On May 16, 2023 Boundless Bio, a clinical stage, next-generation precision oncology company developing innovative therapeutics directed against extrachromosomal DNA (ecDNA) for patients with oncogene amplified cancers, reported the closing of a $100 million Series C financing co-led by Leaps by Bayer, the impact investment arm of Bayer AG, and RA Capital Management, with participation from additional new investors, Sectoral Asset Management and Piper Heartland Healthcare Capital (Press release, Boundless Bio, MAY 16, 2023, View Source [SID1234631797]). Boundless Bio will use the financing to advance BBI-355, the first ecDNA-directed therapy (ecDTx), through meaningful clinical readouts from its ongoing Phase 1/2 clinical trial in patients with oncogene-amplified cancers.

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Historically, targeted therapies and immunotherapies have been largely ineffective in treating patients with oncogene amplified cancers. Boundless Bio is the first company wholly dedicated to developing novel therapeutics for patients with oncogene amplified cancers, specifically those enabled by ecDNA. Absent in normal healthy tissue, ecDNA have been observed in 14% of early-stage cancers and up to 40% of metastatic cancers and drive both oncogenesis as well as resistance to current therapeutic approaches. Boundless Bio is leveraging a unique understanding of the vulnerabilities of ecDNA biology with the aim to deliver potentially transformative therapies to the up to 400,000 patients newly diagnosed in the US each year with previously intractable oncogene amplified cancers.

The capital raised will fund initial clinical development of BBI-355, as a single agent and in combination with select therapies, for multiple cancer indications with oncogene amplifications being evaluated in the ongoing Phase 1/2 POTENTIATE clinical trial (NCT05827614). BBI-355 is an orally available, potent, and selective CHK1 inhibitor, which has been shown preclinically to be synthetically lethal to ecDNA-bearing oncogene-amplified cancer cells. The new funds will also support advancement of Boundless Bio’s preclinical pipeline of differentiated ecDTx candidates and its proprietary ecDNA diagnostic clinical trial assay, ECHO (ecDNA Harboring Oncogenes), which is being developed in partnership with SOPHiA GENETICS.

"At Leaps by Bayer, we invest in fundamental breakthroughs in healthcare," said Juergen Eckhardt, M.D., EVP and Head of Leaps by Bayer. "The ability to address oncogene amplified cancers has remained one of the industry’s greatest challenges in the treatment of cancer. We are thrilled to support Boundless Bio, a company whose innovations have the potential to impact the lives of patients who currently have no effective standard of care."

The Series C financing included participation from existing investors Fidelity Management & Research Company LLC, ARCH Venture Partners, Nextech Invest, Wellington Management, Vertex Ventures HC, Redmile Group, Surveyor Capital (a Citadel company), GT Healthcare Capital Partners, Alexandria Venture Investments, PFM Health Sciences, Logos Capital, and City Hill Ventures. In conjunction with the financing, Fabio Pucci, Ph.D., Senior Director of Venture Investments Health at Leaps by Bayer, will join the Boundless Bio Board of Directors.

"We are excited to have Leaps by Bayer join our world-class investor syndicate and to welcome Fabio Pucci to our Board of Directors," said Zachary Hornby, President and Chief Executive Officer of Boundless Bio. "The support from new investors along with the continued commitment of our existing investors emphasizes our momentum and progress in bringing the first ecDNA-directed therapies to patients with oncogene-amplified cancers."

About BBI-355

BBI-355 is a potentially best-in-class checkpoint kinase 1 (CHK1) inhibitor and the first ecDNA-directed therapy (ecDTx) being investigated to treat patients with oncogene amplified cancer. CHK1 is a master regulator of DNA replication stress (RS), which frequently arises from oncogene amplification on ecDNA. Inhibition of CHK1 by BBI-355 is synthetic lethal in cancer cells with oncogene amplification on ecDNA due to their heightened RS. CHK1 was identified and validated as an ecDNA essential target via Boundless Bio’s proprietary Spyglass research platform, leading Boundless Bio to develop BBI-355, an orally available, potent, and selective CHK1 inhibitor. BBI-355 is being evaluated in a first-in-human trial ("POTENTIATE": Precision Oncology Trial Evaluating Novel Therapeutic Interrupting Amplifications Tied to ecDNA) designed to evaluate the safety, maximum tolerated dose, and recommended Phase 2 dose of BBI-355 as a single agent and in combination with select therapies in patients with locally advanced or metastatic solid tumors with oncogene amplifications (NCT05827614).

On May 16, 2023 Arsenal Biosciences, Inc. (ArsenalBio), a clinical stage programmable cell therapy company engineering advanced CAR T-cell therapies for solid tumors, reported that it will present preclinical data on its integrated circuit T cell therapies, AB-1015 and AB-2100, in an oral abstract session and three posters at the American Society of Gene and Cell Therapy (ASGCT) (Free ASGCT Whitepaper) annual meeting in Los Angeles, Calif., May 16-20, 2023 (Press release, ArsenalBio, MAY 16, 2023, View Source [SID1234631796]).

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"We are looking forward to sharing preclinical data that reflects our ongoing commitment to leveraging our unique CRISPR-based approach to the development of new cell therapies for the potential treatment of ovarian cancer and kidney cancer," said Susie Jun, M.D., Ph.D., ArsenalBio’s Chief Medical Officer. "Utilizing our logic gate and shRNA technologies, we demonstrate the potential to enhance tumor specificity and anti-tumor activity of CAR T-cell therapy in solid tumor model systems."

ArsenalBio’s oral abstract session will detail preclinical data on AB-1015, currently in phase 1 clinical development (NCT05617755) for patients with ovarian cancer, that incorporates ArsenalBio’s technologies designed to address the barriers to successful adoptive T cell therapy. The three posters will disclose features and findings on AB-2100, a novel integrated circuit T cell therapeutic candidate engineered for the treatment of kidney cancer. AB-2100 is ArsenalBio’s second pipeline program which is targeting the initiation of a phase 1 trial in 2024.

