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A pilot study of treatment of active ulcerative colitis with natalizumab, a humanized monoclonal antibody to alpha-4 integrin

A pilot study of treatment of active ulcerative colitis with natalizumab, a humanized monoclonal antibody to alpha-4 integrin
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  A pilot study of treatment of active ulcerative colitis withnatalizumab, a humanized monoclonal antibody to alpha-4 integrin F. H. GORDON*, M. I. HAMILTON*, S. DONOGHUE  , C. GREENLEES  , T. PALMER  ,D. ROWLEY-JONES  , A. P. DHILLON  , P. L. AMLOT§ & R. E. POUNDER* *Centre for Gastroenterology, Royal Free and University College Medical School, London, UK;   Elan Pharmaceuticals EuropeLtd, Stevenage, Hertfordshire, UK;   Department of Histopathology, Royal Free and University College Medical School,London, UK; and   § Department of Clinical Immunology, Royal Free and University College Medical School, London, UK  Accepted for publication 8 November 2001 INTRODUCTION Integrins are heterodimeric glycoproteins, consisting of  a  and  b  subunits, which are important mediators of celladhesion. 1 Animal studies suggest that  a 4 integrin, incombination with  b 1 or  b 7 chains, is particularlyimportant in the migration of leucocytes across vascularendothelial cells in the gut. 2 Immunohistochemistry 3 and flow cytometry studies 4, 5 suggest that  a 4 integrinexpression is up-regulated on the surface of lympho-cytes present in inflamed areas of gut mucosa inpatients with inflammatory bowel disease, and hencemay represent a useful therapeutic target. Monoclonalantibodies to the  a 4 subunit in general, or  a 4 b 7 integrinspecifically, have been shown to inhibit the migration of lymphocytes to rat mesenteric lymph nodes and Peyer’spatches  in vivo , 6 and to ameliorate colitis in thespontaneously colitic cotton-top tamarin, an animalmodel of inflammatory bowel disease. 7, 8 A randomized,placebo-controlled study of Act-1, a monoclonal anti-body to  a 4 b 7 integrin, has demonstrated promisingefficacy in patients with active ulcerative colitis,although larger confirmatory studies of this antibodyare awaited. 9 Natalizumab (Antegren; Elan Pharmaceuticals Inc.,South San Francisco, CA, USA) is a recombinant SUMMARY Background  : Alpha-4 integrins facilitate leucocytemigration across vascular endothelium. Aim : To assess the safety and efficacy of natalizumab(Antegren), a humanized antibody to alpha-4 integrin,in patients with active ulcerative colitis. Methods : Ten patients with active ulcerative colitis,defined by a Powell-Tuck activity score > 4, received asingle 3 mg/kg natalizumab infusion. The primary end-point was the change in Powell-Tuck score at 2 weekspost-infusion. Results : Significant decreases in the median Powell-Tuck score were observed at 2 and 4 weeks post-infusion (7.5 and 6, respectively) compared to themedian baseline score (10). Five of 10 patients achieveda good clinical response at 2 weeks and one morepatient by 4 weeks, defined by a Powell-Tuck score of  £  5. Significant improvements in quality of life scoreswere found at week 4. Rescue medication was requiredby two (20%), three (30%) and eight (80%) patients byweeks 2, 4 and 8, respectively (median, 34 days; range,8–43 days). One patient remained in remission at12 weeks. The median C-reactive protein at 2 weeks(6 mg/L) was lower than that pre-treatment (16 mg/L). Conclusions : A single 3 mg/kg infusion of natalizumabwas well tolerated by ulcerative colitis patients. Thepositive efficacy demonstrated in this study meritsfurther investigation by randomized, placebo-controlledtrials. Correspondence to: Dr F. H. Gordon, Centre for Gastroenterology, 10thFloor, Royal Free and University College Medical School, Rowland HillStreet, London NW3 2PF, UK.E-mail: Aliment Pharmacol Ther 2002; 16: 699–705.   2002 Blackwell Science Ltd  699  humanized antibody to  a 4 integrin, which has beenderived from a murine monoclonal antibody(AN100226m) raised against human  a 4 integrin(VLA-4). 10 The complementarity-determining region of the hypervariable region of the AN100226m gene wasgrafted onto a human IgG4 framework to formhumanized natalizumab (Antegren).  