the independent research enabler research poster template … · 2017-04-14 · analysis and...
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Target Residence Time -a Novel Parameter in Drug Design
Introduction • Traditionally, a drug candidate is optimized according to standard
pharmacological parameters (e.g. affinity, potency and intrinsic activity). • Despite these intensive efforts, the clinical success of a candidate drug is
disappointingly low. Only 5% of the clinical candidates make it to the market and the reason for failure in phase II is often due to little efficacy (51%) or toxicity (19%).
• We propose to add an additional parameter, residence time (RT), to optimize and select candidate drugs in early drug discovery.
• The target of choice for this project is a class A G protein-coupled receptor (GPCR), the CCR2 chemokine receptor.
• The CCR2 receptor has been implicated in several chronic diseases, such as neuropathic pain, for which no efficacious drugs are available currently.
• The development of CCR2 antagonists has been challenging and several clinical candidates (for inflammatory diseases) failed due to lack of efficacy.
Principal Investigator: Ad IJzerman, Leiden University
Contact: Ad IJzerman Principal Investigator, [email protected] or Laura H. Heitman Project Manager, [email protected] partners TI Pharma project D1-301
Full project title: Target residence time in translational drug research. The CCR2 chemokine receptor as a case in point. Laura H. Heitman1, Martine J. Smit2, Dean Stamos3, John Saunders3, Adriaan P. IJzerman1
1 Dept. Medicinal Chemistry, LACDR, University of Leiden, NL, 2 Dept. Medicinal Chemistry, LACDR, VU University Amsterdam, NL, 3 Vertex Pharmaceuticals Inc., San Diego, CA, USA
Future plans
Aim of the study • Identify and optimize novel CCR2 receptor antagonists using a structure-
residence time-relationship (SRTR) approach as opposed to more traditional structure-affinity-relationships (SAR).
• Investigate whether compounds with longer CCR2 residence times display improved efficacy in in vivo models of pain.
CCR2 receptor and its ligands
Figure 1. CCR2 receptor and its ligands. A) Homology model of CCR2 receptor and its endogenous ligand CCL2. B) Some known CCR2 antagonists, which can be divided in two groups according to our findings (orthosteric/surmountable and allosteric/insurmountable; see below).
A B
General approach
Medicinal chemistry • Synthesize library of reference and novel CCR2 antagonists • Synthesize radiolabeled small molecule radioligand • Compute a pharmacophore model for CCR2 antagonists
Molecular pharmacology • Develop ‘traditional’ in vitro binding and functional assays • Develop in vitro assay to measure SRTR • Test synthesized CCR2 antagonists
Rat models of neuropathic pain • Develop in vivo rat pain efficacy model • Test novel long RT CCR2 antagonist in pain model
Project 1) Multiple CCR2 receptor binding sites The following approaches were taken: • Three ligands were (made) available in radiolabeled form to study the receptor (Fig.1) • Equilibrium radioligand binding assays with 125I-CCL2, [3H]INCB3344 and [3H]CCR2-RA
were developed • Site-directed mutagenesis was performed on conserved amino acid known to be important
for orthosteric antagonist binding on chemokine receptors (E291A7.39) • Functional assays were developed and antagonists were assayed for their mode of
antagonism (surmountable vs. insurmountable)
Label – free technologies • Construct tagged CCR2 receptors, express and purify CCR2
protein for use in SPR measurements • Explore novel ‘label-free’ SPR technology (Biacore) to study
residence time phenomenon
+
Project 2) SRTR of orthosteric CCR2 antagonists The following approaches were taken: • A novel dual-point kinetic screening assay with [3H]INCB3344 was developed to yield
Kinetic Rate Index (KRI) values, which are indicative of a compound’s RT • A library of orthosteric compounds was synthesized and screened for their affinity and KRI • Additional synthesis was performed based on hits to investigate SRTR of one scaffold
CCR2-RA JNJ-27141491 N
O
N
NS H F
F
OO
Buntinx et al. J Pharmacol. Exp. Ther. 2008 Bangoo et al. Mol Pain 2007
N
OOH
O
F
Cl
INCB3344
RS504393 Teijin
O
N N
O
N H
O
O
NN
N
Cl
O
FF
F
O
O
OH
N
O
NH
NH
F
F
FO
O
Mirzadegan et al. J Biol Chem 2000 Moree et al. Bioorg Med Chem Letts 2004
Xue et al. Bioorg Med Chem Letts 2010
INCB3344 - like CCR2-RA - like
Structure basic, often includes +charged nitrogen
acidic (-SH/-OH)
Binding site orthosteric – E2917.39 allosteric – intracellular?
