WO1995033475A1

WO1995033475A1 - Use of copolymer-1 for the manufacture of a medicament for the treatment of optic neuritis

Info

Publication number: WO1995033475A1
Application number: PCT/EP1995/002125
Authority: WO
Inventors: Edna Kott; Anat Kesler
Original assignee: Yeda Research & Development Company Limited; Orvet Bv
Priority date: 1994-06-06
Filing date: 1995-06-05
Publication date: 1995-12-14
Also published as: AU2787495A; CA2192218A1; IL113992A0; GB9411292D0; EP0767672A1; JPH10500695A; ZA954469B

Abstract

Use of copolymer-1 to treat visual impairments associated with multiple sclerosis.

Description

USE OF C0P0LYMER-1 FOR THE MANUFACTURE OF A MEDICAMENT

FOR THE TREATMENT OF OPTIC NEURITIS FIELD OF INVENTION

The present invention relates to the use of copolymer-1 in 5 treating visual impairments associated with multiple sclerosis .

PRIOR ART

Throughout this application, various references are referred to. 10 Disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains.

Multiple sclerosis (MS) is a slow progressive CNS disease

15 characteri..ed by disseminated patches of demyelination in the brain and spinal cord, resulting in multiple and varied neurological symptoms and signs, usually with remissions and exacerbations (relapses) . A common symptom prior to diagnosis of MS is some degree of visual impairment,frequently optic neuritis

20 or retrobulbar optic neuritis. Alternatively, these and other visual impairments may only develop after a diagnosis of MS has been confirmed. These symptoms may also develop during the progression of the disease alongside other associated visual problems.

25

Several studies have concentrated on assessing whether optic neuritis is a reliable predictor of multiple sclerosis (Cohen MM et al., Neurology (1979) .29. 208-213, Rizzo JF et al., Neurology (1988) 28_.185-199, Beck R et al., Neurology (1992) 42.1133-1135

30 and New Eng J Med (1993) 326 581-588).

Copolymer-1 is a synthetic polypeptide analog of yelin basic protein (MBP) , which is a natural component of the myelin sheath. It has been suggested as a potential therapeutic agent~^"for '3.5 multiple sclerosis (E r. J. Immunol. [1971] 1:242; and J. Neurol. Sci. [1977] 31:433). Copolymer-1 was developed by Drs. Sela, Arnon, and their co- workers at the Weizmann Institute (Rehovot, Israel) . It has been shown to be beneficial for patients with the exacerbating- remitting form of multiple sclerosis (N. Engl. J. Med. [1987] 317: 408) .

SUMMARY OF THE INVENTION

It has recently been observed that patients when treated with copolymer-1 have a lower than expected chance of suffering from visual impairments. This is believed to be of considerable advantage to the general well-being of such patients.

Thus, the present invention relates to the use of copolymer-1 in the manufacture of a medicament for the treatment of visual impairment associated with multiple sclerosis.

In an alternative embodiment the invention relates to the use of copolymer-1 in the manufacture of a medicament for the treatment of optic neuritis.

The present invention includes a method of treating a patient suffering from visual impairment related to multiple sclerosis, comprising administering to said patient a therapeutically effective amount of copolymer-1.

The present invention further includes a method of treating a patient suffering from optic neuritis, comprising administering to said patient a therapeutically effective amount of copolymer- 1.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

According to the present invention treatment with copolymer-1 may result in a prevention of any deterioration in visual impairment associated with MS, or in a reduction in the rate of such deterioration. Said treatment may also result in an improvement in vision. Examples of the types of visual impairment associated with MS include deteriorations in visual acuity, state of the optic disc, pupil reaction, visual field and ocular motility. Particular conditions that are associated with visual impairment in MS include optic neuritis, retrobulbar optic neuritis, diplopia, dimness of vision and scotomas.

Similarly in the treatment of optic neuritis, treatment with copolymer- 1 may result in prevention of further episodes of optic neuritis, delaying of further episodes or return vision to an unimpaired state.

Copolymer-1 , according to the present invention, may be prepared by methods known in the art, for example, the process disclosed in US

Patent 3,849,550, wherein the N-carboxyanhydrides of tyrosine, alanine, -benzyl glutamate and E-N-trifluoro-acetyllysine are polymerised at ambient temperature in anhydrous dioxane with diethyiamine as initiator. The deblocking of the y-carboxyl group of the glutamic acid is effected by hydrogen bromide in glacial acetic acid and is followed by the removal of the trifluoroacetyl groups from the lysine residues by 1 M piperidine. As used herein the terms "ambient temperature" and "room temperature" are used to indicate temperatures from about 20°C to about 26°C.