In vitro , natal-izumab has been shown to block the adhesion of human Jurkat  a 4 b 1-expressing cells to recombinant vascularcell adhesion molecule-1 and  a 4 b 7-expressing RPMI-8866 cells to recombinant mucosal addressin celladhesion molecule (MAdCAM-1) (T. Yednock, personalcommunication, 1999). It also produces the clearanceof leucocytes in the central nervous system of guineapigs with experimental allergic encephalomyelitis, 11 adisease thought to be mediated by the interaction of leucocyte  a 4 b 1 integrin and vascular cell adhesionmolecule-1. A multicentre study of natalizumab inpatients with active multiple sclerosis and a small phaseI study in 26 healthy male volunteers have shown thata single 3 mg/kg intravenous dose is safe and welltolerated. 12, 13 In patients with mild to moderatelyactive Crohn’s disease, natalizumab has been found tobe safe and efficacious by randomized, double-blind,placebo-controlled trial. 14, 15 Corticosteroids are the mainstay of remission inductiontreatment for inflammatory bowel disease, but manypatients experience debilitating side-effects, 16 and evi-dence already exists showing that, in the long term,these agents are ineffective in controlling Crohn’sdisease or ulcerative colitis; hence, there is a need todevelop alternative methods of disease control. The aimof this open study was to assess the safety and efficacy of natalizumab in patients with active ulcerative colitis. METHODS Patients Patients with active ulcerative colitis, whose Powell-Tuck score was > 4, 17 were assessed for trial eligibility.The disease was required to have been diagnosed atleast 3 months prior to trial entry and to have beenconfirmed by at least two of the following diagnosticcriteria: clinical history, histology, radiology or endo-scopy. 18 Female participants were required to have anegative pregnancy test at study entry and to useeffective contraception throughout the study. Patientsreceiving oral corticosteroids (dose equivalent to £  40 mg prednisolone daily) or 5-aminosalicylic acid-derived drugs (dose  £  2.4 g daily) were included, pro-vided that the dose had not been increased within2 weeks of study entry. Likewise, patients receivingazathioprine (dose  £  2 mg/kg daily) were eligible, pro-vided that this had not been commenced or the doseincreased within 4 months of study entry. Exclusion criteria The following groups were not included in the study:in-patients; patients who had undergone or who werethought likely to require intestinal surgery up to3 months prior to, or 3 months after, study entry,respectively; patients with proctitis only; patientsreceiving ciclosporin, methotrexate or tacrolimus ther-apy; patients with an ileostomy, colostomy or ilealpouch; patients with laboratory-confirmed intestinalinfection; and patients known to have had malignantneoplasia at any site. Patients weighing more than100 kg, and pregnant or breast-feeding women, werealso excluded. Design Patients were assessed for trial eligibility at an initialscreening visit, at which the following screeninginvestigations were performed: full blood count, eryth-rocyte sedimentation rate, biochemical screen includingimmunoglobulins and C-reactive protein, urinalysis,resting electrocardiogram and sigmoidoscopic examina-tion including rectal biopsy. The proportions of periph-eral blood T cells (TCR ab +) and B cells (CD19+) werealso measured using fluorescence-activated cell-sorteranalysis (Becton Dickinson, Abingdon, UK).  19 Thestudy was approved by the ethics committee of the RoyalFree Hampstead NHS Trust and all patients gave writteninformed consent prior to participating in the study.Patients received a single 3 mg/kg intravenous infu-sion of natalizumab over 25–45 min and were observedfor at least 6 h post-infusion. The Powell-Tuck scorewas calculated, based on patient symptoms and exam-ination findings, at 1, 2, 4, 8 and 12 weeks aftertreatment (Table 1). Sigmoidoscopic examination andrectal biopsies for histology were taken at each follow-up visit. The appearance of the rectal mucosa atsigmoidoscopy was scored as follows: 0, normal; 1,granular mucosa; 2, contact bleeding/spontaneoushaemorrhage; 3, severe changes; ulcers/severely 700 F. H. GORDON  et al .   2002 Blackwell Science Ltd,  Aliment Pharmacol Ther   16 , 699–705  haemorrhagic mucosa and pus present. 20 Biopsies werescored histologically as described by Saverymuttu et al . 