion in the Intent-To-Treat (ITT) group. Subjects in the SanOrg34006 treatment groups were to be followed-up during a four-week period after the final assessments. Objectives: The primary (interrelated) objectives of this study were: • to assess the dose-effect relationship of SanOrg34006 to prevent the recurrence and extension of VTE after a period of initial treatment of symptomatic proximal DVT with enoxaparin; • to determine the optimum dose of SanOrg34006 which will be used in further comparative therapeutic studies. This optimum dose was selected considering efficacy, safety, coagulation markers and overall performance. The secondary objective was to assess population pharmacokinetics of SanOrg34006. Diagnosis and criteria for inclusion: • symptomatic proximal DVT (defined as thrombosis in the Popliteal vein, the Superficial Femoral vein or the Common Femoral vein) confirmed by CUS (Compression Ultra Sound / echo) or venography; • males or non-pregnant females; • signed written informed consent. Duration of treatment: 9-14 Enoxaparin injections per patient (corresponding with 5-7 days of treatment), followed by 12 once-weekly adrninistrations of SanOrg34006 or a 12-week course of Warfarin. Duration of study participation: 6 ± 1 Day enoxaparin treatment and up to 12 Weeks ± 1 Day of randomized treatment, and for the SanOrg34006 treatment groups an additional follow-up of 4 weeks. Criteria for evaluation: • Efficacy Primary efficacy parameter: change in thrombotic burden as assessed by the central adjudication committee using a 3-point ordinal outcome scale for the comparison of CUS and PLS (Perfusion Lung Scan) after 12 weeks of randomized treatment with baseline measurements (i.e. deterioration, normalization, or no relevant change) including a supplementary analysis on substantial improvement. Secondary efficacy parameters: change in thrombotic burden using a binary scale (i.e. deterioration versus no deterioration); change of CUS on a 3-point ordinal scale; change of PLS on a 3-point ordinal scale; the composite clinical outcome (non-fatal symptomatic PE and/or recurrent DVT, death due to PE and/or DVT or unexplained, and any important change in therapeutic management of thrombotic events); coagulation markers: plasma D-dimer (fibrin fragment, released in process of thrombolysis; measure for ongoing thrombosis) and TAT (Thrombin-Antithrombin Complex) concentrations during the study treatment. Safety Primary safety parameters: incidence of major bleeding and decreased platelet count. Secondary efficacy parameters: (serious) adverse events, laboratory parameters (hematology, biochemistry, coagulation status, platelet counts), and vital signs (blood pressure, heart rate, body weight). • Pharmacokinetics Plasma concentrations of SanOrg34006 were assessed within 48 h prior to the administration of SanOrg34006 in Weeks 2, 4 and 7. In addition during Week 7 within the time frames 0.5-2 h, 2-6 h, 6-48 h and 120-168 h post dose. In a subset of patients a more extensive sampling scheme was applied with pre-dose samples before each administration and the serial scheme for Week 7 also applied to Week 1 and 12. The parameters Cmax, Cmin and AU(0-168) were calculated from the more extensive data in Week 7 (and Week 1 and 12 for the aforementioned subset). The P-value for Dose Trend is p=0.388 for SanOrg34006, based on the Cochran-Mantel- Haenszel (non-zero correlation) test for trends across dosage (CMH test), stratifying for active cancer. Conclusions • No statistically significant dose-response relationship was observed for the tested SanOrg34006 doses with respect to the primary and secondary efficacy endpoints. • No differences in efficacy were observed between warfarin and the SanOrg34006 doses tested. • Statistically significantly less bleeding events occurred in the 2.5 mg SanOrg34006 group compared to warfarin. A statistically significant dose trend was observed for the incidence of bleeding events and for major bleeding events. • The 10 mg SanOrg34006 dose group was prematurely discontinued because the stopping rule for major bleedings applied for this dose group. • All SanOrg34006 doses and warfarin were generally