Editorial
Open Access
New Medical Therapies in Inflammatory Bowel Diseases In
2017
Atilla Ertan1* and Jamie Stewart2
1Ertan Digestive Disease Center – Inflammatory Bowel Diseases Center, USA
2University of Texas Health McGovern Medical School (UTMMS) Gastroenterology, Hepatology and Nutrition Division and Memorial Hermann Hospital – Texas Medical Center, USA
2University of Texas Health McGovern Medical School (UTMMS) Gastroenterology, Hepatology and Nutrition Division and Memorial Hermann Hospital – Texas Medical Center, USA
*Corresponding author: Atilla Ertan, The UTMMS-MHH Ertan Digestive Disease Center and Gastroenterology Center of Excellence, 6400 Fannin, Suite 1400, Houston, Texas 77030, USA, Tel: 713-704-5928, 713-704-3450; Fax: 713-704-3485; E-mail:
@
Received: August 11, 2017; Accepted: September 25, 2017; Published: October 09, 2017
Citation: Atilla E, Jamie S (2017) New Medical Therapies in Inflammatory Bowel Diseases In 2017. Gastroenterol Pancreatol Liver Disord 5(1): 1-3. DOI: http://dx.doi.org/10.15226/2374-815X/5/1/001110.
Editorial
A significant progress has been made regarding the
management of inflammatory bowel disease (IBD) over the
past 38 years as shown in Table 1. Our therapeutic goals in
IBD are summarized in Table 2. Only limited treatment options
existed until the introduction of anti-tumor necrosis factor
(anti-TNF) agents, which was a landmark in the management
of these debilitating diseases. It is recommended that patients
with IBD be treated with a combination of anti-TNF agents with
immunomodulator therapy to increase the likelihood of steroidfree
induction and mucosal healing with long–term remission.
According to our own experience and general consensus, the
IBD treat-to-target strategy with anti-TNFs is well-respected
to change the natural history of IBD with a deep remission in
a significant number of IBD patients [1-2]. Early intervention
with top-down therapy may be the future direction in selected
moderate to severe IBD patients with close follow-up and trough
level monitoring as needed. Selected conditions for the top-down
treatment with anti-TNFs are shown in Table 3.
Table 1: History of IBD Treatment
Year Drug 1979 Sulfasalazine, Steroids 1980 Antibiotics, Azathioprine, 6-MP 1993 5-ASA 1994 Budesonide 1995 Methotrexate 1998 Infliximab 2007 Second generation anti-TNF agents 2014 New agents 2015 Biosimilars |
Table 2: Therapeutic Goals in IBD
Clinical improvement Clinical remission Corticosteroid weaning Maintenance of remission Maintained tissue & transmural healing Decrease in hospitalization & surgical interventions Prevention of complications Change natural course of the disease |
Table 3: Selected conditions for the top-down treatment with anti-TNFs
Early age [<30 yrs] & young disease Extensive anatomic involvement Severe ano-rectal disease Deep & extensive ulcerations Stricturing and/or penetrating disease Prior surgical intervention[s] Family history of severe CD Heavy smokers |
Therapies with anti-TNFs have reduced relapse rates and
allowed mucosal healing and, as a result, improved long-term
outcomes in a substantial proportion of patients. According to
a large amount of studies, anti-TNFs induced approximately 30%
clinical remission and 50% clinical response in patients with
moderate to severe Crohn’s disease (CD) who are anti-TNF naïve or
experienced. Moreover, the secondary loss of response may vary
between 10 to 50% per year depending on studies and followup
periods [3-6]. The “gut-selective” humanized, monoclonal
antibody against alfa4beta7 integrin, [Vedolizumab] is now an
established and FDA approved treatment option for patients
with chronic ulcerative colitis (CUC) and CD either before or after
anti-TNF therapy [7]. A recent study showed excellent rates of
clinical remission at 12 months and mucosal healing, with no
PML or other serious adverse events [8]. Recently, a fully human
IgG1k monoclonal antibody that binds the p40 subunit of IL
12/23 [Ustekinumab] was approved by the FDA for patients with
moderate to severe CD [9]. In addition to initial very promising
results with Ustekinumab, the phase III trials in patients with
moderate to severe CD showed 34% clinical remission at week
6. Subsequent European studies with Ustekinumab revealed a
relatively better clinical remission and continued to maintain
clinical remission at 12 months [9-10]. Ustekinumab seems to
be an attractive option with a relatively low immunogenicity, but
its optimal dose has not been determined. All available biologic
agents approved by the FDA are shown in Table 4.
Table 4: FDA Approved Biologic Agents in 2017
Anti-TNF Agents: Infliximab [Remicade] Adalimumab [Humira] Certolizumab [Cimzia] Golimumab [Simponi] Integrin Inhibitor Agents: Natalizumab [Tysabri] Vedolizumab [Entyvio] Anti-IL-12/23 Agent: Ustekinumab [Stelara] Biosimilars: Pending |
Despite the tremendous progress there are a significant
number of patients who are refractory to these available biologic
agents. Our understanding of the gut immune mechanism has
become more sophisticated, but it still remains quite incomplete.
The future looks more promising as several other novel treatment
options have been identified and clinical studies are underway to
determine the efficacy and safety of these therapies. Of note is the
challenge of new clinical trials that have yielded positive earlyphase
results, but do not translate into positive late-phase study
outcomes due to heterogeneity of patients and disease type, high
placebo rates and other factors. Having a number of different
agents available will allow us to offer the best therapies for an
individual patient. The majority of the novel agents in phase of
development of the treatment of IBD are summarized in Table
5. There are novel ways of reducing inflammation by targeting
downstream signaling such as Janus kinase inhibitors, Tofacitinib
and Filgotinib; the target lymphocyte trafficking as new antiintegrin
agent, AJM300 and sphingosine1P1R, Fingolimob; and
antisense oligonucleotides to transforming growth factor-beta,
Mongersen. It is important to note that all above mentioned small
molecules are oral agents [11-18] and extensive clinical research
is pending in our Center and around the world. These agents may
have huge implications and potentially less costly. We have to
wait to see their late phase effectiveness and safety studies within
the next 5-10 years.
