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Item 8.01. Other Events.
On September 1, 2023, Carisma Therapeutics Inc. (the “Company”) issued a press release announcing preliminary findings from the first five patients enrolled in group 2 of the Company’s Phase 1 clinical trial of its lead product candidate, CT-0508, a human epidermal growth factor receptor 2 (“HER2”) targeted chimeric antigen receptor macrophage for the treatment of HER2 overexpressing cancers. The Company will provide an overview of the group 2 data during a presentation at the 8th Annual CAR-TCR Summit on September 1, 2023. A copy of the press release and an excerpt from the presentation are attached hereto as Exhibits 99.1 and 99.2 and are incorporated herein by reference.
The Company is providing the following supportive data for the Phase 1 clinical trial:
The Company initiated a second group to evaluate the safety of bolus dosing of patients, and five patients have been successfully dosed to date with a single-day bolus infusion. Consistent with results from group 1 of the trial, based on preliminary results assessed to date from these five patients enrolled in group 2, CT-0508 has been generally well-tolerated after infusion with no dose-limiting toxicities, was successfully manufactured using macrophages obtained from heavily pre-treated, advanced solid tumor patients, and has shown high CAR expression, viability, and purity. While the results from this early clinical trial data are both preliminary and limited, the Company believes the combined group 1 and group 2 results support the previously presented preliminary results from this trial indicating that CT-0508 can potentially lead to remodeling and activation of the tumor microenvironment (“TME”) and induce anti-tumor adaptive immunity. In group 1, a best overall response (“BOR”) of stable disease was seen in 4 out of 9 patients, and in group 2, the best overall response was progressive disease. Translational analyses combining group 1 and group 2 demonstrated a correlation between TME activation, T cell activation, and HER2 status with BOR of stable disease.
The single-agent arm of the study remains open and up to four additional patients may be enrolled. However, given the clinical findings observing T cell exhaustion as a potential limiting factor, and pre-clinical data demonstrating robust synergy upon combining CT-0508 with T cell checkpoint inhibition, the Company expects to focus its ongoing efforts primarily on enrolling patients in its sub-study administering CT-0508 in combination with pembrolizumab.
Item 9.01. Financial Statements and Exhibits.
|99.1||Press Release issued by Carisma Therapeutics Inc. on September 1, 2023.|
|99.2||Excerpt from Company Presentation, dated September 2023.|
|104||Cover Page Interactive Data File (embedded within the Inline XBRL document).|
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 hereunto duly authorized.
|CARISMA THERAPEUTICS INC.|
/s/ Steven Kelly
|Date: September 1, 2023||Steven Kelly|
|President and Chief Executive Officer|
Carisma Announces Latest Data from Phase 1 Clinical Trial of CT-0508 at 8th Annual CAR-TCR Summit
Group 2 data available to date support primary safety and feasibility endpoints of single-day bolus dosing of CT-0508
New translational analyses combining group 1 & group 2 continue to support CAR-M mechanism of action, demonstrating a correlation between biomarkers and best overall response
PHILADELPHIA, PA – September 1, 2023 – Carisma Therapeutics Inc. (Nasdaq: CARM) (“Carisma” or the “Company”), a clinical stage biopharmaceutical company focused on discovering and developing innovative immunotherapies, will present findings today at the 8th Annual CAR-TCR Summit from its Phase 1 clinical trial of the Company’s lead product candidate, CT-0508, a human epidermal growth factor receptor 2 (“HER2”) targeted chimeric antigen receptor macrophage (“CAR-M”) for the treatment of advanced/metastatic HER2 overexpressing cancers.
The presentation includes data from group 1 (n=9) and group 2 (n=5). Patients in both groups received the same total dose (up to 5x109 CT-0508) either via a fractionated, multi-day infusion regimen (group 1) or via a single-day bolus infusion (group 2). The data are drawn from the ongoing clinical trial led by Kim A. Reiss, MD, principal investigator of the Phase 1 clinical trial and an associate professor of Hematology-Oncology in the Perelman School of Medicine at the University of Pennsylvania.
