Transactions of the
`AMERICAN NEUROLOGICAL
`ASSOCIATION
`1980
`
`Roger C. Duvoisin, M.D.
`
`Editor
`
`SPRINGER PUBLISHING COMPANY, NEW YQRK
`
`
`Page 1 of 5
`
`YEDA EXHIBIT NO. 2014
`MYLAN PHARM. v YEDA
`IPR2014-00644
`
`

`

`Please address all orders to:
`
`Springer Publishing Company
`200 Park Avenue South
`New York, N.Y. 10003
`
`No part of this publication may be reproduced, stored in a
`retrieval system, or transmitted, in any form or by any means,
`electronic, mechanical, photocopying, recording, or otherwise,
`without the prior permission of Springer Publishing Company, Inc.
`
`Copyright @ 1981 by The American Neurological Association
`
`Library of Congress Catalog Card Number: 61-705
`Standard Book Number: 0-8261-0480-0
`
`SPRINGER PUBLISHING COMPANY, INC.
`200 Park Avenue South, New York, N.Y. 10003
`
`Printed in the United States of America
`
`
`Page 2 of 5
`
`YEDA EXHIBIT NO. 2014
`MYLAN PHARM. v YEDA
`IPR2014-00644
`
`

`

`I
`
`I
`
`I
`
`/
`
`I (
`
`"
` lll
`1;
`I I
`" 1%
`/ I1
`:
`'I/
`Pi 1 I
`I; 1;
`
`I
`
`f
`
`I
`
`11
`; IC
`I
`
`Treatment of Multiple Sclerosis with a Synthetic Polypeptide2
`Preliminary Results*
`
`MURRAY B. BORNSTEIN AARON E. MILLER
`
`Bronx, New York
`
`Rehovot, Israel
`
`A synthetic polypeptide (MW 23,000) composed of alanine, glutamic acid,
`lysine, and tyrosine in a molar ratio of 6.0: 1.9:4.7: 1.0, has been demon-
`strated to be nonencephalitogenic and essentially nontoxic in laboratory ani-
`mals. However, it has been shown to be capable of suppressing acute experi-
`mental allergic encephalomyelitis (EAE) in animals challenged with whole
`CNS tissue or myelin-basic protein in complete Freund's adjuvant. These
`studies have included guinea pigs and rabbits (Teitelbaum et al., Eur. J.
`Immunol. 3:273, 1973), monkeys (Teitelbaum et al., Clin. Immunol. Zm-
`munopath. 3:256, 1974), and baboons (Teitelbaum et al., Israel J. Med.
`Sci. 13:1038, 1977). More recently, it has been shown to suppress ohronic
`relapsing EAE in guinea pigs (Keith et al., J. Neurol. Sci. 42:267, 1979).
`In addition, the polypeptide, called Copolymer I (COP I), was given to 3
`patients with acute disseminated encephalomyelitis (ADE) and 4 patients
`in the terminal stages of multiple sclerosis (MS) (Abramsky et al., J. Neurol.
`Sci. 31 :433, 1977). The ADE patients recovered completely within 3 weeks.
`Two of the MS patients showed "some improvement in vision and speech
`capacity." No significant undesirable side reactions were observed.
`About 2 years ago, the FDA granted permission for the first phase of
`clinical feasibility trials of COP I in MS patients. Three questions were to
`be asked: (1) Were there any apparent undesirable side reactions to the ex-
`posure of MS patients to COP I? (2) Were there any apparent favorable
`effects produced by COP I? (3) Could a dosage schedule be established
`for future trials should they be indicated?
`Sixteen patients participated in this phase of the trials--4 of the exacerbat-
`ing-remitting ( E R ) type and 12 of the chronic-progressive (C-P). There
`were 6 males and 10 females ranging in age from 23 to 49. They varied in
`degree of disability from 1 to 8 on the Kurtzke scale. All patients received
`the COP I in an open trial, and all knew that they were being given the
`substance.
`* Supported by NINCDS grant No. NS 11920.
`348
`
`
`Page 3 of 5
`
`YEDA EXHIBIT NO. 2014
`MYLAN PHARM. v YEDA
`IPR2014-00644
`
`