Table 5: New Agents in Development for the Treatment of IBD
Name |
Major Effect |
Product |
Etrolizumab Tocilizumab Secukinumab Risankizumab Tofacitinib* Fingolimod* Mongersen* AJM300* PPC* *PO Agents |
Anti-beta-7 Anti-IL-6 Anti-IL-17 Anti-IL-23 Anti-JAK Sphingosine1P1R Targets SMAD7 Anti-alfa-4 Mucus
|
GI spec. integrin antagonist Humanized MCA Humanized MCA Humanized MCA Immunomodulator Lymph. recept. agonist Antisense oligonucleotide Integrin antagonist Phosphatidylcholine
|
Acknowledgement
This study is supported by A. Ertan Research Education
Foundation.
Conflicts of Interest
The authors are involved in clinical research with AbbVie,
Janssen, Pfizer, Celgene, UCB, Takeda, F. Hoffman-LaRoche and
Bristol-Myers Squibb. The research income stays in the Division
for various other research and educational activities. There is no
financial interest such as honoraria, participation in speakers’
bureaus, membership, employment, consultancies, stock
ownership, or other equity interests.
- Colombel JF, Mahadevan U. Inflammatory bowel disease 2017: Innovations and changing paradigms. Gastroenterology. 2017;152(2):309-312.
- Abraham C, Dulai PS, Vermerie S, Sandborn WJ. Lessons learned from trials targeting cytokine pathways in inflammatory bowel diseases. Gastroenterology. 2017;152(2):374-388. Doi: 10.1053/j.gastro.2016.10.018
- Feagon BG, Lemann M, Befrits R, Connell W, D’Haens G, Ghosh S, et al . Recommendation for the treatment of Crohn’s disease with tumor necrosis factor antagonists: an expert consensus report. Inflamm Bowel Dis. 2012;18(1):152-160. Doi: 10.1002/ibd.21870
- Colombel JF, SanvornWJ, Reinisch W, Mantzaris GJ, Kornbluth A, Daniel Rachmilewitz, et al. Inflisimab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med. 2010;362(15):1383-1395. DOI: 10.1056/NEJMoa0904492
- Rutgeerts P, Van Assche G, Sanborn WJ, Wolf DC, Geboes K, Colombel JF, et al. Adalimumab induces and maintains mucosal healing in patients with Crohn’s disease: data from the EXTEND trial. Gastroenterology. 2012;142(5):1102-1111. Doi: 10.1053/j.gastro.2012.01.035
- Danese S, Colombel JF, Reinisch W, Rutgeerts PJ. Review article: infliximab for Crohn’s disease treatment-shifting therapeutic strategies after 10 years of clinical experience. Aliment Pharmacol Ther. 2011;33(8):857-869. Doi: 10.1111/j.1365-2036.2011.04598.x
- Sandborn WJ, Feagan BG, Rutgeerts P, Hanauer S, Colombel JF, Bruce ES, et al. Vedolizumab as induction and maintenance therpy for Crohn’s disease. N Engl J Med. 2013;369(8):711-721. DOI: 10.1056/NEJMoa1215739
- Dulai PS, Singh S, Colombel JF, Peerani F, Narula N, Chaudrey K, et al. The real-world effectiveness and safety of Vedolizumab for moderate-severe Crohn’s disease: Results from the US Victory Consortium. AJG. 2016;111(8):1147-1155. Doi: 10.1038/ajg.2016.236
- Sandborn WJ, Gasink C, Gao LL, Blank MA, Johanns J, Cynthia Guzzo, et al. Ustekinumab induction and maintenance therapy in refractory Crohn’s disease. N Engl J Med, 2012;367:1519-1528. DOI: 10.1056/NEJMoa1203572
- Khanna R, Afif W. Ustekinumab for Crohn’s disease. Gastroenterology. 2017;152(6):1616-1619.
- Bouguen G, Chevaux JB, Peyrin BL. Recent advances in cytokines: therapeutic applications for inflammatory bowel diseases. World J Gastroenterol. 2011;17(5):547-556. Doi: 10.3748/wjg.v17.i5.547
- Vuitton l, Koch s, Peyrin BL. Janus kinase inhibition with to facitinib: changing the face of inflammatory bowel disease treatment. Curr Drug Targets. 2013;14(12):1385-1391.
- Perrier C, Rutgeerts P. New drug therapies on the horizon for IBD. Dig Dis. 2012;30(suppl 1):100–105. DOI:10.1159/000341133
- Danese S. New therapies for inflammatory bowel disease: from the bench to the bedside. Gut. 2012;61(6):918-932. Doi: 10.1136/gutjnl-2011-300904
- Eietdjik ST, D’Haens GR. Recent developments in the treatment of inflammatory bowel disease. J Dig Dis. 2013;14(6):282-287. Doi: 10.1111/1751-2980.12048
- Neurath MF. New targets for mucosal healing and therapy in inflammatory bowel disease. Mucosal Immunology. 2014;7(1):6-19. Doi: 10.1038/mi.2013.73
- Dupont A, Ertan A. Medical therapy update in Crohn’s disease. SOJ Immunol. 2014;2(1):1-2.
- Neeraj N, Rubin DT, Sands BE. Novel therapies in inflammatory bowel diseases: An evaluation of the evidence. Am J Gastroenterol. 2016;3:38-44. Doi:10.1038/ajgsup.2016.19