In the presentation, Michael Klichinsky, PharmD, PhD, Co-Founder and Chief Scientific Officer at Carisma, will present data demonstrating that, in both groups, CT-0508 was successfully manufactured for patients and that the administration of CT-0508 was well-tolerated after infusion with no dose-limiting toxicities reported to date.
“As the CT-0508 trial progresses, it is promising to see consistent results supporting the safety profile, feasibility, and mechanism of action of this first-in-class CAR-M investigational therapy,” commented Dr. Klichinsky. “We look forward to results from the CT-0508 combination sub-study with pembrolizumab and continued development of CAR-M and CAR-Monocyte therapies.”
Previously, Carisma presented findings from group 1 showing that CT-0508 remodeled and activated the tumor microenvironment (“TME”) and initiated anti-tumor T cell immunity. Translational analyses combining group 1 and group 2 show that various biomarkers including metrics of TME activation, T cell activation, and HER2 status correlate with best overall response (“BOR”) of stable disease, providing further evidence of the CT-0508 mechanism of action.
The Phase 1 study translational analyses further demonstrate an increase in exhausted CD8 T cells on treatment, supporting the ongoing combination sub-study with Merck’s anti-PD1 therapy KEYTRUDA® (pembrolizumab). This latest data readout follows the dosing of the first patient in the ongoing sub-study of the Phase 1 clinical trial of CT-0508 in combination with pembrolizumab for the treatment of HER2 overexpressing cancers.
The Company is filing a Current Report on Form 8-K today with the U.S. Securities and Exchange Commission disclosing the new data from its Phase 1 clinical trial of CT-0508, including an excerpt of the presentation being made at the 8th Annual CAR-TCR Summit.
Editor’s Note: Carisma has licensed certain Penn-owned intellectual property from the University of Pennsylvania, and Penn’s Perelman School of Medicine receives sponsored research and clinical trial funding from the company. Penn may be entitled to receive additional financial benefits from technologies licensed and optioned to Carisma. In addition, Penn is a co-founder of the company and holds equity in Carisma.
CT-0508 is a human epidermal growth factor receptor 2 (HER2) targeted chimeric antigen receptor macrophage (CAR-M). It is being evaluated in a landmark Phase 1 multi-center clinical trial that focuses on patients with recurrent or metastatic HER2-overexpressing solid tumors whose cancers do not have approved HER2-targeted therapies or who do not respond to treatment. Carisma is selecting participants who have tumors of any anatomical origin, but with the commonality of overexpressing the HER2 receptor on the cell surface, which is the target for our CAR-M. The Phase 1 clinical trial marks the first time that engineered macrophages are being studied in humans. The trial continues to enroll patients at seven clinical sites in the U.S., including (i) Penn Medicine’s Abramson Cancer Center, (ii) the University of North Carolina Lineberger Comprehensive Cancer Center, (iii) the City of Hope National Medical Center, (iv) the MD Anderson Cancer Center, (v) the Sarah Cannon Cancer Research Institute, (vi) Oregon Health & Science University and (vii) Fred Hutchinson Cancer Center.
Carisma Therapeutics Inc. is a clinical stage biopharmaceutical company focused on utilizing our proprietary macrophage and monocyte cell engineering platform to develop transformative immunotherapies to treat cancer and other serious diseases. We have created a comprehensive, differentiated proprietary cell therapy platform focused on engineered macrophages and monocytes, cells that play a crucial role in both the innate and adaptive immune response. Carisma is headquartered in Philadelphia, PA. For more information, please visit www.carismatx.com.