well tolerated in terms of adverse events (other than bleeding events), laboratory parameters, and vital signs. • Dose-proportional pharmacokinetics were observed, and steady state had been reached in Week 12 with trough concentrations three times as high and AUC values twice as high as the corresponding values after the first administration. • Body weight and creatinine clearance showed the strongest relationship with SanOrg34006 pharmacokinetics, resulting in an increase in SanOrg34006 exposure with decreasing body weight or creatinine clearance. • Bleeding events (major bleedings and all bleedings) coincided with higher exposure to SanOrg34006, predominantly associated with age and creatinine clearance in covariate analysis. • All plasma concentrations after treatment with 2.5 mg SanOrg34006 remained below the levels associated with an increased bleeding risk. Further Analysis In Figure 2 below is shown the predicted average plasma concentration of SanOrg34006 (idraparinux) versus time profile during treatment of VTE patients with 2.5 mg idraparinux once weekly based on results of above presented study. The range advised by ACCP [see Hyers, et al., ACCP 2001, CHEST 2001; 119:178S] is indicated between the dashed lines. Figure 2. Predicted average plasma concentration of SanOrg34006 (idraparinux) versus time profile during treatment of VTE patients with 2.5 mg idraparinux (once weekly). It is known that if treatment is inadequate during the week that treatment is started this has most impact on further event rates [i.e. later in time, even when accuracy has been restored (ref. Brandjes et al., NEJM 1992;327 (21): 1485-9)]. It is noted that the 'Brandjes' trial relates to inadequacy in acute treatment. However, inadequate treatment AFTER the acute treatment week has even a bigger impact: inadequacy over the next 12 weeks (period of the present study) can result in 25% recurrent VTE (CI Lagerstedt et al., Lancet 1985;Sep 7:515-8; R. Hull et al., NEJM 1979;301(16):855-8). The first SanOrg34006-week in the present study is in fact the second treatment week. Thus, if the treatment with SanOrg34006 had been inadequate early in the treatment period, incidences of deterioration of the thrombotic burden later in the treatment period might have been expected. However, even though the plasma levels of 75% of the patient population of the 2.5 mg dose group was 'too low' in terms of the ACCP guidelines, no increased deterioration was observed when compared with higher dosed populations, within the ACCP range. This is shown in Table 6 below. WE CLAIM : 1. A (dose of 2.5 mg of the pentasaccharide methyl O-(2,3,4-tri-O-methyl-6-O-suIfo-a-D- glucopyranosyl)-(l? 4)-O-(2,3-di-0-methyl-ß-D-glucopyranosyl uronic acid)-(l? 4)-O-(2,3,6- tri-0-sulfo-a-D-glucopyranosyl)-(l?4)-0-(2,3-di-O-methyl-a-L-idopyranosyl uronic acid)-( 1? 4) -2,3,6-tri-O-sulfo-a-D-gIucopyranoside or a pharmaceutically acceptable salt thereof administrable once a week. 2. The dose as claimed in claim 1, wherein the pentasaccharide is in the form of its nonasodium salt (SanOrg 34006). 3. A dose of 2.5 mg of the pentasaccharide methyl O-(2,3,4-tri-0-methyl-6-O-sulfo-a-D- glucopyranosyl)-(l? 4)-O-(2,3-di-O-methyl-ß-D-glucopyranosyl uronic acid)-(l? 4)-O-(2,3,6- tri-O-sulfo- (x-D-glucopyranosyl)-(l? 4)-O-(2,3-di-O-methyl-a-L-idopyranosyl uronic acid)- ( 1? 4) -2,3,6-tri-O-sulfo-a-D-glucopyranoside or a pharmaceutical ly acceptable salt thereof for the preparation of a medicament administrable once a week for/the treatment and/or secondary prophylaxis of venous thromboembolic events (VTE) in patients with deep venous thrombosis (DVT). The invention relates to a dose of 2.5 mg of the pentasaccharide methyl O-(2,3,4-tri-O- methyl-6-O-sulfo-a-D-glucopyranosyl)-(1→4)-O-(2,3-di-0-methyl-β-D-glucopyranosyl uronic acid)-(l→4)-O-(2,3,6-tri-0-sulfo-α-D-glucopyranosyl)-(1→4)-O-(2,3-di-O-methyl-α-L- idopyranosyl uronic acid)-(l→4)-0-2,3,6-tri-O-sulfo-α-D-glucopyranoside or a pharmaceutically acceptable salt thereof for once a week administration, in particular for the treatment and/or secondary prophylaxis of venous thromboembolic events in patients with deep venous thrombosis.

