Clinical trials in progress targeting endogenous stem cells
19 June 2013
Austria
1)Clinical trials in progress
In the past year significant progress has been made with the Endostem clinical trials; the phase 1 trial with Isofen (ibuprofen-Nitric oxide) combination drug reached its main conclusions of demonstrating an excellent safety profile with no serious adverse and that ther was relevant pharmacokinetic interactions between the ibuprofen and nitric oxide component which permits drug dosing flexibility, with better therapy optimisation. The planned phase Iia trial dossier was submitted and first stage clinical trials on patients is set to begin in 2013.
In preparation of the CALLISTO study (Congenital Muscular Dystrophy Ascending Multiple Dose Cohort Study anaLyzing Pharmacokinetics at three dose Levels In children and Adolescents with assessment of Safety and Tolerability of Omigapil) with 24 paediatric CMD patients, a number of prerequisites has been achieved: The Active Pharmaceutical Ingredient (API) has been re-tested and released; For young CMD patients, a taste-masked liquid formulation has been developed which allows flexible dosing over a broad dose range (between 0.2 and 5 mg) and can be applied through a gastric tube; the liquid and powder formulations of the drug have proven to be stable and the clinical protocol for the CALLISTO study was completed.
In February the Orphan Medicinal Product Designation for “givinostat for the treatment of Duchenne Muscular Dystrophy” application was submitted to European Medicines Agency (EMA) by Italfarmaco and in June a positive opinion was received. In August it finalized a clinical protocol, which was amended to add magnetic resonance imaging (MRI) of muscle on the upper limb, if it is possible and if the child is compliant. In the same month, the amendment was submitted to the involved Ethical Committee’s and to the Competent Authoriry (i.e. AIFA). The procedures of start up (i.e. Start Initiation Visits) are ongoing and at the moment 3 of 4 centres are ‘open’ and ready to start the patients selection and screening phase.
For the SEPN trial in which NAC will be used, the protocol was revised as indicated in the last report. We have validated the novel protocol integrating findings from the retrospective natural history study on patients and the preclinical studies in the SEPN1 KO mice. The revised protocol was submitted to the Délégation Interrégionale à la Recherche Clinique (DIRC) Île-de-France and the Direction de la Recherche Clinique et du Développement (DRCD) of the AP-HP (Assistance Publique-Hôpitaux de Paris) and the AP-HP has validated the rationale for the change in trial modality (from international multicentric to national pilot phase II study). They have accepted to be the sponsor. A Project Manager (Mr P. Gallula) has been designated and the Unité de Recherche Clinique (URC) of the Ambroise Paré Hospital have been designated to organize the recruitment of patients, monitoring, collecting of data (eCRF), follow up, data extraction and statistic analysis, in collaboration with the Centre d’Investigation Clinique et Innovation Technologique (CIC-IT) of the Garches Hospital. We expect to start recruiting by the fall 2013. As the novel protocol spans 14 months, the first patients should complete the trial by the end of 2014 prior to the end of the Endostem project.
2)Pre-clinical development
As part of the development of novel therapeutics, Cripto has been selected as relevant candidate to enter preclinical preparation which has been demonstrated to promote repair by activation of satellite cells in the absence of other external stimuli. Data indicate that Cripto expands the pool of transient amplifying myoblasts.
The project has identified and characterized several stem populations in the muscle tissue, such as PW1-positive interstitial cells (PICs) or FibroAdipogenic progenitors (FAPs) in the aim of identifying new pathways and therapeutics that could lead to a better regeneration.
It was shown that PICs produce follistatin that promotes satellite cell proliferation and further blocks the activity of myostatin, and that PICs are preferentially recruited following myostatin inhibition. In addition, exposure to soluble myostatin antagonist prior to muscle damage rescues regenerative capacity in a model in which satellite cells have been reduced by 95%. This suggests that myostatin inhibition results in the activation of PICs which in turn promote a favorable environment for myoblast recruitment and commitment, and that the local muscle stem cell environment can be modified to promote regeneration in the absence or severe depletion of canonical stem cells.
