.,
`iia,7320022aaccsme
`
`Research and Clinical
`Forums
`
`fhe
`Er\\
`
`Peni
`
`VOLUME 20 NUMBER1 1998
`ISSN 0143-3083
`
`Naa
`
`WELLS MEDICAL
`ENGLAND
`
`Cosmo Ex 2009-p.1
`Mylan v Cosmo
`IPR2017-01035
`
`Cosmo Ex 2009-p. 1
`Mylan v Cosmo
`IPR2017-01035
`
`

`

`General Information
`
`Research and Clinical Fontms is an intemational joumal devoted to publishing, in the English language, material
`presented and discussed at medico-scientific and medico-therapeutic congresses and symposia, either in the form of
`selected and collated papers, or as full reports and proceedings. Each issue is devoted to one subject area and may
`consist of the proceedings of, or selected papers from, one particular meeting or may be a compilation of material
`which, while relating to a particular subject, may have been presented at a number of meetings.
`Material presented at congresses, symposia or meetings held anywhere in the world is considered for publication,
`the basic criterion for acceptance being the scientific and medical standard of the material. Each issue of Research and
`Clinical Forums is edited by an independent authority, or panel of assessors, expert in the relevant field. Views and
`factual claims expressed in individual contributions are personal to the respective contributor and are not necessarily
`endorsed by the Editors, Advisers, Assessors, Publishers, Distributors or Sponsors.
`Research and Clinical Forums is published periodically to demand, is distributed to medical schools, medical
`libraries, hospitals and research establishments world-wide, and to all information and retrieval systems.
`Where necessary, issues of Research and Clinical Forums will be translated into languages other than English and
`published as foreign language editions of those issues.
`
`Copyright © 1998 by
`Wells Medical Holdings Ltd
`Speldhurst Place, Speldhurst Road
`Royal Tunbridge Wells
`KentTN40JB
`England
`
`All rights reserved. This publication is copyright under the Berne Convention and the International Copyright
`Convention. Apart from any fair dealing under the UK Copyright Act 1956, Part 1, Section 7, no part of this publica(cid:173)
`tion may be reproduced, stored in a retrieval system or transmitted in any form or by any means without the prior
`permission of the Publisher.
`Although great care has been taken in compiling and checking the infom1ation given in this publication to ensure
`that it is accurate, the Publisher shall not be held responsible for the continued currency of the information or for any
`en·ors, omissions or inaccuracies in this publication. Due to the rapid advances in medical science, it is recommended
`that independent verification of diagnoses and drug dosages should be made. In addition, no responsibility is assumed
`by the Publisher for any injury and/or damage to persons or property arising from any methods, products, instructions,
`ideas or otherwise contained in this publication.
`
`,-(cid:173)
`
`Notes for Contdbutors see inside back cover.
`
`The Publishing Editor
`Research and Clinical Forums
`Speldhurst Place, Speldhurst Road
`Royal Tunbridge Wells
`KentTN40JB
`
`British Library Cataloguing in Publications Data
`Research and Clinical Forums
`Volume 20, No. 1
`1. Inflammatory Bowel Disease 2. Crohn's Disease 3. Ulcerative Colitis 4. Salicylates 5. Sulphasalazine
`610'.5 R31
`ISSN 0143-3083
`
`Research and Clinical Fonnns is in indexed in Directory of Published Proceedings, ExcerfJta Medica/EMBASE,
`Current Contents Proceedings- Medical, Biological, Agricultural and Index to Scientific ancl Technicai1Jrc1Ce(~c!n1.t:;SC!Y
`
`Cosmo Ex 2009-p. 2
`Mylan v Cosmo
`IPR2017-01035
`
`

