Article

Fontolizumab, a humanised anti-interferon gamma antibody, demonstrates safety and clinical activity in patients with moderate to severe Crohn's disease.

Department Gastroenterology and Hepatology, Academic Medical Centre, Amsterdam, the Netherlands.
Gut (Impact Factor: 13.32). 09/2006; 55(8):1131-7. DOI: 10.1136/gut.2005.079392
Source: PubMed

ABSTRACT Interferon gamma is a potent proinflammatory cytokine implicated in the inflammation of Crohn's disease (CD). We evaluated the safety and efficacy of fontolizumab, a humanised anti-interferon gamma antibody, in patients with moderate to severe CD.
A total of 133 patients with Crohn's disease activity index (CDAI) scores between 250 and 450, inclusive, were randomised to receive placebo or fontolizumab 4 or 10 mg/kg. Forty two patients received one dose and 91 patients received two doses on days 0 and 28. Investigators and patients were unaware of assignment. Study end points were safety, clinical response (decrease in CDAI of 100 points or more), and remission (CDAI < or =150).
There was no statistically significant difference in the primary end point of the study (clinical response) between the fontolizumab and placebo groups after a single dose at day 28. However, patients receiving two doses of fontolizumab demonstrated doubling in response rate at day 56 compared with placebo: 32% (9/28) versus 69% (22/32, p = 0.02) and 67% (21/31, p = 0.03) for the placebo, and 4 and 10 mg/kg fontolizumab groups, respectively. Stratification according to elevated baseline C reactive protein levels resulted in a decreased placebo response and pronounced differences in clinical benefit. Two grade 3 adverse events were reported and were considered to be related to CD. One death (during sleep) and one serious adverse event (an elective hospitalisation) occurred, both considered unrelated.
Treating active CD with fontolizumab was well tolerated and resulted in increased rates of clinical response and remission compared with placebo.

Full-text

Available from: János Lonovics, Jun 16, 2015
0 Followers
 · 
314 Views
  • Article: Trial Watch
    [Show abstract] [Hide abstract]
    ABSTRACT: During the last two decades, a number of approaches for the activation of the immune system against cancer has been developed. These include highly specific interventions, such as monoclonal antibodies, vaccines and cell-based therapies, as well as relatively unselective strategies, such as the systemic administration of adjuvants and immunomodulatory cytokines. Cytokines constitute a huge group of proteins that, taken together, regulate not only virtually all the aspects of innate and cognate immunity, but also several other cellular and organismal functions. Cytokines operate via specific transmembrane receptors that are expressed on the plasma membrane of target cells and, depending on multiple variables, can engage autocrine, paracrine or endocrine signaling pathways. The most appropriate term for defining the cytokine network is “pleiotropic”: cytokines are produced by - and operate on - multiple, often overlapping, cell types, triggering context-depend biological outcomes as diverse as cell proliferation, chemotaxis, differentiation, inflammation, elimination of pathogens and cell death. Moreover, cytokines often induce the release of additional cytokines, thereby engaging self-amplificatory or self-inhibitory signaling cascades. In this Trial Watch, we will summarize the biological properties of cytokines and discuss the progress of ongoing clinical studies evaluating their safety and efficacy as immunomodulatory agents against cancer.
    OncoImmunology 07/2012; 1(4):493-506. · 6.28 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The recent success of the anti-integrin antibody Vedolizumab can barely conceal the fact that the biologics armamentarium in Crohn’s disease has barely evolved beyond TNF blockers so far. This contrasts with other immune-related diseases considered mechanistically and genetically closely related, such as psoriasis and rheumatoid arthritis, where approved biologics target a variety of independent biological mechanisms. Several pharmacological assets that entered clinical development have proven ineffective, or less effective than originally anticipated. While blockade of IL-17A and its receptor via Secukinumab and Brodalumab, respectively, worsened Crohn’s disease, the beneficial effect of IL-12/23 p40 blockade via Ustekinumab appeared confined to a subpopulation of Crohn’s disease patients who have previously failed on TNF blockers. Clinical development of the IFNγ blocker Fontolizumab was stopped despite demonstrating some clinical benefit, while the T cell co-stimulation blocker Abatacept did not exhibit any hint towards efficacy in Crohn’s disease. Here I review results from these individual development programmes, and also reflect on the lack of efficacy of the TNF blocker Etanercept. I will discuss aspects of individual trials that might have confounded their interpretation and highlight the evolution in primary and secondary endpoints that have contributed to increasing robustness of results obtained in recent years. Finally, I suggest that mechanistic studies in murine genetic models combined with exploratory immunological studies incorporated in early drug development may represent the key for identifying the next generation of successful pharmacological targets in Crohn’s disease. [235/250 words]
    Baillière&#x027 s Best Practice and Research in Clinical Gastroenterology 06/2014; 28(3). DOI:10.1016/j.bpg.2014.04.005 · 3.28 Impact Factor
  • Journal of Allergy and Clinical Immunology 07/2014; 135(2). DOI:10.1016/j.jaci.2014.05.046 · 11.25 Impact Factor