On January 8, 2025 Vir Biotechnology, Inc. (Nasdaq: VIR) reported initial Phase 1 data from two of its dual-masked T-cell engagers (TCEs): VIR-5818, targeting a variety of HER2-expressing solid tumors; and VIR-5500, targeting PSMA in metastatic castration-resistant prostate cancer (mCRPC) (Press release, Vir Biotechnology, JAN 8, 2025, View Source [SID1234649526]). Data show encouraging preliminary safety and efficacy profiles with no dose-limiting cytokine release syndrome (CRS), maximum tolerated dose (MTD) not yet reached as dose escalation continues, and early clinical response signals observed in heavily pretreated participants. These initial results provide clinical support for Vir Biotechnology’s in-licensed PRO-XTEN masking technology, which is designed to enable the selective activation of TCEs in the tumor microenvironment, mitigating damage to healthy cells and reducing toxicity.

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"Overcoming the toxicity-driven limitations of traditional T-cell engagers could address an important unmet medical need in cancer care," said Marianne De Backer, M.Sc., Ph.D., MBA, Chief Executive Officer, Vir Biotechnology. "Preliminary safety and efficacy data for our dual-masked T-cell engagers VIR-5818 and VIR-5500 are compelling, and we will continue dose escalation with an opportunity to expand the therapeutic window. We are encouraged that our candidates may enable efficacious and well-tolerated treatment regimens, potentially improving outcomes for people living with a range of solid tumors."

VIR-5818: PRO-XTEN Initial Proof-of-Concept and Potential First-in-Class HER2 Immunotherapy

Despite availability of HER2-targeting therapies, there remains a significant unmet need for treatments with novel mechanisms of action to improve tolerability and extend survival. Currently, no HER2-directed immunotherapies are approved for solid tumors. The preliminary safety and efficacy data of VIR-5818 support the tumor-specific activation of PRO-XTEN dual-masked TCEs and the potential of this technology to broaden the therapeutic index of TCEs.

VIR-5818 is being evaluated in a Phase 1 clinical trial (NCT05356741) designed to study its safety and pharmacokinetics alone, and in combination with pembrolizumab, in participants with a variety of HER2-expressing cancers, including breast and colorectal cancer (CRC). The study has enrolled 79 heterogeneous and heavily pretreated participants in monotherapy cohorts.

Early efficacy data indicate that 50% (10/20) of participants receiving VIR-5818 doses ≥400 µg/kg experienced dose-dependent tumor shrinkage across multiple HER2-positive tumor types. This includes participants who had received up to 9 prior lines of therapy. Strong anti-tumor activity was observed in a subset of participants with HER2-positive CRC who have exhausted standard of care. In this subset, confirmed partial responses (cPRs) were seen in 33% (2/6) of participants at early doses, and one patient continued in cPR for more than 18 months as of the data cut-off.

Preliminary safety data demonstrate that VIR-5818 is generally well-tolerated, with minimal grade 1 or 2 CRS (20% and 10%, respectively) and no grade 3 or greater CRS observed in any of the 79 participants across doses up to 1000 µg/kg. Most treatment-emergent adverse events (TEAEs) were low grade, reversible and manageable. The MTD has not yet been reached. Preliminary pharmacokinetics and safety data indicate low systemic unmasking of the TCE, suggesting tumor-specific activation. Dual masking results in a half-life of approximately 6 days, which may enable a less frequent dosing regimen. As a result, Vir Biotechnology is currently evaluating a Q3W dosing regimen.

VIR-5500: First Dual-Masked PSMA-Targeting TCE

Prostate cancer is the second most diagnosed cancer in men1. Despite advancements, there is still a significant unmet need for efficacious, well-tolerated treatments that can extend survival and improve quality of life.

VIR-5500 is being evaluated in a Phase 1 clinical trial (NCT05997615​) designed to assess its safety, pharmacokinetics, and preliminary efficacy in participants with mCRPC. The study has enrolled 18 participants with significant disease burden who have received 3 to 6 prior lines of therapy.

Early efficacy data show encouraging signs of prostate-specific antigen (PSA) responses, and PSA reductions were observed in 100% (12/12) of participants after an initial dose ≥120 µg/kg. PSA50 response was confirmed in 58% (7/12) of participants receiving a first dose ≥120 µg/kg.

