ASCAT 2024 | The promise of pyruvate kinase activators, such as mitapivat, for treating SCD and thalassemia

So, mitapivat has been an exciting development in the sickle cell and thalassemia space. Of course, we all know that it has already been used in PK, pyruvate kinase deficiency, and it has been approved in some parts of the world in that disease for those with pyruvate kinase deficiencies due to missense mutations.

I think what is really interesting is how drugs can be repurposed for other things, which I think is something which is fascinating. We’ve seen that a lot during the COVID pandemic. And I think this is a very good example of understanding the pathophysiology and repurposing established drugs for other diseases.

So what, of course, sickle cell patients have full amount of pyruvate kinase in their red cells. However, giving an agent which will increase or boost their pyruvate kinase activity to the extent that there is more ATP being made, this reduced 2,3-DPG, which will allow more energy, it’s like almost infusing extra batteries into red cells. Having that extra red cell energy through the excess ATP molecules will allow the red cell to preserve its integrity of its membrane and also allow the affinity of the haemoglobin to oxygen to increase a little bit so that there is less hypoxia within the red cell and there is less sickling.

It is, you know, this mitapivat drug has then engendered a whole new generation of drugs in the same class, specifically designed for action in sickle cell and thalassemia, looking at the sort of red cell rheology, improving the red cell functioning by increasing the ATP. So we are excited. We feel that, you know, obviously current data supports a sort of long-term safety of this drug in the sickle cell context. although bearing in mind that there is some sort of stochastic offset of target action and sort of aromatase inhibition in mitapivat, which I believe the newer drugs are probably going to avoid that. So, that’s something which is going to, you know, something to look out for. But other than that, I think, you know, being able to have access to other drugs which is not hydroxyurea and perhaps even combination treatment with hydroxyurea and something else that allows better maintenance of the rheology of the red cells is something that we’re really looking forward to hearing more about and being able to use for our patients.