Compositions of use in the present invention may be formulated by conventional methods known in the art. Preferably, the composition is lyophilized and formed into an aqueous solution suitable for sub¬ cutaneous injection, preferably copolymer-1 is formulated with mannitol. Alternatively, copolymer- 1 may be formulated in any of the forms known in the art for preparing oral, nasal, buccal, or rectal formulations of peptide drugs.

Typically, copolymer- 1 is administered daily to patients at a dosage of 20mg.

The invention will be exemplified but not necessarily limited to the following Examples. EXAMPLE 1

Preparation of Trifluoroacetyl-Copolymer-1

Protected copolymer-1 is prepared as described by Teitelbau et al. Eur. J. Immun. Vol. 1 p. 242 (1971) from the N- carboxyanhydrides of tyrosine (18g) , alanine (50g) , 7-benzyl gluta ate (35g) and trifluoroacetyllysine (83g) dissolved in 3.5 liters of dioxane.

The polymerization process is initiated by the addition of 0.01 - 0.02% diethylamine. The reaction mixture is stirred at room temperature for 24 hours and then poured into 10 liters water. The product (protected copolymer-1) is filtered, washed with water and dried. The removal of the gamma-benzyl blocking groups from the glutamate residue is carried-out by treating the protected copolymer-l with 33% hydrobromic acid in glacial acetic acid at room temperature for 6-12 hours with stirring. The product is poured into excess water, filtered, washed and dried, yielding the trifluoroacetyl-copolymer-1.

Deprotection of copolymer-l

20g of trifluoroacetyl-copolymer-1 are dispersed in 1 liter of water to which lOOg piperidine are added. The mixture is stirred for 24 hours at room temperature and filtered. The solution of crude copolymer-l is distributed into dialysis bags and dialyzed at 10°-20°C against water until a pH=8 is attained. It is then dialyzed against about 0.3% acetic acid and again water until a pH=5.5-6.0 is obtained. This solution is then concentrated and lyophilized to dryness. EXAMPLE 2

Assessment of visual impairment in patients suffering from multiple sclerosis

5 Patients were recruited into the study having fulfilled the following criteria;

- be 18 to 50 years of age,

- have definite MS as defined by Poser et al. (Ann. Neurol. (1983) 13. 227-231) ,

10 - be of the relapsing-remitting or relapsing-progressive type when admitted to the trial,

- have objective evidence of neurological disease that reflects predominantly white matter damage, and

- have had at least two well documented attacks in the two-year 15 period leading up to study entry.

Copolymer-l was administered sub-cutaneously at a daily dose of 20mg, formulated in 40mg of mannitol.

20 Parameters of visual impairment were measured in the opthalmically acceptable manner as known in the art. Visual impairment was assessed at six monthly intervals and the total change over the two year period examined.

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Results

61 patients completed the full two years of the study. Of these patients, 29 did not experience any relapse of MS during the two 30 years.

Out of the patients experiencing a relapse, of MS whilst being > treated with copolymer-l, those who had previous experience of optic neuritis (ON) had a 50% chance of having a further ON v35 experience; Patients who had no previous history of ON had. a 1 in 14 chance of developing ON. These chances are considerably lower than would normally have been expected had these patients not been receiving copolymer-l.

Table 1 below shows that in all visual parameters assessed there was a prevention in the deterioration in visual impairment and in many instances there was an improvement as compared to the degree of visual impairment at the commencement of the study. (RE= right eye, LE= left eye)

Table 1

Improved No Worsened Total change tested

Visual RE 8 43 6 57 acuity

LE 9 44 4 57

Optic RE 11 38 10 59 Disc

LE 15 40 4 59

Pupil RE 11 40 8 59 Reaction

LE 7 46 6 59

Visual RE 6 53 0 59 Field

LE 4 53 2 59

Ocular RE 2 53 6 61 Motility

LE 2 54 5 61

Claims

1 . The use of copolymer-1 in the manufacture of a medicament for the treatment of visual impairment associated with multiple sclerosis.

2. The use of copolymer-l in the manufacture of a medicament for the treatment of optic neuritis.

3. The use of copolymer- 1 in the manufacture of a medicament for the treatment of visual impairment associated with optic neuritis.

4. The use of copolymer- 1 in the manufacture of a medicament for use in slowing the deterioration of visual impairment in optic neuritis.

5. A method of treating a patient suffering from visual impairment related to multiple sclerosis, comprising administering to said patient a therapeutically effective amount of copolymer-1 .

6. A method of treating a patient suffering from optic neuritis, comprising administering to said patient a therapeutically effective amount of copolymer-1 .

7. The use according to any of Claims 1 to 4 wherein the medicament contains 20mg copolymer-1 .

8. The method according to any of Claims 5 to 6 comprising daily administration of 20mg copolymer-1 .