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Continuous Therapy With Certolizumab Pegol Maintains Remission of Patients With Crohn's Disease for up to 18 Months
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2010;8:600 – 609
Continuous Therapy With Certolizumab Pegol Maintains Remission of Patients With Crohn’s Disease for up to 18 Months GARY R. LICHTENSTEIN,* OLE Ø. THOMSEN,‡ STEFAN SCHREIBER,§ IAN C. LAWRANCE,储 STEPHEN B. HANAUER,¶ RALPH BLOOMFIELD,# and WILLIAM J. SANDBORN** on behalf of the PRECiSE 3 STUDY INVESTIGATORS *Gastrointestinal Division, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; ‡Department of Gastroenterology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark; §Hospital for General Internal Medicine, Christian Albrechts University, Kiel, Germany; 储School of Medicine and Pharmacology, University of Western Australia, Fremantle Hospital, Fremantle, Australia; ¶Section of Gastroenterology and Nutrition, University of Chicago Medical Center, Chicago, Illinois; #UCB Pharma, Slough, United Kingdom; and **Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
See Editorial on page 556. BACKGROUND & AIMS: The safety and efficacy of maintenance therapy with the anti–tumor necrosis factor certolizumab pegol has not been reported beyond 6 months. We assessed the long-term efficacy, safety, and immunogenicity of continuous versus interrupted maintenance therapy with subcutaneous certolizumab pegol in patients with Crohn’s disease. METHODS: Patients who responded to induction therapy at week 6 of the PEGylated Antibody Fragment Evaluation in Crohn’s Disease: Safety and Efficacy (PRECiSE) 2 trial were assigned randomly to groups given certolizumab pegol (continuous) or placebo (drug-interruption) during weeks 6 to 26. Patients who completed PRECiSE 2 were eligible to enter PRECiSE 3, an ongoing, prospective, open-label extension trial in which patients have received certolizumab pegol (400 mg) every 4 weeks for 54 weeks to date, and were not offered the option to increase their dose. Disease activity was measured by the Harvey–Bradshaw Index. RESULTS: Harvey– Bradshaw Index responses at week 26 for the continuous and drug-interruption groups were 56.3% and 37.6%, respectively; corresponding remission rates were 47.9% and 32.4%, respectively. Of patients responding at week 26, response rates at week 80 after the start of PRECiSE 2 in the continuous and druginterruption groups were 66.1% and 63.3%, respectively; among patients in remission at week 26, week 80 remission rates were 62.1% and 63.2%, respectively. More patients in the drug-interruption group developed antibodies against certolizumab pegol (and had lower plasma concentrations of certolizumab pegol) than the continuously treated group. CONCLUSIONS: Certolizumab pegol effectively maintains remission of Crohn’s disease for up to 18 months. Continuous therapy is more effective than interrupted therapy. Keywords: Certolizumab Pegol; Crohn’s Disease; Anti–Tumor Necrosis Factor ␣.
C
rohn’s disease is a chronic remitting and relapsing inflammatory disorder of the gastrointestinal tract characterized by symptoms of diarrhea, abdominal pain, weight loss, fever, and rectal bleeding.1 Although the etiology of Crohn’s disease is unknown, the resulting chronic inflammatory process appears to be mediated, at least in part, by the proinflammatory cytokine tumor necrosis factor ␣ (TNF-␣).2–5 Treatment with biologic agents that target and sequester TNF-␣ is effective for
Crohn’s disease. The first 2 anti–TNF-␣ therapies approved for the treatment of Crohn’s disease were the engineered immunoglobulin G1 chimeric antibody infliximab and the human monoclonal antibody adalimumab. In randomized controlled trials, both antibodies proved efficacious in the induction6,7 and maintenance of remission.8,9 Certolizumab pegol is an Fc-free Fab’ anti–TNF-␣ of a monoclonal antibody, conjugated with polyethylene glycol, and recently approved for the treatment of moderate-to-severe active Crohn’s disease. Certolizumab pegol is devoid of the Fc portion and therefore does not induce either complement-dependent cytotoxicity or antibody-dependent cellular cytotoxicity,10 in contrast to the full immunoglobulin G1 anti–TNF-␣ antibodies (infliximab and adalimumab). The engineered Fab’ fragment does retain the high affinity of the original antibody, binding to soluble TNF-␣ with more than twice the potency of infliximab.10,11 The efficacy and tolerability of certolizumab pegol in patients with active Crohn’s disease have been confirmed in 2 large, pivotal, randomized, placebo-controlled, phase III studies, namely, PEGylated Antibody Fragment Evaluation in Crohn’s Disease: Safety and Efficacy 1 (PRECiSE 112) and PRECiSE 2.13 In PRECiSE 2, all patients received open-label certolizumab pegol 400 mg induction; responders (response defined as a reduction in Crohn’s Disease Activity Index [CDAI] score of ⱖ100 points from baseline) at week 6 then received maintenance treatment with either certolizumab pegol 400 mg or placebo at weeks 8, 12, 16, 20, and 24, with final assessment at week 26.13 The primary efficacy end point was clinical response at week 26. Significantly more patients receiving certolizumab pegol versus placebo, who had achieved response at week 6, showed ability to maintain response at week 26: 63% versus 36%, respectively (P ⬍ .001). The PRECiSE 2 trial was conducted over a short time frame (6 months) relative to the natural history of Crohn’s disease. The PRECiSE 3 study is an open-label extension that includes patients who completed the PRECiSE 2 trial; this was designed to determine the long-term safety and efficacy of subcutaneous certolizumab pegol 400 mg every 4 weeks. Although representAbbreviations used in this paper: AE, adverse event; anti-dsDNA, anti– double-stranded DNA antibodies; ANAs, antinuclear antibodies; CDAI, Crohn’s Disease Activity Index; HBI, Harvey–Bradshaw Index; PRECiSE, PEGylated Antibody Fragment Evaluation in Crohn’s Disease: Safety and Efficacy; TNF-␣, tumor necrosis factor ␣. © 2010 by the AGA Institute 1542-3565/$36.00 doi:10.1016/j.cgh.2010.01.014
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ing an open-label maintenance extension of the PRECiSE 2 trial, PRECiSE 3 is unique in 2 important ways. It is a prospective clinical trial beyond 12 months in which patients initially received either continuous or interrupted anti–TNF-␣ therapy and were not offered the option to increase their dose. All patients who completed the 26-week PRECiSE 2 trial were eligible for enrollment in PRECiSE 3. An important aim of the PRECiSE 3 trial was to analyze outcomes in patients who received continuous certolizumab pegol therapy (after induction and maintenance in PRECiSE 2) relative to outcomes in patients who received interrupted certolizumab pegol therapy (responders to induction therapy in PRECiSE 2 who then were randomized to placebo and then received certolizumab pegol in PRECiSE 3). The PRECiSE 3 clinical data presented here report the safety and efficacy results in patients receiving either continuous or interrupted anti–TNF-␣ therapy over a period of 18 months in the absence of an option to increase the dose.
Methods Study Design
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treatment regimen during PRECiSE 2. Therefore, the data have been analyzed to reflect the therapeutically distinct interventions patients received in PRECiSE 2 (Figure 1) as follows: (1) PRECiSE 2 continuous group: responders to certolizumab pegol induction at week 6 of PRECiSE 2 who then received certolizumab pegol maintenance over 18 weeks in PRECiSE 2, followed by continued certolizumab pegol in PRECiSE 3; (2) PRECiSE 2 drug-interruption group: responders to certolizumab pegol induction at week 6 of PRECiSE 2 who then received placebo over 18 weeks in PRECiSE 2, followed by re-exposure to certolizumab pegol in PRECiSE 3. Patients could be withdrawn from PRECiSE 3 at any time if they so requested or if they required defined rescue therapy (ie, infliximab, major change in corticosteroid and/or immunosuppressant dose, surgery, or hospitalization) for exacerbation of Crohn’s disease. The independent ethics committee or institutional review board at each study center approved the study. All participants gave written informed consent.
Assessments
PRECiSE 3 (www.clinicaltrials.gov; NCT00160524) is an ongoing, open-label extension study that included patients who completed 26 weeks of therapy in the PRECiSE 2 trial. The methodology of PRECiSE 2 has been published previously.12,13 All patients were aged 18 years and older with moderate-tosevere Crohn’s disease (defined by a CDAI score between 220 and 450 points) affecting the terminal ileum, colon, or both the ileum and colon for at least 3 months’ duration before screening. Diagnoses were based on conventional radiologic, endoscopic, or histologic diagnostic criteria.14 Patients enrolled in PRECiSE 3 received certolizumab pegol 400 mg every 4 weeks starting 28 weeks after the start of PRECiSE 2. The cut-off date for this analysis was June 2006, at which point all patients who had remained in the study had a minimum of 12 months’ exposure to certolizumab pegol in PRECiSE 3. Therefore, data are presented up to week 54 of PRECiSE 3, corresponding to week 80 from the initiation of PRECiSE 2 (Figure 1). To present the full 80 weeks’ treatment, all timelines and study visits described for PRECiSE 3 refer to baseline (week 0) of PRECiSE 2. Although PRECiSE 3 contained only a single treatment arm, patients did not enter the trial having received the same
Harvey–Bradshaw Index. The Harvey–Bradshaw Index (HBI) was used to measure Crohn’s disease activity in PRECiSE 3.15 The CDAI requires daily completion of a diary card and calculation of various weighting factors for 1 week. In contrast, the HBI only requires scoring from the day before the study visit and involves a lower number of components, making it a simpler alternative measure to the CDAI.16 Importantly, the HBI was shown to be highly correlated (Pearson correlation coefficient, r ⫽ 0.80) to the CDAI in PRECiSE 1 and 217 and in an earlier prospective study of patients with Crohn’s disease (Pearson correlation coefficient, r ⫽ 0.93).15 In PRECiSE 2, data were collected to calculate HBI scores at weeks 0 and 26. In PRECiSE 3, HBI was used to assess treatment efficacy at all visits (ie, at weeks 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, and 80 after the start of PRECiSE 2). An HBI response was defined as a reduction of 3 points or more from baseline and clinical remission was defined as an HBI score of 4 points or less. These values were determined from the correlation between the CDAI and HBI data at weeks 0 and 26 in PRECiSE 2.17 Safety. Safety was evaluated by conducting physical examinations and clinical laboratory tests (hematology, serum
Figure 1. Study design for the PRECiSE 2 and 3 studies.
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biochemistry analyses, and urinalysis) at screening and at all visits during the study. In the case of study withdrawal, a safety follow-up visit was conducted 12 weeks after the last dose. A chest radiograph was obtained at week 80 or at the withdrawal visit. Patients were assessed throughout the study for the possible occurrence of adverse events (AEs). AEs were classified and descriptively summarized by primary system organ class and preferred term according to the Medical Dictionary for Regulatory Activities. All concomitant medications and their dosages were recorded throughout PRECiSE 3. Assays. Blood samples for the determination of plasma certolizumab pegol concentrations and antibodies to certolizumab pegol were collected during the trial and at the safety follow-up visit (12 weeks after the last dose). Certolizumab pegol plasma concentration was measured by a validated enzyme-linked immunosorbent assay (G. R. Lichtenstein, unpublished data, 2007). Antibodies to certolizumab pegol also were measured by an enzyme-linked immunosorbent assay, and a level greater than 2.4 U/mL (an increase by a factor of 2 over the value of a reference population)18 was defined as the lower limit of detection. Blood samples taken at weeks 0, 26 (PRECiSE 2), 52, 80, or withdrawal visit (PRECiSE 3), and at the safety follow-up visit also were assayed for anti– double-stranded DNA (anti-dsDNA) antibodies and antinuclear antibodies (ANAs).