`

`New data on inflammatory bowel disease treatment
`with topical steroids
`
`R. Lofberg, MD, PhD
`Departtnent of Gastroenterology
`Huddinge University Hospital
`Karolinska Institute
`Stockholm
`Sweden
`
`SUMMARY
`Glucocorticosteroids (GCSs) remain the mainstay primary treatment of active inflammatory
`bowel disease (IBD). These agents usually result in a rapid suppression of symptoms but due to
`the ubiquitous nature of the GCS receptor, they also cause systemic side-effects. Recently, new
`GCSs developed mainly for asthma ( eg., budesonide) have been found to counter the problem of
`systemic side-effects due to a greater first-pass metabolism and an increased affinity for the GCS
`receptor, resulting in a predominantly topical mode of action. Budesonide seems particularly
`suitable for IBD conditions. It has been developed for both rectal and oral delivery to the gut and
`has been shown to have good efficacy in both Crohn' s disease and ulcerative colitis with a mild
`side-effect profile.
`
`INTRODUCTION
`Effects and side-effects of glucocorticosteroids
`Glucocorticosteroids ( GCSs) remain the mainstay of medical treatment in active
`inflammatory bowel disease (IBD). The anti-inflammatory effects of GCSs in acute
`attacks of ulcerative colitis (UC) as well as in Crohn's disease (CD) are unsurpassed by
`any other type of drug and a rapid and substantial effect on clinical symptorns is usually
`seen during the first few days of treatment. Glucocorticosteroids exert their actions by
`binding to the intracellular GCS-receptor which is uniformly distributed in all types of
`human cells. Activation of the receptor will evoke a number of responses and effects,
`including inhibition of the production and action of ce~tain key pro-inflammatory
`cytokines.
`The anti-inflammatory effects of conventional GCSs in IBD are commonly offset by
`systemic side-effects: eg., cosmetic or psychological problems such as acne, moonface,
`striae and mood disturbances including insomnia. Others, like hypertension, dyspepsia
`and impaired glucose tolerance, may be of substantial clinical importance. Long-term
`treatment is precluded by the risk for hazardous and sometimes also irreversible
`complications such as osteoporosis and osteonecrosis, cataracts and diabetes mellitus.
`The suppression of endogenous cortisol levels and impairment of the hypothalamic(cid:173)
`pituitary-adrenal gland function, with delayed recovery, are other issues of concern.
`
`Cosmo Ex 2009-p. 3
`Mylan v Cosmo
`IPR2017-01035
`
`

`

`180
`
`R. LOFBERG
`
`Development of GCSs for topical action
`Recent steroid development, primarily aimed at refinement of topical inhalation therapy
`in asthma, has provided us with new GCS compounds such as budesonide and
`ftuticasone, which have 100-200 times higher affinity for the GCS receptor compared
`with hydrocortisone, enabling treatment with much reduced doses. If the drug is
`administered in the gut, the major portion will be cleared through the portal vein to the
`liver where it is, to a large extent, inactivated during the hepatic first,pass metabolism.
`The systemic availability of the new GCSs will therefore be substantially reduced
`compared with that of older GCSs, and this improved ratio of efficacy at the target level
`vs decreased systemic load is the pt:inciple on which new topical steroids for IBD rely1,2.
`Furthermore, other GCS prerequisites for optimal topical action in IBD conditions
`include sufficient water solubility for adequate distribution in the bowel lumen, a high
`mucosal uptake and deep penetration. These enhanced properties of new GCSs are
`dependent on the introduction of lipophilic substitutions in the 16,a and 17,a positions
`on the GCS skeleton.
`Several new GCSs have been evaluated for use in IBD during the last years2, but after
`review3, only a few compounds remain on the market for topical IBD applications.
`
`BECLOMETHASONE
`Beclomethasone, 17,a and 21-dipropionate, given in enema form for active distal UC,
`has previously been shown to have equal efficacy but reduced suppression of plasma
`cortisol levels in comparison with conventional GCS enemas4. Beclomethasone was
`recently compaired with 5-aminosalicylic acid (S,ASA) in a randomised controlled trial
`(RCT); the two drugs were equally effective when given as monotherapy for active
`ulcerative proctitis, but significantly improved results were obtained when a combination
`of the two different compounds (3 mg GCS + 2 g S,ASA in 100 ml) was useds. The
`results need confirmation, but are still of great clinical interest as they indicate that
`therapeutic synergism may be obtained by combining drugs utilising different modes of
`action, maintaining a low toxicity profile6. However, as beclomethasone is now out of
`patent, the commercial interest for a study using this particular drug is probably low and
`it is uncertain if further development for UC will be continued.
`
`BUDESONIDE
`To date, the best documented of the new generation of highly potent 17 ,a, substituted
`GCSs for the treatment in IBD, is budesonide. It is now approved in several countries,
`both as an enema and in an oral preparation (Entocort®, Astra, Sweden). Due to its
`relatively high water solubility, budesonide is readily dissolved, facilitating transport to
`the bowel wall. These hydrophilic properties ensure a high tissue uptake, resulting in
`high concentrations and high activity in the target tissues when the drug is applied
`topically. As shown in animal studies, budesonide has a greater topical uptake and
`remains within the mucosa for a longer period of time than prednisolonel. The drug is
`biotransformed rapidly in the liver via the cytochrome P450 CYP3A4 enzymes, with
`80-90% metabolised in the first pass resulting in low systemic availability.
`
`BUDESONIDE RETENTION ENEMAS IN DISTAL UC AND PROCTITIS
`Recent RCTs evaluating budesonide (Entocort®) 2 mg/100 ml retention enemas in
`active distal UC and proctitis have, to a large extent, confirmed the previously obtained
`
`Cosmo Ex 2009-p. 4
`Mylan v Cosmo
`IPR2017-01035
`
`