Preliminary data show a promising safety profile, with no dose-limiting toxicities observed up to 1000 µg/kg without prophylactic corticosteroids. Safety findings showed minimal grade 1 or 2 CRS (17% and 11%, respectively) and no grade 3 or greater CRS at any dose. Most TEAEs were low grade. No hearing loss has been reported, suggesting safety benefits of dual masking in preventing on-target, off-tumor toxicities. Dose escalation is ongoing, and the MTD for VIR-5500 has not yet been reached. Preliminary pharmacokinetics and safety data indicate tumor-specific activation with minimal unmasking outside the tumor. The dual-masked TCE shows a desirable half-life of 8-10 days, which is enabling Vir Biotechnology to evaluate a Q3W dosing regimen. The safety and tolerability profile observed for VIR-5500 in ongoing dose escalation, together with the observed signs of early anti-tumor activity at low doses, may enable a wide therapeutic index.

About VIR-5818, VIR-5500, VIR-5525

VIR-5818, VIR-5500, VIR-5525 are investigational, clinical candidates currently being evaluated for the treatment of solid tumors. These assets leverage the PRO-XTEN masking technology with three different T-cell engagers (TCEs) targeting HER2, PSMA, and EGFR, respectively.

TCEs are powerful anti-tumor agents that can direct the immune system, specifically T-cells, to destroy cancer cells. The PRO-XTEN masking technology is designed to keep the TCEs inactive (or masked) until they reach the tumor microenvironment, where tumor-specific proteases cleave off the mask and activate the TCEs, leading to killing of cancer cells. By driving the activity exclusively to the tumor microenvironment, we aim to circumvent the traditionally high toxicity associated with TCEs and increase their efficacy and tolerability. Additionally, the mask is designed to help drug candidates stay in the bloodstream longer in their inactive form, allowing them to better reach the site of action and potentially allowing less frequent dosing regimens for patients and clinicians.

On January 8, 2025 Asher Biotherapeutics, a biotechnology company developing precisely-targeted immunotherapies for cancer and infectious diseases, reported a clinical trial collaboration and supply agreement with Amgen (NASDAQ:AMGN) to evaluate etakafusp alfa (formerly known as AB248), Asher Bio’s investigational CD8+ T cell targeted interleukin-2 (IL-2) immunotherapy, in combination with IMDELLTRA (tarlatamab), Amgen’s DLL3-targeting Bispecific T-cell Engager (BiTE) therapy, in patients with extensive-stage small cell lung cancer (ES-SCLC) (Press release, Asher Biotherapeutics, JAN 8, 2025, View Source [SID1234649525]).

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"This clinical trial collaboration and supply agreement with Amgen allows us to further expand on the Phase 1 results for etakafusp alfa in a new combination with IMDELLTRA in a global Phase 1b study in ES-SCLC," said Don O’Sullivan, Ph.D., Chief Business Officer of Asher Bio. "Based on emerging data to date, we believe etakafusp alfa has the potential to improve the efficacy of T cell engagers (TCEs) by selectively expanding the CD8+ T cell population, improving effector function, tumor infiltration and reversing TCE-induced T cell desensitization. We look forward to collaborating with Amgen to assess the potential for the novel combination to improve outcomes for patients with ES-SCLC."

As part of this collaboration agreement, Amgen will sponsor and operationalize a global Phase 1b study to evaluate the safety and early efficacy of etakafusp alfa in combination with IMDELLTRA in patients with ES-SCLC. Asher Bio will retain full ownership of etakafusp alfa and will supply Amgen with etakafusp alfa at no cost.

About SCLC
SCLC is one of the most aggressive and devastating solid tumor malignancies, with a median survival of approximately 12 months following initial therapy and a 3% five-year relative survival rate for ES-SCLC.1,2,3 Current second-line treatments impart a short duration of response (median DoR: 3.3–5.3 months) and limited survival (median OS: 5.8-9.3 months), while current third-line treatments for SCLC, which consist primarily of chemotherapy, yield a short median DoR of 2.6 months and a median OS of 4.4-5.3 months.4-8 SCLC comprises ~15% of the 2.4 million plus patients diagnosed with lung cancer worldwide each year.9-11 Despite initial high response rates to first-line platinum-based chemotherapy, most patients quickly relapse within months and require subsequent treatment options.13

