Certolizumab pegol for the management of Crohn's disease in adults

Clinical Therapeutics/Volume 31, Number 6, 2009

New Drug

Certolizumab Pegol for the Management of Crohn's Disease in Adults Anastasia Rivkin, PharmD, BCPS

Arnoldand Marie Schwartz College ofPharmacy and Health Sciences) Long Island University, Brooklyn) New York ABSTRACT Background: Crohns disease (CD) is an inflammatory disorder that can affect any portion of the gastrointestinal tract, from the mouth to the rectum. The American Gastroenterological Association recommends that treatment with anti-tumor necrosis factor (TNF)-a be considered in patients with moderate to severe CD refractory to concomitant aminosalicylates, corticosteroids, or immunosuppressive treatment, or who have contraindications to or poor tolerance of these agents. Anti-TNF-a agents available in the United States for the management of CD are infliximab, adalimumab, and certolizumab pegol. The latter is a recombinant humanized antibody Fab' fragment against TNF-a. It is conjugated with a 40-kDa polyethylene glycol molecule to increase the t 1l2 of the treatment to ~2 weeks. Objective: The objective of this review was to extract and assess all relevant available data on the efficacy and tolerability of certolizumab pegol in the treatment of CD. Methods: Searches of MEDLINE and International Pharmaceutical Abstracts from 1985 to March 3, 2009, were conducted using the key terms certolizumab pegol, CDP870. and Crohn's disease. Data from all available clinical trials published in English and ongoing trials were included in this review. The reference lists of the identified articles were searched for additional references. Data from abstracts presented at the annual meetings of the American College of Gastroenterology and Digestive Disease Week from 2004 to 2008 were reviewed and included if relevant. Results: A total of 8 studies were included in this review (1474 patients). In Phase II trials, there were no significant differences between certolizumab pegol and inactive vehicle (placebo) in week-4 or week-12 clinical response or remission rates. In the first of 1158

2 Phase III clinical trials, certolizumab pegol was associated with significantly greater rates of response compared with placebo at weeks 6 (37% vs 26%; P = 0.04) and 26 (22% vs 12%; P = 0.05) of induction treatment (data from patients with baseline CRP concentrations ::::10 mgIL). Response was defined as a decrease from baseline in CD activity index ::::100 at week 6 and at both weeks 6 and 26 in patients with baseline C-reactive protein ::::10 mg/L. Remission rates were not significantly different between the 2 groups. In the second Phase III trial, the proportion of patients in whom response was sustained up to 26 weeks was significantly greater with certolizumab pegol compared with placebo (63% vs 36%; P < 0.001). The tolerability profile of certolizumab pegol was similar to those of other anti-TNF-a agents and included an increased risk for infections (including opportunistic infections leg, tuberculosis]) compared with placebo. Infusion and injection-site reactions were infrequent (3%) with certolizumab pegol treatment. The most common adverse events reported with certolizumab pegol treatment included upper respiratory infection (20%), immunogenicity (8%), and urinary tract infection (7%). No new unanticipated adverse events emerged during the 30-month tolerability follow-up. Certolizumab pegol is being assessed in patients with CD refractory to other medications, including other biologic agents. Conclusions: Based on the findings from the present review, certolizumab pegol had moderate efficacy in the treatment of moderate to severe, active CD. In well-designed Phase III clinical trials, certolizumab peg01 was associated with significantly greater response Accepted for publtcation April 28, 2009 dotl 0.1 016/J.c1lnthera.2009.06.01 5 0149-2918/$ - see front matter

© 2009 Excerpta Medica Inc. All rights reserved.

Volume 31 Number 6

A. Rivkin

rates compared with placebo at weeks 6 and 26 of induction treatment. In patients who responded to the 6-week induction, certolizumab pegol administered as a monthly subcutaneous injection was effective in maintaining CD response and remission. Findings from studies of certolizumab pegol in refractory CD are awaited. (Clin Ther. 2009;31:1158-1176) © 2009 Excerpta Medica Inc. Key words: certolizumab pegol, Crohns disease, anti-TNF-a agent, biologic agent.

INTRODUCTION Crohns disease (CD) is an inflammatory disorder that may affect any portion of the gastrointestinal tract, from the mouth to the rectum. The large bowel is involved in 40% to 55% of patients with CD; small bowel, in ~30% to 40%; and colon, in 15% to 25%.! The incidence of CD is on the rise. 2 ,3 According to epidemiologic data from Olmsted County, Minnesota, the incidence of CD increased from 133 cases per 100,000 population in 1991 to 174 cases per 100,000 in 2001, representing a 31 % increase.i-" In 2003, between 10,000 and 47,000 of new CD diagnoses were made in the United States and Canada; ~630,000 patients have been diagnosed with CD in those 2 countries.> In 2000, the direct and indirect costs of managing patients with CD in the United States were estimated at $826 million.f CD is more prevalent in northern regions of the world. The 2004 incidence of CD was greatest in people from North America and Northern Europe (0.7-15.6 cases per 100,000 person-years), followed by Asia (0.5-4.2 cases per 100,000 person-years). The incidence of CD was lowest in people from Latin America (0-0.03 cases per 100,000 person-years) and Africa (0.3-2.6 cases per 100,000 person-years}.' CD may occur at a slightly higher rate (0%-10%) in females compared with males." The incidence of CD was primarily highest in people in their 20s or 30s and secondarily in people in their 50s and 60s. 5 CD generally occurs due to the combination of genetic predisposition, environmental factors, and immune system defects.f Exposure to certain intestinal antigens is thought to trigger an abnormal immune response that might lead to the development of CD in genetically predisposed individuals.S? A decreased tolerance threshold for a patient's own gastrointestinal bacteria or a sole enteric pathogen June 2009

might be the antigen that triggers CD development. Several bacteria and viruses have been implicated in CD development. However, data are inconclusive.s-l'' Abnormal adaptive immune system responses have been observed with both humoral and cell-mediated immunity. Several antibodies, produced by B cells, against microbial components have been identified in patients with CD. Defects in T-cell function include exaggerated T helper (Th) 1 and Th17 responses and defects in apoptosis and regulatory T-cell function. 8 Thl cells predominantly produce interferon and induce transmural granulomatous inflammation. Several genetic defects have been associated with CD. In a study in 180 patients with CD, 70 patients with ulcerative colitis, and 97 controls, a nucleotidebinding oligomerization domain 2 or caspase activation and recruitment domain 15 (NOD-2/CARD-15) genetic mutation was found in ~30% of patients with CD compared with 15% of healthy individuals." Several other genetic polymorphisms have been reported in patients with CD, many linked to regulating innate immune response.f Histologically, CD is characterized by multiple transmural areas of inflammation, which can lead to the development of fistulas, fibrosis, strictures, and/or intestinal obstruction. Macrophages aggregate within local intestinal ulcerations, forming noncaseating granulornas.! The signs and symptoms of CD sometimes overlap with those of other gastrointestinal and extraintestinal illnesses, making the diagnosis of CD in clinical practice challenging. Patients commonly present with symptoms of diarrhea (sometimes bloody), abdominal pain, fever, and weight loss. Cachexia, pallor, abscesses, and fistulas are common clinical signs of CD. Some complications of CD include malabsorption syndromes, intestinal obstruction, gastrointestinal carcinomas, and lymphomas. 1,1 1,12 CD is diagnosed based on endoscopic findings with biopsy combined with clinical signs and symptoms. Radiologic assessment is recommended in some cases but usually is not useful as the sole diagnostic tool. Alternative causes of intestinal inflammation, such as infectious, ischemic, or other inflammatory bowel diseases, should be ruled out. Several antibody tests may be useful for the diagnosis of CD in conjunction with other diagnostic tools. These tests include antineutrophil cytoplasmic antibodies and anti-Saccharomyces cereuisiae antibodies.l-' However, these antibodies have limited sensitivity and specificity and are not recom1159

