Risankizumab Could Usher in Targeted Medicine for Inflammatory Diseases

Marla C. Dubinsky, MD

Ever since the advent of biologics with the approval of infliximab (Remicade) in 1998 for the treatment of Crohn’s disease, many believed targeted treatment for inflammatory bowel disease (IBD) was possible.

Now, with risankizumab (SKYRIZI) approved by the US Food and Drug Administration (FDA), the first interleukin-23 (IL-23) medication approved, the next wave of IBD drugs may focus on this specific cytokine.

What Does This Mean?

For many, IL-23’s represent hope that prescribers will be able to better target patients with inflammatory diseases to specific drugs that are more likely to elicit a response.

One doctor that has sung the praises of the IL-23 class of drugs, including risankizumab and mirikizumab, is Marla Dubinsky, MD, chief, division of pediatric gastroenterology for the Mount Sinai Health System, co-director of the Susan and Leonard Feinstein IBD Center at Mount Sinai.

In an interview with HCPLive®, Dubinsky said the approval of risankizumab could ultimately pave the way for many new IL-23 targeted biologics to come on the market in the coming years that could ultimately replace anti-tumor necrosis factor (anti-TNF) inhibitors as the first option for patients with IBD.

“So I think we're just at the tip of the iceberg,” Dubinsky said. “And I think understanding that it will be probably as simple as TNF or not, or maybe IL-23 or not. That's probably going to be the front door, and then you're like, oh, do I have to open another door?”

A New Era of Precision Medicine

The end goal for the next frontier of drug development is for clinicians to be able to view inflammatory diseases, not just IBD, but also rheumatic diseases like ankylosing spondylitis and rheumatoid arthritis and dermatological diseases like plaque psoriasis, in the prism of specific interleukin targets.

When anti-TNF treatments first became an option for inflammatory diseases, they were seen as a breakthrough for gastrointestinal, rheumatology, and dermatology treatments.

But unlike the drugs that target specific interleukins, anti-TNF treatments target inflammation in general.

“We all understood biologically that all roads leads to TNF,” Dubinsky said. “They are the end game, all immune, inflammatory disease, every pathway ends in TNF. It makes sense that they were the first cytokine-based monoclonals developed because we understood that there’s a lot of this when there’s inflammation.”

And as Dubinsky said, it might just be the tip of the iceberg in this regard, as investigators are beginning to learn more and more about how the immune system works and how certain targets could be more or less effective depending on the inflammatory disease.

“We thought we understood the entirety of the immune system by just going to the end, and shut the tap off at the end,” Dubinsky said. “We started realizing the immune system is obviously much more complex than just TNF.”

And what was ultimately discovered, “turning off” TNF is effective for some, but it is not effective for many patients with inflammatory diseases. Dubinsky said that led to the realization that you need to go above blocking TNF for a group of patients.

And while TNF is likely a part of every individuals inflammatory response, there still needs to be an alternative to block the inflammatory for patients with genetic driven disease characterized by IL-23.

The Risankizumab Approval

The risankizumab approval was based on the ADVANCE and MOTIVATE induction trials and the FORTIFY maintenance trial.

In the trials sponsored by AbbVie, the treatment resulted in significant improvements endoscopic response (defined as a decrease of greater than 50% from the baseline Simple Endoscopic Score in CD [SES-CD or patients with isolated ileal disease and SES-CD of 4, at least a 2-point reduction from baseline and clinical remission, defined as a Crohn's Disease Activity Index (CDAI) of less than 150, compared to placebo.

Dubinsky said the data on risankizumab sets the whole family of IL-23 treatments up for success as it is the first Crohn’s disease drug ever in the regulatory environment to ever have to reach endoscopic response at 12 weeks.

And a lot of the data centered around very sick patients, some of which were on their eighth biologic, leading to confidence in the efficacy of risakizumab when it becomes the first option for patients.

Another doctor agreed with Dubinsky about the future of biologics.

In an interview with HCPLive®, David P. Hudesman, MD, Medical Director of the Inflammatory Bowel Disease Center at NYU Langone Health, explained where he believes drug development will move toward in the coming years and how new biologics are most likely on the table.

“I think there will be in the next 1-5 years more biologics that come to market,” Hudesman said. “A lot of them are going to be similar mechanisms of action and different options for the patient, as well as biosimilars.”

Targeted Therapeutics

In recent years, certain targets for certain diseases have emerged. While IBD is a known IL-23 target, so is psoriatic arthritis and psoriasis, while juvenile idiopathic arthritis is treated with IL-1 inhibitors. In addition, ankylosing spondylitis, psoriatic arthritis, and psoriasis are treated with both IL-17 and IL-23.

All of the different diseases in this discussion all have ending in TNF as the common effector phase but can be targeted specifically with the different interleukin inhibitors.

“IBD is psoriasis of the gut and psoriasis is IBD in the skin, it's a very simple analogy,” Dubinsky said. “This actually shows you why different drugs work in different diseases and not and although blocking TNF is attractive, but hey, you're probably going to get better effect if you go to the true targeted biology, right? TNF to me is untargeted.”

Patients Who Do Not Respond

Much like every other targeted treatment, there will be some patients with IBD who do not respond to IL-23’s. Dubinsky explained that by saying some patients will have non-IL-23 genetics in their disease. For those patients, clinicians should go to the next target if the IL-23s are ineffective.

“We need better precision tools to do that,” she said.

Clinicians can also look at family history of disease and make an educated decision on the potential front-line treatment. Dubinsky said if a patient comes in with a family history of psoriasis or psoriatic arthritis, it wouldn’t make sense to choose an anti-TNF medication over an IL-23 as the first treatment option because IL-23 is organ specific as opposed to a systemic inflammatory response.

“My sort of role for the next five years is to scream from the rooftops the idea that if you have a patient who has a family history of an IL-23 disease, please use 23 If you can,” she said.

Future Studies are Still Needed

But there remains a debate over whether a drug like Risankizumab, which only targets IL-23, is more effective than a treatment like ustekinumab, which targets both IL-12 and IL-23.

Dubinsky said while a head-to-head comparison between ustekinumab and risakizumab has not yet been scheduled, the data right now likely to points to IL-23 being the more effective treatment option compared to an IL-12 and IL-23.

One explanation based on some preliminary data is it is possible that blocking IL-12 negatively impacts blocking IL-23, potentially by doing something with the TNF blockade. Another explanation is that researchers finally achieved the right dosing with the IL-23 research, which has been allusive in the past.

“I think we got the induction dosing right finally,” Dubinsky said. “I think that's why you're going to see better and data now. Does it mean that it's just that or is there also a biologic reason that blocking 12 is not fantastic?”

But while there will be future research on risankizumab and other IL-23 inhibitors, the first approval could hopefully represent a big first step toward a revolution of precision medicine for inflammatory diseases like ulcerative colitis and Crohn’s disease.