UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
WASHINGTON, D.C. 20549
FORM
CURRENT REPORT
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| Item 8.01. | Other Events. |
On June 30, 2022, Talaris Therapeutics, Inc. (“Talaris,” the “Company,” “we,” or “our”) announced a clinical update on its ongoing Phase 3 FREEDOM-1 study in living donor kidney transplant (“LDKT”) recipients.
To date, Talaris has enrolled 22 donor-recipient pairs in the Phase 3 FREEDOM-1 study of FCR001. Seven patients have been successfully dosed at five different trial sites. All three patients who were dosed more than 12 months prior to the data cutoff date have been successfully weaned off all chronic anti-rejection drugs without evidence of rejection and with stable kidney function. All of these patients, including the first patient who is now 24 months post-transplant, continue to remain off all anti-rejection drugs. Furthermore, all patients treated with FCR001 at least three months prior to the data cutoff date have achieved and maintained T-cell chimerism levels >50% at each of the 3-, 6- and 12-month timepoints post-transplant. The safety profile observed was generally consistent with that expected in patients receiving a kidney transplant and an allo-HSCT. Three cases of low-grade acute graft-versus-host disease (“aGvHD”) were reported, all of which were treatment-responsive and have since resolved. One of these patients is more than 12 months post-transplant and has been successfully weaned off all anti-rejection drugs. As a result of an internal review triggered by the GvHD cases, Talaris has modified its mobilization protocol and added a second post-transplant dose of cyclophosphamide for GvHD prophylaxis. Trial enrollment continues.
Phase 3 FREEDOM-1 Highlights1
| • | Enrollment, demographics and degree of HLA mismatching. A total of 22 LDKT donor-recipient pairs have been enrolled to date in the FREEDOM-1 study at 10 different clinical sites. Of these, 13 were randomized to receive FCR001, 8 were randomized to the control arm and 1 failed final screening criteria. Currently, 7 of those randomized to FCR001 have received their kidney transplant and have been dosed with FCR001. The clinical trial continues to enroll donor/recipient pairs across all degrees of HLA mismatch. Figure 1 shows the distribution of all FCR001 recipients dosed to date, by the number of HLA mismatches between the donor and the recipient. |
| • | Efficacy data in FCR001-dosed patients. As shown in Figure 2, a total of 7 patients have been dosed and all patients dosed at least three months prior to the cutoff date have achieved and maintained T-cell chimerism levels >50% at each of the 3-, 6- and 12-month timepoints post-transplant. All 3 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 of these has been followed for 24 months post-transplant. |
In the context of transplantation, chimerism refers to a state wherein both the donor’s and the recipient’s hematopoietic stem cells (“HSCs”) coexist in the recipient’s bone marrow. Talaris believes chimerism to be an important potential study biomarker, predictive of inducing a state of allogeneic tolerance in the recipient, whereby the recipient tolerates the donated organ without the need for chronic anti-rejection drugs. Achieving high levels of durable donor T-cell chimerism in the LDKT recipient is one of the goals of the Company’s Facilitated Allo-HSCT Therapy. In the Company’s Phase 2 study, establishment and maintenance of >50% donor T-cell chimerism in an LDKT recipient at 3, 6 and 12 months after administration of FCR001 all correlated strongly with the patient’s ability to durably discontinue chronic anti-rejection drugs approximately one year after transplant, without subsequent graft rejection.
| • | Safety profile in FCR001-dosed patients. Adverse events (“AEs”) and serious adverse events (“SAEs”) observed in FCR001-dosed patients are consistent with those generally expected in someone receiving both a kidney transplant and an allogeneic stem cell transplant involving non-myeloablative conditioning. Three cases of low-grade (grade II) aGvHD were reported, all of which responded to treatment and resolved. One of these patients is 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 GvHD and is also 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, Talaris conducted an internal review of all GvHD cases in Phase 2 and 3. Through this review, a correlation was identified between these cases and the use of plerixafor as a donor mobilizing agent, the use of which has been higher to date under the Phase 3 mobilization protocol compared with the Phase 2. |
Based on this analysis, the Company has modified the FREEDOM-1 trial protocol to eliminate plerixafor from the donor mobilization regimen in all but exceptional cases, and has also added a second dose of post-transplant cyclophosphamide (“PTCy”) for the FCR001 recipient. The revised mobilization protocol better aligns with current customary donor mobilization practices and the additional dose of PTCy reflects the current standard of care for GvHD prophylaxis in HLA-mismatched allogeneic stem cell transplants. All findings and recommendations were reviewed and endorsed by a panel of external scientific advisors as well as the FREEDOM-1 data monitoring committee, which supported continuation of the trial with these modifications.