Statistical Analyses Efficacy outcomes included the proportion of patients from each treatment group who had achieved clinical response and remission at week 80 and a reduction in HBI score at week 80. Descriptive statistics for the HBI and for all clinical laboratory evaluations, along with absolute values and changes
from baseline, were presented at each scheduled visit. Clinical response and remission in patients exposed to certolizumab pegol were analyzed using the intention-to-treat population from PRECiSE 2. The intention-to-treat analysis makes the assumption that patients discontinuing treatment in PRECiSE 3 were nonresponders and nonremitters for all subsequent time points. Patients who received rescue therapy (ie, infliximab, any increase in corticosteroid and/or immunosuppressant dose, surgery, or hospitalization) also were deemed nonresponders and nonremitters for all subsequent time points. The proportion of patients achieving sustained HBI response (reduction from baseline in total HBI score of ⱖ3 points for all visits up to the visit of interest) was calculated. Similarly, the proportion of patients achieving sustained HBI remission (total HBI score of ⱕ4 for all visits up to the visit of interest) subsequently was calculated. Safety data were summarized for all patients from PRECiSE 2 who received one or more doses of certolizumab pegol in PRECiSE 3. Immunogenicity was compared between patients who continued therapy and those who had a drug interruption with respect to mean plasma certolizumab pegol concentration and antibody production against certolizumab pegol.
Results Patients and Demographics In the PRECiSE 2 study, 428 of 668 patients (64.1%) responded to certolizumab pegol induction therapy at week 6 (ie, CDAI decrease of ⱖ100 points from baseline) and were randomized to receive either certolizumab pegol or placebo maintenance treatment.13 Of the 428 patients, 215 and 210 patients were randomized and received certolizumab pegol or placebo, respectively (3 randomized patients were excluded be-
Table 1. Patient Demographics and Clinical Characteristics of Patients Entering PRECiSE 3 From PRECiSE 2
Baseline variable Mean age, y (range) Male, n (%) Mean body mass index, kg/m2 (SD) Current smoker, n (%) Mean duration of disease, years (range) Location of Crohn’s disease, n (%) Terminal ileum Colon Ileum/colon Resection performed, n (%) Mean HBI score (range) Geometric mean C-reactive protein concentration, mg/L (range) Previous infliximab therapy, n (%) Concomitant medications, n (%)a Patients on steroids at the start of PRECiSE 3b Patients on steroids at the start of PRECiSE 2 Patients on immunosuppressants at the start of PRECiSE 2c Patients on immunosuppressants and steroids at the start of PRECiSE 2 Patients on neither immunosuppressants nor steroids at the start of PRECiSE 2 aPatients
PRECiSE 2 Continuous group (N ⫽ 141)
PRECiSE 2 Drug-interruption group (N ⫽ 100)
38 (18–67) 65 (46) 24.0 (5.9) 38 (27) 8 (⬍1 to 33)
37 (18–69) 55 (55) 24.7 (5.0) 38 (38) 7 (⬍1 to 33)
28 (18) 39 (28) 69 (49) 35 (25) 10 (3–24) 10 (2–131) 27 (19)
26 (26) 23 (23) 45 (45) 31 (31) 10 (4–17) 7 (2–157) 17 (17)
26 (18) 47/215 (22) 59/215 (27) 28/215 (13) 81/215 (38)
19 (19) 44/210 (21) 52/210 (25) 34/210 (16) 80/210 (38)
on steroids at the start of PRECiSE 3 were calculated so as to measure steroid tapering during PRECiSE 3. Data on immunosuppressant use provided here are for the patients who were randomized in the PRECiSE 2 study and have been reported previously.13 bSteroids used were budesonide, prednisone, and prednisolone. cImmunosuppressants used were azathioprine, mercaptopurine, and methotrexate.
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cause of possible unblinding), and 151 patients (69.9%) and 109 patients (51.4%), respectively, successfully completed week 26. A total of 141 of 215 patients who received certolizumab pegol (65.6%) and 100 of 210 patients who received placebo (47.6%) in PRECiSE 2 were enrolled into PRECiSE 3 (Figure 1). As shown in Table 1, the patients enrolled in both treatment arms of PRECiSE 2 who entered PRECiSE 3 were well matched with respect to demographics, disease characteristics, and previous and concomitant medications. A total of 78 patients (32.4%) among those originally enrolled in PRECiSE 2 withdrew prematurely from PRECiSE 3. The reasons for withdrawal are summarized in Table 2.
Efficacy The HBI response rate at week 26 (week 0 of the PRECiSE 3 trial) was 56.3% (121 of 215 patients) in the continuous group and 37.6% (79 of 210 patients) in the druginterruption group. Although reduction in response was evident over time in the continuous and drug-interruption groups, substantial rates of response were sustained in both groups over a further 26 (week 52) and 54 weeks (week 80) of maintenance
Table 2. Incidence of AEs and Patient Discontinuations in Patients From PRECiSE 2 During PRECiSE 3 Follow-Up Evaluation Number (%) of patients
Variable Any AE Total Mild Moderate Severe AE related to study drug Serious AE Infection or infestation AE Serious infection or infestation AE Injection site Pain Reactions Erythema Burning Bruising Hemorrhage Phlebitis Swelling Premature withdrawals AE leading to withdrawal Protocol noncompliance Patient decision Clinical decision Lost to follow-up evaluation Lack of improvement/disease deterioration Other Deaths
Continuous group (N ⫽ 141)
Drug-interruption group (N ⫽ 100)
105 (74.5) 81 (57.4) 74 (52.5) 18 (12.8) 33 (23.4) 27 (19.1) 60 (42.6) 11 (7.8)
73 (73.0) 58 (58.0) 53 (53.0) 12 (12.0) 32 (32.0) 17 (17.0) 55 (55.0) 6 (6.0)
0 1 (0.7) 0 1 (0.7) 1 (0.7) 0 0 0 48 (34.0) 22 (15.6) 2 (1.4) 19 (13.5) 10 (7.1) 1 (0.7) 13 (9.2)
1 (1.0) 1 (1.0) 1 (1.0) 1 (1.0) 1 (1.0) 0 1 (1.0) 1 (1.0) 30 (30.0) 17 (17.0) 1 (1.0) 11 (11.0) 4 (4.0) 1 (1.0) 7 (7.0)
4 (2.8) 0 (0)
2 (2.0) 1 (1.0)
NOTE. AEs occurring during PRECiSE 3 and within 12 weeks of last injection.
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therapy with certolizumab pegol 400 mg (Figure 2A). Among patients who were in response at week 26, response rates were similar between the continuous and drug-interruption groups at both week 52 (74.4% vs 79.7%, respectively) and week 80 (66.1% vs 63.3%, respectively; Figure 2C). Sustained response rates were 62.8% and 47.1% at weeks 52 and 80, respectively, among continuously treated patients who showed a response at week 26. The corresponding values for the drug-interruption group were 63.3% and 45.6%, respectively. Relative to the initial population entering PRECiSE 2 (n ⫽ 668), 97 patients in the continuous group and 71 patients in the interrupted group (28.9% and 21.7%, respectively, of patients achieving response by week 6 of PRECiSE 2) remained in response at week 52; 86 patients in the continuous group and 57 patients in the interrupted group (25.6% and 17.4% of the patients achieving response by week 6 of PRECiSE 2) remained in response at week 80. The HBI remission rate at week 26 of PRECiSE 2 (PRECiSE 3 baseline) was 47.9% (103 of 215 patients) in the continuous group and 32.4% (68 of 210 patients) in the drug-interruption group. Remission rates were evident over time in the continuous and drug-interruption groups, high rates of remission were maintained in both groups by maintenance therapy with certolizumab pegol 400 mg over a further 26 weeks (week 52; 40.9% in the continuous and 30.0% in the drug-interruption group) and 54 weeks (week 80; 36.3% in the continuous and 23.3% in the drug-interruption group; Figure 2B). Among patients who were in remission at week 26, remission rates were similar between the continuous and drug-interruption groups at both week 52 (72.8% vs 73.5%, respectively) and week 80 (62.1% vs 63.2%, respectively; Figure 2D). Sustained remission rates were 49.5% and 33.0% at weeks 52 and 80, respectively, among continuously treated patients in remission at week 26. The corresponding values for the druginterruption group were 44.1% and 30.9%, respectively. The median HBI scores at baseline of PRECiSE 2 patients who continued to PRECiSE 3 were similar in the continuous and drug-interruption groups (9.0 [range, 3–24] and 9.0 [range, 3–21], respectively). By week 26 of PRECiSE 2 (week 0 of PRECiSE 3), the median HBI score had decreased by two thirds in both groups to values of 3.0 (range, 0 –13) and 3.0 (range, 0 –16) points, respectively, and remained low for the duration of PRECiSE 3 up to week 80 (Figure 3). Of note, between week 48 and week 80, median HBI scores for the entire patient population were at or below values that signify Crohn’s disease remission.17
Safety Certolizumab pegol was well tolerated in this study. The incidence of AEs was similar in both the PRECiSE 2 continuous and drug-interruption groups (Table 2). Exacerbation of Crohn’s disease was the most commonly experienced AE, followed by abdominal pain, nasopharyngitis, and arthralgia. The incidence of injection-site reactions, such as bruising, pain, and erythema, was low (ⱕ1%) and no anaphylactic reactions were observed. Most treatment-emergent AEs were of mild or moderate intensity and were considered by the investigators to be unrelated to the study drug (Table 2). The incidence of AEs that were considered to be related to certolizumab pegol was greatest in the drug-interruption group.
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Figure 2. (A) Response rates (reduction from baseline in HBI score, ⱖ3) and (B) remission rates (HBI score, ⱕ4) in PRECiSE 2 and PRECiSE 3 at weeks 26, 52, and 80 (intention-to-treat population). (C) Sustained response and (D) remission rates in PRECiSE 3 in patients who were already in response/remission at week 26 of PRECiSE 2. aHBI scores were not measured at week 6 so response and remission rates for the CDAI are presented in these graphs. bRecalculated CDAI scores. Criterion for entry into maintenance phase of PRECiSE 2 was a CDAI response; therefore, CDAI response rate at week 6 should be 100%. However, as a result of investigator error, such as miscalculated CDAI scores and other protocol deviations, the actual CDAI response rate in the intention-to-treat population is slightly lower.
Approximately one third of patients prematurely withdrew from the study, primarily because of AEs, patient decision, and lack of improvement or deterioration of Crohn’s disease. The incidence of patients who experienced serious AEs (continuous group, 19.1%; drug-interruption group, 17.0%) or AEs leading to premature withdrawal from the study was comparable for both subpopulations. A small-bowel carcinoma was the only malignancy to occur in the PRECiSE 2 patient population who entered into PRECiSE 3. This patient had been treated with continuous certolizumab pegol and rectal hydrocortisone, which was prescribed for rectal bleeding approximately 6 months after the patient entered PRECiSE 3. The rate of serious infections was 6.0% and 7.8% in the drug-interruption and continuous certolizumab pegol groups, respectively. Just under half of the patients with serious infections were receiving either concomitant steroids and/or immunosuppressants. The most common serious infection reported in 5 patients was perianal abscess; 1 patient was taking a concomitant immunosuppressant and 1 patient was receiving both a steroid and an immunosuppressant. There were 2 cases of tuberculosis: a 37-year-old woman from Denmark in the drug-interruption group was diagnosed with disseminated tuberculosis, from which she recovered with sequelae (decreased sense of touch from the middle of the right thigh and distally); and a 57-year-old man from South Africa who had been receiving certolizumab pegol throughout PRECiSE 2 and
3 was diagnosed with pulmonary tuberculosis from which he made a full recovery. The study drug was withdrawn in both cases at the onset of initial problems. Neither patient had been on concomitant immunosuppressants or steroids. Immunologic events were observed in 2 patients, one patient experienced sarcoidosis and the other patient experienced a drug-induced lupus-like reaction (this patient had an ANA-positive status that reverted to negative 1 year later; dsDNA status was negative). In PRECiSE 3, a 50-year-old man who had received placebo previously in PRECiSE 2 after successful induction with certolizumab pegol died from a tracheal obstruction caused by food impaction. His death was considered unrelated to the study drug by the investigator.
