On June 5, 2023 Astrazeneca reported Updated results from the TROPION-Lung02 Phase Ib trial showed that, with additional enrolment and follow-up from the initial presentation, datopotamab deruxtecan (Dato-DXd) in combination with pembrolizumab with or without platinum-based chemotherapy demonstrated promising clinical activity and no new safety signals in both previously untreated or pretreated patients with advanced or metastatic non-small cell lung cancer (NSCLC) without actionable genomic alterations (AGAs) (Press release, AstraZeneca, JUN 5, 2023, View Source [SID1234632485]).

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Results will be presented on 6 June in an oral presentation at the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (#9004).

Datopotamab deruxtecan is a specifically engineered TROP2-directed DXd antibody drug conjugate (ADC) being jointly developed by AstraZeneca and Daiichi Sankyo.

More than one million people are diagnosed with advanced stage NSCLC each year.1,2 While 1st-line treatment with immune checkpoint inhibitors with or without chemotherapy has improved outcomes for patients with NSCLC without AGAs, like EGFR or ALK, most patients eventually experience disease progression.3-5 TROP2 is a protein expressed in more than 90% of NSCLC tumours; there are currently no TROP2-directed ADCs approved for the treatment of lung cancer.6-8

Across previously untreated and pretreated patients, an objective response rate (ORR) of 38% was observed (95% confidence interval [CI], 26-51) in patients receiving doublet datopotamab deruxtecan plus pembrolizumab (Merck & Co., Inc., Rahway, NJ, USA), an anti-PD-1 therapy. In patients receiving triplet datopotamab deruxtecan plus pembrolizumab and platinum chemotherapy, an ORR of 49% was observed (95% CI, 37-61). Disease control rates (DCR) of 84% and 87% were observed in the doublet and triplet cohorts, respectively. Median duration of response (DoR) was not reached across cohorts. Although immature, median progression-free survival (PFS) was 8.3 months (95% CI, 6.8-11.8) in the doublet cohort and 7.8 months (95% CI, 5.6-11.1) in the triplet cohort. Response rates were highest in previously untreated patients with ORRs of 50% (95% CI, 32-68) and 57% (95% CI, 42-70) observed in the doublet and triplet cohorts, respectively, with a consistent DCR of 91% observed across cohorts.

Yasushi Goto, MD, Division of Internal Medicine and Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan, and investigator in the trial, said: "Nearly all patients with advanced non-small cell lung cancer experience disease progression following initial therapy, underscoring the need for novel therapeutic approaches across treatment lines. The updated results from TROPION-Lung02 signal the potential for datopotamab deruxtecan combinations to improve outcomes for patients with non-small cell lung cancer and are a promising development in the pursuit of a new standard treatment option beyond immunotherapy."

Cristian Massacesi, Chief Medical Officer and Oncology Chief Development Officer, AstraZeneca, said: "With more patients and nearly a year of additional follow-up, the updated TROPION-Lung02 results show that datopotamab deruxtecan continues to elicit promising and durable responses in a diverse subset of patients with non-small cell lung cancer. These early data give us confidence in the ongoing Phase III development programme evaluating datopotamab deruxtecan combinations as potential first-line treatment options for patients with advanced lung cancer across tumour histologies and PD-L1 expression levels."

Mark Rutstein, MD, Global Head, Oncology Clinical Development, Daiichi Sankyo said: "We continue to be encouraged by the findings from TROPION-Lung02, the first trial to evaluate the combination of a TROP2-directed antibody-drug conjugate and an immune checkpoint inhibitor with or without platinum chemotherapy in patients with advanced non-small cell lung cancer. These data, alongside previous results for datopotamab deruxtecan combined with an immune checkpoint inhibitor, reinforce the potential of these combinations to improve outcomes for patients with different advanced cancers."

The safety profiles of datopotamab deruxtecan-based combinations were consistent with previous data with no new safety signals observed. Grade 3 or greater treatment-related adverse events (TRAEs) occurred in 31% of patients receiving doublet therapy and 58% of patients receiving triplet therapy. The most frequent adverse events of any Grade in the doublet and triplet cohorts, respectively, were stomatitis (56% and 35%), nausea (41% and 47%), anaemia (21% and 48%) and fatigue (31% and 37%). Across treatment cohorts, there were 27 interstitial lung disease (ILD) or pneumonitis events adjudicated as drug-related by an independent committee. The percentage of ILD events was similar across cohorts. The majority of ILD events were low grade with 23 Grade 1 or Grade 2 and four Grade 3 events. No Grade 4 or Grade 5 ILD events or Grade 5 TRAEs were observed.

