Dr. Amandeep Salrotra explains Tregzi, FDA-Approved Therapy

Leigh Clark: Welcome to Podcasts for Patients. My name is Leigh Clark, Senior Director of Patient Programs at the Aplastic Anemia Aplastic Anemia: (ay-PLASS-tik uh-NEE_mee-uh) A rare and serious condition in which the bone marrow fails to make enough blood cells - red blood cells, white blood cells, and platelets. The term aplastic is a Greek word meaning not to form. Anemia is a condition that happens when red blood cell count is low. Most… & MDS International Foundation. Before we get started with our podcast, I'd like to thank our diamond level sponsors, Alexion, Apellis, Gamida Cell, and Novartis, who, without their support, this podcast would not be possible. I have the pleasure today of speaking with Dr. Salhotra, who is a hematologist hematologist: (hee-muh-TOL-uh-jist) A doctor who specializes in treating blood diseases and disorders of blood producing organs. oncologist oncologist: (on-KAH-luh-jist) A doctor who specializes in the treatment and prevention of cancer. and a professor of medicine at City of Hope National Medical Center in California. He specializes in leukemia, stem cell transplants, and graft-versus-host disease. It's my pleasure to welcome Dr. Salhotra. Welcome, Dr. Salhotra.
Amandeep Salhotra: Good morning. Hello.
Leigh Clark: I'm excited to be able for us to talk about the recent approval. So what is Tregzi?
Amandeep Salhotra: Thank you for having me on this podcast. And Tregzi, it's an allogeneic regulatory T-cell-based immunotherapy and has both hematopoietic stem cells stem cells: Cells in the body that develop into other cells. There are two main sources of stem cells. Embryonic stem cells come from human embryos and are used in medical research. Adult stem cells in the body repair and maintain the organ or tissue in which they are found. Blood-forming (hemapoietic) stem… and T-cells, packaged as a single product. And it's for use in matched donor setting, for patients undergoing an allogeneic stem cell transplantation who are eligible for a myeloablative preparative regimen. In simple terms, what it means is like, traditionally how we do stem cell transplants is we go to the donor, we do a peripheral blood apheresis, which is true for 90% of adult patients. And those unmanipulated cells are infused into the recipients after either a myeloablative or a reduced intensity conditioning. We've done it this way for the last 40, 50 years. It's a highly effective technique.
The downside of using unmanipulated grafts and pharmacologic prophylaxis has been graft versus host disease. Traditionally with tacrolimus tacrolimus: Tacrolimus is in a class of medications called immunosuppressants. It works by decreasing the activity of the immune system. Tacrolimus can be prescribed to treat and prevent graft vs host disease (GVHD). It can also be used as part of combination therapy to treat aplastic anemia in place of… methotrexate or tacrolimus sirolimus sirolimus: A macrolide compound obtained from Streptomyces hygroscopicus that acts by selectively blocking the transcriptional activation of cytokines thereby inhibiting cytokine production. It is bioactive only when bound to IMMUNOPHILINS. Sirolimus is a potent immunosuppressant and possesses both antifungal… -based prophylaxis, the incidence of chronic graft versus host disease has been around 50 to 60%, and it does become a debilitating condition in that setting.
So what this product has done is basically before infusion of these apheresis, peripheral blood stem cells into the patient, there's a separation process where the apheresis graft is separated into CD34 positive stem cells and regulatory T-cells, which are infused on day zero. And around 48 hours later, the patient received conventional T-cells. Splitting this product into two separate infusions allows for a smoother transplant process, and the greatest gains have been in the incidence of reduction of graft versus host disease. And, we'll talk about the clinical trial clinical trial: A type of research study that tests how a drug, medical device, or treatment approach works in people. There are several types of clinical trials. Treatment trials test new treatment options. Diagnostic trials test new ways to diagnose a disease. Screening trials test the best way to detect a… data as well. But essentially, it's an ex vivo manipulated graft to reduce the incidence of chronic GVHD and to reduce the non-relapse mortality, which are kind of linked to a stem cell transplant procedure.
Leigh Clark: Thank you for mentioning the clinical trial and the data. Are there some things that you can tell us about the trial and what led to the approval?
Amandeep Salhotra: Yes. The clinical trial that led to approval of Tregzi was the Precision 3 trial, which is a randomized multicenter phase 3 study, and essentially approximately 190 patients who are enrolled on the study. And for patients to be eligible for enrollment, they should have been eligible for a myeloablative conditioning, either radiation-based or chemotherapy chemotherapy: (kee-moe-THER-uh-pee) The use of medicines that kill cells (cytotoxic agents). People with high-risk or intermediate-2 risk myelodysplastic syndrome (MDS) may be given chemotherapy to kill bone marrow cells that have an abnormal size, shape, or look. Chemotherapy hurts healthy cells along with… -based. They should've have a diagnosis of acute leukemia or MDS, and they should have been eligible donor. Eligible donor would be a fully matched sibling donor or a fully matched unrelated donor unrelated donor: A donor that is not a sibling or other familial relation of the patient (recipient). within the continental United States.
So once the patient met their criteria for allogenic transplant from a recipient and a donor standpoint, patients underwent randomization to the experimental arm where they received Orca-T graft, in a way that I just mentioned to you. So they received their standard myeloablative conditioning followed by instead of pharmacological prophylaxis, they received Orca-T and single agent prophylaxis with tacrolimus. And they compared it to our current standard of care treatment, which is myeloablative conditioning followed by tacrolimus and methotrexate-based conditioning, and GVHD prophylaxis. And methotrexate was at the standard 45 milligram per meter square.
So the primary outcome was the incidence of chronic GVHD free survival at one year. And there were multiple secondary endpoints, including overall survival, relapse-free survival, incidence of acute and chronic GVHD, and a non-relapsed mortality.
Leigh Clark: How does Tregzi change transplant for patients and their donors?
Amandeep Salhotra: That's a good question, Leigh. There are some workload differences which the patients and the transplant centers have to be mindful of, when undergoing a allergenic transplant with Tregzi. And the changes on the recipient side is that there are some limitations in terms of the donor availability. It has to be a fully matched sibling donor. And if it's an unrelated donor, it has to be within the continental United States. And that's just related to the manufacturing of the graft, which is done at the Orca Bio facility up in Sacramento. So that limits the international donors to some extent.
Now, we've been able to use donors in Mexico and Canada, so North American unrelated donors should still be okay. But most of the donors from Europe, currently, they cannot participate in this study.
In terms of the collection, most of the donors were able to collect the standard apheresis graft in a day or two, so it does not change a lot in terms of the collection of the stem cells on the on the donor end.
On the recipient side of things, things actually are pretty much, you know, similar to what we do for our standard of care patients. They receive their myeloablative conditioning; it could either be a radiation-based or a chemotherapy-based conditioning. But the bulk of the changes are on, at the side of the donor in terms of collection.
On the recipient side, of course, with the GVHD prophylaxis with the use of Orca-T, there is a split dosing, which is given. So on day zero, patients received their Orca-T graft, which comprises of stem cells and regulatory T cells. And of course, they have to be infused fresh. And around 24 to 48 hours later they can receive their cryo-preserved, bag of conventional T-cells. And then after they receive their conventional T-cells, then they get their single agent prophylaxis with tacrolimus.
If you allow me a moment, I'll just try to explain the strategy as to why the split dosing is done. So the CD34 cells, of course,  reconstitute their long-term hematopoiesis hematopoiesis: (hi-mat-uh-poy-EE-suss) The process of making blood cells in the bone marrow. , leads to eventual formation of all your blood cells and the immune components. But the regulatory T-cells which are infused on day zero, they undergo in vivo expansion. They inhibit the alloreactive conventional T-cells, which are infused a couple of days later. And the ratio of regulatory T-cells and conventional T-cells, it's skipped at 1 is to 1, which is slightly different than what happens in a unmanipulated graft, and this equalization of the regulatory and the conventional T cells, and this allows the graft to significantly reduce the incidence of chronic graft versus host disease.
In some of the prior studies where we've tried to use CD34 selected grafts, since they were not infused with the, with T-cells, the incidence of infections and non-relapse mortality was low. But infusion of the Tcons on day two prevents some of the infectious complications as, we'll talk a little bit about the readouts in the study data. So the strategy of splitting the doses of regulatory T-cells and conventional T-cells significantly reduces GVHD while preserving the graft-versus infection immunity.
The one-year overall survival in Orca-T was approximately 94% compared to 83% in the tact methotrexate arm. So although there was no significant difference, but patients who were on the Orca-T arm, they tended to have better overall survival compared to tac-methotrexate arm.
Looking at the incidence of moderate to severe chronic GVHD, the true incidence was approximately 44% in the standard of care arm versus 12.6% in the Orca-T arm. So the study met all its primary endpoints of better chronic GVHD survival, lower incidence of chronic GVHD, and non-significant improvement in overall survival.
So overall, the study met its primary endpoint of lower chronic GVHD-free survival without any increase in relapse rate, and the trend towards improvement in overall survival at the one-year mark. It'd be important to see how patients do at long-term follow-up at two and three years, and if we see a separation of curves with longer duration of follow-up.
Leigh Clark: What are the known side effects?
Amandeep Salhotra: A few pointers regarding the safety of this drug. So there were side effects, as we would anticipate in any transplant study. So the incidence of serious treatment emergent adverse events was approximately 40% in the Orca-T arm, and approximately 56% in the standard of care, which was tacrolimus and methotrexate. When we looked at the number of re-hospitalizations, patients admitted to the ICU, they were significantly lower in the Orca-T arm. Number of re-hospitalizations were also lower. When we look at the relapse-free survival, that was similar across both groups. Non-relapse mortality was significantly lower. And the incidence of grade three infections was, again, significantly lower in favor of the Orca-T arm compared to the standard of care arm.
In terms of safety, Leigh, I would say that the infusion was well tolerated. And when we talk about safety of an allogeneic product, we're looking at the incidence of infections, incidents of acute and chronic GVHD. And, at least on those measures, the Orca-T graft scored significantly better compared to the tacrolimus and methotrexate arms, then you worry about infusional reactions or, or manufacturing failures. All of the donors in which the product was collected, they were able to successfully manufacture the Orca-T graft. It was able to meet specifications in majority of the cases. There was no case of graft failure, primary graft failure in patients who received the graft. So the product was safe from an infection standpoint, from long relapse mortality, and from manufacturing standpoint.
Leigh Clark: And what else would you like patients to know about this new approval?
Amandeep Salhotra: Thank you for that question. So yeah, so the main take-home message is that it's a newer way to do stem cell transplants, and the infusion of this graft is definitely associated with lower incidence of chronic GVHD, low rates of infections, and potentially a trend towards improvement in overall survival. Patients need to be eligible for a myeloablative conditioning regimen. So they need to receive either a FTBI-based radiation-based or chemotherapy-based myeloablative regimen. And as long as they have an eligible donor, they would be eligible for this novel stem cell product, and it does a good job in terms of reducing chronic GVHD.
One of the things that I've heard from my colleagues is how does it compare to post-transplant cyclophosphamide cyclophosphamide: Cyclophosphamide is in a class of medications called alkylating agents. When used to treat cancer, it works by slowing or stopping the growth of cancer cells in your body. When cyclophosphamide is used to treat bone marrow failure, it works by suppressing your body's immune system. , which is up and coming and has shown a reduction in chronic GVHD. So those are two of the dominant platforms to reduce GVHD. I would say Orca-T, it's more established on the myeloablative side. And on the reduced intensity side, post-transplant cyclophosphamide is a good approach to reduce GVHD. So in the next few years, it'll be more clear as to which patient populations would benefit from post-transplant cyclophosphamide, which patients' populations would benefit from an Orca-T graft, but our patients now have the option of two very effective strategies to reduce incidents of GVHD.
Leigh Clark: Well, thank you so much, Dr. Salhotra, for spending your time and your expertise with us today, and letting all of us know about the new approval of Tregzi. If you're interested in finding out more information about stem cell transplant, please feel free to find information on our website, which is aamds.org, or you can give the foundation a call at 301-279-7202, and we're happy to answer all of your questions. Thank you for joining us.
Amandeep Salhotra: Thank you.