On December 8, 2023 Arcellx, Inc. (NASDAQ: ACLX), a biotechnology company reimagining cell therapy through the development of innovative immunotherapies for patients with cancer and other incurable diseases, reported new clinical data from its Phase 1 expansion study of CART-ddBCMA, now known as anitocabtagene autoleucel (anito-cel). Anito-cel utilizes a novel D-Domain BCMA binder that is compact and stable, which results in a drug product with a high proportion of CAR+ cells and high-surface expression, potentially enhancing antigen binding and more efficient Multiple Myeloma cell killing (Press release, Arcellx, DEC 8, 2023, View Source [SID1234638319]).

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The data continue to demonstrate robust long-term responses with median duration of response, progression free survival (PFS), and overall survival rate not reached. The data are from an October 15, 2023 data cut, with median follow-up after anito-cel infusion of 26.5 months. These latest study findings will be presented as an oral presentation during the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition on Monday, December 11, 2023 at 5 p.m. PT. The company also has a medical affairs booth (#748) in Hall E of the San Diego Convention Center.

As of October 15, 2023, 38 patients were evaluable for efficacy and safety analysis based on a median follow-up of 26.5 months following treatment. These evaluable patients comprised the dose escalation cohorts for the first dose level (100 (+/- 20) million CAR+ T cells, n=6) and the second dose level (300 (+/- 20) million CAR+ T cells, n=6), and a dose expansion cohort at 100 (+/- 20) million CAR+ T cells (n=26). The median dose administered to patients in the first dose level and dose expansion cohorts was 115 million CAR+ T cells. All patients evaluable for this analysis have poor prognostic factors with 38 of 38 (100%) patients triple-refractory, 26 of 38 (68%) penta-refractory, and 34 of 38 (89%) refractory to last line of treatment under International Myeloma Working Group (IMWG) criteria. Additionally, 9 of 38 (24%) patients had high tumor burden with >60% bone marrow plasma (BMPC) cells, 13 of 38 (34%) patients had extra-medullary disease (EMD), and 11 of 38 (29%) patients had high-risk cytogenetics (Del 17p, t(14;16), t(4;14)) at screening/baseline. Further, 24 of 38 (63%) had at least one high-risk clinical feature, defined as presence of EMD, BMPC >60%, or Beta 2 microglobulin (B2M) >5.5 mg/L at screening/baseline. All 38 patients had at least three prior lines of therapy.

The interim anito-cel Phase 1 clinical results (October 15, 2023 cutoff date) demonstrate deep and durable responses in patients with poor prognostic factors.

All Patients:

Of the 38 evaluable patients with a median follow-up of 26.5 months

•
100% overall response rate (ORR) achieved in all patients per IMWG criteria

•
29 of 38 evaluable patients achieved a complete response (CR) or a stringent complete response (sCR) (>CR rate, 76%)

•
35 of 38 patients achieved a very good partial response or higher (>VGPR rate, 92%)

Of those evaluable for MRD testing to date (n=28), 25 (89%) were MRD-negative at a minimum of 10-5 sensitivity. Median duration of response, progression free survival (PFS), and overall survival were not reached at the time of the October 15, 2023 data cut. While median PFS is yet to be reached, the estimated Kaplan-Meier median progression free survival for the study population was 28 months at the time of the data cut with 26.5 months of median follow-up.

The Kaplan-Meier method estimated PFS rates for 6, 12, 18 and 24 months were 92%, 76%, 64% and 56%, respectively. Durable responses were also observed in patients with high-risk features (EMD, BMPC ≥60%, or B2M ≥5.5 mg/L at baseline) and high-risk cytogenetics.