The following abstracts will be presented as an oral abstract session and three posters during the ASGCT (Free ASGCT Whitepaper) annual meeting.

Abstract 149: Preclinical Development of AB-1015, an Integrated Circuit T Cell Therapy Containing an ALPG/MSLN Logic Gate and FAS/PTPN2 shRNA-miR, for the Treatment of Ovarian Cancer
Session title: Next Generation CAR, TCR, and AAV Technologies for Solid Tumors
Oral Abstract Presentation: Thursday, May 18, 2023, 2:45 – 3:00 p.m., Room 502 AB

CAR T cell activity in solid tumors is limited by off-tumor toxicity, antigen heterogeneity, poor persistence, and functional suppression resulting from the tumor microenvironment (TME). To address these challenges, we have developed AB-1015, an autologous, integrated circuit T (ICT) cell product for the potential treatment of ovarian cancer. The AB-1015 transgene cassette includes two functional modules: an "AND" logic gate designed to limit off-tumor toxicity through dual tumor antigen recognition, and a dual shRNA-miR targeting FAS and PTPN2 to resist TME suppression and to improve ICT cell function. AB-1015 is specific for ALPG/P+MSLN+, in preclinical studies, demonstrates superior potency, expansion, and persistence compared with logic gated T cells alone, and is resistant to ovarian TME suppression. Based on these promising preclinical data, AB-1015 is being studied in a phase I clinical trial (NCT05617755) to assess the safety, pharmacokinetics, immunogenicity, and efficacy for patients with platinum-resistant ovarian cancer.

Abstract 572: A PSMA Neovasculature-Inducible CA9 CAR Resistant to FASL and TGFB Mediated Suppression for the Treatment of ccRCC
Poster Session: Wednesday, May 17, 2023, 12:00 – 2:00 p.m. and 5:30 – 7:00 p.m.

Clinically effective CAR T-cell therapy for solid tumors will require substantial T cell engineering to increase their specificity and potency. We have developed an Integrated Circuit T cell (ICT) that encodes multiple synthetic "modules" to potentially overcome diverse barriers to efficacy in clear cell renal cell carcinoma (ccRCC). ICT cells are generated via CRISPR-mediated, targeted knock-in of a single large transgene into a newly identified safe-harbor locus (GS94). With the goal to improve the therapeutic index of CA9 CAR T cells, we developed an "AND" logic gated ICT cell that requires the presence of two antigens to trigger tumor cell killing, thereby enhancing tumor specificity. Our preclinical findings demonstrate that PSMA x CA9 ICT cells can (i) selectively target antigens that cannot be safely targeted by conventional CARs and (ii) overcome multiple suppressive mechanisms in the tumor microenvironment.

Abstract 1218: High-Throughput Arrayed Screening of Logic-Gated CARs Enables the Selection of Candidates for ccRCC with Optimal Potency and Fidelity Traits
Poster Session: Thursday, May 18, 2023, 12:00 – 2:00 p.m. and 5:30 – 7:00 p.m.

The development of clinically effective CAR T-cell products for solid tumors will require substantial cell engineering to confer sufficient specificity, potency, and persistence. Advances in genome engineering and synthetic biology have provided an increasingly complex set of features that can be introduced into CAR T cells to augment their function. However, combining multiple features may result in unpredictable negative interactions between components. Here, we report the use of high-throughput screening to optimize the design of a highly engineered Integrated Circuit T cell (ICT) product for the treatment of clear cell renal cell carcinoma (ccRCC). We leverage high-throughput screening to generate development-ready candidates for ccRCC with finely tuned desirability criteria in <18 months.

Abstract 1374: Synthetic Pathway Activators (SPAs) Increase Engineered T-Cell Potency and Persistence through Tunable STAT Activation
Poster Session: Friday, May 19, 2023, 12:00 – 2:00 p.m. and 5:30 – 7:00 p.m.

Clinically effective adoptive T cell therapy for the treatment of solid tumors requires robust T cell expansion, persistence, and potency. The Janus-kinase signal transducer and activator of transcription (JAK-STAT) pathway plays a critical role in governing T cell activation and differentiation, making it a potential axis for programming an effective T cell response against solid tumors. To exploit this potential, we synthetically engineered a library of proteins, termed Synthetic Pathway Activators (SPAs), that can constitutively drive STAT signaling at variable levels without external cytokine input. We have developed several classes of SPAs driving different STAT pathways, including what we term Class I SPAs (SPA.I), which primarily drive the STAT3 pathway. The SPA platform allows tuning of T cell biology to engineer T cell therapies with increased antitumor potency and cellular persistence.

On May 16, 2023 Olatec Therapeutics LLC (Olatec), a leader in the developing class of selective NLRP3 inhibitors, reported that it has completed the lower dose cohort and entered the second, and highest, dose cohort of the DREAM Trial, a Phase 1/2 Investigator-initiated clinical study (NCT04971499) (Press release, Olatec Therapeutics, MAY 16, 2023, View Source [SID1234631795]). This trial is evaluating the combination treatment of Olatec’s dapansutrile, an NLRP3 inhibitor, and pembrolizumab (Keytruda) in patients with PD-1 refractory advanced melanoma. The study is being led by Principal Investigator (PI), April Salama MD, Head of the Melanoma Program at The Duke Cancer Research Institute and supported by Olatec and Merck & Co., Inc. (Merck). The aim of the DREAM Trial is to address the unmet need in patients with PD-1 refractory advanced melanoma.

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Olatec’s #dapansutrile, considered to be the first oral #NLRP3inhibitor to be tested in patients w/ advanced refractory #melanoma, is being studied to address inflammatory driven resistance to anti-PD-1 therapies at Duke, supported by Olatec & Merck #DREAM

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Immunotherapy with immune checkpoint inhibitors (e.g., anti-PD-1 therapies) has transformed the treatment of melanoma, significantly improving the outcome of patients with this disease. However, despite its significant benefit, reportedly only about 50% of patients experience lasting clinical improvement from this therapy. A significant proportion of patients have been known to develop PD-1 resistance, making this therapy incomplete for the large melanoma population. As PI, April Salama MD, commented: "While the initial responses to immunotherapy with immune checkpoint inhibitors have been impressive, only a subset of melanoma patients continue to benefit, and new combination approaches are needed."

