On June 5, 2023 Vycellix, Inc., a transformational cell and gene engineering company with the mission to integrate its process-enhancing tools into the development and commercialization of next-generation, donor-derived medicines, including off-the-shelf T cell and natural killer (NK) cell-based cancer therapeutics, reported that its founding Chairman & CEO, Evren Alici, M.D., Ph.D., presented pre-clinical, proof-of-concept results for the Company’s single-step approach to engineer allogeneic cells (VY-UC) at the International Society for Cell & Gene Therapy (ISCT) Annual Meeting in Paris (Press release, Vycellix, JUN 5, 2023, View Source;utm_medium=rss&utm_campaign=vycellix-presents-proof-of-concept-data-for-vy-uc-allogeneic-cell-therapy-platform-at-the-international-society-for-cell-gene-therapy-isct-annual-meeting-paris [SID1234632482]).

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In an oral presentation during "Chief Scientific Officer Showcase", titled "Generation of Universal Cellular Grafts Utilizing Signaling Deficient Membrane-Bound CD45-Engagers", Dr. Alici debuted data showing that the insertion of a novel CD45-engager (VY-UC) into virtually any cell holds the potential to displace complex and costly gene-editing systems such as CRISPR-Cas9 to engineer fully immune privileged cells that in pre-clinical in vitro and in vivo models demonstrate persistence, retention of function, and avoidance of host immune rejection.

Dr. Alici’s studies, conducted by the Cell & Gene Therapy Group, which he leads at Karolinska Institutet (KI), Stockholm, Sweden, potentially position VY-UC as a preferred efficient and cost-effective off-the-shelf cell engineering strategy by focusing on the spatial abrogation of a functional immune synapse against the graft to avoid patient rejection responses towards cellular effector grafts (the donor-derived cells), while retaining the effector graft’s function. CD45-engagers were expressed on multiple cell types, including primary T cells, CAR-T cells, primary NK cells, CAR-NK cells, hepatocytes, and hematopoietic stem cells, and in each series of cell type evaluations, functional immune synapse formation was prevented, resulting in abrogation of cellular immune response, thus, eliminating the risk of graft rejection.

The VY-UC Abstract was recently published in a supplemental version of Cytotherapy (Volume 25, Issue 6 Supplement, S13-S14, May 2023) the official journal of ISCT: View Source(23)00148-2/fulltext

Dr. Alici fielded the following question at ISCT in summarizing the potential broad-reaching impact for VY-UC to redefine the paradigm for engineering "off-the-shelf" donor-derived medicines:

Q: There are multiple gene-editing strategies that claim to solve the challenges associated with engineering donor-sourced therapies, so why is VY-UC potentially disruptive?

A: "The goal for engineering any allogeneic cell is to overcome the risk that the patient’s immune system will recognize and eliminate the donor-sourced foreign cells. Unfortunately, allogeneic cell therapy studies to date do not appear to yet match up to the outcomes achieved by autologous products, especially when measuring cell persistence and durable outcomes. With our single-step CD45-engager program, we can completely avoid using any gene-editing system to ‘knock-out’ HLA Class I and II molecules, nor do we need to ‘knock-in’ any inhibitory ligands. We do not target to kill the host alloreactive population, either. We believe that Vycellix’s VY-UC platform has the potential to transform virtually any donor cell with a simple single transgene to become ‘stealth’ by preventing functional immune synapse formation in a single direction, and thus, avoid donor cell rejection. Our studies have shown complete escape from host-mediated rejection in many types of VY-UC engineered cells, including T cells and NK cells with these effector cells retaining their fitness and cytotoxicity, thus conserving viability, functionality and persistence. We are now preparing to advance the VY-UC platform into human clinical trials for off-the-shelf NK cell therapies targeting cancers, as well as preparing to partner and license our platform for T cell applications," explained Dr. Alici.

Vycellix’s platforms were all discovered by scientists at the world-renowned Karolinska Institutet (KI) in Stockholm, Sweden. The Company is also a collaborative partner in "NextGenNK", an international Competence Center for the development of next-generation NK cell-based cancer immunotherapies based at KI and funded by Sweden’s innovations agency, Vinnova. KI is globally recognized for its Nobel Assembly, which awards the Nobel Prize in Physiology or Medicine.