Estimated PFS rates at 6, 12, 18, and 24- months by Kaplan-Meier method were:

PFS Rates (%)
6-month 12-month 18-month 24-month
All dosed (n=38)

92.1 75.9 63.7 56.0
Age ≥65 years (n=20)

95.0 85.0 74.3 61.3
High Risk Features* (n=24)

91.7 74.2 64.6 58.7
Extramedullary Disease (n=13)

92.3 67.1 67.1 57.5
High Risk Cytogenetics (n=11)

81.8 71.6 71.6 71.6

*
High risk features defined as presence of EMD, BMPC ≥60, or B2M ≥5.5 mg/L. Note: increased from prior presentation from 22 to 24 subjects as a result of database update based on ongoing data review.

Anito-cel dosed at RP2D (115 million (+/- 10) CAR+ T cells) continues to be well-tolerated at the time of the October 15, 2023 data cut:

•
Adverse events with anito-cel, including CRS and ICANS, were manageable

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No cases of grade 3 (or greater) CRS and only one case (3%) of grade 3 ICANS event with no additional cases from previously reported

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No tissue-targeted toxicities were observed

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No cases of delayed neurotoxicity events or parkinsonian symptoms were observed

Matthew J. Frigault, M.D., anito-cel study investigator, Clinical Director of the Cellular Therapy Service at Mass General Cancer Center, and Assistant Professor at Harvard Medical School said, "It is encouraging to see continued deep and durable responses with anito-cel. While access to CAR-T treatment options for patients with multiple myeloma is expanding, it is still limited, and additional therapeutics can help close the treatment gap. In light of this encouraging clinical profile of anito-cel, I look forward to continuing to enroll patients in the iMMagine-1 study."

Arcellx’s Chairman and Chief Executive Officer, Rami Elghandour continued, "This latest data set further underscores our confidence in the potential of anito-cel to become a best-in-class treatment option for patients with relapsed or refractory multiple myeloma. Building on this momentum, we look forward to completing enrollment in our iMMagine-1 study and planning for commercial launch with our partners at Kite."

ASH Presentation Details:

Title: Phase 1 Study of CART-ddBCMA for the Treatment of Patients with Relapsed and/or Refractory Multiple Myeloma: Results from at Least 1-Year Follow-up in All Patients

Speaker: Matthew J. Frigault, M.D., Clinical Director of the Cellular Therapy Service at Mass General Cancer Center, and Assistant Professor at Harvard Medical School

Session Name: 704. Cellular Immunotherapies: Early Phase and Investigational Therapies: CAR-T Cell Therapies for Multiple Myeloma and B Cell Lymphomas

Session Date: Monday, December 11, 2023

Session Time: 4:30—6:00 p.m. PT (Oral presentation for anito-cel will be at 5 p.m. PT)

Location: San Diego Convention Center, Room 6A, San Diego, California

Publication Number: 1023

A copy of the presentation can be accessed from Arcellx’s website at www.arcellx.com on the Scientific Publications page.

Webcast Event:

Arcellx will host a live webcast event with an expert panel of clinicians to discuss the clinical results on Monday, December 11, 2023 at 8 p.m. PT. The event will be accessible from Arcellx’s website at www.arcellx.com in the Investors section. A replay of the webcast will be archived and available for 30 days following the event.

About Multiple Myeloma

Multiple Myeloma (MM) is a type of hematological cancer in which diseased plasma cells proliferate and accumulate in the bone marrow, crowding out healthy blood cells and causing bone lesions, loss of bone density, and bone fractures. These abnormal plasma cells also produce excessive quantities of an abnormal immunoglobulin fragment, called a myeloma protein (M protein), causing kidney damage and impairing the patient’s immune function. Multiple myeloma is the third most common hematological malignancy in the United States and Europe, representing approximately 10% of all hematological cancer cases and 20% of deaths due to hematological malignancies. The median age of patients at diagnosis is 69 years with one-third of patients diagnosed at an age of at least 75 years. Because MM tends to afflict patients at an advanced stage of life, patients often have multiple co-morbidities and toxicities that can quickly escalate and become life-endangering.

