Cellectis Provides Business Update and Reports Fourth Quarter and Full Year 2022 Financial Results

 

Pipeline Highlights

UCART Clinical Development Programs

BALLI-01 (evaluating UCART22) in relapsed or refractory B-cell acute lymphoblastic leukemia (r/r B-ALL)

• UCART22 is an allogeneic CAR T-cell product candidate that targets CD22 and is being evaluated in the BALLI-01 clinical study, a Phase 1/2a open-label dose-escalation and expansion study designed to evaluate the safety and clinical activity of the product candidate in patients with r/r B-ALL.
• On December 13, 2022, Cellectis hosted a Live Webcast reviewing updated clinical data on its BALLI-01 clinical trial. Compared to the last clinical update on BALLI-01 at ASH 2021, the webcast presented data from five additional patients who received UCART22 at dose level 3 (DL3; 5x10 ⁶ cells/kg) after lymphodepletion with fludarabine cyclophosphamide and alemtuzumab (FCA) regimen.

 

• Evidence of UCART22 anti-tumor activity was observed in 60% (n=3) of the five patients at DL3:
  • A patient experienced a durable minimal residual disease (MRD) negative complete response with incomplete count recovery (CRi) that continued beyond 6 months, as of December 2022
  • A patient experienced an MRD negative complete response (CR) that continued beyond Day 70, as of December 2022
  • A patient experienced a morphologic leukemia-free state (MLFS) that continued beyond Day 84 (MRD-negative at Day 84).
• These preliminary data support the continued administration of UCART22 after FCA lymphodepletion in patients with r/r B-ALL.
• On December 22, 2022, Cellectis announced the first dosing of a patient with its in-house manufactured product candidate UCART22. The first patient completed the 28-day dose limiting toxicity observation period without complication. This is a major milestone for Cellectis: the ability to have our manufacturing in-house substantially increases the chances that eligible patients can be treated without delay.
• BALLI-01 study (evaluating UCART22) is now enrolling patients with product candidate manufactured in-house at DL2 (1 x10 ⁶ cells/kg) after FCA lymphodepletion.

 

AMELI-01 (evaluating UCART123) in relapsed or refractory acute myeloid leukemia (r/r AML)

• UCART123 is an allogeneic CAR T-cell product candidate targeting CD123 and is being evaluated in patients with r/r AML in the AMELI-01 Phase 1 dose-escalation clinical study.
• On December 12, 2022, Cellectis presented clinical data in an oral session at the American Society of Hematology (ASH) on its AMELI-01 clinical trial.
• The oral presentation reviewed preliminary data from patients who received UCART123 at one of the following dose levels: dose level 1 (DL1) 2.5x10⁵ cells/kg; dose level 2 (DL2) 6.25x10⁵ cells/kg; intermediate dose level 2 (DL2i) 1.5x10⁶ cells/kg; or dose level 3 (DL3) 3.30x10⁶ cells/kg after lymphodepletion with FC ([n=8], DL1 – DL3) or FCA ([n=9], DL2 & DL2i).

 

• The preliminary data show that adding alemtuzumab to the fludarabine and cyclophosphamide (FC) lymphodepletion regimen was associated with sustained host lymphodepletion and significantly higher UCART123 cell expansion, that correlated with improved anti-tumor activity.
• UCART123: 25% (n=2) of patients at DL2 in the FCA arm achieved meaningful response; one patient who had failed prior allogeneic stem cell transplant experienced a durable minimal residual disease (MRD)-negative complete response that continued beyond 12 months, as of December 2022.
• Overall, these preliminary data support the continued administration of UCART123 after FCA lymphodepletion in patients with r/r AML.
• AMELI-01 study is now enrolling patients in a two-dose regimen arm at DL2.

 

MELANI-01 (evaluating UCARTCS1) in relapsed or refractory multiple myeloma (r/r MM)

 

• UCARTCS1 is an allogeneic CAR T-cell product candidate targeting CS1 and is being evaluated in patients with r/r MM in the MELANI-01 Phase 1 dose-escalation clinical study.
• Cellectis is currently enrolling patients at dose level 1 (DL1) (1 × 10⁶ cells/kg) with FC preconditioning regimen.

