Q&A: Head-to-head studies needed to differentiate mirikizumab from IBD competitors
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Mirikizumab, a monoclonal antibody poised to become first-in-class treatment for ulcerative colitis, has the potential to transform treatment paradigms — if it can distinguish itself in an already saturated and competitive market.
According to Clarivate’s Drugs to Watch 2023 report, mirikizumab (Eli Lilly), which targets the p19 subunit of interleukin-23, is one of many emerging therapies that “will contribute to the growing market share and potentially more efficacious and long-lasting treatment options for patients.”
It was recognized as one of 15 drugs to watch based on positive results from phase 2 studies in patients with Crohn’s disease, which advanced the drug into several phase 3 studies, including VIVID-1, VIVID-2, LUCENT-1 and LUCENT-2. Ongoing studies include LUCENT-3, a long-term extension study evaluating the drug’s safety and efficacy, and SHINE-1, which is assessing the drug in pediatric patients.
Healio spoke with Stephen B. Hanauer, MD, medical director of the Digestive Health Center at Northwestern Medicine and the Clifford Joseph Barborka Professor of Medicine at Northwestern University Feinberg School of Medicine, about mirikizumab’s potential in the inflammatory bowel disease drug market and how it could stand up to the competition.
Healio: Why do you think mirikizumab might shake up the IBD drug market and is it needed?
Hanauer: Mirikizumab is going to be the first specific IL-23 blocker approved for use in ulcerative colitis. We already have IL-23 blockers such as risankizumab (Skyrizi, AbbVie) for Crohn’s disease and soon we will have it for UC. Over the past years, we have had ustekinumab (Stelara, Janssen), which blocks both IL-12 and IL-23, approved for UC and Crohn’s disease.
We are expanding from IL-12/23 blockade over the past years to more specific IL-23 blockade. Whether that is going to be highly significant progress in Crohn’s or ulcerative colitis remains to be determined.
Ustekinumab has been a very effective agent in both Crohn’s and UC, but when tested against IL-23 specific drugs in other immune-mediated diseases, such as psoriasis, there appears to be some numerical advantage to specific IL-23 blockade.
It remains to be determined whether that is actually due to specificity of the IL-23 target or related to subtle differences in dosing between ustekinumab and risankizumab or guselkumab (Tremfya, Janssen), which has also shown improvement compared with ustekinumab in psoriasis.
Thus far in IBD, we do not have head-to-head studies of ustekinumab vs. IL-23 blockers, so we need to look at them somewhat individually.
Healio: What gaps would mirikizumab fill when it comes to market?
Hanauer: If mirikizumab is more efficacious than ustekinumab, it will be the first IL-23 blocker approved for UC. But risankizumab is not far behind for UC. The advantage of the IL-23 and ustekinumab IL-12, 23 blockade has really been in its safety profile compared with TNF blockers.
We are beginning to realize that TNF is more of a systemic cytokine. TNF blockers have been approved for at least 14 different indications across many of the immune-mediated diseases, but we are starting to see some separation between the gut, the skin and the joints with more locally produced cytokines. For instance, IL-23 is produced more in the skin and in the gut but less in the joints. As such, IL-23 blockade has been very effective in IBD, UC and Crohn’s disease, and in psoriasis and psoriatic arthritis, but not so much in rheumatoid arthritis.
In contrast, TNF blockers are effective across these immune-mediated diseases. For instance, IL-17 blockade is very effective in the skin and in the joints but not very effective in the gut, because of differential impacts of these cytokines on different tissues. IL-17 is necessary to maintain the integument of the gut and when it is blocked, the gut becomes leaky. In fact, IL-17 blockers have been associated with worsening IBD.
As we are getting closer to tissue specificity, we are able to harness efficacy and not have the associated risks of systemic TNF blockade in particular infectious complications.
Healio: What hurdles are expected in a market already dominated by Stelara and Entyvio?
Hanauer: Competition. We lack head-to-head studies, although there is a head-to-head study that compared adalimumab (Humira, AbbVie) to ustekinumab in the setting of Crohn’s disease, and those results were comparable, rather than substantially different.
There were some differences: The patients on ustekinumab had more persistence on treatment than patients with adalimumab, but we do not have head-to-head studies in IBD comparing IL-23 blockers to ustekinumab.
Nowadays, we have new oral therapies for UC: There are several Janus kinase inhibitors, like tofacitinib (Xeljanz, Pfizer) and upadacitinib (Rinvoq, AbbVie), and sphingosine 1-phosphate receptor (S1P) modulators ozanimod (Zeposia, Bristol Myers Squibb) and etrasimod (Pfizer) that are nearing market.
There is a lot of competition and in the absence of real head-to-head studies, it is somewhat challenging to position different agents in the setting of UC but also in Crohn’s disease.
Reference:
- The drugs to watch in 2023. https://clarivate.com/blog/the-drugs-to-watch-in-2023/. Published Jan. 10, 2023. Accessed Feb. 14, 2023.
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