`

`RESEARCH AND CLINICAL FORUMS VOL. 20 No. 1
`
`181
`
`positive results7-11. In an American RCT comprising 184 patients with distal UC, the
`budesonide enema was compared with standard hydrocortisone enema. Budesonide
`showed similar therapeutic efficacy, but had significantly less impact on the response to
`an adrenocorticotropic hormone (ACTH) test after 6 weeks of treatment12. Another
`large US study with 223 patients evaluated the budesonide enema in a dose~ranging
`RCT vs placebo, comparing doses of 0.5, 2 and 8 mg given at bedtime. The optimal dose
`was confirmed to be 2 mg/100 ml, although the 8 mg dose provided slightly higher
`remission ratesl3. In line with these results, a recent, Swedish, multicentre RCT
`investigating active distal UC and proctitis treatment using administration of the enema
`bd. could not demonstrate a significant advantage in remission rate over the standard,
`once~daily dose (62% vs 57% bd.) after 8 weeks14. Furthermore, in those patients
`achieving remission, a prolonged treatment with the budesonide enema given twice
`weekly for up to 6 months was not significantly superior to placebo in maintaining
`remission (38% vs 53% relapse rate)14. A clinical trial comparing budesonide enema
`2 mg/100 ml to Pentasa® (mesalazine) 1 g/100 ml in acute distal UC or proctitis for
`4 weeks15 showed equal efficacy in inducing endoscopic and histological remission;
`however, the Pentasa® enema was superior in obtaining clinical remission
`(60% VS 38%; p = 0.03).
`
`BUDESONIDE FOR ORAL USE
`A refined, slow~release delivery system developed for budesonide by Astra Draco AB,
`Sweden uses mm~sized enteric coated (Eudragit L) pellets with a rate~limiting polymer
`containing the active drug16. This time~dependent and pH~dependent delivery system
`(controlled ileal release, [CIR]) results in an absorption of around 70% of the given drug
`in the distal ileum and the caecum, making it appropriate for treatment of active distal
`ileal and/or right~sided colonic CD. Encouraging results in a small pilot trial were
`confirmed by two large multicentre RCTs. The optimal dose of the oral preparation for
`active ileal or ileocaecal CD was found to be 9 mg in a Canadian placebo~controlled,
`dose~ranging study of 25 8 patients 17. Special attention was made to monitor GCS~
`associated side~effects, but interestingly, no significant differences were found between
`the active treatment groups compared with placebo in this respect. The 9 mg dose had
`the best clinical efficacy and a GCS~associated side~effect incidence similar to that of
`placebo (26%); however, significantly lower plasma cortisol was seen after 8 weeks
`treatment in the budesonide group compared to placebo (69% vs 14%; P < 0.001). In a
`European, multicentre, double~blind, double~dummy RCT, comparing 9 mg budesonide
`CIR given with a standard regimen of 40 mg/day of oral prednisolone tapering over a
`10~week period18, no statistical difference in overall remission rate (as determined by a
`Crohn's disease activity index [CDAI]~score < 150) was seen (52% vs 65%; P
`0.12).
`While clinical efficacy was comparable, morning plasma cortisol levels were markedly
`suppressed in the prednisolone group after 8 weeks (P = 0.02). In line with this, GCS~
`associated side~effects were milder and significantly less frequent in the budesonid.e group
`(33% vs 55%; P = 0.003) during the study period.
`These results have recently been confirmed and reinforced by an international
`comparative RCT19, involving 177 patients with active ileocaecal CD. The study
`evaluated two different dosing regimens for budesonide. A once daily vs a twice daily
`dose of 9 mg budesonide CIR was compared with a standard prednisolone treatment
`starting at 40 mg and then tapered down to 5 mg over 12 weeks. After 2 weeks of
`
`Cosmo Ex 2009-p. 5
`Mylan v Cosmo
`IPR2017-01035
`
`

