Kinselby (resminostat) / 4SC, Yakult Honsha, Menarini - LARVOL DELTA

Exploring DNA topoisomerase II alpha in adrenocortical carcinoma through multi-omics analysis: a potential biomarker and therapeutic target. (PubMed, Acta Biochim Biophys Sin (Shanghai)) - "Potential inhibitors targeting TOP2A are discovered, and the therapeutic effects of resminostat and etoposide are confirmed via in vivo assays, suggesting new therapeutic strategies for ACC treatment. In conclusion, TOP2A serves as a crucial biomarker in ACC and is associated with adverse clinical outcomes and a diminished immune response. The identification of potential inhibitors against TOP2A opens new avenues for the development of targeted therapies for ACC patients."

Biomarker • IO biomarker • Journal • Adrenal Cortex Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor • CD8 • TOP2A

EMA signals a Negative CHMP Opinion on the Marketing Authorization Application for Resminostat (Kinselby) (4SC Press Release) - "Today, the Management Board of 4SC AG...has been informed by representatives of the European Medicines Agency (EMA) that a Negative Opinion from the Committee for Medicinal Products for Human Use (CHMP) with respect to the Market Authorization Application (MAA) for Resminostat (Kinselby) for the treatment of patients with advanced stage cutaneous T-cell lymphoma (CTCL) is to be expected on May 22, 2025....The information that a Negative Opinion is to be expected comes despite the extensive efforts made by 4SC to resolve the EMA’s last remaining Major Objection regarding the demonstration of a positive benefit-risk ratio for patients with advanced stage CTCL in an Oral Explanation earlier today....As a result, 4SC is now discontinuing the further development and commercialization of Resminostat (Kinselby)."

CHMP • Discontinued • Cutaneous T-cell Lymphoma

4SC AG: 4SC announces further EMA feedback relating to Resminostat’s (Kinselby) Marketing Authorisation Application (4SC Press Release) - "The Management Board of 4SC AG...was informed by the European Medicines Agency (EMA) today that based on its review of the final data and the Company's response to the Day-180 Assessment Report, 4SC has been invited to an Oral Explanation before the Committee for Medicinal Products for Human Use (CHMP) at its end of May meeting. Following that meeting the CHMP is expected to then take a decision as to whether or not to issue a positive opinion regarding the Company's Market Authorization Application (MAA) for Resminostat (Kinselby) in the EU."

European regulatory • Cutaneous T-cell Lymphoma

4SC publishes Q1 2025 report (4SC Press Release) - "What is most critical for the company in 2025 is the progress, and ultimately the outcome, of our marketing authorization application with the European Medicines Agency. Having filed our MAA in Q1 2024 and received feedback in May we subsequently filed our response as required before the end of 2024. In Q1 this year we received the EMA’s 180 Day Assessment Report and have again responded to the EMA’s major objections in the required timeframe. We are currently awaiting further EMA feedback, which we expect to be end of April 2025, and will continue to keep stakeholders informed of any outcome."

European regulatory • Cutaneous T-cell Lymphoma

RITA: Rituximab and RASi in Patients with IgAN (clinicaltrials.gov) - P4 | N=116 | Completed | Sponsor: Nan Chen,MD | Recruiting ➔ Completed | Trial completion date: Dec 2023 ➔ Mar 2024 | Trial primary completion date: Jul 2023 ➔ Mar 2024

Trial completion • Trial completion date • Trial primary completion date • Glomerulonephritis • IgA Nephropathy • Renal Disease

4SC AG provides update on the regulatory filing for resminostat (Kinselby) [Google translation] (4SC Press Release) - "The Management Board of 4SC AG...decided today, after consultation with the entire 4SC team, external experts, and the Supervisory Board, to formulate a response to the EMA's Day-180 Assessment Report, particularly to the objections, known as 'Major Objections,' and submit it to the EMA within the required deadline. 4SC now expects feedback from the Committee for Medicinal Products for Human Use (CHMP) around the end of April 2025 and will then determine the company's future direction depending on the CHMP's decision."

European regulatory • Cutaneous T-cell Lymphoma

4SC AG: 4SC announces update relating to Resminostat’s (Kinselby) Marketing Authorisation Application (pressetext) - "4SC AG...today announced that it had submitted its responses to the Day-120 List of Questions from the European Medicines Agency (EMA) in December 2024 as planned, following 4SC's initial Marketing Authorisation Application (MAA) filing for resminostat (Kinselby) in March 2024. The EMA has notified 4SC that examination of the Company's MAA shall continue according to schedule. The Day-120 List of Questions were issued by the Committee for Medicinal Products for Human Use (CHMP) as part of the centralized review process for resminostat (Kinselby), an orally available treatment for Cutaneous T-cell Lymphoma (CTCL). Subject to the EMA's decision, marketing authorisation approval is expected around mid-2025."