Autoimmune Antibodies Among those patients evaluable at week 26, ANAs had developed in 16 of 192 patients (8.3%) in the continuous group and 2 of 178 patients (1.1%) in the drug-interruption group.13 At week 80, new ANAs developed in 9 of 82 patients (11.0%) in the continuous group and 7 of 65 patients (10.8%) in the drug-interruption group. In patients evaluable at week 26, anti-dsDNA antibodies had developed in 2 of 192 patients (1.0%) in the continuous group and in 1 of 178 patients (0.6%) in the drug-interruption group.13 At week 80, new anti-dsDNA antibodies had developed
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Figure 3. Activity of Crohn’s disease as measured by the HBI at baseline and throughout PRECiSE 3, and geometric mean plasma concentrations of certolizumab pegol throughout PRECiSE 3. CZP, certolizumab pegol. These data are based on the entire study population, ie, although a patient may have provided an HBI score at a particular visit, they may not have provided a blood sample.
in 3 of 82 patients (3.7%) in the continuous group and 1 of 65 patients (1.5%) in the drug-interruption group. Only 1 patient was positive for ANAs and had anti-dsDNA antibodies present.
Systemic Exposure to Certolizumab Pegol On entry into PRECiSE 3 at week 26 (ie, 2 weeks after the last certolizumab pegol or placebo dose), the geometric mean plasma concentration of certolizumab pegol was 19.6 g/mL in the continuous group and less than 0.41 g/mL (below the limit of quantification) in the drug-interruption group (Figure 3). The predose value at week 28 for the continuous group was 6.9 g/mL and this trough level was maintained through week 80, at which time the geometric mean plasma concentration of certolizumab pegol was 7.7 g/mL. The predose value for the drug-interrupted group at week 32, after a dose of certolizumab pegol at week 28, was 1.9 g/mL and this trough value increased over time and by week 80 was 6.0 g/mL (Figure 3).
Antibodies Against Certolizumab Pegol Patients were considered positive for antibodies against certolizumab pegol if the blood sample assayed was greater than 2.4 U/mL at any time during the study. An antibodypositive status remained with the patient over the course of the study, even if they subsequently reverted back to being antibody-negative over time. Among patients for whom values were available at week 26, antibodies against certolizumab pegol had developed in 17 of 213 patients (8.0%) in the continuous group and 37 of 209 patients (17.7%) in the drug-interruption group.13 The influence of the development of anti– certolizumab pegol antibodies on plasma certolizumab pegol concentrations is shown in Figure 4.
The incidence of AEs was similar in the continuous and drug-interruption groups for patients with and without anti– certolizumab pegol antibodies.
Discussion These results from the PRECiSE 3 trial represent safety and efficacy data from a clinical trial of patients with Crohn’s disease receiving either continuous or interrupted anti–TNF-␣ therapy beyond 12 months without the option to increase the dose. In clinical practice, anti–TNF-␣ therapy might be stopped temporarily when there is a serious infection such as pneumonia. Therefore, clinical trial data on the potential implications of interrupted therapy provide directly relevant clinical information. Until now, the only information available regarding response to anti–TNF-␣ therapy after placebo has been as part of an episodic treatment strategy (ie, patients had to have experienced a disease flare before active treatment was reinstated).8,9,19 Another unique feature of the PRECiSE 3 trial is that patients were not offered the option to increase the medication dose. In the ACCENT I (Crohn’s disease clinical study evaluating infliximab in a new long–term treatment regimen) and CHARM (Crohn’s trial of the fully human antibody adalimumab for remission maintenance) trials of infliximab and adalimumab, patients were offered dose-escalation strategies.8,9 Therefore, although these prior studies have shown efficacy in patients who were randomized initially to placebo and then received open-label anti–TNF-␣ therapy on relapse,8,9 PRECiSE 3 investigated the efficacy and safety of an anti– TNF-␣ agent broken down by continuous versus interrupted therapy in a predetermined scheduled cessation of biological therapy, and we believe that the PRECiSE 3 study provides several key findings.
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Figure 4. Effect of anti– certolizumab pegol antibodies on the geometric mean plasma certolizumab pegol concentrations in PRECiSE 3 for patients from the (A) continuous treatment arm and (B) drug-interruption treatment arm (safety population). CZP, certolizumab pegol.
In PRECiSE 2, the CDAI score was used to determine response and remission. Data from almost 1000 matched pairs showed a positive correlation (0.800, Spearman correlation coefficient) between CDAI and HBI.17 The study by Vermeire et al17 calculated a 3-point change in the HBI that corresponded to a CDAI response of a 100-point improvement and HBI scores of 4 points or less corresponded to clinical remission (CDAI score, ⱕ150 points). Because the HBI is easier to administer and less cumbersome than the CDAI, its use is supported for longterm follow-up assessments, so the HBI was used to determine Crohn’s disease severity—and thus response and remission—in PRECiSE 3. The complex nature of the CDAI also has led to questions about the consistency of results,20 a problem that may be obviated by using the simpler HBI. Results from the preceding 6-month PRECiSE 2 study showed that subcutaneous certolizumab pegol 400 mg induction and maintenance had the capability to stabilize patients with relapsing moderate-to-severe Crohn’s disease by reducing disease activity and inducing remission. In those who were
initially in response and remission at the start of PRECISE 3, response and remission rates were sustained for a further 54 weeks in these patients by continuing certolizumab pegol 400 mg maintenance therapy every 4 weeks. These data are supported by the median HBI scores. Response and remission rates decreased only moderately throughout the study. Response and remission rates at week 26 of the PRECiSE 2 study were highest among patients who were in the continuous treatment group. Although patients who were randomized to placebo in PRECiSE 2 (drug-interruption group) still achieved reasonable long-term response and remission rates in PRECiSE 3, it was clear that the rates were substantially lower than those of their counterparts who received continuous certolizumab pegol. When evaluating the data on certolizumab pegol reported here, it is important to consider that in clinical practice patients would receive induction therapy with a drug and be monitored for a response before determining whether to continue with the drug as maintenance treatment. Therefore, this trial was de-
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signed to reflect clinical practice, in which patients receive induction and then only those who respond continue to receive maintenance therapy. Although between-trial comparisons are difficult because of the differences in trial design, it is interesting to note that the week 52 response rate for the initial population from PRECiSE 2 who received active drug (28.9%) compares favorably with adalimumab in the CHARM trial. In CHARM,9 of the 854 patients who were enrolled, 499 patients (58.4%) responded to induction at week 4; 172 of these responders were randomized to the adalimumab 40-mg biweekly group and, subsequently, 71 (41.3%) of these remained in CDAI-100 response (CDAI decrease of ⱖ100 points from baseline) by week 56, giving a response rate of 24.1%. No new safety signals were identified during continuous or interrupted treatment with certolizumab pegol for up to 18 months. Injection-site reactions, immunologic events, and malignancies each affected 1% or less of patients. There were no cases of anaphylactic reaction. The rate of autoantibody production observed in patients treated with certolizumab pegol was low. The most frequently reported AEs were infections and gastrointestinal disorders. Although 2 cases of tuberculosis were reported in the study, the incidence was similar to that reported for other anti-TNF agents.8,9 In this study, the risk for tuberculosis was 0.8% per year. However, in the ACCENT I,8 CHARM study,9 and combined PRECiSE 2/3, the risk for occurrence of tuberculosis was 0.17 cases/100 patients for infliximab, 0.234 cases/100 patients for adalimumab, and 0.299 cases/100 patients for certolizumab pegol. Although this is higher than that observed in the global population (0.139 cases/100 people; 2006 data),21 this is a known risk for patients who take anti-TNF therapies (as documented in the prescribing information for all anti-TNF therapies). Physicians prescribing these therapies should screen patients for latent tuberculosis before initiating treatment; those testing positive should be treated accordingly.22–24 Even though there was a higher risk of developing antibodies to certolizumab pegol in the drug-interruption group, the safety profiles associated with continuous and interrupted certolizumab pegol use were similar with respect to the incidence, nature, and severity of AEs. Given that response and remission rates were higher in the PRECiSE 2 continuous group than in the drug-interruption group, it therefore reasonably can be argued that continuous maintenance therapy with certolizumab pegol after successful induction may afford the optimal benefit:risk ratio. In conclusion, subcutaneous certolizumab pegol 400 mg every 4 weeks is an efficacious and well-tolerated long-term maintenance therapy for patients with moderate-to-severe Crohn’s disease. Continuous maintenance therapy with certolizumab pegol after initial induction is more likely to produce response and remission than interrupted therapy, without negatively impacting patient safety.
