Could small molecules be used in combination with biologics for inflammatory bowel disease?

KEYWORDS:

• JAK-inhibitors
• biologics
• dual therapy
• inflammatory bowel disease
• Crohn’s disease
• ulcerative colitis

1. Literature evidence

The introduction of biologics and small molecules has revolutionized the management of chronic inflammatory bowel diseases (IBD) implementing the therapeutic armamentarium and providing a viable alternative to surgery [1]. To date, there are several biological drugs approved for treatment of Crohn’s disease (CD) and ulcerative colitis (UC) including anti-TNFα agents, anti-integrins, and an interleukin 12–23 inhibitor [2]. In UC, Janus kinases (JAK) inhibitors (tofacitinib) and anti-sphingosine drugs (ozanimod) are also available [3–5]. Despite this important effort to find new molecules with new mechanisms of action, there is still a high percentage of patients who do not respond or lose response to therapies [6]. These patients often fail multiple therapies and surgery is their last treatment option. Patients refractory to multiple therapies are a challenging issue for clinicians and deserve special attention. They are difficult patients to treat although to date there is still no validated definition of difficult to treat IBD patient [7]. The effort to identify this category of patients aims to early diagnose patients with little chance of response to treatment and to set up a personalized therapy in order to guarantee their optimal management. In rheumatology, for example, there is a clear definition of difficult to treat rheumatoid arthritis [8]. It includes patients who have failed at least two biological drugs with two different mechanisms of action or those who have alarm features (active disease, moderate intensity, impact on quality of life, radiological progression, or inability to taper steroids) or those who seem difficult to treat to the rheumatologist. In IBD, the definition of difficult to treat should take into account not only the number of biologics and small molecules but also the steroid dependency, the number of surgeries, the presence of comorbidities or extraintestinal manifestations, and penetrating or stricturing disease [7]. The proper evaluation of a patient is the first step for an adequate therapy selection. In this patient setting, a more aggressive treatment with the combination of different therapies could be considered. The rationale for this strategy is to block inflammation by acting on several pathways at the same time to increase the likelihood of response to therapy. A recent systematic review and meta-analysis by Ahmed and colleagues investigated the safety and efficacy of dual biologic therapy in combination or with tofacitinib in 288 patients with refractory IBD [9]. Most patients were treated with two biological therapies simultaneously while a small proportion of subjects were treated with tofacitinib in combination with vedolizumab (11%), ustekinumab (6%), or anti-TNFα (3%). After a median follow-up of approximately 8 months, the pooled rates of adverse events and serious adverse events were in line with the literature data for biological drugs and small molecules alone. However, more than half of these refractory patients achieved clinical remission and about a third of them experienced endoscopic remission, suggesting that the combination of two therapies is feasible in selected cases. Another systematic review with meta-analysis by Alayo et al. assessed the safety and efficacy of dual biologic therapy (DBT), or small molecule combined with a biologic therapy (SBT) in IBD patients stratifying the results according to each drug combination [10]. Although DBT was the most frequent approach, the most used combination was tofacitinib with vedolizumab (57 patients, 21.4%) followed by vedolizumab and anti-TNFα (56 patients, 21.0%). Surprisingly, a higher rate of serious adverse events was reported in vedolizumab-anti-TNFα group (9.6%, 95% CI, 1.5–21.4) compared with tofacitinib-vedolizumab arm (1.0%, 95% CI, 0.0–7.6). On the other hand, no increased risk was detected with ustekinumab-anti-TNFα, tofacitinib-ustekinumab, tofacitinib-anti-TNFα, and natalizumab-anti-TNFα. Clinical remission was reported in approximately 50% of all combinations, while endoscopic/radiological remission ranged from 18% with vedolizumab-anti-TNFα to 37.4% with tofacitinib-ustekinumab. Although these data on the use of dual therapy appear promising and reassuring, it must be emphasized that the number of patients analyzed is small and that we need long-term data to draw strong conclusions on the safety profile. While the efficacy advantage associated with the use of two drugs is evident, the data concerning its safety are less clear.