| 1. | All data reported is as of the June 15, 2022 data cutoff date. |
Figure 1:
Figure 2:
A copy of the Company’s presentation materials for the announcement is attached hereto as Exhibit 99.1 to this Current Report on Form 8-K and incorporated herein by reference.
Cautionary Note Regarding Forward-Looking Statements
This report contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, implied and express statements regarding Talaris’ strategy, business plans and focus; the progress and timing of the preclinical and clinical development of Talaris’ programs, including FCR001. The words “may,” “might,” “will,” “could,” “would,” “should,” “expect,” “plan,” “anticipate,” “intend,” “believe,” “expect,” “estimate,” “seek,” “predict,” “future,” “project,” “potential,” “continue,” “target” or the negative of these terms and similar words or expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words.
Any forward-looking statements in this press release are based on management’s current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this press release, including, without limitation, risks associated with: the impact of the ongoing COVID-19 pandemic on countries or regions in which the Company has operations or does business, as well as on the timing and anticipated timing and results of its clinical trials, strategy and future operations, including the expected timing and results from FREEDOM-1, the risk that the results of Talaris’ prior clinical trials may not be predictive of or consistent with future and/or final results in connection with the Company’s ongoing or future clinical trials; the therapeutic benefits expected from FCR001 and the Company’s ability to successfully demonstrate its safety and efficacy. These and other risks and uncertainties are described in greater detail in the section entitled “Risk Factors” in the Company’s Quarterly Report on Form 10-Q for the quarter ended March 31, 2022, as well as any subsequent filings with the Securities and Exchange Commission. In addition, any forward-looking statements represent Talaris’ views only as of today and should not be relied upon as representing its views as of any subsequent date. Talaris explicitly disclaims any obligation to update any forward-looking statements. No representations or warranties (expressed or implied) are made about the accuracy of any such forward-looking statements.
| Item 9.01. | Financial Statements and Exhibits. |
(d) Exhibits.
| Exhibit No. |
Description | |
| 99.1 | Talaris Therapeutics Presentation dated June 30, 2022. | |
| 104 | Cover page interactive data file (embedded within the Inline XBRL document) | |
SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned thereunto duly authorized.
| Talaris Therapeutics, Inc. | ||||||
| Date: June 30, 2022 | By: | /s/ Scott Requadt | ||||
| Scott Requadt President and Chief Executive Officer | ||||||
FREEDOM-1 CLINICAL UPDATE June 30, 2022 Exhibit 99.1
Disclaimer This Presentation contains forward-looking statements and information of Talaris Therapeutics, Inc. (“Talaris,” “we,” “our,”) within the meaning of the Private Securities Litigation Reform Act of 1995. All statements other than statements of historical facts contained in this Presentation, including statements regarding our strategy, future financial condition, future operations, projected costs, prospects, plans, objectives of management and expected market growth, are forward-looking statements. In some cases, you can identify forward-looking statements by terminology such as “may,” “will,” “should,” “expect,” “intend,” “plan,” “anticipate,” “believe,” “estimate,” “target,” “seek,” “predict,” “potential,” “continue” or the negative of these terms or other comparable terminology. Although we believe that the expectations reflected in these forward- looking statements are reasonable, these statements relate to our strategy, future operations, future financial position, future revenue, projected costs, prospects, plans, objectives of management and expected market growth, and involve known and unknown risks, uncertainties and other factors that may cause our actual results, levels of activity, performance or achievements to be materially different from any future results, levels of activity, performance or achievements expressed or implied by these forward-looking statements. Forward-looking statements in this presentation include, but are not limited to, statements about: the initiation, timing, progress, results and cost of manufacturing and conducting clinical trials of FCR001, as well as our research and development programs and our current and future preclinical and clinical studies, including statements regarding the timing of initiation and completion of studies or trials and related preparatory work, the period during which the results of the trials will become available, and our current and future programs; our ability to identify research priorities and apply a risk-mitigated strategy to efficiently discover and develop additional product candidates; our ability to initiate, recruit and enroll patients in and conduct our clinical trials at