CCL2 antagonism surmountable insurmountable
HN
N
OCF3
Br
Cation –π or π–π interactions
Rigidification
Van der Waals interactions
sub-pocket filling properties
Ki = 1.5 nM, KRI = 2.4, RT = 309 min INCB33
44 5 10 15 20 25 30 35 400.0
0.5
1.0
1.5
2.0
2.5
3.0 ControlSimilar RTShorter RTLonger RT
Cmpd #
Kine
tic ra
te in
dex
0 50 100 150 2000
50
100
Control+ Longer RT ligand+ Shorter RT ligand
Association time (min)Spec
ific
[3 H]IN
CB33
44 b
indi
ng (%
)
t1 t2
KRI = Binding @ t1 / Binding @ t2
Target Residence Time -a Novel Parameter in Drug Design
Introduction • Traditionally, a drug candidate is optimized according to standard
pharmacological parameters (e.g. affinity, potency and intrinsic activity). • Despite these intensive efforts, the clinical success of a candidate drug is
disappointingly low. Only 5% of the clinical candidates make it to the market and the reason for failure in phase II is often due to little efficacy (51%) or toxicity (19%).
• We propose to add an additional parameter, residence time (RT), to optimize and select candidate drugs in early drug discovery.
• The target of choice for this project is a class A G protein-coupled receptor (GPCR), the CCR2 chemokine receptor.
• The CCR2 receptor has been implicated in several chronic diseases, such as neuropathic pain, for which no efficacious drugs are available currently.
• The development of CCR2 antagonists has been challenging and several clinical candidates (for inflammatory diseases) failed due to lack of efficacy.
Principal Investigator: Ad IJzerman, Leiden University
Contact: Ad IJzerman Principal Investigator, [email protected] or Laura H. Heitman Project Manager, [email protected] partners TI Pharma project D1-301
Full project title: Target residence time in translational drug research. The CCR2 chemokine receptor as a case in point. Laura H. Heitman1, Martine J. Smit2, Dean Stamos3, John Saunders3, Adriaan P. IJzerman1
1 Dept. Medicinal Chemistry, LACDR, University of Leiden, NL, 2 Dept. Medicinal Chemistry, LACDR, VU University Amsterdam, NL, 3 Vertex Pharmaceuticals Inc., San Diego, CA, USA
Future plans
Aim of the study • Identify and optimize novel CCR2 receptor antagonists using a structure-
residence time-relationship (SRTR) approach as opposed to more traditional structure-affinity-relationships (SAR).
• Investigate whether compounds with longer CCR2 residence times display improved efficacy in in vivo models of pain.
CCR2 receptor and its ligands
Figure 1. CCR2 receptor and its ligands. A) Homology model of CCR2 receptor and its endogenous ligand CCL2. B) Some known CCR2 antagonists, which can be divided in two groups according to our findings (orthosteric/surmountable and allosteric/insurmountable; see below).