About anito-cel

Anito-cel, formerly known as CART-ddBCMA is Arcellx’s BCMA-specific CAR-modified T-cell therapy utilizing the company’s novel BCMA-targeting binding domain for the treatment of patients with relapsed or refractory multiple myeloma. Anito-cel is currently in a Phase 2 study. Arcellx’s proprietary binding domains are novel synthetic proteins designed to bind specific therapeutic targets. Anito-cel has been granted Fast Track, Orphan Drug, and Regenerative Medicine Advanced Therapy Designations by the U.S. Food and Drug Administration.

On December 8, 2023 BridgeBio Pharma, Inc. (Nasdaq: BBIO) ("BridgeBio" or the "Company"), a commercial-stage biopharmaceutical company focused on genetic diseases and cancers, reported that on December 05, 2023, the compensation committee of BridgeBio’s board of directors granted thirty new employees restricted stock units for an aggregate of 147,373 shares of the Company’s common stock (Press release, BridgeBio, DEC 8, 2023, View Source [SID1234638320]). One-fourth of the shares underlying each employee’s restricted stock units will vest on November 16, 2024, with one-twelfth of the remaining shares underlying each such employee’s restricted stock units vesting on a quarterly basis thereafter, in each case, subject to each such employee’s continued employment with the Company or one of its subsidiaries on such vesting dates. All of the above-described awards were made under BridgeBio’s Amended and Restated 2019 Inducement Equity Plan (the "Plan").

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The above-described awards were each granted as an inducement material to the employees entering into employment with the Company in accordance with Nasdaq Listing Rule 5635(c)(4) and were granted pursuant to the terms of the Plan. The Plan was adopted by BridgeBio’s board of directors in November 2019 and amended and restated on February 10, 2023.

On December 8, 2023 SpringWorks Therapeutics, Inc. (Nasdaq: SWTX), a commercial-stage biopharmaceutical company focused on severe rare diseases and cancer, reported the closing of its previously announced underwritten public offering of 10,905,171 shares of its common stock at a public offering price of $29.00 per share, which includes the exercise in full by the underwriters of their option to purchase up to an additional 1,422,413 shares of common stock in this offering (Press release, SpringWorks Therapeutics, DEC 8, 2023, View Source [SID1234638336]). The gross proceeds from the offering, before deducting underwriting discounts and commissions and estimated offering expenses, were approximately $316.25 million.

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Goldman Sachs & Co. LLC, J.P. Morgan Securities LLC, Cowen and Company, LLC and Guggenheim Securities, LLC acted as joint book-running managers for the offering.

An automatic shelf registration statement on Form S-3ASR (including a prospectus) relating to these securities has been filed with the Securities and Exchange Commission (SEC) and has become effective.

The offering was made only by means of a prospectus and prospectus supplement that form part of the automatic shelf registration statement. A copy of the final prospectus supplement and accompanying prospectus relating to the offering has been filed with the SEC and may be obtained from: Goldman Sachs & Co. LLC, Attention: Prospectus Department, 200 West Street, New York, NY 10282, or by telephone at (866) 471-2526 or by email at [email protected]; J.P. Morgan Securities LLC, Attention: Broadridge Financial Solutions, 1115 Long Island Avenue, Edgewood, NY 11717, or by telephone at (866) 803-9204, or by email at [email protected]; Cowen and Company, LLC, 599 Lexington Avenue, New York, NY 10022, by email at [email protected] or by telephone at (833) 297-2926; or Guggenheim Securities, LLC, Attention: Equity Syndicate Department, 330 Madison Avenue, 8th Floor, New York, NY 10017, or by telephone at (212) 518-9544, or by email at [email protected].

This press release shall not constitute an offer to sell or the solicitation of an offer to buy these securities, nor shall there be any sale of these securities in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction.

