FCR001 / Novartis - LARVOL DELTA

Single Center Phase 2 and 3 Experience with Tolerance Induction in Living Donor Renal Transplant Recipients (WTC 2025) - "Pts received nonmyeloablative conditioning consisting of fludarabine (30mg/m2/dose, days -5,-4,-3), cyclophosphamide (50mg/kg/dose, day-3 and+3), 200 cGy TBI (day-1) followed by KTx (day0). Tolerance can be safely and reproducibly established using the FCR001 approach. There are significant long term medical benefits to establishing tolerance. Minimization of GVHD risk may require attention to degree of D/R HLA mismatch, and optimization of both the conditioning regimen and graft engineering."

Clinical • P2 data • Acute Graft versus Host Disease • Cardiovascular • Dyslipidemia • Graft versus Host Disease • Hypertension • Immunology • Infectious Disease • Pneumococcal Infections • Septic Shock • Transplantation

Single Center Experience with the FREEDOM 1 Trial (NCT03995901), a Randomized Controlled Study to Evaluate the Safety, Efficacy, and Overall Benefit of FCR001 Cell Therapy in De Novo Living Donor Renal Transplantation (ATC 2024) - P3 | "A greater than expected incidence of severe GVHD in FR-1 led to 1)elimination of plerixafor use for mobilization, and 2) addition to conditioning of a second post-Tx dose of cyclophosphamide in 2022.* As of 1/2023 30 D/R pairs were consented into FR-1. Tolerance can be established using the FCR001 approach in LDKTx. Enhanced (100%) durable HSC engraftment in FR-1 was associated with increased GVHD risk. Minimization of GVHD risk may require attention to degree of D/R HLA mismatch, and further optimization of the conditioning regimen and graft engineering deployed."

Clinical • Acute Graft versus Host Disease • Graft versus Host Disease • Immunology • Nephrology • Transplant Rejection • Transplantation • CD34

Fifteen Year Follow-Up of a Phase 2 Clinical Trial to Induce Tolerance in Living Donor Renal Transplant Recipients (ATC 2024) - "Recipients were conditioned with fludarabine (30mg/m2/dose, days -5,-4,-3), cyclophosphamide (50mg/kg/dose, day-3 and+3), 200 cGy TBI (day-1) followed by KTx (day0). High levels of durable chimerism and tolerance has been achieved in mismatched recipients of KTx. There are significant long term medical benefits to establishing tolerance in KTx recipients using the FCR001 approach."

Clinical • P2 data • Acute Graft versus Host Disease • Bone Marrow Transplantation • Cardiovascular • Dyslipidemia • Graft versus Host Disease • Hematological Disorders • Hypertension • Immunology • Infectious Disease • Transplantation • CD8

FREEDOM-3: A Safety and Efficacy Study of FCR001 in Adults With Rapidly Progressive Diffuse Cutaneous Systemic Sclerosis (clinicaltrials.gov) - P1/2 | N=0 | Withdrawn | Sponsor: Talaris Therapeutics Inc. | N=18 ➔ 0 | Active, not recruiting ➔ Withdrawn

Enrollment change • Trial withdrawal • Fibrosis • Immunology • Scleroderma • Systemic Sclerosis

Immune tolerance via FCR001 cell therapy compared with maintenance immunosuppression for kidney transplantation: Real-world evidence analysis of safety and efficacy. (PubMed, Clin Transplant) - "At 5 years, FCR001 recipients experienced fewer complications including new-onset diabetes post-transplant, although two patients developed graft versus host disease. In conclusion, RWE demonstrated that KTx combined with non-myeloablative conditioning and FCR001 resulting in superior kidney function without increasing the risk of rejection, graft loss, or death among patients off immunosuppression."

HEOR • Journal • Real-world • Real-world evidence • Diabetes • Graft versus Host Disease • Immunology • Metabolic Disorders • Transplant Rejection • Transplantation

Evaluation of Immunocompetence and Biomarkers of Tolerance in Chimeric and Immunosuppression-free Kidney Allograft Recipients. (PubMed, Transplantation) - "These results suggest that elimination of IS has distinct advantages in living-donor kidney allograft recipients."

Biomarker • IO biomarker • Journal • Bone Marrow Transplantation • Cardiovascular • Dyslipidemia • Hypertension • Nephrology • Transplantation • CD8 • CTLA4 • GZMB

FREEDOM-3: A Safety and Efficacy Study of FCR001 in Adults With Rapidly Progressive Diffuse Cutaneous Systemic Sclerosis (clinicaltrials.gov) - P1/2 | N=18 | Active, not recruiting | Sponsor: Talaris Therapeutics Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Fibrosis • Immunology • Scleroderma • Systemic Sclerosis

TALARIS THERAPEUTICS, INC. Management's Discussion and Analysis of Financial Condition and Results of Operations. (form 10-K) (Market Screener) - "Since our inception, we have devoted substantially all of our resources to developing our lead product candidate, FCR001, building our intellectual property portfolio, business planning, raising capital and providing general and administrative support for these operations. To date, we have principally financed our operations through private placements of convertible preferred stock, payments under a former research collaboration with Novartis, Inc., research grants and most recently, our IPO. Through December 31, 2022, we had received net proceeds of $186.2 million from sales of our convertible preferred stock and net proceeds of $137.2 million, after deducting underwriting discounts and commissions and other expenses, from our IPO."

