[MOL] New antibodies licenced for Crohn's Disease [00983] Medicine On Line

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[MOL] New antibodies licenced for Crohn's Disease

>Commentary Volume 355, Number 9207  11 March 2000
>Lancet 2000; 355: 858 - 859 Download PDF (62 Kb)
>The recent licensing in the USA and Europe of infliximab (Remicade, Centocor, USA), an antibody to tumour necrosis factor
>(anti-TNF-), for the treatment of Crohn's disease offers the potential to alter radically the course of severe cases of this
>disease. Another anti-TNF-, CDP571 (Celltech Chiroscience, Slough, UK), has been clinically evaluated but is not yet licensed for
>use. Controlled randomised trials of these antibodies have shown clinical benefit associated with tissue healing in patients with
>moderately to severely active intestinal disease and fistulae, some of whom were resistant to conventional therapies. However, the
>place of anti-TNF- in the treatment Crohn's disease has yet to be established.
>In infliximab the entire variable domain from a murine antibody is attached to a human IgG1 constant region, so the drug is about
>25% mouse and 75% human (chimeric). In CDP571 only the murine complementarity-determining regions participating in antigen binding
>are attached to a human IgG4 constant region, so the compound is about 5% mouse and 95% human (humanised). Humanised antibodies are
>less immunogenic than chimeric ones. Both infliximab and CDP571 bind free and membrane-bound TNF. The major apparent difference is
>that only infliximab activates complement and causes antibody-dependent cell cytotoxicity of activated CD4-positive T cells and
>There are four published randomised controlled trials of anti-TNF- for Crohn's disease in adults, one with CDP571, and three with
>infliximab (panel). The main measure of efficacy in these trials was a reduction in the Crohn's Disease Activity Index (CDAI), which
>combines clinical and laboratory variables. A score of less than 150 reflects remission, and a score of 200-400 reflects moderately
>active disease. Two of the trials defined a clinical response as a reduction in the CDAI of 70 points, but this drop does not
>necessarily bring the patient into the range reflecting remission. Moreover, fluctuations in subjective symptoms, such as general
>wellbeing, may influence the overall score.
>Anti-TNF- produces a rapid clinical improvement in about two-thirds of patients. The first trial of a single 5 mg/kg dose of CDP571
>in 31 patients with active Crohn's disease showed a fall in median CDAI count of from 263 to 167 (compared with a fall to 247 from
>253 in the placebo group).2 29% of treated patients were in remission at 2 weeks. However, the response lasted only about 2 weeks.
>In a recently presented trial of 169 patients treated with 10 or 20 mg/kg CDP571 every 8-12 weeks for 6 months, 64% of patients
>treated with the lower dose showed a response.3 In a dose-ranging study of 108 patients with active Crohn's disease given a single
>dose of infliximab, the 5 mg/kg dose was best.4 For all the doses combined, the clinical response rate was 65% at 4 weeks and 41% at
>12 weeks.4 A third of treated patients went into remission.4 An impressive feature of response was the restoration of severely
>ulcerated mucosa to normal in some patients, as judged endoscopically and histologically by assessors who were masked as to
>treatment received.5
>Patients unresponsive to one infusion generally do not respond to a further infusion, and the factors that determine lack of
>response are not known. Disease distribution does not seem to influence response.4
>A disabling complication of Crohn's disease is the development of fistulae, which are commonly not responsive to conventional
>treatment. In a trial of 94 patients with predominantly perianal fistulae, closure of at least half of the fistula occurred in 62%
>of patients on infliximab, and complete closure occurred in 46%.6 10% of patients developed an abscess at the fistula site, probably
>because skin closure occurred without track closure. Concomitant use of azathioprine or its metabolite 6-mercaptopurine seemed to
>encourage healing.6
>Placebo-controlled double-blind randomised trials of antibodies to TNF- in Crohn's disease
>Trial Drug Patient Group Follow-up Clinical response Remission or all
>          fistula closed
>Stack et al2 CDP571 CDAI 150-400 8 weeks Fall in median CDAI  CDAI<150 after
>(n=31) 5 mg /kg      after 2 weeks 2 weeks
>  (1 dose)     96 points (CDP571) 29% CDP571
>        6 points (placebo) Placebo not reported
>Targan et al4 Infliximab CDAI 220-400 12 weeks Fall in CDAI70 points  CDAI150 after
>(n=108) 5 mg/kg (37% on   after 4 weeks 4 weeks
>  10 mg/kg azathioprine)   65% infliximab  33% infliximab
>  (1 dose)     17% placebo 4% placebo
>Present et al6 Infliximab Draining perianal 14 weeks 50% reduction number  All fistula closed
