Randomised controlled trial of CDP571 antibody to tumour necrosis factor-α in Crohn's disease

THE LANCET

Randomised controlled trial of CDP571 antibody to tumour necrosis factor-a in Crohn’s disease W A Stack, S D Mann, A J Roy, P Heath, M Sopwith, J Freeman, G Holmes, R Long, A Forbes, M A Kamm, C J Hawkey

Summary Background Tumour necrosis factor-a (TNFa) is thought to have a central role in the pathogenesis of Crohn’s disease. We tested the hypothesis that CDP571, a genetically engineered human antibody t o TNFa, i s effective in modifying disease activity in patients with moderately active Crohn’s disease. Methods In this double-blind, placebo-controlled study, 3 1 patients were randomly assigned to CDP571 (n=21) or placebo (n=10). The primary endpoint was change in Crohn’s disease activity index 2 weeks after a single infusion of CDP571 ( 5 mg/kg), or human albumin as placebo. One p a t i e n t who a t t e n d e d no follow-up assessments was excluded from the analyses (CDP571 grou P). Findings The median Crohn’s disease activity index fell from 2 6 3 ( I Q R 1 8 6 . 5 - 3 2 3 . 5 ) a t baseline t o 1 6 7 (137.5-294.0) at 2 weeks in the CDP571-treated patients ( p = 0 . 0 0 0 3 ) ; t h e change in t h e placebo group ( 2 5 3 [240-3341 to 247 [183-2561) was not significant. In the treated group, there were also significant differences between baseline and 2 weeks in Harvey-Bradshaw score ( p = 0 . 0 0 0 5 ) , key symptom score ( p = 0 . 0 4 9 ) , al-glyco protei n concent ration ( p=0.012), and erythrocyte sedimentation rate (p=O.Ol); concentrations of C-reactive protein fell, but not significantly (p=0.067). Six patients achieved remission (Crohn’s disease activity index ~ 1 5 0 ) and three others had activity indices of 1 5 6 or lower. There were no significant changes in the placebo group. Interpretation A single 5 mg/kg infusion of CDP571 reduced disease activity in Crohn’s disease at 2 weeks. These data suggest that antibody neutralisation of TNFa is a potentially effective strategy in the management of Crohn’s disease. The use of CDP571 in Crohn’s disease requires further study.

Lancet 1997: 349:521-24

Divisions of Gastroenterology, University and City Hospitals, Nottingham ( W A Stack M R C P I , R Long FRCP, Prof C J Hawkey FRCP); St Mark’s Hospital, London ( S D Mann MRCP, A J Roy Pho, A Forbes FRCP, M A Kamm FRCP); Celltech Therapeutics Ltd, Slough (P Heath M R C P , M Sopwith MD); and Derby City and Royal Infirmary, Derby (J Freeman FRCP, G Holmes F R C P ) , UK Correspondence to: Prof C J Hawkey, Division of Gastroenterology, University Hospital, Nottingham NG7 2UH, UK

Vol 349 February 22, 1997

Introduction Increasingly, evidence suggests tumour necrosis factor-a (TNFa) is an important mediator in the pathogenesis of Crohn’s disease. Increased amounts have been detected in the intestinal mucosa and stools of patients with inflammatory bowel TNFa is linked to the development of granulomata‘ and has a central role in stimulating clonal expansion of T ~el1.s.~ Drugs that interfere with T-cell activation and expansion are of benefit in patients with active Crohn’s d i ~ e a s e . ~ - ~ Neutralising antibodies to TNFa inhibit TNFainduced T-cell activation and have proved effective in treatment of rheumatoid Data from uncontrolled studies suggest a substantial benefit in active Crohn’s disease.I3J4 We investigated a genetically engineered antibody to human TNFa, c D P 1 7 1 , ’ ~as a single intravenous infusion for patients with mild to moderately active Crohn’s disease, in a randomised, double-blind, placebo-controlled trial.

