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fresh from the pipeline

Certolizumab pegol
Gil Y. Melmed, Stephan R. Targan, Uma Yasothan, Delphine Hanicq and Peter Kirkpatrick
In April 2008, certolizumab pegol (Cimzia; UCB), a tumour-necrosis factor blocker, was approved by the US FDA for the treatment of adult patients with moderate-to-severe Crohn’s disease who have not responded to conventional therapies.
Crohn’s disease is a chronic inflammatory disorder of the gastrointestinal tract that has symptoms including abdominal pain and diarrhoea1,2. It is one of the two major forms of inflammatory bowel disease, with the other being ulcerative colitis, and together the two disorders are estimated to affect around 1.4 million people in the United States alone3. Traditional treatments for Crohn’s disease include 5-aminosalicylic acid, corticosteroids and azathioprine, but these have limited efficacy in a significant proportion of patients with more severe disease. An important advance came with the introduction of infliximab (Remicade; Centocor) in the late 1990s. Infliximab is a chimeric monoclonal antibody against tumour-necrosis factor-α (TNF-α), which has demonstrated efficacy in patients who do not respond to traditional therapies2,4. Since then, several other biologics have been investigated for the treatment of Crohn’s disease2,5. The fully human anti-TNF-α antibody adalimumab (Humira; Abbott) was approved by the FDA in 2007. This year, it has been joined by natalizumab (Tysabri; Elan/ Biogen-Idec), a humanized antibody against α4 integrin, and most recently, the PEGylated humanized anti-TNF-α antibody fragment certolizumab pegol (Cimzia; UCB). Basis of discovery Various lines of evidence suggest that Crohn’s disease is the result of an exaggerated response against constituents of the mucosal microflora by T cells, leading to the production of pro-inflammatory cytokines such as TNF-α1,2. Such evidence — together with studies showing the antiinflammatory effects of anti-TNF-α antibodies in animal models and the efficacy of antiTNF-α antibodies in rheumatoid arthritis — stimulated the evaluation of infliximab in patients with treatment-resistant Crohn’s disease4. The efficacy of infliximab in this setting led to its approval by the FDA in 1998, and encouraged the assessment of other TNF-α blockers in Crohn’s disease. Drug properties Certolizumab pegol (FIG. 1) is a recombinant, humanized antibody Fab′ fragment with specificity for human TNF-α (manufactured in Escherichia coli), conjugated to a ~40 kDa polyethylene glycol (PEG) to enhance plasma half-life5,6. It neutralizes membrane-associated and soluble human TNF-α, but in contrast to infliximab and adalimumab, it does not fix complement or cause antibody-dependent cell-mediated cytotoxicity in vitro, as it does not contain an Fc region5–7. Clinical data The safety and efficacy of certolizumab pegol were assessed in two double-blind, randomized, placebo-controlled studies in patients aged 18 years and older with moderately to severely active Crohn’s disease, as defined by a Crohn’s Disease Activity Index (CDAI) of 220–450 points6,8,9. The first study was a randomized, placebocontrolled trial involving 662 patients with active Crohn’s disease6,8. Certolizumab pegol (400 mg subcutaneously) or placebo was administered at weeks 0, 2 and 4, and then every 4 weeks up to week 24 (REFS 6,8). Clinical response was defined as at least a 100-point reduction in the CDAI score compared with baseline, and clinical remission was defined as an absolute CDAI score of 150 points or lower6,8. The primary end points were the induction of a response at week 6 and a response at both weeks 6 and 26 (REFS 6,8).
Certolizumab pegol

