Periodic Report Summary 2 - LOULLA'||'&'||'PHILLA (Development of 6-mercaptopurine and Methotrexate oral liquid formulations for the maintenance treatment of Acute Lymphoblastic Leukemia in children)
Project context and objectives:
The main objective of our LOULLA&PHILLA project which has been achieved last 30 April 2012 was the development of an oral liquid formulation of two medicines, namely mercaptopurine (6MP) and methotrexate (MTX) used for the maintenance treatment of the acute lymphoblastic leukaemia, the first cause of cancer in children. Although this leukaemia is almost exclusively affecting children, to date no adapted formulation has been developed and kids have to take adult tablets. In addition to this innovative pharmaceutical development, a first clinical trial was planned on the new developed 6MP formulation.
Beyond this much focussed objective, we also wanted to have an innovative approach for the development and the supply of anti-cancer drugs in an oral liquid form in general. Would it be possible to offer the kids 'the drug I need with the taste I like' and to the parents 'with a precise and safe use for my kid and my family'?
Project results:
We started this development literally from scratch. Before developing the new formulations themselves, it appears that the flavoured liquid should be dissociated from the active ingredient. We then imagine a new packaging with the active ingredient in a cap and the flavoured liquid in the bottle. Parents would have to press the cap and then the active ingredient would fall in the liquid. After a little shaking, parents would take with a graduated syringe the prescribed dose. At the beginning of the project, this new packaging was only in our imagination but it now exist and has been patented. This new packaging is called 'The shaker'. Now that we had the packaging in place, we started the pharmaceutical development.
The pharmaceutical development was a real challenge and focussed on the 6MP. We had in fact three pharmaceuticals development to perform: the active ingredient for the cap, the liquid for the bottle and the reconstituted suspension. After having succeeded in the formulation development (the 6MP formulation is called Loulla, whereas the MTX formulation is called Philla), we demonstrated the stability of the various components and the precision of the dosing syringe.
At the end of the first part of the project, we were ready to start several pre-clinical studies and the clinical development on the new developed 6MP formulation.
The purpose of the non-clinical study was to investigate whether the new formulation had any mucosal toxicity. O4CP developed an animal hamster model. This good laboratory practice (GLP) study was performed and the data indicated that Loulla (6MP oral liquid) was well tolerated.
Based on these results, the consortium performed the following clinical study: An open-label, randomised crossover pharmacokinetic, palatability and safety study to assess the bioavailability of 5 ml of a new 6MP oral liquid formulation by comparison to a currently registered 6MP 50 mg (purinethol).
In compliance with good clinical practice (GCP), O4CP acted as sponsor assisted by cardinal systems which acted as 'clinical research organisation'.
Professor Kjeld Schmiegelow from J. Marie Centre acted as coordinating investigator. Other investigators were the following ones:
1. Prof. Martin Schrappe (Christian Albrechts Universität - Kiel - Germany): partner CAU
2. Prof. Yves Bertrand (IHOP - Lyon - France): partner HCL
3. Dr Brigitte Nelken (Hôpital Jeanne de Flandre - Lille - France): partner CHU Lille
4. Dr Caroline Thomas (Hôpital Mère-Enfant - Nantes - France): partner CHUN
5. Prof. Guy Leverger (Hôpital Trousseau - APHP - Paris - France) and Pr André Baruchel (Hôpital Robert Debré - APHP - Paris - France): partner AP-HP.
The CIC Robert Debré (APHP, Paris ? France) has been involved as an investigational site in collaboration with Prof. Leverger and Prof. Baruchel who addressed their respective patients to the CIC.
In short, the clinical trials has been performed by four investigational sites in France, in Paris (CIC Robert Debré), Lille, Lyon and Nantes, one investigational site in Denmark and one investigational site in Germany.
'First patient first visit' was on 31 August 2010 whereas 'last patient last visit' was on 10 May 2011. In total 15 patients have been recruited.
At the end of this full development (pharmaceutical, non clinical and clinical), O4CP submitted a registration dossier (validated in March 2012) to the European Medical Agency (EMA) for the Loulla product. It has to be noted that Loulla is a paraben free product.
Potential impact:
Overall, the safety and tolerance results, the pharmacokinetic results and the palatability data collected in the 6MP study support the use of this new 6MP oral suspension in children. Despite the relative bioavailability of the oral suspension is on average lower than that of the reference by approximately one third, this difference is not expected to have any clinical impact on the maintenance therapy results for the individual patient, since it will be compensated for on an individual basis through dose adjustments by pharmacodynamic and/or toxicity markers securing each patient the relevant adequate dose.
Thanks to these results, O4CP the coordinator of the project, is preparing the future distribution of this new formulation. Thus, following the validation of the registration dossier for the new developed 6MP formulation, EMA is currently reviewing it. The process for reviewing the dossier till the marketing authorisation is a long process lasting for about one year. If the evaluation of this complex product is positive, the marketing authorisation should be granted in 2013.
In addition, O4CP has now developed a new patented technology, i.e. 'The shaker, which allows the development of paraben free formulation for children. This will have a major impact on the formulation and product development for children.
