On December 15, 2025 Link Cell Therapies ("Link"), an oncology cell therapy company, reported its official launch from stealth with a $60 million Series A financing that was led by Johnson & Johnson, through its corporate venture capital organization, Johnson & Johnson Innovation – JJDC, Inc. , with participation from founding investors Samsara BioCapital and Sheatree Capital, as well as Wing Venture Capital and other new strategic and financial investors.

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Link’s proprietary logic-gating technologies allow for safe targeting of multiple antigens that are co-expressed on cancer cells but do not overlap or only minimally overlap in their normal healthy tissue expression. This platform enables the creation of next-generation CAR-T therapeutics for solid and liquid cancers built upon an entirely new landscape of "clean" target pairs.

"We recognized that for most cancer types, particularly solid tumors, the promise of CAR-T therapies is limited by a dearth of cancer-specific targets and abundant expression of most solid tumor targets in normal vital tissue," said Co-Founder Robbie Majzner, MD of the Dana-Farber Cancer Institute and Harvard Medical School. "Link is advancing a technology that we developed while at Stanford University that allows for logic-gated CAR-T cell control. The Link-based CAR activates and kills target cells only when a combination of antigens is co-localized on the tumor, thereby bypassing normal tissues that express only one of those targets. We believe this approach will enable potent CAR-T therapies to attack a wide range of tumors while sparing healthy tissue."

The Series A financing, which follows a 2022 Seed Round led by Samsara and Sheatree, adds a number of strong financial and strategic investors to the syndicate, including JJDC, Inc, Bristol Myers Squibb, Kyowa Kirin, Wing Venture Capital, and Sherpa Healthcare Partners.

"It has been a pleasure to support Link Cell Therapies since its founding," said Abraham Bassan, Member of the Link Board of Directors and Partner at Samsara BioCapital. "The team at Link has advanced a unique technology that could enable the development of multiple, impactful treatments for patients with cancer. I have been impressed with the team’s achievements and the progress on Link’s lead program and pipeline."

Link’s Progress and Development Status

Link’s lead program, LNK001 for the treatment of renal cell carcinoma ("RCC"), is on track for an Investigational New Drug (IND) application and initiation of dosing in a Phase I clinical trial in 2026. LNK001 targets two antigens that are uniquely and highly co-expressed in most RCC tumors. LNK001 is designed to enable tumor-specific efficacy while avoiding on-target, off-tumor toxicity that has limited prior experimental therapies targeting each individual antigen.

Link’s second program being developed for colorectal cancer will target Development Candidate selection in 2026 and initiation of human clinical studies in 2027. The company has multiple additional CAR-T programs in earlier development in solid and liquid cancers that will be developed internally or through partnerships.

(Press release, Link Cell Therapies, DEC 15, 2025, View Source [SID1234661425])

On December 15, 2025 AstraZeneca and Daiichi Sankyo reported that Enhertu (trastuzumab deruxtecan) in combination with pertuzumab has been approved in the US for the 1st-line treatment of adult patients with unresectable or metastatic HER2-positive breast cancer, as determined by a Food and Drug Administration (FDA)-approved test.

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The approval follows Priority Review and Breakthrough Therapy Designation by the FDA and is based on the results of the DESTINY-Breast09 Phase III trial. The data were presented at the 2025 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting and published in The New England Journal of Medicine.1

Sara Tolaney, MD, MPH, Chief of the Division of Breast Oncology, Dana-Farber Cancer Institute and principal investigator for the trial, said: "Trastuzumab deruxtecan plus pertuzumab is the only 1st-line treatment approved in more than a decade to demonstrate a statistically significant improvement in progression-free survival over the current standard regimen for patients with HER2-positive metastatic breast cancer. With a median progression-free survival exceeding three years, versus approximately two years with THP, trastuzumab deruxtecan combined with pertuzumab should become a new 1st-line standard of care in this setting."

Dave Fredrickson, Executive Vice President, Oncology Haematology Business Unit, AstraZeneca, said: "With this approval, we are bringing Enhertu to the earliest setting for HER2-positive metastatic breast cancer, where optimising efficacy has an important impact on long‑term outcomes. The treatment approach with Enhertu plus pertuzumab in DESTINY-Breast09 sets a new benchmark of more than three years without disease progression or death for patients in this setting."