`

`182
`
`R. L6FBERG
`
`treatment the remission rate was highest in the 9 mg budesonide om. group ( 48% vs 3 7%
`for prednisolone). At 8 weeks, the rate was 60%, both in the budesonide om. and the
`prednisolone group, which was not significantly different from 42 o/o in the bd.
`budesonide group (P = 0.062). No overall difference in frequency of GCS~associated
`side~effects were seen, but in the prednisolone group the incidence of moonface was
`three times that of the budesonide groups (P = 0.0005 ). Moreover, suppression of the
`ACTH~stimulated adrenal gland response was also significantly more common with
`prednisolone.
`In another recent, 16~week, multicentre, European RCT, only presented in abstract
`form20, budesonide CIR 9 mg om. was compared to 2 g bd. of a S~ASA compound with
`uniform release throughout the gut (Pentasa®), and was found to be superior for
`induction of remission in active ileocaecal CD. The study comprised 182 patients with
`the remission rates being 44% for budesonide vs 37% for Pentasa® (ns.) after 2 weeks,
`48% vs 39% at 4 weeks (ns.) and 69% vs 45% at 8 weeks (P < 0.01 ). After 16 weeks of
`treatment budesonide was still clearly superior (62% vs 36%; P < 0.01). There was also a
`significantly larger improvement in the subjective psychological well~being index in the
`budesonide group. No difference in the overall side~effect pattern was found, although
`the S~ASA group had twice as many severe adverse events; however only one of the
`severe adverse events in each group was classified as being possibly related to study
`medication. After 16 weeks of treatment, 20% of the budesonide group had an
`impairment of the ACTH~test against none among the S~ASA group.
`
`EUDRAGIT~COVERED BUDESONIDE
`An Eudragit L~type resin, dissolving at a pH value > 5.5, is used to coat another oral
`budesonide formulation not yet approved ( Budenofalk, Falk Co., Germany).
`Pharmacokinetic studies21 indicate that the systemic availability of this formulation is
`9-14%, with a substantial portion (up to 37%) of drug being delivered to the colon. A
`German, multicentre RCT evaluated this preparation for active CD in a dose of 3 mg
`tds. vs 48 mg of 6~methylprednisolone, given in a tapered fashion over 8 weeks22. Sixty~
`seven patients were included and the intention to treat analysis showed a remission rate
`of 56% for budesonide and 73% for 6~methylprednisolone (P
`0.24 ). Steroid~related
`side~effects appeared in 29% of the budesonide treated patients compared with 70% in
`those treated with 6~methylprednisolone (P = 0.0015 ).
`A daily dose of 9 mg was judged to be optimal in a dose~ranging trial comprising 104
`CD patients, although an increased efficacy was seen with 18 mg/day at the expense of a
`higher systemic impact and more GCS~related side~effects23. In a randomised,
`controlled, dose~ranging study from the same group of investigators24, the Eudragit L
`preparation ofbudesonide was given to 80 patients with active CD and 126 with inactive
`CD, treated with prednisolone in doses ranging from 5-30 mg/day. Budesonide was given
`in three different dose levels ranging from 2-6 mg tds. and was able to replace
`successfully the systemic GCSs. No significant differences were found between the three
`dose levels, either in terms of clinical efficacy nor side~effect frequency.
`
`Maintenance treatment
`A pooled analysis of three similarly designed, placebo~controlled studies which used
`budesonide CIR 6 or 3 mg/day as maintenance therapy for up to 1 year in patients with
`ileocaecal CD, having achieved remission by a preceding course of GCS treatment, was
`
`Cosmo Ex 2009-p. 6
`Mylan v Cosmo
`IPR2017-01035
`
`