Clinical Therapeutics

mended in the American College of Gastroenterology (ACG) guideline to be used for CD screening.J? C-reactive protein (CRP) concentrations can be obtained but are not specific for CD inflammation. 1 Tumor necrosis factor (TNF)-a plays an important role in CD pathophysiology. TNF-a is a 51-kDa cytokine secreted by monocytes, macrophages, and Tlymphocytes. TNF-a may play an important role in proinflamrnatory signaling, neutrophil recruitment to the sites of inflammation, activation of coagulation and fibrinolysis pathways, and initiation of granuloma formation. Increased TNF-producing cells, as well as increased secretion of TNF-a from lamina propria cells, are commonly found in patients with active CD. 14,15 On colonic biopsy in patients with active CD, TNF-a secretion is enhanced, but there are depressed amounts of soluble TNF receptor in lamina propria mononuclear cells.16 TNF-a concentrations in the stool and blood in children with active CD are elevated, making TNF-a an important target of pharmacotherapy for CD.17,18 Guidelines for the management of CD were published in 2001 and updated in 2009. 11,12 Treatment options vary depending on disease severity, location, and complications. Mild to moderate CD is generally treated with aminosalicylates (mesalamine or sulfasalazine), metronidazole, or ileal-release budesonide. In moderate to severe disease, guidelines advocate the use of systemic oral corticosteroids (prednisone) for symptomatic exacerbations, and immunosuppressants (azathioprine, 6-mercaptopurine, or methotrexate) for the maintenance of remission. The American Gastroenterological Association (AGA) recommends the addition of antiTNF-a agents in patients with disease refractory to concurrently administered aminosalicylates, corticosteroids, and immunosuppressants, or who have contraindications to or poor tolerance of these agents. 19 Natalizumab, the humanized antibody to a 4 integrin, can be used in patients with disease refractory to, or who are unable to tolerate, standard CD medications and antiTNF-a agents. Patients with severe fulminant disease should undergo hospitalization and surgical consultation for the assessment of abscess formation. Parenteral corticosteroids are indicated in the absence of abscess. The AGA guideline recommends not using antiTNF-a agents for severe fulminant CD due to a lack of clinical data in this setting. Perianal and fistulizing disease should be managed using surgical drainage, antibiotics (metronidazole with or without ciprofloxacin), immunosuppressants, or infliximab. 1160

For maintenance of response or remission, the AGA guideline advocates the use of immunosuppressive agents (azathioprine, 6-mercaptopurine, or methotrexate), as well as anti-TNF-a agents (infliximab, adalimumab, or certolizumab pegol).12 Natalizumab has also been found to be effective for maintenance. However, its use has been associated with an increased risk for reactivation of latent virus associated with central nervous system infection, possibly leading to progressive multifocal leukoencephalopathy. To minimize the risk for this complication, natalizumab should be administered only as monotherapy, and patients willing to receive natalizumab are required to enroll in the mandatory safety-monitoring program. Mesalarnine, metronidazole, infliximab, or immunosuppressive maintenance treatment reduces the risk for symptomatic recurrence of CD after ileocolonic resection. To specifically address the appropriate use of biologics in inflammatory bowel disease, the AGA issued a consensus statement in 2007 based on available evidence.!? According to the statement, anti-TNF-a treatment should be considered in patients with moderate to severe CD refractory to concurrently administered aminosalicylates, corticosteroids, or immunosuppressive treatment, or who have contraindications to or poor tolerance of these agents. Anti-TNF-a agents may also be indicated in patients who are corticosteroid or immunosuppressor dependent or refractory. However, this indication has not been assessed with certolizumab pegol. Treatment with an anti-TNF-a agent may also be tried in patients who have not responded to treatment with other anti-TNF-a agents. However, this indication has not been approved by the US Food and Drug Administration (FDA).Patients with CD complicated by fistulas or extraintestinal symptoms may derive additional benefit from anti-TNF-a agents. However, fistula closure rates with certolizumab pegol have not been adequately assessed. Emerging data on biologic agents in CD and other diseases suggest a potential to modify disease progression. However, due to insufficient evidence, the consensus statement does not recommend their use as firstline agents. 20,21 Use of biologic agents before treatment with corticosteroids may be considered in some scenarios, such as poor tolerance of or contraindications to corticosteroids. The CD activity index (CDAI) is a validated scale derived from the assessment of the occurrence of symptoms over 7 days in patients with CD.22 The CDAI consists of 8 components: number of liquid stools, Volume 31 Number 6

A. Rivkin

severity of abdominal pain, perception of general wellbeing, number of disease-related complications, use of diphenoxylate or loperamide for diarrhea, presence of abdominal mass, hematocrit level, and weight. CDAI scores (0 = not severe to 600 = extremely severe) can be used to assess baseline disease activity and the efficacy of CD treatments. CDAI 0:;150 is consistent with disease remission, whereas ::::450 indicates very severe disease. A CDAI score decrease from baseline of 60 to 100 defines clinical response to CD treatment.vOther validated tools are available for the assessment of CD activity. However, the CDAI has been most widely used for >25 years to assess the efficacy of CD trearments-"; therefore, it is considered the assessment tool of choice by the AGA.1 9

CDP870. and Crohn's disease. Data from all available published clinical trials in the English language and ongoing trials were included. Ongoing trials were identified using the clinicaltrials.gov Web site. Due to the paucity of available studies, study design was not specified in the inclusion criteria. The reference lists of the identified articles were also searched for additional references. Abstracts presented at the annual meetings of the ACG and Digestive Disease Week from 2004 to 2008 were reviewed and included if relevant.

The Inflammatory Bowel Disease Questionnaire (IBDQ) is a validated 32-item quality-of-life assessment tool that focuses on patients' perceptions of bowel function, emotional status, systemic symptoms, and social functioning. Scores range from 32 to 224, with lower scores indicating a poorer quality of life. The IBDQ is frequently used to assess secondary end points in clinical trials of CD treatments. 23,24 The AGA recommends that anti-TNF-a treatment be considered in moderate to severe CD that does not respond to concurrent aminosalicylates, corticosteroids, or immunosuppressive treatment, or in patients who have contraindications to or poor tolerance of these agents. 19 The anti-TNF-a agents available in the United States for the management of CD are inflixirnab, adalimumab, and certolizumab pegol. The latter is a recombinant humanized antibody Fab' fragment against TNF-a. It is conjugated with a 40-kDa polyethylene glycol molecule to increase the tIll of the treatment to ~2 weeks.P Certolizumab pegol was approved by the FDA in 2008 for reducing signs and symptoms of CD and maintaining clinical response in adult patients with moderate to severe active disease who have had an inadequate response to conventional treatment. It was approved by the FDA in 2009 for treatment of adults with moderate to severe active rheumatoid arthritis. The objective of the present review was to extract and assess all relevant available data on the efficacy and tolerability of certolizumab pegol in the treatment of CD.

Mechanism of Action/Pharmacology of Certolizumab Pegol Certolizumab pegol is a recombinant humanized antibody Fab' fragment against TNF-a. It is conjugated with a 40-kDa polyethylene glycol molecule to increase t 1l2 to ~2 weeks.P Certolizumab pegol selectively binds and neutralizes human membrane-bound and soluble TNF-a without neutralizing TNF-~. Certolizumab pegol lacks the fragment crystallizable (Fc) region generally present on all intact antibodies. Due to this structural feature, certolizumab pegol does not induce apoptosis of activated lymphocytes and monocytes in vitro. 26 In addition, certolizumab pegol does not induce in vitro complement-mediated cytotoxicity or antibody-dependent cellular cytotoxicity in cells expressing membrane TNF,27 This is in contrast to other anti-TNF-a-agents, infliximab, adalirnumab, and, to a lesser degree, etanercept-which have been associated with apoptosis, complement-mediated cytotoxicity, or antibody-dependent cellular cytotoxicity in vitro due to the presence of intact human immunoglobulin G1 Fc. 27,28 Due to the established efficacy of inflixirnab and adalimumab in CD, the induction of apoptosis was considered to have an important role in the mechanism of action of these agents in CD. However, the clinical efficacy of certolizumab pegol in patients with CD, despite a lack of ability to induce apoptosis, may be explained by other mechanisms associated with the efficacy of anti-TNF-a agents in CD.26

MATERIALS AND METHODS Searches of MEDLINE and International Pharmaceutical Abstracts from 1985 to March 3, 2009, were conducted using the key terms certolizumab pegol,

Pharmacokinetic Properties Limited data available on certolizumab pegol pharmacokinetics come from 2 small studies in 40 healthy male volunteers.i" Single-dose certolizumab pegol was

June 2009

RESULTS A total of 8 clinical studies were included in this review (1474 patients).