Ken Keller, Global Head of Oncology Business, and President and CEO, Daiichi Sankyo, said: "Since its initial approval six years ago, Enhertu has transformed the treatment of HER2-positive metastatic breast cancer. With this approval of Enhertu in the 1st-line HER2-positive metastatic setting, Enhertu once again offers significant improvements in progression-free survival and has practice-changing potential when used in combination with pertuzumab."

In the trial, Enhertu in combination with pertuzumab reduced the risk of disease progression or death by 44% versus a taxane, trastuzumab and pertuzumab (THP) (based on a hazard ratio of 0.56; 95% confidence interval [CI] 0.44-0.71; p<0.0001) as a 1st-line treatment for patients with HER2-positive metastatic breast cancer. Median progression-free survival (PFS) was 40.7 months with Enhertu plus pertuzumab compared to 26.9 months for THP. The PFS benefit for Enhertu plus pertuzumab versus THP was consistent across subgroups.1

The safety profile of Enhertu plus pertuzumab in DESTINY-Breast09 was consistent with the known profiles of each individual therapy with no new safety concerns identified.

Enhertu is a specifically engineered HER2-directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo and being jointly developed and commercialised by AstraZeneca and Daiichi Sankyo.

This application was approved under the FDA’s Real-Time Oncology Review (RTOR), an initiative by the FDA to ensure safe and effective treatments are available to patients as early as possible.

This US regulatory submission was also reviewed under Project Orbis, which provides a framework for concurrent submission and review of oncology medicines among participating international partners. As part of Project Orbis, the Enhertu plus pertuzumab 1st-line regimen is under review by Switzerland’s Swissmedic (SMC) and Singapore’s Health Sciences Authority (HSA). Separate regulatory applications are also under review in other countries.

Financial considerations
Following this approval in the US, an amount of $150m is due from AstraZeneca to Daiichi Sankyo as a milestone payment for the 1st-line unresectable or metastatic HER2-positive breast cancer indication. Sales of Enhertu in the US are recognised by Daiichi Sankyo. For further details on the financial arrangements, please consult the collaboration agreement from March 2019.

Notes

HER2-positive metastatic breast cancer
Breast cancer is the second most common cancer and one of the leading causes of cancer-related deaths worldwide.2 More than two million breast cancer cases were diagnosed in 2022, with more than 665,000 deaths globally.2 In the US, more than 300,000 cases of breast cancer are diagnosed annually with more than 42,000 deaths.3 While survival rates are high for those diagnosed with early breast cancer, only about 30% of patients diagnosed with or who progress to metastatic disease are expected to live five years following diagnosis.4

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumours including breast cancer.5 HER2 protein overexpression may occur as a result of HER2 gene amplification.6 Approximately one in five cases of breast cancer are considered HER2-positive.7

HER2-positive metastatic breast cancer is an aggressive disease driven by overexpression or amplification of HER2.8 Approximately 10,000 patients are treated each year in the 1st-line HER2-positive metastatic setting in the US.9 While HER2-targeted therapies have improved outcomes, prognosis remains poor with most patients experiencing disease progression within two years of 1st-line treatment with THP, which has been the standard of care for more than a decade.6,10-12 Approximately 25% to 30% of patients do not receive any treatment following 1st-line therapy due to discontinuation or death.13-15

DESTINY-Breast09
DESTINY-Breast09 is a global, multicentre, randomised, open-label, Phase III trial evaluating the efficacy and safety of Enhertu (5.4 mg/kg) either alone or in combination with pertuzumab versus standard of care THP as a 1st-line treatment in patients with HER2-positive metastatic breast cancer.

Patients were randomised 1:1:1 to receive either Enhertu monotherapy with a pertuzumab matching placebo; Enhertu in combination with pertuzumab; or THP. Randomisation was stratified by prior treatment (de novo metastatic disease versus progression from early-stage disease), hormone receptor (HR) status and PIK3CA mutation status.

The primary endpoint of DESTINY-Breast09 is PFS as assessed by blinded-independent central review in the Enhertu monotherapy and Enhertu combination arms. Secondary endpoints include investigator-assessed PFS, overall survival, objective response rate, duration of response, pharmacokinetics and safety. The investigational arm assessing Enhertu monotherapy versus THP remains blinded to patients and investigators and will continue to the final PFS analysis.