`

`RESEARCH AND CLINICAL FORUMS VOL. 20 No. 1
`
`183
`
`recently presented25. The analysis combined the results from two separate maintenance
`studies, previously described in detai126,27, with the results from a study which was a
`continuation of the trial performed by Campieri et al19 and included a total of 2 70
`patients. Patients treated with 6 mg of budesonide had a significantly l~nger median time
`to relapse (CDAI score > 150) or discontinuation of treatment compared with the 3 mg
`or the placebo groups (263 vs 170 vs 154 days; P = 0.03 ); however, the results of the
`individual studies pooled in this analysis showed no significant difference in relapse rate
`after 1 year (approximately 60% relapsed in all treatment groups). Glucocorticosteroid
`related side~effects were mild and did not differ between the budesonide and placebo
`groups.
`An interim analysis of an RCT, comprising 180 CD patients having achieved GCS
`induced remission who were treated with 3 mg daily of Eudragit~covered budesonide for
`up to 1 year, failed to show superiority in relapse prevention compared with placebo28.
`
`POSTOPERATIVE RECURRENCE PREVENTION
`In order to elucidate if topical GCS treatment has a role in preventing recurrence of CD
`following surgical resection, a European, multicentre RCT of 129 patients, which
`compared budesonide CIR 6 mg/day vs placebo, for up to 1 year, was conducted29. There
`were no general benefits when the rate of endoscopic recurrence was compared
`(63% in both groups). However, when the patients were stratified with respect to
`indication for surgery, those operated on due to inflammatory activity rather than
`because of stenosis had a lower recurrence rate if treated with budesonide (32% vs 65%
`for placebo after 12 months; P = 0.048).
`A pilot study of 30 patients with short ileocaecal or rectosigmoid stenoses treated
`successfully with balloon dilation30, then subsequently treated with a combination of
`oral budesonide CIR and azathioprine vs placebo, indicated a clear benefit for
`budesonide and azathioprine during a l~year follow~up (3 vs 8 failures; P = 0.021 ). A
`larger, multicentre study is now being undertaken.
`
`ORAL BUDESONIDE FOR EXTENSIVE AND LEFT~SIDED UC
`A preliminary colonic preparation, utilising retarded release of budesonide (Astra,
`Sweden), was evaluated for active, extensive and left~sided UC in a 9~week pilot RCT31.
`The trial showed that 10 mg/day was almost as efficacious as an oral prednisolone
`regimen starting at 40 mg/day (mean endoscopic score decreased by 1.20 and 1.36 in the
`budesonide and prednisolone groups respectively- maximum score of 3 ). However, there
`was no appreciable suppression of mean morning plasma cortisol levels in the
`budesonide~treated group, indicating that the GCS effects achieved with budesonide in
`that preparation were likely to have been induced mainly topically. An improved release
`profile in the distal colon is necessary before this formulation will gain approval for use in
`more extensive colonic IBD.
`
`FURTHER DEVELOPMENT AND CONSIDERATIONS
`The use of a pro drug, such as budesonide~~~D~glucuronide, offers an alternate delivery
`mode for budesonide at the site of inflammation in the colon32. Enhanced GCS
`compounds, with higher potency, in combination with more rapid and extensive first~
`pass metabolism may possibly improve the ratio between topical effects and systemic
`side~effects even further.
`
`Cosmo Ex 2009-p. 7
`Mylan v Cosmo
`IPR2017-01035
`
`