1161

Clinical Therapeutics

administered at 20, 60, and 200 mg SC (n = 24) or at 0.3, 1,3, and 10 mg/kg IV infusion over 1 hour (n = 16). Certolizumab pegol exhibited linear pharmacokinetics, with increases in mean serum Crn ax and AUC proportional to the dose increase.i" The mean elimination t 1l2 was 311 hours. The mean apparent volume of distribution was 45 mL/kg, and the mean clearance rate was 0.72 mLlkg/h. Pharrnacokinetic modeling predicted a bioavailability of nearly 100%. According to the prescribing information, the bioavailability of subcutaneously administered certolizumab pegol ranges from 76% to 88% compared with that of intravenous certolizumab pegol administration (100%).30 The route of certolizumab pegol elimination has not been established. The literature search did not identify any studies on the pharmacokinetics of certolizumab pegol in patients with renal or hepatic impairment. According to the manufacturer, renal impairment may alter the pharmacokinetics of the polyethylene glycol fraction of the certolizumab pegol molecule.I'' However, no data are available to make specific dosing recommendations. The numbers of patients with hepatic impairment in clinical trials have been insufficient for the recommendation of certolizumab pegol dose modifications.

Special Populations The mean ages of patients included in the 2 large Phase III studies of certolizumab pegol were 37 and 38 years. 31,32 The clinical development program of certolizumab pegol did not include a sufficient number of patients aged >65 years. 31-34 According to the manufacturer, there were no apparent differences in certolizumab pegol pharmacokinetics based on age. 30 Caution is recommended in treating elderly patients with certolizumab pegol due to a potential increased risk for infectious complications. Certolizumab pegol use has not been assessed in patients <18 years of age. Certolizumab pegol is classified as pregnancy category B based on a study in which doses up to 100 mg/kg were not associated with harm to the fetus or mother in a rat model. No reproductive studies of certolizumab pegol in humans have been conducted.I"

Drug-Drug Interactions According to the manufacturer, concurrent administration of certolizumab pegol and anakinra or other anti-TNF-a agents is not recommended due to a potential increased risk for serious infection or neutropenia.s'' 1162

Concurrent administration of certolizumab pegol and live or attenuated vaccines is not recommended. Administration of certolizumab pegol may be associated with falsely elevated activated partial thromboplastin time. However, it has not been associated with changes in coagulation parameters.I'' Preclinical Studies Anti-TNF-a agents have been compared in in vitro studies to assess their relative potency in neutralizing soluble and membrane bound TNF-a. 26,35 Certolizumab pegol, infliximab, and adalimumab have similar potency in neutralizing membrane-bound TNF-a signaling through p55 and p75 TNF-a receptors, both expressed in many cell types. Certolizumab pegol was found to be at least 2-fold more potent than infliximab and adalimumab in neutralizing soluble TNF-a signaling-" The mechanism of action and comparative efficacy of anti-TNF-a agents were assessed using a TNF 6.5 cell line, which expressed human TNF-a on cell surface (membrane bound) and in secreted form (solublel.i" The relative potency in neutralizing soluble TNF-a by 4 anti-TNF-a agents was assessed in 2 cell-based in vitro systems: measurement of soluble TNF-a-induced death of murine L 929 cells and soluble TNF-a-induced luciferase activity. Etanercept, adalimumab, infliximab, and certolizumab pegol were associated with neutralized soluble TNF-a in both in vitro systems. Similar to results obtained from the prior study,35 in the L 929 cell line, certolizumab pegol was associated with a stronger potency to neutralize soluble TNF-a signaling compared with infliximab and adalimumab (concentrations required to neutralize 90% of the soluble TNF-a in the assay, 3, 9, and 9 ng/mL, respectively). Binding to membrane TNF-a was measured using fluorescence-activated cell sorter analysis of the TNF 6.5 cell line. All 4 agents were associated with concentration-dependent, membrane-bound TNF-a inhibition. Inhibition of membrane-bound TNF-a mediated signaling was not significantly different between certolizumab pegol, inflixirnab, and adalimurnab. However, etanercept was 2-fold less potent.i''

Efficacy Clinical Studies Phase /I A Phase II, multicenter, randomized, double-blind, placebo-controlled, dose-response study assessed the efficacy and tolerability of 3 certolizumab pegol doses Volume 31 Number 6

A. Rivkin

in patients with moderate to severe CD (Table).33 A total of 292 patients were randomly assigned to receive certolizumab pegol100, 200, or 400 mg or inactive vehicle (placebo) SC at weeks 0, 4, and 8. The majority of patients (78.1 %) received the full course of study medication. Most of the patients (96.6%) were white, and the proportions of women were 14% to 17% higher in the certolizumab pegol 200-mg and placebo groups compared with the certolizumab pegol 100- and 400-mg groups, respectively. Otherwise, baseline characteristics were well balanced between the 4 groups. The primary end points were the percentages of patients who achieved clinical response (decrease from baseline CDAI ::::100) and clinical remission (overall CDAI 0:;150) at week 12. IBDQ scores, CDAI, and tolerability were assessed every 2 weeks until week 12. After trial completion, an extended week-20 tolerability assessment was conducted.v' At week 2, all 3 doses of certolizumab pegol were associated with significantly higher clinical response rates compared with placebo (29.7%, 30.6%, and 33.3 % with 100, 200, and 400 mg, respectively, vs 15.1 % with placebo; P = 0.033, P = 0.026, and P = 0.01, respectively). Compared with placebo, the clinical response rates were significantly greater with certolizumab pegol 200 and 400 mg at week 4 (P 0:; 0.05 and Po:; 0.01, respectively), certolizumab pegol100 and 400 mg at week 8 (P 0:; 0.05 and Po:; 0.01), and certolizumab pegol400 mg at week 10 (P 0:; 0.01). The week-12 response rates were not significantly different between certolizumab pegol and placebo (mean [95% CI]: 36.5% [24.8%-48.1 %],36.1 % [24.3%-47.9%], and 44.4% [32.3%-56.6%] with 100, 200, and 400 mg, respectively, vs 35.6% [23.9%-47.3%] with placebol-" Clinical remission was achieved with all 3 certolizumab pegol doses at week 4 (P 0:; 0.05). At week 8, remission rates were significantly greater with the 100- and 400-mg doses than placebo (both, P 0:; 0.01). The week-12 remission rates were not significantly different between certolizumab pegol and placebo (mean [95% CI]: 27% [16.2%-37.8%],19.4% [9.6%-29.3%], and 26.4% [15.5%-37.3%] with 100,200, and 400 mg, respectively, vs 23.3% [12.9%-33.7%] with placeboi.f The lack of statistically significant differences in the primary end point was probably due to the unusually high placebo response rate in this study-35.6% at week 12 compared with the expected 12% in the power analysis calculation. Other contributing factors June 2009

