The assignee for this patent application is Teva Pharmaceutical Industries, Ltd.
Reporters obtained the following quote from the background information supplied by the inventors: "Multiple Sclerosis (MS) is a neurological disease affecting more than 1 million people worldwide. It is the most common cause of neurological disability in young and middle-aged adults and has a major physical, psychological, social and financial impact on subjects and their families, friends and bodies responsible for health care (EMEA Guideline, 2006).
"It is generally assumed that MS is mediated by some kind of autoimmune process possibly triggered by infection and superimposed upon a genetic predisposition. It is a chronic inflammatory condition that damages the myelin of the Central Nervous System (CNS). The pathogenesis of MS is characterized by the infiltration of autoreactive T-cells from the circulation directed against myelin antigens into the CNS (Bjartmar, 2002). In addition to the inflammatory phase in MS, axonal loss occurs early in the course of the disease and can be extensive over time, leading to the subsequent development of progressive, permanent, neurologic impairment and, frequently, severe disability (Neuhaus, 2003). Symptoms associated with the disease include fatigue, spasticity, ataxia, weakness, bladder and bowel disturbances, sexual dysfunction, pain, tremor, paroxysmal manifestations, visual impairment, psychological problems and cognitive dysfunction (EMEA Guideline, 2006).
"MS disease activity can be monitored by magnetic resonance imaging (MRI) of the brain, accumulation of disability, as well as rate and severity of relapses. The diagnosis of clinically definite MS as determined by the Poser criteria (Poser, 1983) requires at least two neurological events suggesting demyelination in the CNS separated in time and in location. A clinically isolated syndrome (CIS) is a single monosymptomatic attack suggestive of MS, such as optic neuritis, brain stem symptoms, and partial myelitis. Patients with CIS that experience a second clinical attack are generally considered to have clinically definite MS (CDMS). Over 80 percent of patients with a CIS and MRI lesions go on to develop MS, while approximately 20 percent have a self-limited process (Brex, 2002; Frohman, 2003).
"Various MS disease stages and/or types are described in Multiple Sclerosis Therapeutics (Duntiz, 1999). Among them, relapsing-remitting MS (RRMS) is the most common form at the time of initial diagnosis. Many subjects with RRMS have an initial relapsing-remitting course for 5-15 years, which then advances into the secondary progressive MS (SPMS) disease course. Relapses result from inflammation and demyelination, whereas restoration of nerve conduction and remission is accompanied by resolution of inflammation, redistribution of sodium channels on demyelinated axons and remyelination (Neuhaus, 2003; Noseworthy, 2000).
"In April 2001, an international panel in association with the National MS Society of America recommended diagnostic criteria for MS. These criteria became known as the McDonald Criteria. The McDonald Criteria make use of MRI techniques and are intended to replace the Poser Criteria and the older Schumacher Criteria (McDonald, 2001). The McDonald Criteria was revised in March 2005 by an international panel (Polman, 2005) and updated again in 2010 (Polman, 2011).
"Intervention with disease-modifying therapy at relapsing stages of MS is suggested to reduce and/or prevent accumulating neurodegeneration (Hohlfeld, 2000; De Stefano, 1999). There are currently a number of disease-modifying medications approved for use in relapsing MS (RMS), which includes RRMS and SPMS (The Disease Modifying Drug Brochure, 2006). These include interferon beta 1-a (Avonex.RTM. and Rebif.RTM.), interferon beta 1-b (Betaseron.RTM.), glatiramer acetate (Copaxone.RTM.), mitoxantrone (Novantrone.RTM.), natalizumab (Tysabri.RTM.) and fingolimod (Gilenya.RTM.). Most of them are believed to act as immunomodulators. Mitoxantrone and natalizumab are believed to act as immunesuppressants. However, the mechanisms of action of each have been only partly elucidated. Immunosuppressants or cytotoxic agents are used in some subjects after failure of conventional therapies. However, the relationship between changes of the immune response induced by these agents and the clinical efficacy in MS is far from settled (EMEA Guideline, 2006).
"Other therapeutic approaches include symptomatic treatment which refers to all therapies applied to improve the symptoms caused by the disease (EMEA Guideline, 2006) and treatment of acute relapses with corticosteroids. While steroids do not affect the course of MS over time, they can reduce the duration and severity of attacks in some subjects.
"Thalamus and Thalamic Damage
"The human thalamus is a nuclear complex located in the diencephalon and comprising of four parts, the hypothalamus, the epythalamus, the ventral thalamus, and the dorsal thalamus. The thalamus is a relay centre subserving both sensory and motor mechanisms. Thalamic nuclei (50-60 nuclei) projects to one or a few well-defined cortical areas. Multiple cortical areas receive afferents from a single thalamic nucleus and send back information to different thalamic nuclei. The corticofugal projection provides positive feedback to the 'correct' input, while at the same time suppressing irrelevant information. Topographical organization of the thalamic afferents and efferents is contralateral, and the lateralization of the thalamic function affects both sensory and motoric aspects. Symptoms of lesions located in the thalamus are closely related to the function of the areas involved. An infarction or haemorrhage thalamic lesion and develop somatosensory disturbances and/or central pain in the opposite hemibody, analgesic or purely algesic thalamic syndrome characterized by contralateral anaesthesia (or hypaesthesia), contralateral weakenss, ataxia and, often, persistent spontaneous pain (Trinidad Herrero, 2002). Other diseases and conditions which have been associated with damage to the thalamus include movement disorders, dystonia, athetosis, chorea, tremor, jerky, myoclonic movements, involuntary movements, ataxia, pain, tremor, spasticity Alzheimer's disease, Huntington's disease, MS and Dejerine-Roussy syndrome (thalamic pain syndrome) (Kim, 2001; Jong, 2008; Kassubek, 2005; Tuling, 1999; Lee, 1994; Sheline, 2003, Torres, 2010; Stachowiak, 2007).