Appendix The following were investigators for the PRECiSE 3 trial: Australia: P. Bampton, Flinders Medical Centre, Bedford Park, Adelaide; F. Dudley, The Alfred Hospital, Melbourne; D. Hetzel, Royal Adelaide Hospital, Adelaide; I. Lawrance, Fremantle Hospital, Fremantle; P. Pavli, The Canberra Hospital, Garran; W. Selby, RPAH Medical Centre, Newtown; Canada: F. Anderson, Liver & Intestinal Research Centre, Vancouver; C. Bernstein, Health Sciences Centre, Winnipeg; A. Cohen, Sir
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Mortimer B. Davis–Jewish General Hospital, Montreal; R. Enns, St. Paul’s Hospital, Vancouver; G. Greenberg, Mount Sinai Hospital, Toronto; M. Khaliq-Kareemi, Dalhousie University, Halifax, Nova Scotia; P. Laflamme, Centre Hospitalier Regionale de Lanaudiere, Quebec; Denmark: P. Bytzer, Amtssygehuset I Glostrup, Glostrup; J. F. Dahlerup, Aarhus Kommunehospital, Arhus C; E. Ejlersen, Vejle Sygehus, Vejle; J. Fallingborg, Aalborg Sygehus, Afsnit Syd, Aalborg; E. Langholz, Amtssygehuset I Gentofte, Hellerup; K. Lauritsen, Odense University Hospital, Odense C; A. Mertz-Nielsen, Hvidovre Hospital, Hvidovre; E. Philipsen, Bispebjerg Hospital, Copenhagen; M. Staun, Rigshospital, Copenhagen; O. O. Thomsen, Herlev Hospital, University of Copenhagen, Herlev; Germany: A. Dignass, Charite–Campus Virchow Klinikum, Berlin; J. Emmrich, University Rostock, Rostock; P. Herzog, Reinhard-Nieter-Krankenhaus, Wilhelmshaven; S. Howaldt, University of Hamburg, Hamburg; W. Kreisel, Universität Freiburg, Freiburg; T. Krummenerl, University of Münster, Münster; G. Ramadori, Universitätsklinikum Göttingen, Göttingen; I. Schiefke, Hospital of the University of Leipzig, Leipzig; S. Schreiber, Hospital for General Internal Medicine, Christian-Albrechts University, Kiel; A. Stallmach, Hospital Essen-Nord, Essen; C. von Tirpitz, University of Ulm, Ulm; Hungary: L. Bene, Peterfy Teaching Hospital, Peterfy, Budapest; Z. Gurzó, Pándy Kálmán Hospital, Gyula; L. Lakatos, Veszprém County Csolnoky Ferenc Hospital, Veszprém; I. Rácz, Petz Aladar County Teaching Hospital, Gyor; G. Székely, St Janos Hospital, Budapest; L. Varga Szabó, Szent Pantaleon Hospital, Dunaújváros; T. Zágoni, Semmelweis University, Budapest; Ireland: D. Kelleher, St James’ University Hospital, Dublin; F. Murray, The Beaumont Hospital, Dublin; D. O’Donaghue, St Vincents Hospital, Dublin; Israel: I. Dotan, Tel Aviv Sourasky Medical Center, Tel Aviv; R. Elyakim, Rambam Medical Center, Haifa; A. Fich, The Soroka University Medical Center, Beer Sheva; G. M. Fraser, Rabin Medical Center, Petah Tikva; E. Goldin, Hadassah Medical Organization, Jerusalem; A. Lavy, Bnai-Zion Medical Center, Haifa; E. Scapa, Assaf Harofeh Medical Center, Beer Yaakov; Lithuania: L. Kupcinskas, Kaunas Medical University Hospital, Kaunas; J. Valantinas, Public Institution Vilnius University Hospital, Vilnius; New Zealand: M. Barclay, Christchurch Hospital, Christchurch; M. Lane, Auckland Hospital, Auckland; D. Shaw, Tauranga Hospital, Tauranga; I. Wallace, Shakespeare Specialist Group, Auckland; F. Weilert, Waikato Hospital, Hamilton; J. Wyeth, Wellington Hospital, Wellington; Norway: K. Bakkevold, Haugesund Hospital, Bedriftspostkontoret Haugesund; J. R. Florholmen, University Hospital of Tromsø, Tromsø; J. Jahnsen, Aker University Hospital, Oslo; I. Lygren, Ullevål University Hospital, Oslo; N. Stray, Diakonhsemaets Hospital, Oslo; R. Torp, Sentralsjukehuset I Hedmark, Hamar, Hamar; H. L. Waldum, Regionsykehuset I Trondheim, Trondheim; Poland: A. Bochenek, Centrum Leczenia Chorob Ul, Waszawa; E. Czajkowska-Kaczmarek, Nzoz Polimedica, Ul, Lodz; M. Horynski, Centrum Medyczne “SOPMED” Sp. z o.o. Sopot; J. Leszczyszyn, EuroMediCare Instytut Medyczny Wrocław; R. Petryka, Np. Zoz Vivamed, Warsaw; J. Rudzinski, 10 Szpital Wojskowy w Bydgoszczy, Warszawy, Bydgoszcz; J. Sasiewicz, Wojewo ˇdzki ´niadeckiego, Białystok; Serbia: N. Jojic, Szpital Zespolony im.J.S KBC Zvezdara, Belgrade; M. Krstic, KBC Srbije, Belgrade; N. Milinic, KBC Bezanijska Kosa, Belgrade; A. Nagorni, KBC Nis, Nis; D. Tarabar, Military Medical Academy, Belgrade; Singapore: K. Y. Ho, National University Hospital; C. J. Ooi, Singapore General Hospital; South Africa: E. Fredericks, Greenacres
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Hospital, Port Elizabeth; L. Jackson, Linksfield Park Clinic, Johannesburg; K. Karlsson, Johannesburg General Hospital, Johannesburg; O. Mwantembe, Pretoria Academic Hospital, Pretoria; K. E. Pettengell, Parklands Hospital, Durban; S. J. Schmidt, Medpark Building, Cape Town; P. R. Spies, Kloof Hospital, Pretoria; M. Strimling, Rosebank Clinic, Johannesburg; G. A. A. Watermeyer, New Groote Schuur Hospital, Cape Town; C. C. M. Ziady, Kloof Hospital, Pretoria; Spain: J. Panés Díaz, Hospital Clinic de Barcelona, Barcelona; Ukraine: N. Chukhriyenko, City Hospital No 7, Dniepropetrovsk; R. Dutka, Lviv City Clinic No 5, Konovaltsa Str 22; I. Klyaritskaya, Crimean Medical University, Crimean Autonomy; E. Levchenko, Odessa Clinical Regional Hospital, Odessa; T. Pertseva, City Clinical Hospital No. 6, Dniepropetrovsk; M. P. Zakharash, Hospital of the Security Service of Ukraine, Kiev; United States: M. Bennett, Medical Associates Research Group, San Diego, CA; J. Breiter, Center for Medicine Research, LLC, Manchester, CT; W. Chey, Rochester Institute for Digestive Diseases, Rochester, NY; S. Desautels, Mountain West Gastroenterology, Salt Lake City, UT; A. Ertan, Houston, TX; E. J. Eyring, Wasatch Clinical Research, LLC, Salt Lake City, UT; D. J. Geenen, Wisconsin Center for Advanced Research, Milwaukee, WI; C. A. Goetsch, Clinical Research Associates, Huntsville, AL; C. G. Gross, Harmony Clinical Research, Oro Valley, AZ; D. R. Hassman, Comprehensive Clinical Research, Berlin, NJ; V. Hee, The Vancouver Clinic Inc PS, Vancouver, WA; J. Hogin, Lynn Health Science Institute, Oklahoma City, OK; R. Holmes, Piedmont Medical Research Associates, Winston-Salem, NC; D. James, Gastroenterology United of Tulsa, Tulsa, OK; W. D. Koltun, Medical Center for Clinical Research, San Diego, CA; S. D. Lee, University of Washington Medical Center, Seattle, WA; J. E. Lowe, Advanced Research Institute, LLC, South Ogden, UT; D. Lutter, Targeted Research, Dayton, OH; S. Malhotra, GI and Hepatology Associates, Alexandria, VA; S. P. Marcuard, Carolina Research Center, Greenville, NC; R. Movva, Midwest Clinical Research Associates Ltd, Moline, IL; D. J. Pambianco, Charlottesville Medical Research, Charlottesville, VA; L. Peters, Bethany Medical Center, High Point, NC; S. D. Pletcher, Southeastern Indiana Gastroenterology, Columbus, IN; W. M. Priebe, Tacoma Digestive Research Center, Tacoma, WA; M. Raikhel, Torrance Clinical Research, Torrance, CA; M. Ringold, New River Valley Research Institute, Christiansburg, VA; B. A. Salzberg, Atlanta Gastroenterology Associates, Atlanta, CA; W. Schonfeld, Southern Clinical Research Consultants, Hollywood, FL; D. Schwartz, Vanderbilt University Medical Center, Nashville, TN; A. Shafii, Lynn Institute of the Rockies, Colorado Springs, CO; J. P. Smith, Penn State University Milton Hershey, Hershey, PA; D. Stanton, Community Clinical Trials, Orange, CA; C. Stone, Washington University–School of Medicine, St. Louis, MO; J. Wang, Jefferson City Medical Group, Jefferson City, MO; L. M. Weiss, Clinical Research of West Florida, Inc, Clearwater, FL.
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References 1. Travis SP, Stange EF, Lemann M, et al. European evidence based consensus on the diagnosis and management of Crohn’s disease: current management. Gut 2006;55(Suppl 1):i16 –i35. 2. Schreiber S, Nikolaus S, Hampe J, et al. Tumour necrosis factor alpha and interleukin 1 beta in relapse of Crohn’s disease. Lancet 1999;353:459 – 461. 3. Braegger CP, Nicholls S, Murch SH, et al. Tumour necrosis factor
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23. 24.
alpha in stool as a marker of intestinal inflammation. Lancet 1992;339:89 –91. MacDonald TT, Hutchings P, Choy MY, et al. Tumour necrosis factor-alpha and interferon-gamma production measured at the single cell level in normal and inflamed human intestine. Clin Exp Immunol 1990;81:301–305. Murch SH, Lamkin VA, Savage MO, et al. Serum concentrations of tumour necrosis factor alpha in childhood chronic inflammatory bowel disease. Gut 1991;32:913–917. Hanauer SB, Sandborn WJ, Rutgeerts P, et al. Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn’s disease: the CLASSIC-I trial. Gastroenterology 2006;130:323–333. 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 –1035. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 2002;359:1541–1549. Colombel JF, Sandborn WJ, Rutgeerts P, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM trial. Gastroenterology 2007;132: 52– 65. Nesbitt A, Fossati G, Bergin M, et al. Mechanism of action of certolizumab pegol (CDP870): in vitro comparison with other anti-tumor necrosis factor alpha agents. Inflamm Bowel Dis 2007;13:1323–1232. Nesbitt AM, Henry AJ. High affinity and potency of the PEGylated Fab’ fragment CDP870. A direct comparison with other anti-TNF agents. Am J Gastroenterol 2004;99:S253. Sandborn WJ, Feagan BG, Stoinov S, et al. Certolizumab pegol for the treatment of Crohn’s disease. N Engl J Med 2007;357:228 – 238. Schreiber S, Khaliq-Kareemi M, Lawrance IC, et al. Maintenance therapy with certolizumab pegol for Crohn’s disease. N Engl J Med 2007;357:239 –250. Nikolaus S, Schreiber S. Diagnostics of inflammatory bowel disease. Gastroenterology 2007;133:1670 –1689. Harvey RF, Bradshaw JM. A simple index of Crohn’s-disease activity. Lancet 1980;1:514. Best WR. Predicting the Crohn’s disease activity index from the Harvey-Bradshaw Index. Inflamm Bowel Dis 2006;12:304 –310. Vermeire S, Schreiber S, Sandborn WJ, et al. Correlation between the Crohn’s Disease Activity and Harvey–Bradshaw indices in assessing Crohn’s disease severity. Clin Gastroenterol Hepatol 2010;8:357--363. Choy EHS, Hazleman B, Smith M, et al. Efficacy of a novel PEGylated humanized anti-TNF fragment (CDP870) in patients with rheumatoid arthritis: a phase II double-blinded, randomized, dose-escalating trial. Rheumatology 2002;41:1133–1137. Rutgeerts P, Feagan BG, Lichtenstein GR, et al. Comparison of scheduled and episodic treatment strategies of infliximab in Crohn’s disease. Gastroenterology 2004;126:402– 413. Sands BE, Ooi CJ. A survey of methodological variation in the Crohn’s disease activity index. Inflamm Bowel Dis 2005;11:133– 138. WHO. Report 2008: global tuberculosis control—surveillance, planning, financing. Available at: http://www.who.int/tb/publications/ global_report/2008/key_points/en/index.html. Accessed December 11, 2009. REMICADE prescribing information. Available at: http://www. centocor.com/centocor/assets/remicade.pdf. Accessed May 29, 2008. HUMIRA (adalimumab) [prescribing information]. Abbott Park, IL: Abbott Laboratories, 2009. Cimzia (certolizumab pegol) [prescribing information]. Brussels, Belgium: UCB Inc, 2009.