21 Quality of life was assessed by the InflammatoryBowel Disease Questionnaire 22 at screening and4 weeks after treatment. Venous blood was taken ateach visit for the haematological, biochemical andfluorescence-activated cell-sorter analyses describedabove, and for measurement of serum natalizumaband anti-natalizumab antibody levels. Statistical analysis Differences between pre-treatment and week 2 Powell-Tuck scores, C-reactive protein, erythrocyte sedimenta-tion rate, platelet counts and albumin concentrationswere analysed by the Wilcoxon signed rank test. Thestudy end-point was the change in Powell-Tuck score at2 weeks. The number of patients who required ‘rescue’medication at 2 weeks was used as a secondary end-point. ‘Rescue’ medication was defined as the initiationof or increase in daily dose of any of the following drugsby any route of administration: corticosteroids,5-aminosalicylates or azathioprine/6-mercaptopurine.The ‘last-observation-carried-forward’ principle wasapplied to analyses of the Powell-Tuck scores for thosepatients who had received rescue medication or whohad been withdrawn. RESULTS Five of the 15 screened patients did not enter the studybecause of a failure to meet disease activity criteria onthe day of treatment (one patient) or personal reasons(four patients). The clinical characteristics of the 10patients who received natalizumab are shown inTable 2, nine of whom completed the post-infusionfollow-up to 12 weeks. One patient was withdrawnfrom the study at 2 weeks post-infusion due to severedisease requiring urgent colectomy. Disease activity The median Powell-Tuck score of 6 at 2 weeks post-infusion was significantly less than the baseline medianscore of 10 ( P ¼ 0.004). Significant improvement in thePowell-Tuck score was also found at weeks 1 ( P ¼ 0.02)and 4 ( P ¼ 0.008) post-treatment. True remission isdefined by a Powell-Tuck score of zero, which wasachieved by two patients. During the study (i.e.  posthoc ), the investigators felt that a good clinical responseshould be defined as a Powell-Tuck score of   £  5, as thepatients’ scores were in the range 8–12 at study entry.This was achieved in five of the 10 patients at 2 weekspost-infusion, and in one further patient by week 4(Figure 1). The mean decreases in the Powell-Tuck Table 1. Sample Powell-Tuck colitisactivity index score sheet. Adapted fromPowell-Tuck  et al . 17 Disease factor ScoreGeneral health: 0 ¼ good, 1 ¼ slightly impaired, 2 ¼ activities reduced,3 ¼ unable to workAbdominal pain: 0 ¼ absent, 1 ¼ with bowel actions only, 2 ¼ prolongedepisodesNumber of bowelmotions daily:0 ¼ < 3, 1 ¼ 3–6, 2 ¼ > 6Stool consistency: 0 ¼ formed, 1 ¼ semiformed, 2 ¼ liquidBlood in stools: 0 ¼ absent, 1 ¼ trace, 2 ¼ frankExtra-intestinalmanifestations:Iritis/uveitis, arthralgia/arthritis, erythema nodosum orpyoderma gangrenosum, mouth ulcers (1 point each formild, 2 points for severe)Abdominal tenderness: 0 ¼ absent, 1 ¼ mild, 2 ¼ marked, 3 ¼ reboundNausea and vomiting: 0 ¼ no, 1 ¼ yesAppetite: 0 ¼ normal, 1 ¼ reducedFever: 0 ¼ absent, 1 ¼ 37.1–38   C, 2 ¼ > 38   CTotal score NATALIZUMAB IN ULCERATIVE COLITIS 701   2002 Blackwell Science Ltd,  Aliment Pharmacol Ther   16 , 699–705  score were 4.0 and 4.8 points at weeks 2 and 4,respectively, i.e. scores fell from 9.7 points at baseline to5.7 and 4.9 points at weeks 2 and 4, respectively.ThemedianInflammatoryBowelDiseaseQuestionnairequality of life score improved significantly from 101 atbaseline to 162 at 4 weeks post-infusion ( P ¼ 0.02) inthe eight patientsfor whomboth data sets were available(Figure 2; range of possible scores, 32–224).Rescue medication was required by two (20%), three(30%) and eight (80%) patients by weeks 2, 4 and 8,respectively (median, 34 days; range, 8–43 days). Twoof the eight patients rescued at week 8 initiallydemonstrated a good clinical response (Powell-Tuckscore  £  5), but experienced a subsequent return of theirsymptoms. Adverse events Adverse events were infrequent and were generallythought to be unrelated to natalizumab. The mostcommonly reported events were ‘aggravated ulcerativecolitis’, representing either a worsening or return of disease symptoms (six patients), headache, vomiting,lethargy and sore throat (each of which was reported bytwo patients). Three patients required hospital admis-sion during the study, one of whom had failed to respondto natalizumab and required colectomy at 2 weeksdespite rescue with oral and intravenous corticosteroids(patient 10). A second patient (patient 4) was admittedwith  Campylobacter jejunii  enteritis, caused by a food-related infection, at 28 days post-infusion, and a thirdpatient (patient 5) developed nausea, vomiting andrigors after commencing oral azathioprine at 53 dayspost-infusion. None of these admissions were assessed asbeing related to natalizumab. Patient SexAge(years)Disease duration(months)Powell-Tuckscore Medication1 Male 24.8 23 8 Mesalazine