DESTINY-Breast09 enrolled 1,157 patients across multiple sites in Africa, Asia, Europe, North America and South America. For more information about the trial, visit ClinicalTrials.gov.

Enhertu
Enhertu is a HER2-directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC Technology, Enhertu is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced programme in AstraZeneca’s ADC scientific platform. Enhertu consists of a HER2 monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.

Enhertu (5.4mg/kg) in combination with pertuzumab is approved in the US as a 1st-line treatment for adult patients with unresectable or metastatic HER2-positive (IHC 3+ or ISH+) breast cancer, as determined by an FDA-approved test based on the results from the DESTINY-Breast09 trial.

Enhertu (5.4mg/kg) is approved in more than 90 countries/regions worldwide for the treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+ or ISH+) breast cancer who have received a prior anti-HER2-based regimen, either in the metastatic setting or in the neoadjuvant or adjuvant setting, and have developed disease recurrence during or within six months of completing therapy based on the results from the DESTINY-Breast03 trial.

Enhertu (5.4mg/kg) is approved in more than 85 countries/regions worldwide for the treatment of adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who have received a prior systemic therapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy based on the results from the DESTINY-Breast04 trial.

Enhertu (5.4mg/kg) is approved in more than 55 countries/regions worldwide for the treatment of adult patients with unresectable or metastatic hormone receptor (HR)-positive, HER2-low (IHC 1+ or IHC 2+/ ISH-) or HER2-ultralow (IHC 0 with membrane staining) breast cancer, as determined by a locally or regionally approved test, that have progressed on one or more endocrine therapies in the metastatic setting based on the results from the DESTINY-Breast06 trial.

Enhertu (5.4mg/kg) is approved in more than 60 countries/regions worldwide for the treatment of adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumours have activating HER2 (ERBB2) mutations, as detected by a locally or regionally approved test, and who have received a prior systemic therapy based on the results from the DESTINY-Lung02 and/or DESTINY-Lung05 trials. Continued approval in China and the US for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Enhertu (6.4mg/kg) is approved in more than 70 countries/regions worldwide for the treatment of adult patients with locally advanced or metastatic HER2-positive (IHC 3+ or IHC 2+/ISH+) gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01, DESTINY-Gastric02 and/or DESTINY-Gastric06 trials. Continued approval in China for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Enhertu (5.4mg/kg) is approved in more than 10 countries/regions worldwide for the treatment of adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumours who have received prior systemic treatment and have no satisfactory alternative treatment options based on efficacy results from the DESTINY-PanTumor02, DESTINY-Lung01 and DESTINY-CRC02 trials. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Enhertu development programme
A comprehensive global clinical development programme is underway evaluating the efficacy and safety of Enhertu as a monotherapy, in combination or sequentially with other cancer medicines across multiple HER2-targetable cancers.

(Press release, AstraZeneca, DEC 15, 2025, View Source [SID1234661445])

On December 15, 2025 Orca Bio, a late-stage biotechnology company committed to transforming the lives of patients through high-precision cell therapy, reported the publication of the Precision-T Phase 3 study results of its lead investigational allogeneic T-cell immunotherapy, Orca-T, in Blood, a journal of the American Society of Hematology (ASH) (Free ASH Whitepaper). The study compared Orca-T to a conventional allogeneic hematopoietic stem cell transplant (alloHSCT) in patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), myelodysplastic syndrome (MDS) and mixed-phenotype acute leukemia (MPAL). These results were first presented on April 2, 2025, at the 51st Annual Meeting of The EBMT in Florence, Italy, and further analyses were presented at the 67th ASH (Free ASH Whitepaper) Annual Meeting on December 6, 2025.

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In the randomized Precision-T study, Orca-T plus single-agent tacrolimus (TAC) demonstrated a significant improvement in the primary endpoint of survival free from moderate-to-severe chronic graft versus host disease (cGFS) compared to alloHSCT plus tacrolimus/methotrexate (TAC/MTX). The rate for patients who received Orca-T was 78% (95% CI: 65%, 87%) compared to 38.4% (95% CI: 26%, 51%) for patients who received an alloHSCT (HR 0.26; p<0.00001), an improvement driven by a reduction in moderate-to-severe chronic graft versus host disease (cGvHD) and fewer patient deaths.