Cautionary Note on Forward-Looking Statements
Statements in this press release about future expectations, plans and prospects, as well as any other statements regarding matters that are not historical facts, may constitute "forward-looking statements" within the meaning of The Private Securities Litigation Reform Act of 1995. These statements include, but are not limited to, statements relating to Carisma’s business, strategy, future operations, cash runway, the advancement of Carisma’s product candidates and product pipeline, and clinical development of Carisma’s product candidates, including expectations regarding timing of initiation and results of clinical trials and ability to replicate in later clinical trials positive results found in preclinical studies and early-stage clinical trials of its product candidates. The words "anticipate," "believe," "contemplate," "continue," "could," "estimate," "expect," "goals," "intend," "may," "might," "outlook," "plan," "project," "potential," "predict," "target," "possible," "will," "would," "could," "should," and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words.
Any forward-looking statements are based on management's current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in, or implied by, such forward-looking statements. For a discussion of these risks and uncertainties, and other important factors, any of which could cause Carisma's actual results to differ from those contained in the forward-looking statements, see the "Risk Factors" set forth in the Company's Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission on August 10, 2023, as well as discussions of potential risks, uncertainties, and other important factors in Carisma's other recent filings with the Securities and Exchange Commission. Any forward-looking statements that are made in this press release speak as of the date of this press release. Carisma undertakes no obligation to revise the forward-looking statements or to update them to reflect events or circumstances occurring after the date of this press release, whether as a result of new information, future developments or otherwise, except as required by the federal securities laws.
HARNESSING THE POWER OF ENGINEERED MACROPHAGES Michael Klichinsky, PharmD PhD Co-Founder & Chief Scientific Officer CAR-TCR September 2023
2 Cautionary Note Regarding Forward-Looking Statements Regarding Carisma Statements in this press release about future expectations, plans and prospects, as well as any other statements regarding matters that are not historical facts, may constitute "forward-looking statements" within the meaning of The Private Securities Litigation Reform Act of 1995. These statements include, but are not limited to, statements relating to Carisma’s business, strategy, future operations, cash runway, the advancement of Carisma’s product candidates and product pipeline, and clinical development of Carisma’s product candidates, including expectations regarding timing of initiation and results of clinical trials. The words ““anticipate,” “believe,” “contemplate,” “continue,” “could,” “estimate,” “expect,” “goals,” “intend,” “may,” “might,” “outlook,” “plan,” “project,” “potential,” “predict,” “target,” “possible,” “will,” “would,” “could,” “should,” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements are based on management's current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in, or implied by, such forward-looking statements. These risks and uncertainties include, but are not limited to, (i) Carisma’s ability to obtain, maintain and protect its intellectual property rights related to its product candidates; (ii) Carisma’s ability to advance the development of its product