List of websites:
https://www.fp7-loullaphilla.eu/
The main objective of our LOULLA&PHILLA project which has been achieved last 30 April 2012 was the development of an oral liquid formulation of two medicines, namely mercaptopurine (6MP) and methotrexate (MTX) used for the maintenance treatment of the acute lymphoblastic leukaemia, the first cause of cancer in children. Although this leukaemia is almost exclusively affecting children, to date no adapted formulation has been developed and kids have to take adult tablets. In addition to this innovative pharmaceutical development, a first clinical trial was planned on the new developed 6MP formulation.
Beyond this much focussed objective, we also wanted to have an innovative approach for the development and the supply of anti-cancer drugs in an oral liquid form in general. Would it be possible to offer the kids 'the drug I need with the taste I like' and to the parents 'with a precise and safe use for my kid and my family'?
Project results:
We started this development literally from scratch. Before developing the new formulations themselves, it appears that the flavoured liquid should be dissociated from the active ingredient. We then imagine a new packaging with the active ingredient in a cap and the flavoured liquid in the bottle. Parents would have to press the cap and then the active ingredient would fall in the liquid. After a little shaking, parents would take with a graduated syringe the prescribed dose. At the beginning of the project, this new packaging was only in our imagination but it now exist and has been patented. This new packaging is called 'The shaker'. Now that we had the packaging in place, we started the pharmaceutical development.
The pharmaceutical development was a real challenge and focussed on the 6MP. We had in fact three pharmaceuticals development to perform: the active ingredient for the cap, the liquid for the bottle and the reconstituted suspension. After having succeeded in the formulation development (the 6MP formulation is called Loulla, whereas the MTX formulation is called Philla), we demonstrated the stability of the various components and the precision of the dosing syringe.
At the end of the first part of the project, we were ready to start several pre-clinical studies and the clinical development on the new developed 6MP formulation.
The purpose of the non-clinical study was to investigate whether the new formulation had any mucosal toxicity. O4CP developed an animal hamster model. This good laboratory practice (GLP) study was performed and the data indicated that Loulla (6MP oral liquid) was well tolerated.
Based on these results, the consortium performed the following clinical study: An open-label, randomised crossover pharmacokinetic, palatability and safety study to assess the bioavailability of 5 ml of a new 6MP oral liquid formulation by comparison to a currently registered 6MP 50 mg (purinethol).
In compliance with good clinical practice (GCP), O4CP acted as sponsor assisted by cardinal systems which acted as 'clinical research organisation'.
Professor Kjeld Schmiegelow from J. Marie Centre acted as coordinating investigator. Other investigators were the following ones:
1. Prof. Martin Schrappe (Christian Albrechts Universität - Kiel - Germany): partner CAU
2. Prof. Yves Bertrand (IHOP - Lyon - France): partner HCL
3. Dr Brigitte Nelken (Hôpital Jeanne de Flandre - Lille - France): partner CHU Lille
4. Dr Caroline Thomas (Hôpital Mère-Enfant - Nantes - France): partner CHUN
5. Prof. Guy Leverger (Hôpital Trousseau - APHP - Paris - France) and Pr André Baruchel (Hôpital Robert Debré - APHP - Paris - France): partner AP-HP.
The CIC Robert Debré (APHP, Paris ? France) has been involved as an investigational site in collaboration with Prof. Leverger and Prof. Baruchel who addressed their respective patients to the CIC.
In short, the clinical trials has been performed by four investigational sites in France, in Paris (CIC Robert Debré), Lille, Lyon and Nantes, one investigational site in Denmark and one investigational site in Germany.
'First patient first visit' was on 31 August 2010 whereas 'last patient last visit' was on 10 May 2011. In total 15 patients have been recruited.
At the end of this full development (pharmaceutical, non clinical and clinical), O4CP submitted a registration dossier (validated in March 2012) to the European Medical Agency (EMA) for the Loulla product. It has to be noted that Loulla is a paraben free product.
Potential impact:
Overall, the safety and tolerance results, the pharmacokinetic results and the palatability data collected in the 6MP study support the use of this new 6MP oral suspension in children. Despite the relative bioavailability of the oral suspension is on average lower than that of the reference by approximately one third, this difference is not expected to have any clinical impact on the maintenance therapy results for the individual patient, since it will be compensated for on an individual basis through dose adjustments by pharmacodynamic and/or toxicity markers securing each patient the relevant adequate dose.
Thanks to these results, O4CP the coordinator of the project, is preparing the future distribution of this new formulation. Thus, following the validation of the registration dossier for the new developed 6MP formulation, EMA is currently reviewing it. The process for reviewing the dossier till the marketing authorisation is a long process lasting for about one year. If the evaluation of this complex product is positive, the marketing authorisation should be granted in 2013.
In addition, O4CP has now developed a new patented technology, i.e. 'The shaker, which allows the development of paraben free formulation for children. This will have a major impact on the formulation and product development for children.
List of websites:
https://www.fp7-loullaphilla.eu/