Alzheimer : 2 phases --- lien

New clinical trials of masitinib for Alzheimer's disease

Friday 08 February 2013

French biotech company AB Science has begun recruitment for two new studies of its masitinib molecule for Alzheimer's disease.

The first is a phase 3 study in people with mild to moderate Alzheimer's disease. This will compare the safety and efficacy of masitinib or placebo during 24 weeks, in addition to a stable dose of cholinesterase inhibitors and/or memantine. During a phase 2 study, Masitinib demonstrated statistically significant improvement on the ADAS-Cog scale (see weblink below).

The other trial is a phase 1 pharmacokinetics study that will evaluate the impact of masitinib on the pharmacokinetic profile of galantamine and donepezil.

Masitinib is a tyrosine kinase inhibitor (TKI) that is typically used in cancer drugs. AB Science is also running phase 2/3 trials of masitinib for various cancers, inflammatory diseases and Multiple
Sclerosis.


http://www.alzheimer-europe.org/News/Science-Watch/Friday-08-February-2013-New-clinical-trials-of-masitinib-for-Alzheimer-s-disease

http://www.faqs.org/patents/app/20130072474

nouveau lien trés interessant

dont ça:

autres sources:

http://www.freepatentsonline.com/y2013/0072474.html

sur la phase II alzheimer qui a mené à la phase III

Conclusion

This exploratory double-blind, multicenter, randomized, phase 2 study, was conducted in a limited number of patients suffering from mild to moderate Alzheimer's disease who were treated with masitinib at a starting dose of 3 or 6 mg/kg/day or placebo, in association with the current standard of care in Alzheimer's disease, i.e. a acetylcholinesterase inhibitor and/or the NDMA inhibitor memantine.

In this study, masitinib shows efficacy in the treatment of patients suffering from mild to moderate Alzheimer disease, particularly in the improvement of cognitive functions (ADAS-Cog score over placebo), and the functional domain (statistically significant improved ADCS-ADL score over placebo). A statistically significant improvement was also obtained with masitinib on the MMSE and CDR scores.

Analysis of the safety data shows that the tolerance of masitinib in phase 2 study in this elderly population suffering from Alzheimer's disease is similar to that observed in other non-oncology indications. In particular, the profile of the most frequent AEs reported (edema, nausea/vomiting, rash, diarrhea) is similar to those observed in other phase 2 non-oncology studies and can be explained by the mechanism of action of masitinib. Anorexia is probably the consequence of digestive disorders. No patients died and nine of the masitinib-treated patients (35%) withdrew from their treatment due to masitinib-related AEs. Of note, the majority of AEs were mild to moderate in intensity, and the incidence and frequency was similar in the two treatment arms (3.0 and 6.0 mg/kg/day).

In conclusion, these results and the risk/benefit balance in this indication are promising for treatment of human patients with mild to moderate Alzheimer's disease with masitinib at 3.0 to 6.0 mg/kg/day in association with a acetylcholinesterase inhibitor and/or memantine.

y'a tout ce qu'il faut avant sur l'etude avec stats et tout
Me semble que ça a jamais été post
recommander 0 reporter un abus

Réponses au sujet
Participer

Bouli13 19:12 - 23.09.2013
autres parties intéressantes:

Masitinib was first described in U.S. Pat. No. 7,423,055 and EP1525200B1. A detailed procedure for the synthesis of masitinib mesilate is given in WO2008/098949.

Aberrations in cell signaling pathways are the cause of many human and animal proliferative diseases and many human inflammatory diseases. Protein tyrosine kinases play a fundamental role in signal transduction and deregulated activity of these enzymes has been observed in cancer, benign proliferative disorders, and in inflammatory diseases. Therefore, specific inhibitors of tyrosine kinases could have potential therapeutic applications in proliferative and inflammatory pathologies.

Protein tyrosine kinases are classified into sub-groups with similar organization and sequence similarity within the kinase domain. They can be associated with receptors in the cell membrane or have an intracellular location. c-Kit is an example of a receptor tyrosine kinase.

Role of c-Kit and Mast Cells in Inflammatory Diseases

Mast cells (MCs) are predominantly found in tissues at the interface between the host and the external environment, such as lung, connective tissue, lymphoid tissue, gut mucosa, and skin. Immature MC progenitors circulate in the bloodstream and differentiate in tissues. These differentiation and proliferation processes are under the influence of cytokines; one of utmost importance is stem cell factor (SCF), also termed Kit Ligand (KL), Steel factor or Mast Cell Growth Factor (MCGF). The SCF receptor is encoded by the proto-oncogene c-Kit.

c-Kit encodes a hematopoietic growth factor (HGF) receptor with tyrosine kinase activity. Kit receptor activity appears essential for the development of melanoblasts, germ cells as well as hematopoietic cells. The W (White Spotting) and Sl (Steel) loci encode Kit and its ligand, SCF, respectively, and mutations in these genes cause pigmentation defects, infertility and deficiencies in the hematopoietic system, including decreased numbers of MCs. It has been shown that SCF regulates the migration, maturation, proliferation, and activation of MCs in vivo. Binding of SCF to the c-Kit receptor induces c-Kit dimerization followed by its transphosphorylation, leading to the recruitment and activation of various intracytoplasmic substrates. These activated substrates induce multiple intracellular signaling pathways responsible for cell proliferation and activation.