Full Text

The invention relates to a specific dose of SanOrg 34006 for use in the treatment and secondary
prophylaxis of venous thromboembolic events (VTE) in patients with deep venous thrombosis
(DVT).
Recurrence of VTE after treatment of acute DVT is a common clinical feature after the acute
treatment of the disease with antithrombotic therapy has been completed. Therefore, to decrease
the long-term recurrence rates long-term antithrombotic therapy is required. Usually,
unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), thrombolytic agents,
and warfarin are used to treat VTE. The currently accepted approach of acute treatment of DVT
followed by long-term therapy is to begin heparin and oral anticoagulant therapy (warfarin or
another coumarin) together at the time of diagnosis and to discontinue the heparin therapy
between the fourth and seventh day. Several randomized trials in patients with VTE have shown
that 5 to 7 days of initial heparin therapy coupled with early warfarin initiation and treatment for
at least 3 months is effective and safe [Hyers, et al., ACCP 2001, CHEST 2001; 119:180S]. For
effective treatment, both animal and human studies have shown that a plasma heparin level in the
range of 0.2 - 0.4 IU/mL inhibits thrombus propagation [Hyers, et al., ACCP 2001, CHEST
2001; 119-.178S].
Surprisingly and contrary to common practice in the art, it has now been found that a dose of as
low as of 2.5 mg of the pentasaccharide methyl O-(2,3,4-tri-O-methyl-6-O-sulfo-a-D-
^ glucopyranosyl)-(l?4)-O-(2,3-di-O-methyl-ß-D-glucopyranosyl uronic acid)-(l?4)-O-(2,3,6-
tri-O-sulfo-a-D-glucopyranosyl)-(l?4)-O-(2,3-di-O-methyl-a-L-idopyranosyl uronic acid)-
(l?4)-2,3,6-tri-0-sulfo-a-D-glucopyranoside or a pharmaceutically acceptable salt thereof (in
particular its nonasodium salt SanOrg34006, see e.g. US 5,378,829) is effective and safe for the
treatment and secondary prophylaxis of VTE in patients with DVT when adrninistered once a
week. After administration of the dose of 2.5 mg of SanOrg34006 the plasma through levels
(Cmin = 126 ± 63 ng/mL) correspond with 0.09 - 0.26 anti-Xa U/mL, whereas 0.2 - 0.4 IU/mL
D-GLUCOPYRANOSIDE OR A PHARMACEUTICALY ACCEPTABLE SALT THEREOF"
UFH plus additional anti-IIa activity is generally considered effective in VTE-treatment (vide
supra).
Since therapeutic regimens for the treatment and secondary prophylaxis of VTE in patients with
DVT may be associated with increased bleeding risk, the lowest dose of an anticoagulant which
is effective and safe is the most preferred dose. The once-a-week administration of the low dose
of SanOrg34006 according to the present invention results in very low plasma levels which
unexpectedly are still effective in the prophylaxis and treatment of VTE.
The therapeutic regimen of the present invention does not require subsequent monitoring and
dose adjustment.
The term "pharmaceutically acceptable salt" means a salt with counter-ions like alkali or earth-
alkali metal ions, like sodium, calcium, or magnesium.
The dose of the pentasaccharide of this invention is administered as a subcutaneous injection to
the patient undergoing treatment. Preferably, the patient is a human.
The pentasaccharide may be used as a pharmaceutical composition comprising said
pentasaccharide together with pharmaceutically acceptable auxiliaries and optionally other
therapeutic agents. The term "acceptable" means being compatible with the other ingredients of
the composition and not deleterious to the recipients thereof.
The pharmaceutical composition for parenteral administration of the dose of the pentasaccharide
of this invention may be presented in unit-dose or multi-dose containers, e.g. injection liquids in
predetermined amounts, for example in sealed vials and ampoules, and may also be stored in a
freeze dried (lyophilized) condition requiring only the addition of sterile liquid carrier, e.g. water,
prior to use.
Mixed with such pharmaceutically acceptable auxiliaries and liquids, e.g. as described in the
standard reference, Gennaro et al., Remington's Pharmaceutical Sciences, (18th ed Mack
Publishing Company, 1990, see especially Part 8: Pharmaceutical Preparations and Their
Manufacture), the pentasaccharide can be applied as a fluid composition, an injection
preparation, in the form of a solution, suspension or emulsion. Aqueous suspensions, isotone
saline solutions and sterile injectable solutions may be used, containing pharmaceutically
acceptable dispersing agents and/or wetting agents, such as propylene glycol or butylene glycol.