may have been the inclusion of patients with concomitant undiagnosed irritable bowel syndrome or inflammatory processes, as well as misclassification of the severity of CD at baseline (ie, the inclusion of patients with mild disease).36 CRP concentrations were significantly reduced at weeks 2 and 4 in the 100- and 400-mg certolizumab pegol groups, respectively, compared with placebo (95% CIs for the mean CRP concentrations did not overlap). Over 12 weeks, the 200- and 400-mg certolizumab pegol doses were associated with suppression of CRP that was not significantly greater compared with those with the 100-mg dose or placebo (absolute difference in CRP geometric means, ~2 mg/dL), suggesting that certolizumab pegol has an anti-inflammatory effect. Therefore, CRP may be a better objective measure of disease activity compared with CDAI, which has a high subjective component and might contribute to high placebo response rates.I" In an attempt to clarify study findings, a post hoc analysis was conducted to stratify response and remission rates according to the baseline CPR concentrations.s-' It has been proposed that some patients with low CRP concentrations may not have active CD despite having increased CDAI scores.I" Of 290 patients in whom baseline CRP concentrations were available, 119 (41%) had CRP concentrations ::::10 mg/L. When only patients with elevated CRP concentrations were included in the efficacy analysis, certolizumab pegol 400 mg was associated with significantly improved response rates (all, P 0:; 0.01) and remission rates (all, P 0:; 0.05) at all time points through 12 weeks. In patients with low baseline CRP concentrations, patients who received certolizumab pegol did not achieve clinical responses that were significantly greater than those in the placebo group. In fact, the placebo response at week 12 was greater than those found with active treatment. Certolizumab pegol antibodies were detected in 12.3 % of patients in the 400-mg group (data for other doses were not reported). However, clinical response rates were not different in those patients compared with those in whom antibodies were not detected.v' IBDQ scores were significantly improved in patients who received certolizumab pegol 400 mg compared with placebo throughout the 12-week study period (all, P < 0.05). At week 12, mean (SD) IBDQ scores were ~ 16 points higher with certolizumab pegol 400 mg compared with placebo (156.4 [37.36] vs 140.5 [35.88]; P < 0.05).33 1163

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Tab le. Summ ary of key pub lished Phase II a nd III clinical stud ies of ce rto lizumab pegol in patien ts with Crohn 's dis ease (CD).

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Design Pha se II , multi center, rand omi zed , doub le b lind, placeb o co nt ro lled dose resp on se

No . of Patients

Inclusion/ Exclus io n Crit eria

292

Inclu sion: Age ~ 1 8 yea rs Mod er ate to severe CD (CDAI 220-4 50) Exclus io n: Intestinal a bsce ss, perforati o n, bowel resection , a fun ction al co losto my o r ileo stomy Presen ce of co lo nic pa th ogen History of tubercul osis Treatm en t with sodium cro mog lycate, mycoph enol ate, o r cyclospo rine in the 4 weeks before t he stu d y Receipt of an a nt i-T NF age nt in th e 12 weeks before th e stu d y Pati ents who expe rienced a n immu ne-m edi ated infusion reaction to a prior a nt i-TNF treatment o r nonresp o nse to prior a nt i-T NF tr eatment

Study Dru gs

End Po ints

Certolizum a b pegol 100, 200, or 400 mg or placeb o SC a t weeks 0, 4, a nd 8, with a 20 -week to lera bility exte nsio n beginning at week 12

Prima ry end point: Percentage of pa tients ac hieving clinical resp on se (decrea se from bas elin e CDAI ~ 1 0 0 o r increase from baseline) or remission (o ve ra ll CDAI ~ 1 5 0 ) at week 12 Secondary e nd points: IBDQ scores, CDAI, and tol erab ility

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Findin gs

III

Week-12 response rates were not s ignific a nt ly different between ce rto lizuma b pego l a nd p laceb o (36.5% [95% CI, 24 .8%-48 .1 %] with 100 mg; 36 .1% [95 % CI, 24 .3%-47.9%] with 200 mg ; 44.4% [95% CI, 32.3%- 56 .6%] with 400 mg; vs 35.6% [95% CI, 23.9-47.3] with p laceb o). Week-12 remi ssion rates were not sign ifica ntly different bet ween ce rt o lizuma b pego l and placebo (27 % [95% CI, 16 .2%- 37.8%] w ith 100 mg ; 19.4% [95% CI, 9.6%-2 9.3%] wit h 200 mg; 26.4% [95% CI, 15 .5%- 37.3%] with 400 mg; vs 23.3% [95% CI, 12 .9%- 33 .7%] with p laceb o).

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Study Winter et a l34

Desig n Pha se II , multi cen t er, sing le do se, d oub le b lind , pla ceb o co nt ro lled, paral lel gro u p

No . of Pa tien t s

Inclu sion / Exclusio n Criteria

92

Inclu sion: Age ;:::18 years Moder ate to seve re CD (CDAI 22 0 -450) Exclus io n: Fistula a bscess, ulcer a t ive co litis Bow el per fora tion , o bst ruc t io n, o r exte nsive res ection Fun ctional co losto my o r ileo stomy Presen ce of co lo nic pa th o gen History of se rious infection s or tuber cu losis Treated with a nt i-T NF age nts eit he r in clinical pr a ctice o r in a clinical t ria l in t he 12 weeks before th e stud y History of immun emedi a ted infu sion rea ction to a prior a nt i-TNF tr eatment o r non respon se to a nt i-T NF tr ea tm en t

Study Dru gs

End Po ints

CDP870 5, 10, o r 20 5 mg/kg o r pla ceb o IV over 3 0 minu tes (single d ose)

Coprimarye nd po int: Pe rcenta ge of pati ents ac hieving clini ca l resp o nse (dec rease in CDAI sco re by ;:::10 0 o r incr ea se from bas eline) a nd clinica l rem ission (overall CDAI :S: 150) at wee k 4 Secondary e nd poin t s: Clinical resp onse a t week s 2,8 , a nd 12 Percentage of pa tients ac hieving CDAI ;:::70; CRP co nce nt ra t io n; to lera bility to 12 week s a fter a d m inist ratio n

Find ings Week-4 resp on se rat es wer e no t signif ica nt ly d iffe rent between CDP8 70 a nd pla ceb o (60% [95% CI, 38 .8%-81.2%] with 5 mg/kg ; 58 .8% [95% CI, 32. 5%-85.2% ] with 10 mg/ kg ; 47.8% [95% CI, 25. 2%- 70.4%] w ith 20 mg/kg; vs 5 6% [95% CI, 34. 5%- 77.5%] with pla ceb o). Week-2 clin ica l remission was ac hieved in s ignifica nt ly more pati ents in 10 mg/ kg CDP 870 g ro u p co m pa red with pla ceb o at week 2 (47.1% vs 16%, P > 0.0 41). Week-1 2 rem ission rat es wer e no t s ustained w ith 23. 5% (95% CI, 0.4%-4 6.6%) in rem ission in 10 mg/kg CDP870 g ro up ver su s 32% (95% CI, 11.7%52.3%) in remi ssio n in placeb o g ro u p.

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Stud y PRECISE 131

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No. of Pa tients

Inclu sio n/ Exclusion Crite ria

662

Inclu sion: Moder a te to severe CD (CDAI 220 450) fo r z S mo nt hs Exclu sion: Int estin al a bscess , short bowel syn drome, os to my O bst ructio n with st rictures History of tubercul os is, positive find ings on c hest radiography, positive ppD, d emy elin a tin g disea se, o r malign an cy Receip t of an y a nti -T NF-a age nt in th e 3 mon t hs before th e stu d y, history of severe infusi on rea ction to a n an t iTN F-a t reat me nt or non resp on se to an t iTNF-a tr eatm ent

"'0

I'D

Study Dru gs Certo lizumab pegol 400 mg SC o r pla ceb o a t wee ks 0, 2, 4, a nd every 4 wee ks t he reafte r for 26 weeks

End Po ints Prim ar y end poin t : Decr ea se from bas eline CDAI ;:::10 0 a t week 6 and at both we eks 6 a nd 26 co m b ined in pa t ients w it h bas elin e CRP ;:::10 mg /L Secondary end po ints: Clinical remission (CDAI ~ 1 5 0 ) at week 6 a nd at both we eks 6 a nd 26 co m b ined in pa t ien ts with ba selin e CRP ;:::10 mg/L Decreas e in CDAI ;:::10 0 a nd remi ssion a t week 6 a nd at bo th we eks 6 a nd 26 in a ll pati ents

...;:;.c

Findings

III

O f 14 6 pa ti ent s in ce rto lizuma b pegol gro u p w ho ha d CRP co nce nt ra t io ns ;:::10 mg/L at baseline, 3 7% had th e d ecrea se from base line CDAI ;:::10 0 a t week 6 vs 26% in t he pla cebo g ro u p (P = 0.04). At wee ks 6 a nd 26 , 22% ha d t he de crea se in CDAI ;:::10 0 in ce rto lizuma b pego l g ro u p co m pa red w it h 12% in t he pla ceb o g ro u p (P = 0.05 ). Rates o f clinica l remissio n wer e no t stat ist ica lly differ ent between ce rto lizuma b pego l a nd p la ceb o g ro u ps irresp ective of base line CRP co nce nt ra t io n at week 6 (22% a nd 17%, resp ect ively; P = NS) a nd week s 6 a nd 26 (14% a nd 10%, resp ectively; P = NS).