In the doublet cohort of TROPION-Lung02, 58% of patients were previously untreated and 42% were previously treated with platinum chemotherapy (38%) or immunotherapy (19%). In the triplet cohort, 75% of patients were previously untreated and 25% were previously treated with platinum chemotherapy (24%) or immunotherapy (25%). Eighty percent of patients in the doublet cohort and 73% of patients in the triplet cohort had PD-L1 tumour proportion scores of less than 50%, including 36% and 40% of patients who had PD-L1 tumour proportion scores of less than 1% in the doublet and triplet cohorts, respectively. As of the April 7, 2023 data cut-off, 36% and 46% of patients remained on the doublet and triplet therapy, respectively.

Summary of Results

Overall Population

Doublet (n=64)

Triplet (n=72)

Study Duration (range)

14.8 months (1-30.2)

12.9 months (2.6-23.4)

Efficacy Measure

Doublet (n=61)

Triplet (n=71)

ORR, %i (confirmed and pending) (95% CI)

38% (n=23) (26-51)

49% (n=35) (37-61)

CR, % (confirmed)

0% (n=0)

1% (n=1)

CR, % (pending confirmation)

0% (n=0)

0% (n=0)

PR, % (confirmed)

34% (n=21)

48% (n=34)

PR, % (pending confirmation)

3% (n=2)

0% (n=0)

SD, %

49% (n=30)

38% (n=27)

Median DoR (months) (95% CI)

NR (8.8-NR)

NR (5.8-NR)

Median PFS (months) (95% CI)

8.3 months (6.8-11.8)

7.8 months (5.6-11.1)

DCR, % ii

84% (n=51)

87% (n=62)

1st-Line Therapy

Efficacy Measure

Doublet (n=34)

Triplet (n=53)

ORR, %i (confirmed and pending) (95% CI)

50% (n=17) (32-68)

57% (n=30) (42-70)

CR, % (confirmed)

0% (n=0)

2% (n=1)

CR, % (pending confirmation)

0% (n=0)

0% (n=0)

PR, % (confirmed)

44% (n=15)

55% (n=29)

PR, % (pending confirmation)

6% (n=2)

0% (n=0)

SD, %

47% (n=16)

34% (n=18)

Median DoR (months) (95% CI)

NR (5.5-NR)

NR (5.7-NR)

DCR, %ii

91% (n=31)

91% (n=48)

CI, confidence interval; CR, complete response; DCR, disease control rate; DoR, duration of response; NR, not reached; ORR, objective response rate; PFS, progression-free survival; PR, partial response; SD, stable disease iORR is CR + PR iiDCR is best overall response of confirmed CR + confirmed PR + SD

AstraZeneca and Daiichi Sankyo have three Phase III trials evaluating datopotamab deruxtecan as a potential 1st-line treatment option for patients with advanced or metastatic NSCLC without AGAs compared to the respective standard of care for the patient population of each study:

· TROPION-Lung07 is evaluating datopotamab deruxtecan plus pembrolizumab with or without chemotherapy in patients with non-squamous disease and PD-L1 expression less than 50%.

· TROPION-Lung08 is evaluating datopotamab deruxtecan plus pembrolizumab in patients with PD-L1 expression of 50% or greater.

· AVANZAR is evaluating datopotamab deruxtecan plus Imfinzi (durvalumab) and platinum chemotherapy in patients regardless of PD-L1 expression or tumour histology.

Notes
Non-small cell lung cancer
More than one million people are diagnosed with advanced stage NSCLC each year. 1,2 While targeted therapies and immune checkpoint inhibitors have improved patient outcomes, advanced NSCLC has a poor prognosis and is associated with worsening outcomes after each line of subsequent therapy.3-5

Most patients with NSCLC have tumours that do not express a known AGA (e.g., EGFR, ALK, ROS1, NTRK, BRAF, RET or MET).9-11 The current 1st-line standard of care for these patients is treatment with immune checkpoint inhibitors with or without platinum-based chemotherapy. Approximately 40-60% of tumours will not respond to this initial treatment and while these therapies may improve survival for patients whose tumours do respond, most will experience disease progression.5,7

TROP2, a transmembrane glycoprotein, is expressed in more than 90% of NSCLC tumours.6 There are currently no TROP2-directed ADCs approved for the treatment of lung cancer.7,8

TROPION-Lung02
TROPION-Lung02 is an ongoing global, open-label, six-cohort Phase Ib trial evaluating the safety and efficacy of datopotamab deruxtecan at two dose levels (4 mg/kg and 6 mg/kg) in combination with pembrolizumab (200 mg) with or without four cycles of platinum chemotherapy (carboplatin or cisplatin) in both previously untreated and pretreated patients with advanced or metastatic NSCLC without AGAs (e.g., EGFR, ALK, ROS1, NTRK, BRAF, RET, MET or other known AGAs).