Infliximab Chimeric mouse–human IgG1 monoclonal antibody

Adalimumab Human IgG1 monoclonal antibody

At week 6, the proportion of clinical responders was statistically significantly greater for patients receiving certolizumab pegol compared with placebo (35% versus 27%, respectively)6,8. The difference in clinical remission rates was not statistically significant at week 6 (REFS 6,8). The difference between the proportion of patients who had a clinical response in the two groups at both weeks 6 and 26 was statistically significant (23% for patients in the certolizumab pegol group versus 16% for patients in the placebo group)6,8. The second study was a randomized treatment-withdrawal study in patients with active Crohn’s disease6,9. All patients who entered the study were initially dosed with 400 mg of certolizumab pegol at weeks 0, 2 and 4, and then assessed for a clinical response at week 6 (as defined by at least a 100-point reduction in the CDAI score)6,9. At week 6, a group of 428 clinical responders was randomized to receive either certolizumab pegol (400 mg) or placebo, every 4 weeks starting at week 8, as maintenance therapy through to week 24 (REFS 6,9). Non-responders at week 6 were withdrawn from the study6. The final evaluation was based on the CDAI score at week 26 (REFS 6,9). At week 26, a statistically significantly greater proportion of week-6 responders in the group receiving certolizumab pegol had a clinical response and were in clinical remission compared with the group receiving placebo (63% versus 36% in clinical response, and 48% versus 29% in clinical remission, respectively)6,9. Baseline use of immunosuppressants or corticosteroids had no impact on the clinical response to certolizumab pegol6. Tuberculosis, invasive fungal infections and other opportunistic infections, some fatal, have occurred in patients receiving certolizumab pegol, and the drug label contains a black-box warning of the risk of serious infections6. Indications Certolizumab pegol is approved by the FDA for reducing the signs and symptoms of Crohn’s disease and maintaining clinical response in adult patients with moderately to severely active disease who have had an inadequate response to conventional therapy6. ▶
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PEG PEG

Certolizumab pegol Humanized Fab′ fragment linked to two PEG molecules

Figure 1 | Characteristics of tumour-necrosis factor blockers. Adapted from REF. 5. Discovery Nature Reviews | Drug
NATURE REVIEwS | drug disCovery

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N e w s & a N a ly s i s
AnAlysis | Crohn’s DIsease
▶ Analysing issues for biologics in Crohn’s

disease are Gil Y. melmed, m.D., Director of Clinical Trials, and Stephan R. Targan, m.D., Director, at the Cedars-Sinai Inflammatory Bowel Disease Center, UClA School of medicine, los Angeles, California, USA.

Certolizumab pegol is the fourth monoclonal antibody drug to be approved for the treatment of Crohn’s disease, and the third in its class of TNF-α inhibitors. Importantly, the efficacy and safety of certolizumab pegol appear similar to infliximab and adalimumab, the other two TNF-α inhibitors approved so far10. Its place in the treatment armamentarium remains to be determined. Issues surrounding the use of antiTNF-α drugs in Crohn’s disease include clinical attenuation, use of concomitant immunomodulators and timing of treatment. Clinical experience with monoclonal antibodies in Crohn’s disease, as well as in rheumatoid arthritis, has demonstrated that attenuation of efficacy occurs, which is probably related to antibody formation against the drug. For patients who have an initial response to an anti-TNF-α agent but then lose their response over time or develop intolerance, evidence supports switching within-class to another agent, albeit with slightly diminished overall response to the second agent11. Given the similar efficacy and safety profiles of the approved anti-TNF-α drugs, the availability of certolizumab pegol may mean that decisions about which anti-TNF-α agent to start with Box 1 | Market for Crohn’s disease

or to switch to are increasingly influenced by factors such as cost and convenience. In this respect, certolizumab pegol is distinguished by its monthly, home-injection maintenance dosing. options for reducing attenuation of response include maintenance treatment, and concomitant use of 6-mercaptopurine, azathioprine or methotrexate. However, although such immunotherapy does reduce antibody formation, there is no clear evidence for improved clinical efficacy. Certolizumab pegol may induce neutralizing antibodies; in the PRECISE-2 study, 9% of patients had detectable antibodies against certolizumab pegol9. moreover, the small risks for serious infections and lymphoma have raised questions about using concurrent immunomodulators. It is expected that about two-thirds of patients with Crohn’s disease will respond to initial anti-TNF-α therapy, and those who do not respond are theoretically unlikely to improve with another anti-TNF-α agent. They may benefit from alternative agent types, such as natalizumab, a biologic that inhibits T-cell trafficking to the gut, which is approved for those not responding to or intolerant of anti-TNF-α therapy. A sub-analysis of the PRECISE-2 study of certolizumab pegol showed that improved response and remission rates were achieved in those with disease duration of less than 2 years. This phenomenon, noted in other studies as well12, suggests that early intervention with biologics may have greater beneficial impact

