TNX-1500 / Tonix, Massachusetts General Hospital - LARVOL DELTA

TONIX-1500: (TNX-1500) in Kidney Transplant Recipients (clinicaltrials.gov) - P2 | N=5 | Not yet recruiting | Sponsor: Ayman Al Jurdi, MD | Trial completion date: Jun 2029 ➔ Nov 2029 | Initiation date: Jul 2026 ➔ Nov 2026 | Trial primary completion date: Sep 2028 ➔ Sep 2029

Trial completion date • Trial initiation date • Trial primary completion date • Transplant Rejection • Transplantation

Phase 2 investigator-initiated study in adult kidney transplant at Massachusetts General Hospital (MGH) expected to initiate in the 2nd half of 2026 pending U.S. Food and Drug Administration (FDA) clearance of MGH’s Investigational New Drug (IND) application. (The Manila Times)

New P2 trial • Transplant Rejection

Tonix Pharmaceuticals Announces Publication of Phase 1 Clinical Data of TNX-1500, an Fc-Modified anti-CD40L (CD154) Monoclonal Antibody, in the Peer-Reviewed Journal of Clinical Immunology (The Manila Times) - "TNX-1500 was generally well tolerated, with no serious adverse events, and no discontinuations due to adverse events. The only treatment-emergent adverse event (TEAE) deemed possibly related to study drug was aphthous ulcer, which occurred in 1 participant in each of the three TNX-1500 groups; all TEAEs were rated as mild and resolved in 2-10 days. No TEAEs were determined to be related to KLH administration."

P1 data • Immunology • Transplant Rejection

First-in-Human, Phase 1, Randomized, Double-Blind, Placebo-Controlled Study of TNX-1500, an Fc-Modified anti-CD154 Monoclonal Antibody, Evaluating the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single-Ascending Doses in Healthy Adults. (PubMed, J Clin Immunol) - "TNX-1500 administration was associated with immediate and sustained reduction in soluble CD154. Overall, TNX-1500 demonstrated a safety profile and pharmacologic properties that support further development as an agent with potential for prevention of organ transplant rejection and treatment for autoimmune conditions."

Clinical • First-in-human • Journal • P1 data • PK/PD data • Cardiovascular • Hematological Disorders • Immunology • Thrombosis • Transplant Rejection • Transplantation • CD40LG • FCGR2A

A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of TNX-1500 in Healthy Subjects (clinicaltrials.gov) - P1 | N=26 | Completed | Sponsor: Tonix Pharmaceuticals, Inc.

New P1 trial

TONIX-1500: (TNX-1500) in Kidney Transplant Recipients (clinicaltrials.gov) - P2 | N=5 | Not yet recruiting | Sponsor: Ayman Al Jurdi, MD | Trial completion date: Dec 2028 ➔ Jun 2029 | Initiation date: Jan 2026 ➔ Jul 2026 | Trial primary completion date: Mar 2028 ➔ Sep 2028

Trial completion date • Trial initiation date • Trial primary completion date • Transplant Rejection • Transplantation

Tonix Pharmaceuticals teams up with MGH to advance Phase 2 trial of TNX-1500 (Proactiveinvestors) - "The study will assess TNX-1500, an anti-CD40 ligand monoclonal antibody, alongside a low-dose regimen of tacrolimus. The goal is to reduce or potentially eliminate the need for conventional immunosuppressive therapy."

New P2 trial • Immunology • Transplantation

Tonix Pharmaceuticals Presented an Update on Fc-modified anti-CD40L mAb, TNX-1500, at the 61st Annual Congress of the Japan Society for Transplantation (GlobeNewswire) - "'We are encouraged by the favorable safety and biomarker data from the Phase 1 study, which support the continued development of TNX-1500 as a novel immunomodulatory approach in transplantation and autoimmune diseases.'...The talk....outlined next steps toward Phase 2 development for the prevention of kidney transplant rejection and the treatment of autoimmune indications."

P1 data • Trial status • Immunology • Transplant Rejection

Proteinuria Remains a Significant Hurdle to Successful Pig Kidney Xenotransplantation Despite an Effective Immunosuppressive Regimen. (PubMed, Transplantation) - "Despite the efficacy of the immunosuppressive regimen, we suggest that proteinuria may lead to inadequate immunosuppressive therapy through loss of the therapeutic antibody, thus increasing the risk of rejection. Further research is needed to develop strategies to prevent this complication."