A B
General approach
Medicinal chemistry • Synthesize library of reference and novel CCR2 antagonists • Synthesize radiolabeled small molecule radioligand • Compute a pharmacophore model for CCR2 antagonists
Molecular pharmacology • Develop ‘traditional’ in vitro binding and functional assays • Develop in vitro assay to measure SRTR • Test synthesized CCR2 antagonists
Rat models of neuropathic pain • Develop in vivo rat pain efficacy model • Test novel long RT CCR2 antagonist in pain model
Project 1) Multiple CCR2 receptor binding sites The following approaches were taken: • Three ligands were (made) available in radiolabeled form to study the receptor (Fig.1) • Equilibrium radioligand binding assays with 125I-CCL2, [3H]INCB3344 and [3H]CCR2-RA
were developed • Site-directed mutagenesis was performed on conserved amino acid known to be important
for orthosteric antagonist binding on chemokine receptors (E291A7.39) • Functional assays were developed and antagonists were assayed for their mode of
antagonism (surmountable vs. insurmountable)
Label – free technologies • Construct tagged CCR2 receptors, express and purify CCR2
protein for use in SPR measurements • Explore novel ‘label-free’ SPR technology (Biacore) to study
residence time phenomenon
+
Project 2) SRTR of orthosteric CCR2 antagonists The following approaches were taken: • A novel dual-point kinetic screening assay with [3H]INCB3344 was developed to yield
Kinetic Rate Index (KRI) values, which are indicative of a compound’s RT • A library of orthosteric compounds was synthesized and screened for their affinity and KRI • Additional synthesis was performed based on hits to investigate SRTR of one scaffold
CCR2-RA JNJ-27141491 N
O
N
NS H F
F
OO
Buntinx et al. J Pharmacol. Exp. Ther. 2008 Bangoo et al. Mol Pain 2007
N
OOH
O
F
Cl
INCB3344
RS504393 Teijin
O
N N
O
N H
O
O
NN
N
Cl
O
FF
F
O
O
OH
N
O
NH
NH
F
F
FO
O
Mirzadegan et al. J Biol Chem 2000 Moree et al. Bioorg Med Chem Letts 2004
Xue et al. Bioorg Med Chem Letts 2010
INCB3344 - like CCR2-RA - like
Structure basic, often includes +charged nitrogen
acidic (-SH/-OH)
Binding site orthosteric – E2917.39 allosteric – intracellular?
CCL2 antagonism surmountable insurmountable
HN
N
OCF3
Br
Cation –π or π–π interactions
Rigidification
Van der Waals interactions
sub-pocket filling properties
Ki = 1.5 nM, KRI = 2.4, RT = 309 min IN
CB3344 5 10 15 20 25 30 35 40
0.0
0.5
1.0
1.5
2.0
2.5
3.0 ControlSimilar RTShorter RTLonger RT
Cmpd #
Kin
etic
rate
inde
x
0 50 100 150 2000
50
100
Control+ Longer RT ligand+ Shorter RT ligand
Association time (min)Spec
ific
[3 H]IN
CB
3344
bin
ding
(%)
t1 t2
KRI = Binding @ t1 / Binding @ t2
Mechanism-Based PK-PDModeling Platform 2.0
Introduction & Aim Drug discovery and development is associated with high attrition rates largely due to a lack of efficacy and unexpected safety concerns of new drugs. An important question is therefore how to improve the prediction of drug efficacy and safety. Approach PKPD platform 2.0 aims at the development of novel mechanism-based PKPD modeling concepts for stationary and non-stationary biological systems and builds on the mechanism-based PKPD modeling platform. The research program is a systems pharmacology approach which focuses on the development and application of novel mechanism-based pharmacokinetic-pharmacodynamic (PKPD) modeling concepts. The developed mechanism-based PKPD models contain expressions to describe, in a quantitative manner, processes on the causal path between plasma concentration and effect. To this end mechanism-based PKPD modeling utilizes concepts from physiologically-based pharmacokinetic modeling, receptor theory, dynamical systems analysis and disease systems analysis. This research program will yield a mechanism-based PKPD model library and database which can be used for 1) drug candidate selection, 2) design and evaluation of early ‘proof of concept’ studies in man, 3) optimization of phase-3 clinical trials, and 4) prediction of long-term outcome of drug treatment. In addition to the generation of models the platform educates a new generation of PKPD modelers.
Organization
Principal Investigator: Meindert Danhof, Leiden University
Set-up PKPD Platform 2.0 is a continuation of the mechanism-based PKPD modeling platform (D2-104). Expertise and knowledge acquired in the latter platform is exploited in PKPD platform 2.0. In particular the models constructed within the areas of cardiovascular safety, schizophrenia, developmental changes in pediatrics and osteoporosis will be further developed in PKPD platform 2.0 Data sharing To create the mechanism-based PKPD models, existing and newly generated data sets from academic and industrial partners are shared with the modelers employed by PKPD platform 2.0.