NLRP3 activation has been shown to induce proliferation of immunosuppressive cells and to suppress anti-tumor immunity leading to tumor progression. In its preclinical studies, Olatec has demonstrated that inhibition of NLRP3 with dapansutrile reduces the pro-tumor inflammatory cytokine, IL‑1β, in human melanoma cells and restores immune surveillance function in in vivo mouse models leading to reduced tumor progression (see publications in PNAS, Frontiers in Immunology and JCI). In mice, it was also demonstrated that the addition of dapansutrile to anti-PD-1 therapy increased the efficacy of the respective monotherapies. For more detailed explanation, see "About PD-1 Immunotherapies and the Rationale for NLRP3 to Mitigate Resistance" below.

Charles Dinarello MD, CSO of Olatec, remarked: "We are optimistic that our findings in animal studies in melanoma could now translate in humans. The DREAM Trial may likely show that co-administration of dapansutrile and pembrolizumab could re-sensitize human anti-tumor pathways in restoring targeted cancer cell eradication by the combination of these therapies."

The DREAM Trial is designed in two parts: part 1 addresses the safety and tolerability of the escalating doses of dapansutrile in combination with pembrolizumab, and part 2 addresses the preliminary efficacy. Both parts 1 and 2 will initiate with a 14-day period of dapansutrile monotherapy to monitor for the safety profile of the novel medication in participants with melanoma and to assess the effects of dapansutrile monotherapy on the NLRP3-PD-1 immunological pathway. Subsequently, preliminary efficacy of the treatment in restoring pembrolizumab sensitivity will be measured and quantified by the ORR (objective response rate) and PFS (progression free survival).

Alberto Mantovani MD, Olatec SAB member commented, "I believe the results from the DREAM study could identify NLRP3 inhibition as a key target in the design of future clinical studies in multiple treatment-resistant cancers beyond melanoma."

"By reducing NLRP3 inflammasome activation, dapansutrile has the potential to become an important therapeutic in combination therapy improving patient outcomes in treatment-resistant melanoma as well as other cancers," stated Damaris Skouras, CEO of Olatec.

About PD-1 Immunotherapies and the Rationale for NLRP3 to Mitigate Resistance
PD-1 immunotherapies are considered one of the more novel approaches to metastatic cancer treatment that is able to target disease, reducing tumor progression by activating CD8+ T cells of the immune system to selectively target aberrant cells. PD-1, short for programmed cell death protein 1, is a receptor expressed on the surfaces of T cells. Upon engagement of PD-1 with its ligand, program cell death ligand 1 (PD-L1), T cell-mediated immune responses are shut off. PD-L1 is normally expressed on innate immune cells, such as macrophages, and is an important mechanism in promoting self-tolerance through regulation of T cell activity. However, tumor cells expressing PD-L1 have been shown to use the PD-1/PD-L1 axis to evade the immune system. Administration of the monoclonal antibody, pembrolizumab, binds PD-1, thereby preventing engagement with PD-L1 and freeing CD8+ T cells to mobilize and kill the tumor cells.

Changes in the tumor microenvironment, shown to be facilitated by activation of the NLRP3 inflammasome, induce proliferation of immunosuppressive cells that suppress anti-tumor immunity. This immunosuppressive outcome of aberrant NLRP3 activation have been corroborated by preclinical studies showing that inhibition of NLRP3 with dapansutrile reduces the pro-tumor inflammatory cytokine, IL‑1β, in human melanoma cells and restores immune surveillance function in in vivo mouse models leading to reduced tumor progression (see publications in PNAS, Frontiers in Immunology and JCI). Therefore, Olatec’s preclinical work supports the hypothesis that co-administration of dapansutrile and pembrolizumab could restore an efficient immune response toward targeted cancer cell eradication.

About Melanoma
Skin cancer is the most common form of cancer in the United States, and melanoma accounts for the vast majority of skin cancer deaths. Among young adults, it is the second most common invasive cancer and, according to the American Academy of Dermatology Association, 1 in every 5 people in the United States suffers from skin cancer. In 2023, according to the American Cancer Society about 97,000 people in the US are expected to develop melanoma requiring systemic therapy. The most common form of systemic treatment is immunotherapy.

About Dapansutrile’s Preclinical Cancer Research
Dapansutrile is being studied in multiple murine models of cancer and immunomodulation, including: melanoma, breast cancer and pancreatic cancer. To date, Olatec has demonstrated that treatment with dapansutrile halts tumor progression by limiting the NLRP3/IL‑1 mediated immunosuppression which allows melanoma tumor cells to grow unabated. Dapansutrile, as a monotherapy, was shown to reduce tumor growth by up to 65% in a melanoma mouse model. Olatec’s team has demonstrated that the concentration of dapansutrile in the tumors was at levels sufficient to inhibit the NLRP3 inflammasome formation. Moreover, reduction in tumor volumes in dapansutrile treated mice had increased survival when compared to untreated mice. Furthermore, data demonstrated that the combination of NLRP3 inhibition with dapansutrile and anti-PD-1 immunotherapy restores the host’s antitumor response and results in a greater reduction in the melanoma tumor than either treatment alone. Specifically, mice that received dapansutrile plus the checkpoint inhibitor/anti-PD-1 antibody showed a further reduction in tumor growth of 66% when compared to the control group. The combination therapy (dapansutrile + anti-PD-1) further reduced tumor volume by 51% compared to anti-PD-1 immunotherapy only. Overall, these findings support the concept that the NLRP3 inhibition added to anti-PD-1 immunotherapy may have greater efficacy in reducing tumor growth compared to either agent as a monotherapy (see publications in PNAS and Frontiers in Immunology).