 

NATHALI-01 (evaluating UCART20x22) in relapsed or refractory non-Hodgkin lymphoma (r/r NHL)

• UCART20x22 is Cellectis’ first allogeneic dual CAR T-cell product candidate being developed for patients with r/r NHL.
• On August 1, 2022, the U.S. Food and Drug Administration (FDA) cleared Cellectis’ Investigational New Drug (IND) application to initiate a Phase 1/2a clinical trial of UCART20x22 for patients with r/r NHL.
• Cellectis is now enrolling patients in the NATHALI-01 trial.

 

Research Data & Preclinical Programs

UCARTCS1

• On November 3, 2022, Cellectis in collaboration with the Amsterdam University Medical Center (VUmc) announced the release of an abstract on product candidate UCARTCS1, which was accepted for poster presentation at the ASH 2022 Annual Meeting.
• The abstract includes preclinical data evaluating in vitro activity of UCARTCS1 against multiple myeloma (MM) cell lines and bone marrow samples from MM patients, as well as in vivo activity in a MM mouse model. The potential impact of previous therapy and tumor characteristics on the in vitro efficacy of UCARTCS1 was also investigated.
• The preclinical data presented demonstrate anti-tumor activity in vitro and in vivo supporting the potential benefit of our UCARTCS1 first in-human study, MELANI-01, a Phase 1, open-label, dose-escalation trial for patients with r/r MM.

 

UCART20x22

• On April 8, 2022, Cellectis released preclinical data on its product candidate UCART20x22 at the American Association for Cancer Research (AACR) Annual Meeting. The data showed robust pre-clinical proof of concept with the potential to overcome common mechanisms of resistance to CAR T-cell therapies in relapsed or refractory Non-Hodgkin Lymphoma (r/r NHL), such as single-antigen escape or tumor heterogeneity.

 

UCART123

• On April 28, 2022, Cellectis announced the publication of two manuscripts in Nature Communications on its product candidate UCART123, currently being evaluated in the Phase 1 dose-escalation trial AMELI-01 in patients with r/r AML

 

• Allogeneic TCRαβ Deficient CAR T-cells Targeting CD123 in Acute Myeloid Leukemia - This preclinical study, led by Dr Monica Guzman, Ph.D., Division of Hematology and Oncology, Department of Medicine Weill Cornell Medical College, demonstrated that Cellectis’ product candidate UCART123 effectively eliminates AML cells in vitro and in vivo with improvements in overall survival and minimal impact against normal hematopoietic progenitors.
• While the majority of the few CD123 T-cell therapies evaluated to date rely on autologous approaches with complex clinical and logistical barriers, this set of preclinical results strongly supports the potential benefits of the allogeneic CAR T approach in AML

 

• Targeting CD123 in Blastic Plasmacytoid Dendritic Cell Neoplasm using Allogeneic Anti-CD123 CAR T Cells - This preclinical study, led by Professor Marina Konopleva, M.D., Ph.D., Department of Leukemia, University of Texas MD Anderson Cancer Center, demonstrated the antitumor activity of UCART123 in preclinical models of blastic plasmacytoid dendritic cell neoplasm (BPDCN).
• These preclinical results support our rationale of using allogeneic CD123 CAR T cells to treat AML. Cellectis’ UCART123 is the first allogeneic product candidate to demonstrate elimination of AML and BPDCN cells in PDX mouse experiments, with significant benefits in overall survival and low impact on hematopoietic progenitor cells.

 

TALEN®-edited smart CAR T-cells

 

• On November 10, 2022, Cellectis presented two posters at the Society for Immunotherapy of Cancer’s (SITC) Annual Meeting:
• A poster: Multi-armored allogeneic MUC-1 CAR T-cells efficiently control triple negative breast cancer tumor growth. MUC1 is a tumor-associated antigen that is overexpressed in a number of solid tumor malignancies including triple-negative breast cancer (TNBC). Preclinical data showed that we can efficiently generate allogeneic CAR T-cells and engineer them to overcome several key challenges of immune suppressive solid tumors.