candidates under the timelines it anticipates in planned and future clinical trials; (iii) Carisma’s ability to replicate in later clinical trials positive results found in preclinical studies and early-stage clinical trials of its product candidates; (iv) Carisma’s ability to realize the anticipated benefits of its research and development programs, strategic partnerships, research and licensing programs and academic and other collaborations; (v) regulatory requirements or developments and Carisma’s ability to obtain and maintain necessary approvals from the U.S. Food and Drug Administration and other regulatory authorities; (vi) changes to clinical trial designs and regulatory pathways; (vii) risks associated with Carisma’s ability to manage expenses; (viii) changes in capital resource requirements; (ix) risks related to the inability of Carisma to obtain sufficient additional capital to continue to advance its product candidates and its preclinical programs; and (x) legislative, regulatory, political and economic developments. For a discussion of other risks and uncertainties, and other important factors, any of which could cause the Carisma’s actual results to differ from those contained in the forward-looking statements, see the "Risk Factors" set forth in Exhibit 99.3 to Carisma’s Current Report on Form 8-K filed with the Securities and Exchange Commission on August 10, 2023, Carisma’s Annual Report on Form 10-K for the year ended December 31, 2022 filed with the Securities and Exchange Commission on February 28, 2023, Carisma’s Quarterly Report on Form 10-Q for the quarter ended June 30, 2023 filed with the Securities and Exchange Commission on August 10, 2023, as well as discussions of potential risks, uncertainties, and other important factors in Carisma’s most recent filings with the Securities and Exchange Commission. Any forward-looking statements that are made in this presentation speak as of the date of this presentation. Carisma undertakes no obligation to revise the forward-looking statements or to update them to reflect events or circumstances occurring after the date of this presentation, whether as a result of new information, future developments or otherwise, except as required by the federal securities laws. 9/1/2023
Lead Program CT-0508 Anti-HER2 CAR-M Phase I Trial
10 CT-0508: HER2 Targeted CAR-Macrophage First-in-class & first-in-human engineered macrophage Cells: Autologous monocyte derived macrophages Vector: Ad5f35 Phenotype: M1 Target: HER2 CAR: 1st Generation Single Agent Days 1 / 3 / 5 Dosing (n=9) Single Agent Day 1 Bolus Dosing (n=up to 9) CT-0508 + Pembro Combination (n=9) Study Summary • Pts pre-mobilized with G-CSF • Dose: 1 to 5 x 109 cells • No pre-conditioning • Endpoints • Feasibility • Safety • PK and MOA Program Overview • HER2 2+/3+ metastatic solid tumor basket trial • Phase I multi-center, open-label study open at 7 US sites • Cohorts: • Group 1 (Fractionated dosing): Complete – data presented at ‘22 SITC • Group 2 (Bolus dosing): Enrolling – Early data included today • CT-0508 + pembrolizumab: Enrolling Cohorts 9/1/2023
11 • Source: autologous mobilized peripheral blood monocytes • Mfg time: ~1 week • Vein to vein: ~3 weeks • Vector: Ad5f35 • Process: Automated • Format: Cryopreserved • Successful manufacturing: - CAR-M Manufacturing Process Manufacturing Partners: Viability mean % 86% Purity mean % 89% CAR+ mean % 79% Total cells based on label (cells) 2.06E+09 9/1/2023
12 Successful CT-0508 Manufacturing: Functional M1 Polarized CAR-M Generated High viability, purity, and CAR expression Patient Derived CT-0508 Healthy Donor Derived CT-0508 P atie nt H e alth y D o n or 0 20 40 60 80 100 % Via ble P atie nt H e alth y D o n or 0 20 40 60 80 100 % Pro d u ct P urity P atie nt H e alth y D o n or 0 20 40 60 80 100 % C A R E x pre s sio n All patient CT-0508 batches show M1 polarization Monocytes CT-0508 M1 signature score 9/1/2023
