Novel Agents Sotatercept and Rigosertib Show Potential in MDS

Guillermo Garcia-Manero, MD

Several novel agents are being investigated for the treatment of myelodysplastic syndromes (MDS), including the activin receptor antagonist sotatercept (ACE-011) and small molecule inhibitor rigosertib (Estybon), which simultaneously inhibits PI3K and PLK signaling pathways. Both have shown promising results in clinical trials, but require further exploration before steps can be taken toward regulatory approval.

Findings from an ongoing phase II dose-finding study of sotatercept in patients with lower-risk MDS with anemia, as well as a phase III trial of rigosertib versus best supportive care in patients with higher-risk MDS after failure of hypomethylating agents, were recently presented at the 2015 International MDS Symposium.

OncLive spoke with the author of both studies, Guillermo Garcia-Manero, MD, professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, regarding the significance of sotatercept and rigosertib and their potential as therapies in MDS.

OncLive: What have been the findings regarding sotatercept for patients with lower-risk MDS with anemia to date?

Dr Garcia-Manero: Sotatercept is a modulator of the TGF beta-signaling pathway. Clinical models have shown that it can actually enhance red cell formation, both in someone with renal failure and someone with MDS. In our ongoing study, we found that sotatercept has minimal side effects. When the study was designed, there was some concern that this drug could cause issues with blood pressure; however, we have not seen anything like that. What we have seen is that there is a subset of the MDS population that has a very good response to sotatercept. The half-life of this compound is also long. This may be a very important new class of compounds to treat anemia for patients with MDS.

What are the next steps for this compound?

There are two similar compounds developed by Acceleron Pharma, a biopharmaceutical company developing protein therapeutics: sotatercept and ACE-536. First, it will have to be decided which drug to move forward with. Once we finish our study on sotatercept and determine if it is safe, which so far it seems to be, we will focus on starting the process of moving toward an approval.

It will be interesting to see what the phase III design of a clinical trial for sotatercept will be and what the endpoint will be for it. That is now under discussion. I think you will also see some investigation into what the true activity of this compound is. There has been almost no approach to this disease, in terms of going down a regulatory path.

What are the differences between sotatercept and ACE-536?

They are very similar and have been developed in parallel ways. When you look at the data, the results appear very similar. Therefore, Acceleron is going to have to look at the toxicities of each and the activity profiles of both compounds and make a decision about which to move forward with. I believe these drugs have potential outside of MDS as well.

You are also involved in a phase III study of rigosertib versus best supportive care in patients with higher-risk MDS. What is the significance of this study?

This is a very important study. In December 2014, we presented the first analysis of the phase III trial of high-risk MDS patients after failure of hypomethylating agents. This was the first and only phase III trial for this indication. The study did not meet its endpoint, as we did not have significant hazard ratio P value. However, when you look at the data, there were other positives. Patients treated with rigosertib had prolonged survival, even if it wasn’t incredibly significant compared to the control arm.

Most importantly, the study demonstrated that patients with primary refractory disease to hypomethylating agents had very different outcomes than those with secondary refractory disease in response to rigosertib. Patients with primary refractory disease had a significant improvement in survival. Unfortunately, we did not really define this in the clinical trial. The study was not stratified by primary versus secondary failure.

The question we have now is, “Why did the more difficult-to-treat patients do better with this compound when others did not?” We don’t really understand why that is the case yet. However, it is very clear from that data that the subset of patients benefited.

This data is now the basis for a subsequent phase III trial. We intend to have the first patient on this study on September 1, 2015. This trial will be redone to focus on primary refractory disease, and I believe this will be the first phase III trial in this indication. We really need to move this forward because this is a major need in the community. It may not be the cure, but there is a lot of potential.

What can you tell us about rigosertib as a therapy for MDS?

This is an interesting drug. This drug is a multikinase inhibitor. It is not specific to one kinase, and I think this is critical. There are multiple kinases that may be involved in this type of resistance. What we are attacking here is the deregulated kinase pathway. Part of this clinical trial is going to be looking at the genomics of the patients that are and are not responding to the drug.

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