Figure - available from: Biomedicines
This content is subject to copyright.
List of different biologics and small molecule drugs with their targets and current clinical trial status.
Source publication
Crohn’s disease (CD) and ulcerative colitis (UC), known as inflammatory bowel diseases (IBD), are characterized by chronic inflammation of the gastrointestinal tract. Over the last two decades, numerous medications have been developed and repurposed to induce and maintain remission in IBD patients. Despite the approval of multiple drugs, the major...
Citations
... Timeline for the different biologicals and small molecules approved by FDA and in the development process for the treatment of IBD. Adapted from [7], MDPI, 2023. ...
... Table 6. Classification of small molecules in IBD [7]. ...
Inflammatory bowel disease (IBD) is a group of heterogeneous chronic inflammatory diseases of the gut presenting with intestinal and extraintestinal manifestations. Most cases fit in predominantly two types, namely, ulcerative colitis and Crohn’s disease. The incidence of IBD has been increasing steadily in the past three decades. Focused research has resulted in many therapeutic options. Biologics (derived from humans or animals) and small molecules have emerged as the cornerstone in the management of IBD and have become widely available. Currently, monoclonal antibodies against tumor necrosis factor-alpha (infliximab, adalimumab, certolizumab, and golimumab), integrins (vedolizumab and natalizumab), and interleukin (IL)-12 and IL-23 antagonists (ustekinumab), along with small molecules (tofacitinib), are approved for use. This article summarizes various aspects of these drugs, like clinical pharmacology, indications for use in IBD, safety in pregnancy and lactation, and the adverse effects profile based on the studies leading to their approval. This review also focuses on the recent advances and future perspectives specific to biologics in IBD.
... Currently, applied therapeutic approaches are based on biologics, immunomodulators, aminosalicylates, and corticosteroids [5]. Due to a highly heterogeneous patient cohort considering individual risk factors, pathophysiologic mechanisms, location of adverse health effects, disease initiation and progression, amongst others, therapeutic efficacy and outcomes are highly individual and any prognosis is rather vague challenging the treatment strategy. ...
Inflammatory bowel disease (IBD) is a global health burden which carries lifelong morbidity affecting all age groups in populations with the disease-specific peak of the age groups ranging between 15 and 35 years, which are of great economic importance for the society. An accelerating incidence of IBD is reported for newly industrialised countries, whereas stabilising incidence but increasing prevalence is typical for countries with a Westernised lifestyle, such as the European area and the USA. Although the aetiology of IBD is largely unknown, the interplay between the genetic, environmental, immunological, and microbial components is decisive for the disease manifestation, course, severity and individual outcomes. Contextually, the creation of an individualised patient profile is crucial for the cost-effective disease management in primary and secondary care of IBD. The proposed pathomechanisms include intestinal pathoflora and dysbiosis, chronic inflammation and mitochondrial impairments, amongst others, which collectively may reveal individual molecular signatures defining IBD subtypes and leading to clinical phenotypes, patient stratification and cost-effective protection against health-to-disease transition and treatments tailored to individualised patient profiles—all the pillars of an advanced 3PM approach. The paradigm change from reactive medical services to predictive diagnostics, cost-effective targeted prevention and treatments tailored to individualised patient profiles in overall IBD management holds a promise to meet patient needs in primary and secondary care, to increase the life-quality of affected individuals and to improve health economy in the area of IBD management. This article analyses current achievements and provides the roadmap for future developments in the area in the context of 3P medicine benefiting society at large.
... The implementation of a precision medicine strategy, with clear pathways and algorithms, is necessary to achieve best outcomes for patients. This will require knowledge of individual patient histories, including predictors of response and disease characteristics [7,81]. Conversely, the recently published guidelines on the use of biomarkers in Crohn's disease list three biomarkers for the routine monitoring of patients; calprotectin, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) [9], with less reliance on colonoscopy. ...