On June 5, 2023 SpringWorks Therapeutics, Inc. (Nasdaq: SWTX), a clinical-stage biopharmaceutical company focused on developing life-changing medicines for patients with severe rare diseases and cancer, reported that the U.S. Food and Drug Administration (FDA) has updated the Prescription Drug User Fee Act (PDUFA) action date for the New Drug Application (NDA) for nirogacestat for the treatment of adults with desmoid tumors (Press release, SpringWorks Therapeutics, JUN 5, 2023, View Source [SID1234632479]). The previously disclosed August 27, 2023 PDUFA date has been extended by the standard extension period of three months.

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The FDA notified SpringWorks on June 2, 2023 that it required more time to review additional analyses of previously submitted data that had been provided by SpringWorks in response to the FDA’s information requests. The submission of this additional information was determined by the FDA to constitute a Major Amendment to the NDA, thereby resulting in an extension of the PDUFA action date. No additional data or studies have been requested by the FDA at this time.

"We are confident that the comprehensive data from our Phase 3 DeFi trial demonstrate the transformative benefits that nirogacestat can bring to people with desmoid tumors, who currently do not have an approved therapy," said Saqib Islam, Chief Executive Officer of SpringWorks. "We remain committed to bringing this much needed therapy to patients and believe that our operational and manufacturing readiness positions us well to rapidly serve the desmoid tumor community following an approval. We look forward to continuing to work closely with the FDA as they complete their review of the nirogacestat NDA."

The NDA for nirogacestat was granted Priority Review upon its acceptance by the FDA in February 2023 and is being reviewed under the FDA’s Real-Time Oncology Review (RTOR) program. It is based on positive data from the Phase 3 DeFi trial which were published in the March 9, 2023 edition of the New England Journal of Medicine.1 The FDA previously granted Breakthrough Therapy, Fast Track and Orphan Drug designations for nirogacestat. In addition, SpringWorks expects to file a Marketing Authorization Application for nirogacestat with the European Medicines Agency in 2024.

About DeFi

DeFi (NCT03785964) is a global, randomized (1:1), double-blind, placebo-controlled Phase 3 trial evaluating the efficacy, safety and tolerability of nirogacestat in adult patients with progressing desmoid tumors. The double-blind phase of the study randomized 142 patients (nirogacestat, n=70; placebo n=72) to receive 150 mg of nirogacestat or placebo twice daily. Key eligibility criteria included tumor progression by ≥20% as measured by Response Evaluation Criteria in Solid Tumors (RECIST 1.1) within 12 months prior to screening. The primary endpoint was progression-free survival, as assessed by blinded independent central review, or death by any cause. Secondary and exploratory endpoints included safety and tolerability measures, objective response rate (ORR), duration of response, changes in tumor volume assessed by magnetic resonance imaging (MRI), and changes in patient-reported outcomes (PROs). DeFi includes an open-label extension phase, which is ongoing.

About Desmoid Tumors

Desmoid tumors are rare, aggressive, locally invasive, potentially morbid tumors of the soft tissues.2,3 While they do not metastasize, desmoid tumors are associated with a high rate of recurrence.3,4,5 Sometimes referred to as aggressive fibromatosis, or desmoid fibromatosis, these soft tissue tumors can be serious, debilitating, and in rare cases when vital organs are impacted, they can be life-threatening.3,6

Desmoid tumors are most commonly diagnosed in patients between the ages of 20 to 44 years, with a two-to-three times higher prevalence in females.5,7,8,9 It is estimated that there are 1,000-1,650 new cases diagnosed per year in the United States.8,9,10

Historically, desmoid tumors were treated with surgical resection, but this approach has become less favored due to a high recurrence rate after surgery.2,5,11 There are currently no FDA-approved therapies for the treatment of desmoid tumors.