In Olatec’s studies of metastatic breast cancer in mice, dapansutrile showed reduced infiltration of myeloid-derived suppressor cells (MDSCs) and increased CD8+ T cells. Specifically, it was shown that, in combination with an anti-PD-1 immunotherapy, dapansutrile increased efficacy of immunotherapy (see publication in Pharmaceuticals).

In 2022, Carlo Marchetti, PhD, Olatec senior scientist and assistant research professor at University of Colorado, secured grant funding to investigate the role of NLRP3 in Pancreatic Ductal Adenocarcinoma (PDAC).

About Dapansutrile
Dapansutrile (lab code: OLT1177) is an investigational small molecule, new chemical entity that specifically binds to and blocks NLRP3 (nucleotide-binding and oligomerization domain [NOD]‑, leucine rich repeat-, pyrin domain-containing 3), the sensor molecule integral in the formation of the NLRP3 inflammasome. Inflammasomes are multiprotein complexes involved in intracellular surveillance of danger signals that trigger an intense inflammatory response, via generation of bioactive IL-1β and IL-18 through caspase-1 activation. Dapansutrile has been shown to prevent the formation of the NLRP3 inflammasome, which in turn inhibits the production of IL-1β and IL‑18. NLRP3 is one of the most characterized inflammasome sensors due to its involvement in a wide range of disorders, including sterile inflammation, infections, and rare genetic autoimmune syndromes. Dapansutrile has been well tolerated and shown to improve clinical outcomes in patients with acute gout flare (see The Lancet Rheumatology) and heart failure (see Journal of Cardiovascular Pharmacology). Dapansutrile has also been observed to have anti-inflammatory properties and other promising activity in a broad spectrum of over 20 preclinical animal models including arthritis, asthma, acute myocardial infarction (AMI), heart failure, contact dermatitis, multiple sclerosis, melanoma, pancreatic and breast cancers, spinal cord injury (SCI), Parkinson’s and Alzheimer’s disease. For a complete list of Olatec’s original publications on dapansutrile in various preclinical and clinical disease areas, please refer to Olatec’s publication page, here.

On May 16, 2023 Trueline Therapeutics Inc., an oncology-focused subsidiary of Anji Pharmaceuticals, reported the successful completion of IND-enabling studies with MCL1 inhibitor TTX-810, a highly potent and selective macrocyclic compound to treat patients with solid tumor or hematological cancers (Press release, Trueline Therapeutics, MAY 16, 2023, View Source [SID1234631794]). A distinguishing feature of TTX-810 is a rapid clearance profile to minimize the potential risks of sustained MCL1 inhibition in non-cancerous tissues.

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"The completion of IND-enabling studies marks the culmination of over a decade’s work to truly understand the safest and most effective way to approach MCL1 inhibition," said Ulla Rauh, Ph.D., CEO/CSO of Trueline Therapeutics. "With our rapid-clearance strategy further de-risked, we are excited to progress TTX-810 into cancer patients and finally unlock the therapeutic potential of MCL1 inhibition."

TTX-810 was discovered by a partnership between the Broad Institute of Harvard and MIT and Bayer Pharmaceuticals. The exquisite potency of TTX-810 was achieved by structure-guided design and comprehensive profiling versus over 500 cancer cell lines to define the optimal cellular context for rapid and selective induction of cell death. Following candidate selection, Trueline Therapeutics scientists designed and executed the IND-enabling program in preparation for first-in-human testing.

"When we first saw the TTX-810 data package, our key questions were ‘Will it work?’ and ‘Will it be safe?’ given the challenges other therapeutic candidates with more traditional clearance profiles are encountering," said Michael Serrano-Wu, Ph.D., Chief Scientific Officer of Anji Pharmaceuticals. "This approach benefits from the rapid and irreversible effects of MCL1 inhibition, which we believe offers a therapeutic window not attainable with longer-acting compounds. We customized our IND-enabling program to address these questions, and now it is full steam ahead to demonstrate the clinical advantages of this unique profile."

On May 16, 2023 Legend Biotech Corporation ("Legend Biotech" or the "Company") (NASDAQ: LEGN), a global biotechnology company developing, manufacturing and commercializing novel therapies to treat life-threatening diseases, reported that new and updated data from the CARTITUDE Clinical Development Program evaluating ciltacabtagene autoleucel (cilta-cel) will be presented at the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting and the European Hematology Association (EHA) (Free EHA Whitepaper)’s (EHA) (Free EHA Whitepaper) 2023 Hybrid Congress (Press release, Legend Biotech, MAY 16, 2023, View Source [SID1234631793]). Five-year follow-up data from Legend-2 (NCT03090659), an investigator-initiated trial that has been assessing a similar CAR construct since 2015, will also be presented at the meetings.

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"We are pleased that the latest data from the CARTITUDE-4 study will be officially presented at the meetings. We are continuing to investigate cilta-cel in earlier lines of treatment and the readout from this study is crucial to how we move forward"

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From the CARTITUDE Clinical Development Program, the first analysis of the Phase 3 CARTITUDE-4 study was accepted as a late breaking abstract at ASCO (Free ASCO Whitepaper) and will be presented as an oral presentation at both ASCO (Free ASCO Whitepaper) and in a plenary session at EHA (Free EHA Whitepaper). CARTITUDE-4 (NCT04181827) is the first international, randomized, open-label Phase 3 study investigating the treatment of adult patients with relapsed and lenalidomide-refractory multiple myeloma who have received cilta-cel vs standard-of-care regimens, including pomalidomide, bortezomib and dexamethasone (PVd) or daratumumab, pomalidomide and dexamethasone (DPd), following one to three prior lines of therapy.

"We are pleased that the latest data from the CARTITUDE-4 study will be officially presented at the meetings. We are continuing to investigate cilta-cel in earlier lines of treatment and the readout from this study is crucial to how we move forward," said Ying Huang, Ph.D., Chief Executive Officer of Legend Biotech. "We also eagerly anticipate the presentation of the five-year follow-up data from Legend-2 at ASCO (Free ASCO Whitepaper). This was the study that showed — in front of the international community back in 2017 —promising results in heavily pretreated patients with multiple myeloma. Since then, we have taken significant steps toward advancing the treatment landscape for myeloma patients in the CARTITUDE Development Program and are exploring the potential of other agents in our pipeline for this and other indications."

