Biologic Therapies for Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) describes the spectrum of chronic intestinal inflammation from Crohn's disease (CD) to ulcerative colitis (UC). Although this term is very misleading (because there are much more diseases which also imply intestinal inflammation, such as infective diarrhea for example) it is universally used as synonym of the CD/UC pair.
IBD seems to occur as a consequence of a persistent and inappropriate immunologic response to gut luminal antigens. The absence of enteric parasites, in developed countries, and defects in mucosal innate defenses are recent additions to the many hypotheses on the pathogenesis, which remains very doubtful and unknown. However, independently from the cause, CD and UC usually respond to a similar range of anti-inflammatory and immuno-modulator therapy to induce and maintain the remission stage.

Inflammatory bowel disease (IBD) describes the spectrum of chronic intestinal inflammation from Crohn's disease (CD) to ulcerative colitis (UC). Although this term is very misleading (because there are much more diseases which also imply intestinal inflammation, such as infective diarrhea for example) it is universally used as synonym of the CD/UC pair.
IBD seems to occur as a consequence of a persistent and inappropriate immunologic response to gut luminal antigens. The absence of enteric parasites, in developed countries, and defects in mucosal innate defenses are recent additions to the many hypotheses on the pathogenesis, which remains very doubtful and unknown. However, independently from the cause, CD and UC usually respond to a similar range of anti-inflammatory and immuno-modulator therapy to induce and maintain the remission stage.
There are no specific nor pathognomonic diagnostic blood tests for IBD per se, although erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and complete blood count (CBC) are useful markers of disease activity (active inflammation).
The natural history of IBD is of frequent flares of the condition in response to unknown triggers. In CD, for example, 75% of patients have a chronic intermittent course, 15% have chronically active disease, and 10% remain in remission. The management of active disease can be divided into pharmacologic therapy, surgery, and non-pharmacologic interventions.

The latest drugs approved for the treatment of IBD and other non-GI highly inflammatory diseases (mainly Rheumatologic/Auto-Immune) belong to the newer big class so called “Biologic Therapies” (a.k.a. “Anti-Cytokine Therapies”); corresponding to very, very expensive monoclonal antibodies (mainly) targeted against specific cytokines, which play a key role in the pathogenesis/pathophysiology of inflammation, such as Tumor Necrosis Factor alpha (TNF-a) and InterLeukines (ILs) 1, 6, 8 (IL-1, IL-6, IL-8). In what respects to IBD, anti-TNF-a monoclonal antibodies are, by far, the most important subclass of “Biologic Therapies”, as it will be discussed below.
Analyzing the pharmacologic etymology of monoclonal antibodies, there is a rule which is almost always present (some exceptions occur) – their name usually ends with the suffix “mab”, which is derived from “Monoclonal AntiBodies”. So, in medical slang, they are the “Mabs”.

Part 2 – Anti-TNF-a “Mabs”(Infliximab, Adalimumab, Certolizumab)

Infliximab is a chimeric monoclonal antibody (75% human, 25% mouse) targeted against the TNF-a molecule, so inhibiting its binding to receptors and further biological phenomena; what leads to induction of apoptosis in activated lymphocytes; and it also appears to reduce the number of inflammatory cells at the sites of mucosal inflammation, possibly by inhibiting leukocyte migration.
Infliximab, in 1999, began to be commercially available for treatment of rheumatoid arthritis in patients who failed to have therapeutic success with methotrexate treatment. Meanwhile, infliximab was first tested on patient with CD – it was a 94 patient phase 2 clinical trial showing that infliximab was effective in fistulizing CD [Present D, Rutgeerts P, Targan S, Hanauer S, Mayer L, van Hogezand R, Podolsky D, Sands B, Braakman T, DeWoody K, Schaible T, van Deventer S (1999). "Infliximab for the treatment of fistulas in patients with Crohn's disease". N Engl J Med 340 (18): 1398–405. doi:10.1056/NEJM199905063401804. PMID 10228190].
A later and larger Phase 3 clinical trial (ACCENT = A Crohn's disease Clinical study Evaluating infliximab in a New long term Treatment regimen), elapsed through 2 sequential phases, demonstrated (thus confirming) the efficacy of infliximab in the maintenance of remission in luminal and fistulizing CD [Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet. 2002;359:1541-1549] + [Sands BE, Anderson FH, Bernstein CN, et al. Infliximab maintenance therapy for fistulizing Crohn's disease. N Engl J Med. 2004;350:876-885]. This resulted in FDA approval of infliximab for reducing signs and symptoms and inducing and maintaining clinical remission in adult and pediatric patients with moderately to severely active luminal and fistulizing CD who have had an inadequate response to conventional therapy. In fact, infliximab induces and maintains remission in patients with luminal and fistulizing CD. It is given as an intravenous (IV) infusion over 2 hours at 0, 2, and 6 weeks, and 8 weeks thereafter to maintain remission. In patients with CD, approximately 60% of patients respond within 2 weeks, and 30% to 50% of responders maintain response for up to 1 year.