About Nirogacestat

Nirogacestat is an oral, selective, small molecule gamma secretase inhibitor in Phase 3 clinical development for desmoid tumors. SpringWorks is also evaluating nirogacestat as a potential treatment for patients with ovarian granulosa cell tumors and for patients with multiple myeloma as part of several B-cell maturation agent (BCMA) combination therapy regimens in collaboration with leaders in industry and academia. Nirogacestat is an investigational drug for which safety and efficacy have not been established.

The U.S. Food and Drug Administration (FDA) granted Priority Review for the New Drug Application (NDA) for nirogacestat for the treatment of adults with desmoid tumors, which is being reviewed under the FDA’s Real-Time Oncology Review program, in February 2023. The FDA also previously granted Fast Track and Breakthrough Therapy Designations to nirogacestat for the treatment of adult patients with progressive, unresectable, recurrent or refractory desmoid tumors or deep fibromatosis. In addition, nirogacestat has received Orphan Drug Designation from the FDA for the treatment of desmoid tumors and from the European Commission for the treatment of soft tissue sarcoma.

Gamma secretase cleaves multiple transmembrane protein complexes, including Notch, which is believed to play a role in activating pathways that contribute to growth of desmoid and ovarian granulosa cell tumors. Gamma secretase has also been shown to directly cleave membrane-bound BCMA, resulting in the release of the BCMA extracellular domain (ECD) from the cell surface. By inhibiting gamma secretase, membrane-bound BCMA can be preserved, increasing target density while reducing levels of soluble BCMA ECD, which may serve as decoy receptors for BCMA-directed therapies. SpringWorks is evaluating nirogacestat as a BCMA potentiator and has several collaborations with industry-leading BCMA developers and academic partners to evaluate nirogacestat in BCMA combinations across modalities.

On June 5, 2023 Shanghai Escugen Biotechnology Co., Ltd. ("Escugen"), a partner of Levena (Suzhou) Biopharma Co., Ltd. ("Levena"), a wholly owned subsidiary of Sorrento Therapeutics, Inc. (Sorrento), reported preliminary results from a first-in-human study of ESG401, a trophoblast cell-surface antigen 2 (TROP2) antibody drug conjugate (ADC), in patients with locally advanced/metastatic solid tumors at the 2023 Annual Meeting of ASCO (Free ASCO Whitepaper), the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper), held June 2-6 in Chicago, IL (Press release, Sorrento Therapeutics, JUN 5, 2023, View Source [SID1234632478]). ESG401 is an innovative ADC developed by Escugen and Levena. Escugen and Levena Biopharma jointly own the domestic and international patents of this ADC and share global rights for the product. ESG401 is composed of a humanized anti-Trop2 IgG1 monoclonal antibody (mAb) conjugated to a topoisomerase I inhibitor SN38 via a proprietary stable covalent linker with a drug antibody ratio (DAR) of 8. ESG401 has potential differentiated advantages over its competitors in terms of safety, effectiveness and process robustness. Using an innovative, highly stable and cleavable linker, this ADC demonstrated that it releases very little free toxin during circulation, which may reduce off target toxicity in a series of preclinical studies. Additionally, premature release of the mAb may compete for binding sites with the ADC to reduce its efficacy. The ADC highly enriches in tumor tissues and rapidly endocytoses, thereby effectively killing tumor cells and inhibiting tumor growth.

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In the Phase I study, adult ESG401 patients with locally advanced/metastatic solid tumors refractory to or relapsed from standard treatments with measurable disease (RECIST v1.1) were eligible. ESG401 was administered by IV infusion initially in an ascending dose safety study by designated dose and regimen until unacceptable toxicity or progressive disease and followed by expansion cohorts. The Bayesian Optimal Interval (BOIN) design was used to establish the maximum tolerated dose (MTD). As of February 3, 2023, 35 heavily pretreated patients with a median age of 53 years were treated with at least one dose of ESG401 during dose escalation, 2 to 20 mg/kg administered every 3 weeks (Regimen A), or 12 to 16 mg/kg on day 1, 8, and 15 in a 4-week cycle (Regimen B). Eighty percent of the patients had an ECOG status of 1. Sixty-three percent of the patients had received at least 3 lines of prior therapy and overall the number of lines of prior therapy was a median of 4 (range 2-10). A total of 94% of patients had visceral metastases (11% brain, 63% liver, 60% lung) at baseline. From the ASCO (Free ASCO Whitepaper) poster, patient demographics and baseline characteristics is shown below:

While one patient at 20 mg/kg reported a dose limiting toxicity (grade 4 neutropenia and grade 3 febrile neutropenia), the MTD was not reached. The most common treatment-related adverse events were leukopenia, neutropenia, anemia, fatigue and nausea or vomiting. The most common grade 3 events were leukopenia (29%) and neutropenia (31%) with no grade 3 thrombocytopenia, diarrhea, skin rash or oral mucositis. There was no evidence of interstitial lung disease. The frequency of TEAEs > 15% regardless of causality is shown below.

Of the 33 efficacy evaluable patients, 12 achieved partial responses and 4 achieved stable disease lasting at least 24 weeks. The dose of 16 mg/kg was identified as the therapeutically relevant dose. The overall response rate and disease control rate were 36% (4 of 11 patients) and 64% (7 of 11 patients), respectively, in patients with triple negative breast cancer, and 62% (8 of 13 patients) and 77% (10 of 13 patients), respectively, in patients who were HR+/HER2- breast cancer. Three patients have been on treatment for at least 12 months. These data demonstrate that ESG401 is well tolerated and demonstrates efficacy in heavily pretreated patients. Additional studies are ongoing with this innovative promising treatment. A waterfall plot of the data demonstrating the best % change in sum of longest dimension in target lesions from baseline is shown below for patients who received the therapeutic relevant dose (16 mg/kg).

On June 5, 2023 Precision BioSciences, Inc. (Nasdaq: DTIL) a clinical stage gene editing company developing ARCUS-based in vivo gene editing and ex vivo allogeneic CAR T therapies, reported that members of management will participate in the following investor conferences in June 2023 (Press release, Precision Biosciences, JUN 5, 2023, View Source [SID1234632477]):

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Jefferies Global Healthcare Conference 2023
Date: Friday, June 9, 2023
Time: 10:30 am ET

Goldman Sachs 44th Annual Global Healthcare Conference
Date: Thursday, June 15, 2023
Time: 8:40 am PT (11:40 am ET)

A live webcast of each presentation will be accessible on the Company’s website www.precisionbiosciences.com, under the Investors & Media section. An archived replay of the webcasts will be available for approximately 30 days following each event.

On June 5, 2023 Papyrus Therapeutics Inc., an emerging biotechnology company pioneering the development of tumor suppressor restoration treatments for solid cancers, reported that the United States Patent and Trademark Office ("USPTO") has issued a Notice of Allowance for multiple claims related to the company’s patent filings on unique design features for the development of a platform of novel tumor suppressor therapies for a variety of solid cancers (Press release, Papyrus Therapeutics, JUN 5, 2023, View Source;utm_medium=rss&utm_campaign=papyrus-therapeutics-notice-of-allowance-from-uspto-enhances-tumor-suppressor-therapy-ip-portfolio [SID1234632476]).

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"This notice of allowance provides further validation of Papyrus’ novel approach to treat cancers with our lead OPCML candidate, PYTX-004, a unique recombinant protein that restores the natural tumor suppression in over 40% of solid tumors," said Dr. Paul Blake FRCP, CEO of Papyrus Therapeutics. "These patents represent a critical step in protecting our technology, expanding our therapeutic platform, and establishing Papyrus Therapeutics as the leader in novel tumor suppressor treatments."

About OPCML and PYTX-004

OPCML is a normally expressed potent tumor suppressor protein that is lost during cancer development and it works by binding to the external leaflet of the cancer cell membrane. PYTX-004 is a Fc-fused form of OPCML that is designed to suppress tumor growth and demonstrate circulating characteristics of an antibody to enable IV use.

Papyrus Therapeutics’ PYTX-004

PYTX-004 inhibits the MEK-ERK and PI3K-AKT pathways as part of its potent tumor suppressor action. As such, PYTX-004 is not an RTK inhibitor, it is a native engineered protein replacement that is anticipated to be a well tolerated treatment as it targets only cancer cells without damaging healthy cells, unlike chemotherapy.