Challenges WP1: Creation of generic brain distribution model, and prospective validation,
extension and extrapolation of models developed in mechanism-based PKPD modeling platform (D2-104)
WP2: Prediction of drug efficacy from exposure and biomarkers in antibacterial disease using a mechanistic middle-out approach model
WP3: Integration of sub models for the prediction of QTc prolongation from D2-104 and evaluation for prediction of clinical QTc effects and set-up of thorough QT studies acceptable to regulatory authorities
WP4: Prediction of clearance and/or absorption of existing or new drugs with pediatric covariate models for CYP3A, UGT and renal function developed in D2-104
WP5: Extension of osteoporosis model developed in D2-104 to other treatments and to prediction of fracture risk in elderly
Use of HbA1c data to predict effectiveness of anti-diabetic drugs using real-life data and translation to cardiovascular risk
Contact: Meindert Danhof Principal Investigator , [email protected] or Margot Beukers Project Manager, [email protected] partners TI Pharma project D2-501
Current Status Recruitment is on-going Availability of datasets is investigated and gaps are identified Research plans are being put together
Fast Facts Full project title: PKPD platform 2.0 Start date: November 1, 2012 End date: December 31, 2013 (continuation independent of TI Pharma till November 1, 2017) Project size: 9 FTE: among which 2 PhD students and 5 Post-docs Total budget: ~3.5 M€
Coordination
• Scientific Director • Project Manager
Computer Framework • Software Development • Maintenance
Support • Financial • Legal • Website
WP2: Infectious Diseases antibact
WP1: Brain
Distribution
WP4: Prediction
of PKPD
in pediatrics
WP3: CV
safety QTc
WP5: Efficacy
Osteoporosis &
Diabetes
WP6: Education &
Training of modelers and
stakeholders
PKPD 2.0 Platform
Content Schematic representation Ownership and accessInput:Individual raw anonimized data sets(existing and newly generated)
Proprietary information of partner providing the data set
Merged Raw anonimized Data sets
Input for modeling work by project researchers
Output:Models and their parameters
Models and theirparameters are available to all partners of PKPD platform 2.0
Mechanism-Based PK-PDModeling Platform 2.0
Introduction & Aim Drug discovery and development is associated with high attrition rates largely due to a lack of efficacy and unexpected safety concerns of new drugs. An important question is therefore how to improve the prediction of drug efficacy and safety. Approach PKPD platform 2.0 aims at the development of novel mechanism-based PKPD modeling concepts for stationary and non-stationary biological systems and builds on the mechanism-based PKPD modeling platform. The research program is a systems pharmacology approach which focuses on the development and application of novel mechanism-based pharmacokinetic-pharmacodynamic (PKPD) modeling concepts. The developed mechanism-based PKPD models contain expressions to describe, in a quantitative manner, processes on the causal path between plasma concentration and effect. To this end mechanism-based PKPD modeling utilizes concepts from physiologically-based pharmacokinetic modeling, receptor theory, dynamical systems analysis and disease systems analysis. This research program will yield a mechanism-based PKPD model library and database which can be used for 1) drug candidate selection, 2) design and evaluation of early ‘proof of concept’ studies in man, 3) optimization of phase-3 clinical trials, and 4) prediction of long-term outcome of drug treatment. In addition to the generation of models the platform educates a new generation of PKPD modelers.
Organization
Principal Investigator: Meindert Danhof, Leiden University
Set-up PKPD Platform 2.0 is a continuation of the mechanism-based PKPD modeling platform (D2-104). Expertise and knowledge acquired in the latter platform is exploited in PKPD platform 2.0. In particular the models constructed within the areas of cardiovascular safety, schizophrenia, developmental changes in pediatrics and osteoporosis will be further developed in PKPD platform 2.0 Data sharing To create the mechanism-based PKPD models, existing and newly generated data sets from academic and industrial partners are shared with the modelers employed by PKPD platform 2.0.