Methods Patients were eligible for inclusion in the study if aged 18-80 years with mild to moderately active Crohn’s disease, as indicated by a Crohn’s disease activity indexI6 between 150 and 400. A firm diagnosis of Crohn’s disease previously made on a combination of radiological and histological criteria was required. Patients were allowed to enter the study if receiving azathioprine ( 2 mg/kg daily or less and stable for > I month), salicylates (2.4 g mesalazine daily or less and stable for a1 week), or prednisolone ( < l o mg daily and stable for 3 2 weeks). The main exclusion criteria were: t r e a t m e n t with metronidazole, sodium cromoglycate, or cyclosporin within the previous 3 months, positive stool culture for enteric pathogens, perforation or significant obstructive symptoms, and a history of asthma. A negative pregnancy test at trial entry and effective contraception for G months after completing the study were also required. The study was approved by the ethics committee of each participating hospital. All patients gave informed written consent to take part in the trial. By standard in-house procedure of the quality assurance department of Celltech Biologics, patients were randomly assigned treatment with CDP571 or placebo, in blocks of three (twoione). The unbalanced randomisation was to ensure that the majority of patients received active treatment. Individual concealed randomisation code envelopes were held by the development division of Celltech Therapeutics Ltd and the pharmacy of each participating hospital. CDP571 at a dose of 5 mgikg was given as a 5 rngimL solution by slow intravenous infusion over 60 min. Patients assigned to placebo received an equivalent volume of human serum albumin, at a concentration of 5 mgimL. Patients were kept under direct observation during administration of CDP57 1 or placebo, and for 2 h afterwards. At baseline and 2, 4, 6, and 8 weeks after infusion, patients were reviewed in outpatient clinics. Patients kept a daily diary card recording wellbeing, abdominal pain, number of bowel actions, proportion of soft or liquid stools, use of loperamide, evening temperature, and key symptom score from 1 week before

52 1

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Mean (SO) age (years)

Placebo (n.10)

CDPS71(n=20)

38.6 (15.7)

4 1 6 (13.9)

w F

5 f5

Mean (SD) years from diagnosis

8.2 (7.4)

Site of disease Duodenum Ileum Right colon Transverse colon Left colon Rectum Perianal

0 8 3 2 3 4 3

Concomitant medication Prednisolone alone Azathioprine alone kathioprine and prednisolone Median (range) CDAl Median (range) Harvey-Bradshaw score

2

2 2 253 (235350) 6.4 (4-11)

I

J

9/11 10.4 (9.1)

I

Total base population about 2500

IEligible patients considered = 38

1

I Eligible patients registered = 31 I

16 11

10 11 11

5

I

(Randomised to CDP571= 2 1

5 4 5

I

J. Randomised to placebo = 10

+

analysis = 20

Available for primary analvsis = 1 0

Withdrawals = 4

+

Withdrawals = 2

8-week assessment = 1 6

8-week assessment = 8

263 (150-490) 10 (2-8)

CDAl=Crohn’s disease activity index.

Baseline characteristics of patients studied

to 8 weeks after infusion. Crohn’s disease activity index and Harvey-Bradshaw score” were calculated by direct questioning based on diary card records, clinical examination, and laboratory data. At the start of the study, patients identified a key symptom that was scored on a 10 cm visual analogue scale (O=excellent a n d lO=awful) a t each visit. C-reactive protein, a I-glycoprotein, and erythrocyte sedimentation rate were used as additional laboratory measures reflecting Crohn’s disease activity. Based on existing pharmacokinetic data” and results in patients with rheumatoid arthritis,”,” the main endpoints were changes from baseline in disease activity at 2 weeks. The primary endpoint was change in Crohn’s disease activity index and the main secondary endpoint was change in Harvey-Bradshaw index, in all patients randomised who had undergone at least one posttreatment efficacy measurement. Other secondary endpoints included changes in the key symptom score and in laboratory measures of Crohn’s disease activity. Remission of Crohn’s disease was defined as an activity index of 150 or less. Although it is possible that CDP571 could alter the natural history of the disease, we specified disease activity at 2 weeks as the primary endpoint because of the small number of patients. However, patients were followed up for 8 weeks to see whether there were any late changes that outlasted disappearance of the antibody. Wilcoxon signed rank-sum test was used for analysis of individual changes, from baseline to 2 weeks, in the primary and secondary endpoints. Calculations of sample size were based on published data giving an SD between patients for activity index of patients with active Crohn’s disease of 116.” The study was designed to have 80% power to detect a fall in Crohn’s disease activity index of 7 3 (two-sided a=0.05) o r 6 5 (two-sided a=O.lO). A two-tailed p value of 0.05 was regarded as significant.

