About Talaris Therapeutics

Talaris Therapeutics, Inc. operates as a late-clinical stage, cell therapy company. The company is developing an innovative method of allogeneic hematopoietic stem cell transplantation (allo-HSCT) that has the potential to transform the standard of care in solid organ transplantation, certain severe autoimmune diseases and certain severe blood, immune and metabolic disorders. The company’s proprietary therapeutic approach, which the company calls Facilitated Allo-HSCT Therapy, could prevent organ rejection without the morbidity and mortality that has been associated with the use of lifelong anti-rejection medicines, also known as chronic immunosuppression. Beyond the organ transplant setting, the company’s Facilitated Allo-HSCT Therapy also has the potential to treat a range of severe autoimmune diseases and severe blood, immune and metabolic disorders, in each case with potential for similar outcomes to what has previously been observed with hematopoietic stem cell transplantation (HSCT), while mitigating the toxicities, morbidities and extended hospital stay associated with the conditioning regimen typically required by HSCT. The company’s target indications, individually and collectively, represent a significant unmet need and commercial opportunity. In February 2023, the company announced the discontinuation of the company’s FREEDOM-1 and FREEDOM-2 clinical trials evaluating FCR001’s ability to induce durable tolerance in living donor kidney transplant (LDKT) recipients. This decision was primarily attributable to the pace of enrollment and the associated timeline to critical milestones. In connection with the evaluation of strategic alternatives and in order to extend the company’s resources, the company implemented a restructuring plan that included reducing the company’s workforce by approximately one-third, with remaining employees primarily focused on maintaining the company’s cell therapy CMC capabilities and executing FREEDOM-3. In February 2023, the company also announced a comprehensive review of strategic alternatives focused on maximizing stockholder value, including but not limited to, an acquisition, merger, possible business combinations and/or a divestiture of the company’s cell therapy chemistry, manufacturing and controls (CMC) capabilities. In March 2023, pending the outcome of the company’s review of strategic alternatives, the company voluntarily paused enrollment in its FREEDOM-3 Phase 2 clinical trial evaluating FCR001’s ability to induce tolerance in diffuse systemic sclerosis, a severe autoimmune disease, while continuing to evaluate patients for potential future enrollment. The company’s lead product candidate, FCR001, which is central to the company’s Facilitated Allo-HSCT Therapy, is a novel allogeneic cell therapy consisted of stem and immune cells that are procured from a healthy donor, who is also the organ donor in the case of organ transplantation. FCR001 is rapidly processed in the company’s good manufacturing practices (GMP) facility using the company’s proprietary manufacturing methods. Then, at the time of transplant, FCR001 is administered to the recipient following nonmyeloablative conditioning, which is designed to be less toxic than myeloablative conditioning. A fully myeloablative conditioning regimen consists of a combination of agents and high doses of total body irradiation that destroy hematopoietic stem cells (HSCs) in the bone marrow and results in profound depletion of HSC-derived cells within one to three weeks following administration that is irreversible, and in most instances is fatal unless rescued by a stem cell transplant. The nonmyeloablative conditioning for FCR001 entails lower doses of chemotherapy and total body irradiation, causes less depletion of blood cells and does not require stem cell support for the recipient to resume the production of blood cells and platelets. The company does not outsource any key aspect of its cell processing. The company has focused on developing FCR001 as a pipeline-in-a-product with the potential to address the therapeutic areas described above. FREEDOM-1 was a randomized, controlled, open-label Phase 3 registration trial in the United States of FCR001 in 120 adult LDKT recipients. The intention of this trial was to evaluate the potential of FCR001, when administered the day after the kidney transplant, to induce durable, drug-free immune tolerance in the recipient of the transplanted kidney. In November 2021, June 2022 and October 2022, the company provided updates on patients dosed in the FREEDOM-1 Phase 3 clinical trial. In November 2021, the company announced that all patients treated with FCR001 at least three months prior had achieved T-cell chimerism levels greater than 50% at each of the 3-, 6-, and 12-month timepoints post-transplant, which has correlated strongly with the patient’s ability to durably discontinue chronic immunosuppression (IS) without subsequent graft rejection. Further, the company announced that the overall safety profile of Phase 3 patients dosed at the time with FCR001 was consistent with that observed in the company’s Phase 2 study of FCR001. In June 2022, the company provided further updates on patients dosed in the FREEDOM-1 trial, announcing that a total of seven patients had been