 

• A poster: TALEN®-edited smart CAR T-cells leverage solid tumor microenvironment for specific and effective immunotherapy. This proof-of-concept study demonstrates the feasibility of developing CART cell engineering strategies that can improve solid tumor targeting while mitigating potential safety risks, paving the way for clinical development.

 

TALEN®- based gene therapy preclinical programs

• On October 11, 2022, at the European Society of Gene and Cell Therapy (ESGCT), Cellectis presented pre-clinical data that leverages TALEN® gene editing technology to develop a hematopoietic stem and progenitor cell (HSPCs)-based gene therapy for the treatment of sickle cell disease, and a TALEN®-based gene editing approach that reprograms HSPCs to secrete alpha-L-iduronidase (IDUA), a therapeutic enzyme missing in Mucopolysaccharidosis type I (MPS-I).
• The pre-clinical data presented at ESGCT further demonstrate our ability to leverage TALEN® gene editing technology to potentially address genetic diseases, namely sickle cell disease and lysosomal storage diseases. By correcting a mutation or inserting a corrected gene at the HSPC level, Cellectis aims to provide a lifelong supply of healthy cells in a single intervention.

 

TALEN® and TALE Base Editors (TALE-BE)

• On November 10, 2022, Cellectis published a manuscript in Frontiers Bioengineering and Biotechnology demonstrating the feasibility of efficient multiplex gene engineering using a combination of two different molecular tools: TALEN® gene editing technology (TALE nuclease) and TALE Base Editors (TALE-BE)
• A multiplex/multitool strategy presents several advantages: firstly, it prevents the creation of translocations often observed with the simultaneous use of several nucleases. Secondly, it allows for the possibility of going beyond multiple knock-outs while still allowing gene knock-in at the nuclease target site, altogether extending the scope of possible application. The precise positional rules we have determined for TALE-BE position Cellectis to unleash the potential of these technologies for future applications.

 

Novel Immune-Evasive Universal Allogeneic CAR T-cells

• On May 16, 2022, Cellectis presented its first research data on the development of a novel universal CAR T-cell with immune-evasive properties using TALEN®-gene editing at the American Society of Cell and Gene Therapy (ASGCT)
• Universal CAR T-cell therapies are poised to revolutionize cancer treatment and to improve patient outcomes. Realizing these advantages in an allogeneic setting requires universal CAR T cells that can kill target tumor cells, avoid depletion by the host immune system, and proliferate without attacking host tissues. Cellectis’ research suggested that ΔTRACCARΔB2MHLAE T-cells evade NK cell and alloresponsive T-cell attacks and showed prolonged antitumor activity in the presence of cytotoxic levels of NK cells. This new cellular scaffold could enable the broad use of universal CAR T-cells in allogeneic settings and holds great promise for clinical applications
• On June 30, 2022, following its presentation at ASGCT, Cellectis published its research data in Nature Communications

 

Licensed Allogeneic CAR T-cell Development Programs

Allogene Therapeutics, Inc.’s CAR T programs utilize Cellectis technologies.

ALLO-501 and ALLO-501A are anti-CD19 products being jointly developed under a collaboration agreement between Servier and Allogene based on an exclusive license granted by Cellectis to Servier (the “Servier Agreement”). Servier grants to Allogene exclusive rights to ALLO-501 and ALLO-501A in the U.S. while Servier retains exclusive rights for all other countries. In September 2022, Servier communicated to us and Allogene that it was discontinuing its involvement in the development of in-licensed CD19 products and purporting to provide Allogene with the ability to elect to obtain a license to the CD19 products outside of the United States. We are evaluating all available options and contractual remedies to address the foregoing matters and other performance issues, which we believe may involve material breaches of the Servier Agreement by Servier. Allogene’s anti-BCMA and anti-CD70 programs are licensed exclusively from Cellectis by Allogene and Allogene holds global development and commercial rights to these programs.