po2 Female 49.8 54 8 Mesalazine po3 Female 45.8 351 12 Mesalazine po4 Male 28.9 62 10 Mesalazine po + prAzathioprine po5 Female 41.2 53 8 Nil6 Male 37 30 11 Mesalazine po7 Female 25.5 49 8 Mesalazine po8 Male 50.2 79 11 Prednisolone po + pr9 Male 56.7 152 10 Mesalazine po10 Female 44.3 63 10 Mesalazine poPrednisolone prMedian 42.7 59 10 po, oral; pr, per rectum. Table 2. Demographic and treatmentcharacteristics of 10 patients with activeulcerative colitis prior to receiving a single3 mg/kg natalizumab infusion                                                                                                Figure 1. Individual Powell-Tuck colitis activity scores of 10ulcerative colitis patients prior to and 1, 2, 4 and 8 weeks after3 mg/kg natalizumab infusion. Boxes indicate time point at whichrescue therapy commenced.                                                           Figure 2. Inflammatory Bowel Disease Questionnaire (IBDQ)quality of life scores of eight ulcerative colitis patients prior to and4 weeks after a single 3 mg/kg natalizumab infusion. Highervalues indicate improved quality of life. 702 F. H. GORDON  et al .   2002 Blackwell Science Ltd,  Aliment Pharmacol Ther   16 , 699–705  Haematological and biochemical indices The median C-reactive protein value of 6 mg/L at2 weeks post-infusion was significantly less than that atbaseline (16 mg/L) (Figure 3), but serum albumin anderythrocyte sedimentation rate values were unchangedat 1 and 2 weeks post-infusion. No significant changesoccurred in haemoglobin, platelet counts or serumbiochemistry (except C-reactive protein) post-infusion of natalizumab. Drug levels and antibodies The mean serum half-life of natalizumab in the 10patients treated was 3.8 days. The mean serum con-centrations of natalizumab achieved during the first4 weeks post-infusion are shown in Figure 4. At8 weeks, the serum concentration of natalizumab wasnegligible (< 0.05  l g/mL) in all patients. Low-titre(3.4–16  l g/mL) anti-idiotype antibodies to natalizumabdeveloped transiently in one patient (patient 6) andwere detected at weeks 4, 8 and 12. The patient had agood clinical response to natalizumab and did notrequire rescue therapy until week 8 (Figure 1). Fluorescence-activated cell-sorter analysis of peripheralblood lymphocytes A significant increase in total lymphocyte countoccurred post-infusion of natalizumab (Figure 5) from1.66 ± 1.03 (mean ± s.d.) pre-infusion to 3.32 ± 1.07,2.88 ± 0.78 and 2.01 ± 0.62 at 1, 2 and 4 weeks,respectively (Figure 5;  P  < 0.05 compared to baseline).Fluorescence-activated cell-sorter analyses revealed thatthis increase was due to a rise in both B-cell (CD19+)and T-cell (TCR ab +) counts. Other findings There were no significant differences in sigmoidoscopicappearance scores following natalizumab treatment,although six of the 10 (60%) patients demonstrated animprovement in their sigmoidoscopic score at 2 and4 weeks post-infusion. There were also no significanthistological changes observed between pre-treatmentrectal biopsies (mean score, 6.0 ± 3.0) and those per-formed at 1, 2 and 4 weeks post-infusion (mean scores,6.2 ± 2.2, 6.3 ± 2.0 and 5.9 ± 3.5, respectively).                                                                                                                                  Figure 3. Median serum C-reactive protein (CRP,  j ) levels anderythrocyte sedimentation rate (ESR,  h ) values of 10 ulcerativecolitis patients prior to and following a single 3 mg/kg natal-izumab infusion. Bars are ± s.d. and asterisk denotes significantdifference from baseline value ( P  < 0.05). 0 10 20 30 40 50 60010203040506070Days post-infusion      S   e   r   u   m   n   a    t   a     l     i   z   u   m     b        (     µ    g     /   m     L     ) Figure 4. Mean serum natalizumab levels of 10 ulcerative colitispatients following a single 3 mg/kg natalizumab infusion. Barsare ± s.d. Mean  t ½ ¼ 3.8 days (s.d. 1.5). 0 1 2 4 8012345 ********** *** * * B cellsT cellsTotalWeeks post-infusion      L   y   m   p     h   o   c   y    t   e   c   o   u   n    t   s   x     1     0      6      /   m     L Figure 5. Total, B and T lymphocyte counts of 10 patients withactive ulcerative colitis before and after a single 3 mg/kg infusionof natalizumab. Asterisks denote significant changes from baselinevalues (** P  < 0.005; * P  < 0.05). NATALIZUMAB IN ULCERATIVE COLITIS 703   2002 Blackwell Science Ltd,  Aliment Pharmacol Ther   16 , 699–705
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