We know from previous studies that there is an increased activation of hedgehog signaling in dermal fibroblasts patients with sclerotic GvHD leading to collagen deposition and fibrosis. The inhibition of this product’s been shown to ameliorate sclerotic features in animal models.
So, given this background, this was an investigator-initiated Phase I dose escalation trial where we evaluated glasdegib, an oral hedgehog signal inhibitor in patients with refractory sclerotic chronic GvHD...
We know from previous studies that there is an increased activation of hedgehog signaling in dermal fibroblasts patients with sclerotic GvHD leading to collagen deposition and fibrosis. The inhibition of this product’s been shown to ameliorate sclerotic features in animal models.
So, given this background, this was an investigator-initiated Phase I dose escalation trial where we evaluated glasdegib, an oral hedgehog signal inhibitor in patients with refractory sclerotic chronic GvHD. 20 patients were included in this study. These were heavily pretreated patients with severe sclerosis and at least two lines of treatment with a median of four lines of prior therapy. Some patients had received even up to 10 lines of therapy. So, overall, a very challenging patient population. Glasdegib was administered in continuous 28-day cycles, and for the analysis that we present here at EHA, the data that was at the end of cycle 12.
So, starting with the safety side, we encountered a high incidence of on-target adverse events. These were class effects that have been described in the use of different hedgehog signal inhibitors. Hedgehog signaling is characteristically silent in many adult tissues, but it still plays important signaling roles in the homeostasis of some tissues, like muscle, hair follicles, or taste buds. So, alopecia, dysgeusia issues can be side effects of this inhibitor. Some were, in fact, frequently reported. However, the main limitation here in this trial was a high incidence of massive cramps and other known glasdegib-related effects, which were severe in a number of patients, 70% presented at least grade II events and 30% grade III events with two events that qualified as dose limited in toxicities in the 100 milligram cohort. This led to the halt of dose escalation to study the maximum tolerated dose of 50 milligrams per day, as compared to the 100 mg dose approved in combination with a low dose Ara-C in AML.
It’s quite interesting that in the trials in the AML setting this toxicity, although reported in some patients, did not represent a major obstacle. So, I think that this patient with the sclerotic GvHD who can present muscle cramps for a number of the different reasons in the context of GvHD may be primed to develop this toxicity. Also, the fact that we kept seeing on-target adverse events, even at the 50 milligram dose, says that we were probably achieving significant biological activity despite this lower dosing. Overall, this muscle cramps had a significant impact on tolerability, but it is worth nothing that half of the patients continued treatment beyond cycle 12.
Then with respect to clinical efficacy, one of the challenges that we face in this setting is that we currently lack good tools to capture clinical responses in a sclerotic GvHD in an objective standardized manner, but this fact, this limitation, the [inaudible] the data the full report here are encouraging. So, using [inaudible] scale for the physical assessment of sclerosis, 13 out of 20 patients achieved at least a two point improvement. This improvement seen [inaudible] were actually quite remarkable in some patients, also correlated with patient assessed outcomes that were responses per NIH criteria with a 60% overall response rate or partial response.
Importantly, these responses appear to be sustained [inaudible] patients showing responses lasting more than the six months. We have additional studies still ongoing to also evaluate potential pharmacodynamic correlates of response, and to characterize the immune [inaudible] in these patients, but so far, we have not been able to detect any immunomodulatory effects upon treatment with glasdegib.
Overall, this proof of concept is indicative that glasdegib could have a role in treatment of these particularly hard to treat GvHD subtype. Tolerability is certainly an issue, however there was variability in the development of muscle cramps with patients that tolerated treatment fairly well. I think that alternative, not continuous dosing schedule, may have optimized tolerability at [inaudible]. In other studies, in the solid tumor space, we saw that hedgehog signaling inhibitors, but we don’t know if these alternative schedules may compromise efficacy. There are some other trial ongoing, led by Professor Stephanie Lee at Fred Hutch evaluating glasdegib in a similar patient population. It will be important to see what data emerge from that trial as we move forward.