and potentially alter the natural history of the disease, in contrast to the traditional step-up approach of introducing sequentially more potent therapies. There is limited but growing evidence that top-down strategies may achieve steroid sparing, shorter time to remission and mucosal healing13. Finally, future and ongoing studies that identify immunological and genetic factors that are associated with response to anti-TNF-α and other biologic agents will ultimately improve the selection of patients with Crohn’s disease who are most likely to respond to early treatment, and thus optimize clinical benefit-to-risk assessments.
Gil. Y. Melmed and Stephan R. Targan are at the CedarsSinai Inflammatory Bowel Disease Center, UCLA School of Medicine, Los Angeles, California 90048, USA. Uma Yasothan and Delphine Hanicq are at IMS Health, 7 Harewood Avenue, London NW1 6JB, UK. Peter Kirkpatrick is at Nature Reviews Drug Discovery. e-mails: targans@cshs.org; UYasothan@de.imshealth. com; p.kirkpatrick@nature.com doi:10.1038/nrd2654
1. 2. 3. Bouma, G. & Strober, W. The immunological and genetic basis of inflammatory bowel disease. Nature Rev. Immunol. 3, 521–533 (2003). Korzenik, J. R. & Podolsky, D. K. Evolving knowledge and therapy of inflammatory bowel disease. Nature Rev. Drug Discov. 5, 197–209 (2006). Loftus, E. V. Jr. Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences. Gastroenterology 126, 1504–1517 (2004). Targan, S. R. et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor α for Crohn’s disease. Crohn’s Disease cA2 Study Group. N. Engl. J Med. 337, 1029–1035 (1997). Chang, J. T. & Lichtenstein, G. R. Drug insight: antagonists of tumor-necrosis factor-α in the treatment of inflammatory bowel disease. Nature Clin. Pract. Gastroenterol. Hepatol. 3, 220–228 (2006). Food and Drug Administration. FDA labelling information. FDA web site [online], <http://www.fda. gov/cder/foi/label/2008/125160s000lbl.pdf> (2008). Nesbitt, A. et al. Mechanism of action of certolizumab pegol (CDP870): in vitro comparison with other antitumor necrosis factor α agents. Inflamm. Bowel Dis.13, 1323–1332 (2007). Sandborn, W. J. et al. Certolizumab pegol for the treatment of Crohn’s disease. N. Engl. J. Med. 357, 228–238 (2007). Schreiber, S. et al. Maintenance therapy with certolizumab pegol for Crohn’s disease. N. Engl. J. Med. 357, 239–250 (2007). Peyrin-Biroulet, L. et al. Efficacy and safety of tumor necrosis factor antagonists in Crohn’s disease: meta-analysis of placebo-controlled trials. Clin. Gastroenterol. Hepatol. 6, 644–653 (2008). Sandborn, W. J. et al. Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial. Ann. Intern. Med. 146, 829–838 (2007). Colombel, J. F. et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM trial. Gastroenterology 132, 52–65 (2007). D’Haens, G. et al. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn’s disease: an open randomised trial. Lancet 371, 660–667 (2008). IMS Health Analysis, IMS MIDAS Quantum, MAT (2007).

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Analysing the market for anti-tnf-α therapies for Crohn’s disease are Uma yasothan and Delphine hanicq, ims health, london, UK. in 2007, the market for biologics to treat inflammatory bowel disease — in particular, Crohn’s disease and ulcerative colitis — was worth ~ Us$1 billion14. Analysts estimate that this market will continue to grow, reaching $5 billion by 2011. Agents against tumour-necrosis factor-α (tnf-α) are widely used to treat Crohn’s disease. infliximab (remicade; Centocor), a chimeric monoclonal antibody against tnf-α, has been used for nearly a decade. it had sales of $11.2 million in 2007 for the Crohn’s disease indication in the United states and in the five leading european markets (based on the number of prescriptions)14, a significant decrease from the previous year. in 2007, the human antitnf-α monoclonal antibody adalimumab (humira; Abbott), which is also approved for several other autoimmune diseases, was approved for Crohn’s disease. Adalimumab had sales of $51.4 million in Crohn’s disease in 2007, and has shown double-digit growth in overall sales in the past 2 years14. Certolizumab pegol (Cimzia; UCB) is a humanized, peGylated anti-tnf-α antibody fragment that was approved by the fDA in April 2008 for patients with moderate-to-severe Crohn’s disease who have not responded to conventional therapies. Analyst expectations for the sales of certolizumab pegol are initially ~$50 million in the year of launch. UCB has agreed to conduct further trials in Crohn’s disease that include paediatric, long-term observational and long-term safety studies, as well as re-exposure after a variable interval for patients who withdrew from previous studies. positive results from these trials could drive indication expansion and thus the sales expectations for certolizumab pegol, and would also address in part the safety issues inherent to any immunomodulatory agent.

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G.Y.M. and S.R.T. declare competing financial interests: see web version for details.

Competing financial interests

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