The primary endpoints of TROPION-Lung02 are dose-limiting toxicities and treatment-emergent adverse events. Secondary endpoints include ORR, DoR, PFS as assessed by investigator, overall survival, pharmacokinetics and anti-drug antibodies for datopotamab deruxtecan and pembrolizumab.

TROPION-Lung02 is one of three clinical trials, alongside TROPION-Lung07 and TROPION-Lung08, in a collaboration and supply agreement between Daiichi Sankyo, AstraZeneca and a subsidiary of Merck & Co., Inc., Rahway, NJ., USA to evaluate the combination of datopotamab deruxtecan and pembrolizumab.

Datopotamab deruxtecan (Dato-DXd)
Datopotamab deruxtecan (Dato-DXd) is an investigational TROP2-directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC technology, datopotamab deruxtecan is one of the three lead ADCs in the oncology pipeline of Daiichi Sankyo, and one of the most advanced programs in AstraZeneca’s ADC scientific platform. Datopotamab deruxtecan is comprised of a humanized anti-TROP2 IgG1 monoclonal antibody, developed in collaboration with Sapporo Medical University, attached to a number of topoisomerase I inhibitor payloads, an exatecan derivative, via tetrapeptide-based cleavable linkers.

A comprehensive development program called TROPION is underway globally with more than 12 trials evaluating the efficacy and safety of datopotamab deruxtecan across multiple tumours, including NSCLC, triple-negative breast cancer and hormone-receptor positive, HER2-low or negative breast cancer. Beyond the TROPION programme, datopotamab deruxtecan is also being evaluated in novel combinations in several ongoing trials.

On June 5, 2023 Morphogenesis, Inc. ("Morphogenesis"), a privately-held Phase 2/3 clinical-stage biotechnology company developing novel personalized cancer vaccines and tumor microenvironment modulators to overcome primary and acquired resistance to current immunotherapies, and CohBar, Inc. (NASDAQ: CWBR) ("CohBar"), reported positive initial results from an exploratory analysis of anti-tumor responses to rechallenge with an ICI following protocol directed IFx-Hu2.0 therapy among patients with advanced MCC or cSCC who exhibited primary resistance to ICIs (Press release, Morphogenesis, JUN 5, 2023, View Source [SID1234632484]).

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The abstract titled, "Phase 1b trial of IFx-Hu2.0, a novel personalized cancer vaccine, in checkpoint inhibitor resistant Merkel cell carcinoma and cutaneous squamous cell carcinoma," was presented by Andrew Brohl, MD, H. Lee Moffitt Cancer Center and Research Institute in a poster presentation as part of the Melanoma/Skin Cancers – Advanced/Metastatic Diseases session held at the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, taking place June 2-6, 2023 in Chicago, IL.

"While patients with advanced Merkel cell carcinoma and cutaneous Squamous cell carcinoma exhibit high response rates to immune checkpoint inhibitor therapy, the approximately 50% of patients who fail to respond have limited treatment options. We are particularly encouraged by the results in patients with advanced Merkel cell who exhibited primary resistance to ICIs, where 4 of 5 (80%) achieved long lasting, major objective anti-tumor responses on rechallenge with an ICI within the same checkpoint axis," noted Dr. James Bianco, Chief Executive Officer of Morphogenesis. "The potential for IFx-Hu2.0 adjunctive therapy to pembrolizumab in the first line treatment of advanced MCC could overcome primary resistance, allowing higher response rates than pembrolizumab alone."

IFx-Hu2.0 is Morphogenesis’ lead personalized cancer vaccine candidate that is designed to overcome primary resistance to checkpoint inhibitors. In a Phase 1 study in advanced melanoma, biomarker analyses demonstrated robust immune priming effects of IFx administration. The ongoing Phase 1b study evaluates IFx-Hu2.0 in a two-stage study design to assess safety and to examine the effects of repeated weekly dosing up to 3 weeks on the magnitude of the ensuing systemic immune response to determine the optimal dose and schedule for the company’s planned Phase 2/3 registration directed trial.