The preferred pharmaceutical composition is an isotone saline solution of the pentasaccharide.
The pharmaceutical composition according to the invention may also be presented in the form of
a veterinary composition, such compositions may be prepared by methods conventional in the
art.
The invention is further illustrated by the following example.
EXAMPLE
Clinical data demonstrating both efficacy and safety of the (use of the) dose of 2.5 mg of
SanOrg34006 in the treatment and secondary prophylaxis of venous thromboembolic
events (VTE) in patients with deep venous thrombosis (DVT) when compared to warfarin.
Overall study design
The study was a phase n, multicenter, randomized study in five parallel groups, double blind for
the dose of SanOrg34006, and open label, assessor blind for oral warfarin (comparator group).
The study design is illustrated in Figure 1.
After an initial treatment of 9-14 injections (corresponding to 6 ± 1 days) with enoxaparin
(representing the LMWHs) for all patients, a total of 650 patients with confirmed symptomatic
proximal DVT were to be randomly assigned to one of the treatment groups (2.5 mg, 5 mg,
7.5 mg, or 10 mg SC SanOrg34006, or oral warfarin). Each treatment group was to consist of
130 patients, of which at least 100 patients eligible for inclusion in the Intent-To-Treat (ITT)
group. Subjects in the SanOrg34006 treatment groups were to be followed-up during a
four-week period after the final assessments.
Objectives:
The primary (interrelated) objectives of this study were:
• to assess the dose-effect relationship of SanOrg34006 to prevent the recurrence and
extension of VTE after a period of initial treatment of symptomatic proximal DVT with
enoxaparin;
• to determine the optimum dose of SanOrg34006 which will be used in further comparative
therapeutic studies. This optimum dose was selected considering efficacy, safety, coagulation
markers and overall performance.
The secondary objective was to assess population pharmacokinetics of SanOrg34006.
Diagnosis and criteria for inclusion:
• symptomatic proximal DVT (defined as thrombosis in the Popliteal vein, the Superficial
Femoral vein or the Common Femoral vein) confirmed by CUS (Compression Ultra Sound /
echo) or venography;
• males or non-pregnant females;
• signed written informed consent.
Duration of treatment:
9-14 Enoxaparin injections per patient (corresponding with 5-7 days of treatment), followed by
12 once-weekly adrninistrations of SanOrg34006 or a 12-week course of Warfarin.
Duration of study participation:
6 ± 1 Day enoxaparin treatment and up to 12 Weeks ± 1 Day of randomized treatment, and for
the SanOrg34006 treatment groups an additional follow-up of 4 weeks.
Criteria for evaluation:
• Efficacy
Primary efficacy parameter: change in thrombotic burden as assessed by the central
adjudication committee using a 3-point ordinal outcome scale for the comparison of CUS
and PLS (Perfusion Lung Scan) after 12 weeks of randomized treatment with baseline
measurements (i.e. deterioration, normalization, or no relevant change) including a
supplementary analysis on substantial improvement.
Secondary efficacy parameters: change in thrombotic burden using a binary scale (i.e.
deterioration versus no deterioration); change of CUS on a 3-point ordinal scale; change of
PLS on a 3-point ordinal scale; the composite clinical outcome (non-fatal symptomatic PE
and/or recurrent DVT, death due to PE and/or DVT or unexplained, and any important
change in therapeutic management of thrombotic events); coagulation markers: plasma
D-dimer (fibrin fragment, released in process of thrombolysis; measure for ongoing
thrombosis) and TAT (Thrombin-Antithrombin Complex) concentrations during the study
treatment.
Safety
Primary safety parameters: incidence of major bleeding and decreased platelet count.
Secondary efficacy parameters: (serious) adverse events, laboratory parameters (hematology,
biochemistry, coagulation status, platelet counts), and vital signs (blood pressure, heart rate,
body weight).
• Pharmacokinetics
Plasma concentrations of SanOrg34006 were assessed within 48 h prior to the administration of
SanOrg34006 in Weeks 2, 4 and 7. In addition during Week 7 within the time frames 0.5-2 h,
2-6 h, 6-48 h and 120-168 h post dose. In a subset of patients a more extensive sampling scheme
was applied with pre-dose samples before each administration and the serial scheme for Week 7
also applied to Week 1 and 12. The parameters Cmax, Cmin and AU(0-168) were calculated from
the more extensive data in Week 7 (and Week 1 and 12 for the aforementioned subset).