Additional data at this year’s meetings will include longer-term results from the final protocol-specified analysis of the CARTITUDE-1 study (NCT03548207), which will be shared as a poster presentation at ASCO (Free ASCO Whitepaper) and an oral presentation at EHA (Free EHA Whitepaper). CARTITUDE-1 is a Phase 1b/2 study evaluating cilta-cel for the treatment of heavily pretreated patients with relapsed or refractory multiple myeloma. The study’s 18-month follow-up data supported the U.S. Food and Drug Administration (FDA) approval of CARVYKTI (ciltacabtagene autoleucel; cilta-cel) in February 2022.

Data from the 5-year follow-up analysis of LEGEND-2 will be presented as a poster at ASCO (Free ASCO Whitepaper) and EHA (Free EHA Whitepaper). This first-in-human, Phase 1 study evaluates LCAR-B38M CAR-T cells in patients with relapsed and refractory multiple myeloma. It is the longest follow-up for any BCMA-targeted CAR-T cell therapy study to be presented at the meetings.

A select list of abstracts from the meetings can be found below.

ASCO Presentations (June 2-6, 2023)

Abstract Number

Title

Information

Abstract #106

Oral Presentation

First Phase 3 results from CARTITUDE-4: Cilta-cel versus standard of care (PVd or DPd) in lenalidomide-refractory multiple myeloma

Session Title: Clinical Science Symposium – Moving Cellular Therapy into Earlier Lines of Treatment in Hematologic Malignancies: Latest Efficacy Data and The Need to Improve Access

Date/Time: June 5, 2023, 9:45 am – 11:15 am CDT

Location: Hall D1 & On Demand

Abstract #8009

Poster Discussion

CARTITUDE-1 final results: Phase 1b/2 study of ciltacabtagene autoleucel in heavily pretreated patients with relapsed/refractory multiple myeloma

Session Title: Hematologic Malignancies – Plasma Cell Dyscrasia

Date/Time: June 5, 2023, 8:00 am – 11:00 am CDT (poster), 3:00 pm – 4:30 pm (discussion)

Location: Hall A & On Demand

Abstract #8010

Poster Discussion

Long-term remission and survival in patients with relapsed or refractory multiple myeloma after treatment of LCAR-B38M CAR-T – at least 5-year follow-up in LEGEND-2

Session Title: Hematologic Malignancies – Plasma Cell Dyscrasia

Date/Time: June 5, 2023, 8:00 am – 11:00 am CDT (poster), 3:00 pm – 4:30 pm (discussion)

Location: Hall A & On Demand

EHA Presentations (June 8-11, 2023)

Abstract Number

Title

Information

Abstract #P904

Poster Presentation

LocoMMotion: A prospective, observational, multinational study of real-life current standards of care in patients with relapsed/refractory multiple myeloma – final analysis at 2-year follow-up

Friday June 9, 2023

18:00 – 19:00 CEST

Abstract #S100

Plenary Session

Encore: First Phase 3 results from CARTITUDE-4: cilta-cel versus standard of care (PVd or DPd) in lenalidomide-refractory multiple myeloma

Saturday June 10, 2023

14:45-15:00 CEST

Abstract #S202

Oral Presentation

Encore: CARTITUDE-1 final results: Phase 1b/2 study of ciltacabtagene autoleucel in heavily pretreated patients with relapsed/refractory multiple myeloma

Sunday, June 11, 2023

12:00 –12:15 CEST

Abstract #P874

Poster Presentation

Encore: Long-term remission and survival in patients with relapsed or refractory multiple myeloma after treatment of LCAR-B38M CAR-T – at least 5-year follow-up in LEGEND-2

Friday June 9, 2023

18:00 – 19:00 CEST

Abstract #P922

Poster Presentation

Adjusted comparisons of ciltacabtagene autoleucel with therapies from real-world clinical practice: two-year follow-up analysis from CARTITUDE-1 and the prospective LocoMMotion study

Friday, June 9, 2023

18:00 – 19:00 CEST

ABOUT CARVYKTI (CILTACABTAGENE AUTOLEUCEL; CILTA-CEL)

Ciltacabtagene autoleucel is a BCMA-directed, genetically modified autologous T-cell immunotherapy, which involves reprogramming a patient’s own T-cells with a transgene encoding a chimeric antigen receptor (CAR) that identifies and eliminates cells that express BCMA. BCMA is primarily expressed on the surface of malignant multiple myeloma B-lineage cells, as well as late-stage B-cells and plasma cells. The cilta-cel CAR protein features two BCMA-targeting single domain antibodies designed to confer high avidity against human BCMA. Upon binding to BCMA-expressing cells, the CAR promotes T-cell activation, expansion, and elimination of target cells.1

In December 2017, Legend Biotech entered into an exclusive worldwide license and collaboration agreement with Janssen Biotech, Inc. (Janssen) to develop and commercialize cilta-cel.

In February 2022, cilta-cel was approved by the U.S. Food and Drug Administration (FDA) under the brand name CARVYKTI for the treatment of adults with relapsed or refractory multiple myeloma.2 In May 2022, the European Commission (EC) granted conditional marketing authorization of CARVYKTI for the treatment of adults with relapsed and refractory multiple myeloma.3 In September 2022, Japan’s Ministry of Health, Labour and Welfare (MHLW) approved CARVYKTI.4 Cilta-cel was granted Breakthrough Therapy Designation in the U.S. in December 2019 and in China in August 2020. In addition, cilta-cel received a PRIority MEdicines (PRIME) designation from the European Commission in April 2019. Cilta-cel also received Orphan Drug Designation from the U.S. FDA in February 2019, from the European Commission in February 2020, and from the Pharmaceuticals and Medicinal Devices Agency (PMDA) in Japan in June 2020. In March 2022, the European Medicines Agency’s Committee for Orphan Medicinal Products recommended by consensus that the orphan designation for cilta-cel be maintained on the basis of clinical data demonstrating improved and sustained complete response rates following treatment.5

ABOUT CARTITUDE-1

CARTITUDE-1 (NCT03548207) is a Phase 1b/2, open-label, single arm, multi-center trial evaluating cilta-cel for the treatment of adult patients with relapsed or refractory multiple myeloma, who previously received at least three prior lines of therapy including a proteasome inhibitor (PI), an immunomodulatory agent (IMiD) and an anti-CD38 monoclonal antibody. Of the 97 patients enrolled in the trial, 99 percent were refractory to the last line of treatment and 88 percent were triple-class refractory, meaning their cancer did not respond, or no longer responds, to an IMiD, a PI and an anti-CD38 monoclonal antibody.

