Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Food or edible as carrier for pharmaceutical
Reexamination Certificate
2001-01-25
2003-02-04
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Food or edible as carrier for pharmaceutical
C424S400000, C424S464000
Reexamination Certificate
active
06514519
ABSTRACT:
The invention relates to edelfosine (INN; 1-octadecyl-2-methyl-sn-glycero-3-phosphocholine, frequently also referred to as ET180CH3) for the treatment of primary and secondary brain tumors originating from solid and nonsolid tumors.
Permanent cure of a malignant brain tumor is, according to the present state of knowledge, impossible, i.e. there are at present no curative therapeutic approaches to malignant gliomas. The aim is always individual treatment taking account of any losses of function by surgical procedures and a prolongation of the survival time with the best possible quality of life.
The incidence of brain tumors is continuing to increase and becomes more marked as people age. Thus, for example, the average incidence is 1.8/100,000 people 15-24 years of age but about 18.4/100,000 of those 65-79 years of age. The age peak is between 55 and 73 years, although increasing numbers of young patients with glioblastomas have been recorded in recent years. The annual incidence of a primary brain tumor in Germany is about 7000 people, of whom most die within the first year. Despite surgery and irradiation, the people survive on average for only 11 months. The tumor has by then become so large, and such large amounts of fluids have escaped that the brainstem is crushed and functions important to life fail.
The tumors which occur most commonly originate from astrocytes, ependymocytes and oligodendrocytes. The prognosis of brain tumors in principle is poor. Malignant gliomas are the most widespread brain tumors, and of these in turn gliobastoma multiforme and anaplastic astrocytoma, which together account for about 80% of all malignant gliomas, have the poorest prognosis. Especially with these tumors only partial resection is frequently possible.
The currently available nonsurgical therapeutic options—irradiation and chemotherapy—are all associated with adverse drug reactions, some of which are severe, which represents a limiting factor especially for chemotherapeutic approaches for an increasingly aging population with multiple pathologies.
One of the main problems is, however, the fact that recurrence of these tumors is unavoidable even with, or despite, the use of aggressive therapeutic regimen. Long-term therapy with chemotherapeutics is not possible because of the toxicity of these substances, and repeated use is not worthwhile because the response rates then approach zero. The limit for radiation exposure is likewise reached relatively quickly if it is intended to treat even the primary tumor effectively. Thus, the situation is still such that after completion of the first therapeutic regimen it is necessary to “wait” until there has been renewed occurrence. Even the most frequent checks are unable to alter this in any way.
In principle, primary brain tumors are categorized as tumors for which even now there are no effective, curative therapeutic approaches. In a very recent decision in Italy, malignant gliomas were even categorized as an orphan drug indication because effective therapeutic approaches are lacking. An additional factor is that of the approx. 2,000,000 cancers reported annually around the world, 800,000—which is 40%—are a priori resistant to chemotherapy, and thus real alternative therapies are still required even more urgently than ever.
Therapeutic Approaches Currently in Use
Malignant brain tumors are among the most malignant tumors of all; their prognosis is unfavorable. Even with a combination of surgery, irradiation and chemotherapy, the survival time from the date of diagnosis of patients with highly differentiated gliomas is usually less than one year.
Surgical removal of a malignant tumor with total removal of the tumor, i.e. with the objective of cure, is always the therapy of choice. However, inoperability frequently pertains; thus, for example, of all astrocytomas diagnosed, only a little more than 20% are operable, and only partial resection is possible in most cases.
The only possibility remaining is therefore often radioactive irradiation, which is, however, likewise associated with side effects and has the disadvantage of a therapy which can be used only locally. Most tumor foci have an edge with distinct margins which can be visualized even by computed tomography (CT) or magnetic resonance imaging (MRI), so that inevitably a considerable portion of healthy tissue must be included in the area to be irradiated. The tolerance or lack of resistance of this healthy tissue is therefore the limiting factor. However, since the local treatment modalities are becoming increasingly aggressive, an increase in radiation-induced damage must be assumed. This comprises either 1. acute reactions: development of an edema within a few hours, accompanied by headaches, nausea/vomiting, somnolence, fever, deterioration in neurological symptoms; 2. early delayed reactions: a few weeks to 4 months after irradiation owing to temporary demyelinization or radiation-induced change in the permeability of the capillaries; is manifested by temporary neurological deterioration, somnolence and focal (focal=originating from a focus) encephalopathy; 3. late reactions: several months to years after the treatment. These are in fact the most severe and are manifested by strokes, neuropsychological disorders, dementia, atrophy of the cerebral cortex (in up to 39% of patients with whole brain irradiation).
Chemotherapies are in principle used only in the form of an adjuvant therapy, i.e. immediately after surgical removal of the tumor. However, chemotherapy almost always fails for brain tumors because the blood-brain barrier—a natural barrier to toxins and pathogens—prevents the penetration of most drugs into the brain. Although there are some medicines (substances predominantly from the nitrosourea class) able to overcome the blood-brain barrier, their effect is extremely controversial. Correspondingly, it has not yet been possible to establish a standard chemotherapy. The WHO accordingly classifies brain tumors as tumors which are insensitive or only extremely marginally sensitive to cytotoxic treatment.
Even the most recently developed drugs do not denote a genuine advance in the sense of novel molecular therapeutic approaches. The cytostatic carmustine, a nitrosourea derivative, is implanted in the form of medicine-impregnated wafers into the tumor cavity even during the operation but, even then, shows only a moderate effect or none. Apart from this, it can be used only for operable cases. In addition, this cytostatic if given systemically has, as a molecule with a nonselective effect like all known cytostatics, a harmful effect on the body's normal cells, i.e. its use is associated with corresponding unwanted side effects (such as, for example, genetic damage, pulmonary toxicity, myelosuppression inter alia). This also applies to other cytostatics occasionally used for treating brain tumors, such as “procarbazine”, “cyclophosphamide”, “vincristine”. In many treatment centers, therefore, patients with glioblastomas and poor prognostic criteria are excluded from chemotherapy from the outset.
Because the activity of the known cytostatics is in principle lacking or, at the most, moderate for primary or secondary brain tumors, in the final analysis the question of whether cytotoxic substances are able to overcome the blood-brain barrier or not is purely academic (cf. DeVita & al. 1997, p. 2041).
REFERENCES:
patent: 5925669 (1999-07-01), Katz et al.
patent: 6235729 (2001-05-01), Chen et al.
W. J. Zeller et al., “Interstitial chemotherapy of experimental gliomas”,Cancer Treatment Reviews, 17:2-3:183-189 (Sep. 1990).
Olav Engebraaten et al., “Effect of alkyl-lysophosphospholipid on glioblastoma cell invasion into fetal rat brain tissue in vitro”,Cancer Research, 51(6): 1713-1719 (1991).
Wolfgang, E. Berdel et al., “Cytotoxicity of alky-lysophospholipid derivatives and low-alkyl-cleavage enzyme activities in rat brain tumor cells”,Cancer Research, 43(2):541-545 (1983).
Wolfgang E. Berdel et al., “Cytoxic effects of alky-lysophospholipids in human brain tumor cells”,Onco
Evans Claresse
Fulbright & Jaworski
Med-Mark Pharma GmbH
Page Thurman K.
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