dosed and that all patients dosed at least three months prior to the cutoff date had achieved and maintained T-cell chimerism levels >50% at each of the 3-, 6- and 12-month timepoints post-transplant. All three of the patients dosed more than 12 months prior to the data cutoff date have been successfully weaned off all chronic anti-rejection drugs. The longest at that time had been followed for 24 months post-transplant. The company also reported three cases of low-grade (grade II) acute graft versus host disease (aGvHD). One of these patients was more than 12 months post-transplant and, notwithstanding their treatment-responsive aGvHD, has been weaned off all anti-rejection drugs. One of the three aGvHD patients was subsequently diagnosed with moderate chronic graft versus host disease (GvHD) and at that time was responding to treatment. No trial stopping rules were triggered by the GvHD cases, and trial screening and enrollment continued. However, to investigate these aGvHD cases, the company conducted an internal review of all GvHD cases in Phase 2 and 3 clinical trials. This review prompted implementation of an amendment to the trial protocol. 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 candidate. The company also noted a correlation between the use of plerixafor as a donor mobilizing agent and an increased risk of GvHD, as plerixafor significantly increased CD34+ and total nucleated cell counts in the FCR001 product. At that time, the company introduced two risk mitigation measures for GvHD in the amended trial protocol: the elimination of plerixafor as a donor mobilizing agent, and the addition of a second post-transplant dose of cyclophosphamide, which has been demonstrated to reduce the risk of severe GvHD in haplo-identical allogeneic hematopoietic stem cell transplants (Elmariah H, Fuchs EJ. Post-transplantation cyclophosphamide to facilitate HLA-haploidentical hematopoietic cell transplantation: Mechanisms and results. Semin Hematol. 2019 Jul;56(3):183-189). In October 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 reported this event and the DMC’s recommendation to the U.S. Food and Drug Administration (FDA). The patient had been hospitalized with grade IV GvHD that was complicated by serious infections leading to respiratory and renal failure, and ultimately death. The company also reported that, as of October 2022, the other two FREEDOM-1 patients who were previously reported to have had grade II aGvHD have since experienced complete resolution of their aGvHD symptoms, although one patient experienced additional flares that were also responsive to treatment. After reviewing the data, the DMC concluded that the FREEDOM-1 protocol modifications implemented in June 2022 should be sufficient to mitigate the risk of GvHD going forward, and recommended continuation of the trial without further modifications. Despite this recommendation, trial enrollment remained below expectations, and the company ultimately terminated its clinical trials in LDKT. The primary endpoint of the company’s Phase 2 trial was to determine whether the administration of FCR001 can induce durable tolerance to the donated kidney and substantially reduce or eliminate the requirement for immunosuppression within 12 months following transplant. In the company’s Phase 2 trial, 26 of 37 LDKT patients treated with FCR001 (70%) were able to completely discontinue their chronic immunosuppression approximately one year after receiving their transplant. After mid-course optimizations to the Phase 2 protocol, 14 of the last 17 patients (82%) in the trial were able to discontinue their chronic immunosuppression by approximately one year post-transplant. Every transplant recipient who was weaned off immunosuppression has remained off chronic immunosuppression, without any organ rejection, for the duration of their follow-up through March 1, 2023. As of that date, the company had followed these patients for a median of 9.0 years post-transplant, and the longest for 14.0 years post-transplant. These results were achieved despite significant degrees of immune system human leukocyte antigen (HLA) mismatch between the donors and recipients, and the degree of immune mismatch between the donor and recipient did not appear to impact the safety or efficacy of the company’s therapy candidate. The company identified a near-term surrogate marker, chimerism, that highly predictive of the ability of an organ transplant recipient to durably discontinue chronic immunosuppression at one year post-transplant without rejecting the transplanted organ. Chimerism refers to a state whereby the recipient’s and donor’s blood and immune cells co-exist in the recipient, creating a reciprocal state of immune tolerance called allogeneic tolerance. The company uses a simple blood test to measure and regularly monitor the degree of donor chimerism in the recipient, which has as of December 31, 2022 shown a close association in the company’s research with long-term immune tolerance in patients who have received FCR001. In the company’s Phase 2 trial of FCR001, the company observed that 26 of 27 recipients (96%) who achieved donor chimerism at six months post-transplant were successfully weaned off chronic immunosuppression over approximately the next six months, including recipients