 

Servier and Allogene: anti-CD19 programs 

In October 2022, Allogene announced it had initiated “the industry’s first potentially pivotal  Phase 2” allogeneic CAR T clinical trial with ALLO-501A. The single-arm trial is enrolling patients with relapsed/refractory (r/r) large B cell lymphoma (LBCL) and utilizes a single dose of ALLO-501A (120 million CAR+ cells) with the FCA90 (fludarabine, 30mg/m2, cyclophosphamide 300 mg/m2 and ALLO-647 30 mg, daily for 3 days) lymphodepletion regimen. The ALPHA2 trial will enroll approximately 100 patients who have received at least two prior lines of therapy and have not received prior anti-CD19 therapy. The primary endpoint of this trial is overall response rate (ORR), and the key secondary endpoint is duration of response (DoR). Patients may receive treatment as an outpatient at the investigator’s discretion.

 

In November 2022, Phase 1 data from the ALPHA trial with ALLO-501 and ALPHA2 trial with ALLO-501A for the treatment of r/r LBCL was presented at Allogene’s R&D Showcase. Data from the Phase 1 trials of ALLO-501 and ALLO-501A support the ability of a single administration of CAR T cells to generate deep and durable responses comparable to those with approved autologous CAR T therapies. Highlights included:

 

• As of the October 25, 2022 data cutoff, the ORR and Complete Response (CR) rate was 67% and 58%, respectively, among the 12 patients treated with the Single Dose FCA90 regimen using Alloy™ process material. The median duration of response was 23.1 months.
• Of patients who received single dose FCA90 and were evaluable at six months, the ongoing CR rate was 50% and all CRs at six months were durable at 12 months. The longest CR ongoing at 26+ months.
• Phase 1 trials demonstrated a manageable safety profile with no observed dose limiting toxicities (DLTs), graft-vs-host disease (GvHD) or severe immune effector cell-associated neurotoxicity syndrome (ICANS).
• Among patients treated with Single Dose FCA90, there was no Grade 3+ CRS. One patient (8%) experienced a Grade 3+ infection and two (17%) experienced prolonged Grade 3+ cytopenia.
• 92% of all enrolled patients received product with 100% of infused product manufactured and released per product specifications. Patients were able to initiate treatment within two days of enrollment.

Allogene has announced it is preparing for a Phase 3 study in earlier line LBCL targeting trial initiation in 1H 2024.

Allogene is developing ALLO-647, its proprietary anti-CD52 monoclonal antibody intended to enable expansion and persistence of AlloCAR T product candidates, including ALLO-501A. Allogene expects that the EXPAND trial, which is intended to demonstrate the contribution of ALLO-647 to the lymphodepletion regimen, will be open to enrollment early in the second quarter.

 

Allogene: anti-BCMA program

 

Data from the Phase 1 UNIVERSAL trial with ALLO-715 for the treatment of relapsed or refractory multiple myeloma (MM r/r) was also presented at Allogene’s R&D Showcase and subsequently published in Nature Medicine, accompanied by an editorial. The UNIVERSAL trial is the first allogeneic anti-BCMA CAR T to demonstrate proof-of-concept in MM with response rates that are similar to an approved autologous CAR T therapy. Allogene’s highlights include:

 

·         Dose expansion cohorts demonstrated substantial and durable responses.

·       Through a median follow-up of 14.8 months as of the October 11, 2022 data cutoff,  ORR was 67% in the FCA60 cohort and the very good partial response or better rate (VGPR+) was 42%. All VGPR+ were minimal residual disease (MRD) negative.

·         The median DoR was 9.2 months, with the longest response ongoing at 24 months.

·         92% of all enrolled patients received product with 100% of infused product manufactured and released as per product specifications. None of the patients received bridging therapy and patients were able to initiate treatment immediately following enrollment. Median time from enrollment to lymphodepletion was 5 days.

·         Safety profile was manageable with low-grade and reversible neurotoxicity and no  GvHD. Eight patients (29%) experienced Grade 3+ infections and eight patients experienced prolonged Grade 3+ cytopenias.

Allogene is evaluating manufacturing processes improvements across its BCMA candidates to achieve optimal performance.

