On October 21, 2024 Elevar Therapeutics, Inc., a majority-owned subsidiary of HLB Co., Ltd., reported the U.S. Food and Drug Administration (FDA) accepted the resubmission of a new drug application (NDA) for its investigational drug rivoceranib, an oral VEGF-TKI, in combination with camrelizumab, a PD-1 inhibitor, as a first-line systemic treatment for unresectable or metastatic hepatocellular carcinoma (uHCC) (Press release, Elevar Therapeutics, OCT 21, 2024, View Source [SID1234647283]). The FDA assigned a Prescription Drug User Fee Act (PDUFA) target action date of March 20, 2025.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"We believe rivoceranib plus camrelizumab has the potential to change the clinical practice in the first-line setting for patients with advanced liver cancer. The results of the pivotal CARES-310 trial demonstrated significant improvements in overall survival, with a very manageable safety profile compared with currently approved uHCC therapies. Elevar is committed to working with the FDA to bring this combination to market for patients and healthcare providers," commented Chris Galloway, M.D., senior vice president of clinical and medical affairs at Elevar Therapeutics.

The resubmission included the final analysis of the Phase 3 CARES-310 study presented during the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting on June 1, which reported median overall survival (mOS) of 23.8 months, the longest mOS for any treatment in a global Phase 3 trial for patients with uHCC, confirming the combination of camrelizumab and rivoceranib continued to show sustained long-term survival as a first-line treatment for patients with uHCC.[i]

With the efficacy results generally consistent across all subgroups, the data suggest the combination has the potential to benefit a global uHCC population. The data also demonstrated consistent efficacy across patients with both viral and non-viral etiologies.

About CARES-310

The CARES-310 study, an international, randomized, open-label, Phase 3 trial, with 543 patients with uHCC who had not previously received systemic treatment was the first to demonstrate significant progression-free survival (PFS) and overall survival (OS) benefits with immunotherapy plus an anti-angiogenic tyrosine kinase inhibitor (TKI) over standard TKI as first-line treatment for uHCC. In the primary analysis of PFS (data cut-off [DCO], May 10, 2021) and interim analysis of OS (DCO, Feb. 8, 2022), significant improvements were observed with camrelizumab (C; anti-PD-1 antibody) + rivoceranib (R; VEGFR2-TKI) vs. sorafenib (S).

In the final analysis (FA) of the CARES-310 study, after an additional follow-up of ~16 months, median OS was significantly prolonged with C+R vs. S (23.8 mo [95% CI 20.6-27.2] vs. 15.2 mo [95% CI 13.2-18.5]; hazard ratio (HR) 0.64 [95% CI 0.52-0.79]; 1-sided p <0.0001). OS rate with C+R vs. S was 49.0% vs. 32.6% at 24 mo, and 37.7% vs. 24.8% at 36 mo. OS benefits with C+R was generally consistent across subgroups, regardless of geographical region, race, and etiology. Benefits in PFS, objective response rate (ORR) and duration of response (DoR) with C+R vs. S were also sustained after prolonged follow-up. Safety data aligned with the interim OS analysis, with no new signals noted. In the FA, C+R continued to show clinically meaningful survival improvement compared with S, with manageable safety. The extended follow-up further confirmed the favorable benefit-to-risk profile of C+R, supporting it as a new first-line treatment option for uHCC.

About Hepatocellular Carcinoma

Worldwide each year more than 800,000 people are diagnosed with liver cancer[ii] and the disease is the cause of more than 830,000 deaths.[iii] Hepatocellular Carcinoma (HCC) is the most common type of liver cancer and most frequently develops in people with chronic underlying liver inflammation which may be from viral and non-viral causes. HCC typically has a poor prognosis with limited treatment options and continues to be a diagnosis with an ongoing urgent medical need.

About Rivoceranib

Rivoceranib, a small-molecule tyrosine kinase inhibitor (TKI), is a highly selective inhibitor of vascular endothelial growth factor receptors (VEGFRs), a primary pathway for tumor angiogenesis. VEGFR inhibition is a clinically validated target to limit tumor growth and disease progression. Rivoceranib is currently being studied as a monotherapy and in combination with chemotherapy and immunotherapy in various solid tumor indications. Several clinical studies were completed in patients with uHCC (in combination with camrelizumab), gastric cancer (as a monotherapy and in combination with paclitaxel), adenoid cystic carcinoma (as a monotherapy) and colorectal cancer (in combination with Lonsurf). Rivoceranib, under the name apatinib (Aitan), was the first TKI approved in gastric cancer in China (October 2014). It was also approved in China in combination with camrelizumab as a first-line treatment for uHCC (January 2023). The drug has been studied in more than 6,000 patients worldwide and was well tolerated in clinical trials with a comparable safety profile to other TKIs and VEGF inhibitors. Orphan drug designations have been granted for gastric cancer (U.S., EU and South Korea), adenoid cystic carcinoma (U.S.) and uHCC (U.S. and EU). Elevar Therapeutics, Inc. holds the global rights (excluding China) to rivoceranib and has partnered for its development and marketing with HLB-LS in South Korea. Jiangsu Hengrui Pharmaceuticals Company Ltd., (Hengrui Pharma), is the Chinese -territory license-holder of rivoceranib.

