Phase II evaluation of anti-MAdCAM antibody PF-00547659 in the treatment of Crohn's disease: report of the OPERA study

Abstract

Objective: This phase II, randomised, double-blind, placebo-controlled clinical trial was designed to evaluate the efficacy and safety of PF-00547659, a fully human monoclonal antibody that binds to human mucosal addressin cell adhesion molecule (MAdCAM) to selectively reduce lymphocyte homing to the intestinal tract, in patients with moderate-to-severe Crohn's disease (CD).

Design: Eligible adults were aged 18-75 years, with active moderate-to-severe CD (Crohn's Disease Activity Index (CDAI) 220-450), a history of failure or intolerance to antitumour necrosis factor and/or immunosuppressive agents, high-sensitivity C reactive protein >3.0 mg/L and ulcers on colonoscopy. Patients were randomised to PF-00547659 22.5 mg, 75 mg or 225 mg or placebo. The primary endpoint was CDAI 70-point decrease from baseline (CDAI-70) at week 8 or 12.

Results: In all, 265 patients were eligible for study entry. Although CDAI-70 response was not significantly different with placebo versus PF-00547659 treatment at weeks 8 or 12, remission rate was greater in patients with higher baseline C reactive protein (>5 mg/L vs >18.8 mg/L, respectively). Soluble MAdCAM decreased significantly from baseline to week 2 in a dose-related manner and remained low during the study in PF-00547659-treated patients. Circulating β7+ CD4+ central memory T-lymphocytes increased at weeks 8 and 12 with PF-00547659 treatment. No safety signal was seen.

Conclusions: Clinical endpoint differences between PF-00547659 and placebo did not reach statistical significance in patients with moderate-to-severe CD. PF-00547659 was pharmacologically active, as shown by a sustained dose-related decrease in soluble MAdCAM and a dose-related increase in circulating β7+ central memory T cells.

Trial registration number: NCT01276509; Results.

Keywords: crohn’s disease; inflammatory bowel disease; integrins; pharmacotherapy.

Conflict of interest statement

Competing interests: WJS has received grant support, personal fees and non-financial support from Pfizer during the conduct of the study; grant support from Pfizer, Exact Sciences, Amgen, the American College of Gastroenterology and the Broad Foundation; grant support and personal fees from Prometheus Laboratories, AbbVie, Boehringer Ingelheim, Takeda, Atlantic Pharmaceuticals, Janssen, Bristol-Myers Squibb, Genentech and Nutrition Science Partners and personal fees from Kyowa Hakko Kirin, Millennium Pharmaceuticals, Celgene Cellular Therapeutics, Santarus, Salix Pharmaceuticals, Catabasis Pharmaceuticals, Vertex Pharmaceuticals, Warner Chilcott, Gilead Sciences, Cosmo Pharmaceuticals, Ferring Pharmaceuticals, Sigmoid Biotechnologies, Tillotts Pharma, Am Pharma BV, Dr August Wolff, Avaxia Biologics, Zyngenia, Ironwood Pharmaceuticals, Index Pharmaceuticals, Nestle, Lexicon Pharmaceuticals, UCB Pharma, Orexigen, Luitpold Pharmaceuticals, Baxter Healthcare, Ferring Research Institute, Amgen, Novo Nordisk, Mesoblast, Shire, Ardelyx, Actavis, Seattle Genetics, MedImmune (AstraZeneca), Actogenix NV, Lipid Therapeutics Gmbh, Eisai, Qu Biologics, Toray Industries, Teva Pharmaceuticals, Eli Lilly, Chiasma, TiGenix, Adherion Therapeutics, Immune Pharmaceuticals, Celgene, Arena Pharmaceuticals, Ambrx, Akros Pharma, Vascular Biogenics, Theradiag, Forward Pharma, Regeneron, Galapagos, Seres Health, Ritter Pharmaceuticals, Theravance, Palatin, Biogen and the University of Western Ontario (owner of Robarts Clinical Trials) outside the submitted work. In addition, WJS reports patents related to the use of topical azathioprine to treat inflammatory bowel disorders (US 5,691,343), topical formulations of azathioprine to treat inflammatory bowel disorders (US 5,905,081), colonic delivery of nicotine to treat inflammatory bowel disease (South African patent 97/1020; US 5,846,983, 5,889,028 and 6,166,044; Mexico patent 209636; Europe patents 0954337 and 893998; Hong Kong patent HK1019043; China patent ZL97192177; Czech patent 293616; Canada patent 2,246,235), the use of azathioprine to treat Crohn’s disease (US 5,733,915), azathioprine compositions for colonic administration (New Zealand patent 306062; Singapore patent 45647; Australia patent 707168; Czech patent 290428), intestinal absorption of nicotine to treat nicotine responsive conditions (Australia patent 718052; US 6,238,689), the use of topical azathioprine and thioguanine to treat colorectal adenomas (US 6,166,024), enema and enterically coated oral dosage forms of azathioprine (US 6,432,967), a pharmaceutical composition for the treatment of inflammatory bowel disease (US 7,341,741), intestinal absorption of nicotine to treat nicotine responsive conditions (Canada patent 2,260,909) and obesity treatment and device (US 7,803,195 B2). SDL has received financial support for research from UCB, Janssen, Abbvie, Genentech, Amgen, Takeda and Pfizer; and consulting fees from UCB, Janssen and Takeda. DT reported no disclosures. EL has received educational grants from MSD, Abbvie; speaker fees from Abbvie, Ferring, MSD, Chiesi, Mitsubishi Pharma, Hospira, Janssen and Takeda and has served on advisory boards for Abbvie, Ferring, MSD, Takeda, Mitsubishi Pharma, Celltrion and Prometheus. MK has received speaker fees from Abbvie, Alvogen, Ferring and Takeda and fees for travel/accommodations/meeting expenses from Ferring, Alvogen and Abbvie. JK reported no disclosures. WR has received financial support for research from Abbott Laboratories, Abbvie, Aesca, Centocor, Falk Pharma GmbH, Immundiagnsotik and MSD; has served as a consultant for Abbott Laboratories, Abbvie, Aesca, Amgen, AM Pharma, Astellas, AstraZeneca, Avaxia, Bioclinica, Biogen IDEC, Boehringer-Ingelheim, Bristol-Myers Squibb, Cellerix, Chemocentryx, Celgene, Centocor, Celltrion, Covance, Danone Austria, Elan, Falk Pharma GmbH, Ferring, Galapagos, Genentech, Gilead, Grünenthal, ICON, Index Pharma, Inova, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, MedImmune, Millenium, Mitsubishi Tanabe Pharma, MSD, Nestle, Novartis, Ocera, Otsuka, PDL, Pharmacosmos, Pfizer, Procter & Gamble, Prometheus, Robarts Clinical Trial, Schering-Plough, Second Genome, Setpointmedical, Takeda, Therakos, Tigenix, UCB, Vifor, Zyngenia and 4S and as a speaker for Abbott Laboratories, Abbvie, Aesca, Aptalis, Centocor, Celltrion, Danone Austria, Elan, Falk Pharma GmbH, Ferring, Immundiagnostik, Mitsubishi Tanabe Pharma, MSD, Otsuka, PDL, Pharmacosmos, Schering-Plough, Shire, Takeda, Therakos, Vifor and Yakult. XH has served on advisory boards for Abbvie, Fresenius Kabi, Janssens and Takeda and has participated in educational activities for Abbvie, Arard, Ferring, Fresenius Kabi, Mayoly Spindler, MSD, Nestlé, Norgine, Nutricia and Takeda. DIP reported no disclosures. SS has received consulting/speaker fees from AbbVie, Biogen, BMS, Boehringer, Celltrion, Ferring, Hospira/Pfizer, Jansen, Merck, Novartis, Takeda and UCB. SN, AB, LSB and MHZ are employees of Pfizer. AA, FC,KJG, JBC and RC were employees of Pfizer during the OPERA study. GRD’H has served as a consultant for Abbvie, Ablynx, Amakem, AM Pharma, Avaxia, Biogen, Bristol Myers Squibb, Boerhinger Ingelheim, Celgene, Celltrion, Cosmo, Covidien, Ferring, Dr FALK Pharma, Engene, Ferring, Galapagos, Gilead, GlaxoSmithKline, Hospira, Johnson and Johnson, Medimetrics, Millenium/Takeda, Mitsubishi Pharma, Merck Sharp Dome, Mundipharma, Novonordisk, Pfizer, Prometheus laboratories/Nestle, Receptos, Robarts Clinical Trials, Salix, Sandoz, Setpoint, Shire, Teva, Tigenix, Tillotts, Topivert, Versant and Vifor and has received speaker fees from Abbvie, Ferring, Johnson and Johnson, Merck Sharp Dome, Mundipharma, Norgine, Pfizer, Shire, Millenium/Takeda, Tillotts and Vifor.