the pace that we project; our ability to scale-up our manufacturing and processing approaches to appropriately address our anticipated commercial needs, if FCR001 is approved; obtain and maintain regulatory approval of our product candidates, and any related restrictions, limitations or warnings in the label of any of our product candidates, if approved; our ability to compete with companies currently marketing or engaged in the development of treatments that our product candidates are designed to target; our reliance on third parties to conduct our clinical trials and to manufacture drug substance for use in our clinical trials; the size and growth potential of the markets for any of our current product candidates or other product candidates we may identify and pursue, and our ability to serve those markets; our ability to identify and advance through clinical development any additional product candidates; the commercialization of our current product candidates and any other product candidates we may identify and pursue, if approved, including our ability to successfully build a specialty sales force and commercial infrastructure to market our current product candidates and any other product candidates we may identify and pursue; the scope of protections we are able to establish and maintain for intellectual property rights covering our product candidates and our Facilitated Allo-HSCT Therapy; our ability to retain and recruit key personnel; our expectations regarding government and third-party payor coverage and reimbursement; our estimates of our expenses, ongoing losses, capital requirements and our needs for or ability to obtain additional financing; our expected uses of the net proceeds to us from this offering; the potential benefits of strategic collaboration agreements, our ability to enter into strategic collaborations or arrangements, and our ability to attract collaborators with development, regulatory and commercialization expertise; our financial performance; developments and projections relating to our competitors or our industry; the effect of the on-going COVID-19 pandemic, including mitigation efforts and economic effects, on any of the foregoing or other aspects of our business operations, including but not limited to our preclinical studies and future clinical trials. We caution the Recipient not to place considerable reliance on the forward-looking statements contained in this presentation. The forward-looking statements in this presentation speak only as of the date of this document, and we undertake no obligation to update or revise any of these statements. Our business is subject to substantial risks and uncertainties, including those referenced above. Any forward-looking statements are based on management's current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this press release, including, without limitation, risks associated with the impact of the on-going COVID-19 pandemic where the Company has operations or does business, as well as on the timing and anticipated timing and results of its clinical trials; the risk that the strategy and future operations of the Company, including the expected timing, enrollment, and results from FREEDOM-1 will not meet expectations; the risk that early data from the FREEDOM-1 study may not be predictive of or consistent with future and/or final results; the risk that the results of Talaris’ earlier clinical trials may not be predictive of results in any of the Company’s ongoing or future clinical trials; and the risk that the Company may not be able to successfully demonstrate the safety and efficacy of its drug candidates, including FCR001. These and other risks and uncertainties are described in greater detail in the section entitled “Risk Factors” in the Company’s Quarterly Report on Form 10-Q for the quarter ended March 31, 2022, as well as any subsequent filings with the Securities and Exchange Commission. In addition, any forward-looking statements represent Talaris’ views only as of today and should not be relied upon as representing our views as of any subsequent date. Talaris explicitly disclaims any obligation to update any forward-looking statements. No representations or warranties (expressed or implied) are made about the accuracy of any such forward-looking statements. Certain information contained in this Presentation relates to or is based on studies, publications, surveys and other data obtained from third-party sources and the Company's own internal estimates and research. While the Company believes these third-party sources to be reliable as of the date of this Presentation, it has not independently verified, and makes no representation as to the adequacy, fairness, accuracy or completeness of, any information obtained from third-party sources. In addition, all of the market data included in this Presentation involves a number of assumptions and limitations, and there can be no guarantee as to the accuracy or reliability of such assumptions. Finally, while we believe our own internal research is reliable, such research has not been verified by any independent source.