Mycobacterium avium ssp. paratuberculosis (MAP) is the cause of Johne’s disease (JD), which is a chronic infectious gastrointestinal disease of ruminants and is often fatal. In humans, MAP has been associated with Crohn’s disease (CD) for over a century, without conclusive evidence of pathogenicity. Numerous researchers have contributed to the subject, but there is still a need for evidence of the causation of CD by MAP. An infectious aetiology in CD that is attributable to MAP can only be proven by bacteriological investigations. There is an urgency in resolving this question due to the rising global incidence rates of CD. Recent papers have indicated the “therapeutic ceiling” may be close in the development of new biologics. Clinical trial outcomes have demonstrated mild or inconsistent improvements in therapeutic interventions over the last decades when compared with placebo. The necessity to revisit therapeutic options for CD is becoming more urgent and a renewed focus on causation is essential for progress in identifying new treatment options. This manuscript discusses newer interventions, such as vaccination, FMT, dietary remediation and gut microbiome regulation, that will become more relevant as existing therapeutic options expire. Revisiting the MAP theory as a potential infectious cause of CD, rather than the prevailing concept of an “aberrant immune response” will require expanding the current therapeutic programme to include potential new alternatives, and combinations of existing treatments. To advance research on MAP in humans, it is essential for microbiologists and medical scientists to microscopically detect CWDM and to biologically amplify the growth by directed culture.
... The IL-23 inhibitor Risankizumab has recently become available in Canada, with studies underway for guselkumab and mirikizumab. 47 Given their novelty, pregnancy safety data are not yet available. One report on pregnancy outcomes among patients with psoriasis, including those on Risankizumab, demonstrated similar outcomes to the general population. ...
This narrative review explores the management of Inflammatory Bowel Disease (IBD) during pregnancy, emphasizing its unique challenges to maternal and fetal health, particularly within the Canadian Gastroenterology setting. Seven key principles are highlighted: 1) Preconception counselling, aiming for steroid-free remission confirmed by objective markers, should be routine for female IBD patients. 2) Medication safety, with an eye to future pregnancies, should be addressed upon initiation. Methotrexate and small molecules are contraindicated during pregnancy, while most 5-ASA therapies, biologics, and thiopurines can be continued throughout pregnancy and breastfeeding. Steroids, though not without risks, can be utilized if necessary. 3) Routine monitoring during remission should include serum biomarkers and fecal calprotectin each trimester. 4) Routine endoscopy and imaging are not required, but if indicated, lower GI endoscopy, ultrasound, and unenhanced MRI can be used. Computed tomography and gadolinium enhanced MRI should be avoided. 5) Caesarean section is advised for patients with previous ileal pouch surgeries or active perianal disease, but other patients should follow obstetric indications for delivery. 6) Postpartum period may see more active disease, requiring continued monitoring. Breastfeeding is encouraged, and routine childhood vaccinations are advised, but live vaccinations in the first 6 months warrant detailed review. 7) Complex IBD patients may benefit from a multidisciplinary approach with robust communication between gastroenterologists and obstetricians.
... Studies have shown that IL-12, 22 and 23 are involved in IBD pathogenesis with IL-12 and 23 playing a crucial role in the maintenance of inflammation. 47 It is suggested that IL-12 is involved in the initiation of intestinal inflammation caused by epithelial barrier disruptions and works together with IL-23 to maintain chronicity. 48 However, there has been more recent research suggesting that IL-12 possesses some anti-inflammatory activity in animal models. ...
The current mainstay treatment modalities for inflammatory bowel disease (IBD) include immunomodulators (methotrexate and thiopurines), biologics (antitumour necrosis factor alpha (TNF-α) being the most commonly used) and other monoclonal antibodies such as the anti-integrins and anti-interleukins (IL-12/23). While ideally treatment should be initiated early in the disease process to avoid relapses and complications, the major recurring issue continues to be primary and secondary loss of response, with often ‘diminishing returns’ in terms of efficacy for the next line of therapies prescribed for patients with IBD. Additional concerns include the long-term risk factors such as malignancy and susceptibility to infections. Recently, there has been an influx of new and emerging medications entering the market that are showing promising efficacy results in patients with moderate-to-severe disease who have previously failed to respond to multiple drugs. This review will focus on these novel and emerging therapies—in essence, ‘horizon scanning’—which includes the antiadhesion agents, cytokine inhibitors, Janus kinase inhibitors, phosphodiesterase inhibitors, sphingosine-1 phosphate receptor modulators and MicroRNA-124 (miR-124) upregulators.
... The development of new molecules is a reality both for previously approved classes and for new therapeutic classes with different targets. As for TNF antagonists, oral formulations such as AVX-470 and OPRX-106 stand out [119]. ...