(continu ed )

c

~

:::l I'D

Tab le (co nti nued ).

N

o o

10

Stud y PRECISE 2 32

..... ..... 0\

'I

Design Pha se II I, mul ti center, ra ndo mized, o pen -la be l indu cti o n, d oubl e b lind mainten an ce, pla ce bo co nt ro lled

No . o f Pa tien ts

Inclu sion / Exclusion Crit er ia

4 28

Inclusio n: Mod erate to severe CD (COAl 22 0 4 50) for z S mont hs Exclu sion : Int estin al a bsce ss, s ho rt bowe l synd ro me , osto my Obstru cti on w it h strictures H ist o ry of t u be rc u los is, po siti ve findin gs o n c hest radi o gr aph y, po sitiv e ppD, d em ye linating dis ease, o r ma lign an cy Pati e nts w ho received a ny a nt i-T NF-a ag e nt within pr evious 3 months , had ex pe rience d a severe infusi on rea ction t o a pri or a nt i-TNF-a treatm e nt o r nonresp onse to an tiT NF-a treatm ent

C OAl = Crohn's d isea se a ctivity ind ex; T NF = tum or necrosis fa ctor; IBOQ Pegyla t ed Antib od y Fra gm ent Evalu ati o n in C O: Safety a nd Effi ca cy; ppO

= =

Study Dru gs

End Po int s

Certo lizum ab pegol 400 mg SC or p la ceb o at weeks 0, 2, 4 , a nd eve ry 4 weeks th er eafter for 26 wee ks

Prim ary end poi nt : Clinica l resp onse at 26 wee ks in pa tien t s with a n e levate d ba se line CRP co nce nt ra t io n (<': 10 mg/L). Seco ndar y e nd points: Response a t week 26 in th e int ent-to -treat popu lati on , remi ss ion (over al l COAl ::; 150) at we ek 26 in the int e nt-to -t rea t popu lati o n, remi ssion a t wee k 26 in pati en t s wit h pr etreatment CRP levels <': 10 mg/ L

Find ings A significantl y g rea te r pr op ortion o f ce rto lizu ma b pegol -treated patients wit h e levated bas eline CRP a chi eved clini ca l response by week 26 co m pa red w it h pla ceb o (62 % vs 34%; P < 0 .001 ). A significa nt ly greater proportion of certo lizu ma b pegol-treated patients in th e intent-to- tr eat popu lati on ac hieved clinica l resp on se at wee k 26 co m pa red with placeb o (63% vs 36%; P < 0.001 ). Rates of remi ssion in the inte ntto -t reat popu la tion we re signif ica nt ly high er in th e ce rto lizu ma b pego l group compared with th e p la ceb o g ro u p at week 26 (48% vs 29% ; P < 0 .00 1). Rates of remissi on in patients with ba se line CRP co nce nt ra t io ns <': 10 mg/L wer e signifi cantl y highe r in th e ce rt o lizu ma b pego l g ro u p co m pa red wit h th e p la ceb o g ro u p a t week 26 (42% vs 26%; P =O.Ol)

Infl a m m a t o ry Bow el d isea se Q uest io n na ire ; CRP p ur ified -protein-d er ivat ive tub er culin s kin t est.

=

C-reac tive protein; PREC ISE =

?> ;;C

~

:::l

Clinical Therapeutics

The prevalences of adverse events were not significantly different between the certolizumab pegol and placebo groups. The most commonly reported events with certolizumab pegol and placebo, respectively, were headache (13.2% and 16.4%), aggravation of CD (11.9% and 13.7%), nausea (11.4% and 5.5%), nasopharyngitis (9.1% and 4.1%), dizziness (6.4% and 4.1 %), abdominal pain (5.9% and 5.5%), arthralgia (5.9% and 2.7%), pharyngolaryngeal pain (5.0% and 5.5%), and pyrexia (5.0% and 4.1 %). Injection-site reactions were reported in 2.7% to 6.8 % of certolizumab pegol-treated patients; all were mild to moderate. No anaphylactic reactions were reported. No cases of lymphoma, systemic lupus erythematosus (SLE), tuberculosis, opportunistic infection, or death were reported.V A Phase II, single-dose, multicenter, double-blind, placebo-controlled, parallel-group study was conducted to assess the efficacy and tolerability of intravenous CDP870 in patients with moderate to severe CD (Tablei.t" A total of 92 patients were randomly assigned to receive a single infusion of CDP870 1.25, 5, or 20 mg/kg IV or inactive vehicle (placebo) over 30 minutes. Because the efficacy of the 1.25-mg/kg dose was found to be inferior to higher doses in studies in rheumatoid arthritis.I? the 1.25-mg/kg dose was replaced with a 10-mg/kg dose. The intravenous route was used because subcutaneous administration of higher doses of CDP870 is impractical. At baseline, patient characteristics were well balanced, with the exception of a higher proportion of women in the placebo group than in the active-treatment groups (76% vs 52%-65%). Patients' races were not reported. The primary efficacy end points were the percentages of patients who achieved clinical response (decrease from baseline CDAI ::::100) and clinical remission (overall CDAI:s; 150) by week 4. Other assessments included clinical response rate at weeks 2, 8, and 12; clinical remission rate at weeks 2, 8, and 12; the percentage of the patients with CDAI ::::70; and CRP concentrations. Tolerability was assessed up to 12 weeks after study drug administration.I" The week-4 response rates were not significantly different between CDP870 and placebo (60% [38.8%-81.2%],58.8% [32.5%-85.2%], and 47.8% [25.2%-70.4%] with 5, 10, and 20 mg/kg, respectively, vs 56% [34.5%-77.5%]). No statistically significant differences in response rates were detected throughout the 12-week study period. High placebo response rates were noted at all time points.J" 1168

The clinical remission rate was significantly greater in the CDP870 10-mg/kg group compared with placebo at week 2 (47.1 % vs 16%; P = 0.041). Remission rates were not sustained, with 23.5% (95% CI,0.4%-46.6%) in the CDP870 10-mg/kg group versus 32% (95% CI, 11.7%-52.3%) in the placebo group at week 12. 34 Mean CRP concentrations were apparently lower in all of the CDP870-treated groups compared with the placebo group at weeks 2 and 4 (no statistical analysis reported). At week 2, a significantly lower geometric mean CRP concentration was achieved with certolizumab pegol 20 mg/kg (5.2 mg/L [95% CI, 3.1-8.8 mg/L]) compared with placebo (10 mg/L [95% CI, 6.3-15.8 mgIL]).34 The lack of significant differences in the primary end points might be attributable to the route of administration or other factors, such as the concurrent use of other medications, lack of stratification based on baseline CRP concentrations, and/or CDAI inadequacy for end point assessment.I" The prevalences of adverse events were not significantly different between the combined CDP870 and placebo groups. A total of 164 events were reported in 43 patients in the certolizumab pegol groups; the most common events were headache (35 patients), aggravation of CD (7), urinary tract infection (5), abdominal pain (4), nausea (4), and pyrexia (4). Rates of infections were not significantly different between the combined CDP870 and placebo groups up to week 4; the infection rate started to increase in the combined CDP870 group after week 4 (19.1 % vs 12.5% with placebo; no statistical analysis reported). The majority of the infections were urinary tract infection, pharyngitis, or nasopharyngitis. Eleven serious adverse events were reported during the study, most gastrointestinal. Three of the serious adverse events were considered study drug related: aggravated CD and perianal abscess in 2 patients in the CDP870 20-mg/kg group, and erythematous rash in a patient who received placebo. No infusion reactions; deaths; or new cases of lymphoma, SLE, tuberculosis, or opportunistic infections were reported.I" In the Phase II trials included in the present analysis, the differences in prespecified primary end points between certolizumab pegol and placebo did not reach statistical significance.