The P-value for Dose Trend is p=0.388 for SanOrg34006, based on the Cochran-Mantel-
Haenszel (non-zero correlation) test for trends across dosage (CMH test), stratifying for active
cancer.
Conclusions
• No statistically significant dose-response relationship was observed for the tested
SanOrg34006 doses with respect to the primary and secondary efficacy endpoints.
• No differences in efficacy were observed between warfarin and the SanOrg34006 doses
tested.
• Statistically significantly less bleeding events occurred in the 2.5 mg SanOrg34006 group
compared to warfarin. A statistically significant dose trend was observed for the incidence of
bleeding events and for major bleeding events.
• The 10 mg SanOrg34006 dose group was prematurely discontinued because the stopping
rule for major bleedings applied for this dose group.
• All SanOrg34006 doses and warfarin were generally well tolerated in terms of adverse events
(other than bleeding events), laboratory parameters, and vital signs.
• Dose-proportional pharmacokinetics were observed, and steady state had been reached in
Week 12 with trough concentrations three times as high and AUC values twice as high as the
corresponding values after the first administration.
• Body weight and creatinine clearance showed the strongest relationship with SanOrg34006
pharmacokinetics, resulting in an increase in SanOrg34006 exposure with decreasing body
weight or creatinine clearance.
• Bleeding events (major bleedings and all bleedings) coincided with higher exposure to
SanOrg34006, predominantly associated with age and creatinine clearance in covariate
analysis.
• All plasma concentrations after treatment with 2.5 mg SanOrg34006 remained below the
levels associated with an increased bleeding risk.
Further Analysis
In Figure 2 below is shown the predicted average plasma concentration of SanOrg34006
(idraparinux) versus time profile during treatment of VTE patients with 2.5 mg idraparinux once
weekly based on results of above presented study. The range advised by ACCP [see Hyers, et
al., ACCP 2001, CHEST 2001; 119:178S] is indicated between the dashed lines.

Figure 2. Predicted average plasma concentration of SanOrg34006 (idraparinux) versus time profile during
treatment of VTE patients with 2.5 mg idraparinux (once weekly).
It is known that if treatment is inadequate during the week that treatment is started this has most
impact on further event rates [i.e. later in time, even when accuracy has been restored (ref.
Brandjes et al., NEJM 1992;327 (21): 1485-9)]. It is noted that the 'Brandjes' trial relates to
inadequacy in acute treatment. However, inadequate treatment AFTER the acute treatment week
has even a bigger impact: inadequacy over the next 12 weeks (period of the present study) can
result in 25% recurrent VTE (CI Lagerstedt et al., Lancet 1985;Sep 7:515-8; R. Hull et al.,
NEJM 1979;301(16):855-8).
The first SanOrg34006-week in the present study is in fact the second treatment week. Thus, if
the treatment with SanOrg34006 had been inadequate early in the treatment period, incidences
of deterioration of the thrombotic burden later in the treatment period might have been expected.
However, even though the plasma levels of 75% of the patient population of the 2.5 mg dose
group was 'too low' in terms of the ACCP guidelines, no increased deterioration was observed
when compared with higher dosed populations, within the ACCP range. This is shown in Table 6
below.
WE CLAIM :
1. A (dose of 2.5 mg of the pentasaccharide methyl O-(2,3,4-tri-O-methyl-6-O-suIfo-a-D-
glucopyranosyl)-(l? 4)-O-(2,3-di-0-methyl-ß-D-glucopyranosyl uronic acid)-(l? 4)-O-(2,3,6-
tri-0-sulfo-a-D-glucopyranosyl)-(l?4)-0-(2,3-di-O-methyl-a-L-idopyranosyl uronic acid)-( 1?
4) -2,3,6-tri-O-sulfo-a-D-gIucopyranoside or a pharmaceutically acceptable salt thereof
administrable once a week.
2. The dose as claimed in claim 1, wherein the pentasaccharide is in the form of its
nonasodium salt (SanOrg 34006).
3. A dose of 2.5 mg of the pentasaccharide methyl O-(2,3,4-tri-0-methyl-6-O-sulfo-a-D-
glucopyranosyl)-(l? 4)-O-(2,3-di-O-methyl-ß-D-glucopyranosyl uronic acid)-(l? 4)-O-(2,3,6-
tri-O-sulfo- (x-D-glucopyranosyl)-(l? 4)-O-(2,3-di-O-methyl-a-L-idopyranosyl uronic acid)-
( 1? 4) -2,3,6-tri-O-sulfo-a-D-glucopyranoside or a pharmaceutical ly acceptable salt thereof for
the preparation of a medicament administrable once a week for/the treatment and/or secondary
prophylaxis of venous thromboembolic events (VTE) in patients with deep venous thrombosis
(DVT).