`

`184
`
`R. LOFBERG
`
`The experience with long~term maintenance therapy, including postoperative
`recurrence prevention, highlights the problems in identifying the appropriate patient
`subgroups that may benefit most from topical GCS treatment, for longer periods of time.
`The use of pulse treatment with higher doses, on demand or flexible dosing, and
`combined rectal and oral therapy, all need to be elucidated further. Combination therapy
`with budesonide and other types of drugs, eg., immunosuppressives30, aminosalicylates5
`and possibly antibiotics, should also be addressed in future studies.
`
`CONCLUSIONS
`The first long~term studies with .oral budesonide indicate a benign toxicity profile when
`considering the systemic impact of the drug. At an oral dose of 6 mg/day or lower, the
`risk for sustained adrenal gland suppression seems to be reassuringly low. However, other
`issues, particularly the impact on bone metabolism and other potential metabolic side~
`effects need to be studied longitudinally before the role of topical GCS in the treatment
`of IBD can be fully established.
`
`REFERENCES
`1. BRATTSAND, R. Concepts of topical steroid therapy. Res. Clin. For., 1996; 18: 57-65.
`2. L6FBERG, R. New steroids for inflammatory bowel disease. Inflamm. Bowel. Dis., 1995; I: 135-
`141.
`3. RUTGEERTS, P. Topical glucocorticoids for the treatment of inflammatory bowel disease. Res.
`Clin. For., 1995; 17: 143-149.
`4. BANSKY, G., BUHLER, H., STAMM, B., HACKl\ W.H. and BUCHMANN, P. Treatment of distal
`ulcerative colitis with beclomethasone enemas: High therapeutic efficacy without endocrine
`side effects. Dis. Colon Rectum, 1987; 30: 288-292.
`5. MULDER, C.].]., FoCKENS, P., MEIJER, J.W.R., VAN DER HEIDE, H., WILTINK, E.H.H. and
`TYTGAT, G.N.J. Beclomethasone diproprionate (3mg) versus 5~aminosalicylic acid (2g) versus
`the combination of both. (3mg/2g) as retention enemas in active ulcerative proctitis. Eur. ] .
`Gastroenterol. Hepatol., 1996; 8: 549-553.
`6. L6FBERG, R. Combination therapy in active distal ulcerative colitis and proctitis ~ more
`studies are warranted. Eur. ]. Gastroenterol. Hepatol., 1996; 8: 541-542.
`7. THE DANISH BUDESONIDE STUDY GROUP. Budesonide enema in distal ulcerative colitis. A
`randomised dose~response trial with prednisolone enema as positive control. Scand. ] .
`Gastroenterol., 1991; 26: 1225-1230.
`8. DANIELSSON, A., L6FBERG, R., PERSSON, T., SALDE, L., SCHIOLER, R., SUHR, 0. and WILLEN, R.
`A steroid enema, budesonide, lacking systemic effects for the treatment of distal ulcerative
`colitis or proctitis. Scand. ] . Gastroenterol., 1992; 27: 9-12.
`9. L6FBERG, R., 0STERGAARD~THOMSEN, 0., LANGHOLZ, E., SCHIOLER, R., DANIELSSON, A.,
`SUHR, 0., GRAFFNER, H., PAHLMAN, L., MARZAN, P., MOELLER~PEDERSEN, ].F., HALVORSEN, L.,
`HOVENAK, L., WILLEN, R. and PERSSON, T. A comparative study of budesonide versus
`prednisolone retention enema in active distal ulcerative colitis. A Scandinavian multicenter
`study. Aliment. Pharmacal. Ther., 1994; 8: 623-629.
`10. BIANCHI PORRO, G., PRANTERA, C., CAMPIER!, M., PETRILLO, M., CAMPANINI, M.C.,
`G!OCHETTI, P., GRANDINETTI, G., MANGIAROTTI, R., BRUNETTI, G. and RANZI, T.
`Comparative trial of methylprednisolone and budesonide enema in active distal ulcerative
`colitis. Eur.]. Gastroenterol. Hepatol., 1994; 6: 125-130.
`11. TARPILA, S., TURUNEN, U., SEPPALA, K., AUKEE, S., PIKKARAINEN, P., ELOMAA, I., KARVONEN,
`A.L., KAARIAINEN, l., SIPPONEN, P., TOIVANEN, E., HEIKUS, B., NURMISS, H., TUNTURI'~
`HIHNNALA, H., BURNHAM, W.R., COWAN, R.E., HINE, K.R., PERSSON, T. and SALDE, L.
`Budesonide enema in active haemorrhagic proctitis ~ a controlled trial against hydrocortisone
`foam enema. Aliment. Pharmacal. Ther., 1994; 8: 591-595.
`12. BAYLESS, T., SNINSKY, C. and THE US BUDESONIDE ENEMA STUDY GROUP. Budesonide enema
`is an effective alternative to hydrocortisone enema in active distal ulcerative colitis.
`Gastroenterology, 1995; 108: A 778.
`
`Cosmo Ex 2009-p. 8
`Mylan v Cosmo
`IPR2017-01035
`
`

