EHA 2021 | EQUATE: itolizumab for acute GvHD

The EQUATE study is a study reporting on the preliminary safety and efficacy of a novel medication called itolizumab, which is a targeted anti-CD6 therapy for the initial or upfront treatment of patients with severe acute graft-versus-host disease. We’re reporting our Phase I results, which are dose finding results, and we’re highlighting the preliminary safety, the pharmacodynamics in terms of the ability of the drug to hit its CD6 target on the surface of immune cells, and the preliminary efficacy of this intervention in terms of inducing a response in patients with this condition, severe acute graft-versus-host.

What we did was we investigated the three different doses of itolizumab, 0.4, 0.8 and 1.6 milligrams per kilo for patients with grades three to four acute graft-versus-host disease. This is a clinical grading system based on the severity of involvement of different organ systems known to be implicated in the severity of this disease. So, we look at the skin in terms of extent of rash or peeling of skin. We look at the gut in terms of diarrhea and intestinal inflammation. And we look at the liver in terms of liver dysfunction, specifically the bilirubin. And so, patients with the higher grades are considered grade three and four. And in that setting, we are evaluating these three doses of itolizumab in conjunction with standard doses of systemic corticosteroids, such as prednisone at a standard dose of two milligrams per kilo.

And what we’re reporting is the initial dose findings. So, those three dose levels, as well as a expanded cohort of patients at the two higher dose levels, at the 0.8 and 1.6 milligrams per kilo dose. And in that, we have broadened the indications, we are allowing patients with slightly less severe acute graft-versus-host disease, grade two, so long as they have biomarkers suggesting that they actually have more aggressive disease. And we’re also allowing a slightly broader time interval of up to seven days as, as opposed to the initial 72-hour or three-day window for the start of steroids prior to the use of itolizumab. So, combining these two, we have around 20 patients that we’re reporting results on.

I think the highlights of the presentation really speak to the fact that, at these three dose levels, what we are showing is that itolizumab is able to do what we expect it to do. In other words, at the pharmacodynamic level what we find is, particularly for the two higher those levels of 0.8 of 1.6, we’re able to successfully cause a reduction in the cell surface expression of the CD6 target that this drug is obviously working against, that the reduction in the level of CD6 on the surface of these immune cells leads to their being less pro-inflammatory and less proliferative, and thereby less able to sustain immune toxicity of graft-versus-host disease. So, that is the pharmacodynamic effect.

In terms of their safety and tolerability, we show that for the majority of patients dosing at these dose levels, was indeed feasible. We did document some toxicity, some adverse events in all treated patients. That is not unusual in an extremely sick population of hospitalized patients, such as these. What we do highlight is that none of the patients had fatal side effects from this medication that were attributable to its use. Some infections were noted. But again, infections are expected in this population, so their existence per se doesn’t mean that they’re due to the drug, but that is clearly something we need to continue keeping an eye on.

In terms of the effectiveness of the drug, we saw an up to 70% response rate for patients treated with itolizumab when added to systemic steroids. This is higher than one might expect with the use of systemic steroids alone, though I will emphasize there’s not a controlled comparator within the study, so we’re basing that on reports in the literature from other experiences in similar patients. The response were actually, the majority of the patients who responded actually had complete responses, which is highly gratifying because that’s ideally what you would like to see in a disease as severe as this. And as a correlate, what we are able to show is, for these responders, there is a very substantial ability to taper systemics corticosteroid use to the extent of up to 70% in patients who were on treatment through day 28. And that response was durable even beyond the day 28 mark and indeed, even beyond the discontinuation of the itolizumab treatment, which was for a total of eight weeks or up to day 56.

So all in all, we feel that based on the safety profile, based on the immune effect profile and based on the clinical response and extended duration of response that itolizumab, particularly at the two higher dose levels of 0.8 and 1.6, is indeed promising and worthy of further exploration in ongoing and future studies.