Rare Disease Report

Principal Study Investigator Discusses Rigel's ITP Therapy Approval

APRIL 20, 2018
James Bussel, M.D.
James Bussel
James Bussel, M.D.
On Tuesday, Rigel Pharmaceuticals, Inc. announced that the U.S. Food and Drug Administration (FDA) approved fostamatinib disodium hexahydrate (Tavalisse) tablets for the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia.

James Bussel, M.D., professor emeritus of pediatrics at Weill Cornell Medicine and the principal study investigator on the FIT Phase 3 program, and has served as a consultant and paid member of the advisory board for Rigel Pharmaceuticals, Inc. Rare Disease Report sat down with Dr. Bussel to discuss the news.

RDR: What does Tuesday’s approval of fostamatinib mean for the ITP community?

Dr. Bussel: It’s definitely a promising therapy. I believe that it will be very good to have another treatment with a unique mechanism of action that can be taken orally without a specific diet. This is very important for the field. We will see how it impacts the disease space going forward.

RDR: Before the approval, what could an individual expect once diagnosed with ITP?

Dr. Bussel: I think the problem has always been that there is really no standard of care. If an adult was diagnosed with a reasonably typical case of ITP, and was going to be given treatment, it would very likely be steroids; that could be prednisone or it could be high doses of oral dexamethasone. Some people would also be given IVIG.

If the platelet count did not stay up after 1-3 months of steroids, the ideal would be to go on to another treatment, but there is absolutely no standard of care as to what that treatment is or should be. Many people, at least in the United States, would use a thrombopoetic agent, and many would try rituximab. Very few people at this time would go on to splenectomy without waiting for a while, e.g. perhaps 1 year.

The indication that the package insert (label) the FDA gave to fostamatinib was that patients would be eligible for it as one of these second-line treatments after failing steroids (or another treatment). When and how it would be used would be based on the individual judgement of the physician with input from the patients.

RDR: How far back was it that research for fostamatinib in the indication was initiated?

Dr. Bussel: Rigel started working clinically with fostamatinib in 2005, and I met with the medical director then, and we agreed to do a study in ITP. We did a small study because that was the time that the TPO agents were doing big studies, and I was heavily involved in those also. The study was very successful and we published results in Blood in 2009.

Rigel decided to sell clinical rights to the fostamatinib/tavalisse to AstraZeneca, who then explored it in rheumatoid arthritis. It worked very well, but not quite well enough to be licensed in this area. They amassed a huge safety database, emphasizing that fostamatinib/Tavalisse was safe and tolerable. When that finished, AstraZeneca gave the rights to fostamatinib back to Rigel.  

Rigel then re-explored the possibility of using the drug in ITP, and set up 2 randomized, placebo-controlled trials after a meeting with the FDA. Both trials were finished, and both trials showed very similar results. The primary endpoint was rather rigid requiring multiple good counts in a limited time frame, so the response was only in the order of 18% in each of the 2 trials. However, an ad hoc endpoint that was very practical because it essentially worked out to be most counts greater than 30,000 and many over 50,000 was successful in over 40% of cases.

Things that worked against the two fostamatinib/Tavalisse trials having a better outcome were: 1. Half the patients had been on a TPO agent prior to entering this trial (the first time this had happened in ITP studies), and were generally entering only because they had not done well with prior treatments including not only TPO agents but also rituximab and splenectomy; and 2.  the median duration of ITP of people entering both trials was over 8 years. This is a very long time of having ITP, also unprecedented in other ITP trials. There was a hint in the studies that people entering the study earlier, in terms of their ITP (prior to 1 year or prior to 3 years), would do better, but it was only a hint, not a strong signal.

The FDA recognized the efficacy of fostamatinib/Tavalisse (including the post hoc endpoint), and also recognized that the unique mechanism of action, blocking platelet destruction that was mediated by antibodies to platelets, was important. This latter point was suported by seeing responses in patients who had not responded to TPO agents.

RDR: What’s next, now that the drug has been approved?

Dr. Bussel: There is an ongoing open-label extension (OLE) study.  At the moment, there is no reason to believe, as there is no reason to believe for the thrombopoetic agents, that fostamatinib/Tavalisse is a primarily curative therapy. Rigel has been conducting this OLE study, and fostamatinib/Tavalisse has been very effective in that patients who have responded, including those who have the post hoc response, have been able to stay on Rigel with continuing responses, some of them for over two years. In general, 2/3rds to 3/4s of patients who went on this OLE study because they responded are still on ifostamatinib/Tavalisse and still responding.

This is a novel therapy with a unique mechanism of action, but we do not yet know where fostamatinib/Tavalisse will fit in because the patients who were treated were so far down the line in their ITP journey. I think Rigel will, hopefully, do a study enrolling patients with a shorter duration of ITP to further evaluate the mechanism of action and better determine the true response rate.

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