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Investigating the Use of Fostamatinib in ITP

Insights From: James B. Bussel, MD, NewYork-Presbyterian/Weill Cornell Medical Center
Published: Thursday, Jan 25, 2018



Transcript: 

James B. Bussel, MD: In the current treatment landscape, people aren’t too worried about what you would do upfront when somebody’s diagnosed. But when it comes time to choosing a second treatment, there’s a lot of controversy. Nobody’s really exactly sure how to pick the next treatment. In the old days, people would automatically proceed to splenectomy once somebody didn’t respond to steroids any more. That might be within 3 to 6 months of diagnosis. However, people now think that patients might get better on their own, or with treatments. They would rather avoid splenectomy, especially since there’s some newer data suggesting an increased risk of stroke, for example, after you have one.

Rituximab was very exciting, but then we and others discovered that the later effects of rituximab, in adults, generally only led to a cure in perhaps 20% of patients. It might be a little higher if patients were treated immediately after diagnosis. So, this wasn’t as good as we had originally hoped it would have been: 40%, 50%. We have tried with other things, but those really didn’t work as well as we had hoped, except in women with disease of less than 1-year duration at the time they’re treated with rituximab.

The thrombopoietic (TPO) agents have been a big asset and had a big effect in idiopathic thrombocytopenia purpura. But unfortunately, not everybody responds. Some people have side effects. A really, consistently, good response is only going to be seen in 40% to 50% of patients, not 80% to 90% like most people think. And finally, there is no data that clarifies how long people, if they stay on them, will stay on them, and then be able to discontinue them.

A newer treatment that was presented at this meeting, which is exciting, is fostamatinib, which is an inhibitor of Syk. This is a novel mechanism of effect. Therefore, what’s very good about this, aside from how well it might work on its own, is that it could ideally be combined with other agents if necessary. It is likely to be a very productive combination partner because of this novel mechanism. People have already talked about the idea that it could be combined with a thrombopoietic agent or an immunosuppressive agent, and that it might be very useful.

The data that were presented involved the results of 2 parallel phase III studies that were identical. Each had 75 patients: 50 on active drug, 25 on placebo. In each case, the study was for 24 weeks. You needed to have a platelet count of less than 30,000 and have received at least 1 other therapy. The primary endpoint was a platelet count greater than 50,000 on 4 of 6 of the last 6 visits. Since they were biweekly, this would be weeks 14, 16, 18, 20, 22, and 24.

On the one hand, it was slightly disappointing that the response rate to active drug in the 2 studies was 18%. This was very statistically significant compared to placebo, which, in the combined studies, was 2%. However, this was confirmed by the fact that the patients who had been on placebo in these 2 studies and then went on active drug had a little bit higher response rate, around 22%, when they were getting fostamatinib rolling over to the open-label extension. It also confirmed the initial study, which was published in Blood in 2009. There was about a 25% sustained response rate. So, all of this was very consistent.

In addition, there were clinically meaningful responses in additional patients who had platelet counts that went over 50,000 and then did not have 2 consecutive counts of less than 30,000. These clinically relevant response rates, including the second category of responses and the stable responses that I already described, resulted in about a 43% clinically relevant response rate. This was very good. And again, this was seen in both studies. This was consistent with what had been seen in the previous study.

The side effects were a little bit of a problem. Twelve of the 115 patients had to discontinue the medication because of side effects. And while there was thrombosis, there was hypertension and gastrointestinal side effects including nausea, diarrhea, and elevated liver tests. This could be monitored and could be treated if, for example, it was diarrhea, with Imodium (loperamide).

Of the people who responded, the ones with the sustained response rates, the primary endpoint, there were 25 of those. Seventeen of them are still in remission, sustaining their stable response. And 82% had their response last more than a year. We still don’t know what the actual median response time will be because more than half of the patients, as indicated, are still responding. They’re out to 28 months, but it will be longer than that.

Overall this looks like a good agent. A couple of preliminary analyses that I’m very excited about show that patients possibly, a little earlier in their disease, do better with this than ones later in their disease. This is particularly relevant because the median time of the patients having had ITP prior to entering the study was over 8 years, which is unheard of for an ITP study. This indicates that the patients, in general, were more difficult and more chronic, by far, than the average in other studies.

The second set of data that’s interesting is that there were plasma platelet antibodies analyzed in a large subset of those on study, and the response rate was better in those who had positive antibody tests. That’s very good because it would contribute to allowing us to know who to treat, and who would do better. In terms of which patients responded, patients who had splenectomy, patients who had previous rituximab, patients who had platelet counts of less than 15,000, and almost half of the patients who had previously been treated with TPO agents responded. This showed that this novel mechanism of effect allowed response in people who had failed the wide variety of previous therapies.

So, these data were very, very good. The side effects were bothersome, but not overwhelming. Overall, fostamatinib could fit very well into the treatment paradigm. Although, at this time, it’s not clear when. Doing further studies in which fostamatinib could be used earlier in ITP might provide a higher response rate, more like those seen with other agents. In addition, in preliminary results for the treatment of autoimmune hemolytic anemia, it seems to work very well there also.

Rigel, the company that makes fostamatinib, has submitted their results to the FDA in the second half of 2017. The very exciting news is that the FDA declined to have an ODAC (Oncologic Drugs Advisory Committee) meeting, implying that they might well approve it and didn’t need advice from their advisory committee. Their PDUFA (Prescription Drug User Fee Act) date for hearing from the FDA is in April 2018, and they’re well on the way to having a discussion about the package insert, which also seems to be going very well.