Journal • Focal Segmental Glomerulosclerosis • Glomerulonephritis • Nephrology • Renal Disease • Transplantation • CD40LG • IL6R

TONIX-1500: (TNX-1500) in Kidney Transplant Recipients (clinicaltrials.gov) - P2 | N=5 | Not yet recruiting | Sponsor: Ayman Al Jurdi, MD

New P2 trial • Transplant Rejection • Transplantation

Graft Survival and Rejection Risk with TNX-1500 as Monotherapy or in Combination with Conventional IS Agents in Nonhuman Primate Heart Transplants (WTC 2025) - "*Purpose: TNX-1500 (TNX) is a humanized IgG4 αCD154 mAb engineered to down-modulate FcγR2 binding to reduce the thromboembolism risk associated with ruplizumab (hu5c8 IgG1). Here in a NHP allo heart transplant model we report an expanded series of weekly dose TNX therapy (Rx), alone (monoRx) or in combination with mycophenolate mofetil (MMF), Rapamycin (Rapa), or Tacrolimus (Tac).* TNX was evaluated as mono Rx (30mg/kg 2x/wk x2, then 20mg/kg/wk; n=19) and combined with TNX+MMF (200 mg/d PO; n=4), TNX+Rapa (target trough 5-10 ng/ml; n=13), or TNX+Tac (target trough 3-5 ng/ml; n=7)... TNX-1500 demonstrated robust efficacy to prevent graft rejection during treatment in NHP, both as monoRx and in combination with conventional immunosuppressive agents. Notably, TNX+Rapa provided superior protection from CAV scores in the later post-Tx intervals. The absence of thromboembolic events predicts safety in clinical translation."

Combination therapy • Monotherapy • Anemia • Cardiovascular • Hematological Disorders • Transplant Rejection • Transplantation

Dual Blockade of CD154 and CD28 Co-Stimulation Pathways Mitigates Pathogenic Allo-Immunity and Enhances Survival in Cynomolgus Cardiac Transplantation (WTC 2025) - "*Purpose: TNX-1500 (TNX) is a novel humanized αCD154 mAb that contains the hu5c8 Fab region and an IgG4 Fc region engineered to modulate FcγR2 binding to reduce the risk of thromboembolic events seen with ruplizumab (hu5c8 IgG1) in previous clinical trials... The dual blockade of CD154 and CD28 co-stimulation pathways confers durable protection against pathogenic allo immunity in this stringent preclinical model, suggesting its potential for clinical translation."

Cardiovascular • Hematological Disorders • Hematological Malignancies • Lymphoma • Thrombosis • Transplantation • CD40LG • CTLA4

Is Proteinuria the Final Hurdle to Successful Pig Kidney Xenotransplantation? (WTC 2025) - "Group A baboons (n=3) received induction Rx with anti-thymocyte globulin, anti-CD20 mAb, and C1-esterase inhibitor, followed by maintenance Rx with 20mg/kg TNX-1500, rapamycin, +/- methylprednisolone, and +/- IL-6R blockade (tocilizumab). An optimized TNX-1500-based regimen prevented AMR and prolonged xenograft survival. However, proteinuria remains a critical challenge, causing urinary loss of therapeutic antibody, leading to inadequate immunosuppression and AMR. Overcoming proteinuria may be essential for achieving consistent long-term pig kidney graft survival."

Antibody-mediated Rejection • Cardiovascular • Chronic Kidney Disease • Focal Segmental Glomerulosclerosis • Glomerulonephritis • Hematological Disorders • Infectious Disease • Nephrology • Peptic Ulcer • Pneumonia • Renal Disease • Respiratory Diseases • Thrombosis • Transplantation • CD40LG • IL6R

Tonix Pharmaceuticals and Makana Therapeutics Announce Collaboration Combining Tonix’s Anti-CD40L Monoclonal Antibody (TNX-1500) with Makana’s Genetically Engineered Organs in Preclinical and Clinical Xenotransplantation Studies (GlobeNewswire) - "Tonix Pharmaceuticals Holding Corp...and Makana Therapeutics, Inc...today announced a collaborative research agreement under which Tonix and Makana will study Tonix’s anti-CD40L (CD40 ligand, also called CD154) monoclonal antibody candidate, TNX-1500, in combination with Makana’s human-compatible organs and cells for the treatment of organ failure. The preclinical research and development collaboration has the potential to span multiple Makana programs including kidney, heart and islet cell transplant. The goal of the preclinical studies is to support the submission of an investigational new drug application (IND) to the U.S. Food and Drug Administration (FDA) to support compassionate use for patients undergoing xenotransplantation."