 

Allogene: solid tumor program

ALLO-316, Allogene’s first AlloCAR T candidate for solid tumors, targets CD70, an antigen expressed on clear cell renal cell carcinoma (RCC) and other malignancies. At Allogene’s R&D Showcase, Allogene presented initial data demonstrating promising anti-cancer activity in the subset of nine patients with confirmed CD70-positive RCC from the ongoing Phase 1 TRAVERSE trial. Allogene’s highlights include:

·         As of the data cutoff date of November 17, 2022, the disease control rate (DCR) in patients who were CD70+ was 100% including three patients who achieved a partial response (PR) (two confirmed and one unconfirmed with the longest response lasting until month eight).

·         Cell expansion in patients with CD70 positive tumor was robust, and there was a trend toward greater tumor shrinkage in patients with high CD70 expression.

·         Across all patients treated in the trial, ALLO-316 has demonstrated a generally manageable safety profile with no GvHD. One dose limiting toxicity of auto-immune hepatitis occurred in the second dose level. Grade 3+ prolonged cytopenia was observed in three patients (18%). Grade 3 CRS was observed in one patient.  Neurotoxicity was low grade, reversible and seen in only three patients (18%). 

 

Allogene is deploying a new investigational in vitro companion diagnostic (IVD) assay designed to prospectively assess CD70 expression levels to enhance patient selection. TRAVERSE will continue to explore varying cell dose and lymphodepletion regimens, including FC and FCA. Subject to ongoing results in the TRAVERSE trial, Allogene intends to complete planned dose exploration and initiate expansion cohort enrollment in 2023. Allogene may also investigate ALLO-316 for other CD70 expressing solid tumors and hematologic indications, or in combination with other anticancer therapies such as immune checkpoint inhibitors.

 

Gene Editing Partnerships

Iovance Biotherapeutics, Inc. (“Iovance”)

 

• On October 10, 2022, Iovance announced that the first patient was dosed and completed the safety observation period in the IOV-GM1-201 clinical trial of Iovance’s first genetically modified TIL therapy in development, IOV-4001, for the treatment of previously treated advanced melanoma or metastatic NSCLC.
• To inactivate the gene coding for the PD-1 protein, IOV-4001 utilizes the gene-editing TALEN® technology licensed from Cellectis. This single genetic modification in IOV-4001 has the potential to enhance the antitumor activity of the TIL mechanism to directly target and kill tumor cells.
• Dosing the first patient with IOV-4001 is an important first step in providing proof-of-concept for delivering genetically modified TIL therapy to solid tumor patients with significant unmet needs and few treatment options.

 

Cytovia Therapeutics, Inc. (“Cytovia”)

• On February 12, 2021, Cellectis entered into a research collaboration and non-exclusive license agreement with Cytovia, which provided for an upfront payment or equity stake in Cytovia of $20 million (the “Upfront Payment”). On April 27, 2022, in connection with Cytovia’s entry into a business combination agreement with a publicly traded Special Purpose Acquisition Company, Cellectis entered into an amendment to the license agreement and received a $20 million convertible note (the “2022 Convertible Note”), which superseded and replaced the Upfront Payment obligation, as well as a warrant (the “SPAC Warrant”) to purchase additional shares of Cytovia following its combination with a publicly traded Special Purpose Acquisition Company (SPAC).

 

• Cellectis and Cytovia entered into an amended and restated note, which became effective as of December 22, 2022 (the “Amended and Restated 2022 Note”). The Amended and Restated 2022 Note provides for automatic conversion into Cytovia common stock in the case of certain fundamental transactions where Cytovia becomes a public company and for conversion at Cellectis’ option in connection with certain financing transactions, upon a company sale and at final maturity. In each case conversion is subject to a 9.9% ownership cap, with the balance issuable in the form of pre-funded warrants.  The Amended and Restated 2022 Note increased the interest rate to 10% per annum, subject to a 10% step up upon the occurrence and continuation of an event of default, provided for the repayment of 50% of the outstanding amount on April 30, 2023 and extended the final maturity date for the repayment of the remaining outstanding amount to June 30, 2023. The SPAC Warrant remains outstanding, but only applies in connection with Cytovia’s business combination with a SPAC.