ABOUT CARTITUDE-4

CARTITUDE-4 (NCT04181827) is the first international, randomized, open-label Phase 3 study evaluating the efficacy and safety of cilta-cel versus pomalidomide, bortezomib and dexamethasone (PVd) or daratumumab, pomalidomide and dexamethasone (DPd) in adult patients with relapsed and lenalidomide-refractory multiple myeloma who received one to three prior lines of therapy.

ABOUT LEGEND-2

LEGEND-2 (NCT03090659) is a single arm, open-label, multi-center, Phase 1/2 study, to determine the safety and efficacy of LCAR-B38M CAR-T cells in treating patients diagnosed with refractory/relapsed multiple myeloma.

ABOUT LOCOMMOTION

LocoMMotion (NCT04035226) is a prospective, multinational, observational study of real-life current standards of care in patients with relapsed and/or refractory multiple myeloma who received at least 3 prior lines of therapy including a PI, IMiD and CD38 monoclonal antibody treatment.

ABOUT MULTIPLE MYELOMA

Multiple myeloma is an incurable blood cancer that starts in the bone marrow and is characterized by an excessive proliferation of plasma cells.6 In 2023, it is estimated that more than 35,000 people will be diagnosed with multiple myeloma, and more than 12,000 people will die from the disease in the U.S.7 While some patients with multiple myeloma have no symptoms at all, most patients are diagnosed due to symptoms that can include bone problems, low blood counts, calcium elevation, kidney problems or infections.8 Although treatment may result in remission, unfortunately, patients will most likely relapse.9 Patients who relapse after treatment with standard therapies, including protease inhibitors, immunomodulatory agents, and an anti-CD38 monoclonal antibody, have poor prognoses and few treatment options available.10,11

CARVYKTI INDICATIONS AND USAGE

CARVYKTI (ciltacabtagene autoleucel) is a B-cell maturation antigen (BCMA)-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory multiple myeloma, after four or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

CARVYKTI IMPORTANT SAFETY INFORMATION

WARNING: CYTOKINE RELEASE SYNDROME, NEUROLOGIC TOXICITIES, HLH/MAS, and PROLONGED and RECURRENT CYTOPENIA

Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients following treatment with CARVYKTI. Do not administer CARVYKTI to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), which may be fatal or life-threatening, occurred following treatment with CARVYKTI, including before CRS onset, concurrently with CRS, after CRS resolution, or in the absence of CRS. Monitor for neurologic events after treatment with CARVYKTI. Provide supportive care and/or corticosteroids as needed.

Parkinsonism and Guillain-Barré syndrome and their associated complications resulting in fatal or life-threatening reactions have occurred following treatment with CARVYKTI.

Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (HLH/MAS), including fatal and life-threatening reactions, occurred in patients following treatment with CARVYKTI. HLH/MAS can occur with CRS or neurologic toxicities.

Prolonged and/or recurrent cytopenias with bleeding and infection and requirement for stem cell transplantation for hematopoietic recovery occurred following treatment with CARVYKTI.

CARVYKTI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the CARVYKTI REMS Program.

WARNINGS AND PRECAUTIONS

Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred following treatment with CARVYKTI in 95% (92/97) of patients receiving ciltacabtagene autoleucel. Grade 3 or higher CRS (2019 ASTCT grade) occurred in 5% (5/97) of patients, with Grade 5 CRS reported in 1 patient. The median time to onset of CRS was 7 days (range: 112 days). The most common manifestations of CRS included pyrexia (100%), hypotension (43%), increased aspartate aminotransferase (AST) (22%), chills (15%), increased alanine aminotransferase (ALT) (14%) and sinus tachycardia (11%). Grade 3 or higher events associated with CRS included increased AST and ALT, hyperbilirubinemia, hypotension, pyrexia, hypoxia, respiratory failure, acute kidney injury, disseminated intravascular coagulation and hemorrhage, HLH/MAS, angina pectoris, supraventricular and ventricular tachycardia, malaise, myalgias, increased Creactive protein, ferritin, blood alkaline phosphatase and gamma-glutamyl transferase.

Identify CRS based on clinical presentation. Evaluate for and treat other causes of fever, hypoxia and hypotension. CRS has been reported to be associated with findings of HLH/MAS, and the physiology of the syndromes may overlap. HLH/MAS is a potentially life-threatening condition. In patients with progressive symptoms of CRS or refractory CRS despite treatment, evaluate for evidence of HLH/MAS. One patient with CRS and suspected HLH/MAS developed a fatal retroperitoneal hemorrhage in the setting of thrombocytopenia, coagulopathy and anticoagulation.

Sixty-nine of 97 (71%) patients received tocilizumab and/or a corticosteroid for CRS after infusion of ciltacabtagene autoleucel. Forty-four (45%) patients received only tocilizumab, of whom 33 (34%) received a single dose and 11 (11%) received more than one dose; 24 patients (25%) received tocilizumab and a corticosteroid, and one patient (1%) received only corticosteroids. Ensure that a minimum of two doses of tocilizumab are available prior to infusion of CARVYKTI.

Monitor patients at least daily for 10 days following CARVYKTI infusion at a REMS-certified healthcare facility for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for at least 4 weeks after infusion. At the first sign of CRS, immediately institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids.

Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time.