"Today, treating patients with serious blood cancers using conventional allogeneic stem cell transplants often forces a difficult risk–benefit trade-off, as clinicians work to cure the disease while avoiding life-threatening complications like GvHD," said lead author Everett Meyer, M.D., Ph.D., hematologist and associate professor of medicine in Blood and Marrow Transplantation and Cellular Therapy at Stanford Medicine. "The Precision-T results showed that Orca-T can meaningfully shift that balance, delivering improved GvHD-free survival alongside less toxicity, including fewer serious infections and lower non-relapse mortality. Orca-T has the potential to become an important new therapy for patients and a valuable new option for the providers who care for them."

In the study, all patients (n=187) with a median age of 43.6 years (range 19-65 years) were randomized 1:1 to Orca-T plus TAC or alloHSCT plus TAC/MTX. Patients across both groups received myeloablative conditioning and used a related or unrelated matched donor. Patients had a median follow-up time of 11.4 months (range 0.2-24.3 months) across both arms. Additional results from the Precision-T study at one year include:

A secondary endpoint of cumulative incidence of moderate-to-severe cGvHD was 12.6% (95% CI: 5%, 23%) and 44.0% (95% CI: 31%, 56%) in the Orca-T and alloHSCT arms, respectively (HR 0.19; p<0.00002).
The overall survival (OS), another secondary endpoint, was 93.7% (95% CI: 86%, 97%) in the Orca-T arm and 83.2% (95% CI: 73%, 90%) in the alloHSCT arm (HR 0.49; p=0.11823).
A secondary endpoint of GvHD and relapse-free survival (GRFS) was 63.1% and 30.9% with Orca-T and alloHSCT (p<0.001 in a post hoc analysis), respectively.
The cumulative incidence of non-relapse mortality (NRM) was 3.4% (95% CI: 0.9%, 8.8%) for Orca-T versus 13.2% (95% CI: 6.8%, 21.6%) for alloHSCT (HR 0.27 [95% CI: 0.08, 0.93]; p=0.03 in a post hoc analysis).

Additional safety findings were consistent with previous studies. The cumulative incidence for grade III or IV acute GvHD at day +180 was reduced with Orca-T with 6.2% (95% CI: 2.3, 12.9) versus 16.5% (95% CI: 9.4, 25.3) with alloHSCT (HR 0.37 [95% CI: 0.13, 1.02]; p=0.044 in a post hoc analysis). Grade 3+ infections were less common with Orca-T, with a one-year estimated incidence of 8.4% (95% CI: 3.6%, 16%) for Orca-T and 16.1% (95% CI: 9.2%, 25%) for alloHSCT.

An exploratory endpoint evaluated health-related quality of life (HRQoL) and hospitalization patterns and found Orca-T delivered marked improvements over conventional alloHSCT. In the data presented at ASH (Free ASH Whitepaper) 2025, patients receiving Orca-T experienced faster recovery to, and higher improvement above, baseline HRQoL, fewer ICU stays, lower likelihood of rehospitalization and higher rehospitalization-free survival, suggesting better early post-treatment recovery and a lower burden of GvHD symptoms.

Rehospitalizations due to adverse events occurred less frequently among Orca-T recipients (27.3% [24] vs. 45.7% [43]), with fewer total hospitalization days per patient (30.6 vs. 40.8). Rehospitalization-free survival at 18 months was also significantly improved with Orca-T, reaching 66.4% (95% CI: 54.0, 76.2) compared to 33.8% (95% CI: 18.5, 49.9) for conventional alloHSCT (p=0.0096 in a post hoc analysis; HR 0.53 [0.32, 0.86]).

"As the first Treg-based immunotherapy to show improved outcomes for patients with acute leukemias and myelodysplastic syndrome compared with a conventional transplant, Orca-T has the potential to become a new standard of care," said Nate Fernhoff, Ph.D., co-founder and chief executive officer at Orca Bio. "The Phase 3 results published in Blood underscore our ability to potentially redefine how blood cancers are treated today. We look forward to continuing to work closely with the FDA on the review of our application with the goal of making Orca-T available to patients who need it."

The safety and efficacy of Orca-T have not been determined by any regulatory authority. Orca-T is currently being evaluated under Priority Review by the U.S. Food and Drug Administration (FDA) with a Prescription Drug User Fee Act (PDUFA) target action date of April 6, 2026.