In the past year significant progress has been made with the Endostem clinical trials; the phase 1 trial with Isofen (ibuprofen-Nitric oxide) combination drug reached its main conclusions of demonstrating an excellent safety profile with no serious adverse and that ther was relevant pharmacokinetic interactions between the ibuprofen and nitric oxide component which permits drug dosing flexibility, with better therapy optimisation. The planned phase Iia trial dossier was submitted and first stage clinical trials on patients is set to begin in 2013.
In preparation of the CALLISTO study (Congenital Muscular Dystrophy Ascending Multiple Dose Cohort Study anaLyzing Pharmacokinetics at three dose Levels In children and Adolescents with assessment of Safety and Tolerability of Omigapil) with 24 paediatric CMD patients, a number of prerequisites has been achieved: The Active Pharmaceutical Ingredient (API) has been re-tested and released; For young CMD patients, a taste-masked liquid formulation has been developed which allows flexible dosing over a broad dose range (between 0.2 and 5 mg) and can be applied through a gastric tube; the liquid and powder formulations of the drug have proven to be stable and the clinical protocol for the CALLISTO study was completed.
In February the Orphan Medicinal Product Designation for “givinostat for the treatment of Duchenne Muscular Dystrophy” application was submitted to European Medicines Agency (EMA) by Italfarmaco and in June a positive opinion was received. In August it finalized a clinical protocol, which was amended to add magnetic resonance imaging (MRI) of muscle on the upper limb, if it is possible and if the child is compliant. In the same month, the amendment was submitted to the involved Ethical Committee’s and to the Competent Authoriry (i.e. AIFA). The procedures of start up (i.e. Start Initiation Visits) are ongoing and at the moment 3 of 4 centres are ‘open’ and ready to start the patients selection and screening phase.
For the SEPN trial in which NAC will be used, the protocol was revised as indicated in the last report. We have validated the novel protocol integrating findings from the retrospective natural history study on patients and the preclinical studies in the SEPN1 KO mice. The revised protocol was submitted to the Délégation Interrégionale à la Recherche Clinique (DIRC) Île-de-France and the Direction de la Recherche Clinique et du Développement (DRCD) of the AP-HP (Assistance Publique-Hôpitaux de Paris) and the AP-HP has validated the rationale for the change in trial modality (from international multicentric to national pilot phase II study). They have accepted to be the sponsor. A Project Manager (Mr P. Gallula) has been designated and the Unité de Recherche Clinique (URC) of the Ambroise Paré Hospital have been designated to organize the recruitment of patients, monitoring, collecting of data (eCRF), follow up, data extraction and statistic analysis, in collaboration with the Centre d’Investigation Clinique et Innovation Technologique (CIC-IT) of the Garches Hospital. We expect to start recruiting by the fall 2013. As the novel protocol spans 14 months, the first patients should complete the trial by the end of 2014 prior to the end of the Endostem project.
2)Pre-clinical development
As part of the development of novel therapeutics, Cripto has been selected as relevant candidate to enter preclinical preparation which has been demonstrated to promote repair by activation of satellite cells in the absence of other external stimuli. Data indicate that Cripto expands the pool of transient amplifying myoblasts.
The project has identified and characterized several stem populations in the muscle tissue, such as PW1-positive interstitial cells (PICs) or FibroAdipogenic progenitors (FAPs) in the aim of identifying new pathways and therapeutics that could lead to a better regeneration.
It was shown that PICs produce follistatin that promotes satellite cell proliferation and further blocks the activity of myostatin, and that PICs are preferentially recruited following myostatin inhibition. In addition, exposure to soluble myostatin antagonist prior to muscle damage rescues regenerative capacity in a model in which satellite cells have been reduced by 95%. This suggests that myostatin inhibition results in the activation of PICs which in turn promote a favorable environment for myoblast recruitment and commitment, and that the local muscle stem cell environment can be modified to promote regeneration in the absence or severe depletion of canonical stem cells.