Bruce Sands, MD, on the VEGA Study of Combination Biologic Therapy in UC

Dr Sands provides an overview of the VEGA study, the first of its kind to combine 2 biologic agents to attempt to achieve higher rates of remission among patients with ulcerative colitis.

Bruce Sands, MD, is the Dr. Burrill B. Crohn Professor of Medicine and chief of the Dr. Henry D. Janowitz Division of Gastroenterology at the Icahn School of Medicine at Mt Sinai in New York, New York.

TRANSCRIPT:

Gastroenterology Learning Network: Welcome to this podcast from the Gastroenterology Learning Network. I'm your moderator, GLN: Mashaw. I'm delighted to have here today Dr. Bruce Sands, who is the Dr. Burrill B. Crohn Professor of Medicine and Chief of the Dr. Henry D. Janowitz Division of Gastroenterology at the Icahn School of Medicine at Mount Sinai in New York. Thank you so much for taking the time today to talk to us about the VEGA study in ulcerative colitis.

Dr. Bruce Sands: My pleasure, Rebecca. Thanks for inviting me.

GLN: So, let's get started by having you give us a brief overview of the study. What were you looking at and what was the overall purpose of this trial?

Dr Sands: Yes. Well, if you look at clinical trials with advanced therapeutic agents for ulcerative colitis and for Crohn's disease, we're doing better and better with these advanced therapies. These are biologics and small molecule agents, but we're still not reaching a very substantial proportion of patients. We, at best, maybe we're getting 40% in remission by the end of a year, and that would be an overestimate for most of our agents.

So, we're looking for new approaches to overcome that plateauing of efficacy that we've been observing. So, there are probably 2 ways around this. One would be precision medicine approach. Can we pick out the patients for whom a particular agent will be transformatively effective using a predictive biomarker? Another way would be to do what has been done in other areas, which is to employ combination therapy. So, we see this in infectious disease where we use multiple agents to treat tuberculosis. We see this in cancer where we use multiple chemotherapeutic approaches to really get control of the disease. But we haven't really much done this with our advanced agents in IBD.

So, this is the first study ever to combine 2 biologic agents prospectively to see if that combination will be more effective than either one alone. And this was done on the basis of in vivo animal models of colitis showing that, in this case, a combination of an anti-TNF, in this case golimumab, and an anti-IL-23 antibody called guselkumab, which is under investigation in its own right for ulcerative colitis. Each of those as monotherapies did not do as well in the animal model as combining both of them. And then there were also in silico experiments showing that if you gave both of these together, it was predicted that you would effectively hit manyfold more pathways of disease than you would with either one alone. So, there was a good preclinical rationale.

So, the VEGA study really took patients with moderate to severely active ulcerative colitis and they were randomized in a 1-to-1-to-1 fashion to get golimumab, again approved already for treating ulcerative colitis, or guselkumab monotherapy, which is under investigation for ulcerative colitis, or the combination of both of them.

GLN: And the hypothesis was that these two agents would take different pathways to deal with the inflammation and the other symptoms and biomarkers of ulcerative colitis?

Dr Sands: That's right. That the combination would hit more pathways and therefore be more effective. And while I can't tell you what pathways were hit at this moment, because that's more of a basic science question, we do have the clinical trial results from both induction and what was reported out at ACG were the 38-week results.

GLN: So, tell us about the results that you've seen. What were your primary endpoints and did you hit those?

Dr Sands: For the induction part of the study at week 12, combination therapy was statistically, and I would say clinically, significantly better than either golimumab or guselkumab as monotherapies. We see this in clinical response, but even more so in clinical remission where at week 12, we had about one-third of patients achieving the rigorous outcome of clinical remission with combination therapy, but only about 20%, 21%, 22% for either monotherapy alone.

And if you extended those observations out to week 38, mind you, the patients who were assigned to combination therapy after week 12 then continued on guselkumab alone, the anti-IL23 antibody, the monotherapy patients continued on their prior monotherapy after week 12. But the ones who had been on combination induction and then went on to monotherapy guselkumab from weeks 12 to 38, they actually had 43.7% rates of clinical remission compared to 31% for guselkumab alone or 22.2% for golimumab alone. And that was a very remarkable outcome. Basically, you're seeing a doubling of efficacy over golimumab monotherapy and a 1½- fold increase in efficacy over guselkumab monotherapy at week 38.

GLN: This study also included the endpoint of composite histologic endoscopic healing, which is more or less a new endpoint in studies for IBD. What does that add to the findings? What does that tell you that you weren't learning before this endpoint came along?

Dr Sands: Yes, this is a newer endpoint that really was first studied with ustekinumab in ulcerative colitis in the UNIFI study. And you can think of it as the broad view of endoscopy, its effect on healing ulcers, and the micro view of histology on what it's doing histologically to the disease. And by and large, the disease is the presence of neutrophils in the epithelium and the mucosa.

So, when we combine these things, we end up with a much more rigorous and more difficult outcome. But there's mounting evidence that if you can achieve that outcome, you're going to have more sustained benefits for the patient. And so with regard to that outcome, by week 38, the patients who had combination therapy guselkumab and golimumab and then went to monotherapy guselkumab after week 12, they achieved that really rigorous outcome of histologic remission with endoscopic improvement in 42.3% of patients as compared to just 21% with guselkumab monotherapy and only 13.9% on golimumab monotherapy. So, these are effect sizes in excess of 20% and highly statistically significant, really a remarkable outcome.

GLN: How about the safety of this combination?

Dr Sands: Of course, that is a key question because here we're combining 2 immunologically active agents and all we can say is the sample size is limited. We have really just about 71 patients in each of the 3 groups, and we have follow-up to week 38, which is not years on end. So, we need much more data. But at least so far it looks like the safety of combination therapy is very similar to what was seen in the other monotherapy groups. Really no emerging differences and most especially you'd be concerned about increased risk of infection. We really don't see that.

GLN:  Did any of the results you've seen so far surprise you?

Dr Sands: I think we just didn't know what to expect from a trial like this because it simply hasn't been done before. And I think this is approaching, if not transformative efficacy, at least a big jump forward in what we're seeing with monotherapy agents. Maybe we could compare this to the efficacy of upadacitinib, which recently has also been reported out, and that's a JAK1 selective inhibitor. That's an oral agent, a monotherapy, but it also comes with safety baggage of JAK inhibition and it's positioned as a second line therapy in the treatment of ulcerative colitis because of black box warnings.

GLN: So, you may have just answered my question about what's most important about this trial and about the general approach of combining biologics. It does have the potential, you think, to be transformative?

Dr Sands: That's the hope. I think really what we're all interested in knowing is these were patients who were all naive to an anti-TNF and naive also to ustekinumab, which has some similarity of modality, mode of action, to anti-IL23 because ustekinumab blocks both 12 and 23, guselkumab blocks only IL23. So, these were relatively naive patients. What we'd love to know is will this perform as well in more treatment refractory patients? And that remains to be seen.

GLN: Do you have a plan for a study of those treatment refractory patients?

Dr Sands: Everyone can look on clinicaltrials.gov and see that DUET CD and DUET UC are studies that are in the works and hopefully starting to recruit soon. That may answer these further questions.

GLN: Well, this is very interesting and we'll certainly look forward to catching up with you later and hearing how the DUET studies, what results they produce. Thank you very much for your time.

Dr Sands: My pleasure. Thank you, Rebecca.