"Laquinimod is a novel synthetic compound with high oral bioavailability which has been suggested as an oral formulation for the treatment of MS (Polman, 2005; Sandberg-Wollheim, 2005). Laquinimod and its sodium salt form are described, for example, in U.S. Pat. No. 6,077,851.
"The mechanism of action of laquinimod is not fully understood. Animal studies show it causes a Th1 (T helper 1 cell, produces pro-inflammatory cytokines) to Th2 (T helper 2 cell, produces anti-inflammatory cytokines) shift with an anti-inflammatory profile (Yang, 2004; Bruck, 2011). Another study demonstrated (mainly via the NFkB pathway) that laquinimod induced suppression of genes related to antigen presentation and corresponding inflammatory pathways (Gurevich, 2010). Other suggested potential mechanisms of action include inhibition of leukocyte migration into the CNS, increase of axonal integrity, modulation of cytokine production, and increase in levels of brain-derived neurotrophic factor (BDNF) (Runstrom, 2006; Bruck, 2011). Laquinimod showed a favorable safety and tolerability profile in two phase III trials (Results of Phase III BRAVO Trial Reinforce Unique Profile of Laquinimod for Multiple Sclerosis Treatment; Teva Pharma, Active Biotech Post Positive Laquinimod Phase 3 ALLEGRO Results)."
In addition to obtaining background information on this patent application, NewsRx editors also obtained the inventors' summary information for this patent application: "This invention provides a method for inhibiting or reducing thalamic damage in a subject afflicted with a form of MS or presenting a CIS, comprising orally administering to the subject an amount of laquinimod so as to thereby inhibit or reduce thalamic damage in the subject, wherein the subject is a human patient who has been determined to have thalamic damage at baseline.
"This invention also provides a method for inhibiting or reducing thalamic damage in a subject afflicted with a disease or disorder other than a form of MS or a CIS, comprising administering to the subject an amount of laquinimod so as to thereby inhibit or reduce thalamic damage in the subject.
"This invention also provides a method for inhibiting or reducing tremor or spasticity in a subject afflicted by tremor or spasticity, comprising administering to the subject an amount of laquinimod so as to thereby inhibit or reduce the tremor or the spasticity in the subject.
"This invention also provides laquinimod for use in inhibiting or reducing thalamic damage in a human patient who has been determined to have thalamic damage at baseline.
"This invention also provides a pharmaceutical composition comprising an amount of laquinimod for use in inhibiting or reducing thalamic damage in a human patient who has been determined to have thalamic damage at baseline.
"This invention also provides laquinimod for use in inhibiting or reducing thalamic damage in a subject afflicted with a disease or disorder other than a form of MS or a CIS.
"This invention also provides a pharmaceutical composition comprising an amount of laquinimod for use in inhibiting or reducing thalamic damage in a subject afflicted with a disease or disorder other than a form of MS or a CIS.
"This invention also provides laquinimod for use in inhibiting or reducing thalamic damage in a subject not afflicted with a form of MS or presenting a CIS.
"This invention also provides a pharmaceutical composition comprising an amount of laquinimod for use in inhibiting or reducing thalamic damage in a subject not afflicted with a form of MS or presenting a CIS.
"This invention also provides laquinimod for use in inhibiting or reducing tremor or spasticity in a subject.
"This invention also provides a pharmaceutical composition comprising an amount of laquinimod for use in inhibiting or reducing tremor or spasticity in a subject.
BRIEF DESCRIPTION OF THE DRAWINGS
"FIG. 1 is a graph of Patient Disposition from Example 2. (*For technical reasons, baseline and/or post-baseline scans from two patients in the laquinimod arm and three patients in the placebo arm were not evaluable. These patients were excluded from this analysis.)"
For more information, see this patent application: Filippi, Massimo; ; Comi, Giancarlo; ; Rocca, Maria Assunta;. Laquinimod for Reducing Thalamic Damage in Multiple Sclerosis. Filed October 9, 2013 and posted April 24, 2014. Patent URL: http://appft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=2126&p=43&f=G&l=50&d=PG01&S1=20140417.PD.&OS=PD/20140417&RS=PD/20140417
Keywords for this news article include: Pain, Antibiotics - Antineoplastics, Pharmaceutical Companies, Brain, Drugs, Ataxia, Genetics, Thalamus, Dyskinesias, Diencephalon, Mitoxantrone, Neurosurgery, Therapeutics, Psychological, Neuroimmunology, Multiple Sclerosis, Demyelinating Diseases, Immune System Diseases, Neurologic Manifestations.
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