Ulcerative colitis (UC), an inflammatory bowel disease, is characterised by inflammation and ulcers in the large intestine, often causing symptoms that impact a patient’s quality of life, including diarrhoea, abdominal pain and cramping, fatigue, weight loss and pain. While the exact cause of UC remains unknown, it is often associated with immune system malfunction.

Many of the mainstay drugs for the treatment of moderate to severely active UC, such as anti-tumour necrosis factor (anti-TNF) agents like infliximab, target inflammatory mediators that are dysregulated in this condition. While there are several agents indicated for UC with a variety of mechanisms of action (MOAs), the pipeline remains strong with many novel MOAs and new routes of administration. This pipeline includes agents such as Abivax’s obefazimod; InDex Pharmaceuticals’ cobitolimod; three interleukin-23 (IL-23) inhibitors, namely AbbVie’s Skyrizi (risankizumab), Eli Lilly’s mirikizumab, and Janssen’s Tremfya (guselkumab); and Takeda’s subcutaneous formulation of Entyvio (vedolizumab) in the US.

Cobitolimod, an agent being developed for patients with moderate to severely active UC, has both a novel MOA and a route of administration that is unique among marketed agents. Cobitolimod is a toll-like receptor 9 (TLR9) agonist that is administered locally to the large intestine via rectal enema. The TLR9 agonist is currently being investigated in the Phase III CONCLUDE trial (NCT04985968), with an expected study completion date of August 2023. While data from the Phase III trial is not yet available, the Phase IIb CONDUCT trial (NCT03178669) assessed the efficacy and safety of cobitolimod in patients with moderately to severely active UC and demonstrated promising results and a strong safety profile. One potential benefit of cobitolimod’s unique route of administration is that local administration via rectal enema has the potential to limit systemic absorption and the immune-related side effects that plague some marketed agents.

Abivax is developing obefazimod, another agent with a first-in-class mechanism. Obefazimod is a micro-RNA-124 upregulator that ultimately inhibits the production of inflammatory mediators associated with UC. In a Phase IIb induction trial (NCT03760003) evaluating the drug’s efficacy and safety in patients with moderate-to-severe UC, the primary endpoint of a statistically significant reduction of Modified Mayo Score was met with once-daily administration of obefazimod at week 8. In addition, interim analysis of the maintenance study results demonstrated strong efficacy. Obefazimod also demonstrated efficacy in patients who had previously been exposed to biologics or JAK inhibitors. This is an important population to target, as it is well-documented that a number of patients are intolerant or non-responsive to first-line biologics like infliximab or adalimumab. Based on the results from the Phase II trials, Abivax is currently planning to launch a Phase III programme globally.

There are currently three companies developing IL-23 inhibitors for moderate-to-severe UC patients: AbbVie’s Skyrizi, Eli Lilly’s mirikizumab, and Janssen’s Tremfya. While all three agents are currently undergoing Phase III trials, GlobalData expects Eli Lilly’s mirikizumab to be the first IL-23-specific inhibitor to be approved for this indication. In May this year, Eli Lilly announced interim data from its Phase III LUCENT-2 trial (NCT03524092), which demonstrated strong efficacy. GlobalData expects regulatory approval of mirikizumab for UC in the US and European Union (EU) next year. AbbVie’s Skyrizi is currently undergoing a Phase III trial (NCT03398135) with an estimated completion date of next year, while Janssen’s Tremfya is currently undergoing the combination Phase IIb/III QUASAR trial (NCT04033445). Data from the QUASAR induction study demonstrated positive efficacy and safety results. KOLs interviewed by GlobalData have been positive regarding the effects of IL-23 inhibitors compared to Janssen’s already-marketed Stelara (ustekinumab), an IL-12/IL-23 inhibitor.

Takeda’s intravenous formulation of Entyvio is a strong competitor in the UC market. To improve ease of administration, Takeda has developed a subcutaneous (SC) formulation. The SC formulation has been approved in many markets around the world, including the EU. Citing feedback from the US Food and Drug Administration (FDA) regarding labelling and device design for the SC formulation of Entyvio, it is not yet approved in the US. GlobalData anticipates regulatory approval of Entyvio SC in the US next year. Once approved, Entyvio SC will be a useful addition to the treatment options for UC, as this formulation allows for self-administration, which can be accomplished at home instead of in healthcare settings.

While there are many agents available for the treatment of UC, GlobalData believes novel agents such as cobitolimod, obefazimod and the IL-23 inhibitors will prove to be useful and effective additions. These new treatment options will be especially beneficial for patients who are intolerant or non-responsive to biologics currently used for the treatment of moderate-to-severe UC, such as anti-TNF agents.