On December 8, 2023 Intensity Therapeutics, Inc. (Nasdaq: INTS), a clinical-stage biotechnology company focused on the discovery and development of proprietary, novel immune-based intratumoral cancer therapies designed to kill tumors and increase immune system recognition of cancers, reported that safety, tolerability, efficacy and immune activation data from the company’s Phase 2 INVINCIBLE trial of INT230-6 in patients with early-stage breast cancer without chemotherapy was presented at a Podium Poster Spotlight discussion session today during the 2023 San Antonio Breast Cancer Symposium (SABCS) (Press release, Intensity Therapeutics, DEC 8, 2023, View Source [SID1234638352]). Information on the presentation is below.

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Concurrent Poster Spotlight Session Block #6
PS16 Enhancing Immunotherapy for Triple Negative Breast Cancer: Novel Therapies and Biomarkers
Moderator: Hope S. Rugo, MD, FASCO, University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, California
Title: Intra-tumoral dosing of INT230-6 in early-stage breast cancer patients induces tumor cell necrosis and immunomodulatory effects: A phase II randomized window-of-opportunity study – the INVINCIBLE trial
Presentation #: PS16-03
Date and Time: Friday, December 8, 7:00 – 8:00 a.m. CT
Location: Stars at Night Ballroom 3 & 4
Presenter: Angel Arnaout, M.D., MSc, Ottawa Hospital Research Institute, Ontario Institute for Cancer Research
Discussant: Sangeetha Reddy, M.D., M.S.C.I., UT Southwestern Medical Center, Dallas, Texas

Copies of the presentation materials are available on Intensity’s website on the publications, papers and posters page.

"A large unmet need in the treatment of breast cancer is that the majority of breast cancers are immune quiescent; resulting in minimal response to immunotherapies. INT230-6 has the potential to fill this unmet need for multiple subtypes, including triple negative breast cancer, through its unique multiple anti-cancer mechanisms of action that cause tumor cell necrosis, ignition of an anti-cancer immune-based activation, increasing the diversity of the T-cell repertoire systemically that can enter into the tumor and its microenvironment," said Angel Arnaout, M.D.,MSc., Breast Surgical Oncologist at the Ottawa Hospital, Scientist at the Ottawa Hospital Research Institute, Professor of Surgery at the University of Ottawa and Co-Lead of the Ontario Institute for Cancer Research’s Window-of-Opportunity Network. "The ability for INT230-6 to induce necrosis and noted immune effects prior to a patient’s surgery, while maintaining a favorable safety profile, would be a major move forward for the treatment paradigm of breast cancer and potentially many other cancers."

"I am encouraged by the immune-related data being reported and the potential of INT230-6 as a presurgical treatment for women suffering from early-stage breast cancer," said Melanie Spears, Ph.D., Co-Director of Diagnostic Development and Co-Lead of the Window-of-Opportunity Network at the Ontario Institute for Cancer Research. "The localized effect of increased CD4 T-cells and NK cells within injected tumors and systemically increased T-cell diversity from baseline in these patients is quite interesting and remarkable for a locally-delivered therapy."

The INVINCIBLE Trial is a Phase 2, randomized study that enrolled women with newly diagnosed, operable early-stage intermediate or high-grade T1-T2 invasive breast cancers 2 to 5 weeks prior to surgery (lumpectomy or mastectomy). Drug dose was set by the diameter of the tumor. Subjects were randomly allocated (2:1) prior to resection to 1-3 IT injections of INT230-6 versus either no treatment (part 1 N=29) or saline sham injection (part 2 N=58). Several markers normally associated with systemic treatment were evaluated.

Efficacy Data:
The INVINCIBLE Phase 2 trial of INT230-6 demonstrated a high order of necrosis in presurgical breast cancer tumors in the period from diagnosis to surgery, with some patients in the Phase 2 study experiencing greater than 95% necrosis of the tumor. A functional pathway enrichment analysis was conducted and confirmed positive changes in T-cell activation, lymphocyte activation and inflammatory response. Further, INT230-6 treated patients experienced differential gene expression with an increase in median clonal diversity compared to baseline as well as significant changes in the immune cell composition, including CD4 T-cell and NK cells.