Commercial • Immunology • Systemic Sclerosis

A Single-Arm, Multicenter, Open-Label, Proof-of-Concept Safety and Efficacy Study of FCR001 Cell-Based Therapy in Adults with Early Rapidly Progressive Diffuse Cutaneous Systemic Sclerosis at Risk for Organ Failure (FREEDOM-3) (TCT-ASTCT-CIBMTR 2023) - P1/2 | "The study will utilize the American College of Rheumatology Composite Response Index in Systemic Sclerosis and modified Rodnan skin scores as efficacy measures. The data from the FREEDOM-3 trial may support the applicability of FCR001 to treat other systemic autoimmune diseases."

Clinical • Bone Marrow Transplantation • Fibrosis • Graft versus Host Disease • Immunology • Rheumatology • Scleroderma • Systemic Sclerosis • Transplant Rejection • Transplantation

A Single-Arm, Multicenter, Exploratory, Safety and Efficacy Study of FCR001 Cell-Based Therapy to Induce Donor-Specific Tolerance in Previously Transplanted Recipients of a Kidney from a Living Donor, and Safety in FCR001 Donors (FREEDOM-2 study) (TCT-ASTCT-CIBMTR 2023) - P2 | "The trial is currently enrolling patients. Positive proof of the delayed induction of tolerance concept from the FREEDOM-2 trial may open the door to broader clinical application of the Facilitated Allo-HSCT Therapy to recipients of a kidney from a deceased donor."

Clinical • Bone Marrow Transplantation • Solid Organ Transplantation • Transplant Rejection • Transplantation

A Randomized, Controlled, Multicenter, Safety and Efficacy Study of FCR001 Cell-Based Therapy Relative to a Tacrolimus- and Mycophenolate-Based Regimen in De Novo Living-Donor Kidney Transplant Recipients, and Safety in FCR001 Donors (FREEDOM-1 study) (TCT-ASTCT-CIBMTR 2023) - P3 | "The trial is currently enrolling patients, with plans to enroll 120 donor/recipient pairs. Data from the FREEDOM-1 trial may support the use of FCR001 to eliminate the need for chronic IS in LDKT recipients."

Clinical • Bone Marrow Transplantation • Graft versus Host Disease • Immunology • Infectious Disease • Oncology • Transplant Rejection • Transplantation

Hematopoietic Stem Cell Transplantation with FCR001 Can Induce Durable Red Blood Cell Chimerism in a Majority of Recipients: Results of a Phase II Trial (ASH 2022) - "We previously demonstrated durable WBC and T cell donor chimerism in 26 of 37 living donor kidney recipients treated in a Phase 2 study utilizing non-myeloablative conditioning with Fludarabine (30 mg/kg) for 3 days, a single dose of Cyclophosphamide (50 mg/kg), and a single fraction of TBI (200 cGy) prior to infusion with FCR001 the day following a living donor kidney transplant from the same donor (median follow up 7.8 years, range 4-12). An ongoing, randomized Phase 3 trial (FREEDOM-1) has been initiated in the living donor kidney transplant population, and a Phase 2 trial (FREEDOM-3) has been initiated with FCR001, to explore its potential as a treatment for scleroderma. These studies will enable further analysis of the FCR001 stem cell product to achieve multi-lineage chimerism in additional patients, allowing further exploration of potential new indications in other acquired and genetic disease states amenable to stem cell transplantation."

P2 data • Bone Marrow Transplantation • Chronic Graft versus Host Disease • Fibrosis • Genetic Disorders • Graft versus Host Disease • Hematological Disorders • Immunology • Scleroderma • Sickle Cell Disease • Systemic Sclerosis • Transplant Rejection • Transplantation • CD34 • CD8 • CSF3

FREEDOM-1: A Safety and Efficacy Study of FCR001 vs Standard of Care in de Novo Living Donor Kidney Transplantation (clinicaltrials.gov) - P3 | N=15 | Terminated | Sponsor: Talaris Therapeutics Inc. | N=240 ➔ 15 | Trial completion date: Apr 2025 ➔ Feb 2023 | Recruiting ➔ Terminated; Talaris decided to discontinue living donor kidney transplant development program

Enrollment change • Trial completion date • Trial termination • Transplantation

A Safety and Efficacy Study of FCR001 Cell Therapy in Previously Transplanted Living Donor Kidney Recipients (clinicaltrials.gov) - P2 | N=0 | Withdrawn | Sponsor: Talaris Therapeutics Inc. | N=15 ➔ 0 | Trial completion date: Feb 2029 ➔ Feb 2023 | Recruiting ➔ Withdrawn | Trial primary completion date: Dec 2028 ➔ Feb 2023

Enrollment change • Trial completion date • Trial primary completion date • Trial withdrawal • Transplantation