Neurologic toxicities, which may be severe, life-threatening or fatal, occurred following treatment with CARVYKTI. Neurologic toxicities included ICANS, neurologic toxicity with signs and symptoms of parkinsonism, Guillain-Barré Syndrome, immune mediated myelitis, peripheral neuropathies, and cranial nerve palsies. Counsel patients on the signs and symptoms of these neurologic toxicities, and on the delayed nature of onset of some of these toxicities. Instruct patients to seek immediate medical attention for further assessment and management if signs or symptoms of any of these neurologic toxicities occur at any time.

Overall, one or more subtypes of neurologic toxicity described below occurred following ciltacabtagene autoleucel in 26% (25/97) of patients, of which 11% (11/97) of patients experienced Grade 3 or higher events. These subtypes of neurologic toxicities were also observed in two ongoing studies.

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS): Patients may experience fatal or life-threatening ICANS following treatment with CARVYKTI, including before CRS onset, concurrently with CRS, after CRS resolution, or in the absence of CRS. ICANS occurred in 23% (22/97) of patients receiving ciltacabtagene autoleucel including Grade 3 or 4 events in 3% (3/97) and Grade 5 (fatal) events in 2% (2/97). The median time to onset of ICANS was 8 days (range 1-28 days). All 22 patients with ICANS had CRS. The most frequent (≥5%) manifestation of ICANS included encephalopathy (23%), aphasia (8%) and headache (6%).

Monitor patients at least daily for 10 days following CARVYKTI infusion at the REMS-certified healthcare facility for signs and symptoms of ICANS. Rule out other causes of ICANS symptoms. Monitor patients for signs or symptoms of ICANS for at least 4 weeks after infusion and treat promptly. Neurologic toxicity should be managed with supportive care and/or corticosteroids as needed.

Parkinsonism: Of the 25 patients in the CARTITUDE-1 study experiencing any neurotoxicity, five male patients had neurologic toxicity with several signs and symptoms of parkinsonism, distinct from immune effector cell-associated neurotoxicity syndrome (ICANS). Neurologic toxicity with parkinsonism has been reported in other ongoing trials of ciltacabtagene autoleucel. Patients had parkinsonian and non-parkinsonian symptoms that included tremor, bradykinesia, involuntary movements, stereotypy, loss of spontaneous movements, masked facies, apathy, flat affect, fatigue, rigidity, psychomotor retardation, micrographia, dysgraphia, apraxia, lethargy, confusion, somnolence, loss of consciousness, delayed reflexes, hyperreflexia, memory loss, difficulty swallowing, bowel incontinence, falls, stooped posture, shuffling gait, muscle weakness and wasting, motor dysfunction, motor and sensory loss, akinetic mutism, and frontal lobe release signs. The median onset of parkinsonism in the 5 patients in CARTITUDE-1 was 43 days (range 15-108) from infusion of ciltacabtagene autoleucel.

Monitor patients for signs and symptoms of parkinsonism that may be delayed in onset and managed with supportive care measures. There is limited efficacy information with medications used for the treatment of Parkinson’s disease, for the improvement or resolution of parkinsonism symptoms following CARVYKTI treatment.

Guillain-Barré Syndrome: A fatal outcome following Guillain-Barré Syndrome (GBS) has occurred in another ongoing study of ciltacabtagene autoleucel despite treatment with intravenous immunoglobulins. Symptoms reported include those consistent with Miller-Fisher variant of GBS, encephalopathy, motor weakness, speech disturbances and polyradiculoneuritis.

Monitor for GBS. Evaluate patients presenting with peripheral neuropathy for GBS. Consider treatment of GBS with supportive care measures and in conjunction with immunoglobulins and plasma exchange, depending on severity of GBS.

Immune Mediated Myelitis: Grade 3 myelitis has occurred 25 days following treatment in another ongoing study. Symptoms reported included hypoesthesia of the lower extremities and the lower abdomen with impaired sphincter control. Symptoms improved with the use of corticosteroids and intravenous immune globulin. Myelitis was ongoing at the time of death from other cause.

Peripheral Neuropathy: Six patients in CARTITUDE-1 developed peripheral neuropathy. These neuropathies presented as sensory, motor or sensorimotor neuropathies. Median time of onset of symptoms was 62 days (range 4-136 days), median duration of peripheral neuropathies was 256 days (range 2-465 days) including those with ongoing neuropathy. Patients who experienced peripheral neuropathy also experienced cranial nerve palsies or GBS in other ongoing trials of ciltacabtagene autoleucel. Monitor patients for signs and symptoms of peripheral neuropathies.

Cranial Nerve Palsies: Three patients (3.1%) experienced cranial nerve palsies in CARTITUDE-1. All three patients had 7th cranial nerve palsy; one patient had 5th cranial nerve palsy as well. Median time to onset was 26 days (range 21-101 days) following infusion of ciltacabtagene autoleucel. Occurrence of 3rd and 6th cranial nerve palsy, bilateral 7th cranial nerve palsy, worsening of cranial nerve palsy after improvement, and occurrence of peripheral neuropathy in patients with cranial nerve palsy have also been reported in ongoing trials of ciltacabtagene autoleucel. Monitor patients for signs and symptoms of cranial nerve palsies. Consider management with systemic corticosteroids, depending on the severity and progression of signs and symptoms.

Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS): Fatal HLH occurred in one patient (1%), 99 days after ciltacabtagene autoleucel. The HLH event was preceded by prolonged CRS lasting 97 days. The manifestations of HLH/MAS include hypotension, hypoxia with diffuse alveolar damage, coagulopathy, cytopenia, and multi-organ dysfunction, including renal dysfunction.

One patient with grade 4 HLH/MAS developed fatal intracerebral and gastrointestinal hemorrhage in the setting of coagulopathy and thrombocytopenia 12 days after treatment in another ongoing study. Patients who develop HLH/MAS have an increased risk of severe bleeding. Monitor hematological parameters in patients with HLH/MAS and transfuse per institutional guidelines.