About Camrelizumab

Camrelizumab (SHR-1210) is a humanized monoclonal antibody that binds to the programmed death-1 (PD-1) receptor. Blockade of the PD-1/PD-L1 signaling pathway is a therapeutic strategy showing success in a wide variety of solid and hematological cancers. Camrelizumab is developed by Hengrui Pharma and has been studied in more than 5,000 patients. Currently, 50 clinical trials are underway in a broad range of tumors (including liver cancer, lung cancer, gastric cancer, and breast cancer, etc.) and treatment settings. Camrelizumab, under the brand name AiRuiKa, is currently approved for eight indications in China, including monotherapy for the treatment of HCC (second-line), in combination with rivoceranib as a treatment for uHCC (first-line), relapsed/refractory classic Hodgkin’s lymphoma (third-line), esophageal squamous cell carcinoma (second-line) and nasopharyngeal carcinoma (third-line or further) and in combination with chemotherapy for the treatment of non-small cell lung cancer (non-squamous and squamous), esophageal squamous cell carcinoma and nasopharyngeal carcinoma in the first-line setting. The U.S. Food and Drug Administration granted Orphan Drug Designation to camrelizumab for advanced HCC in April 2021 and by the European Medicines Agency in August 2024.

In October 2023, Elevar licensed camrelizumab, an anti-PD-1 antibody, for commercialization from Jiangsu Hengrui Pharmaceuticals Co., Ltd. (Hengrui Pharma) worldwide excluding Greater China and Korea.

On October 21, 2024 BullFrog AI Holdings, Inc. (NASDAQ:BFRG; BFRGW) ("Bullfrog AI" or the "Company"), a technology-enabled drug development company using artificial intelligence (AI) and machine learning to enable the successful development of pharmaceuticals and biologics, reported it has closed its previously announced definitive agreement for the purchase and sale of an aggregate of 1,565,000 shares of common stock (or common stock equivalents in lieu thereof) in a registered direct offering and, in a concurrent private placement, common warrants to purchase up to 1,565,000 shares of common stock (together with the registered direct offering) at a combined purchase price of $2.00 (Press release, Bullfrog AI, OCT 21, 2024, View Source [SID1234647282]). The warrants will have an exercise price of $2.00 per share, are initially exercisable on the date that is six months from the date of issuance and will expire five years from such initial exercise date.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The gross proceeds from the offering are expected to be approximately $3.13 million, excluding any proceeds that may be received upon exercise of the warrants and before deducting the placement agent’s fees and other offering expenses payable by the Company.

WallachBeth Capital, LLC acted as sole placement agent for the registered direct offering and private placement.

The shares of common stock, the pre-funded warrants and the shares of common stock underlying the pre-funded warrants (but not the common warrants or the shares of common stock underlying the common warrants) will be issued in a registered direct offering pursuant to an effective shelf registration statement on Form S-3 (File No. 333-281341) previously filed with the U.S. Securities and Exchange Commission ("SEC"), under the Securities Act of 1933, as amended (the "Securities Act"), and declared effective by the SEC on August 21, 2024. The common warrants to be issued in the concurrent private placement and the shares issuable upon exercise of such common warrants were offered pursuant to an exemption from the registration requirements of the Securities Act under Section 4(a)(2) thereof and Regulation D promulgated thereunder and have not been registered under the Securities Act or applicable state securities laws. The offering of the shares of common stock and pre-funded warrants is made only by means of a prospectus, including a prospectus supplement, forming a part of the effective registration statement. A prospectus supplement describing the terms of the proposed registered direct offering will be filed with the SEC and available on the SEC’s website located at View Source Electronic copies of the prospectus supplements may be obtained, when available, from WallachBeth Capital, LLC, via email at [email protected], by calling +1 (646) 237-8585, or by standard mail at WallachBeth Capital LLC, Attn: Capital Markets, 185 Hudson St., Suite 1410, Jersey City, NJ 07311, USA. This press release shall not constitute an offer to sell or the solicitation of an offer to buy these securities, nor shall there be any sale of these securities in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction.