Talaris Therapeutics Announces Plans to Explore Strategic Alternatives and Implements Restructuring Plan (GlobeNewswire) - "Talaris Therapeutics, Inc...today announced that it has completed a review of its business and program prospects. Based on this review, Talaris has decided to discontinue its FREEDOM-1 and FREEDOM-2 clinical trials evaluating FCR001’s ability to induce durable tolerance in living donor kidney transplant recipients. This decision was primarily attributable to the pace of enrollment and the associated timeline to critical milestones. The company will continue to enroll its FREEDOM-3 Phase 2 clinical trial evaluating FCR001’s ability to induce tolerance in scleroderma...'It was an exceptionally difficult decision to discontinue further development of FCR001 in kidney transplantation tolerance despite the promising early data....As of December 31, 2022, the Company’s cash, cash equivalents and short- and long-term marketable securities were approximately $181.3 million."

Commercial • Discontinued • Enrollment status • Trial termination • Immunology • Scleroderma • Systemic Sclerosis • Transplant Rejection • Transplantation

Ch. 2: FCR001: An Investigational Cell Therapy to Induce Immune Tolerance (YouTube) - https://www.youtube.com/watch?v=u4OjftPEr78

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Ch. 5: FREEDOM-1 Phase 3 Trial With FCR001, Designed to Induce Immune Tolerance in LDKT Recipients (YouTube) - "FREEDOM-1 Phase 3 Trial With FCR001, an Investigational Cell Therapy Designed to Induce Immune Tolerance in Living Donor Kidney Transplant Recipients."

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Ch. 6: FREEDOM-2 Phase 2 Trial with FCR001, Designed to Induce Immune Tolerance in LDKT Recipients (YouTube) - "FREEDOM-2 Phase 2 Trial With FCR001, an Investigational Cell Therapy Designed to Induce Immune Tolerance in Living Donor Kidney Transplant Recipients."

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Ch. 4: Phase 2 Data with FCR001, Designed to Induce Immune Tolerance in LDKT Recipients (YouTube) - https://www.youtube.com/watch?v=6l5QNjwtZRQ

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Exploring the Potential Role of FCR001 (YouTube) - https://www.youtube.com/watch?v=iOmddSyqIoU

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Ch. 3: Protocol for Living Donor Kidney Transplant with FCR001, Designed to Induce Immune Tolerance (YouTube) - https://www.youtube.com/watch?v=tE_H9JVAiXg

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Talaris Therapeutics Announces Third Quarter Financial Results and Corporate Update (GlobeNewswire) - "Three clinical trials continue enrollment...FREEDOM-3, a Phase 2 clinical trial evaluating the safety and efficacy of FCR001 in adults with a severe form of scleroderma, a systemic autoimmune disease."

Enrollment status • Immunology • Scleroderma • Systemic Sclerosis

Immune Cell Transcriptome in Living-Donor Kidney Transplant Patients Tolerized With Allogeneic Hematopoietic Stem Cell Transplantation Therapy (KIDNEY WEEK 2022) - "FREEDOM-1 is a randomized, controlled, open-label Phase 3 study of FCR001 in adult LDKT patients...Conclusion This study represents the first longitudinal evaluation of PBMCs from LDKT patients underlying mechanisms of tolerance at single cell resolution. Unique patterns of immune cell types, cell states, and transcriptional activity were identified with NK cell subclusters playing a critical role."

Clinical • Bone Marrow Transplantation • Transplantation • CD14 • PD-L1

A Regimen of Nonmyeloablative Conditioning and CD8+/TCR- Facilitating Cells Tips the Balance Towards Immune Downregulation and Away From Cytopathic Activity in Kidney Allograft Recipients (KIDNEY WEEK 2022) - "Background We tested the hypothesis that tolerance induced with a regimen of nonmyeloablative conditioning and CD8+/TCR- facilitating cells (FCR001) is associated with immune down regulation and away from cytopathic activity...Conclusion Tolerance induced with a nonmyeloablative conditioning regimen and CD8+/TCR- facilitating cells is characterized by tipping of the balance towards immune down regulation and away from cytopathic activity. Table 1"

Solid Organ Transplantation • Transplantation • CD8 • CTLA4 • GZMB

Talaris Therapeutics Provides Update on FREEDOM-1 Phase 3 Clinical Trial (GlobeNewswire) - "Talaris Therapeutics...today announced a status update on its Phase 3 FREEDOM-1 study in living donor kidney transplant (LDKT) recipients. On October 18, 2022, the Company received a report of a patient death, which triggered a pre-specified, temporary stopping requirement and review by the FREEDOM-1 Data Monitoring Committee (DMC). After their review of this case, the DMC determined that trial enrollment and dosing may continue. The Company has reported this event and the DMC’s recommendation to the U.S. Food and Drug Administration (FDA)....The Company reported that the incidence of GvHD in FCR001 subjects was correlated with high CD34+ cell counts and high total nucleated cell counts in the FCR001 product."

DSMB • Trial status • Graft versus Host Disease • Transplant Rejection