As reported at ASCO (Free ASCO Whitepaper), following completion of protocol directed therapy, 5 patients with advanced MCC and 2 patients with cSCC who, prior to study entry, failed anti-PD(L)1 therapy were re-treated with anti-PD(L)1 monotherapy: pembrolizumab (3) or avelumab (2) in MCC and cemiplimab (2) in cSCC. Four of 5 (80%) patients with advanced MCC and 1 of 2 (50%) patients with cSCC, or 5 of 7 total (71%), experienced objective anti-tumor responses to ICI rechallenge in this setting, with duration of response ongoing in 4 patients (7+, 8+, 9+, 20+ months) and one response lasting 23 months. All 4 patients with advanced MCC with post-protocol response to anti-PD(L1) therapy had previously experienced progression to this same drug class prior to treatment on protocol.

Based on the positive preliminary results seen to-date, an additional 11 patients are planned for enrollment in the expansion stage of the Phase 1b study using the weekly x 3 dosing schedule. Additional exploratory/biomarker analyses are planned.

For more information about the company’s ongoing Phase 1b IFx-Hu2.0 study, visit Clinicaltrials.gov and reference Identifier NCT04160065.

Morphogenesis and CohBar recently announced that they have entered into a definitive merger agreement for an all-stock transaction to form a company combining expertise and resources to advance a late-stage oncology pipeline. The combined company will focus on advancing Morphogenesis’ two technologies that seek to overcome the major obstacles that limit the effectiveness of current immunotherapies in treating cancer. The combined company is expected to operate under the name "TuHURA Biosciences, Inc." and to trade on The Nasdaq Capital Market ("Nasdaq"). The transaction is expected to close in the third quarter of 2023.

About Immune Fx (IFx) Personalized Cancer Vaccines

IFx-Hu2.0 administration involves a simple injection into the patient’s tumor of a proprietary gene that encodes for an immunogenic bacterial protein which is expressed on the surface of the tumor cell. Recognizing the bacterial protein as being foreign, the patient’s immune system is activated "ingesting" the tumor cell and educating the immune system to all of the patient’s tumor’s neoantigens resulting in the production of tumor specific antibodies and cytotoxic T cells. The presence of activated T cells overcomes resistance to checkpoint inhibitors allowing checkpoint released activated T cells to seek out and destroy the tumor.

Additionally, Morphogenesis is advancing its CD22 targeted, mRNA vaccine (IFx-Hu3.0), toward IND-enabling studies in 2024 for intravenous or autologous whole cell administration for the treatment of B cell malignancies like diffuse large B-cell lymphoma (DLBCL).

On June 5, 2023 NexImmune, Inc. (Nasdaq: NEXI), a biotechnology company developing a novel approach to immunotherapy designed to orchestrate a targeted immune response by directing the function of antigen-specific T cells for liquid and solid malignancies, reported results from its Phase 1/2 clinical trial of NEXI-001 in patients with relapsed/refractory acute myeloid leukemia (AML) post-allogeneic hemopoietic stem cell transplant (allo-HSCT) (Press release, NexImmune, JUN 5, 2023, View Source [SID1234632483]). In this clinical trial to date, NEXI-001 is well tolerated with a favorable safety profile while eliciting an immune response to target antigens and a clinical effect in some patients. The data describing two patients from the dose escalation study of NEXI-001 are being presented in a poster session at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2023 Annual Meeting in Chicago on Monday, June 5 at 8 AM in Hall A.

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"We are pleased that NEXI-001, our donor derived multi-antigen-specific T cell product candidate, is demonstrating evidence of dose response and tolerability in the initial Phase 1 dose escalation portion of this clinical trial," said Kristi Jones, NexImmune’s Chief Executive Officer. "We have seen a clinical response maintained for seven months, which is an additional update from the data reported in our poster. These data have established the ability of our AIM nanoparticles to expand healthy, multi-antigen-specific T cells with anti-tumor activity. The data also show these T cells persist and maintain their memory phenotype at the site of tumor. We expect to provide an additional update on Cohort 3 later this year with more details from the patients in this study, and plan to apply learnings from this trial to inform future trials for NexImmune products in cancer.

"We believe that NexImmune’s multi-antigen-specific product candidates, alone or in combination with other immunotherapies, offer the potential to benefit patients with challenging cancers such as AML, for which treatment options with meaningful benefit and tolerability has remained elusive. The safety profile of our product candidate to date also presents the potential to investigate trials in patients with lower burden disease where significant unmet need remains," added Ms. Jones.

Study Design

The goals of the NEXI-001 Phase 1 clinical trial are to evaluate the safety, tolerability, immune response, and clinical activity of the antigen-specific CD8+ NEXI-001 T cells, as well as to inform the range of patient characteristics and to determine the recommended Phase 2 dose. The dose escalation phase of the study included patients who have relapsed acute myeloid leukemia (AML) post allo-HSCT and are refractory to salvage therapy. All patients in the study, except one, relapsed after, or were refractory to, subsequent salvage therapies (one to three prior therapies). A majority of patients had three-to-four adverse risk characteristics linked to poor prognosis in addition to poor prognostic patients with extramedullary disease.