On October 21, 2024 BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160; SSE: 688235), a global oncology company, reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency issued positive opinions recommending an extended authorization for TEVIMBRA (tislelizumab) in gastric or gastroesophageal junction (G/GEJ) adenocarcinoma and esophageal squamous cell carcinoma (ESCC) (Press release, BeiGene, OCT 21, 2024, View Source [SID1234647281]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

In G/GEJ adenocarcinoma, the CHMP positive opinion is for TEVIMBRA in combination with platinum- and fluoropyrimidine-based chemotherapy for the first-line treatment of adult patients with HER2-negative locally advanced unresectable or metastatic G/GEJ cancer whose tumors express PD-L1 with a tumor area positivity (TAP) score ≥ 5%. In ESCC, the CHMP positive opinion is for TEVIMBRA in combination with platinum-based chemotherapy for the first-line treatment of adult patients with unresectable, locally advanced or metastatic ESCC whose tumors express PD-L1 with a TAP score ≥ 5%.

"Survival rates in the advanced stages of gastric/gastroesophageal and esophageal cancers are among the lowest of all cancer types despite recent advances, and new treatment options are needed," said Prof. Florian Lordick, Director and Professor of Oncology of the University Cancer Center Leipzig, Germany. "The RATIONALE-305 and 306 trials showed that tislelizumab plus chemotherapy improved survival compared to treatment with placebo plus chemotherapy, highlighting its potential to deliver better outcomes for eligible patients."

"TEVIMBRA is foundational for BeiGene’s solid tumor portfolio. In line with our commitment to help patients affected by cancer in Europe and across the globe, we recently launched TEVIMBRA in the EU for eligible patients in both the first- and second-line NSCLC settings and second-line ESCC," said Mark Lanasa, M.D., Ph.D., Chief Medical Officer, Solid Tumors at BeiGene. "With these CHMP opinions, we are one step closer to bringing this innovative therapy to eligible patients with untreated G/GEJ cancer and ESCC , who face a poor prognosis and limited treatment options."

The extension of indication application for first-line G/GEJ cancer is based on results from BeiGene’s RATIONALE-305 (NCT03777657), a randomized, double-blind, placebo-controlled, global Phase 3 trial to evaluate the efficacy and safety of TEVIMBRA in combination with chemotherapy as a first-line treatment for patients with advanced unresectable or metastatic G/GEJ cancer. The study enrolled 997 patients at research centers across Europe, North America and Asia-Pacific. The study met its primary endpoint and demonstrated a statistically significant and clinically meaningful overall survival (OS) benefit with a median OS of 15.0 months for patients treated with TEVIMBRA in combination with investigator’s choice of chemotherapy compared to 12.9 months for patients treated with placebo plus chemotherapy (n=997; HR: 0.80 [95% CI: 0.70, 0.92]; P=0.0011), resulting in a 20% reduction in the risk of death. In the PD-L1 ≥ 5% population, the median OS was 16.4 months for TEVIMBRA plus chemotherapy compared to 12.8 months for the placebo arm (HR: 0.71 [95% CI, 0.58-0.86]), which represents a 29% reduction in the risk of death.

The extension of indication application for first-line ESCC is based on results from BeiGene’s RATIONALE-306 (NCT03783442), a randomized, placebo-controlled, double-blind, global Phase 3 study to evaluate the efficacy and safety of TEVIMBRA in combination with chemotherapy as a first-line treatment in patients with unresectable, locally advanced recurrent or metastatic ESCC. The study enrolled 649 patients at research centers across Europe, North America and Asia-Pacific. The study met its primary endpoint, with first-line TEVIMBRA in combination with chemotherapy resulting in statistically significant and clinically meaningful OS benefit compared with placebo plus chemotherapy in the intent-to-treat population. The median OS was 17.2 months for TEVIMBRA with chemotherapy versus 10.6 months for placebo plus chemotherapy (HR: 0.66 [95% CI, 0.54-0.80, 1-sided p-value of < 0.0001]), a 34% reduction in the risk of death. Three-year OS in the PD-L1 ≥ 5% population was also substantially improved in favor of the TEVIMBRA arm (median 19.1 versus 10.0 months, respectively; HR: 0.62 [95% CI, 0.49-0.79]), demonstrating a 38% reduction in the risk of death.