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Reprint requests Address requests for reprints to: Gary R. Lichtenstein, MD, Gastrointestinal Division, Department of Medicine, University of Pennsylvania School of Medicine, Hospital of the University of Pennsylvania, 3400 Spruce Street, 3rd Floor Ravdin Building, Philadelphia, Pennsylvania 19104-4283. e-mail: [email protected]; fax: (215) 3496915. Acknowledgments Medical writing assistance was provided by Lisa Thomas, PhD (PAREXEL, West Sussex, UK) and was funded by UCB, Brussels. A committee of academic investigators and UCB scientists designed the study. The trial was registered with clinicaltrials.gov (NCT00160524). Data were collected by ICON Clinical Research, Hampshire, United Kingdom, and were analyzed by UCB. The academic authors vouch for the veracity and completeness of the data and data analyses. Conflicts of interest The authors disclose the following: Gary R. Lichtenstein reports receiving consulting fees from Abbott Laboratories, Centocor, Ferring, Tanabe, Schering-Plough, Elan Pharmaceuticals, Genentech, Given Imaging, Millennium Pharmaceuticals, Proctor and Gamble, Prometheus, Salix, Shire, UCB Pharma, and Wyeth; receiving lecture fees from Abbott Laboratories, Centocor, Proctor and Gamble, Salix, and UCB
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Pharma; research with Abbott Laboratories, AstraZeneca, Bristol-Meyers Squibb, Proctor and Gamble, Salix, and Shire. Ole Ø. Thomsen reports receiving consulting fees from UCB and Zealand Pharma and receiving lecture fees from AstraZeneca, Dr Falk Pharma, Ferring, Otsuka Pharma, Pfizer, Schering-Plough, and UCB. Stefan Schreiber reports receiving consulting fees from Abbot Laboratories, ScheringPlough and its subsidiary Essex Pharma Solvay, and UCB; receiving lecture fees from Abbott Laboratories, Essex/Schering Plough, and UCB Pharma; and receiving grant support from Abbott and UCB Pharma. Ian C. Lawrance reports serving on the scientific advisory board and receiving consulting fees from Merck & Co, Abbott Laboratories, Pharmatel Fresenius Kabi, Janssen-Cilag Pharmaceuticals, Ferring Pharmaceuticals, and Schering-Plough; and receiving grant support from Abbott Laboratories and Orphan Australia. Stephen B. Hanauer reports serving as a consultant to and has been involved in clinical research with Abbot Laboratories, Bristol-Myers Squibb, Centocor, Elan Pharmaceuticals, Ferring Pharmaceuticals, Genentech, Proctor & Gamble, Prometheus, Salix, Shire, and UCB Pharma and serving as a consultant for AstraZeneca, GlaxoSmithKline, and Millennium Pharmaceuticals. Ralph Bloomfield is an employee of UCB. William J. Sandborn has received research support and served as a consultant for UCB Pharma, Centocor, and Abbott Laboratories. Funding This study was funded by UCB, Brussels, Belgium.
Continuous Therapy With Certolizumab Pegol Maintains Remission of Patients With Crohn’s Disease for up to 18 Months GARY R. LICHTENSTEIN,* OLE Ø. THOMSEN,‡ STEFAN SCHREIBER,§ IAN C. LAWRANCE,储 STEPHEN B. HANAUER,¶ RALPH BLOOMFIELD,# and WILLIAM J. SANDBORN** on behalf of the PRECiSE 3 STUDY INVESTIGATORS *Gastrointestinal Division, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; ‡Department of Gastroenterology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark; §Hospital for General Internal Medicine, Christian Albrechts University, Kiel, Germany; 储School of Medicine and Pharmacology, University of Western Australia, Fremantle Hospital, Fremantle, Australia; ¶Section of Gastroenterology and Nutrition, University of Chicago Medical Center, Chicago, Illinois; #UCB Pharma, Slough, United Kingdom; and **Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
See Editorial on page 556. BACKGROUND & AIMS: The safety and efficacy of maintenance therapy with the anti–tumor necrosis factor certolizumab pegol has not been reported beyond 6 months. We assessed the long-term efficacy, safety, and immunogenicity of continuous versus interrupted maintenance therapy with subcutaneous certolizumab pegol in patients with Crohn’s disease. METHODS: Patients who responded to induction therapy at week 6 of the PEGylated Antibody Fragment Evaluation in Crohn’s Disease: Safety and Efficacy (PRECiSE) 2 trial were assigned randomly to groups given certolizumab pegol (continuous) or placebo (drug-interruption) during weeks 6 to 26. Patients who completed PRECiSE 2 were eligible to enter PRECiSE 3, an ongoing, prospective, open-label extension trial in which patients have received certolizumab pegol (400 mg) every 4 weeks for 54 weeks to date, and were not offered the option to increase their dose. Disease activity was measured by the Harvey–Bradshaw Index. RESULTS: Harvey– Bradshaw Index responses at week 26 for the continuous and drug-interruption groups were 56.3% and 37.6%, respectively; corresponding remission rates were 47.9% and 32.4%, respectively. Of patients responding at week 26, response rates at week 80 after the start of PRECiSE 2 in the continuous and druginterruption groups were 66.1% and 63.3%, respectively; among patients in remission at week 26, week 80 remission rates were 62.1% and 63.2%, respectively. More patients in the drug-interruption group developed antibodies against certolizumab pegol (and had lower plasma concentrations of certolizumab pegol) than the continuously treated group. CONCLUSIONS: Certolizumab pegol effectively maintains remission of Crohn’s disease for up to 18 months. Continuous therapy is more effective than interrupted therapy. Keywords: Certolizumab Pegol; Crohn’s Disease; Anti–Tumor Necrosis Factor ␣.
C
rohn’s disease is a chronic remitting and relapsing inflammatory disorder of the gastrointestinal tract characterized by symptoms of diarrhea, abdominal pain, weight loss, fever, and rectal bleeding.1 Although the etiology of Crohn’s disease is unknown, the resulting chronic inflammatory process appears to be mediated, at least in part, by the proinflammatory cytokine tumor necrosis factor ␣ (TNF-␣).2–5 Treatment with biologic agents that target and sequester TNF-␣ is effective for
Crohn’s disease. The first 2 anti–TNF-␣ therapies approved for the treatment of Crohn’s disease were the engineered immunoglobulin G1 chimeric antibody infliximab and the human monoclonal antibody adalimumab. In randomized controlled trials, both antibodies proved efficacious in the induction6,7 and maintenance of remission.8,9 Certolizumab pegol is an Fc-free Fab’ anti–TNF-␣ of a monoclonal antibody, conjugated with polyethylene glycol, and recently approved for the treatment of moderate-to-severe active Crohn’s disease. Certolizumab pegol is devoid of the Fc portion and therefore does not induce either complement-dependent cytotoxicity or antibody-dependent cellular cytotoxicity,10 in contrast to the full immunoglobulin G1 anti–TNF-␣ antibodies (infliximab and adalimumab). The engineered Fab’ fragment does retain the high affinity of the original antibody, binding to soluble TNF-␣ with more than twice the potency of infliximab.10,11 The efficacy and tolerability of certolizumab pegol in patients with active Crohn’s disease have been confirmed in 2 large, pivotal, randomized, placebo-controlled, phase III studies, namely, PEGylated Antibody Fragment Evaluation in Crohn’s Disease: Safety and Efficacy 1 (PRECiSE 112) and PRECiSE 2.13 In PRECiSE 2, all patients received open-label certolizumab pegol 400 mg induction; responders (response defined as a reduction in Crohn’s Disease Activity Index [CDAI] score of ⱖ100 points from baseline) at week 6 then received maintenance treatment with either certolizumab pegol 400 mg or placebo at weeks 8, 12, 16, 20, and 24, with final assessment at week 26.13 The primary efficacy end point was clinical response at week 26. Significantly more patients receiving certolizumab pegol versus placebo, who had achieved response at week 6, showed ability to maintain response at week 26: 63% versus 36%, respectively (P ⬍ .001). The PRECiSE 2 trial was conducted over a short time frame (6 months) relative to the natural history of Crohn’s disease. The PRECiSE 3 study is an open-label extension that includes patients who completed the PRECiSE 2 trial; this was designed to determine the long-term safety and efficacy of subcutaneous certolizumab pegol 400 mg every 4 weeks. Although representAbbreviations used in this paper: AE, adverse event; anti-dsDNA, anti– double-stranded DNA antibodies; ANAs, antinuclear antibodies; CDAI, Crohn’s Disease Activity Index; HBI, Harvey–Bradshaw Index; PRECiSE, PEGylated Antibody Fragment Evaluation in Crohn’s Disease: Safety and Efficacy; TNF-␣, tumor necrosis factor ␣. © 2010 by the AGA Institute 1542-3565/$36.00 doi:10.1016/j.cgh.2010.01.014
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ing an open-label maintenance extension of the PRECiSE 2 trial, PRECiSE 3 is unique in 2 important ways. It is a prospective clinical trial beyond 12 months in which patients initially received either continuous or interrupted anti–TNF-␣ therapy and were not offered the option to increase their dose. All patients who completed the 26-week PRECiSE 2 trial were eligible for enrollment in PRECiSE 3. An important aim of the PRECiSE 3 trial was to analyze outcomes in patients who received continuous certolizumab pegol therapy (after induction and maintenance in PRECiSE 2) relative to outcomes in patients who received interrupted certolizumab pegol therapy (responders to induction therapy in PRECiSE 2 who then were randomized to placebo and then received certolizumab pegol in PRECiSE 3). The PRECiSE 3 clinical data presented here report the safety and efficacy results in patients receiving either continuous or interrupted anti–TNF-␣ therapy over a period of 18 months in the absence of an option to increase the dose.
Methods Study Design
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treatment regimen during PRECiSE 2. Therefore, the data have been analyzed to reflect the therapeutically distinct interventions patients received in PRECiSE 2 (Figure 1) as follows: (1) PRECiSE 2 continuous group: responders to certolizumab pegol induction at week 6 of PRECiSE 2 who then received certolizumab pegol maintenance over 18 weeks in PRECiSE 2, followed by continued certolizumab pegol in PRECiSE 3; (2) PRECiSE 2 drug-interruption group: responders to certolizumab pegol induction at week 6 of PRECiSE 2 who then received placebo over 18 weeks in PRECiSE 2, followed by re-exposure to certolizumab pegol in PRECiSE 3. Patients could be withdrawn from PRECiSE 3 at any time if they so requested or if they required defined rescue therapy (ie, infliximab, major change in corticosteroid and/or immunosuppressant dose, surgery, or hospitalization) for exacerbation of Crohn’s disease. The independent ethics committee or institutional review board at each study center approved the study. All participants gave written informed consent.
Assessments
PRECiSE 3 (www.clinicaltrials.gov; NCT00160524) is an ongoing, open-label extension study that included patients who completed 26 weeks of therapy in the PRECiSE 2 trial. The methodology of PRECiSE 2 has been published previously.12,13 All patients were aged 18 years and older with moderate-tosevere Crohn’s disease (defined by a CDAI score between 220 and 450 points) affecting the terminal ileum, colon, or both the ileum and colon for at least 3 months’ duration before screening. Diagnoses were based on conventional radiologic, endoscopic, or histologic diagnostic criteria.14 Patients enrolled in PRECiSE 3 received certolizumab pegol 400 mg every 4 weeks starting 28 weeks after the start of PRECiSE 2. The cut-off date for this analysis was June 2006, at which point all patients who had remained in the study had a minimum of 12 months’ exposure to certolizumab pegol in PRECiSE 3. Therefore, data are presented up to week 54 of PRECiSE 3, corresponding to week 80 from the initiation of PRECiSE 2 (Figure 1). To present the full 80 weeks’ treatment, all timelines and study visits described for PRECiSE 3 refer to baseline (week 0) of PRECiSE 2. Although PRECiSE 3 contained only a single treatment arm, patients did not enter the trial having received the same
Harvey–Bradshaw Index. The Harvey–Bradshaw Index (HBI) was used to measure Crohn’s disease activity in PRECiSE 3.15 The CDAI requires daily completion of a diary card and calculation of various weighting factors for 1 week. In contrast, the HBI only requires scoring from the day before the study visit and involves a lower number of components, making it a simpler alternative measure to the CDAI.16 Importantly, the HBI was shown to be highly correlated (Pearson correlation coefficient, r ⫽ 0.80) to the CDAI in PRECiSE 1 and 217 and in an earlier prospective study of patients with Crohn’s disease (Pearson correlation coefficient, r ⫽ 0.93).15 In PRECiSE 2, data were collected to calculate HBI scores at weeks 0 and 26. In PRECiSE 3, HBI was used to assess treatment efficacy at all visits (ie, at weeks 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, and 80 after the start of PRECiSE 2). An HBI response was defined as a reduction of 3 points or more from baseline and clinical remission was defined as an HBI score of 4 points or less. These values were determined from the correlation between the CDAI and HBI data at weeks 0 and 26 in PRECiSE 2.17 Safety. Safety was evaluated by conducting physical examinations and clinical laboratory tests (hematology, serum
Figure 1. Study design for the PRECiSE 2 and 3 studies.
