Saturday, December 2, 2023
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Professor of Medicine and Clinical Pharmacology, University of Chicago, Chicago, Illinois; Director, Section of Gastroenterology, Hepatology and Nutrition, University of Chicago, Chicago, Illinois
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Professor of Medicine and Clinical Pharmacology, University of Chicago, Chicago, Illinois; Director, Section of Gastroenterology, Hepatology and Nutrition, University of Chicago, Chicago, Illinois
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This year's Digestive Disease Week (DDW) meeting featured a series of reports describing the expanding potential of biologic therapies for the treatment of Crohn's disease and ulcerative colitis (the inflammatory bowel diseases [IBD]). Since the 1998 introduction of infliximab, a chimeric monoclonal antibody targeting tumor necrosis factor (TNF)-alpha as a medical therapy for Crohn's disease, the door has opened to reveal a large number of biochemical and cellular targets in the control of the exaggerated immune responses observed in these chronic inflammatory conditions. Improvements in targeting TNF-alpha, as well as the emergence of novel therapeutic targets, were presented during these meeting proceedings. This report discusses some of the more key highlights in this context, emphasizing their potential impact on clinical practice.
Adalimumab* is a fully human IgG1 antibody that binds to circulating and membrane-bound TNF-alpha in a manner similar to infliximab, but which has the potential for less immunogenicity and the possibility for self-administration by patients.
Data presented at DDW 2004 demonstrated that, similar to infliximab, adalimumab induces apoptosis of monocytes and T cells.[1] Induction of apoptosis of membrane TNF-positive cells has been proposed as a likely mechanism of action for these IgG1 antibodies -- a mechanism different from that of other antibody subclasses and the soluble TNF receptors, etanercept and onercept, as discussed by Dr. Sander Van Deventer in an outstanding state-of-the-art lecture.[2] These other humanized anti-TNF-alpha therapies, although effective in rheumatoid arthritis, have not been observed to be effective in Crohn's disease.
Hanauer and colleagues[3] evaluated the efficacy and tolerability of adalimumab in a multicenter, placebo-controlled, randomized, double-blind trial involving 299 patients with active Crohn's disease (Crohn's Disease Activity Index [CDAI] 220-450) over a 4-week period. Approximately 25% of enrolled patients were receiving concomitant corticosteroids and over 50% were on immunosuppressants, documenting the "refractory" nature of the evaluated population. Patients were randomized to receive subcutaneous adalimumab or placebo at baseline and after 2 weeks. Dosing of adalimumab was as follows: 160 mg at week 0 (ie, baseline loading dose) followed by 80 mg at week 2 (160/80 mg); 80 mg at week 0 followed by 40 mg at week 2 (80/40 mg); or 40 mg at week 0 followed by 20 mg at week 2 (40/20 mg). The primary study endpoint was the percentage of patients in the 2 higher adalimumab dose groups in remission at 4 weeks compared with placebo-treated patients. Remission was achieved in 30% of patients in the high-dose adalimumab groups (36% and 24% in the 160/80-mg group and 80/40-mg group, respectively) compared with 12% of the placebo-treated group. There was evidence of remission and improvement by 2 weeks. Similarly, higher proportions of patients achieved the secondary endpoints -- reduction in CDAI by 70 points (60% and 59% in the 160/80-mg and 80/40-mg adalimumab groups, vs 37% in the placebo group) and by 100 points (50% and 40% in the 160/80-mg and 80/40-mg adalimumab groups, vs 25% in the placebo group). Adalimumab was well tolerated, and the most common adverse event was minor injection-site burning or pain.
In a second, open-label trial, Sandborn and colleagues[4] evaluated adalimumab administered at 80 mg at week 0, followed by 40 mg every other week, in a group of 24 patients who had either developed intolerance to infliximab due to the development of acute or delayed infusion reactions, or who had lost their response to infliximab. All patients tolerated adalimumab, and by 12 weeks the therapeutic results were similar to those reported in the randomized trial. Most patients (19 of 24) required 40-mg injections weekly to sustain their response and to wean off concomitant corticosteroids. Phase 3 maintenance trials are under way to identify appropriate maintenance dosing schedules, although it appears that adalimumab will provide an alternative anti-TNF strategy for Crohn's disease that is similar to its efficacy in rheumatoid arthritis. Of note, higher dosing requisites are not uncommon for the anti-TNF and other immunomodulatory agents in Crohn's disease compared with in rheumatoid arthritis; this is likely secondary to the increased antigenic drive from gut lumen contents compared with joints.