Talaris at a Glance Novel, single-dose, investigational cell therapy with potential to transform standard of care in solid organ transplantation and multiple severe immune and non-malignant blood disorders Lead product, FCR001, in open-label Phase 3 to induce durable immune tolerance in living donor kidney transplant (LDKT) recipients Compelling Phase 2 data Highly predictive, near-term surrogate marker of long-term success identified in Phase 2 Phase 3 protocol substantially mirrors optimized Phase 2; Orphan drug and RMAT designation from FDA Reported encouraging initial results on first patients in late 2021 FCR001 has pipeline-in-a-product potential across multiple therapeutic applications Large market opportunity Two additional Phase 2 studies initiated Q4 2021 Robust, reproducible and fully in-house manufacturing Strong IP position and high barriers to entry Well-financed; ~$225M cash on hand as of March 31, 2022
Allogeneic Tolerance and Chimerism Allogeneic tolerance: An approach to enable donor HSCs to coexist with recipient HSCs in the recipient’s bone marrow (“chimerism”), and mature into mutually-tolerated, functional immune cells and blood cells Goal: facilitate allogeneic tolerance by establishing durable chimerism Nobel Prize 1960* *Nobel Prize in Physiology or Medicine 1960 was awarded jointly to Sir Frank Macfarlane Burnet and Peter Brian Medawar ‘for discovery of acquired immunological tolerance.’
Allogeneic Tolerance and Chimerism Allogeneic tolerance: An approach to enable donor HSCs to coexist with recipient HSCs in the recipient’s bone marrow (“chimerism”), and mature into mutually-tolerated, functional immune cells and blood cells Nobel Prize 1960* Goal: facilitate allogeneic tolerance by establishing durable chimerism *Nobel Prize in Physiology or Medicine 1960 was awarded jointly to Sir Frank Macfarlane Burnet and Peter Brian Medawar ‘for discovery of acquired immunological tolerance.’
Proprietary composition of donor’s CD34+ cells, Facilitating cells and αβ T-cells FCR001: A Modified, Allogeneic HSC-based Therapy Unique, tolerogenic “non-stem cells” (CD8+, TCR-) Potential to: Promote stem cell engraftment in unmatched recipients Prevent GvHD in mouse models Induce antigen-specific Treg Induce Breg Facilitating Cell FCR001 is administered with non-myeloablative conditioning, at doses and using protocols optimized over two decades of study Broad, issued composition of matter patents
Our Pipeline FREEDOM - 1 FREEDOM – 2* REPROGRAM: Solid Organ Transplantation FCR001 FCR001 or FCR002 Living Donor Kidney Transplant (LDKT) LDKT Delayed Tolerance Induction Deceased Donor Kidney Transplant FREEDOM – 3* RESTORE: Severe Autoimmune Disease FCR001 Scleroderma REPLACE: Severe Blood, Immune, and Metabolic Disorders FCR001 Severe blood, immune, or metabolic disorders CANDIDATE INDICATION PRECLINICAL PHASE 1 PHASE 2 PHASE 3 ~ 6,500/year ~ 6,000 to 10,000 ~ 16,500/year ~ 5,000 to 6,000/year TBD based on indication US PATIENT POPULATION * Open IND permits us to move directly into Phase 2 based on existing FCR001 safety data ** Organ transplant population estimates based on UNOS/OPTN data; scleroderma estimates derived from epidemiology and third-party market research; LDKT Delayed Tolerance Induction patient numbers based on 1 year to 18 months delayed from incident LDKT; Scleroderma estimated point prevalence of diffuse cutaneous SSc patients with early, rapidly progressing disease and internal organ involvement