Phase 11/ PRECISE 1. PRECISE 1 (Pegylated Antibody Fragment Evaluation in CD: Safety and Efficacy 1)31 was Volume 31 Number 6

A. Rivkin

a 26-week, Phase III, multicenter, randomized, doubleblind, placebo-controlled, manufacturer-cosponsored study of the efficacy and tolerability of certolizumab pegol (Table). A total of 662 patients with moderate to severe active CD (CDAI 220-450; duration, at least 3 months) were randomly assigned to receive certolizumab pegol 400 mg SC or inactive vehicle (placebo) at weeks 0, 2, 4, and every 4 weeks thereafter. Continuation of concurrent, stable-dose CD treatment was permitted. Patients were stratified according to baseline CRP concentration (<10 vs :::: 10 mgIL) and the concurrent use of corticosteroids or immunosuppressive medications. The primary efficacy end points were the proportions of patients with decreases from baseline CDAI ::::100 at week 6 and at both weeks 6 and 26 combined in patients with baseline CRP ::::10 mglL. The 2 secondary efficacy end points were clinical remission (overall CDAI 0:;150) at week 6 and at both weeks 6 and 26 in patients with baseline CRP ::::10 mglL, decrease in CDAI ::::100, and remission rates at week 6 and at both weeks 6 and 26 in all patients. Healthrelated quality of life was assessed using the IBDQ at weeks 0, 6, 16, and 26. IBDQ response was defined as an increase in IBDQ score ::::16 points. Tolerability was monitored at 2- to 4-week intervals.U Of 331 patients in the certolizumab pegol group, 146 (44%) had CRP concentrations ::::10 mglL at baseline. Of these, 37% had a decrease from baseline CDAI ::::100 at week 6 versus 26% in the placebo group (P = 0.04). At weeks 6 and 26, 22 % of patients with CRP concentrations ::::10 mglL at baseline met the primary end point in the certolizumab pegol group compared with 12% in the placebo group (P = 0.05). Rates of clinical remission were not statistically different between the certolizumab pegol and placebo groups irrespective of baseline CRP concentration at both time points assessed (week 6 and combined weeks 6 and 26). Rates of remission were significantly different at weeks 4 and 26 (both, P < 0.05). However, these time points were not prespecified in the primary end point assessment. In the overall population, the proportion of patients who achieved a decrease from baseline CDAI ::::100 was significantly greater in the certolizumab pegol group compared with the placebo group at 6 weeks (35% vs 27%; P = 0.02) and at weeks 6 and 26 (23% vs 16%; P = 0.02). IBDQ response was reported in 42 % of the certolizumab pegol group and 33% of the placebo group at week 26 (P = 0.01).3! June 2009

The most common adverse event was headache (18% in the certolizumab pegol group and 16% in the placebo group). Events that occurred in a significantly different proportion of patients treated with certolizurnab pegol compared with placebo were nasopharyngitis (13 % vs 8 %, respectively; P = 0.04), injectionsite reaction (3% vs 14%; P < 0.001), and injection-site pain (1% vs 7%; P < 0.001). Other common events included abdominal pain (11 % and 11 %), exacerbations of CD (10% and 11 %), nausea (8% and 8%), urinary tract infection (8% and 5 %), arthralgia (7% and 5%), and pyrexia (6% and 7%). No anaphylactic reactions were reported. One patient who received 3 doses of certolizurnab pegol died 10 months after study completion secondary to myocardial infarction, hypertensive heart disease, and metastatic lung cancer. Malignancies developed in 4 patients during the study period: 2 in the certolizumab pegol group (lung cancer and adenocarcinoma of the rectum), and 2 in the placebo group (cervical carcinoma in situ, Hodgkin's lymphoma). Rates of serious infection and antinuclear antibody development were low and not significantly different between the active-treatment and placebo groups (serious infections, 2% vs <1%; antinuclear antibodies, 2% vs 1%). Anticertolizumab antibodies developed in 26 of 331 patients (8%) in the certolizumab pegol group; this rate was lower in patients receiving concurrent immunosuppressive therapy compared with patients who did not receive concurrent immunosuppressants (4% vs 10%).3! This hallmark study found an 8 % absolute difference in clinical response at week 6, and a 7% absolute difference in clinical response at weeks 6 and 26, with an acceptable tolerability profile, with certolizumab pegol. Although clinical remission rates did not reach significance at the predefined time points, they were significant at weeks 4 and 26 (absolute differences, 8% and 11%, respectively, vs placebo; both, P < 0.05). Based on the findings from that study, baseline CRP concentrations did not influence response or remission rates, in contrast to previously published findings.e ' Certolizumab pegol appears to be mildly effective as an add-on treatment to stable CD treatment regimens in patients with moderate to severe CD.3! PRECISE 2. PRECISE 2 was a multicenter, randomized, open-label-induction, double-blind-maintenance, placebo-controlled, manufacturer-sponsored trial of maintenance treatment with certolizumab pegol in pa1169

Clinical Therapeutics

tients with a history of response to induction treatment, conducted in 2004-2005 (Table).32 All patients received certolizumab pegol 400-mg SC injection as induction treatment at weeks 0 (baseline), 2, and 4. Patients were assessed at week 6 for clinical response (decrease from baseline CDAI ::::100) or remission (overall CDAI 0:;150). Patients with clinical response at week 6 were randomly assigned to continue maintenance treatment with certolizurnab pegol 400 mg SC or inactive vehicle (isotonic saline) at weeks 8, 12, 16,20, and 24 (intent-to-treat [ITT] population). Patients were followed up for efficacy and tolerability until week 26. Of 668 patients who received induction treatment, 428 (64%) achieved response and 289 (43%) achieved remission at week 6. The ITT population comprised all responders, with the exception of 3 patients who were excluded due to unblinding. The primary end point, clinical response at 26 weeks in patients with a pretreatment CRP concentration :::: 10 mg/L, was achieved in 62 % of the certolizumab pegol group and 34% of the placebo group (P < 0.001). The 3 secondary end points-response and remission at week 26 in the ITT population, and remission at week 26 in patients with pretreatment CRP ::::10 mgIL-were achieved in 63% versus 36% (P < 0.001),48% versus 29% (P < 0.001), and 42% versus 26% (P = 0.01) of patients in the certolizumab pegol and placebo groups, respectively.V The efficacy of certolizumab pegol in inducing clinical response was apparently not affected by the concurrent use of immunosuppressive agents, prior infliximab use, or glucocorticoid use. For instance, response rates in patients receiving concurrent immunosuppressive agents at week 26 were 61 % in the certolizumab pegol group and 33% in the placebo group (P < 0.001). Corresponding rates in those who were not receiving concurrent immunosuppressive agents at week 26 were 64% and 39% (P < 0.001). Corresponding rates at week 26 were also significantly different in patients who had previously received infliximab (44% vs 25%; P = 0.02) and who had not received infliximab (69% vs 40%; P < 0.001).32 In a post hoc analysis of PRECISE 2 data, several patient-specific factors were identified as predictors of response to certolizumab treatment. Younger age (<36 years) (P = 0.011), disease duration <2 years (P = 0.006), having not previously been treated with infliximab for CD (P = 0.002), and no history of 1170