Mannon and investigators[5] described the results of a safety and efficacy trial involving a human anti-interleukin (IL)-12 antibody* in 79 patients with active Crohn's disease. IL-12 is an important cytokine that is produced in excess in the mucosa of patients with Crohn's disease; it drives T cells towards a TH (T-helper)-1 response. Inhibition of IL-12 has been shown to ameliorate inflammation in several animal models of IBD. This monoclonal antibody reacts with the p40 subunit of the IL-12 heterodimer and therefore has some cross-reactivity with the newly identified IL-23, which has an identical p40 subunit.
In this study, Mannon and coworkers randomly assigned patients to receive 7 weekly subcutaneous injections of 1 or 3 mg/kg of antibody, or placebo, with either a 4-week interval between the first and second injection or no interruption. Responses were best in the 3-mg/kg anti-IL-12 antibody group receiving continuous injections, where remission rates were 38% at the end of treatment and 50% at 12-week follow-up, compared with 0% for placebo. Reduction of the CDAI by more than 100 points was observed in 75% and 69% of patients receiving weekly 3-mg/kg infusions of anti-IL-12 antibody at the end of therapy and at 12-week follow-up, compared with 25% and 13% of patients receiving placebo. The antibody was well tolerated, and injection-site reactions were the most common adverse event differentiating study drug from placebo. However, more patients randomized to the intermittent infusion schedule developed antibodies to the human antibody. Mucosal cytokine levels of IL-12, interferon gamma, and TNF-alpha were reduced in samples of lamina propria lymphocytes. It remains to be determined how this promising agent will be further developed and where it will fall into the therapeutic armamentarium for Crohn's disease.
In another late-breaking abstract, Hommes and colleagues[6] reported the results of a randomized trial of fontolizumab* -- a humanized anti-interferon-gamma antibody for the treatment of moderate-to-severe Crohn's disease -- according to baseline C-reactive protein (CRP) levels. CRP has recently been used along with the CDAI to better separate placebo responders from responders to active drug in trials with anti-TNF and other biologic therapies (see discussion below). In this current trial, 133 patients with CDAI scores between 250 and 450 were randomized to receive placebo, fontolizumab 4 mg/kg, or fontolizumab 10 mg/kg at baseline or 2 infusions at days 0 and 28. For the 35 patients who had elevated CRP levels > 10 mg/L, the response (decrease in CDAI by > 100 points) and remission (CDAI < 150) rates at day 56 were significantly superior to placebo in the 4-mg/kg and 10-mg/kg fontolizumab groups (placebo: response rate = 14% and remission rate = 0%; fontolizumab 4 mg/kg: response rate = 77% and remission rate = 54%; fontolizumab 10 mg/kg: response rate = 71% and remission rate = 57%). The antibody was well tolerated when administered in 2 infusions, with all but 1 adverse reaction (sudden death of a 65-year-old man in his sleep) attributed to the underlying Crohn's disease. This early-phase trial will require additional support to demonstrate the appropriate dosing, timing, concurrent therapies, and patient selection to determine the ultimate role for interferon-gamma inhibition in Crohn's disease.
Natalizumab*, a humanized monoclonal IgG4 antibody to alpha-4 integrin, was first reported to have benefits in active Crohn's disease in a report by Gosh and colleagues.[7] This agent, which disrupts adhesive interactions between leukocytes and vascular endothelium and inhibits recruitment and migration of alpha-4-expressing leukocytes into gut tissue, was evaluated in a phase 3 study that enrolled 905 adult patients with active Crohn's disease.[8] Subjects were randomized 4:1 to receive either natalizumab 300 mg or placebo every 4 weeks for a total of 3 intravenous infusions (ENACT-1 [Evaluation of Natalizumab as Continuous Therapy-1). Although the primary endpoint of this trial was not achieved, in those patients who had received prior anti-TNF therapy (360 of the 905 patients), 54.3% of the natalizumab-treated group compared with 34.8% of the placebo-treated group demonstrated a clinical response (≥ 70-point decrease in CDAI) at week 10 (P = .004). These results were amplified in patients who had an elevated CRP level at baseline. In this group, 53.6% of the natalizumab-treated patients vs 30% of the placebo group achieved a clinical response, and 35% of the natalizumab-treated patients vs 20% of the placebo-treated patients achieved a clinical remission (CDAI, 150; P = .03). The same, fixed-dose regimen of 300 mg natalizumab given intravenously once monthly was sufficient to maintain alpha-4-receptor saturation comparable to that of patients treated on a mg/kg basis.[9]
Sandborn and colleagues[10] then rerandomized 339 patients who had achieved response or remission in the ENACT-1 trial to receive natalizumab 300 mg (intravenously) once monthly or placebo for up to an additional 12 months. These investigators reported the first 6-month outcome of this maintenance trial. After 6 months, 61% of the natalizumab-treated subjects continued to meet the criteria for a clinical response, compared with 29% of patients randomized to placebo infusions (P < .001). In addition, 44% of natalizumab-treated patients maintained remission compared with only 25% of patients rerandomized to placebo (P < .001). There were no significant differences in side effects between the treatment groups.