+

Figure 1:Trial profile

75.5 pg/mL (95% CI 61 4-92.9) immediately after infusion and fell progressively over the next 2 months with an apparent mean half-life of 4-5 days (figure 2). In patients receiving CDP571, there was a significant fall in median Crohn’s disease activity index from 263 (IQR 186.5-323.5) to 167 (137.5-294.0; p=0.0003), at 2 weeks (figure 3). These changes were accompanied by significant reductions in the Harvey-Bradshaw score (figure 3 ) from 10 (6-12) to 5 (4.0-7.5; p=0.0005), and the key symptom score from 5.3 (3.1-7.0) to 3-9 (2.2-5.1; p=0.049). Six patients who received CDP571 achieved remission at 2 weeks, and three near remission (disease activity index S 156). Figure 4 shows changes in symptom scores and laboratory indicators of disease activity during the 8 weeks of follow-up. C-reactive protein concentrations fell in the CDP57 1-treated patients to values similar to the placebo group, but the reduction was not sustained after 4 weeks. Similarly, concentrations of (Y 1-glycoprotein and erythrocyte sedimentation rate fell significantly in the actively treated patients (p=0.012 and p=O.OI), but the changes did not persist.

ResuIts The baseline characteristics of the patients are shown in the table and the flow of patients through the trial in figure 1. The groups were fairly well matched for age and sex, but those assigned CDP571 had somewhat more active, extensive disease than placebo recipients. One patient did not attend for follow-up after infusion so could not be included in efficacy analyses, although 3 months later he was in remission. This patient was included in the safety analysis. Patients tolerated the CDP57 1 infusion well. Although five of the 21 patients receiving CDP571 reported mild adverse reactions on the day of infusion (including dizziness, abdominal pain, increased flatus), four of the ten placebo recipients experienced similar symptoms. CDP571 plasma concentrations rose to a mean of 522

Time since infusion (weeks) Figure 2: Mean (with 95% CI) CDP571 plasma concentrations ( I*g/mL)

-

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Harvey Bradshaw score

-

1816 -

400 -

3001

0

Placebo ~ ~ ~

5

7

1

14 12 -

300 -

10-

Q

-0-

8200 100

-c-

-

6-

42-

m 0’ -0 2 0 2 Week Week Figure 3: Changes in Crohn’s disease activity index (CDAI) and Harvey-Bradshaw score from baseline to 2 weeks after infusion of CDP571

In placebo recipients, the median Crohn’s disease activity index before treatment was 253 (240-334) compared with 247 (183-256) 2 weeks after treatment. The median Harvey-Bradshaw score was 6.5 (5-10) before and 6.5 (5-9) after treatment. The median key symptom score rose marginally from 4.8 (2-4.8) to 5.3 (2.2-6.7). No placebo recipients were in remission 2 weeks after infusion, but one had a Crohn’s disease activity index below 156. Of the six patients who achieved remission at week 2 in the CDP57 1 group, four were still in remission at week 6, and three at week 8. Three patients who received placebo improved spontaneously and achieved remission at week 8. Differences in the placebo and CDP571 reponses were not due to differences in the initial activity, since there was no correlation between initial activity and response. Moreover, at the 2-week assessment the Crohn’s disease activity index was lower among the treated than the placebo group. After 2 weeks, median scores tended to revert towards initial values (figure 4), and there was no significant difference from placebo at weeks 4, 6, and 8 which suggests that a major beneficial effect did not outlast the presence of the antibody. However, these later assessments should be interpreted with caution because some patients left the study after the primary assessment and the small numbers mean that the confidence intervals are wide. Concomitant treatment with azathioprine and prednisolone did not affect later responses to CDP57 1. On average there were 1.8 adverse drug reactions per patient for those receiving placebo and 2.05 for those receiving CDP571. Of these 0.01 per patient (placebo) and 0.14 per patient (CDP571) were probably related to treatment. In 7 patients, there was a small but significant and sustained rise in antibodies directed against CDP57 1. These patients did not develop any allergic symptoms.