`

`Bornstein et al. - Treatment of MS with Synthetic Polypeptide 349
`
`~
`
`At fist, patients were hospitalized for 3 weeks at the institution of COP
`I treatment, but this was soon discontinued in view of the absence of any
`signs of undesirable side reactions. The dosage schedule varied at different
`times during the course of the trial. In the beginning, the plan was to give
`5 mg in 1 ml of saline i.m., 5 times a week for 3 weeks, 3 times a week for
`3 weeks, twice a week for 3 weeks, and then once a week for a total period
`of 6 months. During the early phases of the study, patients reported and
`demonstrated improvement in a number of different areas of neurological
`function such as balance, vision, gait, bladder control, tremor, strength, and
`sensory involvement. However, in time and as the dosage was decreased,
`signs and symptoms returned to previous levels and, in most cases, continued
`to progress. During the succeeding months, the dosage of COP I was grad-
`ually increased until most patients were being given 20 mg in 1 ml of sterile
`saline i.m. daily. The overall results to date are as follows:
`
`1. No significant undesirable side reactions have been reported or observed.
`Some patients had a transient eosinophilia, reaching 16% in one in-
`stance.
`2. Two E-R and 2 C-P patients improved. The 2 E-R patients experi-
`enced a remarkable cessation of their previously recurrent exacerbations;
`and 1, a reduction of enduring symptoms. Recently, both have experi-
`enced an atypically brief and mild episode. Of the 2 C-P patients, 1 has
`been arrested and possibly improved after a 5-year progressive course.
`The other continued her previous chronic progression during the k s t 4
`months of treatment and was finally confined to a wheelchair. However,
`she then began 'to improve and, on continuting treatment, now walks with
`little if any difficulty. However, she still tires easily.
`
`All other patients have continued to follow their previous courses.
`
`At present, these studies are being extended into a placebo-controlled, '
`double-blind, randomized clinical trial involving a total of 40 E-R patients.
`At a dosage of 20 mg of COP I in 1 ml. of saline or saline alone daily, for
`a period of 2 years, the questions being asked are: (1) Whether there is a
`significant decrease in the incidence of attacks. (2) Whether there is a sig-
`nificant decrease in the severity and duration of attacks. (3) Whether there
`is a difference in the progression of disability over the 2-year period.
`
`DISCUSSION
`
`DAVID PLEASURE (Chairman): Dr. Abramsky is in the audience and mentioned
`that he had some further experience with the copolymer. I wonder if he would like
`to make a comment.
`ODED ABRAMSKY (Jerusalem, Israel) : Drs. Knowlton, Teitelbaum, and Sela from
`
`
`Page 4 of 5
`
`YEDA EXHIBIT NO. 2014
`MYLAN PHARM. v YEDA
`IPR2014-00644
`
`

`

`350 Bornstein et al. - Treatment of MS with Synthetic Polypeptide
`
`the Weitman Institute asked us a couple of years ago to try COP I in a few patients
`with multiple sclerosis. We gave COP I to 11 patients with chroni~progressive or chron-
`ic-relapsing disease. It was not a double-blind study. We saw two or three remissions
`but we could not say they were due to the COP I. Two patients with severe disease
`died within 1 to 3 years. Two other patients suffered a relapse during the time of treat-
`ment. We discontinued the treatment and later administered it again, and the patient
`got a second relapse. During that time the in vitro lymphocyte transformation was posi-
`tive with both COP I and myelin-basic protein. I cannot say whether the relapses and
`lymphocyte transformation were the result of the COP I treatment. But, in any case,
`we discontinued the trial.
`STANLEY KOVAN (Washington, D.C.): If there is no apparent toxic effect of this
`polypeptide, and if lowering the dose seems to cause reexacerbation of symptoms in
`some patients, why not raise the dose you're giving to the patients who aren't re-
`sponding?
`MURRAY BORNSTEIN: That's a good question. It really is very difficult to deter-
`mine what a proper dosage should be. Sometimes I feel very strongly that we may
`be underdosing the patients. But we have, in fact, 4 patients who are better, and I
`think that's a reasonable dose to continue to see whether or not this treatment is going
`to be effective.
`AUGUSTUS ROSE (Los Angeles, California): Murray, what is the theoretical basis
`for the use of this material?
`MURRAY BORNSTEIN: The theoretical basis, as I understood it, was that this ma-
`terial would increase the suppressor T-cell population. We have just gotten our cell
`sorter and we will surely be looking at that question. I really don't know whether that
`hypothesis will work or not. If it doesn't work out, we'll have to find some other
`hypothesis. I really don't care what the hypothesis is if the patients get better.
`
`Association with Autoimmune Diseases and Cellular Immune Response
`to the Neuritogenic Protein in Guillain-Barrk Syndrome
`
`Jerusalem, Israel
`
`Rehovot, Israel
`
`Fifty-one patients (26 females and 25 males) with Guillain-BarrC syndrome
`(GBS) were hospitalized in the Department of Neurology, Hadassah-Hebrew
`University Hospital, during the years 1963-1979. Forty-four (86.3%) had
`an acute monophasic episode (AM-GBS), and 7 (13.7%) had a chronic
`and/or relapsing course (CR-GBS) . The clinical, laboratory, and electro-
`diagnostic criteria were according to the definitions of the ad hoc NINCDS
`committee (Ann. Neurol. 3:565, 1978). Seven patients (13.7%; 6 females
`and 1 male), with AM-GBS, had associated autoimmune diseases.
`
`
`Page 5 of 5
`
`YEDA EXHIBIT NO. 2014
`MYLAN PHARM. v YEDA
`IPR2014-00644
`
`