who were highly HLA-unmatched and/or unrelated to their donors. In addition, donor chimerism at three months post-transplant, which the company observed in 26 of 29 recipients (90%), was also highly predictive of successful weaning off chronic immunosuppression at approximately one year post-transplant. Through the termination of the company’s clinical trials in LDKT, the company monitored the patients in its Phase 2 trial for long term safety and durability of effect. Through March 1, 2023, the company had accumulated approximately 316 patient-years of exposure to FCR001 in LDKT, and the safety profile in the company’s patients is generally consistent with that expected if a patient were to separately receive both a standard kidney transplant and an allo-HSCT with nonmyeloablative conditioning. Specifically in the company’s Phase 2 population, through March 1, 2023, there were four deaths and two cases of GvHD, which is a condition that occurs when donated stem cells attack the recipient. The most commonly reported serious adverse events were fever, deep vein thrombosis, including among several patients who had predisposing factors, such as central venous catheter placements or Factor V deficiency, diarrhea, pneumonia and febrile neutropenia (or low white blood cell counts with a high fever). Preliminary data indicates that patients who were able to be weaned off immunosuppression with FCR001 had preserved kidney function and third-party data suggests a markedly lower reliance on cardiovascular medications at four years post-transplant compared to traditional transplants with chronic immunosuppression over a similar time frame. Based on the data generated from the company’s Phase 2 trial, FDA has granted Regenerative Medicine Advanced Therapy (RMAT) and Orphan Drug Designation for FCR001 for LDKT. Under the company’s open investigational new drug application (IND), the FDA has cleared the company, based in part upon the data as of December 31, 2022 from the company’s ongoing Phase 2 trial, to proceed with an updated protocol for the company’s Phase 2 FREEDOM-2 trial, which the company initiated in the fourth quarter of 2021. In FREEDOM-2, the company had been evaluating the potential of FCR001 to induce durable immune tolerance in patients who have previously received a kidney from a living donor, which is a process called delayed tolerance. In this trial, FCR001 either was or would have been administered between three and twelve months after the initial kidney transplant. Additionally, the FDA has cleared the company’s IND, based in part upon the data as of December 31, 2022 from the company’s ongoing Phase 2 trial, to proceed with the company’s Phase 2 FREEDOM-3 trial, which the company initiated in the fourth quarter of 2021. In FREEDOM-3, the company was evaluating the safety and efficacy of FCR001 in adults with a severe form of scleroderma, a debilitating autoimmune disease. In the company’s Phase 2 LDKT trial, all seven LDKT patients who required a kidney transplant as a result of a kidney-related autoimmune disease, and who achieved durable chimerism and could be withdrawn from chronic immunosuppression at one year, have not experienced recurrence of their prior kidney-related autoimmune disease. This observation, as well as the current use of HSCT for severe scleroderma, supports the potential of the company’s therapy in autoimmune diseases. Positive data in the FREEDOM-3 trial in severe scleroderma patients could support the potential applicability of FCR001 to other severe, systemic autoimmune diseases. The company manufactures FCR001 in less than a day at its GMP cell processing facility, employing robust, reproducible, proprietary methods, which remain substantially unchanged since the company progressed FCR001 from Phase 2 to the Phase 3 FREEDOM-1 clinical trial. The company does not outsource any key aspect of the company’s cell processing. Licenses and Collaborations License Agreement with University of Louisville Research Foundation, Inc. In October 2018, the company entered into an amended and restated exclusive license agreement (ULRF License Agreement) with University of Louisville Research Foundation, Inc. (ULRF) as an agent of the University of Louisville, relating to certain licensed patent rights and know-how related to human facilitating cells for the company’s Facilitated Allo-HSCT Therapy. Pursuant to the ULRF License Agreement, ULRF granted the company an exclusive, worldwide license under such patents and a nonexclusive royalty-bearing, worldwide license for such know-how to research, develop, commercialize and manufacture FCR001 and products containing FCR001 in all fields, without limitation. ULRF also granted the company the right to grant sublicenses in accordance with the ULRF License Agreement. Intellectual Property As of December 31, 2022, the company’s patent portfolio included four patent families, which were exclusively in-licensed from ULRF in the company’s field. These families include issued patents and pending applications related generally to the company’s facilitating cell product, methods of making its facilitating cell product, methods of using the company’s facilitating cell product therapeutically, and methods of evaluating the viability or potency of the company’s facilitating cell