General Updates | The potential of mitapivat in thalassemia: results of the ENERGIZE and ENERGIZE-T trials

First of all, I have to say that mitapivat is one of the, let’s say, novel pharmacological approach to treat thalassemia. Also, the other one, luspatercept, has been discussed during ASCAT. Luspatercept is already approved for treating anemia in TDT and NTDT, that is NTDT approved in Europe but not yet by the FDA. Besides Luspatercept we have data provided by Phase three clinical trials for mitapivat. Mitapivat is a molecule which activates pyruvate kinase and it was originally developed to treat patients with PK deficiency, and that is reasonable because, you know, the PK enzyme is extremely important for the energy of the red cells because the pathway from PK reaches the production of ATP, which is the energy for red cells. So in deficient subjects, the deficiency of ATP production leads to hemolysis. The red cell undergo hemolysis.

Why mitapivat in thalassemia or for the future, even for sickle cell disease or even for other rare hemolytic anemia? Because although these conditions have a wild type PK, so the PK is normal, the gene is normal and the amount of PK produced is normal. But those conditions require more activity of the red cells because the demand of red cells is increased due to oxidative stress, due to the hyper activity of red cells in thalassemia and sickle and in other conditions. So the idea was, let’s try mitapivat even in this condition and see what happens. In reality, that was not only theory, but the phase two clinical trial, which was conducted in 20 subjects with TDT and NTDT, showed a reduction of blood consumption and an increase of hemoglobin in NTDT, and a reduction in TDT. So based on that, two clinical trials have been completed now, and the papers are submitted to the agency. 

One is ENERGIZE-T. T means for transfusion-dependent thalassemia. And the results that I presented last year at ASH and also at EHA some other markers have been presented, showed a significant reduction of blood transfusion. The primary end point was a reduction of 50% of blood transfusion compared to baseline over 12 weeks, during the 48 weeks of the core design of the study. And this primary end point was achieved, and I’m not going to mention the other three secondary end point, which were looking at the reduction of 50% of transfusion in every 24 weeks, or 33% in other frames of the study. So the end points were clearly achieved with statistical significance. The adverse events or side effects, were tolerable, manageable, very similar to those seen in PK deficiency. Mainly the patients complain at the beginning a bit of some insomnia, headache, gastrointestinal disturbances, but nothing really relevant.

ENERGIZE is a similar study, but in non-transfusion dependent thalassemia patients. And in this case, the primary endpoint was an increase of hemoglobin of at least one gram or one or more. Primary endpoints have been achieved statistically significant. And in this cohort of patients, there was another important aspect to evaluate, and that was the PRO – the patient reported outcomes. Because of course, we have to show that increasing 1 or 1.5 gram of hemoglobin goes with an improvement of the outcome. So couple of tests and tools have been used and some items of the tools have been achieved. And particularly what was improved other than that was the six minute walks, which was definitely higher compared to the placebo group. I didn’t say that both of the study were placebo controlled, so all the two had the placebo arms and after the core of the study, the placebo patients, the patients in placebo can switch off and move to the treatment.

There is another interesting point that I want to underline. To my knowledge, these are both the first studies, including patients with alpha-thalassemia. Now, there are clinical trials ongoing for alpha, even with luspatercept. But these are the first producing results in alpha thalassemia, and the results are quite convincing and quite good.

So hopefully, the drug should be registered, and I personally believe that this is a good alternative option to luspatercept just because patients respond differently to one drug to the other. So, that can be an opportunity for those who are not responding to luspatercept. The other, let’s say difference is that this is oral, luspatercept is given every three weeks subcutaneously. So there is room, space for using these compounds, and the expectations of patients are very, very high. And as far as I know, the agency are evaluating the data produced by the companies.

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