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
*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 4(7): 1-3. DOI: http://dx.doi.org/10.15226/2374-815X/4/7/001110.
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.
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