EMA approval • Cutaneous T-cell Lymphoma

4SC AG announces EMA feedback on the marketing authorization application for Resminostat (Kinselby) (4SC Press Release) - "The Management Board of 4SC AG...was informed today by the European Medicines Agency (EMA) that, after reviewing the final data and the Company’s responses to questions, the application for resminostat (Kinselby), an orphan medicinal product for the treatment of patients with CTCL, is currently not eligible for approval as 'major objections' have been identified that preclude the recommendation for marketing authorization at this time (Day-180 Assessment Report). 4SC will now evaluate the feedback and decide how best to respond to the EMA's objections and list of open questions within the one-month response period."

European regulatory • Cutaneous T-cell Lymphoma

Phase I-IV Drug Trials on Hepatocellular Carcinoma in Asian Populations: A Systematic Review of Ten Years of Studies. (PubMed, Int J Mol Sci) - "Eighteen studies compared the efficacy of sorafenib with that of other drugs, including lenvatinib, cabozantinib, tepotinib, tigatuzumab, linifanib, erlotinib, resminostat, brivanib, tislelizumab, selumetinib, and refametinib. This study provides comprehensive insights into effective treatment interventions for HCC in Asian populations. The overall assessment indicates that sorafenib, used alone or in combination with atezolizumab and bevacizumab, has been the first treatment choice in the past decade to achieve better outcomes in patients with HCC in Asian populations."

Journal • Review • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • Transplantation

Staphylococcus aureus - induces drug resistance in cancer T cells in Sézary syndrome (EORTC-CLTG 2024) - "Supernatant from patient-derived, SE-producing S aureus and recombinant SE significantly inhibit cell death induced by histone deacetylase (HDAC) inhibitor romidepsin in primary malignant T cells from patients with SS...Importantly, SE also triggers resistance to other HDAC inhibitors (vorinostat and resminostat) and chemotherapeutic drugs (doxorubicin and etoposide)...Inversely, SE cannot rescue from cell death induced by the proteasome/NF-κB inhibitor bortezomib...These findings suggest that S aureus enterotoxins cause clinical treatment resistance in patients with SS, and antibacterial measures may improve the outcome of cancer-directed therapy in patients harboring S aureus. Abstract from Vadivel CK et al Blood (2024) 143 (15): 1496–1512."

IO biomarker • Cutaneous T-cell Lymphoma • Hematological Malignancies • Lymphoma • Oncology • Sezary Syndrome • T Cell Non-Hodgkin Lymphoma

RESMAIN: Results of a multicenter, randomized, double blind, placebocontrolled trial to evaluate RESminostat for MAINtenance treatment in advanced stage Mycosis fungoides or Sézary syndrome (EORTC-CLTG 2024) - P2 | "Conclusions The RESMAIN trial is the first to prove the benefit of a maintenance treatment strategy in advanced CTCL. Resminostat significantly prolonged PFS compared with placebo and demonstrated clinically meaningful benefit in a broad population of advanced stage MF/SS patients."

Clinical • Metastases • Cutaneous T-cell Lymphoma • Mycosis Fungoides • Oncology • Sezary Syndrome • Skin Cancer

Combination of JAKi and HDACi Exerts Antiangiogenic Potential in Cutaneous T-Cell Lymphoma. (PubMed, Cancers (Basel)) - "Moreover, the combination of ruxolitinib with resminostat blocked angiogenesis by significantly reducing the number of blood vessel formation by 49% and 34% in both MyLa and SeAx, respectively (p < 0.05), indicating that the proposed combination exerted significant anti-angiogenic effects in the CAM CTCL model. Overall, these data provide valuable insights into potential therapeutic strategies targeting angiogenesis in CTCL, paving the way for more effective treatment approaches in the future."

