Inflammatory bowel disease (IBD) refers to diseases characterized by chronic inflammation of the gastrointestinal tract. The most common are Crohn’s disease and ulcerative colitis. Chronic chronic inflammation can impair the normal functioning of affected gastrointestinal organs, leading to symptoms such as persistent diarrhea, abdominal pain, rectal bleeding, weight loss and fatigue.
Historically, IBD has been found primarily in industrialized countries, with the highest prevalence reported in North America and Europe. In the United States alone, approximately 1.6 million people have Crohn’s disease or ulcerative colitis, and as many as 70,000 new cases of IBD are diagnosed each year. Although the incidence of IBD in North America and Europe has stabilized or declined, the burden is still heavy due to the prevalence of IBD exceeding 0.3%. In addition, the incidence of IBD has increased in emerging industrialized countries such as Africa, Asia, and South America over the past 30 years.
The exact cause of IBD is not fully understood, but it involves interactions between the immune system, genes and environmental factors. In terms of genetics, studies have shown that 5% -20% of infected people have first-degree relatives (parents, children, or siblings) with one of these diseases. Many IBD-related genes and gene mutations have been confirmed, including mutations in the NOD2 / CARD15 gene. NOD2 / CARD15 mutations can occur in up to 20% of IBD patients in North America and Europe. Although genetic testing is feasible, it is not yet part of the diagnosis process of IBD, and genetic testing can only identify a person’s potential risk of IBD, but cannot predict whether IBD will develop.
There is currently no cure for IBD. The goal of current treatment is to reduce the inflammation that causes the condition, thereby providing short-term or long-term relief and reducing the risk of complications. The treatment of IBD usually includes medication or surgery. Drugs used to treat IBD include anti-inflammatory drugs, immunosuppressants, biological agents and antibiotics.
Anti-inflammatory drugs are usually the first step in the treatment of inflammatory bowel disease and include corticosteroids and aminosalicylate (5-ASA), such as Mesalazine by Elgin, Salixazone and Budesonide by Salix Pharma And AstraZeneca’s Entocort EC.
Immunosuppressive agents can prevent the intestinal wall from releasing immune-inducing chemicals to the immune response. Related drugs include azathioprine (Azasan, Imuran), thiopurine (Purinethol, Purixan), cyclosporine (Gengraf, Neoral, Sandimmune) and methotrexate (Otrexup, Rasuvo, Rheumatre Dose Pack, Trexall, Xatmep).
Biologics-Tumor necrosis factor (TNF) -α inhibitors are a class of drugs that inhibit the body’s natural response to TNF (a protein produced by white blood cells involved in early inflammatory events). Examples include Humira (adalimumab) from Abbey and Simponi (golimumab) from Janssen. Other commonly used biotherapies are Tysabri (natalizumab), Entyvio (vitalizumab), and Stellara (usulinumab).
Antibiotics can be used with other medicines or when patients have infection problems. Commonly used antibiotics include ciprofloxacin (Cipro) and metronidazole (Flagyl).
New drug pipeline
Multiple targeted therapies are currently being explored through clinical trials. In addition to TNF-α inhibitors, aminosalicylate, and glucocorticoids, common targets and mechanisms include:
i. Janus kinase (JAK) 3 inhibitor. The JAK pathway is thought to play an important role in the inflammatory process because they are involved in the signaling of more than 50 cytokines and growth factors, many of which drive immune-mediated diseases.
ii. Selective S1P receptor modulators. S1P receptors are involved in the regulation of a variety of biological responses including autoimmune diseases.
iii. Human interleukin (IL) -12, IL-22, IL-23, and IL-36 inhibitors. IL is a class of inflammatory cytokines and is a type of protein involved in the inflammatory response as part of the immune system.
iv. Dihydroorotate dehydrogenase (DHODH) inhibitors. DHODH inhibition has selective immunoregulatory effects on activated immune cells.
As of October 2019, clinicaltrials.gov lists 730 IBD-related clinical trials (Recruiting, Not yetrecruiting, Active, notrecruiting, Enrolling by invitation Studies). Of these trials, 268 were carried out in the United States and the rest were carried out worldwide. If divided by stages, there are 63 phase I trials, 132 phase II trials, 101 phase III trials, and the rest are phase IV or other types of research.
The following analysis (not comprehensive) of selected drugs under development will briefly discuss the mechanism of action of each drug and the clinical trial phase. As of October 2019, this information is current.