About Precision-T
Precision-T (NCT05316701) is a randomized, open-label multi-center study that evaluated the safety, efficacy and tolerability of Orca Bio’s lead investigational allogeneic T-cell immunotherapy, Orca-T, compared to conventional allogeneic hematopoietic stem cell transplant (alloHSCT). Orca Bio received guidance from the U.S. Food and Drug Administration on the design of Precision-T, which evaluated Orca-T in patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), high-risk myelodysplastic syndrome (MDS) and mixed-phenotype acute leukemia (MPAL). There are 19 leading treatment centers participating in the trial, which enrolled 187 patients across the U.S.

About Orca-T
Orca-T is an investigational allogeneic T-cell immunotherapy under evaluation for the treatment of multiple hematologic malignancies including acute leukemias and myelodysplastic syndromes. Orca-T is composed of highly purified regulatory T-cells, hematopoietic stem cells and conventional T-cells derived from either related or unrelated matched donors. Orca-T has received Regenerative Medicine Advanced Therapy (RMAT) and Orphan Drug Designation for the prevention of graft versus host disease or death in patients eligible for hematopoietic stem cell transplant from the U.S. Food and Drug Administration (FDA). The Biologics License Application (BLA) for Orca-T is currently under Priority Review with the FDA with a Prescription Drug User Fee Act (PDUFA) target action date of April 6, 2026.

(Press release, Orca Bio, DEC 15, 2025, https://orcabio.com/orca-bio-announces-positive-results-from-the-pivotal-phase-3-study-of-investigational-orca-t-compared-to-allogeneic-stem-cell-transplant-for-the-treatment-of-hematologic-malignancies-2/?utm_source=rss&utm_medium=rss&utm_campaign=orca-bio-announces-positive-results-from-the-pivotal-phase-3-study-of-investigational-orca-t-compared-to-allogeneic-stem-cell-transplant-for-the-treatment-of-hematologic-malignancies-2 [SID1234661426])

(Press release, Orca Bio, DEC 15, 2025, https://orcabio.com/orca-bio-announces-positive-results-from-the-pivotal-phase-3-study-of-investigational-orca-t-compared-to-allogeneic-stem-cell-transplant-for-the-treatment-of-hematologic-malignancies-2/?utm_source=rss&utm_medium=rss&utm_campaign=orca-bio-announces-positive-results-from-the-pivotal-phase-3-study-of-investigational-orca-t-compared-to-allogeneic-stem-cell-transplant-for-the-treatment-of-hematologic-malignancies-2 [SID1234661426])

On December 15, 2025 Pilatus Biosciences Inc., a biopharmaceutical company developing novel metabolic checkpoint immunotherapies for liver and gastrointestinal cancers, reported that the U.S. Food and Drug Administration (FDA) has cleared the company’s Investigational New Drug (IND) application for PLT012, a first-in-class anti-CD36 monoclonal antibody, to enter clinical development for the treatment of solid tumors. Pilatus plans to initiate this Phase 1 clinical trial in the first quarter of 2026.

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PLT012 is a first-in-class metabolic checkpoint antibody designed to block CD36-mediated lipid uptake and immune suppression within the tumor microenvironment. CD36 is an immunometabolic regulator highly expressed on exhausted T cells, regulatory T cells, and tumor-associated macrophages, but is far less prevalent in healthy tissues.

By targeting CD36, PLT012 is engineered to restore metabolic fitness in cytotoxic T cells, reduce immunosuppressive cell populations, and promote stronger anti-tumor immune responses. In preclinical models, PLT012 demonstrated monotherapy activity across immune-hot and immune-cold tumors and showed potential synergy with PD-1/PD-L1 inhibitors, supporting its development as both a single agent and a combination therapy.

"PLT012 represents a fundamentally new approach to treating solid tumors by addressing the metabolic dysfunction that underlies immune exhaustion," said Raven Lin, Ph.D., Co-Founder and CEO, Pilatus Biosciences. "Leveraging our deep expertise in metabolic immunology, PLT012 was developed to simultaneously enhance effector T cell function and suppress tumor-promoting immune populations, while maintaining a favorable safety profile. We believe this dual-action metabolic checkpoint mechanism has the potential to deliver meaningful benefits for patients whose tumors do not respond to existing immunotherapies. We look forward to initiating our Phase 1 clinical trial of PLT012 early next year."