Unmet Need in Organ Transplant: Challenges of Chronic Immunosuppression Immunosuppression is not disease-modifying; requires lifelong chronic immunosuppression Kidney toxicity ~35% of living donor transplants and ~50% of deceased donor transplants fail within 10 years1 Significantly increased risk of cancer2 Hypertension, diabetes, high cholesterol, weight gain3 Cardiovascular (CV) issues are leading cause of post-transplant mortality Increased risk of serious infection4 High cost, pill burden (>20 pills/day for life) and decreased QoL Cost ~$25K in first year and $5K-$10K annually for life of organ1 Poor compliance can lead to rejection or organ loss Sleep disturbance, CNS issues, depression, and other AEs affecting QoL “Ideally you want to avoid getting sick or being around sick people because your immune system is suppressed. Unfortunately, in the world we live in, you’re going to get sick. The first couple of times I got sick, I was terrified.” - Male living donor kidney recipient in 40’s “While others might breeze out the door in the morning, I am already preoccupied with preventing rejection, infection, and cancer.” - FDA Voice of the Patient Panellist Sources: patientslikeme; The Voice of the Patient FDA Meeting (Sep 2016): Patients who Have Received an Organ Transplant USRDS 2020 Annual Data Report, Fig 6.16: https://adr.usrds.org/2020/end-stage-renal-disease/6-transplantation Engels et al JAMA 2011; 306(17): 1891-1901 Nankivell BJ et al, Lancet 2011, 378:1428-37 Karuthu et al, Clin J Am Soc Nephrol. 2012 Dec;7(12):2058-70 QoL: Quality of life; CNS: Central Nervous System
Highlights from our Phase 2 Study (+ long-term followup)* 37 adult living donor kidney transplant (LDKT) patients were dosed with our therapy at two leading US transplant sites between 2009 - 2016 Across all HLA-mismatches 82% success rate (14 of last 17) once key parameters were optimized * Data as of January 31, 2022. Includes 33 patients under Phase 2 protocol and 4 compassionate use patients ** One year after transplant *** Kienzl-Wagner 2018, Lim 2019, Moroni 2019 Median follow up: >6 yrs Six patients > 10 years Longest >12 yrs Recurrence ordinarily seen in 20% - 60% of patients*** **
Strong Phase 2 Results Across All Degrees of HLA-Match 19/26 (73%) durably off all chronic immunosuppression had HLA match of 3 or less between LDKT donor & recipient Comparable kidney and patient survival for all FCR001 vs standard of care (SoC) LDKT patients FCR001 safety & tolerability data generally consistent with separate SoC kidney transplant + allogeneic HSCT with non-myeloablative conditioning No acute rejection or donor-specific antibodies in FCR001 patients off immunosuppression Number of HLA matches between donor & recipient # of patients Data as of January 31, 2022 Phase 2 FCR001 patients weaned off all chronic immunosuppression
Phase 2 Three- and Six-Month Chimerism Results Were Highly Predictive of Durable Immune Tolerance “Chimerism” % of recipient’s T-cells that are donor-derived Simple blood test, measured at multiple time points 26/29 patients (90%) who achieved chimerism at month 3 were able to be weaned off chronic immunosuppression (IS) 26/27 patients (96%) who achieved chimerism at month 6 were able to be weaned off chronic IS Every patient weaned off chronic IS by month 12 has remained off chronic IS for full duration of follow up Median follow up >6 years Longest follow up >11 years Values are mean +/- standard deviation. N indicates the number of FCR001 treated patients weaned off IS at approximately one year post-transplant for whom % whole blood and T-cell donor chimerism were measured at that time point 50% chimerism Data as of January 31, 2022
FREEDOM-1 Phase 3 Registration Study STUDY OVERVIEW Study Design Open-label, randomized, controlled, parallel group study of FCR001 in 120 first time, adult living donor kidney transplant (LDKT) recipients, randomized 2:1 between FCR001 : standard of care (SoC) Five-year follow up for safety Protocol; inclusion / exclusion criteria Near-identical to optimized Phase 2 protocol Primary Endpoint Proportion of FCR001 recipients who are free from chronic immunosuppression, without biopsy proven acute rejection (BPAR), at Month 24 post-transplant Key Secondary Endpoint In FCR001 recipients only, no meaningful decline in renal function from post-transplant baseline (Month 1) to Month 24 Additional Endpoints Chimerism, kidney function, safety Sites / Territory Targeting ~20 sites in U.S. (17 active sites as of June 15, 2022) Neither primary nor key secondary endpoint involves statistical comparison to the SoC patients