Three dose-ascending cohorts of patients were enrolled in the study, with potential doses ranging from a single dose of 50 million NEXI-001 T cells to multiple doses of up to a total of 1.2 billion NEXI-001 T cells. To date, the maximum dose evaluated has been 600 million NEXI-001 T cells.

The study includes a lymphodepletion chemotherapy (Flu / Cy 30/300) following a baseline bone marrow biopsy. To date, 11 patients have completed the dose-limiting toxicity (DLT) period and one patient is currently ongoing in the first month of protocol treatment.

"I am very encouraged by the responses and the tolerability profile observed in these difficult-to-treat refractory patients," said Dr. Monzr M. Al Malki, MD, Associate Professor of Hematology, Director of BMT and Transplant, City of Hope and an investigator for NEXI-001. "These patients are frequently fragile and lack effective and tolerable options. Responses for these patients, if any, are typically short-lived and there is an urgent need for better options. As highlighted in the ASCO (Free ASCO Whitepaper) poster, achieving and maintaining a durable clinical response in extramedullary disease is clinically meaningful and supports the potential of NEXI-001 to provide significant benefit to these patients."

Key Data Highlights

Through all dose levels to date, NEXI-001 maintains a favorable tolerability profile with no grade 3 or greater treatment related SAEs. Two patients experienced grade 2 CRS which resolved within 24 hours with tocilizumab therapy. No cases of ICANS have occurred as of May 2023.
Patients treated with NEXI-001 experienced rapid reconstitution of both CD8+ and CD4+ T-cell subtypes after lymphodepletion chemotherapy.
Clinicians observed persistence of antigen-specific T cells in both peripheral blood and bone marrow with evidence of clinical activity including tumor burden reduction, increased chimerism and improved ECOG scores.
The antigen-specific T cells maintain less-differentiated immunophenotypes, including stem-cell-like T cells (Tscm) over time in both blood and bone marrow. Additionally, a marked increase in the antigen specificity of CD8+ T cells in the bone marrow resulted with increasing dose levels.
Six of 11 patients across all dose levels experienced stable disease for some period, including a stable clinical response (MRD+) in one patient and one CR (MRD-) for up to 9 months in cohort 2 (200 million NEXI-001 T cells, administered once), which was reported in the ASCO (Free ASCO Whitepaper) poster. Data continue to support potential dose response with 600 million total cells infused during Cycle 1 being the maximum dose evaluated as of May 2023. Additional cycles or dose increases are anticipated to offer benefit in the designed expansion phase of the study.
One patient in Cohort 3 with a poor prognostic extramedullary relapse of AML manifested by pericardial and bilateral pleural effusions (cytology positive for AML blasts) resulting in symptoms of moderate to severe dyspnea was enrolled in the highest dosing cohort (200 million NEXI-001 T cells administered weekly for three weeks). After one cycle of protocol therapy the patient became asymptomatic and repeat PET/CT scans document that the effusions regressed to minimal volumes. This extramedullary clinical response has been maintained for up to 7 months and is updated from the 3 months described in the ASCO (Free ASCO Whitepaper) poster.
These data indicating both immunologic and clinical dose responses and observed durability in the patient at the higher dose support further clinical study of NEXI-001.
Poster Presentation:

Title: An Analysis of a First-In-Human Study of NEXI-001 Donor-Derived Antigen-Specific CD8+ T-Cell Treatment of Relapsed AML after Allogeneic Hematopoietic Cell Transplantation (HCT)

Abstract #: 7043 (Poster Board #173)

Session Title: Hematologic Malignancies – Leukemia, Myelodysplastic Syndromes, and Allotransplant

Authors: Monzr M. Al Malki, MD1, Juan C. Varela MD, PhD2, Sumithira Vasu, MBBS3, Dipenkumar Modi, MD4, Suzanne Afonso-Smith, PhD5, Sojung Kim, PhD5, Emily Lu, PhD5, Robert D. Knight, MD5, and Mathias Oelke, PhD5

(1)Hematology/Hematopoietic Cell Transplant, City of Hope National Medical Center, Duarte, CA, (2)Advent Health Blood and Marrow Transplant Program, Orlando, FL, (3)Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus Ohio, (4)Division of Oncology, Karmanos Cancer Center/Wayne State University, Detroit, MI, (5)NexImmune, Inc., Gaithersburg, MD

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.