The IBD market consists of pharmaceutical and biotechnology companies of different sizes. The market share is dominated by Janssen, which has five drugs under investigation in all phases (phase I-III trials): Golimumab, Ulinusumab, JNJ-64304500 (JNJ-4500 / IPH-2301 / NN- 8555), JNJ-67864238, gusekumab monotherapy and combination therapy with golimumab.
Other companies include Pfizer’s five drugs in Phase I and II trials: PF-06687234, [124I] IB-PF-06687234, PF-06651600, PF-06700841: PF-06651600, PF-06480605. Roche and Genentech have three drugs in phase I-III trials: UTTR1147A / RG7880, etralimumab (RG7413), and RO7049665. AbbVie has three drugs in Phase II, Phase II / III, and Phase III trials: ABBV-323, Risankizumab (ABBV-066), and Upatinib (ABT-494)
Inline Drugs-Phase I
Aevi Genomics has partnered with Kyowa Kirin to develop AEVI-002, a fully human monoclonal antibody that combines an inflammatory protein called LIGHT found in intestinal tissues. Related trials are evaluating the efficacy of AEVI-002 in the treatment of severe Crohn’s disease in children, and preliminary data are expected to be released in the second half of 2019.
Assembly Biosciences is conducting a Phase Ib clinical trial of ABI-M201, a candidate for a live biotherapeutic product (LBP), in patients with mild to moderately active ulcerative colitis. Assembly and Allergan have begun working together to develop LBP compounds for ulcerative colitis, Crohn’s disease, and irritable bowel syndrome. ABI-M201 is the first LBP drug candidate for this collaboration.
Enterome collaborated with Takeda to develop and commercialize a first-in-class, non-systemic, oral small molecule EB8018 (TAK018). EB8018 can block the expression of bacterial toxic factor FimH (a key inducer of the intestinal cascade of inflammation), thereby reducing intestinal inflammation in patients with Crohn’s disease. Preliminary data for the Phase Ib clinical trial of EB8018 for Crohn’s disease is expected to be completed in 2019. Takeda plans to start phase II trials in November 2019.
Gossamer Bio is developing GB004, an oral HIF-1α stabilizer. Patient registration for the active mild-to-moderate ulcerative colitis Phase Ib study will begin in the second quarter of this year, and the company expects to announce the main results of the study in the first half of 2020.
OSE Immunotherapeutics has a drug pipeline for immune tumors and autoimmune diseases. OSE-127 is one of the drugs in this pipeline. It is a monoclonal immunomodulatory antibody that targets the CD127 receptor (the alpha chain of the IL-7 receptor), and has a strong antagonistic effect on effector T lymphocytes. Blocking of the IL-7 receptor prevents the migration of pathogenic T lymphocytes while retaining regulatory T lymphocytes that have a positive effect on autoimmune diseases. The first patients underwent a phase I trial in December 2018.
Inline Drugs-Phase II
Bridge Biotherapeutics is evaluating BBT-401, a small molecule inhibitor of Pellino-1. Pellino-1 is a ligase that is considered a key mediator of multiple immune receptor signaling pathways. BBT-401 was proven to be well tolerated and safe in a Phase I study of 80 healthy volunteers. In addition, there are studies that show that it has no or only minimal characteristics of systemic exposure. A randomized, placebo-controlled, dose-escalating phase II trial is currently enrolling 48 patients with ulcerative colitis.
Bristol-Myers Squibb’s BMS-986165 is an oral, selective tyrosine kinase 2 (TYK2) inhibitor. TYK2 is an intracellular signaling kinase that mediates cytokine-driven immune and pro-inflammatory signaling pathways and plays a key role in the chronic inflammatory cycle of immune-mediated diseases. The 2018 phase II trial of patients with psoriasis was successfully completed. Two phase II trials are currently underway, one each for Crohn’s disease and ulcerative colitis.
Eli Lilly is developing mirikizumab (LY 3074828), a humanized IgG4 mAb that binds to and inhibits the p19 subunit of IL-23. Crohn’s disease patients reported positive results in both the Phase II SERENITY trial and the Phase II trial of ulcerative colitis. Both trials have shown that patients treated with mirikizumab have significantly improved clinical response rates and reduced endoscopic symptoms at 12 weeks compared to placebo. Eli Lilly is currently conducting Phase II and III clinical trials of Crohn’s disease and ulcerative colitis.