13 Patient CT-0508 CAR-dependent cytokine secretion Patient CT-0508 are functional in vitro: Each batch demonstrated target killing, phagocytosis, M1 polarization, and cytokine release M SLN HER2 0 500 1000 1500 TNFα p g/ml ✱✱✱✱ M SLN HER2 0 500 1000 1500 2000 IL-6 p g/ml ✱✱✱✱ M SLN HER2 0 50 100 150 IL-1β p g/ml ✱✱ M SLN HER2 0 100 200 300 400 500 IL-18 p g/ml ✱✱✱✱ M SLN HER2 0 10000 20000 30000 40000 50000 MIP-1α (CCL3) p g/ml ✱✱✱✱ M SLN HER2 0 10000 20000 30000 40000 MIP-1β (CCL4) p g/ml ✱✱✱✱ M SLN HER2 0 10 20 30 40 GM-CSF p g/ml ✱✱✱ All CT-0508 batches kill HER2+ tumor cells 0 24 48 72 0.00 0.25 0.50 0.75 1.00 1.25 SKOV3 (ovarian cancer) N orm aliz e d to T u m or B urd e n 0 24 48 72 0.00 0.25 0.50 0.75 1.00 1.25 Time (hr) N orm aliz e d to T u m or B urd e n 0 24 48 72 0.00 0.25 0.50 0.75 1.00 1.25 AU565 (breast cancer) N orm aliz e d to T u m or B urd e n 0 24 48 72 0.00 0.25 0.50 0.75 1.00 1.25 Time (hr) N orm aliz e d to T u m or B urd e n 9/1/2023
14 CT-0508 Study 101 patient demographics (n=14) Summary of Participant and Tumor Characteristics Characteristic N = 14 Characteristic N = 14 Median age (range), years 58 (45, 81) Tumor Type, n (%) Breast Cancer Esophageal Cancer Salivary Carcinoma Cholangiocarcinoma Ovarian Cancer 8 (57.1) 2 (14.3) 2 (14.3) 1 (7.1) 1 (7.1) Gender, n (%) Male Female 4 (28.6) 10 (71.4) Race, n (%) White 14 (100) Median Number of Prior Cancer Therapies, n (range) 5 (2, 12) ECOG PS, n (%) 0 1 9 (64.3) 4 (28.6) Median Number of Prior Anti-HER2 Therapies, n (range) Subjects with Prior Anti-HER2 Therapy 2 (0, 9) 13 (92.9) HER2 Overexpression, n (%) IHC 3+ IHC 2+/FISH+ 9 (64.3) 5 (35.7) Prior Radiotherapy, n (%) Yes 9 (64.3) Microsatellite Instability (MSI)* MSS/MSI-Low MSI-High Unknown 13 (92.9) 0 (0) 1 (7.1) Tumor Mutational Burden (TMB)* Low (<10 mut/Mb) High (≥10 mut/Mb) Unknown 11 (78.6) 2 (14.3)† 1 (7.1) * MSI-high and TMB high are known biomarkers associated with improved response to immune checkpoint † 1 patient had received 11 lines of prior therapy and 1 patient has demonstrated HLA-A and HLA-C loss of Heterozygosity 9/1/2023
15 CT-0508 is Well Tolerated with No Dose Limiting Toxicities Similar safety profile between Group 1 and Group 2 9/1/2023 Majority of Adverse Events were Grade 1-2 Group 1 & Group 2 Combined • No dose limiting toxicities. • No severe CRS or ICANS. • All SAEs related to treatment were due to hospitalization for monitoring of either Grade 2 CRS or Grade 2 infusion reaction. Group 1 Group 2 Combined Patients Treated N=9 (%) N=5 (%) N=14 (%) Infusion Reaction 2 (22.2%) 1 (20.0%) 3 (21.4%) Grade 1 1 (11.1%) 0 (0.0%) 1 (7.1%) Grade 2 1 (11.1%) 1 (20.0%) 2 (14.2%) CRS (cytokine release syndrome) 6 (66.7%) 3 (60.0%) 9 (64.2%) Grade 1 4 (44.4%) 1 (20.0%) 5 (35.7%) Grade 2 2 (22.2%) 2 (40.0%) 4 (28.6%) Grade 3-4 (Severe) 0 (0.0%) 0 (0.0%) 0 (0.0%) ICANS 0 (0.0%) 0 (0.0%) 0 (0.0%) SAEs Related To Treatment 2 (22.2%) 3 (60.0%) 5 (35.7%) # of events Similar safety profile between Group 1 and Group 2
16 Transient Elevations of Pro-Inflammatory Cytokines Day 1 Day 3 Day 5 Day 7 Concentration (pg/mL) Day 1 Day 3 Day 5 Day 7 Day 1 Day 3 Day 5 Day 7 9/1/2023
17 CT-0508 rapidly extravasates from peripheral blood and were detected in the tumor of 8/9 patients CT-0508 detection in the TME: CT-0508 was detected in the TME of 8/9 pts. CT-0508 peripheral blood pharmacokinetics: Rapid egress out of peripheral blood following each dose. ND Infusion Infusion Infusion Infusion ND CT-0508 Transgene (copy number/µg of DNA) 9/1/2023
