EXHIBIT NO. 1009 Page 1
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` AMNEAL
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` EXHIBIT NO. 1009 Page 2
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` AMNEAL
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` EXHIBIT NO. 1009 Page 3
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` AMNEAL
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` EXHIBIT NO. 1009 Page 4
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` AMNEAL
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` EXHIBIT NO. 1009 Page 5
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` AMNEAL
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` EXHIBIT NO. 1009 Page 6
`
` AMNEAL
`
`

`
`COPOLYMER 1 IN RELAPSING—REMITTING MULTIPLE SCLEROSIS 217
`
`Table 25.3. M Adverse effects of copolymer 1 occurring
`
`at ieast 5"/oiofthe patients
`
`No. of patients reporting
`at least once
`
`% patients reporting at
`least once
`
`Injection-site reactions
`Systemic post-injection reaction*
`Systemic (other)1
`Asthenia
`Pruritus
`Dizziness
`
`*Temporar||y related to treatment administration. includes chest pain or flushing together with dyspnoea, peipitation and/or anxiety.
`ilncludes any of the above symptoms. appearing not in combination with the others.
`
`No clinically significant changes were noted
`in any of the routine laboratory examinations,
`including haematology, blood electrolytes, and
`liver and kidney function, as well as in a variety
`of other routine serum chemistry tests and
`
`Reiapses during study
`
`In the group of 107 patients who completed two
`years of
`treatment, 54.2 per cent remained
`relapse-free after two years (Table 25.4 and
`Figure 25.2), 23.4 per cent experienced one
`relapse and 12.2 per cent had two relapses. The
`
`D--B--Ci
`
`SPIR
`
`Percentageofpatients
`
`Months in trial
`
`Figure 25.1 Cumulative proportion of patients reporting adverse events as a function of time in trial. The data
`includes all patients enrolled (n=271). Results presented are for the total (AE). local and systemic post-injection
`reactions (SPIR).
`
`AMNEAL
`
`EXHIBIT NO. 1009
`
` AMNEAL
`
`

`
`218 FRONTIERS IN MULTIPLE SCLEROSIS
`
`annual relapse rate for the patients who com-
`pleted two years on treatment (n=107) dropped
`from 1.4 (:l:O.60) in the two years prior to study
`entry to 0.3 (:l:0.5) during the study. This repre-
`sents a 73.4 per cent reduction in annu_al relapse
`rate and is highly statistically significant (Wil-
`coxon, p=0.0001). The time to first relapse was
`10.3 (:l: 10.8) months. The majority of the patients
`developed their relapses during’ the first six
`months (Figure 25.2). The annual relapse rate
`during each succeeding year decreased (Figure
`25.3), with a concomitant increase in the propor-
`tion of relapse-free patients: while during the
`first year of treatment 69.2 per cent of the
`patients were relapse-free (74 of the 107 who
`were followed-up for at least two years), 77.6
`per cent (83 of 107) were relapse-free during
`the second year. This trend was also observed
`during the third year, where 84.4 per cent of the
`patients (38 of 45) were relapse-free.
`
`( n.me2s.4 ..;r;...;.,.-r...........t.a...i
`¢°'fiP'91€dfW¢’¥¢?f§l!'§1§!F$i¥
`1
`
`Number of relapses
`
`0 (Relapse-free)
`
`There was no statistically significant differ-
`ence in the number of on-study relapses
`reported by patients who withdrew from the
`study and those who continued treatment. As
`is apparent from the survival curves presented
`
`-’*‘""°"‘A Patients In trial
`
`0-—-0—0 Wllhdrawers
`
`
`
`Survivaldistribution
`
`12
`
`21;!
`
`30
`
`36
`
`Time to ilrst relapse (months)
`
`Figure 25.2 Kaplan—Meier analysis of the probability of remaining re|apse~free during treatment. Results are
`shown for patients in trial (n=140) and for patients who withdrew prematurely (n=131).
`
`AMNEAL
`
`EXHIBIT NO. 1009 Page 8
`
` AMNEAL
`
`

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` EXHIBIT NO. 1009 Page 9
`
` AMNEAL
`
`

`
`220 FRONTIERS IN MULTIPLE SCLEROSI5
`
`“"‘*“A Patients in trial
`
`0—0-0 Wlthdrawers
`
`
`
`Survivaldistribution
`
`12
`
`24
`
`Time to progression (months)
`
`Figure 25.4 Kaplan-Meier analysis of the probability of remaining progression-free during treatment. Progression
`was defined as a sustained (290 days) increase of at least 1 point on the EDSS. Results are shown for patients In
`trial (n=140) and for patients who withdrew prematurely (n=131).
`
`by the results of a multi-centre double-blind
`phase III trial recently completed in the US.”
`Another support for the validity of our results
`is the fact that the results for the four participat-
`ing centres in Israel are similar (data not shown).
`A most interesting observation was that over
`the course of
`treatment
`the proportion of
`patients remaining relapse-free increased, indi-
`cating that the beneficial effects of copolymer-1
`are maintained and even enhanced with time on
`treatment. Similar results were obtained in the
`double-blind phase IH trial.” The . reduced
`relapse rate and the fact that a large number of
`patients remained relapse-free, changed the
`quality of life of many subjects at a low cost of
`adverse reactions (13. Kott et al, unpublished
`data).
`In summary, we can conclude that copoly-
`mer-1 is a safe, well-tolerated medication and
`that the AEs observed are minor. Our results
`
`support and extend the safety and efficacy of
`copolymerl, reported in several controlled trials,
`for the treatment of RR MS.
`
`ACKNOWLEDGEMENTS
`
`The following persons contributed to the success
`of this multi-centre trial: Michal Mor RN, Harma
`Avrahami, Hadassah University Hospital, Ein
`Karem, Jerusalem. Jehuda Yochai RN, Bianca
`Gutman MD, Naomi_Shilman, Meir Hospital,
`Kfar-Saba. Emma Bakaleinik RN, Tel-Aviv Med-
`ical Center, Ichilov Hospital, Tel-Aviv. Leora
`Ben-Bassat, Assaf Harofeh Medical Centre, Zri-
`fin. Yafit Stark PhD, lrit Pinchasi PhD, Rivka
`Riven-Kreitman PhD, Paul Bendeheim MD,
`Shaul Kadosh MS, Haim Singal MS, Maria Gur-
`evich RN, Teva Pharmaceutical Industries Ltd,
`Pethah Tiqva, Israel.
`
`AMNEAL EXHIBIT NO. 1009 Page 10
`
` AMNEAL
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` EXHIBIT NO. 1009 Page 11
`
` AMNEAL