 

• Cellectis is developing custom TALEN®, which Cytovia uses to edit iPSCs. Cytovia is responsible for the differentiation and expansion of the gene-edited iPSC master cell bank into NK cells and is conducting the pre-clinical evaluation, clinical development, and commercialization of the mutually-agreed-upon selected therapeutic candidates. Cellectis has granted Cytovia a worldwide license under the patent rights over which Cellectis has control in this field, including in China, in order for Cytovia to modify NK cells to address multiple gene-targets for therapeutic use in several cancer indications.

 

• In November 2022, Cytovia presented preclinical data on TALEN® gene-edited, induced pluripotent stem cells (iPSC)-derived Natural Killer (NK) cells at the Society for Immunotherapy of Cancer’s (SITC) Annual Meeting.

 

• These data highlight the progress of Cellectis’ research and development collaboration with Cytovia to develop TALEN®-edited iPSC NK and CAR-NK cells. Cellectis has developed custom TALEN® which Cytovia is using to edit iPSCs in a safe and effective manner.

 

Primera Therapeutics, Inc. (“Primera”)

• On December 29, 2022, Cellectis and Primera announced the execution of a Collaboration Agreement under which the companies will work collaboratively to edit mutations in the mitochondrial DNA (mtDNA) in vivo to treat the root cause of associated diseases. Primera, together with Cellectis, will be co-developing a mtDNA engineering toolbox that could enable effective therapies for mitochondrial diseases.
• The companies agreed to enter supplemental agreements, under which Cellectis would receive a 19% equity ownership stake in Primera and would take a seat on Primera’s Board of Directors.

 

• Pursuant to the Collaboration Agreement, Primera has a right to exercise an exclusive worldwide option for a license from Cellectis on up to five product candidates developed under the collaboration (the “partnership products”). Upon Primera exercising the option, Cellectis will be eligible for up to $750 million of development and sales milestones for the partnership products, as well as high single-digit royalty payments on the net sales of partnership products.

 

2022 Corporate Updates

On December 28, 2022, Cellectis entered into a €40 million credit facility with the European Investment Bank (EIB) to support its research, development and innovation activities. This finance contract provides for funding in three tranches of €20.0 million, €15.0 million and €5.0 million, respectively, with each tranche’s disbursement subject to certain conditions, including, among others, the execution of a warrant agreement for the issuance at the time of disbursement of a specified number of warrants for the benefit of EIB. Borrowings under the finance contract mature with respect to each tranche six years following disbursement and accrue interest at a rate of 8.0% per annum (for the first tranche), 7.0% per annum (for the second tranche) and 6.0% per annum (for the third tranche).

The Company plans to use the facility toward the development of its pipeline in the field of allogeneic CAR T-cell product candidates, UCART22, UCART20x22, UCART123 and UCARTCS1.

 

Appointments

 

• On June 28, 2022, Cellectis announced that during the annual shareholders meeting, Axel-Sven Malkomes and Donald Bergstrom, M.D., Ph.D., were appointed as Directors of the Company’s Board of Directors, with immediate effect.
• Previously, Donald A Bergstrom, M.D., Ph.D., was appointed as a Board Observer on the Company’s Board of Directors on November 4, 2021. Dr. Bergstrom currently serves as Executive Vice President, Head of Research and Development at Relay Therapeutics, Inc., a clinical-stage precision medicines company.
• Axel-Sven Malkomes joined the management of Cardior Pharmaceuticals GmbH as Chief Financial Officer on November 1, 2022. Cardior is a leading clinical-stage biopharmaceutical company active in discovery and development of non-coding RNA-based therapeutics designed to prevent, repair and reverse diseases of the heart. He brings with him over 25 years of experience in the healthcare sector. Previously, Mr. Malkomes served as Chief Financial Officer & Chief Business Officer at Medigene AG, a clinical stage immuno-oncology company focusing on the development of T-cell immunotherapies for the treatment of cancer.