Licensing / partnership • Preclinical • Transplant Rejection

Experience with a Novel Delayed Immune Tolerance Protocol in Nonhuman Primates Based on αCD154, αCD2 and αCD28 (ISHLT 2025) - "Induction treatment for donor bone marrow transplantation (BMT) was administered after a 4-month delay period under TNX-1500; BMT induction was comprised of one (Group 1) or two (Group 2) doses of total body irradiation, thymic irradiation, and horse anti-thymocyte globulin (ATG) followed by two (Group 1) or five (Group 2) weekly doses of αCD2 and five weekly treatments with αCD28 and TNX-1500.Results One graft rejected during the delay period; two others exhibited moderate rejection while five exhibited normal histology...In Group 2, two monkeys succumbed during the post-BMT treatment period to CMV, with one achieving high lymphocyte chimerism. Three Group 2 animals developed lymphocyte chimerism but developed lethal post-transplantation lymphoproliferative disease at end of the treatment period.Conclusion Although the combination of αCD2 with αCD28 promotes lymphocyte chimerism in this delayed BMT model, the high incidence of PTLD and opportunistic infection with CMV..."

Clinical • Bone Marrow Transplantation • Cytomegalovirus Infection • Infectious Disease

Tonix’s TNX-1500 Shows Promise in Preventing Organ Transplant Rejections of Either Human or Pig Organs; Autoimmune Diseases Also a Target (Tonix Pharma Press Release) - "Earlier animal studies indicated that TNX-1500 is active at preventing rejection of organ grafts and preserving graft function, either as a single agent or in combination with low doses of traditional immunosuppressants. TNX-1500 is active whether the organ comes from the same species or from genetically engineered pigs. So far, TNX-1500 treatment in these animal transplantation studies has shown a dramatic reduction in thrombotic events, indicating that the protein engineering of TNX-1500's Fc region achieved its design goals...Although the lead indication for Tonix's TNX-1500 product candidate is the prevention of rejection of transplanted human kidneys, Tonix is also pursuing development of TNX-1500 for preventing rejection of genetically engineered pig organs. Ultimately, Tonix also plans to develop TNX-1500 as a treatment for autoimmune diseases."

Preclinical • Immunology • Transplant Rejection

Costimulation blockade: the next generation. (PubMed, Curr Opin Organ Transplant) - "The focus in transplantation is shifting toward safer, long-term therapies with greater accessibility. Investigational agents with subcutaneous delivery methods could overcome logistical challenges, improve adherence, and redefine posttransplant care. These advancements in costimulation blockade may enhance long-term graft survival and transform the management of KT recipients."

Journal • Cardiovascular • Transplantation • CD40LG

Tonix Pharmaceuticals Announces Positive Topline Results from Phase 1 Trial for TNX-1500, a Next Generation anti-CD40L mAb Candidate for Prevention of Kidney Transplant Rejection and Treatment of Autoimmune Diseases (GlobeNewswire) - P1 | N=NA | "The only treatment-emergent adverse event (TEAE) occurring in ≥ 3 participants among all TNX-1500 groups was aphthous ulcer, occurring in one participant each in the 3 mg/kg, 10 mg/kg, and 30 mg/kg groups; all were rated as mild, possibly related, and resolved in 2-10 days. There were no TEAEs assessed as related to KLH administration. No TEAEs led to study discontinuation and there were no serious adverse events...TNX-1500 at 10 mg/kg and 30 mg/kg blocked both the primary and secondary anti-KLH Ab responses, evidenced by the mean Ab level at all sampled timepoints (through Day 120) being below the lower limit of quantitation (400 µg/L). TNX-1500 at 3 mg/kg blocked the primary response to KLH Day 2 challenge and reduced the peak secondary response to KLH Day 29 challenge by approximately two thirds (69%) relative to the peak response to placebo."

P1 data • Immunology • Transplant Rejection

Enhanced Costimulation Blockade With αCD154, αCD2, and αCD28 to Promote Heart Allograft Tolerance in Nonhuman Primates. (PubMed, Transplantation) - "Intensive costimulation pathway blockade with αCD2, αCD154, and αCD28 promotes lymphocyte chimerism at the cost of high incidence of posttransplantation lymphoproliferative disease and opportunistic infections, preventing assessment of the effectiveness of the regimen to promote alloimmune tolerance."