Challenges WP1: Creation of generic brain distribution model, and prospective validation,
extension and extrapolation of models developed in mechanism-based PKPD modeling platform (D2-104)
WP2: Prediction of drug efficacy from exposure and biomarkers in antibacterial disease using a mechanistic middle-out approach model
WP3: Integration of sub models for the prediction of QTc prolongation from D2-104 and evaluation for prediction of clinical QTc effects and set-up of thorough QT studies acceptable to regulatory authorities
WP4: Prediction of clearance and/or absorption of existing or new drugs with pediatric covariate models for CYP3A, UGT and renal function developed in D2-104
WP5: Extension of osteoporosis model developed in D2-104 to other treatments and to prediction of fracture risk in elderly
Use of HbA1c data to predict effectiveness of anti-diabetic drugs using real-life data and translation to cardiovascular risk
Contact: Meindert Danhof Principal Investigator , [email protected] or Margot Beukers Project Manager, [email protected] partners TI Pharma project D2-501
Current Status Recruitment is on-going Availability of datasets is investigated and gaps are identified Research plans are being put together
Fast Facts Full project title: PKPD platform 2.0 Start date: November 1, 2012 End date: December 31, 2013 (continuation independent of TI Pharma till November 1, 2017) Project size: 9 FTE: among which 2 PhD students and 5 Post-docs Total budget: ~3.5 M€
Coordination
• Scientific Director • Project Manager
Computer Framework • Software Development • Maintenance
Support • Financial • Legal • Website
WP2: Infectious Diseases antibact
WP1: Brain
Distribution
WP4: Prediction
of PKPD
in pediatrics
WP3: CV
safety QTc
WP5: Efficacy
Osteoporosis &
Diabetes
WP6: Education &
Training of modelers and
stakeholders
PKPD 2.0 Platform
Content Schematic representation Ownership and accessInput:Individual raw anonimized data sets(existing and newly generated)
Proprietary information of partner providing the data set
Merged Raw anonimized Data sets
Input for modeling work by project researchers
Output:Models and their parameters
Models and theirparameters are available to all partners of PKPD platform 2.0
Introduction • Traditionally, a drug candidate is optimized according to standard
pharmacological parameters (e.g. affinity, potency and intrinsic activity). • Despite these intensive efforts, the clinical success of a candidate drug is
disappointingly low. Only 5% of the clinical candidates make it to the market and the reason for failure in phase II is often due to little efficacy (51%) or toxicity (19%).
• We propose to add an additional parameter, residence time (RT), to optimize and select candidate drugs in early drug discovery.
• The target of choice for this project is a class A G protein-coupled receptor (GPCR), the CCR2 chemokine receptor.
• The CCR2 receptor has been implicated in several chronic diseases, such as neuropathic pain, for which no efficacious drugs are available currently.
• The development of CCR2 antagonists has been challenging and several clinical candidates (for inflammatory diseases) failed due to lack of efficacy.
Contact: Ad IJzerman Principal Investigator, [email protected] or Laura H. Heitman Project Manager, [email protected] partners TI Pharma project D1-301
Full project title: Target residence time in translational drug research. The CCR2 chemokine receptor as a case in point. Laura H. Heitman1, Martine J. Smit2, Dean Stamos3, John Saunders3, Adriaan P. IJzerman1
1 Dept. Medicinal Chemistry, LACDR, University of Leiden, NL, 2 Dept. Medicinal Chemistry, LACDR, VU University Amsterdam, NL, 3 Vertex Pharmaceuticals Inc., San Diego, CA, USA
Future plans
Aim of the study • Identify and optimize novel CCR2 receptor antagonists using a structure-
residence time-relationship (SRTR) approach as opposed to more traditional structure-affinity-relationships (SAR).
• Investigate whether compounds with longer CCR2 residence times display improved efficacy in in vivo models of pain.
CCR2 receptor and its ligands
Figure 1. CCR2 receptor and its ligands. A) Homology model of CCR2 receptor and its endogenous ligand CCL2. B) Some known CCR2 antagonists, which can be divided in two groups according to our findings (orthosteric/surmountable and allosteric/insurmountable; see below).
