IL-12/23 Inhibitor Shows Efficacy and Safety in Real-World Use

The interleukin (IL) 12/23 inhibitor ustekinumab has proven effective and safe in treating both Crohn disease and ulcerative colitis, but newer therapeutics in clinical trials now may prove even better, David T. Rubin, MD, told the attendees at the Advances in Inflammatory Bowel Diseases (AIBD) virtual regional meeting on August. 7

Dr Rubin is the Joseph B. Kirsner professor of medicine and chief of the section of gastroenterology, hepatology, and nutrition at the University of Chicago.

“As we try to select our therapies or sequence them, thinking about other organ systems or what other labeled indications exist might be a way we can select treatments with a little more thought than just giving patients what’s next on our list,” he explained.

Dr Rubin explained that he refers to ustekinumab as “an anti-p40 antibody because I want to distinguish it from the emerging anti-p19s.” P40 is a shared subunit of both IL-12 and IL-23, blocking both cytokines, while p19 is present only on IL-23.

Ustekinumab is approved for the treatment of plaque psoriasis, psoriatic arthritis, Crohn disease (CD), and ulcerative colitis (UC). Dr Rubin reviewed the results of the UNITI trials, which led to the approval of ustekinumab for CD in patients who were unexposed to biologics (UNITI-1) and to patients with previous exposure to biologics (UNITI-2). Both found that ustekinumab was superior to placebo in inducing remission of CD; the weight-based dose of 6 mg/kg achieved the most favorable results. “There was significant reduction in endoscopic disease activity at week 8 of induction therapy,” he noted.

The IM-UNITI maintenance study for CD found that dosing 90 mg every 8 weeks achieved marked improvement in endoscopic appearance and healing.

Real-world studies have shown that shortened intervals of treatment can lead to improved clinical symptoms and biological disease activity, Dr Rubin stated. In a study conducted at the University of Chicago, of 506 patients with moderate to severe CD being treated with ustekinumab, 20% needed dose escalation from every 8 weeks to every 4 weeks to achieve remission. Among patients who were dose-escalated, he said, “usually 2 or 3 doses enabled recapture of those patients, and dose interval shortening proved safe and effective.”

Ustekinumab has also shown effectiveness in treating perianal disease, Dr Rubin stated, noting that a in post-hoc analysis, between one-quarter and one-third of patients with perianal disease had overall response better than placebo.

Dr Rubin also received 2 major studies involving ustekinumab: STARDUST, a prospective study of patients with moderate to severe CD who were randomized to either to ustekinumab or to standard of care; and SEAVUE, a head-to-head trial of adalimumab vs ustekinumab for moderate to severe CD.

In the STARDUST trial, endoscopy at week 16 was set as a decision point for dose escalation of ustekinumab followed by regular assessment of C-reactive protein (CRP) and fecal calprotectin, and clinical symptoms as measured by the Crohn Disease Activity Index (CDAI). Following results of the endoscopy, dosing of patients in the treat-to-target arm was adjusted as needed to achieve the target. Standard of care patients received dose adjustment based on disease flare and physician assessment of disease activity.

At week 48, the treat-to-target arm was numerically more like to achieve endoscopic response than the standard of care arm. However, Dr Rubin stated, “You can argue that the glass is really half-empty here, because more than half of these patients, despite dose escalation, didn’t get to endoscopic improvement. So clearly there’s a lot of room for us to improve, but also to better understand the nature of endoscopic improvement, the timing of it, and how we might achieve it with greater success with other therapies.”

He continued, “Of interest, beyond the endoscopic appearance, was also the normalization of CRP and drug levels. What it showed was that, if you decrease the interval, as we might have expected, in many patients it led to an increased serum concentration of ustekinumab; and the serum concentrations, when looked at in a quartile analysis, were associated with a greater likelihood of normalizing the CRP If you actually adjust these results based on the PK of the therapy you can demonstrate that it actually is doing what we hoped it would do—which is when you reduce the interval, you increase the amount of the drug, you have a greater likelihood of an objective result. Very interesting results.”

SEAVUE was a “highly anticipated study” presented at Digestive Disease Week, Dr Rubin stated, in which biologic naïve patients were randomized to either adalimumab or ustekinumab; no dose escalation was allowed. The  endpoint was clinical remission as assessed by CDAI at week 52, and the hypothesis was that ustekinumab would be more effective than adalimumab.

In reality, SEAVUE showed that the two therapies were equally likely to achieve the primary endpoint. “The response over time was very similar,” Dr Rubin said, with “one remarkable result—that biologic naïve patients achieved results of 60% remission.”

One distinct advantage of ustekinumab is that it has very low immunogenicity—perhaps 2% of patients, Dr Rubin said, and this did not require discontinuation of the drug. Further, he noted, the use of an immunomodulator did not improve outcomes among patients treated with ustekinumab, so “we can probably treat patients with monotherapy.”

Dr Rubin also reviewed the UNIFI study, which examined the use of ustekinumab among patients with UC, and used a novel endpoint of histoendoscopic healing. As in the UNITI studies, the trial showed that 8-week maintenance dosing yielded numerically better results. Further, he said, “When the drug works, it works fast. You can see improvement in stool frequency and reduction of rectal bleeding within 7 days.”

The long-term extension of UNIFI shows that patients continue to maintain stable remission out to week 92 regardless of TNF exposure. “If you achieved remission in trials, you’re likely to remain in remission over the long term,” Dr Rubin stated. Ustekinumab “works in these tough-to-treat patients” who are TNF-exposed but did not achieve or lost response to previous treatments.

Trials of upcoming second- and third-generation drugs in this class are showing significant promise, Dr Rubin stated. Trials of braziikumab for treatment of moderate to severe CD show not only that the drug is clearly effective, but also that serum IL-22 levels were predictive of subsequent response to this therapy, he noted. “Might we have a therapeutic biomarker? This is very interesting.”

Other upcoming therapies include guselkumab, mirikizumab, and risankizumab, all of which are showing good results in clinical trials. Dr Rubin stated, “What’s of great interest is that it appears that IL-23 selective inhibition without the IL-12 part might be better than IL-12/13; focusing on the p19 subunit may be better than p40.”

There is also what Dr Rubin calls a third generation—the TYK-2 inhibitors. He reported that there are 2 drugs in development that are oral small molecules, “that actually are JAK inhibitors that block TYK2 that could potentially offer us an oral equivalent to the IL-12/13 inhibitors, and we’re very interested to see what happens with that.”

In summary, Dr Rubin stated, ustekinumab has proved effective in both CD and UC, in biologic-naïve and biologic-exposed patients, and “it appears superior to vedolizumab as a second-line therapy in CD after anti-TNF therapy. IL-12/23 inhibitors have favorable safety profiles and low to negligible immunogenicity. The new p19 inhibitors may be even more effective.”

--Rebecca Mashaw

Rubin, DT. Optimal use and future use of IL-12/23 for the management of IBD. Presented at: Advances in Inflammatory Bowel Diseases regional meeting. August 7, 2021. Virtual.