Safety Data:
Data show that INT230-6 has a favorable safety profile and is well tolerated. Over 95% of treatment-emergent adverse events (TEAEs) were low grade 1 or 2 primarily localized pain, fatigue, and nausea.

"We continue to be impressed with the safety and efficacy of INT230-6. Today’s news about the increase in mean systemic T-cell clonal diversity is truly exciting because it is a signal of the strength of adaptive immune response systemically. We believe that the ability to cause large levels of necrosis on a single dose of our locally-delivered drug with immune effects in a relatively cold cancer type such as breast cancer prior to surgery shortly after diagnosis is truly a new weapon in the war on cancer," said Lewis H. Bender, President and Chief Executive Officer of Intensity. "In addition to our anticipated Phase 3 program in metastatic sarcoma using INT230-6 as a monotherapy, we are underway in our preparations for a Phase 2/3 clinical program to test INT230-6 in combination with standard of care neoadjuvant therapy. We see the potential opportunity for our technology and drug products in both the metastatic and presurgical settings for many types of cancers."

About T-Cell Repertoire
The adaptive immune system is one of the body’s most powerful defenses. By being able to adapt, the body’s immune cells can be trained to attack undesirable cells or viruses anywhere in the body. T-cells are an important systemic component of the adaptive immune system that aid in the destruction of invaders. Immune repertoire refers to all the unique T-cell receptor (TCR) and B-cell receptor (BCR) genetic rearrangements. Only lymphocytes that encounter an antigen with the right receptor to bind to it will be activated and proliferate during an immune response, forming a clone of cells with identical antigen receptors for attack. A greater diversity of T-cell repertoire means there is higher likelihood for a T-cell to bind to the foreign entity (e.g. cancer cells) and increase the specific T-cell clonal population to destroy the invader.

About INT230-6
INT230-6, Intensity’s lead proprietary investigational product candidate, is designed for direct intratumoral injection. INT230-6 was discovered using Intensity’s proprietary DfuseRx℠ technology platform. The drug is composed of two proven, potent anti-cancer agents, cisplatin and vinblastine, and a penetration enhancer molecule (SHAO) that helps disperse potent cytotoxic drugs throughout tumors for diffusion into cancer cells. These agents remain in the tumor resulting in a favorable safety profile. In addition to local disease control, direct killing of the tumor by INT230-6 releases a bolus of neoantigens specific to the patient’s malignancy, leading to engagement of the immune system and systemic anti-tumor effects. Importantly, these effects are mediated without immunosuppression that so often occurs with systemic chemotherapy.

On December 8, 2023 Onconova Therapeutics, Inc. (NASDAQ: ONTX), ("Onconova" or "the Company"), a clinical-stage biopharmaceutical company focused on discovering and developing novel products for patients with cancer, reported preclinical data highlighting narazaciclib’s multi-kinase profile, broad anti-tumor activity and increased anti-tumor immunity, compared to palbociclib and other CDK4/6 inhibitors, in a poster presented at the San Antonio Breast Cancer Symposium (SABCS) on December 8, 2023 (Press release, Onconova, DEC 8, 2023, View Source [SID1234638337]).

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"We are very pleased to share new data characterizing narazaciclib’s differentiated activity, compared to palbociclib and other CDK4/6 inhibitors, especially in breast and ovarian cell lines, in a poster presentation at this year’s San Antonio Breast Cancer Symposium (SABCS 2023)," said Steve Fruchtman, M.D., President and Chief Executive Officer.

Dr. Fruchtman continued, "Narazaciclib impacts a wider array of kinase targets and produced a more substantial reduction in cell viability across several large panels of breast and ovarian cell lines carrying a range of mutations, compared to palbociclib. In addition, narazaciclib treatment induced higher levels of T-cell recruiting chemokines, supporting greater anti-tumor immune activity."