Transcript Edited for Clarity 
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Transcript: 

James B. Bussel, MD: In the current treatment landscape, people aren’t too worried about what you would do upfront when somebody’s diagnosed. But when it comes time to choosing a second treatment, there’s a lot of controversy. Nobody’s really exactly sure how to pick the next treatment. In the old days, people would automatically proceed to splenectomy once somebody didn’t respond to steroids any more. That might be within 3 to 6 months of diagnosis. However, people now think that patients might get better on their own, or with treatments. They would rather avoid splenectomy, especially since there’s some newer data suggesting an increased risk of stroke, for example, after you have one.

Rituximab was very exciting, but then we and others discovered that the later effects of rituximab, in adults, generally only led to a cure in perhaps 20% of patients. It might be a little higher if patients were treated immediately after diagnosis. So, this wasn’t as good as we had originally hoped it would have been: 40%, 50%. We have tried with other things, but those really didn’t work as well as we had hoped, except in women with disease of less than 1-year duration at the time they’re treated with rituximab.

The thrombopoietic (TPO) agents have been a big asset and had a big effect in idiopathic thrombocytopenia purpura. But unfortunately, not everybody responds. Some people have side effects. A really, consistently, good response is only going to be seen in 40% to 50% of patients, not 80% to 90% like most people think. And finally, there is no data that clarifies how long people, if they stay on them, will stay on them, and then be able to discontinue them.

A newer treatment that was presented at this meeting, which is exciting, is fostamatinib, which is an inhibitor of Syk. This is a novel mechanism of effect. Therefore, what’s very good about this, aside from how well it might work on its own, is that it could ideally be combined with other agents if necessary. It is likely to be a very productive combination partner because of this novel mechanism. People have already talked about the idea that it could be combined with a thrombopoietic agent or an immunosuppressive agent, and that it might be very useful.

The data that were presented involved the results of 2 parallel phase III studies that were identical. Each had 75 patients: 50 on active drug, 25 on placebo. In each case, the study was for 24 weeks. You needed to have a platelet count of less than 30,000 and have received at least 1 other therapy. The primary endpoint was a platelet count greater than 50,000 on 4 of 6 of the last 6 visits. Since they were biweekly, this would be weeks 14, 16, 18, 20, 22, and 24.

On the one hand, it was slightly disappointing that the response rate to active drug in the 2 studies was 18%. This was very statistically significant compared to placebo, which, in the combined studies, was 2%. However, this was confirmed by the fact that the patients who had been on placebo in these 2 studies and then went on active drug had a little bit higher response rate, around 22%, when they were getting fostamatinib rolling over to the open-label extension. It also confirmed the initial study, which was published in Blood in 2009. There was about a 25% sustained response rate. So, all of this was very consistent.

In addition, there were clinically meaningful responses in additional patients who had platelet counts that went over 50,000 and then did not have 2 consecutive counts of less than 30,000. These clinically relevant response rates, including the second category of responses and the stable responses that I already described, resulted in about a 43% clinically relevant response rate. This was very good. And again, this was seen in both studies. This was consistent with what had been seen in the previous study.

The side effects were a little bit of a problem. Twelve of the 115 patients had to discontinue the medication because of side effects. And while there was thrombosis, there was hypertension and gastrointestinal side effects including nausea, diarrhea, and elevated liver tests. This could be monitored and could be treated if, for example, it was diarrhea, with Imodium (loperamide).

Of the people who responded, the ones with the sustained response rates, the primary endpoint, there were 25 of those. Seventeen of them are still in remission, sustaining their stable response. And 82% had their response last more than a year. We still don’t know what the actual median response time will be because more than half of the patients, as indicated, are still responding. They’re out to 28 months, but it will be longer than that.

Overall this looks like a good agent. A couple of preliminary analyses that I’m very excited about show that patients possibly, a little earlier in their disease, do better with this than ones later in their disease. This is particularly relevant because the median time of the patients having had ITP prior to entering the study was over 8 years, which is unheard of for an ITP study. This indicates that the patients, in general, were more difficult and more chronic, by far, than the average in other studies.

The second set of data that’s interesting is that there were plasma platelet antibodies analyzed in a large subset of those on study, and the response rate was better in those who had positive antibody tests. That’s very good because it would contribute to allowing us to know who to treat, and who would do better. In terms of which patients responded, patients who had splenectomy, patients who had previous rituximab, patients who had platelet counts of less than 15,000, and almost half of the patients who had previously been treated with TPO agents responded. This showed that this novel mechanism of effect allowed response in people who had failed the wide variety of previous therapies.

So, these data were very, very good. The side effects were bothersome, but not overwhelming. Overall, fostamatinib could fit very well into the treatment paradigm. Although, at this time, it’s not clear when. Doing further studies in which fostamatinib could be used earlier in ITP might provide a higher response rate, more like those seen with other agents. In addition, in preliminary results for the treatment of autoimmune hemolytic anemia, it seems to work very well there also.

Rigel, the company that makes fostamatinib, has submitted their results to the FDA in the second half of 2017. The very exciting news is that the FDA declined to have an ODAC (Oncologic Drugs Advisory Committee) meeting, implying that they might well approve it and didn’t need advice from their advisory committee. Their PDUFA (Prescription Drug User Fee Act) date for hearing from the FDA is in April 2018, and they’re well on the way to having a discussion about the package insert, which also seems to be going very well.

Transcript Edited for Clarity 
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