In beta thalassemia there is a lack of beta chain synthesis and as a result the patient can produce only red cells with beta-haemoglobin and they become very anaemic. So to survive they need transfusion and some patients are not transfusion dependent but because we have observed in the bone marrow what we call ineffective erythropoiesis, so patients produce a lot of red cells in the bone marrow but they die before being able to go out into the blood. So for these patients currently the only way to treat these patients is to transfuse them or to use iron chelators because we know that ineffective erythropoiesis results in iron absorption increase which leads to organ failure.
What can you tell us about your new molecular target?
We have seen that in the bone marrow of these patients this ineffective erythropoiesis, these red cells proliferate too much so when we are not able to make beta-haemoglobin. As a result you see this expansion of abnormal erythroid cells which prevent the production of erythroid cells in which you have the beta-haemoglobin. So these patients experience some extra hematopoietic hematopoiesis, extra-medullary hematopoiesis, and we found that this was due to the production of a new cytokine, the name is GDF-11. GDF-11 induces the expansion of erythroid cells, abnormal erythroid cells, because they do not die, it prevents apoptosis of these cells. If you do block GDF-11 you induce cell death of these abnormal erythroid cells and the normal ones can go to the blood and you increase haemoglobin levels.
What is the normal role of GDF-11?
GDF-11 was a cytokine of the TGF-beta member family. The role was not very well known until recently and in fact it plays a critical role in heart development, for example, or in muscle development. In hematopoiesis now we have shown that it prevents erythroid differentiation and physiologically its role is to prevent the differentiation of red cells to induce more red cells. But when it’s highly produced you block completely the erythroid differentiation and you cannot produce any more red cells.
What about the fusion protein you have been using as an inhibitor?
We use activin receptors fused to the Fc gamma of the IgG. This receptor is a trap receptor, It binds to TGF-beta member family. GDF-11 binds to the activin receptors and, in fact, at the beginning it was this receptor that was made to block metastases and bone lesions in patients with metastases. We found that these patients increased their haemoglobin, these patients with cancer, so we tried to understand the mechanism and we found it wasn’t activin but Gdf-11 which binds to this receptor.
What did the study entail?
First we did a mouse model to understand this precise mechanism of action. Now we present a phase I/II study to assess the efficacy of blocking GDF-11 and to assess the efficacy to reduce the transfusion burden and to increase the haemoglobin level. We found that in patients with thalassemia we could, in non-transfusion dependent patients, increase haemoglobin levels, reduce iron overload and in patients who are transfusion dependent we can reduce by 50% the transfusion burden and hopefully when we increase the dose of the drugs we may see some patients who were previously transfusion dependent will become transfusion independent.
How safe is sotatercept?
We didn’t see any severe adverse events. Only one patient stopped the trial because of bone pain which might be due to the activity of the bone marrow and the reduction of red cells, so the only measured side effect. In the long term run because it blocks the activin receptor we may see some endocrine disruption so we have to look in the long term run if blocking activin is associated with possibly, uh, disrupting this.
Could this be clinically applied to other conditions?
Yes, I think the application might be very large. Why? Because in some other examples, myelodysplastic syndrome which is a cancer of the bone marrow, we have ineffective erythropoiesis which might be due to a high level of GDF-11 production by erythroid cells. So we can improve anaemia in myelodysplastic syndrome. Second of all, in cancer in which you have a production of the cytokines the cells won’t die and if you block the cytokines you may induce killing of tumour cells.
To physicians who take care of patients with beta-thalassemia I think for the first time, we have therapy [that] offers hope to improve the status and increase overall survival of these patients. This is the main message and the second message is probably these findings may be applicable to other conditions in which you have ineffective erythropoiesis.
Which ones?
First myelodysplastic syndrome and we can expect to increase overall survival in these patients.