We Now Have 17 Active FREEDOM-1 Sites Weill-Cornell Georgetown Mayo AZ Scripps Oregon U. Nebraska U. Michigan Northwestern Ohio St U. Minnesota Mayo Rochester Baylor UCSF U. Penn VCU Duke Mayo Jacksonville Data as of June 15, 2022
Phase 3 Update: Enrollment, Demographics 22 1 13 10 different clinical sites have enrolled D/R pairs Screen Fail Dosed Pending Enrollment & Demographics Active 8 Control 5 7 1 Withdrew/Other 7 D/R pairs successfully dosed at 5 different sites Pending 2 4 2 Withdrew Dosed Data as of June 15, 2022
Study Continues to Enroll Across Degrees of HLA Mismatch HLA Mismatch of FREEDOM-1 Subjects (n=7) In addition to HLA mismatching data, high-resolution (HR) matching data (using a 12-point scale) is used in the BMT medical community. HR matching, however, is not available at all sites. Pairs for which HR matching data is available include 3/12, 6/12, 6/12 and 7/12 matches. # of donor/recipient pairs
Phase 3 Update: FCR Chimerism and Chronic IS Status * Chimeric: Achieved and maintained >50% T-cell chimerism at each designated study visit timepoint All FCR-001 patients have achieved and maintained chimerism* No instances of BPAR or DSA in any FCR-001 patients All have maintained stable kidney function Longest follow up: 24 months with no BPAR Data through June 15, 2022 Time since kidney transplant # of Patients Dosed # of Patients Achieving Chimerism at each time pt <3 months >3 months >6 months >12 months Off Anti-Rejection Meds 3 100% (3/3) 100% (3/3) 2 100% (2/2) NA 1 100% (1/1) NA 1 NA 7 TOTAL Chimeric* through 6-mth visit NR Not reported; patient has not reached 3-month timepoint Chimeric* at 3-mth visit Chimeric* through 12-mth visit
Phase 3 Update: Safety Profile Summary of safety profile in FCR001 patients AEs and SAEs observed are consistent with those generally expected with kidney and allogeneic stem cell transplantation involving non-myeloablative conditioning No events occurred that caused data monitoring committee (DMC) to stop the study; no stopping rules triggered Three cases of low-grade aGvHD; all cases were treatment responsive and resolved Cases were grade II, with symptoms limited to skin and/or GI One of these three patients also diagnosed with moderate cGvHD and is responding to treatment One of the patients with aGvHD who is more than 12 months post-transplant has been successfully weaned from tacrolimus and MMF Trial enrollment continues without interruption Talaris proactively conducted a full review Review findings and subsequent recommendations reviewed and endorsed by both external scientific advisory panel and DMC * Data through June 15, 2022
Phase 3 Update: GvHD Review & Protocol Adjustment Plerixafor introduced in mid-Phase 2 as option for donor mobilization Used in mobilization protocol to reduce potential need for second mobilizations Used much more frequently in Phase 3 than Phase 2 Identified a correlation between aGvHD cases and increased use of plerixafor in Phase 3 Evident in four of five aGvHD cases when analyzing across Phase 2 and Phase 3 cohorts Plerixafor was associated with increased cell counts and decreased recoveries of FCs in our product Eliminated plerixafor from donor mobilization regimen* and added second post-transplant dose of cyclophosphamide (PTCy) for recipient GvHD prophylaxis Since completion of our Phase 2 trial in 2016, two doses of PTCy has emerged as the standard of care in allo-HSCT settings *Plerixafor may be used in exceptional circumstances after consultation with patient and investigator