product. Specifically, the company has exclusively in-licensed a patent portfolio that includes at least three issued U.S. patents, 31 patents issued in foreign jurisdictions, and 10 patent applications pending worldwide. The issued patents from three of the four families in the company’s portfolio are expected to expire around 2029, and any patents that issue from the fourth family in the company’s portfolio are expected to expire around 2038, absent any applicable patent term adjustments or extensions. The first family includes issued patents in Australia, Canada, and Europe; there are no pending applications in this family. All of the issued claims in this family are directed to compositions that include at least 30% facilitating cells, methods of making such compositions, and/or methods of using such compositions. The European patent is validated in five European countries, including France, Germany, Italy, Spain, and the United Kingdom. This family of patents is in-licensed under an exclusive license agreement with ULRF, and is expected to expire in 2029, absent any applicable patent term adjustments or extensions. The second family includes one issued U.S. patent, with claims directed to methods of increasing the number of facilitating cells by exposing them to the DOCK-2 protein. This patent is in-licensed under the same exclusive license agreement with ULRF, and is expected to expire in 2032, absent any applicable patent term adjustments or extensions. The third family includes two issued U.S. patents and one pending U.S. application; at least one issued patent in each of Australia, China, Europe, India, and Japan; and a pending application in Canada. The claims in this family are directed to compositions that include at facilitating cells, methods of making such compositions, and/or methods of using such compositions absent a requirement for any particular amount of facilitating cells. The European patent is validated in 17 European countries, including Austria, Belgium, Denmark, France, Germany, Greece, Hungary, Ireland, Italy, the Netherlands, Norway, Poland, Spain, Sweden, Switzerland, Turkey, and the United Kingdom; and also is validated in Hong Kong. This family of patents is in-licensed under the same exclusive license agreement with ULRF. The U.S. members of this family claim the benefit of priority to members of the first family (i.e., as a Continuation-in-Part), and are expected to expire in 2029, while the non-U.S. members of this family are expected to expire in 2031, absent any applicable patent term adjustments or extensions. The fourth family includes pending applications in the U.S., Australia, Canada, China, Europe, India, Japan, and Russia. These pending applications generally have claims directed to determining the potency of a composition that includes facilitating cells. This family of patents is co-owned by the company and ULRF; this family of patents also falls within the same exclusive license agreement with ULRF. Patents that issue in this family are expected to expire in 2038, absent any applicable patent term adjustments or extensions. The company has filed and obtained U.S. Registration No. 6180755 for the TALARIS THERAPEUTICS character mark for ‘biological preparations in the nature of allogeneic cell therapies for use in treating organ transplant patients’ in International Class 5 and ‘providing laboratory services to hospitals and transplant centers involving manipulation of allogeneic cells used for cell therapy treatment of organ transplant patients’ in International Class 42. The company plans to register trademarks in connection with future products. Government Regulation In addition to the foregoing, state and federal laws regarding environmental protection and hazardous substances, including the Occupational Safety and Health Act, the Resource Conservancy and Recovery Act, and the Toxic Substances Control Act, affect the company’s business. As with the U.S. Foreign Corrupt Practices Act of 1977 (FCPA), these laws generally prohibit the company and its employees and intermediaries from authorizing, promising, offering, or providing, directly or indirectly, improper or prohibited payments, or anything else of value, to government officials or other persons to obtain or retain business or gain some other business advantage. The U.K. Bribery Act 2010 also imposes liability for failing to prevent a person associated with the company from committing a bribery offense. In the United States, the company’s operations are subject to regulation by various federal, state and local authorities in addition to the U.S. Food and Drug Administration (FDA), including but not limited to, the Centers for Medicare & Medicaid Services (CMS), other divisions of the U.S. Department of Health and Human Services (HHS) (such as the Office of Inspector General, Office for Civil Rights and the Health Resources and Service Administration), the U.S. Department of Justice (DOJ), and individual U.S. attorney offices within the DOJ, and state and local governments. Research and Development The company’s research and development expenses were $57.0 million for the year ended December 31, 2022. History Talaris Therapeutics, Inc. was founded in 1988. The company was incorporated under the laws of the state of Delaware in 2002.