2. Pros and cons of dual therapy in IBD

Since they were approved, the main limitation to the wide use of biologics and small molecules is an increased risk of infections and the suspected association with an increased risk of malignancy and other adverse events. Current evidence confirms an increased risk of infections in patients treated with biologics and small molecules but there is no data to support an increased risk of malignancy [11–14]. Another limitation to the widespread use of dual therapies is the relevant increase in direct healthcare costs. On the other hand, these therapies allowing for greater treatment efficacy could reduce the number of IBD-related hospitalizations and surgeries and improve patient productivity by reducing the number of working days lost due to illness. It is therefore legitimate to hypothesize that the association of two different therapies is a possible option. However, it is essential to define when this approach should be recommended in order to avoid overtreatment and expose patients to the risk of adverse events.

3. Expert opinion

Dual therapy should only be considered in patients who fail more than one advanced treatment with different mechanisms of action in a short time. It could also be used in patients with IBD and extraintestinal manifestations where one of the two diseases is well controlled with ongoing biological therapy, while the other requires therapy enhancement. In addition, it could be used for paradoxical post-therapy inflammation. Paradoxical inflammation can lead to the development of immune-mediated diseases such as psoriasis [15]. Such paradoxical events are frequently reported with the use of anti-TNFα (incidence rate of 10%) [15,16]. Strangely, the drugs causing paradoxical inflammation are generally used to treat such pathologies. The pathogenesis is unknown, but it is plausible that this effect is due to the cytokine imbalance caused by the therapy. The dual therapy could allow to continue an effective treatment for intestinal disease, adding a drug for the management of the paradox event. Regarding the drugs to be combined instead, the decision should be personalized and tailored according to the patient characteristics. Indeed, previous failed therapies, age, and comorbidities should be considered. Of note, the patient’s will and needs are also important. For this reason, therapeutic decisions should be shared with the patient and the caregivers, allowing them to be more engaged in the disease management. Patients may be frightened by the need for two periodic infusions or by the frequent administration of subcutaneous medications [17]. In this context, oral drugs such as ozanimod and tofacitinib represent a reliable option. The small molecules are suitable for combination therapy as they have favorable pharmacokinetics (very short half-life) and can be rapidly interrupted if necessary [18]. Unlike biologics which remain in circulation for several weeks after their administration, small molecules are completely eliminated within 24 hours of their discontinuation. Furthermore, the combination with oral small molecules could allow a better patient quality of life and fewer accesses to the hospital. Currently there are no data regarding the combination of different small molecules, but it cannot be excluded that in the near future this hypothesis may become true.

In the absence of data, our hypothesis is that combination of a biologic and a small molecule can be considered in patients with severe disease, high risk of complications, relative contraindications to surgery (i.e. high risk of short bowel syndrome), or concomitant extraintestinal manifestations and active luminal disease where one drug is not enough. Further data confirming this hypothesis or opening new scenarios for the use of this combination are strongly needed.

In conclusion, the dual therapy with biologics and small molecules is a promising therapeutic option that could allow the achievement of therapeutic targets and make the goal of a deep and lasting remission more concrete. However, in the absence of long-term safety data, it is right to be cautious and choose this option on a case-by-case basis, sharing the pros and cons of therapy with the patient.

Declaration of interest

S Danese has served as a speaker, consultant, and advisory board member for Schering-Plough, AbbVie, Actelion, Alphawasserman, AstraZeneca, Cellerix, Cosmo Pharmaceuticals, Ferring, Genentech, Grunenthal, Johnson and Johnson, Millenium Takeda, MSD, Nikkiso Europe GmbH, Novo Nordisk, Nycomed, Pfizer, Pharmacosmos, UCB Pharma and Vifor. G Fiorino received consultancy fees from Ferring, MSD, AbbVie, Takeda, Janssen, Amgen, Sandoz, Samsung Bioepis, Celltrion. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

F D’Amico wrote the article. S Danese and G Fiorino critically revised the manuscript. The final version of the manuscript was approved by all authors to be published.

Data availability statement

No new data were created or analyzed in this study.

Additional information

Funding

This paper was not funded.