A B
General approach
Medicinal chemistry • Synthesize library of reference and novel CCR2 antagonists • Synthesize radiolabeled small molecule radioligand • Compute a pharmacophore model for CCR2 antagonists
Molecular pharmacology • Develop ‘traditional’ in vitro binding and functional assays • Develop in vitro assay to measure SRTR • Test synthesized CCR2 antagonists
Rat models of neuropathic pain • Develop in vivo rat pain efficacy model • Test novel long RT CCR2 antagonist in pain model
Project 1) Multiple CCR2 receptor binding sites The following approaches were taken: • Three ligands were (made) available in radiolabeled form to study the receptor (Fig.1) • Equilibrium radioligand binding assays with 125I-CCL2, [3H]INCB3344 and [3H]CCR2-RA
were developed • Site-directed mutagenesis was performed on conserved amino acid known to be important
for orthosteric antagonist binding on chemokine receptors (E291A7.39) • Functional assays were developed and antagonists were assayed for their mode of
antagonism (surmountable vs. insurmountable)
Label – free technologies • Construct tagged CCR2 receptors, express and purify CCR2
protein for use in SPR measurements • Explore novel ‘label-free’ SPR technology (Biacore) to study
residence time phenomenon
+
Project 2) SRTR of orthosteric CCR2 antagonists The following approaches were taken: • A novel dual-point kinetic screening assay with [3H]INCB3344 was developed to yield
Kinetic Rate Index (KRI) values, which are indicative of a compound’s RT • A library of orthosteric compounds was synthesized and screened for their affinity and KRI • Additional synthesis was performed based on hits to investigate SRTR of one scaffold
CCR2-RA JNJ-27141491 N
O
N
NS H F
F
OO
Buntinx et al. J Pharmacol. Exp. Ther. 2008 Bangoo et al. Mol Pain 2007
N
OOH
O
F
Cl
INCB3344
RS504393 Teijin
O
N N
O
N H
O
O
NN
N
Cl
O
FF
F
O
O
OH
N
O
NH
NH
F
F
FO
O
Mirzadegan et al. J Biol Chem 2000 Moree et al. Bioorg Med Chem Letts 2004
Xue et al. Bioorg Med Chem Letts 2010
INCB3344 - like CCR2-RA - like
Structure basic, often includes +charged nitrogen
acidic (-SH/-OH)
Binding site orthosteric – E2917.39 allosteric – intracellular?
CCL2 antagonism surmountable insurmountable
HN
N
OCF3
Br
Cation –π or π–π interactions
Rigidification
Van der Waals interactions
sub-pocket filling properties
Ki = 1.5 nM, KRI = 2.4, RT = 309 min IN
CB3344 5 10 15 20 25 30 35 40
0.0
0.5
1.0
1.5
2.0
2.5
3.0 ControlSimilar RTShorter RTLonger RT
Cmpd #
Kin
etic
rate
inde
x
0 50 100 150 2000
50
100
Control+ Longer RT ligand+ Shorter RT ligand
Association time (min)Spec
ific
[3 H]IN
CB
3344
bin
ding
(%)
t1 t2
KRI = Binding @ t1 / Binding @ t2
The Independent Research Enabler
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And No Period at the End
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Research poster template
Width may be divided into 1, 2, or 4 columns. Always snap to one of these blocks.
Experts on Praziquantel and committed to eliminate Schistosomiasis
New Pediatric Formulation to Fight Schistosomiasis in Young Children A Public Private Consortium consisting of Merck KGaA, Astellas Pharma Inc., Swiss Tropical and Public Health Institute, and TI Pharma
Contact: Jutta.Reinhard-Rupp@ merckgroup.com
Penetration of Schistosoma in forearm
A Neglected Tropical Disease Schistosomiasis is a water-‐borne parasitic disease caused by trematodes (Ulatworms) belonging to the Schistosoma genus
Impact • At least 240 million infected people • About 780 million people at risk • > 200,000 deaths in Africa • High burden of disease (disabled children with chronic inUlammation) • High prevalence of infection in young children (up to 75% in certain areas)
Geography Endemic in 78 countries across Africa, South America, Middle East and Asia, with more than 70% of the global burden in 10 countries in Africa.