Phase 3 Update: Summary Efficacy: All FCR patients have achieved and maintained > 50% T-cell chimerism at all measured timepoints Observed durable chimerism (irrespective of HLA mismatch) and immunosuppression weaning and/or withdrawal at multiple clinical sites Longest follow-up is 24 months with no biopsy-proven acute rejection (BPAR) Safety: Three grade II, treatment-responsive and resolved aGvHD cases; one of these three patients also diagnosed with moderate chronic GvHD and is responding to treatment Revised protocol better aligns with customary donor mobilization practices as well as emerging standard of care for GvHD prophylaxis in haplo-identical allo-HSCT Enrollment: Sites continuing to enroll; donor apheresis and FCR001 dosing proceeding
A Path to Significant Value Creation LDKT (Ph 3) Robust Ph 2 shows potential to reprogram immune system and achieve durable immune tolerance to kidney 6,500 cases/yr in US Delayed LDKT Near-term opportunity to expand FCR001 kidney franchise Opens door to prevalent LDKT population Scleroderma* Proof of principle for FCR001 to restore self-tolerance in severe autoimmune disease ~5,000 – 6,000 cases/yr Validation in dcSSC opens door to additional severe autoimmune disorders Leverage LT safety data for FCR001 Other autoimmune Validation as safer alternative to standard allo-HSCT offers potential to use more broadly in non-malignant blood, immune & metabolic indications Other Blood/ Immune * Diffuse cutaneous systemic sclerosis (dcSSc) patients with early, rapidly progressive disease Other deceased donor transplant ~15,000 cases/yr Deceased donor kidney transplant Leverage solid organ transplant franchise and logistics to 2x larger market opportunity ~16,500 cases/yr Initial Indication - Blood/Immune Replace diseased blood or immune cells with those of healthy, HLA-unmatched donor Non-myeloablative conditioning Drivers of near-term value Drivers of medium-term value Drivers of longer-term value FCR001 Facilitated Therapy Franchise: Drivers of Value
Summary Lead product, FCR001, in Phase 3 to induce durable immune tolerance in living donor kidney transplant (LDKT) recipients; initial clinical results continue to be encouraging FCR001 has pipeline-in-a-product potential across multiple therapeutic applications Robust, reproducible and fully in-house manufacturing Strong IP position and high barriers to entry ~$225M cash on hand as of March 31, 2022 Novel, single-dose, investigational cell therapy with potential to transform standard of care in solid organ transplantation and multiple severe immune and blood disorders
Backup Slides
Potential to Extend Across Solid Organ Transplant Current & planned FREEDOM-1 centers perform ~25% of all US LDKT procedures Highest volume LDKT centers Current or proposed FREEDOM-1 sites (circle size proportional to LDKT volume)
Durable Immune Tolerance: The “Holy Grail” of Transplant
Facilitating Cell Mechanism of Action Black text= Ildstad laboratory publications Red text = external publications Gene arrays of mouse and human FC show strong B cell signature Manuscript in Preparation Nupur, Exp Hematol 2007, 5:1847-1857 Enhances homing and migration Wen, Stem Cells. 2014; 32(1): 2732-43 Kaufman, Blood 1994, 84:2436-2446 Gandy, Immunity 1999, 11:579-590 Bridenbaugh, Blood 2008, 111:1735-1738 Prevents GVHD in Mice Manuscript in Preparation Taylor KN. J Immunol. 2007; 179 (4): 2153-62 Colson, Blood 2004, 104:3829-3835 Induces IL-10+ Breg in vitro Manuscript in Preparation Nupur, Exp Hematol 2007, 5:1847-1857-1857 Induces antigen-specific Treg in vivo Taylor KN. J Immunol. 2007; 179 (4): 2153-62 Huang Y. Blood. 2011; 117(8):2494-2505 Colson, Blood 2004, 104:3829-3835 Prevents apoptosis of HSC and enhances clonogenicity of HSC Rezzoug F. J Immunol. 2008; 180(1);49-57 Fugier-Vivier I. J Exp Med. 2005; 201(3) 373-383