About Etakafusp Alfa (AB248)
Etakafusp Alfa (AB248) is a novel CD8+ T cell selective IL-2, generated by fusing a reduced potency IL-2 mutein to an anti-CD8β antibody. It was specifically engineered to selectively and potently activate CD8+ T-cells which are the immune cells that drive anti-tumor efficacy, while avoiding natural killer (NK) cells, which can act as a pharmacological sink and contribute to toxicity, and regulatory T (Treg) cells, which are immunosuppressive. Asher Bio is currently evaluating etakafusp alfa in a Phase 1a/1b clinical trial, AB248-101. The trial consists of a dose escalation and expansion phase to investigate the safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity of etakafusp alfa alone and in combination with pembrolizumab in subjects with locally advanced/metastatic solid tumors who failed prior therapies. Initial pharmacokinetic and pharmacodynamic data from the ongoing Phase 1a/1b clinical trial support etakafusp alfa’s proof of mechanism and activity with a highly differentiated clinical profile. Early data shows potent and selective CD8+ T cell activation without substantial changes to Treg and NK cell numbers and initial evidence of anti-tumor activity, including confirmed objective responses, with a generally well-tolerated safety profile. Please refer to www.clinicaltrials.gov (NCT05653882) for additional details related to this Phase 1a/1b clinical trial.

On January 8, 2025 Ambry Genetics, a leader in clinical genomic testing, reported its contribution to a study published in Nature that significantly advances our understanding of BRCA2 gene variants (Press release, Ambry Genetics, JAN 8, 2025, View Source [SID1234649524]). As the uptake of genetic testing continues to grow, the need for scalable interpretation of the vast number of variants detected has become critical. This study was designed to leverage CRISPR/cas-9 gene editing to aid in the functional characterization of nearly 7,000 BRCA2 variants, helping to resolve variants of uncertain significance (VUS) and guide better clinical management.

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BRCA2 is a well-established and clinically actionable gene associated with cancer predisposition.1 Testing BRCA2 has long been a staple of hereditary cancer testing, as pathogenic variants in the gene are associated with cancers of the breast, ovary, prostate, and pancreas.2-5 Despite the well-understood importance of BRCA2, at the time of this research, more than 5,000 BRCA2 variants are categorized as VUS in the National Institute of Health’s (NIH) ClinVar database (a catalogue of genomic variants and their classifications). Many of these are classified as VUS because there has been insufficient evidence to their classification.6

The study, led by Fergus J. Couch, PhD, of Mayo Clinic, brought together an interdisciplinary team of researchers from Mayo Clinic, H. Lee Moffitt Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Hospital Clinico San Carlos, Memorial Sloan Kettering Cancer Center, and Duke University, as well as Ambry Genetics, to understand and evaluate BRCA2 variants for their functional contributions to cancer pathogenesis.

The results of this study were integrated into a ClinGen/ACMG/AMP model for clinical interpretation, resulting in a 91% rate of classification showing the promise for improving the future of hereditary cancer testing results across all test providers.

"These findings illustrate the power of integrating functional genetic data with clinical analysis to improve understanding of hereditary cancer risk and optimize clinical management approaches," said Marcy Richardson, PhD, Associate Director of Clinical Research at Ambry Genetics. "Functional testing of cancer-associated genes enables the clinical community to offer patients better data-informed recommendations on how best to mitigate cancer risk."

"These findings demonstrate the value of collaborative research in advancing our understanding of BRCA2 variants, improving classification methods that support more accurate risk assessments and informed clinical care," said Fergus Couch, Ph.D., Professor at Mayo Clinic and lead author of the study. "By integrating functional studies with clinical data, we can provide clinicians with valuable tools to guide patients in managing their hereditary cancer risks."

"Genetic testing and variant analysis are paving the way towards truly personalized clinical care for patients before they have cancer, moving us well beyond the time when clinical decision-making based on family history left many clinicians and patients feeling powerless to intervene prior to cancer onset," said Elizabeth Chao, MD, FACMG, Chief Medical Officer at Ambry Genetics. "Improving the quality of data available in our genetic databases allows us to better classify variants across diverse populations, offering a more inclusive approach to genetic testing, giving clinicians new tools for recommending measures to prevent cancer."

