Novel Therapies for Non–Transfusion-Dependent and Transfusion-Dependent Thalassemia

At the 2022 Lymphoma, Leukemia & Myeloma Congress in New York, Sujit Sheth, MD, Weill Cornell Medicine, New York, NY, gave a presentation on the pathophysiology of thalassemia and outlines novel therapies addressing unmet needs in this treatment landscape, including therapies with curative intent and those without curative intent.

Transcript:

Hello, I'm Sujit Sheth. I'm a professor of pediatrics at Weill Cornell Medicine and director of the thalassemia program. I presented to the Leukemia, Lymphoma & Myeloma Congress 2022 an update on novel therapies for thalassemia. The focus of this talk was to bring everybody up to speed with the pathophysiology of thalassemia, and then what the unmet needs are that we can address with these novel therapies. Broadly, the novel therapies can be categorized as 2 separate groups. One is therapies with curative intent, and that includes the gene therapies. Then the other is therapies not with curative intent, but more to affect the underlying pathophysiology of the disease, ameliorate the complications, and improve the quality of life.

Let's talk about the second group of drugs first. Luspatercept, which is an active and receptor 2B antagonist, was approved by the FDA in 2019. This is an erythroid differentiation agent that allows the bone marrow to produce red cells more effectively, thereby improving anemia in patients with non-transfusion beta-thalassemia and reducing transfusion requirement in transfusion-dependent patients. This is now in full clinical use, and we went through the data that resulted in its approval, and a little bit about the current everyday use of luspatercept.

The other agents which are not with curative intent, include the pyruvate kinase activators. There are 2 of those, mitapivat and etavopivat. Again, the rationale there is improving pyruvate kinase activity in the developing precursors as well as the red blood cells, thereby improving the output of the bone matter, reducing ineffective erythropoiesis, as well as prolonging the life of the red blood cell in circulation.

Once again, the clinical trials are on in non-transfusion benefit patients to show an improvement in hemoglobin level. This was born out by phase 2 studies in both alpha and beta thalassemia patients. The other study is in transfusion-dependent patients with thalassemia, where again, increasing the output of the bone marrow will reduce the transfusion requirement as well. Those 2 are in clinical trials.

The other therapeutic approach has been to affect the hepcidin axis. As we know hepcidin is the mass regulator of hormone that regulates iron metabolism. In thalassemia patients, typically hepcidin levels are inappropriately low. If you can increase hepcidin levels, this would reduce the amount of iron being absorbed from the gut, as well as reduce the redistribution of iron from normal storage sites to organs where it can deposit and cause problems.

Further, the idea is that based on the animal model where using hepcidin mimetics or affecting hepcidin pathway to increase hepcidin levels resulted in an improvement in ineffective erythropoiesis and an increased output of red blood cells as well. That is the focus of these agents, and there are several of them. There is hepcidin mimetics, there's a tmprss6 inhibitor as well as a drug that is a ferroportin inhibitor, all of which would serve to increase hepcidin levels.

Those are about to enter clinical trials as well. Finally, we'll talk about therapies with curative intent and that includes the gene therapies.

We went through the different approaches, and we focused on 2 approaches. One is a gene addition approach using a lentiviral vector. This therapy, the vector is called BB305, produced by a company called Bluebird Bio. This was approved by the FDA in August of 2022 for use in transfusion-dependent thalassemia patients. The clinical trials showed that about 90% of patients who underwent this autologous transplant-like therapy became transfusion independent. And this transfusion independence was durable and we now have up to 5 years’ worth of follow-up data as well.

And finally, we talked about a gene editing approach. This approach uses CRISPR cas9 to knock down BCL11A, which is a repressor of gamma globin expression. If you can repress gamma globin expression, you make more gamma globin, you have something to bind to alpha globin to make fetal hemoglobin, and that raises your hemoglobin novels.

In the clinical trial for CTX001, which is what this therapy is called, 42 or 44 patients did become transfusion independent following this therapy. This is also administered the same way, following an autologous transplant with modified cells. Both of these transplant approaches require myeloablation and single agent busulfan is used for the myeloablation. And most of the adverse events related to gene therapy are related to the conditioning regimen and the transplant procedure itself.

Overall, I think it's fair to say that we have entered a new era of novel therapies for thalassemia that can address both the underlying pathophysiology as well as offer the promise of a cure for patients who don't have a match related donor to undergo an allogeneic stem cell transplant.

Source:

Sheth, S. Novel Therapies in Thalassemia. Presented at Lymphoma, Leukemia & Myeloma Congress; October 18-22, 2022. New York, NY.