EDITORIALS Still in Pursuit See “Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis,” by Sandborn WJ, Feagan BG, Marano C, et al, on page 85 and “Subcutaneous golimumab maintains clinical response in patients with moderate-tosevere ulcerative colitis,” by Sandborn WJ, Feagan BG, Marano C, et al, on page 96.

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he titles tell it all. Subcutaneous golimumab induces clinical response and (clinical) remission and maintains clinical response in (out) patients with moderate-tosevere ulcerative colitis.1,2 However, this is not the full story. As the authors state, infliximab and adalimumab have been shown to be effective for induction and maintenance (of clinical responses) for patients with moderate-to-severe symptoms and endoscopic evidence of ulcerative colitis despite ongoing therapy with aminosalicylates, corticosteroids, or thiopurines.3–5 This is a heterogenous group of patients receiving differing concoctions of therapies, at varied doses, with a spectrum of mucosal disease extent and severity, and disease duration. As exemplified in the PURSUIT population, the average duration of disease was 6 years. The average Mayo score of 8 and low mean Inflammatory Bowel Disease Questionnaire (IBDQ) score suggests a degree of symptoms that has a substantial impact on quality of life for the enrolled population. The primary endpoint—clinical response—was at least a 30% improvement and a 3-point improvement in the Mayo score which, given the average patient, would be a Mayo score of around 5, just below the entry criteria for inclusion definition of moderate disease activity. Secondary endpoints for the induction component were clinical remission (Mayo score 1000 patients enrolled are reassuring but cautionary. In particular, in endemic regions 4 cases of tuberculosis developed despite baseline screening, and a few serious infections were encountered, consistent with the expanded experience with golimumab in rheumatoid arthritis and the anti-tumor necrosis factor (TNF) class, in general. One must keep in perspective that this was a controlled clinical trial whose primary purpose was to gain regulatory approval for the marketing of golimumab for ulcerative colitis and, indeed, the efforts were rewarded with US Food and Drug Administration approval for “adults with moderately to severely active ulcerative colitis for inducing and maintaining clinical response, improving endoscopic appearance of the mucosa during induction, inducing clinical remission, and achieving and sustaining clinical remission in induction responders, who have demonstrated corticosteroid dependence or who have had an inadequate response to or failed to tolerate oral aminosalicylates, oral corticosteroids, azathioprine, or 6-mercaptopurine.6” This was not a study meant to optimize treatment with golimumab in clinical practice, compare golimumab with other induction or maintenance therapies (including infliximab or adalimumab), identify patient subgroups or those not included within the entry criteria, or analyze cost effectiveness. No clinical trials are perfect and imperfections are inherent in a trial of this magnitude and complex design incorporating patients and outcomes from unpublished intravenous trials, dose-ranging phase II studies, and the ultimate phase III randomized-responder population described in the accompanying manuscripts. The primary outcome, although duplicative of prior studies with infliximab and adalimumab, is a “weak” endpoint such that the vast majority of patients who successfully achieve a clinical response are still symptomatic, on concomitant steroids, and without a “normal or inactive” mucosal appearance. In

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consideration of the endoscopic assessment, many of the current authors have advocated central reading7 that was not incorporated into the current trial design that engaged 251 centers including North America, Eastern and Western Europe, North and South Africa, Asia, and the Pacific (also without central histologic confirmation of disease). The analysis did not identify substantial site biases, although we are not privy to comprehensive site data and the perils and pitfalls of large multinational clinical trials are exemplified by the subsequent removal of data from 1 trial site found to not be following “good clinical practice.” Although dose escalation was allowed for patients who lost response in the maintenance phase, despite the magnitude of the trial there was inadequate power to assess dose adjustments. We also do not know the proportions of patients who had a normal IBDQ at conclusion of the maintenance phase. I find several aspects of the trial illuminating and, likely, interacting. The predictors of response were milder disease based on Mayo score, fecal lactoferrin and Creactive protein at baseline. However, the most important area for further exploration, as emphasized by the authors, is the exposure–response relationship. In both the induction and maintenance phases, the quartile of patients with the highest serum levels of golimumab had the best clinical responses. We have yet to observe a leveling off of this relationship such that there remains a strong possibility that optimal dosing was not achieved. The authors are astute in describing this in both manuscripts and, in other papers, have identified aspects of monoclonal antibody clearance that impact on drug levels and clinical response.8 Indeed, greater disease severity may be correlated with more rapid clearance, perhaps explaining why the less-severe patients had the better response. The authors’ call for further exploration of the exposure–response relationship for golimumab and all monoclonal antibodies in IBD is pertinent for the eventual personalization of drug therapy. Finally, the introduction of the induction manuscript states that “there remains a need for additional treatment options” (for ulcerative colitis). Although golimumab is another option, we do not have sufficient data to determine its ultimate positioning relative to other therapies. The trial was performed in anti-TNF–naïve patients, and for the fourth anti-TNF monoclonal antibody introduced into the US marketplace for IBD, the inclusion criteria presented rather “low-hanging” fruit. Outstanding issues for anti-TNF monoclonal antibodies in ulcerative colitis include: the role for combination therapy with immunosuppressants (and aminosalicylates) and/or how to optimize therapy with therapeutic drug monitoring with mono- or combination therapy. With novel agents of different classes such as anti-adhesion molecules and JAK inhibitors on the near horizon we need to continue assessing our therapeutic algorithms for moderate-to-severe ulcerative colitis.9 Thus, although we are still in pursuit of more effective and safe therapies for ulcerative colitis, we still have plenty of trail (and trials) ahead.