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biochemistry analyses, and urinalysis) at screening and at all visits during the study. In the case of study withdrawal, a safety follow-up visit was conducted 12 weeks after the last dose. A chest radiograph was obtained at week 80 or at the withdrawal visit. Patients were assessed throughout the study for the possible occurrence of adverse events (AEs). AEs were classified and descriptively summarized by primary system organ class and preferred term according to the Medical Dictionary for Regulatory Activities. All concomitant medications and their dosages were recorded throughout PRECiSE 3. Assays. Blood samples for the determination of plasma certolizumab pegol concentrations and antibodies to certolizumab pegol were collected during the trial and at the safety follow-up visit (12 weeks after the last dose). Certolizumab pegol plasma concentration was measured by a validated enzyme-linked immunosorbent assay (G. R. Lichtenstein, unpublished data, 2007). Antibodies to certolizumab pegol also were measured by an enzyme-linked immunosorbent assay, and a level greater than 2.4 U/mL (an increase by a factor of 2 over the value of a reference population)18 was defined as the lower limit of detection. Blood samples taken at weeks 0, 26 (PRECiSE 2), 52, 80, or withdrawal visit (PRECiSE 3), and at the safety follow-up visit also were assayed for anti– double-stranded DNA (anti-dsDNA) antibodies and antinuclear antibodies (ANAs).
Statistical Analyses Efficacy outcomes included the proportion of patients from each treatment group who had achieved clinical response and remission at week 80 and a reduction in HBI score at week 80. Descriptive statistics for the HBI and for all clinical laboratory evaluations, along with absolute values and changes
from baseline, were presented at each scheduled visit. Clinical response and remission in patients exposed to certolizumab pegol were analyzed using the intention-to-treat population from PRECiSE 2. The intention-to-treat analysis makes the assumption that patients discontinuing treatment in PRECiSE 3 were nonresponders and nonremitters for all subsequent time points. Patients who received rescue therapy (ie, infliximab, any increase in corticosteroid and/or immunosuppressant dose, surgery, or hospitalization) also were deemed nonresponders and nonremitters for all subsequent time points. The proportion of patients achieving sustained HBI response (reduction from baseline in total HBI score of ⱖ3 points for all visits up to the visit of interest) was calculated. Similarly, the proportion of patients achieving sustained HBI remission (total HBI score of ⱕ4 for all visits up to the visit of interest) subsequently was calculated. Safety data were summarized for all patients from PRECiSE 2 who received one or more doses of certolizumab pegol in PRECiSE 3. Immunogenicity was compared between patients who continued therapy and those who had a drug interruption with respect to mean plasma certolizumab pegol concentration and antibody production against certolizumab pegol.
Results Patients and Demographics In the PRECiSE 2 study, 428 of 668 patients (64.1%) responded to certolizumab pegol induction therapy at week 6 (ie, CDAI decrease of ⱖ100 points from baseline) and were randomized to receive either certolizumab pegol or placebo maintenance treatment.13 Of the 428 patients, 215 and 210 patients were randomized and received certolizumab pegol or placebo, respectively (3 randomized patients were excluded be-
Table 1. Patient Demographics and Clinical Characteristics of Patients Entering PRECiSE 3 From PRECiSE 2
Baseline variable Mean age, y (range) Male, n (%) Mean body mass index, kg/m2 (SD) Current smoker, n (%) Mean duration of disease, years (range) Location of Crohn’s disease, n (%) Terminal ileum Colon Ileum/colon Resection performed, n (%) Mean HBI score (range) Geometric mean C-reactive protein concentration, mg/L (range) Previous infliximab therapy, n (%) Concomitant medications, n (%)a Patients on steroids at the start of PRECiSE 3b Patients on steroids at the start of PRECiSE 2 Patients on immunosuppressants at the start of PRECiSE 2c Patients on immunosuppressants and steroids at the start of PRECiSE 2 Patients on neither immunosuppressants nor steroids at the start of PRECiSE 2 aPatients
PRECiSE 2 Continuous group (N ⫽ 141)
PRECiSE 2 Drug-interruption group (N ⫽ 100)
38 (18–67) 65 (46) 24.0 (5.9) 38 (27) 8 (⬍1 to 33)
37 (18–69) 55 (55) 24.7 (5.0) 38 (38) 7 (⬍1 to 33)
28 (18) 39 (28) 69 (49) 35 (25) 10 (3–24) 10 (2–131) 27 (19)
26 (26) 23 (23) 45 (45) 31 (31) 10 (4–17) 7 (2–157) 17 (17)
26 (18) 47/215 (22) 59/215 (27) 28/215 (13) 81/215 (38)
19 (19) 44/210 (21) 52/210 (25) 34/210 (16) 80/210 (38)
on steroids at the start of PRECiSE 3 were calculated so as to measure steroid tapering during PRECiSE 3. Data on immunosuppressant use provided here are for the patients who were randomized in the PRECiSE 2 study and have been reported previously.13 bSteroids used were budesonide, prednisone, and prednisolone. cImmunosuppressants used were azathioprine, mercaptopurine, and methotrexate.
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cause of possible unblinding), and 151 patients (69.9%) and 109 patients (51.4%), respectively, successfully completed week 26. A total of 141 of 215 patients who received certolizumab pegol (65.6%) and 100 of 210 patients who received placebo (47.6%) in PRECiSE 2 were enrolled into PRECiSE 3 (Figure 1). As shown in Table 1, the patients enrolled in both treatment arms of PRECiSE 2 who entered PRECiSE 3 were well matched with respect to demographics, disease characteristics, and previous and concomitant medications. A total of 78 patients (32.4%) among those originally enrolled in PRECiSE 2 withdrew prematurely from PRECiSE 3. The reasons for withdrawal are summarized in Table 2.
Efficacy The HBI response rate at week 26 (week 0 of the PRECiSE 3 trial) was 56.3% (121 of 215 patients) in the continuous group and 37.6% (79 of 210 patients) in the druginterruption group. Although reduction in response was evident over time in the continuous and drug-interruption groups, substantial rates of response were sustained in both groups over a further 26 (week 52) and 54 weeks (week 80) of maintenance
Table 2. Incidence of AEs and Patient Discontinuations in Patients From PRECiSE 2 During PRECiSE 3 Follow-Up Evaluation Number (%) of patients
Variable Any AE Total Mild Moderate Severe AE related to study drug Serious AE Infection or infestation AE Serious infection or infestation AE Injection site Pain Reactions Erythema Burning Bruising Hemorrhage Phlebitis Swelling Premature withdrawals AE leading to withdrawal Protocol noncompliance Patient decision Clinical decision Lost to follow-up evaluation Lack of improvement/disease deterioration Other Deaths
Continuous group (N ⫽ 141)
Drug-interruption group (N ⫽ 100)
105 (74.5) 81 (57.4) 74 (52.5) 18 (12.8) 33 (23.4) 27 (19.1) 60 (42.6) 11 (7.8)
73 (73.0) 58 (58.0) 53 (53.0) 12 (12.0) 32 (32.0) 17 (17.0) 55 (55.0) 6 (6.0)
0 1 (0.7) 0 1 (0.7) 1 (0.7) 0 0 0 48 (34.0) 22 (15.6) 2 (1.4) 19 (13.5) 10 (7.1) 1 (0.7) 13 (9.2)
1 (1.0) 1 (1.0) 1 (1.0) 1 (1.0) 1 (1.0) 0 1 (1.0) 1 (1.0) 30 (30.0) 17 (17.0) 1 (1.0) 11 (11.0) 4 (4.0) 1 (1.0) 7 (7.0)
4 (2.8) 0 (0)
2 (2.0) 1 (1.0)
NOTE. AEs occurring during PRECiSE 3 and within 12 weeks of last injection.
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therapy with certolizumab pegol 400 mg (Figure 2A). Among patients who were in response at week 26, response rates were similar between the continuous and drug-interruption groups at both week 52 (74.4% vs 79.7%, respectively) and week 80 (66.1% vs 63.3%, respectively; Figure 2C). Sustained response rates were 62.8% and 47.1% at weeks 52 and 80, respectively, among continuously treated patients who showed a response at week 26. The corresponding values for the drug-interruption group were 63.3% and 45.6%, respectively. Relative to the initial population entering PRECiSE 2 (n ⫽ 668), 97 patients in the continuous group and 71 patients in the interrupted group (28.9% and 21.7%, respectively, of patients achieving response by week 6 of PRECiSE 2) remained in response at week 52; 86 patients in the continuous group and 57 patients in the interrupted group (25.6% and 17.4% of the patients achieving response by week 6 of PRECiSE 2) remained in response at week 80. The HBI remission rate at week 26 of PRECiSE 2 (PRECiSE 3 baseline) was 47.9% (103 of 215 patients) in the continuous group and 32.4% (68 of 210 patients) in the drug-interruption group. Remission rates were evident over time in the continuous and drug-interruption groups, high rates of remission were maintained in both groups by maintenance therapy with certolizumab pegol 400 mg over a further 26 weeks (week 52; 40.9% in the continuous and 30.0% in the drug-interruption group) and 54 weeks (week 80; 36.3% in the continuous and 23.3% in the drug-interruption group; Figure 2B). Among patients who were in remission at week 26, remission rates were similar between the continuous and drug-interruption groups at both week 52 (72.8% vs 73.5%, respectively) and week 80 (62.1% vs 63.2%, respectively; Figure 2D). Sustained remission rates were 49.5% and 33.0% at weeks 52 and 80, respectively, among continuously treated patients in remission at week 26. The corresponding values for the druginterruption group were 44.1% and 30.9%, respectively. The median HBI scores at baseline of PRECiSE 2 patients who continued to PRECiSE 3 were similar in the continuous and drug-interruption groups (9.0 [range, 3–24] and 9.0 [range, 3–21], respectively). By week 26 of PRECiSE 2 (week 0 of PRECiSE 3), the median HBI score had decreased by two thirds in both groups to values of 3.0 (range, 0 –13) and 3.0 (range, 0 –16) points, respectively, and remained low for the duration of PRECiSE 3 up to week 80 (Figure 3). Of note, between week 48 and week 80, median HBI scores for the entire patient population were at or below values that signify Crohn’s disease remission.17
Safety Certolizumab pegol was well tolerated in this study. The incidence of AEs was similar in both the PRECiSE 2 continuous and drug-interruption groups (Table 2). Exacerbation of Crohn’s disease was the most commonly experienced AE, followed by abdominal pain, nasopharyngitis, and arthralgia. The incidence of injection-site reactions, such as bruising, pain, and erythema, was low (ⱕ1%) and no anaphylactic reactions were observed. Most treatment-emergent AEs were of mild or moderate intensity and were considered by the investigators to be unrelated to the study drug (Table 2). The incidence of AEs that were considered to be related to certolizumab pegol was greatest in the drug-interruption group.