18 Best Overall Response of Stable Disease Change in Target Lesion From Baseline (%) Evaluated Participants N = 14* Best Overall Response (RECIST 1.1) Stable Disease: 4 (28.6%) Change in Target Lesion From Baseline (%) Best Overall Response Change in Tumor Burden Over Time Best Overall Change in Tumor Burden 9/1/2023
19 HER2 expression (3+) correlated with Best Overall Response* Correlation between HER2 status and Best Overall Response * Per RECIST 1.1 Trend toward decrease in HER2+ tumor cells in pts with SD Evaluated Participants N = 14* HER2 2+ SD: 0/5 (0.00%) HER2 3+ SD: 4/9 (44.4%) Screening Day 8 Week 4 HER2 mRNA Expression (Log2) Best Overall Response n=5 PD n=4 SD n=5 PD HER2 2+ HER2 3+ SD: n=4 PD: n=5 PD: n=5 9/1/2023 RNA Seq
TME remodeling correlated with Best Overall Response* Immune Cell Recruitment Related Genes Tumor Inflamed Signature Related Genes** Antigen Presentation Machinery Related Genes Best Overall Response * Per RECIST 1.1 ** 18 gene Tumor Inflammation Signature developed by Nanostring T cell activation Related Genes 9/1/2023 20
21 TME remodeling correlated with Best Overall Response* Best Overall Response * Per RECIST 1.1 **Calculated using gene set variation analysis (GSVA) using the gene sets presented on the previous slide 9/1/2023 T cell activation Immune cell Recruitment Tumor inflamed signature Antigen presentation machinery 0 1 -1 Score change (screening to week 4)**
22 T cell expansion in the blood & TME correlated with Best Overall Response* Expansion of T cell clones in blood correlates w/ BOR * Per RECIST 1.1 # of clones Best overall response # of clones Expanding clones Emergent clones Accumulation of peripherally expanded clones in the TME Sum frequency Sum frequency Expanding clones Emergent clones Blood TME 9/1/2023
23 CT-0508 increased T cell clonality in TME and activated dominant clones suggesting epitope spreading Expanding clonotype: T Lymphocytes Repertoire clonality Blood Repertoire clonality TME CT-0508 increased T cell clonality Best Overall Response
Naïve-like Central Memory TEMRA Effector Memory Exhausted Proliferating 24 CT-0508 increased the frequency of central memory, effector memory, and exhausted CD8 T cells in the TME 0 Naïve-like Central Memory Effector Memory TEMRA Exhausted Proliferating Screening Week 4 Screening Week 4 Screening Week 4 Screening Week 4 Screening Week 4 Screening Week 4 9/1/2023 0
25 Early trends suggest improved baseline T cell fitness* correlates with Best Overall Response SD PD 0 2 4 6 CD4/CD8 in Aph C D 4 / C D 8 r a tio o f A p h e r e sis ( F r o m CIT E - S e q ) SD PD 0 20 40 60 CD8+CD27+CD45RO- of CD8 in Aph % C D 2 7 + C D 4 5 R O - o f C D 8 T c ells (F r o m CIT E - S e q) CD4/ CD8 ratio Frequency of CD8 Tscm Higher CD4/CD8 ratio and % of CD8 Tscm associated with improved T cell fitness * Based on peripheral blood T cell CD4/CD8 ratio and frequency of CD8+ T stem central memory in apheresis material 9/1/2023
FEASIBILITY • CT-0508 was successfully manufactured from autologous mobilized monocytes • Patient product demonstrated high CAR expression, purity, viability, M1 polarization and confirmed functionality • No lymphodepletion 26 CT-0508 Study 101 Interim Data Supports CAR-M Hypothesis and Combination with Pembrolizumab MECHANISM OF ACTION • CT-0508 tumor infiltration detected • TME remodeling correlates with clinical outcome • T cell expansion and fitness correlates with clinical outcome • Exhausted T cells increase on treatment PRELIMINARY CLINICAL PROFILE • No dose limiting toxicities • No severe CRS, no ICANS, and no major organ system toxicity observed • Best overall response of SD • SD in HER2 3+ population 44.4% (n=4/9); SD in HER2 2+ population 0% (n=0/5) • Group 2 enrolling 9/1/2023