... While the HIBISCUS and GARDENIA trials found that although Etrolizumab (an anti-integrin monoclonal antibody that binds to the β7 subunit of α4β7 and αEβ7 integrins) was effective in inducing but ineffective in maintaining clinical remission, further analysis identified that microRNAs expressed in patients with UC may indicate patients with a better outcome to this drug [119,120]. Other drugs that act on leukocyte trafficking are under study, such as PN-943, an orally administered α4β7 antagonist, and PF-00547659, a human mAb that binds to a mucosal cell adhesion molecule (MadCAM) [119]. ...
... While the HIBISCUS and GARDENIA trials found that although Etrolizumab (an anti-integrin monoclonal antibody that binds to the β7 subunit of α4β7 and αEβ7 integrins) was effective in inducing but ineffective in maintaining clinical remission, further analysis identified that microRNAs expressed in patients with UC may indicate patients with a better outcome to this drug [119,120]. Other drugs that act on leukocyte trafficking are under study, such as PN-943, an orally administered α4β7 antagonist, and PF-00547659, a human mAb that binds to a mucosal cell adhesion molecule (MadCAM) [119]. ...
Inflammatory Bowel Diseases had their first peak in incidence in countries in North America, Europe, and Oceania and are currently experiencing a new acceleration in incidence, especially in Latin America and Asia. Despite technological advances, 90 years after the development of the first molecule for the treatment of IBD, we still do not have drugs that promote disease remission in a generalized way. We carried out a narrative review on therapeutic advances in the treatment of IBD, the mechanisms of action, and the challenges facing the therapeutic goals in the treatment of IBD. Salicylates are still used in the treatment of Ulcerative Colitis. Corticosteroids have an indication restricted to the period of therapeutic induction due to frequent adverse events, while technologies with less systemic action have been developed. Most immunomodulators showed a late onset of action, requiring a differentiated initial strategy to control the disease. New therapeutic perspectives emerged with biological therapy, initially with anti-TNF, followed by anti-integrins and anti-interleukins. Despite the different mechanisms of action, there are similarities between the general rates of effectiveness. These similar results were also evidenced in JAK inhibitors and S1p modulators, the last therapeutic classes approved for the treatment of IBD.
... Today, there are many biological agents used in UC treatment. First, anti-tumor necrosis factor (TNF) drugs were introduced, including infliximab and adalimumab, and now, there are many agents like the anti-adhesion molecule vedolizumab, the interleukin inhibitor ustekinumab, the Janus kinase (JAK) inhibitor tofacitinib and many other therapeutic targets being explored in the treatment of UC in various clinical phases [1,5]. ...
Background and Objectives: Ulcerative colitis is chronic and/or progressive inflammation of the colorectal mucosa and submucosa and represents one of two major inflammatory bowel diseases. Ulcerative colitis has been associated with increased risk of arteriosus and venous thrombosis. There are numerous factors responsible for this; one of them is platelet activation and aggregation. The objective of our study was to determine if different treatment options for ulcerative colitis have an impact on platelet aggregation. Materials and Methods: This research was a prospective, observational study and included 94 newly diagnosed patients with UC divided into four treatment groups. For all patients, we measured platelet aggregability by using an impedance aggregometry method with a multiplate analyzer before and after treatment with infliximab, adalimumab, vedolizumab and azathioprine. A Paired Samples t test was performed in order to determine the difference in platelet aggregability before and after a certain therapy, since the data followed a normal distribution. Taking into account the impact of some clinical characteristics, multiple linear regression was conducted for the purpose of estimating the effect of therapy on the level of reduction in platelet aggregability. Results: All four drugs significantly reduced platelet aggregability. After we excluded the influence of clinical and endoscopic scores and disease localization on the results, we found that infliximab had the greatest anti-platelet activity. Conclusions: In addition to the well-known traditional risk factors for atherosclerosis, activation and aggregation of platelets play a significant role in the development of arterial thrombosis, and our results suggested that therapy use for the treatment of UC, especially infliximab, can have a great impact on cardiovascular morbidity and mortality by decreasing platelet aggregability.