`

`RESEARCH AND CLINICAL FORUMS VOL. 20 No. 1
`
`185
`
`13. HANAUER, S., ROBINSON, M. and THE US BUDESONIDE STUDY GROUP. Dose ranging study of
`budesonide enema in active distal ulcerative colitis. Gastroenterology, 1995; 108: A832.
`14. LINDGREN, S., SUHR, 0., PERSSON, T. and PANTZAR, N. Treatment of active distal ulcerative
`colitis (UC) and maintenance of remission with Entocort® enema- a randomised controlled
`dosage study. Gut, 1997; 41: (abstract).
`15. LEMANN, M., GALIAN, A., RUTGEERTS, P., VAN HEUVERZWI)N, R., CORTOT, A., VITEAU, j.M.,
`ELEWAUT, A., BELAICHE, ]., FROGUEL, E. and MODIGLIANI, R. Comparison of budesonide and
`5-aminosalicylic acid enemas in active distal ulcerative colitis. Aliment. Pharmacal. Ther.,
`1995; 9: 557-562.
`16. LOFBERG, R. Oral formulation ofbudesonide for IBD. Res. Clin. Forum, 1993; 15: 91-96.
`17. GREENBERG, G., FEAGAN, B., MARTIN, F., SUTHERLAND, L.R., THOMSON, A.B.R., WILLIAMS,
`C.N., NILSSON, L.G., PERSSON, T. and THE GLOBAL BUDESONIDE STUDY GROUP. Oral
`budesonide for the treatment of active Crohn's disease. N. Engl. ] . Med., 1994; 331: 836-841.
`18. RUTGEERTS, P., LOFBERG, R., MALCHOW, H., LAMERS, C., OLAISON, G., ]EWELL, D.,
`DANIELSSON, A., GOEBELL, H., THOMSEN, 0.0. and LORENZ-MEYER, H. A comparison of
`budesonide with prednisolone for active Crohn's disease. N. Engl.]. Med., 1994; 331: 842-
`845.
`19. CAMPIER!, M., FERGUSON, A., DOE, W., PERSSON, T., NILSSON, L.G. and THE GLOBAL
`BUDESONIDE STUDY GROUP. Oral budesonide is as effective as prednisolone in active Crohn's
`disease. Gut, 1997; 41: 209-214.
`20. THOMSEN, 0.0., CORTOT, A., ]EWELL, D.P., WRIGHT, J.P., WINTER, T., VELOSO, F.T., VATN,
`M., PERSSON, T., NYLANDER, l. and THE INTERNATIONAL BUDESONIDE-MESALAZINE STUDY
`GROUP. Budesonide CIR is more effective than mesalazine in active Crohn's disease. A 16
`week, international, randomised, double blind, multicenter trial. Gastroenterology, 1997; 112:
`All04.
`21. MOELLMANN, H.W., HOCHHAUS, G., TROMM, A., MOELLMANN, A., DERENDORF, H., BARTH, J.,
`FROELICH, P., ECKER, K.W. and LlNDERMANN, A. Pharmacokinetics and evaluation of systemic
`side effects of budesonide after oral administration of modified release capsules in healthy
`volunteers and patients with Crohn's disease. Gastroenterology, 1996; 110: A972.
`22. GROSS, V., ANDUS, T., CAESAR, l., BISCHOFF, S.C., TROMM, A., SCHULZ, H.J., BAR, U.,
`WEBER, A., GIEREND, M., EwE, K., ScHOLMERICH,]. and THE GERMAN/AUSTRIAN BUDESONIDE
`STUDY GROUP. Oral pH-modified release budesonide versus 6-methylprednisolone in active
`Crohn's disease. Eur. ]. Gastroenterol. HetJatol., 1996; 8: 905-909.
`23. GROSS, V., CAESAR, l., ANDUS, T., VOGELSANG, H., ADLER, G., MALCHOW, H., WEBER, G.,
`M, SCHOLMERICH, ]. and and THE GERMAN/AUSTRIAN BUDESONIDE STUDY GROUP. Dose(cid:173)
`finding study with oral budesonide in patients with active Crohn's ileocolitis. Gastroenterology,
`1997; 112: A986.
`24. GROSS, V., CAESAR, l., ANDUS, T., VOGELSANG, H., ADLER, G., MALCHOW, H., WEBER, A.,
`GIEREND, M., SCHOLMERICH, ]. and THE GERMAN/AUSTRIAN BUDESONIDE STUDY GROUP.
`Replacement of systemic steroids by oral budesonide in patients with post-active or chronic
`Crohn's ileocolitis- a dose-finding study. Gastroenterology, 1997; 112: A987.
`25. FEAGAN, B., GREENBERG, G., LOFBERG, R., FERGUSON, A. and PERSSON, T. Budesonide
`controlled ileal release prolongs remission in Crohn's disease. A pooled analysis.
`Gastroenterology, 1997; 112: A970.
`26. LOFBERG, R., RUTGEERTS, P., MALCHOW, H., LAMERS, C., 0LAISON, G., ]EWELL, D.,
`OSTERGAARD-THOMSEN, 0., LORENZ-MEYER, H., GOEBELL, H., HODGSON, H., PERSSON, T. and
`SEIOEGARD, C. Budesonide prolongs time to relapse in ileal and ileocaecal Crohn's disease. A
`placebo controlled one year study. Gut, 1996; 39: 82-86.
`27. GREENBERG, G., FEAGAN, B., MARTIN, F., SUTHERLAND, L.R., THOMSON., A.B.R., WILLIAMS,
`C.N., NILSSON, L.G., PERSON, T. and THE CANADIAN INFLAMMATORY BOWEL DISEASE STUDY
`GROUP. Oral budesonide as maintenance treatment for Crohn's disease: A placebo controlled
`dose-ranging study: Gastroenterology, 1996; 110: 45-51.
`28. GROSS, A., ANDUS, T., ECKER, K.W., RAEDLER, A., LOESCHKE, K., WEBER, A., G!EREND, M.,
`EWE, K. and ScHOLMERICH, ] . Oral pH-modified release budesonide for maintenance of steroid
`induced remission in Crohn's disease- An interim analysis. Gastroenterology, 1995; 108: A828.
`29. HELLERS, G., LOFBERG, R., RUTGEERTS, P., MALCHOW, H., PRANTERA, C., ]EWELL, D.P.
`CORTOT, A., PENA, A.S., PALLONE, F., LEIJONMARCK, C.E., GAD, A., NILSSON, L.G. and
`
`Cosmo Ex 2009-p. 9
`Mylan v Cosmo
`IPR2017-01035
`
`