Journal • Cutaneous T-cell Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Oncology • Solid Tumor • T Cell Non-Hodgkin Lymphoma

RESMAIN: Resminostat for Maintenance Treatment of Patients With Advanced Stage Mycosis Fungoides (MF) or Sézary Syndrome (SS) (clinicaltrials.gov) - P2 | N=201 | Completed | Sponsor: 4SC AG | Active, not recruiting ➔ Completed

Trial completion • Cutaneous T-cell Lymphoma • Dermatology • Hematological Malignancies • Lymphoma • Mycosis Fungoides • Non-Hodgkin’s Lymphoma • Oncology • Sezary Syndrome • T Cell Non-Hodgkin Lymphoma

4SC announces Half-Year Report 2024 and provides update (4SC Press Release) - "4SC AG...today published its Half-Year Report 2024, presenting all material corporate developments up to 30 June 2024 and the Company’s current outlook...'Given the positive topline data from the RESMAIN study, we filed our Marketing Authorization Application for Kinselby to the EMA in February 2024 and received questions at the beginning of July as part of the MAA evaluation. Our goal is to address these questions by end 2024 and hopefully receive authorization to market Kinselby in the EU by the middle of next year.'"

EMA approval • European regulatory • Cutaneous T-cell Lymphoma • Hematological Malignancies • Non-Hodgkin’s Lymphoma • Oncology

4SC receives Orphan Drug Status (ODS) for resminostat (Kinselby) in cutaneous T-cell lymphoma in Switzerland (4SC Press Release) - "4SC AG...received notification from the Swiss Agency for Therapeutic Products (SwissMedic) that it has granted Orphan Drug Status to resminostat for the treatment of CTCL."

Orphan drug • Cutaneous T-cell Lymphoma

AGM highlights – Positive progress in 2023/2024 leaves company well positioned for resminostat commercialisation (4SC Press Release) - "Yakult Honsha – our partner for resminostat in Japan – is preparing its filing with the Japanese PMDA and is currently waiting on data from the rollover arm of RESMAIN and longer-term overall survival outcomes, which will be available in Q4 2024....Domatinostat was successfully partnered with Vuja De, a US biotech company focused on evaluating domatinostat plus Rapamycin, a low-dose FDA-approved oral mTOR inhibitor, in cancers, such as recurrent metastatic osteosarcoma and refractory sarcomas. Vuja De expects to begin the first clinical studies in late 2024."

Licensing / partnership • New trial • P2 data • Cutaneous T-cell Lymphoma • Hematological Malignancies • Lymphoma • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • T Cell Non-Hodgkin Lymphoma

4SC AG: Paediatric Investigation Plan waiver for resminostat from the UK MHRA received (4SC Press Release) - "4SC AG...announces that it has received a Paediatric Investigation Plan (PIP) product-specific waiver from UK Medicines & Healthcare products Regulatory Agency (MHRA) for resminostat (Kinselby), an oral maintenance treatment for advanced stage CTCL....4SC filed its Marketing Authorisation Application with the European Medicines Agency (EMA) in February 2024, for resminostat for the treatment of CTCL in Europe. Filings for the UK and Switzerland are in preparation, and in addition, a pre-New Drug Application (NDA) meeting request was also submitted to the U.S. Food and Drug Administration (FDA) in February 2024."

European regulatory • FDA event • Cutaneous T-cell Lymphoma

4SC: Landmark RESMAIN study data presented at the 5th World Congress of Cutaneous Lymphomas (4SC Press Release) - P2 | N=201 | RESMAIN (NCT02953301) | Sponsor: 4SC AG | "4SC AG...today announces that...Professor Dr. Rudolf Stadler, University Hospital Johannes Wesling, Minden, Germany, will present data from the pivotal RESMAN study of resminostat (Kinselby) at the 5th World Congress of Cutaneous Lymphomas (5WCCL), at the City of Hope, Pasadena, California, USA, April 11-13, 2024....Resminostat (Kinselby) showed a statistically significant improvement in progression free survival of 97.6% compared to placebo, with a risk reduction of 38% in recently announced trial results (median PFS: 8.3 months versus 4.2 months; p=0.015; HR: 0.623 (95%CI: 0.424, 0.916); The median time to next treatment (median TTNT) showed a significant improvement for resminostat (Kinselby) versus placebo, more than doubling to 8.8 months compared to 4.2 months; p= 0.002; HR: 0.594 (95% CI: 0.428, 0.825)..."

P2 data • Cutaneous T-cell Lymphoma

4SC AG provides results for financial year 2023 and outlook for 2024 (4SC Press Release) - "Business outlook for 2024...Filings for the UK and Switzerland are in preparation and, in addition, a pre-New Drug Application (NDA) meeting request was also submitted to the FDA in February 2024. In Japan, Yakult Honsha Co., Ltd. (Yakult Honsha) is responsible for filing the marketing authorization application for resminostat....In addition, 4SC continues to hold discussions with potential partners in the pharmaceutical industry regarding the commercialization of its resminostat program with the assistance of a global investment bank."