"Targeting CD36 represents a promising new way to reshape the tumor microenvironment," said the trial lead principal investigator, Anthony El-Khoueiry, M.D., Verna R. Richter Chair in Cancer Research, Associate Director for Clinical Research and Chief of Section of Developmental Therapeutics/Phase I Program at USC Norris Comprehensive Cancer Center, part of Keck Medicine of USC, and Associate Professor of Clinical Medicine at Keck School of Medicine of USC. "PLT012’s ability to modulate metabolic dysfunction and reinvigorate exhausted T cells positions it as a potentially important therapeutic option for tumors that do not respond to current immunotherapies."

The upcoming Phase 1, first-in-human clinical trial will evaluate safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary signs of clinical activity, with expansion cohorts planned for tumor types strongly influenced by CD36-mediated metabolic dysregulation. Pilatus has also received FDA Orphan Drug Status for PLT012 for the treatment of liver and intrahepatic bile duct cancers.

"The hepatic microenvironment is tolerogenic and macrophage-rich which can dampen effector T-cell activity, contributing to weaker responses to immunotherapy treatments for HCC and liver metastases," said Anthony W Tolcher, M.D., FRCPC, FACP of New Experimental Therapeutics (NEXT), San Antonio, Texas. "Preclinical data has shown that PLT012 can overcome this immunogenically cold environment and elicit strong anticancer effects, which we hope will be translated into improved patient outcomes in the planned Phase 1 clinical trial."

About PLT012

PLT012 is a humanized monoclonal antibody designed to selectively block CD36-mediated lipid uptake, a key mechanism driving immunosuppression and immune exclusion within the tumor microenvironment. By targeting lipid metabolism, PLT012 exerts a unique mechanism of action: it reduces immunosuppressive cell populations, including Tregs and pro-tumor macrophages, while simultaneously enhancing anti-tumor activities of intratumoral NK cell and cytotoxic CD8+ T cell that are otherwise susceptible to lipid-induced exhaustion. In preclinical studies, PLT012 has demonstrated potent monotherapy efficacy in models of liver malignancies, with a favorable safety profile across species. Leveraging its distinct mechanism of action, PLT012 further acts as a potent sensitizer in combination with anti–PD-L1 therapies, effectively overcoming drug resistance in immune "cold" tumors and liver metastases.

(Press release, Pilatus Biosciences, DEC 15, 2025, View Source [SID1234661446])

On December 15, 2025 RedHill Biopharma Ltd. (Nasdaq: RDHL) ("RedHill" or the "Company"), a specialty biopharmaceutical company, reported positive in vivo results, indicating that opaganib combined with venetoclax reduces Chronic Lymphocytic Leukemia (CLL) cells by half compared to controls, and further demonstrates opaganib’s potential as an add-on therapy to venetoclax in venetoclax-resistant CLL.

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"Understanding mechanisms of resistance to targeted therapies such as the BCL-2 inhibitor venetoclax is essential to improve current treatment strategies and may provide key insights to personalize treatment for chronic lymphocytic leukemia (CLL) patients" said Romina Gamberale, PhD, Independent Researcher at CONICET from the Institute of Experimental Medicine (IMEX, CONICET-National Academy of Medicine) in Buenos Aires, Argentina, who led the study. "Our previous ex vivo work has shown that sphingosine kinase 2 (SPHK2) is overexpressed in venetoclax-resistant CLL cells and that inhibiting SPHK2 may reduce T-cell-induced resistance and resensitize previously resistant cells. The results of this in vivo study in mice indicate that adding opaganib, a potent SPHK2 inhibitor, to venetoclax reduced CLL cell counts by 50% compared to controls, showing that opaganib may have a significant role to play in mitigating BCL-2 inhibitor resistance."

Dr. Mark Levitt, Chief Scientific Officer at RedHill said: "Venetoclax is a key CLL therapy and finding ways to maintain its effectiveness, and to reduce the potential for resistance-related treatment failure, could represent a breakthrough in the ability to treat CLL patients. This promising data supports the hypothesis that opaganib, as a potent inhibitor of SPHK2, provides a potential route to maintaining venetoclax effects in treating CLL. Opaganib has shown potential as add-on therapy in several preclinical oncology models and is currently undergoing a Phase 2 clinical trial in combination with darolutamide in advanced prostate cancer. This new data now adds CLL to the list of potential cancer indications where opaganib has shown potential to bring additive therapeutic value."

