Maria Domenica Cappellini:

My name is Nica Cappellini. I’m a Professor of Internal Medicine at the University of Milan, and I’m very pleased to be here today with my colleague, Dr Kevin Kuo from the University of Toronto. Actually, we are both in the field of hemoglobinopathies and we have some exciting new data during this ASH meeting. Kevin, do you want to say something on the novel treatments which have been presented here at the ASH?

Kevin Kuo:

Absolutely. As you know, those sessions are not here yet, but they’ll be here on Monday. There is the gene therapy session, which will be here, more about both CRISPR therapy, CRISPR-Cas9, as well as CRISPR-Cas12a, as well as the long-term study of Bluebird Bio’s bb1111 or the lovo-cel therapy. Those are all very exciting. We see that there is already improvement in quality of life in the long-term treatment up to 6 years, as well as there is also transfusion independence in patients who received the CRISPR-Cas9 therapy. And there’s some preliminary exciting data as well from the CRISPR-Cas12a, which is from Editas.

Maria Domenica Cappellini:

For CRISPR-Cas9, the news which really is exciting was the approval by FDA two days ago for sickle cell disease, and most probably it’ll be also becoming approved for thalassemia. Beside these, let’s say, molecular approaches, which is a cure of the disease, have you been excited by some results of the pharmacological treatment of ineffective erythropoiesis or red cell metabolism? Can you say something to that?

Kevin Kuo:

Yes, absolutely. Nica, you and I well-know that there are limitations with gene therapy, particularly with the use of myeloablation. We can get to that later, but let’s start with the pharmacologic therapy. There is luspatercept. There is now long-term data on the improvement in quality outcome with the BEYOND study. So in that, all of the patients that were on luspatercept, we see that there was a continual sustained improvement in the patient-reported outcomes.

Maria Domenica Cappellini:

And this is a drug already approved either by FDA and EMA, and the, let’s say, approval was for treating anemia in transfusion-dependent or non-transfusion-dependent thalassemia. Nowadays, as you said, we have long-term data, which not only presents a sustained response, but also we start to see an improvement of quality of life. What about PK activator? You are the lead of these studies.

Kevin Kuo:

Well, it’s very exciting to say that we continue on both the ENERGIZE as well as the ENERGIZE study for mitapivat and for the FT-4202, etavopivat. The GLADIOLUS study is also ongoing. We currently do not have data results yet for those two, but I’m eagerly awaiting for future results next year.

Maria Domenica Cappellini:

That’s also, although the mechanism of action is different than luspatercept, but definitely the results of the Phase II were very exciting. We have nowadays a new scenario of treatment of thalassemia as well as sickle cell disease, and in the coming years, for sure, we will have, let’s say, several different approaches to be adapted to patients. So we are moving to precise medicine and the challenge nowadays from my point of view, is to be able to define specific profiles of patients, identifying some biomarkers, which allow to identify those who are more susceptible to be treated in one way or the other. And this is very challenging, but definitely very exciting.

Kevin Kuo:

Nica, as you know, many of our patients still suffer from many complications from thalassemia. Unfortunately, there is no good way of reversing that. Even if, say, they do engage in gene therapy or some other disease-modifying agents. Do we have any news on how to manage them?

Maria Domenica Cappellini:

Yeah, the survival curves now are completely changed compared to the past. We have thalassemia patients over 50, even over 60, and definitely we are starting to see complications or morbidities, which were not common in the past. I look around, there are not many data presented at the ASH, but a few things are underlined.

One is, for example, the increased prevalence of arrhythmia in adult patients, which is not really related to the iron overload because most of these patients are well-chelated. But probably considering that atrial fibrillation is common in a general population, but here is even more common compared by age and it appears earlier. Why is this happening? Is it just because the myocardial tissue is fibrotic? We don’t know, but we have to look at that.

Another morbidity, of course, which is now occurring are tumors, cancer. That’s true particularly for liver cancer, and that can be explained by iron overload, hepatitis C infection, but definitely is more prevalent in adult patients and it is also difficult to treat. And so, we are trying to look now to all these clinical morbidities, which we’re not used to seeing before. So I would like to say that we have to look further and write the history of the adult thalassemia patients in order to see how to treat them or how to prevent them.

Kevin Kuo:

But I think what you just said also highlights the fact that these patients, as they get older, will need some form of treatment.

Maria Domenica Cappellini:

Of course.

Kevin Kuo:

And gene therapy, being so restrictive in terms of inclusion for age, probably is not the right choice. So disease-modifying therapies like luspatercept, for example, or even other compounds, kinase activators would probably be helpful.

Maria Domenica Cappellini:

I definitely think that we should look carefully at the different populations, the different options, and as you said, it’s not our duty, but the cost of gene therapy, genomic editing will definitely limit the application. So selecting the proper patient has a cost benefit, which has to be considered.

Kevin Kuo:

I think it goes beyond cost, right? Because it’s about the resources.

Maria Domenica Cappellini:

Of course.

Kevin Kuo:

It’s not just about the cost of the gene therapy, but it’s also the need for inpatient beds, nursing, the doctors, apheresis, imaging.

Maria Domenica Cappellini:

Exactly. So it is nice to have the possibility to use also, maybe before gene therapy, pharmacological approaches and see how they behave and how those are. So definitely, the coming years will be, for the young physician treating thalassemia, a very fascinating and challenging time. For the patient, of course, they’re starting to see what they were looking for since many years.

Kevin Kuo:

Having choices empowers both the clinicians as well as the patients.

Maria Domenica Cappellini:

The patients, definitely.

Kevin Kuo:

Yeah. Last but not least, I want to bring back the idea of precision therapy.

Kevin Kuo:

You talked about the precision medicine, and I saw something very fascinating today at a gene therapy session. We are currently challenged by the fact that we still need to do full myeloablation for gene therapy. What I did see today though was very fascinating. There was an oral abstract on the use of anti-CD117 ADC in monkeys to deplete the CD34-positive stem cells. I think that is one way of doing myeloablation without the toxicity of chemotherapy. And in that study they showed that the rhesus monkeys were able to reproduce. There was another one where in using both a truncated EPO editing by truncating EPO receptor and also the addition of alpha globin that they were able to rescue the stem cells of the CD34-positive stem cells of alpha thalassemia.

Maria Domenica Cappellini:

Fantastic.

Kevin Kuo:

As we all know, alpha thalassemia major is a huge area of unmet need. I mean, there’s very few of them, but they’re very hard to treat.

Maria Domenica Cappellini:

Those are very… Yeah.

Kevin Kuo:

Yeah. Yes.

Maria Domenica Cappellini:

So that will be a step forward because the myeloablation with busulfan is still a concern because we know the impact of busulfan, and patients sometimes, although they’re keen to have the treatment, when they realize the risk, they step down.

Kevin Kuo:

Exactly.

Maria Domenica Cappellini:

So having another possibility for doing that will be another step forward.