bowel resection (P = 0.027) were significantly associated with response to certolizumab pego1.38 Prior to the initiation of certolizurnab pegol maintenance treatment, 14% (58/425) of patients had draining fistulas. Fistula closure rates were not significantly different between the certolizumab pegol and placebo groups. The absolute number of patients with fistulizing CD included in the study was small, and assessment of the efficacy of certolizurnab pegol in fistula closure was not appropriate based on the study findings.vAt week 26, the rate of IBDQ response (increase from baseline IBDQ score ::::16) was significantly greater with certolizumab pegol compared with placebo (60% vs 43%, respectively; P < 0.001).32 The most common adverse event with certolizumab pegol and placebo use was headache (7% and 7%, respectively; P = NS). Other common events included nasopharyngitis (6% and 4%; P = NS), cough (6% and <1 %; P = 0.01), and exacerbation of CD (4% and 12 %; P = 0.004). Injection-site reactions occurred in 3% and 15% of patients (P < 0.001). Injection-site pain occurred in a significantly greater proportion of patients who received placebo (P = 0.003). The rate of serious infections was 3 % with certolizumab pegol and <1 % with placebo. Pulmonary tuberculosis developed after the administration of 5 doses of certolizumab pegol and concurrent azathioprine in 1 patient. No cases of solid-organ or hematologic abnormalities, demyelinating disease, or SLE were reported during the study. New antinuclear antibodies were detected in 8% of patients in the certolizurnab pegol group and in 1% of patients in the placebo group.V Anticertolizumab antibodies developed in 58 of 668 patients (9%). The rate of antibody development was lower in patients who were receiving concurrent immunosuppressive treatment or continuous certolizumab pegol treatment during the maintenance phase.tThis study found significantly higher rates of response to continued monthly certolizumab pegol maintenance treatment compared with placebo maintenance in patients with response to 4-week induction (absolute difference in response rates at week 26, 27%-28%; P < 0.001). The response rates remained significantly higher in the certolizumab pegol group irrespective of baseline CRP concentrations, concurrent therapies, or prior infliximab use. Response might have been high because only patients Volume 31 Number 6

A. Rivkin

who responded in the induction phase were included in the maintenance phase.V Based on the study findings, in clinical practice, it seems rational to assess patients for response to certolizumab pegol and to continue maintenance only in those who have achieved response by weeks 4 to 6. 19 The benefit of continued maintenance treatment in patients who have not achieved response in this time frame is unclear. PRECISE 3. PRECISE 3 was designed to assess continued maintenance of response.t'v'? Patients who completed PRECISE 2 could enter PRECISE 3 and receive certolizumab pegol 400 mg SC every 4 weeks for up to 5 years. Response and remission rates were assessed using the Harvey-Bradshaw Index (HBI), in which remission was defined as HBI <4 and response was a decrease from baseline HBI >3. Of 428 patients with clinical response by week 6 in PRECISE 2, a total of 215 were randomly assigned to receive maintenance treatment with certolizumab pegol; 210, placebo. At the end of PRECISE 2 (26 weeks), 48% of the ITT population was in remission; 41 % (88/215) were in remission at 12 months; 36% (78/215), at 18 months; 33% (70/215), at 24 months; and 26% (56/215), at 30 months. Serious adverse events occurred most frequently between 6 and 12 months of treatment (19 serious adverse events; no description providedi.t'' PRECISE 4. PRECISE 4 was designed to assess the efficacy of certolizumab pegol reinduction and maintenance after relapse during the randomized phase of PRECISE 2. Relapse was defined as an increase from baseline CDAI >70 or an absolute CDAI >350. Response and remission were assessed using the HBI as in PRECISE 3. Remission was achieved in 28.6% (14/49) of patients who relapsed during the maintenance phase of PRECISE 2. Rates of remission remained stable at 6 and 12 months (both, 34.7% [17/49]). Patients who received placebo in PRECISE 2 (n = 75) could also enter PRECISE 4. Remission was achieved in 44% (33/75) of these patients at 6 months and in 36% (27/75) at 12 months.v? Updated results will be presented at the next Digestive Disease Week conference. MUSIC. Due to criticism of the CDAI as an assessment tool in CD secondary to the substantial part of the assessment being subjective,22 the MUSIC (Endoscopic Mucosal Improvement in Patients With Active Crohns Disease Treated With Certolizumab Pegol) trial was designed to assess the efficacy of certolizurnab pegol in healing intestinal mucosal lesions in June 2009

patients with active CD.41 MUSIC was a 54-week, open-label clinical trial that enrolled 89 patients with active severe CD (CDAI 220-450) and severe endoscopic disease (:;02 segments with endoscopic ulcerative lesions and a Crohns Disease Endoscopic Activity Score [CDEIS] :;08). Certolizurnab pegol was administered at a dose of 400 mg SC at weeks 0, 2, 4, and every 4 weeks thereafter. The primary efficacy end point was the change from baseline CDEIS at week 10. Endoscopic remission (CDEIS <7), endoscopic response (:;04-point change from baseline CDEIS), change from baseline in histologic CD score, and rate of clinical remission (CDAI 0:;150) were secondary end points. At week 10, CDEIS scores were significantly reduced from baseline, to 6.5 (95% CI, -7.5 to -5.3; P < 0.001). The CDEIS remission rate at week 10 was 55.1 %, and the response rate was 74.4%. CDAI remission rate at week 10 was 46.1 %. CDAI and CDEIS were not significantly correlated (r = 0.176). MUSIC is projected to be completed in fall 2009 and will provide more information about the relationship between mucosal healing scores and CD progression and outcomes.i! According to the US National Institutes of Health Web site, there are 10 ongoing trials of certolizumab pegol in CD.42The majority of these trials address longterm efficacy and tolerability of certolizumab pegol. Tolerability A summary of a long-term tolerability data on certolizumab pegol has been reported.f A total of 1313 patients received continuous treatment with certolizurnab pegol during the development program, which included 2 Phase II and 2 Phase III trials. All 1313 patients received at least 4 weeks of treatment: 904 received certolizurnab pegol for :;03 months; 779, for :;06 months; 681, for :;09 months; and 611, for :;012 months. The most common adverse events reported with certolizumab pegol treatment included upper respiratory infection (20%), immunogenicity (8%), and urinary tract infection (7%). The incidences of the most commonly reported adverse events were numerically higher but not statistically different between the different durations of certolizumab pegol exposure. However, the rates of infection were apparently higher with increased duration of certolizumab pegol administration (47.5% at :;04 weeks vs 60.6% at :;06 months; P value not reported) and placebo administration (31. 7% at :;04 weeks vs 40.7% at :;06 months exposure; 1171

Clinical Therapeutics

P value not reported). Rates of infection were not significantly different between 6 and 12 months' exposure to certolizumab pegol. The prevalence of treatmentemergent adverse events was numerically higher than those in patients who received concurrent certolizumab pegol and an immunosuppressive agent compared with those who did not (86% vs 82%; P = NS).43 The prevalences of lymphoma, cardiac failure, hepatic failure, tuberculosis, and death were low and apparently not significantly different between treatment groups in the time frame studied. Infusion and injection-site reactions were numerically lower in the certolizumab pegol group than in the placebo group. No new unanticipated adverse reactions emerged during the longer (up to 12-month) follow-up.fIn a tolerability analysis in 2166 patients with total certolizumab pegol exposure >2160 patientyears, the incidence (95% CI) of tuberculosis was 0.32 (0.13-0.67) per 100 patient-years, with no cases observed in North America. The package insert recommends testing for latent tuberculosis infection prior to treatment initiation.I'' The incidence of death was 0.42 (0.19-0.79) per 100 patient-years, and the incidence of malignancies was 0.32 (0.13-0.67) per 100 patient-years. Up to July 16, 2007, no cases of lymphoma had been described in patients treated with certolizumab pegol. 44 Recently, the FDA issued a warning regarding invasive fungal infections, such as histoplasmosis, coccidioidomycosis, blastomycosis, aspergillosis, and candidiasis' in patients receiving anti-TNF-a agents, including certolizumab pegol. These infections should be suspected in patients receiving anti-TNF-a agents, especially if they live in or travel to areas where these fungi are endemic (eg, Ohio and Mississippi River valleys).45 A "black box" warning about invasive fungal infection appears in the certolizumab pegol prescribing inforrnation.v''