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Figure 2. (A) Response rates (reduction from baseline in HBI score, ⱖ3) and (B) remission rates (HBI score, ⱕ4) in PRECiSE 2 and PRECiSE 3 at weeks 26, 52, and 80 (intention-to-treat population). (C) Sustained response and (D) remission rates in PRECiSE 3 in patients who were already in response/remission at week 26 of PRECiSE 2. aHBI scores were not measured at week 6 so response and remission rates for the CDAI are presented in these graphs. bRecalculated CDAI scores. Criterion for entry into maintenance phase of PRECiSE 2 was a CDAI response; therefore, CDAI response rate at week 6 should be 100%. However, as a result of investigator error, such as miscalculated CDAI scores and other protocol deviations, the actual CDAI response rate in the intention-to-treat population is slightly lower.
Approximately one third of patients prematurely withdrew from the study, primarily because of AEs, patient decision, and lack of improvement or deterioration of Crohn’s disease. The incidence of patients who experienced serious AEs (continuous group, 19.1%; drug-interruption group, 17.0%) or AEs leading to premature withdrawal from the study was comparable for both subpopulations. A small-bowel carcinoma was the only malignancy to occur in the PRECiSE 2 patient population who entered into PRECiSE 3. This patient had been treated with continuous certolizumab pegol and rectal hydrocortisone, which was prescribed for rectal bleeding approximately 6 months after the patient entered PRECiSE 3. The rate of serious infections was 6.0% and 7.8% in the drug-interruption and continuous certolizumab pegol groups, respectively. Just under half of the patients with serious infections were receiving either concomitant steroids and/or immunosuppressants. The most common serious infection reported in 5 patients was perianal abscess; 1 patient was taking a concomitant immunosuppressant and 1 patient was receiving both a steroid and an immunosuppressant. There were 2 cases of tuberculosis: a 37-year-old woman from Denmark in the drug-interruption group was diagnosed with disseminated tuberculosis, from which she recovered with sequelae (decreased sense of touch from the middle of the right thigh and distally); and a 57-year-old man from South Africa who had been receiving certolizumab pegol throughout PRECiSE 2 and
3 was diagnosed with pulmonary tuberculosis from which he made a full recovery. The study drug was withdrawn in both cases at the onset of initial problems. Neither patient had been on concomitant immunosuppressants or steroids. Immunologic events were observed in 2 patients, one patient experienced sarcoidosis and the other patient experienced a drug-induced lupus-like reaction (this patient had an ANA-positive status that reverted to negative 1 year later; dsDNA status was negative). In PRECiSE 3, a 50-year-old man who had received placebo previously in PRECiSE 2 after successful induction with certolizumab pegol died from a tracheal obstruction caused by food impaction. His death was considered unrelated to the study drug by the investigator.
Autoimmune Antibodies Among those patients evaluable at week 26, ANAs had developed in 16 of 192 patients (8.3%) in the continuous group and 2 of 178 patients (1.1%) in the drug-interruption group.13 At week 80, new ANAs developed in 9 of 82 patients (11.0%) in the continuous group and 7 of 65 patients (10.8%) in the drug-interruption group. In patients evaluable at week 26, anti-dsDNA antibodies had developed in 2 of 192 patients (1.0%) in the continuous group and in 1 of 178 patients (0.6%) in the drug-interruption group.13 At week 80, new anti-dsDNA antibodies had developed
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Figure 3. Activity of Crohn’s disease as measured by the HBI at baseline and throughout PRECiSE 3, and geometric mean plasma concentrations of certolizumab pegol throughout PRECiSE 3. CZP, certolizumab pegol. These data are based on the entire study population, ie, although a patient may have provided an HBI score at a particular visit, they may not have provided a blood sample.
in 3 of 82 patients (3.7%) in the continuous group and 1 of 65 patients (1.5%) in the drug-interruption group. Only 1 patient was positive for ANAs and had anti-dsDNA antibodies present.
Systemic Exposure to Certolizumab Pegol On entry into PRECiSE 3 at week 26 (ie, 2 weeks after the last certolizumab pegol or placebo dose), the geometric mean plasma concentration of certolizumab pegol was 19.6 g/mL in the continuous group and less than 0.41 g/mL (below the limit of quantification) in the drug-interruption group (Figure 3). The predose value at week 28 for the continuous group was 6.9 g/mL and this trough level was maintained through week 80, at which time the geometric mean plasma concentration of certolizumab pegol was 7.7 g/mL. The predose value for the drug-interrupted group at week 32, after a dose of certolizumab pegol at week 28, was 1.9 g/mL and this trough value increased over time and by week 80 was 6.0 g/mL (Figure 3).
Antibodies Against Certolizumab Pegol Patients were considered positive for antibodies against certolizumab pegol if the blood sample assayed was greater than 2.4 U/mL at any time during the study. An antibodypositive status remained with the patient over the course of the study, even if they subsequently reverted back to being antibody-negative over time. Among patients for whom values were available at week 26, antibodies against certolizumab pegol had developed in 17 of 213 patients (8.0%) in the continuous group and 37 of 209 patients (17.7%) in the drug-interruption group.13 The influence of the development of anti– certolizumab pegol antibodies on plasma certolizumab pegol concentrations is shown in Figure 4.
The incidence of AEs was similar in the continuous and drug-interruption groups for patients with and without anti– certolizumab pegol antibodies.
Discussion These results from the PRECiSE 3 trial represent safety and efficacy data from a clinical trial of patients with Crohn’s disease receiving either continuous or interrupted anti–TNF-␣ therapy beyond 12 months without the option to increase the dose. In clinical practice, anti–TNF-␣ therapy might be stopped temporarily when there is a serious infection such as pneumonia. Therefore, clinical trial data on the potential implications of interrupted therapy provide directly relevant clinical information. Until now, the only information available regarding response to anti–TNF-␣ therapy after placebo has been as part of an episodic treatment strategy (ie, patients had to have experienced a disease flare before active treatment was reinstated).8,9,19 Another unique feature of the PRECiSE 3 trial is that patients were not offered the option to increase the medication dose. In the ACCENT I (Crohn’s disease clinical study evaluating infliximab in a new long–term treatment regimen) and CHARM (Crohn’s trial of the fully human antibody adalimumab for remission maintenance) trials of infliximab and adalimumab, patients were offered dose-escalation strategies.8,9 Therefore, although these prior studies have shown efficacy in patients who were randomized initially to placebo and then received open-label anti–TNF-␣ therapy on relapse,8,9 PRECiSE 3 investigated the efficacy and safety of an anti– TNF-␣ agent broken down by continuous versus interrupted therapy in a predetermined scheduled cessation of biological therapy, and we believe that the PRECiSE 3 study provides several key findings.
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Figure 4. Effect of anti– certolizumab pegol antibodies on the geometric mean plasma certolizumab pegol concentrations in PRECiSE 3 for patients from the (A) continuous treatment arm and (B) drug-interruption treatment arm (safety population). CZP, certolizumab pegol.
In PRECiSE 2, the CDAI score was used to determine response and remission. Data from almost 1000 matched pairs showed a positive correlation (0.800, Spearman correlation coefficient) between CDAI and HBI.17 The study by Vermeire et al17 calculated a 3-point change in the HBI that corresponded to a CDAI response of a 100-point improvement and HBI scores of 4 points or less corresponded to clinical remission (CDAI score, ⱕ150 points). Because the HBI is easier to administer and less cumbersome than the CDAI, its use is supported for longterm follow-up assessments, so the HBI was used to determine Crohn’s disease severity—and thus response and remission—in PRECiSE 3. The complex nature of the CDAI also has led to questions about the consistency of results,20 a problem that may be obviated by using the simpler HBI. Results from the preceding 6-month PRECiSE 2 study showed that subcutaneous certolizumab pegol 400 mg induction and maintenance had the capability to stabilize patients with relapsing moderate-to-severe Crohn’s disease by reducing disease activity and inducing remission. In those who were
initially in response and remission at the start of PRECISE 3, response and remission rates were sustained for a further 54 weeks in these patients by continuing certolizumab pegol 400 mg maintenance therapy every 4 weeks. These data are supported by the median HBI scores. Response and remission rates decreased only moderately throughout the study. Response and remission rates at week 26 of the PRECiSE 2 study were highest among patients who were in the continuous treatment group. Although patients who were randomized to placebo in PRECiSE 2 (drug-interruption group) still achieved reasonable long-term response and remission rates in PRECiSE 3, it was clear that the rates were substantially lower than those of their counterparts who received continuous certolizumab pegol. When evaluating the data on certolizumab pegol reported here, it is important to consider that in clinical practice patients would receive induction therapy with a drug and be monitored for a response before determining whether to continue with the drug as maintenance treatment. Therefore, this trial was de-
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signed to reflect clinical practice, in which patients receive induction and then only those who respond continue to receive maintenance therapy. Although between-trial comparisons are difficult because of the differences in trial design, it is interesting to note that the week 52 response rate for the initial population from PRECiSE 2 who received active drug (28.9%) compares favorably with adalimumab in the CHARM trial. In CHARM,9 of the 854 patients who were enrolled, 499 patients (58.4%) responded to induction at week 4; 172 of these responders were randomized to the adalimumab 40-mg biweekly group and, subsequently, 71 (41.3%) of these remained in CDAI-100 response (CDAI decrease of ⱖ100 points from baseline) by week 56, giving a response rate of 24.1%. No new safety signals were identified during continuous or interrupted treatment with certolizumab pegol for up to 18 months. Injection-site reactions, immunologic events, and malignancies each affected 1% or less of patients. There were no cases of anaphylactic reaction. The rate of autoantibody production observed in patients treated with certolizumab pegol was low. The most frequently reported AEs were infections and gastrointestinal disorders. Although 2 cases of tuberculosis were reported in the study, the incidence was similar to that reported for other anti-TNF agents.8,9 In this study, the risk for tuberculosis was 0.8% per year. However, in the ACCENT I,8 CHARM study,9 and combined PRECiSE 2/3, the risk for occurrence of tuberculosis was 0.17 cases/100 patients for infliximab, 0.234 cases/100 patients for adalimumab, and 0.299 cases/100 patients for certolizumab pegol. Although this is higher than that observed in the global population (0.139 cases/100 people; 2006 data),21 this is a known risk for patients who take anti-TNF therapies (as documented in the prescribing information for all anti-TNF therapies). Physicians prescribing these therapies should screen patients for latent tuberculosis before initiating treatment; those testing positive should be treated accordingly.22–24 Even though there was a higher risk of developing antibodies to certolizumab pegol in the drug-interruption group, the safety profiles associated with continuous and interrupted certolizumab pegol use were similar with respect to the incidence, nature, and severity of AEs. Given that response and remission rates were higher in the PRECiSE 2 continuous group than in the drug-interruption group, it therefore reasonably can be argued that continuous maintenance therapy with certolizumab pegol after successful induction may afford the optimal benefit:risk ratio. In conclusion, subcutaneous certolizumab pegol 400 mg every 4 weeks is an efficacious and well-tolerated long-term maintenance therapy for patients with moderate-to-severe Crohn’s disease. Continuous maintenance therapy with certolizumab pegol after initial induction is more likely to produce response and remission than interrupted therapy, without negatively impacting patient safety.