This paper is co-published alongside another related study with the NIH, which examines the same issues using a different model. Together, these studies represent a major step forward in variant classification, providing essential data that helps clinicians better assess cancer risks tied to genetic mutations.

On January 8, 2025 Adicet Bio, Inc. (Nasdaq: ACET), a clinical stage biotechnology company discovering and developing allogeneic gamma delta T cell therapies for autoimmune diseases and cancer, reported corporate updates and highlighted upcoming milestones for 2025 (Press release, Adicet Bio, JAN 8, 2025, View Source [SID1234649523]).

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"2024 was a momentous year for Adicet as we amplified our efforts in autoimmune diseases and solid tumors. We dosed our first patients in our clinical trials evaluating our gamma delta 1 chimeric antigen receptor (CAR) T cell candidates, ADI-001 in LN and ADI-270 in ccRCC. Notably, ADI-270 is the first gamma delta CAR T cell therapy to enter clinical development for solid tumors, underscoring our commitment to pioneering innovative treatments. In the first half of 2025, we look forward to reporting preliminary data for both programs," said Chen Schor, President and Chief Executive Officer at Adicet Bio. "Within our autoimmune portfolio, the successful expansion of our Phase 1 trial of ADI-001 into six autoimmune indications, building upon clinical biomarker data demonstrating ADI-001’s robust tissue trafficking and complete CD19+ B cell depletion in secondary lymphoid tissue, further reinforces ADI-001’s potential as an off-the-shelf treatment option.

Mr. Schor continued: "In our oncology pipeline, the initiation of our Phase 1 trial of ADI-270 in ccRCC patients marked a crucial achievement as the first gamma delta 1 CAR T cell product candidate for the treatment of solid tumors. As we look ahead to 2025, we believe we are well positioned to build on this momentum to advance our product candidates to patients living with autoimmune diseases and cancer."

Clinical Program Progress and Upcoming Milestones:

Autoimmune Diseases Clinical Programs

In June 2024, the Company announced that the Food and Drug Administration (FDA) had granted Fast Track Designation to ADI-001 for the potential treatment of relapsed/refractory class III or class IV LN.
In September 2024, Adicet presented clinical biomarker data from the Phase 1 GLEAN trial of ADI-001 at the 9th Annual CAR-TCR Summit demonstrating robust tissue trafficking resulting in high levels of ADI-001, significant CAR T cell activation, and complete CD19+ B cell depletion in secondary lymphoid tissue.
In October 2024, the Company received FDA clearance for an amendment to its Investigational New Drug (IND) application to evaluate ADI-001 in IIM and SPS as part of the Phase 1 trial of ADI-001 in autoimmune diseases. This followed the clearance of an IND amendment in August 2024 to expand clinical development of ADI-001 in the Phase 1 trial beyond LN to include SLE, SSc and AAV.
In November 2024, Adicet announced the dosing of the first LN patient in the Phase 1 trial of ADI-001 in autoimmune diseases. The Company expects to initiate enrollment for patients with SLE, SSc, IIM, and SPS in the first quarter of 2025, and for patients with AAV in the second half of 2025.
Preliminary clinical data from the Phase 1 trial of ADI-001’s LN patient cohort are anticipated in the first half of 2025. Preliminary data from the Phase 1 trial’s other patient cohorts are expected in the second half of 2025.
Hematologic Malignancies and Solid Tumor Clinical Programs

In April 2024, Adicet presented preclinical data for ADI-270 at the American Society of Gene and Cell Therapy (ASGCT) (Free ASGCT Whitepaper) showing robust anti-tumor activity in an in vivo model of ccRCC, including tumor infiltration, resistance to the immunosuppressive tumor microenvironment, and potent activity via CAR and innate-mediated targeting.
In July 2024, the Company announced that FDA Fast Track Designation had been granted to ADI-270 for the potential treatment of patients with metastatic/advanced ccRCC who have been treated with an immune checkpoint inhibitor and a vascular endothelial growth factor inhibitor.
In December 2024, Adicet announced the dosing of the first patient in the Phase 1 clinical trial evaluating ADI-270 in patients with metastatic/advanced ccRCC.
Preliminary clinical data from the ADI-270 Phase 1 trial in ccRCC are expected in the first half of 2025.