Efficacy and Tolerability ofCertolizumab Pegol Versus Other Anti-TNF-a Agents in CD All 3 available anti-TNF-a treatments of CDinfliximab, adalimumab, and certolizumab pegolhave had reported efficacy as maintenance treatment in responders to open-label induction. 32,4 6,4 7 However, direct efficacy or tolerability comparisons between the 3 agents are not currently possible due to a lack of head-to-head randomized, double-blind, controlled clinical trials; a shorter duration of induction trials with 1172

infliximab and adalimumab compared with 26 weeks with certolizumab pegol; and differences in study designs. 48-5o The AGA consensus statement on the appropriate use of biologics in inflammatory bowel disease reports that inflixirnab, adalirnumab, and certolizumab pegol are likely similarly effective in inducing clinical response and remission in patients with CD.19 However, the propensity to generate autoantibodies, convenience and ease of administration, and other variables may differ between agents. The importance of these differences in clinical practice is unknown. Whether failure to respond to one anti-TNF agent precludes response to another also is unknown. PRECISE 2 reported that nonresponders to inflixirnab achieved significantly greater rates of response to certolizumab pegol maintenance treatment compared with placebo (P = 0.02), although the magnitude of response rate was greater in infliximabnaive patients (response at week 26, 44% in inflixirnab-experienced patients vs 69% in infliximabnaive patientsi.V Several positive observational reports of certolizumab pegol use in patients who did not respond to prior CD treatments, including other biologics, were presented at the 2008 American College of Gastroenterology meeting. 51,52 In a small study in 6 patients with CD who did not respond adequately to conventional treatments but who responded to 400-mg induction with certolizumab pegol (2 patients did not respond to prior inflixirnab treatment; 4 patients did not respond to prior inflixirnab and adalimumab treatment),5 patients treated with intensification with certolizumab pegol 200 mg SC every other week were reported to have achieved clinical remission (CDAI 0:; 150; HBI 0:;4).51 In a case report of a 22-year-old female patient with severe refractory CD, certolizumab pegol 400 mg induction administered at weeks 0, 2, and 4 and 400 mg every 4 weeks thereafter, clinical remission (overall CDAI 0:;150) was achieved from week 4 to the end of follow-up (week 34). This patient had been treated with, and lost response to, infliximab and adalimumab in the preceding 5 years. 52 Preliminary results from the Phase IIIb, 26-week, multicenter, open-label WELCOME (26-Week, OpenLabel Trial Evaluating the Clinical Benefits and Tolerability of Certolizumab Pegol Induction and Maintenance in Patients Suffering from CD with Prior Loss of Response or Intolerance to Infliximab) study were Volume 31 Number 6

A. Rivkin

presented at the 2008 AGA meeting. 53 WELCOME assessed the clinical benefits and tolerability of certolizurnab pegol induction and maintenance in patients with CD with prior loss of response to or intolerance of inflixirnab. Preliminary findings in 539 patients at 6 weeks were clinical response in 62.2 % and clinical remission in 39.3%, suggesting that nonresponders to infliximab might achieve response or remission with certolizumab pegol. Certolizumab pegol was effective irrespective of the reason for infliximab nonresponse (loss of response or hypersensitivity) or concurrent pharmacotherapy (corticosteroids or immunosuppressants).54 WELCOME will provide 26-week data on the efficacy and tolerability of certolizumab pegol in patients with a history of nonresponse to infliximab.V

Do sage/Administration Certolizumab pegol is indicated for the treatment of moderate to severe CD in nonresponders to conventional treatments. The recommended dose associated with reduced signs and symptoms and maintenance of clinical response is 400 mg SC at weeks 0, 2, and 4. In patients who respond to certolizumab treatment, maintenance treatment with 400 mg SC every 4 weeks is indicated.v? Certolizumab pegol has been approved by the FDA for the treatment of moderately severe rheumatoid arthritis in adults. Lyophilized certolizurnab pegol is available in 200-mg vials that must be reconstituted with 1 mL sterile water for injection (supplied in the kit) and administered subcutaneously by a health care professional. Reconstitution may require up to 30 minutes. After reconstitution, this agent can be stored at 2°C to 8°C for up to 24 hours. A single-use, prefilled glass syringe containing 200-mg/mL certolizumab pegol became available in May 2009.

Cost According to the 2008 Thomson Red Book. 5 5 one 200-mg vial of certolizumab pegol costs US $1578.82, and a yearly course with monthly subcutaneous administration costs ~$37,892. In comparison, adalimurnab 40 mg costs $830.96, with a yearly course of twice-monthly subcutaneous administration costing ~$21,605. Inflixirnab is administered based on weight; in a 60-kg patient, each dose costs $2091, with intravenous administration every 8 weeks for a year costing $12,548 to $14,640. 56 These costs are drugacquisition costs to health care professionals and not June 2009

to patients. The costs of drug administration or any

other costs were not included. No pharrnacoeconomic data were identified in the assessment of these 3 anti-TNF-a agents in CD. DISCUSSION Certolizumab pegol is an agent in the anti-TNF-a class with moderate activity in severe active CD. Similar to other anti-TNF-a agents, it offers an option in managing CD in patients who do not adequately respond to conventional treatments of CD, such as aminosalicylates, corticosteroids, antibiotics, or immunornodulators. In well-designed Phase III clinical trials, it was associated with significantly greater response rates compared with placebo at weeks 6 and 26 of induction treatment. In patients who respond to a 6-week induction, certolizumab pegol given as a monthly injection was reported to be effective in maintaining CD response and remission. Because the efficacy of certolizumab pegol has not been found to be affected by baseline CRP concentration or previous exposure to infliximab, this agent may represent an option in patients who do not have an adequate response to infliximab (level B recommendation from the AGA [with evidence from studies not rated as high qualityj). Similarly, adalimumab was reported to be effective in patients who did not respond adequately to infliximab treatment. The AGA guideline gives a level A recommendation (with high-quality studies to support this recommendation) for adalimumab use in infliximab nonresponders.l'v''' The adverse events reported with certolizumab pegol are similar to those of other anti-TNF-a agents. The most important safety concerns are an increased risk for infectious complications, especially with opportunistic pathogens such as fungi and tuberculosis. Testing for latent tuberculosis infection is recommended before the initiation of certolizumab pegol treatment. Other important adverse events are the formation of autoantibodies and the induction of autoimmunity, both of which are relatively infrequent with certolizurnab administration based on data available to date. The efficacy of certolizumab pegol in patients with draining fistulas has not been adequately assessed. Whether certolizumab pegol use might result in steroid sparing is unknown. Due to its long t 1/2 , certolizumab pegol may offer a convenient schedule of administration. However, adherence had not been assessed in clinical trials. Moreover, certolizumab pegol must be reconstituted before injection, 1173

Clinical Therapeutics

which may diminish patients' acceptance due to inconvenience. The availability of the prefilled single-use syringes may overcome acceptance and compliance issues. Clinical research is needed to assess the efficacy of certolizurnab pegol in the modification of disease course or slowing of disease progression. CD treatment guidelines underscore the current lack of information regarding optimal approaches to reduce the immunogenicity of biologic treatments. 12 Other areas of research may define the role of certolizumab pegol as maintenance treatment in patients with remission induced by surgery or other agents, in pregnant patients, and/or in patients whose CD involves organ systems other than the gastrointestinal tract. 19 CONCLUSIONS Based on the findings from the present review, certolizumab pegol has moderate efficacy in the treatment of moderate to severe active CD. In well-designed Phase III clinical trials, certolizumab pegol was associated with significantly greater response rates compared with placebo at weeks 6 and 26 of induction. In patients who responded to the 6-week induction, certolizumab pegol administered as a monthly subcutaneous injection was reported to be effective in maintaining CD response and remission. Findings from studies of certolizumab pegol in refractory CD are awaited.

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Fauci AS, Braunwald E, Kasper DL, et ai, eds. Hamson's

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Management of Crohn's disease In adults. AmJ Gasiroenterol. 2001 ;96:635-643.

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Volume 31 Number 6

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Address correspondence to: Anastasia Rivkin, PharmD, BCPS, Arnold and Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, 75 DeKalb Avenue, Brooklyn, NY 11201. E-mail: Anastasia.rivkinwliu.ed Volume 31 Number 6