“Normal” MC activation is followed by the controlled release of a variety of mediators that are essential for the defense of the organism against invading pathogens. By contrast, if hyperactivation of MCs occurs, uncontrolled hypersecretion of these mediators is deleterious for the body.

In vivo and in vitro studies suggest that human MCs are capable of expressing both pro- and anti-inflammatory cytokines, including TNF-α, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL-16, GM-CSF, SCF, basic fibroblast growth factor (bFGF), transforming growth factor beta (TGF-β) and many chemokines such as macrophage inflammatory protein 1 alpha (MIP-1α), and monocyte chemotactic protein 1 (MCP-1).

Human MCs constitutively express a number of receptors for different biological molecules. Among these receptors, whose ligation induces the activation of MCs, the best known is the high affinity receptor for IgE (FccRI). Binding of IgE-multivalent antigen complexes to FceRI leads to receptor aggregation and internalization, signaling, and degranulation. This can be accompanied by the transcription of cytokine genes, thus, perpetuating the inflammatory response. Moreover, triggering of MCs leads to the secretion of diverse preformed and/or de novo synthesized mediators, such as vasoactive amines (histamine, serotonin), sulfated proteoglycans, lipid mediators (prostaglandin D2, leucotrienes), growth factors, proteases, cytokines and chemokines as described previously. These mediators can, either alone or in synergy with macrophage- and T cell-derived cytokines, generate a complex inflammatory response and can induce the recruitment and activation of inflammatory cells to the site of degranulation.

MCs thus play a prominent role in all inflammatory processes because they express receptors for molecules that are usually involved in such reactions and because they release large amounts of various mediators that sustain the inflammatory network. Molecules able to inhibit the survival and/or activation of MCs are being tested for the treatment of inflammatory diseases.

Examination of the brains of patients affected with AD reveals two microscopic changes: senile plaques develop between neurons, and neurofibrillary tangles develop within neurons. These changes are thought to be intricately related to the cause, development and course of the disease. Neurofibrillary tangles are made up partly of a protein called tau (τ), which links together to form filaments. The density of these filaments within neurons is directly related to the severity of dementia. It is unclear why tangles form and whether they are linked to plaque formation. Their ultimate effect, however, is compromised microtubular function, with destruction of the neuron.

It is speculated that inflammation around plaques destroys neighboring neurons. Plaques, which are composed of β-amyloid polypeptides are thought to form as a result of disorders in processing β-amyloid and its precursor protein (St George-Hyslop PH, 2000).

Inflammation surrounding β-amyloid plaques with resultant destruction of neurons is thought to be a key factor in the pathogenesis of AD. Observational studies have found that people who regularly use nonsteroidal anti-inflammatory drugs (NSAID) have a lower incidence of AD. Thus, NSAIDs are likely to have a neuroprotective effect. However, several studies of anti-inflammatory drugs do not show a benefit for treatment (Veld B A et al, 2001).

The abnormal phosphorylation of tau protein on serines and threonines is a hallmark characteristic of the neurofibrillary tangles of AD. The discovery that tau could be tyrosine phosphorylated together with evidence that Aβ signal transduction involved tyrosine phosphorylation, suggested that tyrosine phosphorylation of tau occurs during neurodegeneration (Lee et al, 2004). The authors showed that human tau tyr18 was phosphorylated by the Src family tyrosine kinase Fyn. Moreover, immunocytochemical studies indicate that tyrosine phosphorylated tau was present in the neurofibrillary tangles in AD brain. These data add new support for a role for Fyn in the neurodegenerative process (Lee et al, 2004).

In connection with the present invention, we recently discovered that masitinib inhibits the tyrosine kinase Fyn and we searched into its potential for use in the treatment of dementia of AD type.

We then investigated the effect of masitinib in clinical trials at several dosage regimens combined with NMDA (N-methyl-D-aspartic acid) receptor antagonist and/or acetylcholinesterase inhibitors in patients developing dementia associated with AD. We found a protective effect of masitinib allowing slowdown of disease progression in patients, especially in patients having low or moderate dementia of AD type, in particular in patients with MMSE between 12 to 25

Je poursuis avec le lien publié sur forum bourso (il faut chercher au milieu de la fange, heureusement qu'il y a quelques pseudos dignes) par m2biz :

http://www.biomedcentral.com/content/pdf/alzrt75.pdf

dans lequel on lit page 5 :
masitinib (AB-1010) AB Science USAShort Hills, NJ Alzheimer’s disease Phase III completed

Soit c'est une erreur (p II au lieu de III) soit c'est une vraie nouvelle.

pma