Appendix The following were investigators for the PRECiSE 3 trial: Australia: P. Bampton, Flinders Medical Centre, Bedford Park, Adelaide; F. Dudley, The Alfred Hospital, Melbourne; D. Hetzel, Royal Adelaide Hospital, Adelaide; I. Lawrance, Fremantle Hospital, Fremantle; P. Pavli, The Canberra Hospital, Garran; W. Selby, RPAH Medical Centre, Newtown; Canada: F. Anderson, Liver & Intestinal Research Centre, Vancouver; C. Bernstein, Health Sciences Centre, Winnipeg; A. Cohen, Sir
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Mortimer B. Davis–Jewish General Hospital, Montreal; R. Enns, St. Paul’s Hospital, Vancouver; G. Greenberg, Mount Sinai Hospital, Toronto; M. Khaliq-Kareemi, Dalhousie University, Halifax, Nova Scotia; P. Laflamme, Centre Hospitalier Regionale de Lanaudiere, Quebec; Denmark: P. Bytzer, Amtssygehuset I Glostrup, Glostrup; J. F. Dahlerup, Aarhus Kommunehospital, Arhus C; E. Ejlersen, Vejle Sygehus, Vejle; J. Fallingborg, Aalborg Sygehus, Afsnit Syd, Aalborg; E. Langholz, Amtssygehuset I Gentofte, Hellerup; K. Lauritsen, Odense University Hospital, Odense C; A. Mertz-Nielsen, Hvidovre Hospital, Hvidovre; E. Philipsen, Bispebjerg Hospital, Copenhagen; M. Staun, Rigshospital, Copenhagen; O. O. Thomsen, Herlev Hospital, University of Copenhagen, Herlev; Germany: A. Dignass, Charite–Campus Virchow Klinikum, Berlin; J. Emmrich, University Rostock, Rostock; P. Herzog, Reinhard-Nieter-Krankenhaus, Wilhelmshaven; S. Howaldt, University of Hamburg, Hamburg; W. Kreisel, Universität Freiburg, Freiburg; T. Krummenerl, University of Münster, Münster; G. Ramadori, Universitätsklinikum Göttingen, Göttingen; I. Schiefke, Hospital of the University of Leipzig, Leipzig; S. Schreiber, Hospital for General Internal Medicine, Christian-Albrechts University, Kiel; A. Stallmach, Hospital Essen-Nord, Essen; C. von Tirpitz, University of Ulm, Ulm; Hungary: L. Bene, Peterfy Teaching Hospital, Peterfy, Budapest; Z. Gurzó, Pándy Kálmán Hospital, Gyula; L. Lakatos, Veszprém County Csolnoky Ferenc Hospital, Veszprém; I. Rácz, Petz Aladar County Teaching Hospital, Gyor; G. Székely, St Janos Hospital, Budapest; L. Varga Szabó, Szent Pantaleon Hospital, Dunaújváros; T. Zágoni, Semmelweis University, Budapest; Ireland: D. Kelleher, St James’ University Hospital, Dublin; F. Murray, The Beaumont Hospital, Dublin; D. O’Donaghue, St Vincents Hospital, Dublin; Israel: I. Dotan, Tel Aviv Sourasky Medical Center, Tel Aviv; R. Elyakim, Rambam Medical Center, Haifa; A. Fich, The Soroka University Medical Center, Beer Sheva; G. M. Fraser, Rabin Medical Center, Petah Tikva; E. Goldin, Hadassah Medical Organization, Jerusalem; A. Lavy, Bnai-Zion Medical Center, Haifa; E. Scapa, Assaf Harofeh Medical Center, Beer Yaakov; Lithuania: L. Kupcinskas, Kaunas Medical University Hospital, Kaunas; J. Valantinas, Public Institution Vilnius University Hospital, Vilnius; New Zealand: M. Barclay, Christchurch Hospital, Christchurch; M. Lane, Auckland Hospital, Auckland; D. Shaw, Tauranga Hospital, Tauranga; I. Wallace, Shakespeare Specialist Group, Auckland; F. Weilert, Waikato Hospital, Hamilton; J. Wyeth, Wellington Hospital, Wellington; Norway: K. Bakkevold, Haugesund Hospital, Bedriftspostkontoret Haugesund; J. R. Florholmen, University Hospital of Tromsø, Tromsø; J. Jahnsen, Aker University Hospital, Oslo; I. Lygren, Ullevål University Hospital, Oslo; N. Stray, Diakonhsemaets Hospital, Oslo; R. Torp, Sentralsjukehuset I Hedmark, Hamar, Hamar; H. L. Waldum, Regionsykehuset I Trondheim, Trondheim; Poland: A. Bochenek, Centrum Leczenia Chorob Ul, Waszawa; E. Czajkowska-Kaczmarek, Nzoz Polimedica, Ul, Lodz; M. Horynski, Centrum Medyczne “SOPMED” Sp. z o.o. Sopot; J. Leszczyszyn, EuroMediCare Instytut Medyczny Wrocław; R. Petryka, Np. Zoz Vivamed, Warsaw; J. Rudzinski, 10 Szpital Wojskowy w Bydgoszczy, Warszawy, Bydgoszcz; J. Sasiewicz, Wojewo ˇdzki ´niadeckiego, Białystok; Serbia: N. Jojic, Szpital Zespolony im.J.S KBC Zvezdara, Belgrade; M. Krstic, KBC Srbije, Belgrade; N. Milinic, KBC Bezanijska Kosa, Belgrade; A. Nagorni, KBC Nis, Nis; D. Tarabar, Military Medical Academy, Belgrade; Singapore: K. Y. Ho, National University Hospital; C. J. Ooi, Singapore General Hospital; South Africa: E. Fredericks, Greenacres
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Hospital, Port Elizabeth; L. Jackson, Linksfield Park Clinic, Johannesburg; K. Karlsson, Johannesburg General Hospital, Johannesburg; O. Mwantembe, Pretoria Academic Hospital, Pretoria; K. E. Pettengell, Parklands Hospital, Durban; S. J. Schmidt, Medpark Building, Cape Town; P. R. Spies, Kloof Hospital, Pretoria; M. Strimling, Rosebank Clinic, Johannesburg; G. A. A. Watermeyer, New Groote Schuur Hospital, Cape Town; C. C. M. Ziady, Kloof Hospital, Pretoria; Spain: J. Panés Díaz, Hospital Clinic de Barcelona, Barcelona; Ukraine: N. Chukhriyenko, City Hospital No 7, Dniepropetrovsk; R. Dutka, Lviv City Clinic No 5, Konovaltsa Str 22; I. Klyaritskaya, Crimean Medical University, Crimean Autonomy; E. Levchenko, Odessa Clinical Regional Hospital, Odessa; T. Pertseva, City Clinical Hospital No. 6, Dniepropetrovsk; M. P. Zakharash, Hospital of the Security Service of Ukraine, Kiev; United States: M. Bennett, Medical Associates Research Group, San Diego, CA; J. Breiter, Center for Medicine Research, LLC, Manchester, CT; W. Chey, Rochester Institute for Digestive Diseases, Rochester, NY; S. Desautels, Mountain West Gastroenterology, Salt Lake City, UT; A. Ertan, Houston, TX; E. J. Eyring, Wasatch Clinical Research, LLC, Salt Lake City, UT; D. J. Geenen, Wisconsin Center for Advanced Research, Milwaukee, WI; C. A. Goetsch, Clinical Research Associates, Huntsville, AL; C. G. Gross, Harmony Clinical Research, Oro Valley, AZ; D. R. Hassman, Comprehensive Clinical Research, Berlin, NJ; V. Hee, The Vancouver Clinic Inc PS, Vancouver, WA; J. Hogin, Lynn Health Science Institute, Oklahoma City, OK; R. Holmes, Piedmont Medical Research Associates, Winston-Salem, NC; D. James, Gastroenterology United of Tulsa, Tulsa, OK; W. D. Koltun, Medical Center for Clinical Research, San Diego, CA; S. D. Lee, University of Washington Medical Center, Seattle, WA; J. E. Lowe, Advanced Research Institute, LLC, South Ogden, UT; D. Lutter, Targeted Research, Dayton, OH; S. Malhotra, GI and Hepatology Associates, Alexandria, VA; S. P. Marcuard, Carolina Research Center, Greenville, NC; R. Movva, Midwest Clinical Research Associates Ltd, Moline, IL; D. J. Pambianco, Charlottesville Medical Research, Charlottesville, VA; L. Peters, Bethany Medical Center, High Point, NC; S. D. Pletcher, Southeastern Indiana Gastroenterology, Columbus, IN; W. M. Priebe, Tacoma Digestive Research Center, Tacoma, WA; M. Raikhel, Torrance Clinical Research, Torrance, CA; M. Ringold, New River Valley Research Institute, Christiansburg, VA; B. A. Salzberg, Atlanta Gastroenterology Associates, Atlanta, CA; W. Schonfeld, Southern Clinical Research Consultants, Hollywood, FL; D. Schwartz, Vanderbilt University Medical Center, Nashville, TN; A. Shafii, Lynn Institute of the Rockies, Colorado Springs, CO; J. P. Smith, Penn State University Milton Hershey, Hershey, PA; D. Stanton, Community Clinical Trials, Orange, CA; C. Stone, Washington University–School of Medicine, St. Louis, MO; J. Wang, Jefferson City Medical Group, Jefferson City, MO; L. M. Weiss, Clinical Research of West Florida, Inc, Clearwater, FL.
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Reprint requests Address requests for reprints to: Gary R. Lichtenstein, MD, Gastrointestinal Division, Department of Medicine, University of Pennsylvania School of Medicine, Hospital of the University of Pennsylvania, 3400 Spruce Street, 3rd Floor Ravdin Building, Philadelphia, Pennsylvania 19104-4283. e-mail: [email protected]; fax: (215) 3496915. Acknowledgments Medical writing assistance was provided by Lisa Thomas, PhD (PAREXEL, West Sussex, UK) and was funded by UCB, Brussels. A committee of academic investigators and UCB scientists designed the study. The trial was registered with clinicaltrials.gov (NCT00160524). Data were collected by ICON Clinical Research, Hampshire, United Kingdom, and were analyzed by UCB. The academic authors vouch for the veracity and completeness of the data and data analyses. Conflicts of interest The authors disclose the following: Gary R. Lichtenstein reports receiving consulting fees from Abbott Laboratories, Centocor, Ferring, Tanabe, Schering-Plough, Elan Pharmaceuticals, Genentech, Given Imaging, Millennium Pharmaceuticals, Proctor and Gamble, Prometheus, Salix, Shire, UCB Pharma, and Wyeth; receiving lecture fees from Abbott Laboratories, Centocor, Proctor and Gamble, Salix, and UCB
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Pharma; research with Abbott Laboratories, AstraZeneca, Bristol-Meyers Squibb, Proctor and Gamble, Salix, and Shire. Ole Ø. Thomsen reports receiving consulting fees from UCB and Zealand Pharma and receiving lecture fees from AstraZeneca, Dr Falk Pharma, Ferring, Otsuka Pharma, Pfizer, Schering-Plough, and UCB. Stefan Schreiber reports receiving consulting fees from Abbot Laboratories, ScheringPlough and its subsidiary Essex Pharma Solvay, and UCB; receiving lecture fees from Abbott Laboratories, Essex/Schering Plough, and UCB Pharma; and receiving grant support from Abbott and UCB Pharma. Ian C. Lawrance reports serving on the scientific advisory board and receiving consulting fees from Merck & Co, Abbott Laboratories, Pharmatel Fresenius Kabi, Janssen-Cilag Pharmaceuticals, Ferring Pharmaceuticals, and Schering-Plough; and receiving grant support from Abbott Laboratories and Orphan Australia. Stephen B. Hanauer reports serving as a consultant to and has been involved in clinical research with Abbot Laboratories, Bristol-Myers Squibb, Centocor, Elan Pharmaceuticals, Ferring Pharmaceuticals, Genentech, Proctor & Gamble, Prometheus, Salix, Shire, and UCB Pharma and serving as a consultant for AstraZeneca, GlaxoSmithKline, and Millennium Pharmaceuticals. Ralph Bloomfield is an employee of UCB. William J. Sandborn has received research support and served as a consultant for UCB Pharma, Centocor, and Abbott Laboratories. Funding This study was funded by UCB, Brussels, Belgium.