The safety data in the applications included 1,534 patients who received TEVIMBRA monotherapy at the approved dosing regimen, and 1,319 patients with G/GEJ cancer, ESCC or NSCLC who received TEVIMBRA at the approved dosing regimen (200 mg every 3 weeks) in combination with various chemotherapies. The most common Grade 3 or 4 adverse reactions for TEVIMBRA given in combination with chemotherapy were neutropenia, thrombocytopenia, anemia, fatigue, hypokalemia, hyponatremia, pneumonia, decreased appetite, rash, lymphopenia, alanine aminotransferase increased, aspartate aminotransferase increased, diarrhea, pneumonitis, and hepatitis.

TEVIMBRA is approved in the EU for eligible patients with advanced or metastatic ESCC after prior platinum-based chemotherapy and for three non-small cell lung cancer (NSCLC) indications covering both the first- and second-line settings.

About Gastric and Gastroesophageal Junction (G/GEJ) Adenocarcinoma

Gastric (stomach) cancer is the fifth most common cancer worldwide and the fifth highest leading cause of cancer mortality.1 Nearly 1 million new patients were diagnosed with gastric cancer in 2022, and 660,000 deaths were reported globally. Gastroesophageal junction adenocarcinoma occurs at the area where the esophagus joins the stomach, which is just beneath the diaphragm (the thin sheet of breathing muscle under the lungs).2

About Esophageal Squamous Cell Carcinoma (ESCC)

Globally, esophageal cancer (EC) is the sixth most common cause of cancer-related deaths, and ESCC is the most common histologic subtype, accounting for nearly 90% of ECs. An estimated 957,000 new EC cases are projected in 2040, an increase of nearly 60% from 2020, underscoring the need for additional effective treatments.3 EC is a rapidly fatal disease, and more than two-thirds of patients have advanced or metastatic disease at the time of diagnosis, with an expected five-year survival rate of less than 6% for those with distant metastases.4

About TEVIMBRA (Tislelizumab)

TEVIMBRA is a uniquely designed humanized immunoglobulin G4 (IgG4) anti-programmed cell death protein 1 (PD-1) monoclonal antibody with high affinity and binding specificity against PD-1. It is designed to minimize binding to Fc-gamma (Fcγ) receptors on macrophages, helping to aid the body’s immune cells to detect and fight tumors.

Important Safety Information

The current European Summary of Product Characteristics (SmPC) for TEVIMBRA is available from the European Medicines Agency.

This information is intended for a global audience. Product indications vary by region.

On October 21, 2024 Astex Pharmaceuticals, a pharmaceutical company based in Cambridge, UK, dedicated to the discovery and development of novel small molecule therapeutics for oncology and diseases of the central nervous system, reported that it will make five key data presentations at the 36th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium on molecular targets and cancer therapeutics, 23rd-25th October 2024, Barcelona, Spain (Press release, Astex Pharmaceuticals, OCT 21, 2024, View Source [SID1234647280]). The Astex presentations will focus on its novel small-molecule CBP/p300 HAT domain inhibitor, ASTX528 in preclinical development and its Phase II-ready MDM2 antagonist, ASTX295.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Astex data presentations at 36th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium, 23rd-25th October 2024, Barcelona

Title Presentation Date/Time/Session Title/Presenter Presentation number
A Novel Small-Molecule CBP/p300 HAT Domain Inhibitor Demonstrates Potent In Vivo Activity and a Favourable Safety Profile in Preclinical Species Poster Date: Wed, 23rd Oct 2024
Time: 12:00 – 19:00

Session Title: Molecular Targeted Agents

Presenter: Gianni Chessari, Astex Pharmaceuticals, UK

Catalog #42
Presentation #PB030

Targeting the Catalytic HAT Domain of CBP/p300 for the Treatment of Hormone-Dependent Breast and Prostate Cancers Poster Date: Wed, 23rd Oct 2024
Time: 12:00 – 19:00

Session Title: Molecular Targeted Agents

Presenter: John Lyons, Astex Pharmaceuticals, UK

Catalog #73
Presentation #PB061

From a Preclinical Therapeutic Concept to the Clinic. ASTX295: Discovery of a bone marrow sparing MDM2 antagonist Oral Date: Wed, 23rd Oct 2024
Time: 16:55 -17:15

Session Title: Optimising of preclinical models for drug development

Presenter: Maria Ahn, Astex Pharmaceuticals, UK

Workshop 2
Room 113+114

Identification of Biomarkers Predictive of Response to ASTX295, a Next-Generation MDM2 Antagonist, in Solid Tumors Carrying Wild-type p53 Poster Date: Wed, 23rd Oct 2024
Time: 12:00 – 19:00