On the other hand, the ACT 1 and ACT 2 (Acute ulcerative Colitis Treatment) trials evaluated the therapeutic actions of infliximab in patients with UC, showing that 44-45% of patients treated with infliximab, for a year, maintained a response to the medication, compared to 21% of patients who were treated with placebo. At 2 months, the response was 61-69% for patients treated with infliximab, versus 31% for those who were treated with placebo [Rutgeerts P, Sandborn W, Feagan B, Reinisch W, Olson A, Johanns J, Travers S, Rachmilewitz D, Hanauer S, Lichtenstein G, de Villiers W, Present D, Sands B, Colombel J (2005). "Infliximab for induction and maintenance therapy for ulcerative colitis". N Engl J Med 353 (23): 2462–76. doi:10.1056/NEJMoa050516. PMID 16339095]. Hence, in 2006, FDA approved infliximab for the treatment of UC.
In patients with UC, infliximab is by now indicated for:
1) reducing signs and symptoms;
2) achieving clinical remission and mucosal healing; and
3) eliminating the use of corticosteroids in patients with moderately-to-severely active colitis who have had an inadequate response to conventional therapy.
Side effects of infliximab, beyond the induced “partial immunodeficiency” (which is globally intrinsic to the therapeutic action itself); usually are related to host’s immunologic reactions against infliximab’s molecules themselves, since they contain mouse-derived peptides. Up to 60% of patients receiving infliximab develop anti-infliximab antibodies, which may cause infusion reactions and flu-like illness after subsequent therapy. Fortunately these are usually mild and can be prevented by using prednisone and antihistamines before infusions. Nevertheless, some patient develop life-threating anaphylaxis.
The induced “partial immunodeficiency” can be responsible for the reactivation of latent tuberculosis, which occurs with an incidence of 0.46 per 1000 patient-years; therefore all patients should undergo a purified protein derivative (PPD) test and chest radiograph prior to commencement of therapy. Hepato-splenic T-Cell Lymphoma have been reported in adolescent and young adult patients with CD treated with infliximab. This rare type of T-Cell Lymphoma has a very aggressive disease course and is usually fatal. However, we must not to forget that all of these cases have occurred in patients on concomitant treatment with azathioprine or 6-mercaptopurine; rather than monotheraphy.

Adalimumab is a recombinant human monoclonal antibody, also targeted against the TNF-a molecule. Thus, it acts similarly to (the older, human-murine chimeric) infliximab. However, since it has no mouse peptides (only human peptides), it does not induce immunogenic reactions against itself, what overall decreases side effects, when compared with infliximab (no significant flu-like syndrome nor anaphylaxis). Anyway, the induced “partial immunodeficiency” also is present, and so, like infliximab, there is higher risk of severe infections (including the reactivation of tuberculosis, pneumonia, or even sepsis) and lymphoma. Another advantage of adalimumab over infliximab is on the route of administration – while infliximab is given as an intravenous (IV) infusion, adalimumab is administered subcutaneously.
Adalimumab has shown efficacy on CD treatment (3 main clinical trials – CLASSIC; CHARM; GAIN).
CLASSIC (CLinical assessment of Adalimumab Safety and efficacy Studied as an Induction therapy in Crohn's) was a trial of 299 patients with moderate-to-severe CD; showing induction of remission followed by a maintenance of remission in 275 of the 299 patients.
CHARM trial (Crohn's trial of the fully Human antibody Adalimumab for Remission Maintenance) [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]. CHARM was a double-blind, placebo-controlled, phase 3, multicenter, 56-week trial evaluating the efficacy and safety of adalimumab in maintaining clinical remission in patients with moderate-to-severe CD; and shown adalimumab was highly effective in inducing remission in early CD, suggesting that disease duration is a significant contributor to the likelihood of achieving remission.
GAIN (Gauging Adalimumab efficacy in Infliximab Nonresponders), a four-week induction trial of 325 patients who lost response or were intolerant to infliximab; shown a rapid clinical response to adalimumab in these patients (21% on adalimumab group versus 7% on placebo group).
Then, in 2007, adalimumab has been approved by FDA, for treatment of moderate to severe CD in adults who have not responded well to conventional treatments and who have lost response to, or are unable to tolerate infliximab.