Commercial • European regulatory • FDA event • Cutaneous T-cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma

4SC Files Marketing Authorisation Application with EMA for Resminostat (Kinselby) (4SC Press Release) - "SC AG...announced...that it has filed its Marketing Authorisation Application (MAA) for resminostat (Kinselby) with the European Medicines Agency (EMA) and that its MAA has been accepted by the EMA as sufficient for examination...In September 2023, the Company announced data from its RESMAIN study on resminostat (Kinselby) that showed: A statistically significant improvement in progression free survival (median PFS: 8.3 vs. 4.2 months; p=0.015; HR: 0.623)...Jason Loveridge, Ph.D., CEO of 4SC, commented: 'The team has worked hard to successfully file the Marketing Authorisation Application for resminostat in CTCL ahead of schedule...'"

European regulatory • Cutaneous T-cell Lymphoma • Mycosis Fungoides • Sezary Syndrome

4SC submits marketing authorization application for resminostat (Kinselby) to the EMA [Google translation] (4SC Press Release) - "4SC AG...announced today that it has submitted the marketing authorization application (MAA) for resminostat (Kinselby) to the European Medicines Agency (EMA) and that this application has been accepted by the EMA for review....In September 2023, the company announced data from its RESMAIN study of resminostat (Kinselby)."

European regulatory • Cutaneous T-cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Staphylococcus aureus induce drug resistance in cancer T cells in Sézary Syndrome. (PubMed, Blood) - "Supernatant from patient-derived, SE-producing S. aureus and recombinant SE significantly inhibit cell death induced by HDAC inhibitor romidepsin in primary malignant T-cells from SS patients. Bacterial killing by engineered, bacteriophage-derived, S. aureus-specific endolysin (XZ.700) abrogates the effect of S. aureus supernatant...Importantly, SE also triggers resistance to other HDAC inhibitors (vorinostat and resminostat) and chemotherapeutic drugs (doxorubicin and etoposide)...Inversely, SE cannot rescue from cell death induced by proteasome/NFB inhibitor bortezomib...In conclusion, we show that S. aureus enterotoxins induce drug-resistance in primary malignant T-cells. These findings suggest that S. aureus enterotoxins cause clinical treatment-resistance in SS patients and that anti-bacterial measures may improve the outcome of cancer-directed therapy in patients harboring S. aureus."

Journal • Cutaneous T-cell Lymphoma • Hematological Malignancies • Infectious Disease • Lymphoma • Oncology • Sezary Syndrome • T Cell Non-Hodgkin Lymphoma

Combination of JAKi and HDACi as a potential antiangionenic treatment in a Cutaneous T-cell Lymphoma (CTCL) in vivo chick embryo model (EORTC-CLTF 2023) - "Our results not only suggest the combination of ruxolitinib/ resminostat as a potential therapeutic combination for CTCL treatment but also establish a new dynamic in vivo model for the further investigation of the anti-angiogenic potential of different molecules used as anti-angiogenic drugs in the CTCL treatment."

Preclinical • Cutaneous T-cell Lymphoma • Hematological Malignancies • Lymphoma • Oncology • Solid Tumor • T Cell Non-Hodgkin Lymphoma

RESMAIN: Results of a multicenter, randomized, double blind, placebo-controlled trial to evaluate RESminostat for MAINtenance treatment in advanced stage Mycosis fungoides or Sézary syndrome (EORTC-CLTF 2023) - P2 | "Resminostat is the first drug to show statistically proven PFS improvement in the maintenance setting in advanced CTCL."

Clinical • Metastases • Cutaneous T-cell Lymphoma • Hematological Malignancies • Mycosis Fungoides • Oncology • Sezary Syndrome

4SC provides Q3 highlights and financial forecast (4SC Press Release) - "4SC AG...today provided a business update for the three months ended 30 September 2023, as well as its current outlook. The full report is available for download on 4SC’s website....As at 30 September 2023, 4SC held cash balance/funds of €10.44 million compared to €12.16 million as of 30 June 2023. The decrease of cash funds in the first nine months of 2023 is mainly a result of the expenditure on the ongoing RESMAIN clinical study."

Commercial • Cutaneous T-cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma