Tr1X’s Allogeneic Treg Therapy TRX103 Cleared for US Trial for Preventing GvHD

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In light of the IND clearance, Tr1X anticipates initiating a phase 1 clinical trial within the second quarter of this year.

Monzr M. Al Malki, MD, the lead investigator of the phase 1 study, an associate professor in the Department of Hematology & Hematopoietic Cell Transplantation, and the director of the Unrelated Donor, Haploidentical, and Cord Blood Transplant Programs at City of Hope National Medical Center

Monzr M. Al Malki, MD
Credit: City of Hope

Tr1X’s TRX103, an investigational allogeneic regulatory T-cell (allo-Treg) therapy, has received clearance of an investigational new drug (IND) application from the FDA for a clinical trial for the prevention of graft versus host disease (GvHD) in patients undergoing HLA-mismatched hematopoietic stem cell transplantation.1

In light of the IND clearance, Tr1X anticipates initiating a phase 1 clinical trial in the aforementioned indication within the second quarter of this year. The company ultimately intends to evaluate TRX103 in a range of autoimmune and inflammatory disease indications, however, with its next target being an IND application for a trial in refractory Crohn disease, which Tr1X expects to submit in 2024’s third quarter.

"The FDA's clearance of our IND for TRX103, the first ever allogeneic engineered Tr1 regulatory T-cell product, is an important milestone that could quickly provide us with proof-of-concept data while we continue to develop TRX103 for multiple autoimmune and inflammatory diseases, including Crohn disease," Maria Grazia Roncarolo, MD, the cofounder, president, and head of R&D at Tr1X, said in a statement.1 "Donor-derived autologous Tr1 cells have shown clinical promise in improving immune reconstitution and reducing GvHD but have limited potential due to lack of feasibility and high cost. TRX103, an off-the-shelf product with unique biological properties compared to other Treg and chimeric antigen receptor T-cell therapies, has the potential to reduce inflammation, suppress pathogenic cells, and reset the immune system. TRX103 is currently produced cost effectively at scale in a fully closed end-to-end system using a process that yields billions of cells in a single campaign. This should enable Tr1X to develop further pipeline candidates that address even larger patient populations with equally unmet medical needs."

TRX103 consists of CD4+ T-cells derived from healthy donors that have been engineered to replicate the functionality of Tr1 Tregs. According to Tr1X, the allo-Treg therapy is expected to have the potential to reset the immune system to a healthy state based on the results of preclinical research with disease models. It was also shown to be tolerable in the preclinical models, and is expected to avoid drawbacks—namely limited persistence, cytokine release syndrome, and neurotoxicity—seen in some other cell therapies being tested for autoimmune disease.

Key Takeaways

  • TR1X's TRX103, an engineered allogeneic regulatory T-cell therapy, has received FDA clearance for a clinical trial for prevention of graft versus host disease in patients undergoing HLA-mismatched stem cell transplant.
  • In light of the IND clearance, Tr1X anticipates initiating a phase 1 clinical trial in the aforementioned indication within the second quarter of this year.
  • Tr1X aims to later gain clearance for a phase 1 clinical trial for TRX103 in refractory Crohn disease, with an IND application submission planned for 2024’s third quarter.

"Allogeneic stem cell transplantation is the only curative treatment for many advanced blood cancers and genetic and acquired diseases,” Monzr M. Al Malki, MD, the lead investigator of the phase 1 study, an associate professor in the Department of Hematology & Hematopoietic Cell Transplantation, and the director of the Unrelated Donor, Haploidentical, and Cord Blood Transplant Programs at City of Hope National Medical Center, added to the statement.1 “However, there remains a burden of morbidity and mortality related to GvHD and its complications, including severe infections. As a result, innovative treatments are urgently needed. We look forward to starting this first-in-human trial to evaluate the safety, tolerability, and clinical activity of these allogeneic Tr1 Treg cells and their potential to benefit patients in this setting."

Tr1X is not the only company or institution seeking to apply Treg therapy to autoimmune or inflammatory diseases. At the 2024 Tandem Meetings |Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR, held in San Antonio, Texas, February 21-24, 2024, Joseph Pidala, MD, PhD, of the blood and marrow transplant department at Moffitt Cancer Center and an associate professor of oncology at University of South Florida, presented clinical data indicating minor histocompatibility antigen-specific donor Treg cells may have potential in preventing GvHD in patients receiving matched related donor allogeneic hematopoietic cell transplantation (HCT).2 GentiBio, on the other hand, is currently developing GNTI-122, an autologous engineered Treg product intended to treat type 1 diabetes.3 Furthermore, the lab of David Rawlings, MD, the director of the Center for Immunity and Immunotherapies at Seattle Children's Research Institute, has been conducting preclinical research on the development of antigen-specific engineered Tregs with the intention of eventually using them to treat autoimmune diseases.4

“Putting this all together: The concept of therapy with regulatory T-cells is that if you can target them to the autoimmune tissue of interest—for example, the islet in type 1 diabetes, where the autoimmune process is taking place—then you can have a tissue-specific therapeutic that that turns off an autoimmune process,” Rawlings told CGTLive® in a 2023 interview.

REFERENCES
1. Tr1X announces FDA clearance of first investigational new drug application for TRX103, an allogeneic regulatory t-cell therapy to treat autoimmune diseases. News release. Tr1X, Inc. April 10, 2024. Accessed April 15, 2024. https://www.prnewswire.com/news-releases/tr1x-announces-fda-clearance-of-first-investigational-new-drug-application-for-trx103-an-allogeneic-regulatory-t-cell-therapy-to-treat-autoimmune-diseases-302112587.html
2. Pidala J, Betts BC. Schell M, et al. Expanded Antigen-Specific Donor Regulatory T Cells for Gvhd Prevention. Presented at: 2024 Tandem Meetings, February 21-24, San Antonio, Texas. Abstract #32
3. GNTI-122, an autologous engineered Tregs product designed to treat type 1 diabetes. GentiBio. Website. Accessed April 15, 2024. https://www.gentibio.com/pipeline-programs/new-onset-t1d/
4. Seattle Children’s Researchers Share Progress at American Society of Gene and Cell Therapy Annual Meeting. Seattle Children’s Research Institute. Website. Accessed April 15, 2024. https://www.seattlechildrens.org/research/featured-research/asgct-2023/
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