Although natalizumab has also been effective in the treatment of multiple sclerosis, variations in the dose and dosing regimens for active disease still need clarification. It does appear, however, that patients who do respond to natalizumab will continue to be able to maintain remission with monthly infusions of the drug.
At last year's DDW meeting, Plevy and colleagues[11] described remarkable initial results with visilizumab*, a humanized anti-CD3 monoclonal antibody administered to patients with severe, steroid-refractory ulcerative colitis.
During this year's meeting proceedings, this same group of investigators reported expanded data regarding the therapeutic benefit of visilizumab in ulcerative colitis. Data were reported from a total of 32 patients treated with either 2 daily doses of visilizumab 15 micrograms (mcg)/kg or 10 mcg/kg in this phase 1 dose-finding study.[12] All patients were negative for exposure to Epstein-Barr virus infection. A "cytokine-release syndrome" consisting of fatigue, nausea, vomiting, fever, chills, and dehydration occurred in 75% to 100% of patients treated with the higher dose of drug and in 38% to 75% of patients who were pretreated with corticosteroids and acetaminophen prior to the 10-mcg/kg dose of visilizumab. Most patients were discharged within 1-3 days after visilizumab infusions and were followed up to 1 year. Sixty-three percent of the patients in the 15-mcg/kg dosing group remained relapse-free and off steroids. Among patients in the 10-mcg/kg dose group, 56% remain on study and only 22% have relapsed after a mean of 5 months. T-cell depletion persisted from 1 hour to 2 weeks and returned to baseline levels within 2-6 weeks. Epstein-Barr virus titers rose in 80% of patients, but returned to baseline levels concurrent with T-cell repopulation. Most important, no serious infectious complications were observed, and future trials will continue to explore optimal dosing regimens, long-term efficacy, and the potential risk of infections (including reactivation of Epstein-Barr) in these steroid-refractory patients.
Additional trials in Crohn's disease are also envisioned with this antibody, which transiently depletes T cells and may allow a reset population of unprimed or regulatory T cells to proliferate and replace the "autoreactive" cells that likely contribute to ongoing inflammation.
In distinct contrast to the "high-tech" manufactured proteins described above for the treatment of Crohn's disease and ulcerative colitis, a group of investigators from the University of Iowa has been exploring the potential of helminth therapy to ameliorate IBD.[13] Helminth colonization is linked to downregulation of immune responses, and indeed, IBD is prevalent in areas where parasitic helminths are scarce.
In the first of 2 abstracts presented on this topic, Summers and colleagues[14] described the results of a randomized controlled trial of Trichuris suis (a pig whipworm that does not produce disease in humans) for the treatment of ulcerative colitis. The study involved 54 patients with active ulcerative colitis who were randomized to receive either 2500 T suis ova or placebo, given orally in a charcoal solution every 2 weeks for 12 weeks. At the conclusion of the trial, 43% of patients treated with helminth ova had at least a 4-point decrease in the disease activity index score compared with 17% of patients randomized to placebo solution. It was interesting to note that no worms or ova were reported in the stool. However, Dr. Summers did report seeing worms in the colons of a few patients undergoing colonoscopy.
In the second abstract, Summers and colleagues reported the results of an open-label, uncontrolled trial in patients with Crohn's disease. This study involved 29 patients with a CDAI between 220 and 450. Patients were enrolled in a 24-week open study to receive 2500 T suis ova every 3 weeks while all other medications for Crohn's disease were maintained at the same dose. The investigators reported that, remarkably, 76% of patients responded with a > 100-point decrease in the CDAI and that 62% of patients remitted with a CDAI < 150 after 12 weeks. By week 24, 79% of patients experienced a response and 72% were in remission. No complications or worm infestations were reported.
These very optimistic results must be confirmed in larger controlled trials, and assessment of dose-response requires testing. Although these findings are most intriguing, whether pig whipworms will provide therapeutic properties in controlled trial settings remains to be proven. The concept of helminth infections preventing the development of IBD (and other autoimmune disorders) is distinct from the potential of these "probiotics" to treat ongoing inflammation -- but they provide a great contrast to the manufactured, high-tech, high-cost and potentially toxic, monoclonal antibody therapies in development.
It is hoped that the above discussion serves to highlight the key implications of these studies with emerging biologic therapies for IBD. Clearly, this progress represents a strong path forward for both the IBD patient and the treating physician. Results of future investigations to better elucidate (and understand) the potential role of these therapies in our current armamentarium against IBD are eagerly awaited.
* The United States Food and Drug Administration has not approved this therapy for this use.
