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Sotatercept (ACE-011) Alone and with Ruxolitinib in Patients with MPN-associated Myelofibrosis (MF) and Anemia with Ruxolitinib or Hydroxyurea
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Prithviraj Bose, M.D. presents from ASH 2017 results of sotatercept (ACE-011) alone and with ruxolitinib in patients with MPN-associated myelofibrosis and anemia.

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Hi, this is Prithviraj Bose. I'm an associate professor at MD Anderson, and today I'm going to take you through my oral presentation at ASH 2017 on a phase II investigator initiated trial of Sotatercept or ACE-011, both alone and in combination with ruxolitinib in patients with MPN-associated myelofibrosis and anemia.

Anemia is a major unmet need in myelofibrosis, present in about a third of patients at diagnosis, and eventually developing in all patients. It is also a particular problem in patients on ruxolitinib, which is the only FDA, approved therapy for myelofibrosis and can actually impair dose optimization of ruxolitinib, and even lead to premature discontinuation. So, to find an effective adjunctive therapy that would counteract the anemia caused by, or worsened by, ruxolitinib is an important unmet need.

Sotatercept is a first in class activin receptor type IIA ligand trap. It is basically a fusion protein, as you see on the slide, consisting of the extracellular domain of activin receptor type IIA conjugated to the Fc fragment of human IgG1. What the drug does is that it binds to the ligands of the TGF-beta superfamily, which would otherwise have bound to the activin receptor type IIA. And, through the SMAD family of transcription factors, would have suppressed the terminal stages of erythropoiesis. So by trapping or sequestering these ligands, Sotatercept improves erythropoiesis and anemia.

In this phase II study, we enrolled patients with myelofibrosis who were consistently anemic, defined as hemoglobin less than 10, for a period of 12 weeks or more. There were two cohorts: one in which Sotatercept was used alone, and one in which Sotatercept was added in patients who had been on ruxolitinib for at least six months. These latter patients had to have had a stable dose of ruxolitinib for the preceding two months.

Response on the study had to last 12 weeks at a minimum. Also, in order to be evaluable for response, subjects had to be on the study for at least 12 weeks, or 84 days. There were two categories of response. In subjects who were not transfusion dependent, response could be an anemia response in which the patient had to have a 1.5 gram per deciliter rise in their hemoglobin from the baseline, which would then have to be sustained for at least 84 days. Of note, the baseline is the lowest hemoglobin value in the 84 days preceding the first injection of Sotatercept. The other category of patient, of course, was those who were transfusion dependent according to the IWG-MRT criteria, and in those patients, response was defined as the achievement of transfusion independence.

This slide shows you the baseline characteristics, which are really pretty typical of a myelofibrosis population. I will just point out that all patients here were DIPPS intermediate-2 or high risk, and all patients had MF-2 or MF-3 grades of bone marrow fibrosis. Most were previously treated.

In the monotherapy cohort, there were 24 patients, of whom 18 were evaluable. Like I mentioned, one had to have been on the study for at least 84 days in order to be evaluable for response. Of these 18 patients, seven responded, which is 39%. Of these seven, four had anemia responses and three became transfusion independent, having been transfusion dependent at baseline. Responses were seen at both the dose levels that we tested .75 and one milligram per kilogram. Additionally, there were two other subjects who were not evaluable because they did not receive sufficient number of cycles, or stay on the study for a sufficient length of time, who also had a 1.5 gram per deciliter hemoglobin increase.

The median number of cycles, median time on the study, and median time to the start of the response, remembers responses had to be sustained for at least 84 days, and the median duration of response are all listed on this slide. There are two subjects at this time who continue on the study, and there were actually multiple drug holds in three subjects because their hemoglobin went above 11.5. Per protocol, the shot had to be held until the hemoglobin came back down under 11.
Sotatercept was administered subcutaneously every three weeks. Of the patients that discontinued, which is a total of 22 patients, there were seven that discontinued for lack of response, five for progression of their myelofibrosis in other aspects such as spleen symptoms, et cetera, three that went to transplant, and miscellaneous other reasons.

Moving on to the combination cohort, this is the cohort with the ruxolitinib, patients had to be on ruxolitinib for at least six months with a stable dose over the previous two months. This is 11 patients, and, again, a very typical distribution of the baseline variables. I will just point out that the splenomegaly was actually not present in any of these patients at Sotatercept initiation, because they had already been on ruxolitinib and it had resolved. The median ruxolitinib dose here was 10 milligrams twice a day. Again, actually all the patients were intermediate-2 or high risk by the DIPPS, and the bone myelofibrosis grade in 10 out of the 11 patients was MF-2 or MF-3.

In this cohort, three out of 10 evaluable subjects responded. All these responses actually were anemia responses. This cohort we did not see responses in transfusion dependent subjects. In addition to these three patients, there is another patient who currently has only received three cycles, but who also has had a 1.5 gram per deciliter rise in their hemoglobin. Again, the median number of cycles, median time on study, time to response, and response durations, are listed on the slide.

Five subjects are continuing on the study. This includes the three responders, and it included this one other patient who I said appears to be responding but is not evaluable yet. Six patients have discontinued three for transplant and three for lack of response. In one of the responders here, too, we saw multiple treatment holds because of the hemoglobin being too high. That is, again, above 11.5.

So in conclusion, sotatercept is effective for anemia of MPN-associated myelofibrosis both when used alone and when used in conjunction with ruxolitinib, which, as we all know, is JAK1/2 inhibitor that actually suppresses hemoglobin levels initially before they slowly return to a new lower baseline. The total enrollment in this study is 60 subjects.

There is a related molecule called Luspatercept, which is actually quite promising in lower risk MDS. In fact, a pivotal trial has completed accrual in that population. This drug, also called ACE-536, will now be studied in myelofibrosis, in a multicenter phase II trial very similarly designed to our trial, and that trial has just opened to accrual.

Thank you.