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Figures

Figure 1

Disposition of patients. *Three patients were randomised but did not receive treatment (placebo, n=1; PF-0547659 22.5 mg, n=1; PF-0547659, 75 mg, n=1).

Figure 2

Proportions of patients who achieved a CDAI-70 response (90% CI) with PF-00547659 22.5 mg, 75 mg and 225 mg versus placebo at week 8 and week 12, modified intention-to-treat group. CDAI-70, Crohn’s Disease Activity Index 70-point decrease from baseline.

Figure 3

Proportions of patients who achieved CDAI remission (90% CI) with PF-00547659 22.5 mg, 75 mg and 225 mg versus placebo in subgroups with baseline median hsCRP concentration of (A) >5 mg/L and (B) >18.8 mg/L and with baseline median SES-CD of (C) >10 (25th percentile) and (D) >17. *p<0.05, PF-00547659 versus placebo. CDAI-70, Crohn’s Disease Activity Index; hsCRP, high-sensitivity C reactive protein; SES-CD, Simple Endoscopic Activity Score–Crohn’s Disease.

Figure 4

Relative ratios of α4β7+ central memory CD4+T cells as (A) percentage of overall CD4+expressing cells, (B) absolute number (cells/µL) and (C) MESF for PF-00547659 22.5 mg, 75 mg and 225 mg versus placebo. MESF, molecules of equivalent soluble fluorochrome.

Figure 5

Median percentage of changes from baseline in MESF of β7+ cells after PD-00547659 treatment across pharmacokinetic quartiles. MESF, molecules of equivalent soluble fluorochrome.

Figure 6

Systemic exposure–response relationship between PD-00547659 at week 12 (by dose) and inflammation measured by (A) hsCRP or (B) faecal calprotectin. Data for two patients with a percentage change from baseline in hsCRP >2000 are not shown in (A) to allow clearer presentation of the other points; data for one patient with a percentage change from baseline in faecal calprotectin >1000 are also not shown in (B) for this reason. In addition, data are not included for patients in the placebo group and patients in the active treatment groups with no pharmacokinetic information. hsCRP, high-sensitivity C reactive protein.

Figure 7

Proportions of patients who achieved (A) CDAI-70 and (B) CDAI-100 responses by quartile of exposure at week 12. CDAI-70/CDAI-100, Crohn’s Disease Activity Index 70/100-point decrease from baseline.