Discussion CDP571 is a genetically engineered human antibody to T N F a . An antibody to TNFa was raised in BALB/C mice and the genetic sequence of the complementaritydetermining region and associated residues was determined. This was copied and transferred to a human y4 heavy chain and kappa light chain. The resultant antibody contains about 95% human and 5% murine sequences.15 CDP571 has minimal human immunogenicity and potent anti-TNFa neutralising

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February 22, 1997

p=0.0003

150J 11.5 7

1

12.5

5.0

1 1

l’*

0.8 I

0

I

2

I

4 Time (weeks)

I

6

1 8

Figure 4: Changes (median values) over 8 weeks in Crohn’s disease activity index (CDAI), Harvey-Bradshaw score, C-reactive protein, and d-glycoprotein p values for baseline to 2-week change in CDP571 group.

activity but does not bind or activate complement. Our data show that treatment with CDP571 is safe, and reduces disease activity in patients with mild to moderately active Crohn’s disease. These data further support the notion that T N F a has an important role in the pathogenesis of active Crohn’s disease. 523

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Beneficial changes in Crohn’s disease have been reported for another antibody to TNFa, cA2.I4cA2 differs from CDP571 in that it is a mousehuman chimera based on an IgG, temp1ate.I9 Its chimeric nature gives the cA2 antibody potential to induce antibodies to the murine part.2o Sustained improvements have been claimed in patients treated with the cA2 antibody, implying a diseasemodifying effect that outlives persistence of the antibody. Such an effect would be a theoretically important and clinically useful consequence of T N F u antibody treatment. Whether there is a sustained effect is difficult to judge, since cA2 was administered in an open and uncontrolled study, and many of the patients were also receiving high doses of corticosteroids.I4 Our study excluded patients taking more than 10 mg prednisolone daily. The primary purpose of the placebo group was to blind the study and allow objective assessment of changes in disease activity. Substantial placebo responses in Crohn’s disease activity index occur even when patients know they may receive placebo.l* This possibility was strongly emphasised to our patients and appears to have been successful in that changes seen in the placebo group in the first 2 weeks were negligible (figure 4). This finding, along with improvement of objective laboratory measurements in the CDP57 1-treated group, implies that the changes in actively-treated patients were attributable to CDP57 1. This effect was not maintained at later time points, although our pilot study was not initiated or designed to allow realistic assessment of efficacy at these times. In patients who received CDP571, the maximum effect appeared to reflect plasma concentrations; although some patients experienced sustained remission, others did not. We found no evidence of a therapeutic effect that outlasted the disappearance of CDP571 from the circulation. Elimination of CDP571 seemed to be somewhat faster than in an earlier formal pharmacokinetic smdy,15 and whether the use of higher or repeated dosing would result in a longer-term benefit requires further study. Previous studies in volunteers and patients with rheumatoid arthritis have shown that repeated doses of CDP571 can be given safely.”J5 Further studies are underway to define an optimum dose of CDP571 in Crohn’s disease, and to investigate the efficacy of repeated dosing. We thank Donna Hall, Claire Spencer, and Rosemary Dainty for preparation of the paper, Elizabeth Beaumont for the statistical analysis, and Nigel Cox for his help with the study. The protocol was developed in collaboration between Nomngham GI trials and Celltech Therapeutics Ltd UK and supported by a grant from Celltech Therapeutics Ltd UK.

524

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