Follow-Up on Immunosuppression-Free Recipients Years off Immunosuppression Recipients (n=26) Number of HLA Antigen Matches Recipient/Donor Pairs (n=37) LRD, living related donor; LURD, living unrelated donor. aThe above data represent the time interval between the date each patient discontinued immunosuppression and that patient's last study follow-up visit that occurred prior to January 31, 2021.2 1. Leventhal J et al. Am J Transplant. 2021;21(suppl 3). Accessed February 9, 2022. https://atcmeetingabstracts.com/abstract/long-term-follow-up-of-a-phase-2-clinical-trial-to-induce-tolerance-in-living-donor-renal-transplant-recipients-3/ 2. Data on file. Years Since Discontinuation of Immunosuppression (n=26)1,a HLA Antigen Match out of 6 (n=26)2
FCR001: The Donor-Recipient Journey Our “vein to vein” process and protocols have been fully proceduralized
aPatients demonstrating stable donor chimerism (>50%), no history of rejection, no DSA, no GvHD, not using corticosteroids, and adequate kidney function. bTBI dose of 200 cGy delivered as a single fraction at 10–18 MV at a rate of 15–20 cGy/min are the preferred energy and rate parameters and should be followed when possible. cAdministered using a central or dedicated peripheral line; infusion by gravity. dMethylprednisolone 500 mg IV on Day 0 in OR; 250 mg Day 1 and 125 mg Day 2. eUntil absolute neutrophil count is >1000/mm3 for 3 consecutive days. Mobilization/apheresis Day −84 to Day −36 Product saved at site as safety net Week −12 to −4 Weaninga (0–3 ng/mL) Offa Bx Primary Endpoint: Off IS With No Rejection End of Study Begin prophylactic GCSFe Negative COVID Negative COVID FREEDOM-1: FCR001 Protocol Overview Required for conditioning: Receipt of FCR001 Negative DSA retest Negative COVID Reference chimerism samples adequate Day -4 Day -3 Day -2 Day -1 Day 0 Day 1 Day 2 Day 3 Day 4 Day 5 Mo 6 Mo 60 Mo 9 Mo 12 Mo 24 Mo 36 Mo 48 Conditioning FLU 30 mg/m2 (Days −4, −3, −2) Cy 50 mg/kg (Day −3) Mesna 50 mg/kg (Day −3) Hemodialysis 2–4 hours (Days −4, −3, −2) TBIb 200 cGy; 6–18 MV; 7–20 cGy/min Bx Bx Bx GvHD Prophylaxis Cy (50 mg/kg) Mesna (50 mg/kg) Mycophenolate (MMF/MPA) to Mo 6 Tacrolimus trough levels (8–12 ng/mL) thru Mo 2 (6–8 ng/mL) from Mo 3–9 FCR001 Infusion Within 24 Hoursc Offa Perioperative corticosteroidsd Day -7 Day -6 Day -5 For hemodialysis-naïve patients: Catheter placement (Day -7) Dialysis (Day -6 or Day -5)
Since 2000, average 6,080 cases/year 2019 highest volume on record: 6,867 ~30% of total kidney transplants annually Overview of Living Donor Kidney Transplant (U.S.) Incidence Prognosis and Prevalence Yr. Post LDKT Graft Survival Patient Survival 1 year 97% 99% 5 year 85% 94% 10 year 65% 79% Excellent short-term outcomes with LDKT Unmet need for improved long-term outcomes ~50K prevalent LDKT patients with functioning graft transplanted in past decade Sources: UNOS/OPTN 2019; USRDS 2020 Annual Data Report
Value proposition for “One Transplant for Life” Human Costs: Lost Productivity Impaired QoL Clinical & Economic Costs: IS Complications IS Co-morbidities Graft Loss IS Costs Value From Eliminating Chronic IS Improve outcomes Fewer rejections, graft losses No IS co-morbidities or complications Enhance patient’s QoL and freedom Reduce systematic costs IS and meds to manage co-morbidities Avoid return to dialysis or 2nd transplant Bolster recipients’ productivity
Evidence of Potential Longer-Term Clinical Benefit Results presented at ATC 2019 by Dr. D. Tollerud, based on cardiac and renal dysfunction measures under ESRD-SCL-TM and general health as measured by SF-36 Retrospective analysis by Dr. J Leventhal of transplanted SoC patients at same site between 2009-2012, who met Ph 2 eligibility criteria (n=132) FCR001 patients off all chronic immunosuppression (n=26) FCR001 improved Quality of Life(1), preserved kidney function and enabled lower reliance on cardiovascular medications(2)(3) Cardiovascular Medication Usage SoC vs Durably Chimeric FCR001 Patients Mean Estimated eGFR* Over Time Post- Transplant