Gilead is working with Galapagos NV to develop a highly selective JAK1 inhibitor, filgotinib. The results of the Phase II study FITZROY were published in The Lancet in December 2017. This study explored the efficacy and safety of filgotinib in the treatment of active moderate to severe Crohn’s disease. The data show that compared with placebo, filgotinib treatment significantly increased the number of patients with clinical remission and had acceptable safety. There are currently seven ongoing Phase II and Phase III trials, including MANTA, DIVERSITY, DIVERGENCE2, and SELECTION1.
Immunic Therapeutics is developing an oral tablet of a small molecule drug that inhibits dihydroborate dehydrogenase (DHODH). Immunic completed two phase I studies in 2017 that evaluated healthy volunteers once daily or repeated doses of IMU-838. The results support the tolerance of repeated dosing of up to 50 mg of IMU-838 per day. Immunic’s Phase II trial, CALDOSE 1, is currently studying ulcerative colitis.
Seres Therapeutics ‘SER-287 is an oral capsule developed using Seres’ proprietary microbial therapy platform. It is of biological origin and contains a combination of living and multiple bacterial spores. SER-287 is designed to reduce the triggering of immune activation rather than suppress the immune system. Phase Ib results in patients with ulcerative colitis show that SER-287 microbiome treatment can improve clinical response rates and endoscopic diagnostic scores. The Phase II trial ECO-RESET is currently recruiting 200 adults aged 18-80 years with active mild to moderate ulcerative colitis.
Sublimity Therapeutics uses Sublimity’s proprietary SmPill® drug delivery system to develop an oral cyclosporine formulation called ST-0529. Unlike traditional oral or intravenous cyclosporine, SmPill® technology delivers cyclosporine directly to colonic diseased tissue, minimizing systemic exposure and unnecessary side effects. In a phase IIa study, ST-0529 showed good safety and tolerability. A phase IIb study, AURORA (CYC-202), is currently enrolling 280 patients with moderate to severe ulcerative colitis.
Inline Drugs-Phase III
Arena Pharmaceuticals is developing etrasimod, a new generation of highly selective oral sphingosine 1-phosphate (S1P) receptor modulators to optimize the pharmacology and effects of S1P receptors 1, 4 and 5 Will improve drug efficacy and safety. The phase II OASIS trial reached the primary and all secondary endpoints. Based on these results, Arena launched the global phase III ELEVATE ulcerative colitis program, which includes two global clinical trials and an open-label extension study. In addition, Phase II / III trials for patients with Crohn’s disease are also being planned.
Celgene’s ozanimod targets the S1P-1 and -5 receptors. The results of the Phase II trial were reported in October 2017. In the Phase II STEPSTONE open study, ozanimod showed significant improvement in clinical remission and endoscopic findings in patients with moderate to severe active Crohn’s disease at week 12. Celgene is currently conducting nine active studies on two types of IBD.
Takeda Shire’s ontamalimab (SHP 647) enters phase III development phase. SHP 647 is a fully human IgG2 monoclonal antibody directed against the mucosal localization protein cell adhesion molecule (MADCAM1). Shire obtained permission for the drug from Pfizer in 2016. In 2017, the Lancet published the results of a phase II trial in patients with ulcerative colitis, demonstrating that this therapy is safe and well tolerated in this patient population, and is superior to placebo in inducing remission. Seven phase III trials are currently recruiting patients with ulcerative colitis and Crohn’s disease.
Although significant progress has been made in the treatment of IBD, the current treatment regimens have only resulted in remission. According to an article published in the July 2016 edition of the Gastroenterology & Hepatology journal, the current response rate from biologic therapy is about 20% to 35%, and about 45% to 60% of patients achieve a response. On the contrary, this means that 40% to 55% of patients do not respond to treatment and 65% to 80% of patients do not get a complete response. In addition, over time, patients treated with biologics may lose a durable response to treatment, resulting in recurrence of symptoms.
In addition to continuing development of small RNA inhibitors and intracellular cytokine pathways (such as antisense oligonucleotide therapy and JAK inhibitors) and biologics (such as IL-12 and IL-23 inhibitors, monoclonal antibodies, and S1P inhibitors) In addition, future treatments for IBD include adjusting the gut microbiota and identifying the genomes associated with IBD to develop personalized therapies.
A paper published in the journal Translational Pediatrics entitled “The State and Future of Personalized Drugs for Inflammatory Bowel Disease” also echoes this trend. The article outlines the benefits of a shift in IBD treatment models, discusses the potential for personalized treatment for IBD patients, and considers this to be a major advance in IBD patient management strategies, rather than continuing traditional treatments based on symptoms, outcomes, and complications.