Current Treatment Praziquantel (PZQ) is an oral anti-‐helminthic drug, donated by the Merck – WHO Partnership to Uight Schistosomiasis. Developed in the 1970s, it has proven to be safe and efUicacious. Current drug is a racemic mixture of levopraziquantel (L-‐PZQ) and dextropraziquantel (D-‐PZQ). D-‐PZQ has been reported to be pharmacologically inactive and responsible for a signiUicant contribution to the bitter taste. The Neglected Population
For young children (< 6 years) treatment with the current PZQ tablet is not appropriate: • Bitter taste leads to gagging or vomiting • The size of the current tablet is signiUicant • Not sufUicient clinical data in very young children
Clear need for a new pediatric formulation to treat young children
The consortium was established in 2012 and works on short and long term solutions
Core Project Team (all partners)
Consortium Board (Merck Serono, Astellas, TI Pharma)
International ScientiSic
Advisory Board
including
WHO -Observer
Subteams (CMC, clinical, regulatory)
Subteams Communications &
Gap Filling
Development of a pediatric formulation of the current racemic PZQ • Improvement of taste • More appropriate for use in young children ( > 2 years)
Development of a pediatric formulation of the enantiopure L-‐PZQ • Improvement of taste and fewer intake of medication • Clinical development to support treatment of young children, including the 3months -‐ 2 years age group
Experts on innovative drug formulation strategies
Experts in the Uield of clinical trials in endemic countries and antischistosomal drug discovery
Experts in managing public private partnerships in drug research and development
[email protected] [email protected] [email protected]
The Independent Research Enabler
Arial Bold Title area (max. 2 lines / max ± 70 characters) Title is Written with American Capitalisation –
And No Period at the End
minimum margin
minimum margin
divider orange 1 pt
Caption (Level 5) Arial regular 24 pt Dark blue
Note: NEVER reduce margins
DO reduce font size
Fixed height for header area
Header (Level 1) Cambria Bold 46pt Dark Blue Body (Level 2) Cambria regular 34 pt Dark Blue • Body + bullets (Level 3) • Level 4
logo row
minmum height footnotes / contact info
margin
< 6 partners
margin
margin
2 logo rows
minimum height footnotes / contact info
margin
6 – 12 partners
margin
margin
Arial regular 46 pt subtitle area (max. 1 line)
Cambria Bold 46 pt author(max. 2 lines)
Research poster template
Width may be divided into 1, 2, or 4 columns. Always snap to one of these blocks.
Experts on Praziquantel and committed to eliminate Schistosomiasis
New Pediatric Formulation to Fight Schistosomiasis in Young Children A Public Private Consortium consisting of Merck KGaA, Astellas Pharma Inc., Swiss Tropical and Public Health Institute, and TI Pharma
Contact: Jutta.Reinhard-Rupp@ merckgroup.com
Penetration of Schistosoma in forearm
A Neglected Tropical Disease Schistosomiasis is a water-‐borne parasitic disease caused by trematodes (Ulatworms) belonging to the Schistosoma genus
Impact • At least 240 million infected people • About 780 million people at risk • > 200,000 deaths in Africa • High burden of disease (disabled children with chronic inUlammation) • High prevalence of infection in young children (up to 75% in certain areas)
Geography Endemic in 78 countries across Africa, South America, Middle East and Asia, with more than 70% of the global burden in 10 countries in Africa.
Current Treatment Praziquantel (PZQ) is an oral anti-‐helminthic drug, donated by the Merck – WHO Partnership to Uight Schistosomiasis. Developed in the 1970s, it has proven to be safe and efUicacious. Current drug is a racemic mixture of levopraziquantel (L-‐PZQ) and dextropraziquantel (D-‐PZQ). D-‐PZQ has been reported to be pharmacologically inactive and responsible for a signiUicant contribution to the bitter taste. The Neglected Population
For young children (< 6 years) treatment with the current PZQ tablet is not appropriate: • Bitter taste leads to gagging or vomiting • The size of the current tablet is signiUicant • Not sufUicient clinical data in very young children
Clear need for a new pediatric formulation to treat young children
The consortium was established in 2012 and works on short and long term solutions
Core Project Team (all partners)
Consortium Board (Merck Serono, Astellas, TI Pharma)
International ScientiSic
Advisory Board
including
WHO -Observer
Subteams (CMC, clinical, regulatory)
Subteams Communications &
Gap Filling
Development of a pediatric formulation of the current racemic PZQ • Improvement of taste • More appropriate for use in young children ( > 2 years)
Development of a pediatric formulation of the enantiopure L-‐PZQ • Improvement of taste and fewer intake of medication • Clinical development to support treatment of young children, including the 3months -‐ 2 years age group
Experts on innovative drug formulation strategies
Experts in the Uield of clinical trials in endemic countries and antischistosomal drug discovery
Experts in managing public private partnerships in drug research and development
[email protected] [email protected] [email protected]
New Pediatric Formulation to Fight Schistosomiasis in Young ChildrenA Public Private Consortium consisting of Merck KGaA, Astellas Pharma Inc., Swiss Tropical and Public Health Institute and TI Pharma