>(n=94) 5 mg/kg or abdominal   of fistulae 46% infliximab
>  10 mg/kg fistula   62% infliximab 13% placebo
>  (1 dose)     26% placebo
>Rutgeerts Infliximab Patients who had 36 weeks Fall in CDAI70 points  CDAI150 after
>et al7 10 mg/kg  responded to a   after 8 weeks 8 weeks
>(n=73) 8 weekly single dose of   62% infliximab 53% infliximab
>  (4 doses) 5 mg/kg  37% placebo  20% placebo
>A key objective in the treatment of Crohn's disease is the maintenance of remission. The duration of the response to a single dose
>of anti TNF- is variable, with symptoms recurring in most patients after 6-12 weeks. In responders to a single dose of infliximab,
>four doses of 10 mg/kg of the drug given every 8 weeks maintained remission in half the patients.7 Azathioprine may prolong the
>response to individual doses.7
>Immunological therapies are potentially toxic. Infusions are generally well tolerated, although acute allergic reactions occur with
>about 5% of infusions. Repeat doses may lead to the development of antibodies against these drugs. Antibodies to infliximab develop
>in about 13% of patients with Crohn's disease treated with the drug7 and, although present in low titre in most cases, they increase
>the likelihood of infusion reactions, of shortened half-life of the drug, and of loss of clinical efficacy.8,9 Re-exposure to
>infliximab after a long interval may predispose to the development of a serum-sickness-like reaction, as occurred in a quarter of 40
>patients with Crohn's disease retreated with infliximab after 2-4 years.8 Low titres of antibodies to non-human antigens have been
>detected in 6% of patients treated with CDP571 (Celltech Chiroscience, unpublished). Anti-TNF- drugs may also induce antibodies to
>double-stranded DNA, although lupus-like syndromes have been reported only rarely. Serious infections have not not been commoner
>among groups treated with infliximab or CDP571 than among placebo-treated groups.2,4
>Reports of lymphoma after treatment with anti- TNF- have been a major concern.7 Five of 771 patients who have received infliximab
>for various disorders in controlled trials have subsequently developed lymphoma.10 One was being treated for Crohn's disease, three
>for rheumatoid arthritis, and one for AIDS. Another patient has developed lymphoma in open treatment. Rheumatoid arthritis and AIDS
>carry a disease-related increased risk of lymphoma, whereas the lymphoma risk in Crohn's disease remains controversial.11-13 There
>have been no reports of lymphoma with CDP571. Data on larger numbers of patients followed long term are needed to establish the real
>cancer risk.
>How then should infliximab, the licensed drug, be used? Because the body of evidence on clinical efficacy in maintenance of
>remission and long-term safety is greater for azathioprine12,14 than for other immunosuppressants, the former remains the drug of
>choice for patients with frequently recurring or chronic active disease. In the 10% of patients who are intolerant of or
>unresponsive to azathioprine, the therapeutic options are methotrexate, cyclosporine, and mycophenolate mofetil. Anti-TNF- is a
>potential option, but trials are needed to compare it with the other options and with the newer immunosuppressants, such as
>tacrolimus and thalidomide. Anti-TNF- also has a role for the ill patient in whom an effective treatment is urgently required while
>immunosuppression with azathioprine, which can take up to 6 months, is being established.
>Infliximab is licensed for a single infusion for severe active disease. One infusion of 5 mg/kg costs about UK£1920 for a 70 kg
>patient. Generally, if remission is induced it will need to be maintained with further drug therapy, such as azathioprine. Use of
>infliximab to maintain remission would cost over £12 000 per year. Whether patients are best treated by regular infusions or only as
>the condition demands remains to be established.
>For patients with symptom-producing fistulating disease, anti-TNF- could be considered after 6 months of treatment with azathioprine
>or 6-mercaptopurine. Early use of the antibody as primary therapy in patients with extensive severe perianal disease, while the
>effect of azathioprine is being established, may be useful, although there are no trial data for this effect. Abscesses should be
>drained. The presence of one or more surgically inserted sutures (setons) to maintain drainage may facilitate healing without
>infection. There is no evidence on use of the antibody for maintenance therapy in fistulous disease. In addition, there were too few
>patients for assessment of the value of this treatment for abdominal fistulae.
>Patients with active sepsis or a history of autoimmune disease or cancer are not suitable for anti-TNF-. Those known to have
>strictures have been excluded from trials because of concerns that rapid healing of narrowed segments may further narrow the lumen
>and provoke obstruction.