Journal • Bone Marrow Transplantation • Cytomegalovirus Infection • Infectious Disease • Transplantation • CD40LG

New Developments and Therapeutic Drug Monitoring Options in Costimulatory Blockade in Solid Organ Transplantation: A Systematic Critical Review. (PubMed, Ther Drug Monit) - "The routine use of costimulation blockade in SOT is hindered by problems in efficacy compared with the standard of care. Costimulatory inhibitors could be combined in a calcineurin inhibitor-free regimen. Future PK/pharmacodynamic studies in costimulatory agents and personalized medicine could warrant TDM of these agents."

Journal • Review • Hepatology • Solid Organ Transplantation • Transplantation • CD40LG • CD80 • TNFSF4

Experience with a Novel Delayed Immune Tolerance Protocol in Nonhuman Primates Based on aCD154, aCD2 and aCD28 (ACS-CLINCON 2024) - "Induction treatment for donor bone marrow transplantation (BMT) was administered after a 4-month delay period under TNX-1500; BMT induction was comprised of one (Group 1) or two (Group 2) doses of total body irradiation, thymic irradiation, and horse anti-thymocyte globulin (ATG) followed by two (Group 1) or five (Group 2) weekly doses of αCD2 and five weekly treatments with αCD28 and TNX-1500... Although the combination of αCD2 with αCD28 promotes lymphocyte chimerism in this delayed BMT model, the high incidence of PTLD and opportunistic infection with CMV reflects overly intense immunosuppression and prevented assessment of the regimen’s effectiveness to promote alloimmune tolerance."

Clinical • Bone Marrow Transplantation • Cytomegalovirus Infection • Infectious Disease • Transplantation

A retained native kidney (with ureter ligation) prevents dehydration and calcium/phosphate imbalance after life-supporting TKO pig-to-baboon kidney transplantation (TTS 2024) - "Maintenance therapy comprised anti-CD154mAb (TNX-1500), rapamycin, methylprednisolone, and IL-6R blockade with tocilizumab. (1) Retention of one native kidney compensates for the deficiencies in the renin-angiotensin-aldosterone system documented previously after TKO pig kidney Tx in baboons. (2) Prevention of dehydration mitigates the low serum phosphate and high serum calcium levels documented previously. (3) This study suggests that, in clinical pig kidney xenoTx, retention of the native human kidneys will compensate for any endocrine deficiencies of the pig kidney graft."

Transplantation • CD40LG • IL6R

Delayed Immune Tolerance for Cardiac Allografts in Nonhuman Primates by Targeting CD, CD, and CD Costimulation Pathways (TTS 2024) - "Here we test whether a protocol additionally targeting CD28 and CD2 is sufficient for cardiac allograft acceptance or promotes expansion of regulatory T-cells. Donor bone marrow transplantation (BMT) was administered to recipients of MHC-mismatched heterotopic heart allografts after a 4-month delay period under TNX-1500 (anti-CD154)... The combination of anti-CD28 with multi-dose anti-CD2 often promotes lymphocyte chimerism in this delayed BMT model at levels that predict prolonged graft survival or long-term acceptance in kidney recipients. However, the high incidence of PTLD and opportunistic infection prevented the assessment of the regimen’s effectiveness in promoting alloimmune tolerance. Strategies to improve CMV control and PTLD prophylaxis merit investigation in this model."

Bone Marrow Transplantation • Cardiovascular • Cytomegalovirus Infection • Infectious Disease • CD40LG

Tonix Pharmaceuticals Announces Two Oral Presentations and One Poster Presentation Involving TNX-1500 (Fc-modified humanized anti-CD40L mAb) at the American Transplant Congress 2024 (GlobeNewswire) - "Tonix Pharmaceuticals...today announced two oral presentations and a poster presentation at the American Transplant Congress 2024, being held June 1-5, 2024 at the Pennsylvania Convention Center, Philadelphia, Pa. Details on each presentation can be found below."

Clinical • Transplant Rejection

Combined Blockade of the CD154 and CD28 Co-Stimulation Pathways Attenuates Pathogenic Alloimmunity and Prolongs Survival in Cynomolgus Cardiac Allografts (ATC 2024) - "*Purpose: TNX-1500 (TNX) is a novel humanized αCD154 mAb that contains the hu5c8 Fab region and an IgG4 Fc region engineered to modulate FcγR2 binding to reduce the risk of thromboembolic events seen with ruplizumab (hu5c8 IgG1) in previous clinical trials... Combined blockade of the CD154 and CD28 co-stimulation pathways is associated with durable protection from pathogenic alloimmunity in this stringent model, suggesting a promising approach for clinical translation."

Cardiovascular • Hematological Disorders • Thrombosis • CD40LG