Session Title: Molecular Targeted Agents

Presenter: Maria Ahn, Astex Pharmaceuticals, UK

Catalog #28
Presentation #PB016

Pulsatile Induction of the p53 Pathway by MDM2 Antagonist ASTX295 Shows an Enhanced Therapeutic Index in vivo Poster Date: Thu, 24th Oct 2024
Time: 9:00 – 17:30

Session Title: Translational Studies

Presenter: Andrea Biondo, Astex Pharmaceuticals, UK

Catalog #289
Presentation #PB277

ASTX528 – CBP/p300 HAT Domain Inhibitor – Preclinical

ASTX528 is a novel small molecule CBP/p300 HAT domain inhibitor with potent in vivo activity and a favourable safety profile in preclinical species that was discovered by Astex using its proprietary fragment-based drug discovery approach. CREB binding protein (CBP) and its paralog, EP300 (p300), are lysine acetyltransferases and transcriptional cofactors implicated in human cancers. Dose-limiting tolerability issues have been observed with dual CBP/p300 bromodomain (BRD) inhibitors, which may limit their clinical utility. We hypothesised that a dual inhibitor targeting the histone acetyltransferase (HAT) domain may improve the therapeutic window. Our presentations will describe the effects of CBP/p300 HAT domain inhibition in preclinical models of AR- and ER-driven cancers and the characterisation of ASTX528, a potent, fragment-derived CBP/p300 HAT domain inhibitor with a low predicted human dose and promising preliminary toxicity evaluation. Astex is interested in discussing the further development of ASTX528 with potential partners.

ASTX295 – Bone Marrow-Sparing MDM2 Antagonist, Phase II-ready

ASTX295 is an oral, potent inhibitor of the p53-MDM2 protein-protein interaction that was discovered by Astex using its proprietary structure-based drug design approach. The compound was specifically designed to overcome the on-target toxicity seen in the first generation MDM2 antagonist compounds which have shown dose-limiting haematological toxicities in the clinic. In contrast, ASTX295 is a potent MDM2 antagonist with a clean CYP/hERG profile and a shorter human half-life allowing for pulsatile pathway modulation while avoiding myelosuppression. ASTX295 therefore has bone-marrow sparing characteristics which permit a differentiated safety profile. ASTX295 was discovered by Astex in collaboration with the Cancer Research UK Drug Discovery Unit at Newcastle University. Astex has an exclusive license to research, develop and commercialise ASTX295 under its drug discovery alliance agreement with Newcastle University and Cancer Research Technology Limited.

On October 21, 2024 Adcentrx Therapeutics ("Adcentrx"), a clinical-stage biotechnology company advancing innovative protein conjugates for cancer and other life-threatening diseases, reported that the U.S. Food and Drug Administration (FDA) has cleared the company’s Investigational New Drug (IND) application of ADRX-0405 for the treatment of select advanced solid tumors (Press release, Adcentrx Therapeutics, OCT 21, 2024, View Source [SID1234647278]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

ADRX-0405 is a next-generation antibody-drug conjugate (ADC) composed of a humanized IgG1 antibody targeting six-transmembrane epithelial antigen of the prostate 1 (STEAP1), a cell surface protein that is upregulated in prostate cancer and certain other cancers, yet has limited expression in healthy tissue.

Adcentrx’s proprietary i-Conjugation technology platform is an important component in the design of ADRX-0405. The platform utilizes protease-cleavable linkers and stable conjugation chemistry to enhance payload delivery. This advanced technology ensures a highly stable ADC with a topoisomerase inhibitor payload conjugated at a drug-to-antibody ratio of eight (DAR 8). ADRX-0405 preclinical studies have demonstrated its favorable pharmacokinetics, safety profile, and significant efficacy across multiple tumor models.

"The FDA’s clearance of our second IND marks another major advancement for Adcentrx," said Hui Li, Ph.D., President and CEO of Adcentrx. "We are excited about the first-in-class potential for ADRX-0405 and the opportunity to make a meaningful difference for patients battling advanced cancers, including patients with metastatic castration resistant prostate cancer, who have a significant need for new targeted therapies."

The planned first-in-human Phase 1a/b clinical trial of ADRX-0405 is an open-label, multicenter, non-randomized dose escalation and dose expansion study. The study will enroll patients with select advanced solid tumors, including metastatic castration resistant prostate cancer. The primary objectives of the study will be to characterize the safety and tolerability and to determine the optimal dose of ADRX-0405. The company anticipates the first patient to be enrolled in 4Q 2024, with an estimated initial data readout in 4Q 2025.