HLH is a life-threatening condition with a high mortality rate if not recognized and treated early. Treatment of HLH/MAS should be administered per institutional standards.

CARVYKTI REMS: Because of the risk of CRS and neurologic toxicities, CARVYKTI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the CARVYKTI REMS.

Further information is available at View Source or 1-844-672-0067.

Prolonged and Recurrent Cytopenias: Patients may exhibit prolonged and recurrent cytopenias following lymphodepleting chemotherapy and CARVYKTI infusion. One patient underwent autologous stem cell therapy for hematopoietic reconstitution due to prolonged thrombocytopenia.

In CARTITUDE-1, 30% (29/97) of patients experienced prolonged Grade 3 or 4 neutropenia and 41% (40/97) of patients experienced prolonged Grade 3 or 4 thrombocytopenia that had not resolved by Day 30 following ciltacabtagene autoleucel infusion.

Recurrent Grade 3 or 4 neutropenia, thrombocytopenia, lymphopenia and anemia were seen in 63% (61/97), 18% (17/97), 60% (58/97), and 37% (36/97) after recovery from initial Grade 3 or 4 cytopenia following infusion. After Day 60 following ciltacabtagene autoleucel infusion, 31%, 12% and 6% of patients had a recurrence of Grade 3 or higher lymphopenia, neutropenia and thrombocytopenia, respectively, after initial recovery of their Grade 3 or 4 cytopenia. Eighty-seven percent (84/97) of patients had one, two, or three or more recurrences of Grade 3 or 4 cytopenias after initial recovery of Grade 3 or 4 cytopenia. Six and 11 patients had Grade 3 or 4 neutropenia and thrombocytopenia, respectively, at the time of death.

Monitor blood counts prior to and after CARVYKTI infusion. Manage cytopenias with growth factors and blood product transfusion support according to local institutional guidelines.

Infections: CARVYKTI should not be administered to patients with active infection or inflammatory disorders. Severe, life-threatening or fatal infections occurred in patients after CARVYKTI infusion.

Infections (all grades) occurred in 57 (59%) patients. Grade 3 or 4 infections occurred in 23% (22/97) of patients; Grade 3 or 4 infections with an unspecified pathogen occurred in 17%, viral infections in 7%, bacterial infections in 1%, and fungal infections in 1% of patients. Overall, four patients had Grade 5 infections: lung abscess (n=1), sepsis (n=2) and pneumonia (n=1).

Grade 5 infections reported in other studies include bronchopulmonary aspergillosis, pneumocystis jirovecii pneumonia, and CMV colitis (with HSV-1 hepatitis). Another patient developed mycotic aneurysm due to cerebral aspergillosis and died of subarachnoid hemorrhage.

Monitor patients for signs and symptoms of infection before and after CARVYKTI infusion and treat patients appropriately. Administer prophylactic, pre-emptive and/or therapeutic antimicrobials according to the standard institutional guidelines. Febrile neutropenia was observed in 10% of patients after ciltacabtagene autoleucel infusion and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids and other supportive care, as medically indicated.

In a randomized controlled study of relapsed or refractory multiple myeloma (CARTITUDE- 4), patients treated with ciltacabtagene autoleucel had an increased rate of fatal COVID19 infections compared to the standard therapy arm. Counsel patients on the importance of prevention measures. Follow institutional guidelines for the vaccination and management of immunocompromised patients with COVID-19.

Viral Reactivation: Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients with hypogammaglobulinemia. Perform screening for Cytomegalovirus (CMV), HBV, hepatitis C virus (HCV), and human immunodeficiency virus (HIV), or any other infectious agents if clinically indicated in accordance with clinical guidelines before collection of cells for manufacturing. Consider antiviral therapy to prevent viral reactivation per local institutional guidelines/clinical practice.

Hypogammaglobulinemia was reported as an adverse event in 12% (12/97) of patients; laboratory IgG levels fell below 500 mg/dL after infusion in 92% (89/97) of patients. Monitor immunoglobulin levels after treatment with CARVYKTI and administer IVIG for IgG <400 mg/dL. Manage per local institutional guidelines, including infection precautions and antibiotic or antiviral prophylaxis.

Use of Live Vaccines: The safety of immunization with live viral vaccines during or following CARVYKTI treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during CARVYKTI treatment and until immune recovery following treatment with CARVYKTI.

Hypersensitivity Reactions have occurred in 5% (5/97) of patients following ciltacabtagene autoleucel infusion. Serious hypersensitivity reactions, including anaphylaxis, may be due to the dimethyl sulfoxide (DMSO) in CARVYKTI. Patients should be carefully monitored for 2 hours after infusion for signs and symptoms of severe reaction. Treat promptly and manage appropriately according to the severity of the hypersensitivity reaction.

Secondary Malignancies: Patients may develop secondary malignancies. Monitor life-long for secondary malignancies. In the event that a secondary malignancy occurs, contact Janssen Biotech, Inc., at 1-800-526-7736 for reporting and to obtain instructions on collection of patient samples for testing of secondary malignancy of T cell origin.

Effects on Ability to Drive and Use Machines: Due to the potential for neurologic events, including altered mental status, seizures, neurocognitive decline, or neuropathy, patients are at risk for altered or decreased consciousness or coordination in the 8 weeks following CARVYKTI infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery during this initial period, and in the event of new onset of any neurologic toxicities.

ADVERSE REACTIONS

The most common non-laboratory adverse reactions (incidence greater than 20%) are pyrexia, cytokine release syndrome, hypogammaglobulinemia, hypotension, musculoskeletal pain, fatigue, infections of unspecified pathogen, cough, chills, diarrhea, nausea, encephalopathy, decreased appetite, upper respiratory tract infection, headache, tachycardia, dizziness, dyspnea, edema, viral infections, coagulopathy, constipation and vomiting. The most common laboratory adverse reactions (incidence greater than or equal to 50%) include thrombocytopenia, neutropenia, anemia, aminotransferase elevation and hypoalbuminemia.

Please read full Prescribing Information including Boxed Warning for CARVYKTI.