The invention relates to a dose of 2.5 mg of the pentasaccharide methyl O-(2,3,4-tri-O-
methyl-6-O-sulfo-a-D-glucopyranosyl)-(1→4)-O-(2,3-di-0-methyl-β-D-glucopyranosyl uronic
acid)-(l→4)-O-(2,3,6-tri-0-sulfo-α-D-glucopyranosyl)-(1→4)-O-(2,3-di-O-methyl-α-L-
idopyranosyl uronic acid)-(l→4)-0-2,3,6-tri-O-sulfo-α-D-glucopyranoside or a pharmaceutically
acceptable salt thereof for once a week administration, in particular for the treatment and/or
secondary prophylaxis of venous thromboembolic events in patients with deep venous
thrombosis.

Documents:

964-kolnp-2004-abstract.pdf

964-kolnp-2004-assignment.pdf

964-KOLNP-2004-CLAIMS.pdf

964-KOLNP-2004-CORRESPONDENCE 1.1.pdf

964-kolnp-2004-correspondence.pdf

964-kolnp-2004-description (complete).pdf

964-kolnp-2004-examination report.pdf

964-kolnp-2004-form 1.pdf

964-kolnp-2004-form 13.pdf

964-kolnp-2004-form 18.pdf

964-kolnp-2004-form 3.pdf

964-kolnp-2004-form 5.pdf

964-KOLNP-2004-FORM-27.pdf

964-kolnp-2004-gpa.pdf

964-kolnp-2004-granted-abstract.pdf

964-kolnp-2004-granted-assignment.pdf

964-kolnp-2004-granted-claims.pdf

964-kolnp-2004-granted-correspondence.pdf

964-kolnp-2004-granted-description (complete).pdf

964-kolnp-2004-granted-examination report.pdf

964-kolnp-2004-granted-form 1.pdf

964-kolnp-2004-granted-form 13.pdf

964-kolnp-2004-granted-form 18.pdf

964-kolnp-2004-granted-form 3.pdf

964-kolnp-2004-granted-form 5.pdf

964-kolnp-2004-granted-gpa.pdf

964-kolnp-2004-granted-reply to examination report.pdf

964-kolnp-2004-granted-specification.pdf

964-KOLNP-2004-OTHERS.pdf

964-kolnp-2004-reply to examination report.pdf

964-kolnp-2004-specification.pdf

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Patent Number

235082

Indian Patent Application Number

964/KOLNP/2004

PG Journal Number

26/2009

Publication Date

26-Jun-2009

Grant Date

24-Jun-2009

Date of Filing

09-Jul-2004

Name of Patentee

SANOFI-AVENTIS

Applicant Address

174 AVENUE DE FRANCE

Inventors:

#	Inventor's Name	Inventor's Address
1	VAN AMSTERDAM RONALD GIJSBERTUS MARIA	N.V. ORGANON, P.O. BOX 20, NL-5340 BH OSS

PCT International Classification Number

A61K 31/7024

PCT International Application Number

PCT/EP2003/00696

PCT International Filing date

2003-01-23

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	002075374.5	2002-01-29	EUROPEAN UNION