>Other means of diminishing production of TNF or blocking its activity have been investigated. Thalidomide inhibits TNF production
>and has been promising in small pilot studies, but it is teratogenic. Trials with recombinant soluble human TNF receptors attached
>to immunoglobulin protein (etanercept, Enbrel, Immunex, Seattle, WA, USA) are in progress. Recently, immunisation against self-TNF-
>has been described in mice.15
>In summary, although treatment with anti-TNF- has improved the quality of life for some patients with Crohn's disease, knowledge of
>its proper clinical role will come only with time.
>MAK has received funding from Centocor and Celltech Chiroscience for clinical trials of their antibodies to TNF-. Neither SB nor MAK
>has financial interests in either company.
>Sally Bell, *Michael A Kamm
>Department of Gastroenterology, St Mark's Hospital, Harrow, Middlesex HA1 3UJ, UK
>1 Scallon BJ, Moore MA, Trinh H, Knight DM, Ghrayeb J. Chimeric anti-TNF-alpha monoclonal antibody cA2 binds recombinant
>transmembrane TNF-alpha and activates immune effector functions. Cytokine 1995; 7: 251-59 [PubMed].
>2 Stack WA, Mann SD, Roy AJ, et al. Randomised controlled trial of CDP571 antibody to tumour necrosis factor-alpha in Crohn's
>disease [see comments]. Lancet 1997; 349: 521-24.
>3 Sandborn WJ, Targan S, Wolf SB, et al. A randomized, double-blind, placebo-controlled, multi-centre trial of the engineered human
>antibody to TNF (CDP571) for the induction and maintenance of clinical improvement in patients with moderate to severely active
>Crohn's disease. Gut 1999; 45 (suppl V): A133.
>4 Targan SR, Hanauer SB, van Deventer SJ, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor
>alpha for Crohn's disease. Crohn's disease cA2 Study Group. N Engl J Med 1997; 337: 1029-35 [PubMed].
>5 D'Haens G, Van Deventer S, Van Hogezand R, et al. Endoscopic and histological healing with infliximab anti-tumor necrosis factor
>antibodies in Crohn's disease: a European multicenter trial. Gastroenterology 1999; 116: 1029-34 [PubMed].
>6 Present DH, Rutgeerts P, Targan S, et al. Infliximab for the treatment of fistulas in patients with Crohn's disease. N Engl J Med
>1999; 340: 1398-405 [PubMed].
>7 Rutgeerts P, D'Haens G, Targan S, et al. Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (Infliximab)
>to maintain remission in Crohn's disease. Gastroenterology 1999; 117: 761-69 [PubMed].
>8 Hanauer SB, Rutgeerts P, D'Haens G, et al. Delayed hypersenstivity to infliximab (Remicade) re-infusion after a 2-4 year interval
>without treatment. Gastroenterology 1999; 116: A731.
>9 Baert FJ, Rutgeerts PR. Anti-TNF strategies in Crohn's disease: mechanisms, clinical effects, indications. Int J Colorectal Dis
>1999; 14: 47-51 [PubMed].
>10 Bickston SJ, Lichtenstein GR, Arseneau KO, Cohen RB, Cominelli F. The relationship between infliximab treatment and lymphoma in
>Crohn's disease. Gastroenterology 1999; 117: 1433-37 [PubMed].
>11 Greenstein AJ, Mullin GE, Strauchen JA, et al. Lymphoma in inflammatory bowel disease. Cancer 1992; 69: 1119-23 [PubMed].
>12 Connell WR, Kamm MA, Dickson M, Balkwill AM, Ritchie JK, Lennard-Jones JE. Long-term neoplasia risk after azathioprine treatment
>in inflammatory bowel disease. Lancet 1994; 343: 1249-52 [PubMed].
>13 Connell WR, Sheffield JP, Kamm MA, Ritchie JK, Hawley PR, Lennard-Jones JE. Lower gastrointestinal malignancy in Crohn's disease.
>Gut 1994; 35: 347-52 [PubMed].
>14 Connell WR, Kamm MA, Ritchie JK, Lennard-Jones JE. Bone marrow toxicity caused by azathioprine in inflammatory bowel disease: 27
>years of experience. Gut 1993; 34: 1081-85 [PubMed].
>15 Dalum I, Butler DM, Jensen MR, et al. Therapeutic antibodies elicited by immunization against TNF-alpha. Nat Biotechnol 1999; 17:
>666-69 [PubMed].
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Warmly, lillian
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