EDITORIALS STEPHEN B. HANAUER Section of Gastroenterology, Hepatology and Nutrition University of Chicago Medicine Chicago, Illinois

References 1.

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6. 7.

Sandborn WJ, Feagan BG, Marano C, et al. Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology 2014;146:85–95. Sandborn WJ, Feagan BG, Marano C, et al. Subcutaneous golimumab maintains clinical response in patients with moderate-to-severe ulcerative colitis. Gastroenterology 2014;146:96–109. Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005;353:2462–2476. Reinisch W, Sandborn WJ, Hommes DW, et al. Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial. Gut 2011;60:780–787. Sandborn WJ, van Assche G, Reinisch W, et al. Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology 2012;142:257–265. Biotech J. Simponi package insert. Feagan BG, Sandborn WJ, D’Haens G, et al. the role of centralized reading of endoscopy in a randomized

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controlled trial of mesalamine for ulcerative colitis. Gastroenterology 2013;145:149–157. Ordas I, Feagan BG, Sandborn WJ. Therapeutic drug monitoring of tumor necrosis factor antagonists in inflammatory bowel disease. Clin Gastroenterol Hepatol 2012;10:1079–1087. Danese S. New therapies for inflammatory bowel disease: from the bench to the bedside. Gut 2012;61:918–932.

Reprint requests Address requests for reprints to: Stephen B. Hanauer, MD, Joseph B. Kirsner Professor of Medicine and Clinical Pharmacology, Chief, Section of Gastroenterology, Hepatology and Nutrition, University of Chicago Medicine, 5841 S. Maryland Avenue, MC 4076, Chicago, IL 60637. e-mail: [email protected]

Conflicts of interest The author discloses the following: AbbVie, Consultant, Clinical Research (Institution); Amgen, Consultant, Clinical Research (Institution); Astellas Pharma Global, Consultant; Astra Zeneca, Consultant; Bristol Myers Squibb, Consultant, DSMB; Elan, Consultant; Exagen, Consultant; Ferring, Consultant; Genentech, Consultant, Clinical Research (Institution); Gilead, Consultant; Glycominds, Consultant; GSK, Consultant, Clinical Research (Institution); Hospira, Consultant; Janssen, Consultant, Clinical Research (Institution); Lilly, Consultant, Clinical Research (Institution); Meda, Consultant; Millenium Pharmaceuticals, Consultant, Clinical Research (Institution); Novartis, Consultant, Clinical Research (Institution); Novo Nordisk, Consultant, Clinical Research (Institution); Pfizer, Consultant, Clinical Research (Institution); Prometheus, Consultant, Clinical Research (Institution); Salix, Consultant; Sanofi-Avantis, Consultant, Clinical Research (Institution); Shire, Consultant; Takeda, Consultant, Clinical Research (Institution); UCB Pharma, Consultant, Clinical Research (Institution); WarnerChilcott, Consultant. © 2014 by the AGA Institute 0016-5085/$36.00 http://dx.doi.org/10.1053/j.gastro.2013.11.025

Potential Benefit of Telbivudine on Renal Function Does Not Outweigh Its High Rate of Antiviral Drug Resistance and Other Adverse Effects See “Telbivudine improves renal function in patients with chronic hepatitis B,” by Gane EJ, Deray G, Liaw Y-F, on page 138.

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ive nucleos(t)ide analogs (NUCs) are approved for the treatment of hepatitis B. NUC therapy had been shown to reverse fibrosis and cirrhosis, and to reduce the risk of hepatic decompensation and hepatocellular carcinoma.1,2 Although NUCs are effective in suppressing hepatitis B virus (HBV) replication, they do not eradicate the virus; therefore, most patients require long-term treatment. Long-term efficacy, safety, drug resistance, and costs are the major considerations in determining which NUC should be considered as first-line treatment. NUCs are generally safe and well-tolerated, but side effects have been reported including nephrotoxicity, neuropathy, myopathy, lactic acidosis, and decrease in bone mineral density.1,3–6 Of these, nephrotoxicity associated with adefovir or tenofovir has received the most attention. Nephrotoxicity manifesting as decrease in glomerular filtration rate (GFR)

is more common in patients who are >50 years old, have baseline renal insufficiency, hypertension and/or diabetes mellitus.7 Proximal renal tubular injury—resembling Fanconi syndrome with hypophosphatemia, hypouricemia, aminoaciduria, and glycosuria—had also been reported.8 In most instances, nephrotoxicity is reversible after dose reduction or discontinuation of treatment. The postulated mechanisms of nephrotoxicity associated with adefovir and tenofovir treatment include increased intracellular influx through organic anion transporters and/or a defect in its luminal excretion through multidrug-resistance–associated proteins, or mitochondrial toxicity in the proximal tubular cells of the kidney.9 Lamivudine and entecavir have not been reported to be associated with nephrotoxicity. All NUCs approved for HBV are eliminated by the kidneys and dose adjustments are needed in patients with impaired renal function. Renal impairment is common in patients with decompensated cirrhosis and in liver transplant recipients. Therefore, renal safety is an important factor in deciding which NUC is most appropriate for patients with hepatitis B, particularly those who have other risk factors for renal impairment.

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Still in pursuit.

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