Opaganib has a safety and tolerability profile shown in more than 470 clinical trials / expanded access participants. It targets multiple oncology, virology, inflammation, medical countermeasures, diabetes and obesity indications, with several U.S. government partnerships, including BARDA funding, in place.

Approved by the FDA in 2016, venetoclax (Venclexta and Venclyxto, Abbvie / Genentech), is a first-in-class BCL-2 inhibitor that has become a mainstay of CLL therapy, achieving sales of approximately $2.5 billion in 2024. Venetoclax works by blocking a protein called BCL-2, which is often overproduced in certain cancer cells and prevents the process of apoptosis (programmed cell death) – helping to keep the cancer cells alive and growing. By binding to, and inhibiting, the BCL-2 protein, venetoclax enables the cancer cells to undergo apoptosis and die.

About Chronic Lymphocytic Leukemia (CLL)

CLL is a slow-growing blood and bone marrow cancer that affects a type of white blood cell called lymphocytes. It is the most common type of leukemia in adults and has a highly variable clinical course. It is generally not considered to be curable.

About Opaganib (ABC294640)

Opaganib is a first-in-class, proprietary investigational host-directed and potentially broad-acting orally administered drug with anticancer, anti-inflammatory and antiviral activity. Opaganib is targeted at multiple potential oncology, radioprotection, viral, inflammatory, and gastrointestinal indications, including several cancers, diabetes and obesity-related disorders, gastrointestinal acute radiation syndrome (GI-ARS), COVID-19, Ebola and other viruses as part of pandemic preparedness. Opaganib has also shown positive preclinical results in renal fibrosis.

Opaganib has received orphan-drug designations from the FDA in cholangiocarcinoma and neuroblastoma. It is currently undergoing a Phase 2 clinical trial in combination with darolutamide in advanced prostate cancer and has previously undergone studies in advanced cholangiocarcinoma (Phase 2a). Opaganib also has a Phase 1 chemoradiotherapy study protocol ready for FDA-IND submission.

Opaganib is thought to work through the inhibition of multiple pathways, the induction of autophagy and apoptosis, and disruption of viral replication, through simultaneous inhibition of three sphingolipid-metabolizing enzymes in human cells (SPHK2, DES1 and GCS).

Several U.S. government medical countermeasures and pandemic preparedness programs have selected opaganib for evaluation for multiple indications, including GI-ARS, Ebola virus disease and others. Funding bodies include the Radiation and Nuclear Countermeasures Program (RNCP), led by the National Institute of Allergy and Infectious Diseases (NIAID), part of the U.S. government Department of Health & Human Services’ National Institutes of Health, and the Administration for Strategic Preparedness and Response’s (ASPR) Center for Biomedical Advanced Research and Development Authority (BARDA).

Opaganib has demonstrated antiviral activity against SARS-CoV-2, multiple variants, and several other viruses, such as Influenza A and Ebola. Opaganib delivered a statistically significant increase in survival time when given at 150 mg/kg twice a day (BID) in a United States Army Medical Research Institute of Infectious Diseases (USAMRIID) in vivo Ebola virus study, making it the first host-directed molecule to show activity in Ebola virus disease. Opaganib also recently demonstrated a distinct synergistic effect when combined individually with remdesivir (Veklury, Gilead Sciences Inc.), significantly improving potency while maintaining cell viability, in a U.S. Army-funded and conducted in vitro Ebola virus study.

Being host-targeted, and based on data accumulated to date, opaganib is expected to maintain effect against emerging viral variants. In prespecified analyses of Phase 2/3 clinical data in hospitalized patients with moderate to severe COVID-19, oral opaganib demonstrated improved viral RNA clearance, faster time to recovery and significant mortality reduction in key patient subpopulations versus placebo on top of standard of care. Opaganib has demonstrated its safety and tolerability profile in more than 470 people in multiple clinical studies and expanded access use. Data from the opaganib global Phase 2/3 study was published in Microorganisms.

(Press release, RedHill Biopharma, DEC 15, 2025, View Source [SID1234661428])