Comprehensive overview of novel chemical drugs for ulcerative colitis: focusing on phase 3 and beyond

ABSTRACT

Introduction

Despite the growing number of highly efficacious biologics and chemical drugs for ulcerative colitis (UC), steroid-free disease control is still difficult to achieve in subgroups of patients due to refractoriness, adverse events, primary or secondary failure. New treatments are therefore still required in order to optimize clinical management of patients with UC.

Areas covered

The efficacy and safety of both currently available and newly developed small molecules have been summarized. The PubMed database and clinicaltrials.gov were considered in order to search for phase 2b and 3 trials on new chemical drugs for UC. The study drugs reviewed included Janus kinases (JAK) and sphingosine-1-phosphate receptor (S1Pr) inhibitors, α4 integrin antagonist, and micro-RNA-124 upregulators.

Expert Opinion

Rapidity of onset, low immunogenicity, and safety are the main characteristics of small molecules currently available or under evaluation for treatment patients with UC. Among the currently available chemical drugs, the selective JAK and the S1Pr inhibitors are characterized by a good safety profile combined with the ability to induce clinical remission in UC. A relatively low frequency of endoscopic improvement and healing currently appears associated with their use, being higher in UC patients treated with S1Pr inhibitor Etrasimod. Overall, additional new safe and effective drugs are still required in order to optimize disease control in a larger majority of UC patients.

KEYWORDS:

• JAK
• S1Pr
• α4 integrin
• Mi-RNA-124
• ulcerative colitis
• clinical trials
• chemical drugs
• small molecules

Article highlights

• The key role of the mucosal immune response in the pathogenesis of UC has led in the last decades to the development of highly effective immunomodulatory drugs.

• Mucosal healing is associated with a better clinical outcome, and it can be induced by immunomodulatory treatments, thus representing the current therapeutic target in UC.

• In the last years, orally administered small molecule drugs have been developed and introduced in the market.

• The first oral chemical drug approved for UC treatment was the pan JAK inhibitor Tofacitinib.

• Since the introduction of Tofacitinib, multiple mechanisms of action have been identified leading to the development of new drugs, apart from JAK-inhibition, such as sphingosine-1-phosphate receptor (S1Pr) inhibition, α4 integrin antagonism, and micro-RNA-124 upregulation.

• The safety combined with the ability to induce clinical remission is the most relevant characteristics of the newly proposed chemical drugs for UC.

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

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

Additional information

Funding

This paper was not funded.