... The authors observed that several novel therapeutic targets have been identified and studied by developing small molecules and biologic agents that work on one or several combined targets. However, selecting the most suitable medication for each patient has become a challenge due to the increasing range of therapeutic options for treating IBD [24]. ...
Inflammatory bowel diseases (IBDs) encompass ulcerative colitis (UC) and Crohn’s disease (CD), both of which are inflammatory ailments affecting the gastrointestinal tract [...]
... Currently, there are various drugs available for treating IBD, including immunomodulators (such as thiopurines and methotrexate (MTX)), biologic agents (such as TNFi, anti-integrin, and anti-IL12/23), as well as more recent options including Janus-kinase inhibitors and SP1 modulators [91]. The effectiveness of these treatments has been demonstrated to varying extents in randomized clinical trials, and they are recommended in clinical guidelines [92,93]. ...
... In this case, we may consider the existing evidence from other inflammatory conditions with a larger pool of patient experience to make informed decisions about potential risks [96]. However, it is important to bear in mind that this approach assumes comparable levels of cancer risk and immunosuppressive effects between inflammatory-mediated disorders, and it may not directly apply to dosing regimens specific to IBD [10,[91][92][93]97,98]. ...
... Currently, I-CARE (Inflammatory Bowel Disease Cluster for Assessment of Risk and Epidemiology) is an ongoing investigator-initiated observational European prospective cohort study that aims to provide valuable insights into the long-term benefits and risks associated with biological therapies in patients with IBD [99]. Figure 2 summarizes the risk of developing neoplasms associated with immunomodulators or biological therapy. apply to dosing regimens specific to IBD [10,[91][92][93]97,98]. ...
Background:
Inflammatory bowel disease (IBD) is a group of chronic multifactorial inflammatory disorders including two major entities: Crohn's disease (CD) and ulcerative colitis (UC). Preliminary evidence suggests that patients with IBD may be at increased risk of developing intestinal and extraintestinal cancers (EICs). Actually, little is known about the association between IBD and EICs, and there is ever-growing concern regarding the safety of immunomodulators and biological therapy, which may represent a risk factor for carcinogenesis.
Aims:
The aim of this review is to summarize the evidence regarding the association between IBD and EICs, the safety of immunomodulators and biological therapy and the management of immunomodulators and biologic agents in IBD patients with prior or current EICs.
Results:
IBD patients have a higher risk of developing different forms of extraintestinal solid organ tumors and hematological malignancies. Immunomodulators and biological therapy may increase the risk of developing some types of EICs and may be consciously used in patients with IBD and current or prior history of malignancy.
Conclusions:
Decisions regarding the use of immunomodulators or biological therapies should be made on an individual basis, considering a multidisciplinary approach involving oncologists.
... The swift incorporation of immunomodulators, biologics and small molecules have revolutionized the management of IBD. Current Food and Drug Administration (FDA) approved therapies include thiopurines, tumor necrosis factor (TNF) inhibitors (infliximab, adalimumab, certolizumab pegol and golimumab), anti-integrins (vedolizumab, natalizumab), anti-interleukins (ustekinumab, risankizumab), janus-kinase inhibitors (upadacitinib, tofacitinib) and sphingosine 1-phosphate receptor modulators (ozanimod) [6]. The clinical heterogeneity of IBD is attributed to complex immunopathophysiological responses [7]. ...
Decades of cutting edge innovation in Inflammatory bowel disease (IBD) has yielded a diverse therapeutic armamentarium and warranted a shift in desired clinical endpoint (CE) from symptomatic management towards mucosal healing, histologic outcomes, serial biomarker trends and endoscopic remission. Despite these advancements, disease remission and therapeutic response rates remain suboptimal. This is due to failure to respond to therapy during the induction period (primary non-responder) or a subsequent loss of response (secondary non-responder). To address this area of unmet need, therapeutic drug monitoring (TDM) provides an opportunity to optimize dosing and therapeutic drug concentrations as per desired end clinical targets to improve response rates and offset aggressive disease complications. This further provides a platform for IBD therapeutic stratification based on patient, non-patient related factors and desired CE. In this chapter we aim to discuss a background regarding current TDM applications for various Food and Drug Administration (FDA)-approved IBD therapies and pinpoint deficiencies to enhance its smooth clinical implementation with a view to elucidating precision medicine as a novel therapeutic avenue in IBD.