Certolizumab (formely named “certolizumab pegol”) is a humanized anti-TNF-a Fab' monoclonal antibody fragment linked to polyethylene glycol (this is, a humanized pegylated anti-TNF-a fragment – for short - humanized pegylated TNF-a inhibitor). Its therapeutic and side effects profile seems to be more similar to adalimumab (only human peptides, no mouse peptides, avoiding immunogenic reaction against itself; and also is administered subcutaneously; unlike infliximab).
PRECiSE (Pegylated antibody fRagment Evaluation in Crohn's disease Safety and Efficacy) 1 and 2 trials demonstrated the efficacy of this agent in the induction of response and maintenance of response in patients with moderately to severely active Crohn's disease [Sandborn WJ, Feagan BG, Stoinov S, et al. Certolizumab pegol administered subcutaneously is effective and well tolerated in patients with active Crohn's disease: results from a 26-week placebo-controlled phase III study. (PRECiSE1). Gastroenterology. 2006;130:A-107] + [Sandborn WJ, Colombel JF, Panes J, Scholmerich J, McColm JA, Schreiber S. Higher remission and maintenance of response rates with subcutaneous monthly certolizumab pegol in patients with recent-onset Crohn's disease: data from PRECiSE 2. Am J Gastroenterol. 2006;101:S454-455].
In April 2008, FDA has approved certolizumab pegol for treatment of moderate-to-severe CD. However, since is drug is a “newborn” yet, there is much less information available, about its efficacy and safety, and having adalimumab also available, I recommend you not to use certolizumab right now – it is prudent to wait a little bit more, until more strong evidence will be available.

Part 3 – This time away from TNF-a… Will an older “Mab”(natalizumab) become a new treatment option for IBD?

Natalizumab is a recombinant humanized monoclonal antibody targeted against alpha-4-integrins (a4i). Natalizumab binds to the cell surface receptors called alpha-4-beta-1 (VLA-4) and alpha-4-beta-7. The receptors for the a4i include vascular cell adhesion molecule-1 (VCAM-1), which is expressed on activated vascular endothelium, and mucosal addressin cell adhesion molecule-1 (MAdCAM-1) present on vascular endothelial cells of the gastrointestinal tract. Natalizumab blocks immune cell adhesion to blood vessel walls; thereby it blocks subsequent migration of lymphocytes into tissue.
Natalizumab is administered by intravenous infusion every 28 days.
Natalizumab is not a new drug at all, and its past history reveals dangerous concerns. In 2004 it became available on market during few time only - it was quikly withdrawn by its manufacturer after it was associated with some cases of JC virus-related progressive multifocal leukoencephalopathy (PML). However, in such cases, natalizumab was administered in combination with interferon beta-1a (for treatment of multiple sclerosis); rather than monotheraphy. Hence, we are talking about complicated neurologic patients, who are not the target of this article… In fact, natalizumab is a candidate option to treat patients with multiple sclerosis or CD.
In what respects to CD, there were 2 important clinical trials – ENACT and ENCORE. Both, ENACT and ENCORE trials, have demonstrated efficacy of natalizumab for the induction and maintenance of remission in patients with moderate to severely active Crohn's disease.
ENACT means “Evaluation of Natalizumab as Continuous Therapy” [Sandborn WJ, Colombel JF, Enns R, et al. Natalizumab induction and maintenance therapy for Crohn's disease. N Engl J Med. 2005;353:1912-1925].
ENCORE means “Efficacy of Natalizumab in Crohn's Disease Response and Remission” [Targan SR, Feagan BG, Fedorak RN, et al. Natalizumab for the treatment of active Crohn's disease: results of the ENCORE trial. Gastroenterology. 2007;132:1672-1683].
Although natalizumab is not a new drug, considering its “age”, it is currently an experimental treatment which, in very short time, can become a new approved (eventually recommended) first-line option for treatment of moderate-to-severe CD. However this is just speculation and hope, by now – let’s wait and see if stronger evidence will be available or not…





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4 comments:

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