"We believe that the totality of the data presented at SABCS supports narazaciclib’s multi-kinase activity, its ability to target resistance pathways missed by other CDK4/6 inhibitors, and its differentiated anti-tumor and immunomodulatory activity. We hope to further demonstrate the promise of narazaciclib’s differentiated profile in patients as we progress the clinical program in 2024 towards the definition of a recommended Phase 2 dose (RP2D). We are also preparing to initiate pivotal studies in the lead indication of low grade endometrioid endometrial cancer (LGEEC), and to expand into investigator-sponsored studies in breast and ovarian cancers," concluded Dr. Fruchtman.

Poster Overview

Title: Narazaciclib’s differential targets and kinase inhibitory activity compared to the approved CDK4/6 inhibitors (CDK4/6is) contribute to the enhanced inhibition of tumor growth in preclinical models

Objectives: To explore the activity of narazaciclib and its metabolite, ON1232580, in comparison to the FDA-approved CDK4/6 inhibitor (CDK4/6i) palbociclib, and identify additional targets engaged by narazaciclib. Activity was measured by exposing narazaciclib and other CDK4/6 inhibitors (CDK4/6i’s) to panels of resistant, mutated, or modified tumor cell lines to evaluate each agent’s activity and potency to inhibit growth and reduce cell line viability.

Results:

Comprehensive analysis of cellular targets: "Thermal Shift" assays affirmed that while narazaciclib and palbociclib impact a handful of similar, expected cell pathway targets, including Rb, Akt, and mTOR, narazaciclib and its main metabolite impact more kinases than palbociclib. We believe this observation could contribute to improved efficacy for narazaciclib by overcoming cancer resistance pathways not targeted by other CDK4/6i’s.
Deeper analysis in human breast and ovarian cells/cell lines: Using bioinformatics data from human cancer databases showed that high BUB1 kinase expression is associated with low survival in patients with breast and uterine corpus endometrial carcinomas (UCEC) and was degraded by low doses of narazaciclib. Western blot analysis of data from several breast cancer cell line panels (including those with known mutations or the overexpression of the membrane receptor, FGFr, an independent prognostic factor in some solid tumor cancers and a driver of resistance to CDK4/6 inhibitors), showed that narazaciclib and its metabolite resulted in a more substantial reduction in cell viability compared to other CDK4/6i’s dosed as monotherapy or in combination with autophagy inhibitors. These data support the potential use of narazaciclib in breast cancer and UCEC, either as monotherapy or in combination with other agents.
Ability to induce senescence and T-cell recruiting chemokines: Treatment with narazaciclib/metabolite produced more profound reductions in cell viability in PYMT murine breast cancer cells, compared to palbociclib and other CDK4/6i’s (combined with autophagy inhibitors). In addition, narazaciclib treatment produced significantly higher increases in T-cell recruiting chemokines, including CXCL10, than palbociclib. These results suggest that narazaciclib has the differentiated potential to promote greater levels of anti-tumor immunity, which could enhance its efficacy.
Conclusions: Expansive analysis of narazaciclib and its metabolite, compared to palbociclib and other CDK4/6i’s, shows that narazaciclib has the potential to be differentiated by its:

Multi-kinase profile, including its impact on BUB1 which is associated with poor prognosis in breast and uterine cancers;
Potent ability to inhibit cell viability in a wide range of breast and ovarian cancer cell panels, including those with common mutations and over-expression of the FGFr, with or without autophagy inhibitors;
Ability to produce significantly higher increases in T-cell recruiting chemokines and promote greater anti-tumor immunity.
These data support the potential use of narazaciclib in patients with breast and ovarian cancer, as well as its potential in LGEEC, based on broad, differentiated multi-kinase activity, supported by potential anti-tumor activity and anti-tumor immunity, compared to palbociclib and other CDK4/6i’s. Evaluation across a range of cell lines, mutations, and prognostic factors, with or without autophagy inhibitors, underscores the strength and consistency of these data.