`

`186
`
`R. LOFBERG
`
`PERSSON, T. Oral budesonide for prevention of recurrence following ileocecal resection of
`Crohn's disease. A one year placebo~controlled study. Gastroenterology, 1996; 110: A923.
`30. RAEDLER, A., PETERS, I. and SCHREIBER, S. Treatment with azathioprine and budesonide
`prevents recurrence of ileocolonic stenoses after endoscopic dilation in Crohn's disease.
`Gastroenterology, 1997; 112: A 106 7.
`31. LOFBERG, R., DANIELSSON, A., SUHR, 0., NILSSON, A., SCHIOLER, R., NYBERG, A.,
`HULTCRANTZ, R., KOLLBERG, B., GILLBERG, R., WILLEN, R., PERSSON, T. and SALDE, L. Oral
`budesonide versus prednisolone in patients with active extensive and left~sided ulcerative
`colitis. Gastroenterology, 1996; 110: 1713-1718.
`32. Cui, N., FRIEND, D.R. and FEDQRAK, R.N. A budesonide prodrug accelerates treatment of
`colitis in rats. Gut, 1994; 35: 1439-1446.
`
`Cosmo Ex 2009-p. 10
`Mylan v Cosmo
`IPR2017-01035
`
`

`

`RESEARCH AND CLINICAL FORUtviS VOL. 20 No.1
`
`187
`
`DISCUSSION
`Professor Hanauer: Dr. Munkholm, could you define the use of the terms chronically
`active disease, chronically indolent disease, steroid dependent disease and steroid
`refractory disease. Not everyone in the audience may agree and there may be differences
`in the definitions of these clinical states between groups of workers.
`Dr. Munkholm: We have looked at regional cohort studies where one group is given
`steroids and the other surgery, S~aminosalicylic acid (S~ASA), immunosuppressive drugs
`or steroids also. When you apply surgery as well as medical treatment, the results are
`different from the steroid treated group and therefore there are difference in chronic
`active Crohn's disease (CACD) incidences.
`Professor Hanauer: Dr. Hellers, is surgery the only realistic treatment on offer for
`CACD?
`Dr. Hellers: Yes, surgery.
`Professor Hanauer: Professor Modigliani do you have a better therapy for CACD, other
`than surgery?
`Professor Modigliani: If you mean better therapy than surgery, probably not. I feel the
`best first~ line treatment is surgery.
`Professor Hanauer: Professor Present, do you agree or disagree, do you have a better
`therapy for CACD?
`Professor Present: I do not agree with the use of steroids as a level of 36% dependency is
`too high to be acceptable, however, the use of immunomodulatory agents in certain cases
`of Crohn's disease (CD) is fully justified. I am far more impressed by the observation that
`tumour necrosis factor (TNF)~a antibody ( cA2) induced a 70% response with a single
`infusion, which will alter the immunological process. This may be of key importance in
`the treatment course. This treatment may cause sufficient down regulation to enable
`control of the disease with agents such as azathioprine or S~aminosalicylic acid.
`Professor Hanauer: You have stated a figure of 70%, Professor Present, and Professor
`Modigliani only showed a 30% response with TNF~a antibody treatment. How would
`you explain this?
`Professor Present: Well, it depends on whether you want to define the response as
`complete remission or clinical response. Patients don't have to be in clinical remission to
`be quite happy with their clinical course. If you get a Crohn's disease activity index score
`down to 170, they are going to be very happy with that compared with 350 or 400.
`Professor Hanauer: Professor Lofberg, I am not sure of your data concerning the long