On January 8, 2025 Annals of Oncology (IF: 56.7), a top oncology journal globally, reported remarkable long-term follow-up results of a phase 1b/2 clinical trial on Disitamab Vedotin (DV) (developed by Remegen Co., Ltd) combined with Toripalimab in treating locally advanced or metastatic urothelial carcinoma (la/mUC) (NCT04264936, study ID: RC48-C014) (Press release, RemeGen, JAN 8, 2025, View Source [SID1234649522]). This trial was supervised by Professor Jun Guo and Professor Xi’nan Sheng’s teams from Peking University Cancer Hospital.

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It is the first time that long-term follow-up data has been released for a HER2-targeted antibody-drug conjugate (ADC) and PD-1 inhibitor combination therapy in treating la/mUC, marking it a significant milestone. The nearly-three-year follow-up data revealed an objective response rate (ORR) of 73.2% and median overall survival (OS) of 33.1 months, superior to data published from any other prospective clinical studies on ADC plus PD-1 combination therapies for la/mUC.

New Treatment Options for Patients with La/mUC

UC is the sixth most common cancer worldwide. GLOBOCAN 2022 estimated the year 2021 saw 614,298 new cases and 220,596 deaths of UC. In recent years, the prognosis for patients with la/mUC has significantly improved with new drugs and combination therapies approved, among which ADCs demonstrated outstanding potential.

As a HER2-targeted ADC, DV has been approved in China for patients with HER2-overexpressing (defined as immunohistochemistry [IHC] test results of 2+ or 3+) la/mUC previously treated with platinum-containing chemotherapy. The approval is based on the pooled results of two studies (NCT03507166 and NCT03809013, study IDs: RC48-C005 and RC48-C009) where the ORR registered 50.5% and the median duration of response (DOR) registered 7.3 months.

Multiple clinical studies on la/mUCin recent years have confirmed the synergistic antitumor effects of ADC combined with immunotherapy. NCT04264936 offered stronger evidence as its long-term follow-up results published in the Annals of Oncology demonstrated the high response rate, significant survival benefits, and manageable safety profile of the DV and Toripalimab combination therapy.

DV Combined with Toripalimab: High Response Rate and Prolonged Survival

NCT04264936 is an open-label, multicenter, investigator-initiated phase 1b/2 clinical trial investigating the safety and efficacy of DV in combination with Toripalimab for the treatment of patients with HER2-expressing la/mUC. The dose-escalation study (phase 1b) assessed two dose levels of DV (1.5 and 2.0 mg/kg) combined with Toripalimab (3.0 mg/kg) to determine the recommended phase 2 dose which was then evaluated in the dose-expansion stage (phase 2).

From August 2020 to December 2021, 41 patients were enrolled with a median age of 66 years. 53.7% of the participants were male, 70.7% had an ECOG performance status score of 1, 17 (41.5%) had lung metastasis, and 10 (24.4%) had liver metastasis.

As of March 1, 2024, among all participants, the ORR was 73.2% with 4 (9.8%) achieving complete response and 26 (63.4%) achieving partial response, the DCR was 90.2%, the median progression-free survival (PFS) was 9.3 months, the median DOR was 8.6 months, the median OS was 33.1 months and the 36-month OS rate was 49.2%.

Subgroup analysis revealed ORR benefits across all subgroups regardless of the number of prior lines of systemic treatments, HER2 expression (IHC 1+/2+/3+), and PD-L1 expression status. The ORRs for chemotherapy-naïve patients and those who progressed on platinum-based chemotherapy were 76.0% (19/25) and 68.8% (11/16), respectively. The ORRs for patients with HER2 IHC 3+, 2+, 1+, or 0 were 80.0%, 84.2%, 64.3%, and 33.3%, respectively. Compared with the three HER2 IHC 0 participants (one of whom achieved partial response), those with HER2 expression (IHC 1+/2+/3+) had a higher ORR (76.3% vs 33.3%) and longer PFS (median PFS: 9.3 vs 1.7 months).

In summary, the DV and Toripalimab combination therapy has preliminarily demonstrated promising efficacy and manageable safety profile among patients with la/mUC, wherein those with HER2 expression (IHC 1+/2+/3+) achieved high response rates and long-term survival benefits. These findings support the further exploration and validation of the benefits of DV combined with PD-1 inhibitors in treating la/mUC.