Richter's syndrome

COPENHAGEN, Denmark--( BUSINESS WIRE )--Genmab A/S (Nasdaq: GMAB): Preliminary analyses from the EPCORE ® CLL-1 trial demonstrates overall response rate (ORR) of 61 percent and complete response (CR) rate of 39 percent in heavily pretreated patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) who received epcoritamab monotherapy In the study, 75 percent of evaluable responders achieved undetectable minimal residual disease (MRD), indicating no detectable disease following treatment with epcoritamab The data were selected as part of the 2024 American Society of Hematology’s (ASH’s) Annual Meeting Press Program in the Diagnosing and Treating Blood Cancers and “Almost Cancers” briefing Genmab A/S (Nasdaq: GMAB) today announced results from the Phase 1b/2 EPCORE ® CLL-1 clinical trial evaluating epcoritamab (Abstract #883), a T-cell engaging bispecific antibody administered subcutaneously, demonstrated an overall response rate (ORR) of 61 percent and a complete response (CR) rate of 39 percent in difficult-to-treat adult patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) treated with epcoritamab monotherapy. These results, from the monotherapy expansion (EXP) cohort (n=23) of the trial, along with the first safety data from the optimization (OPT) cohort, were presented at the 66 th Annual Meeting and Exposition of the American Society of Hematology (ASH), during the ASH Annual Meeting Press Program. The data will be presented during an oral session on December 9, 2024. In the EXP cohort, the median time to response was two (2.0) months and the median time to CR was 5.6 months. Among all patients in the cohort, median progression-free survival (PFS) was 12.8 months and median overall survival (OS) was not reached (median follow-up was 22.8 months). An estimated 65 percent of patients were alive at 15 months. Among 12 responders evaluable for minimal residual disease (MRD) by next-generation sequencing in peripheral blood, nine patients (75 percent) had undetectable MRD. The most frequent non-hematologic treatment-emergent adverse events (TEAEs) in the EXP cohort were cytokine release syndrome (CRS; 96 percent), diarrhea (48 percent), peripheral edema (48 percent), fatigue (43 percent), and injection-site reaction (43 percent). Cytopenias were common (anemia, 65 percent; thrombocytopenia, 65 percent; neutropenia, 48 percent); however, most patients had baseline anemia and thrombocytopenia, suggesting that these events were largely disease-related. Three cases of immune effector cell-associated neurotoxicity syndrome (ICANS) were reported (one Grade 1; two Grade 2), and there was one clinical tumor lysis syndrome (CTLS) case (Grade 2). These cases did not lead to treatment discontinuation. Four fatal TEAEs occurred - two cases of pneumonia, one case of sepsis and one case of squamous cell carcinoma of the skin. The EXP cohort followed a 2-step step-up dose regimen, and CRS was manageable and primarily low grade (9 percent Grade 1, 70 percent Grade 2, 17 percent Grade 3). In the first data from the separate OPT cohort, which followed a 3-step step-up dose regimen, CRS severity was substantially reduced with only low-grade events (71 percent Grade 1, 12 percent Grade 2). In both cohorts, CRS events primarily occurred following the first full dose, and none led to treatment discontinuation. No ICANS or CTLS cases were reported in the OPT cohort. “These EPCORE CLL-1 data are encouraging, especially as the majority of patients were heavily pre-treated with at least four lines of therapy,” said Alexey Danilov, MD, PhD, Marianne and Gerhard Pinkus, Professor and Director of Early Clinical Therapeutics and Associate Director of the Toni Stephenson Lymphoma Center, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope. “Despite progress in treating chronic lymphocytic leukemia, there remains a tremendous need for additional therapeutic options for high-risk patients whose disease has progressed following standard chemoimmunotherapy and targeted therapies.” Additional data from the EXP cohort showed high response rates in patients with high-risk factors treated with epcoritamab, including TP53 aberrations, IGHV-unmutated disease and double-exposed disease – prognostic markers that are associated with disease progression and decreased survival. i,ii,iii In patients with TP53 aberrations (n=15), the ORR was 67 percent with a CR of 33 percent. Among patients with IGHV-unmutated disease (n=16), the ORR was 63 percent, and the CR was 44 percent. In double-refractory patients, the ORR was 53 percent, and the CR was 37 percent. All patients in the trial had prior chemoimmunotherapy, and most patients had previously received targeted therapies such as BTK and BCL2 inhibitors (double-exposed) and had high-risk disease characteristics. “Chronic lymphocytic leukemia is incurable, and patients often need a variety of treatments throughout their lifetime, especially if their disease has high-risk prognostic factors, has relapsed or has become refractory to the current standard-of-care, including targeted therapies,” said Dr. Judith Klimovsky, Executive Vice President & Chief Development Officer, Genmab. “These early data show the potential therapeutic applicability of epcoritamab in relapsed or refractory chronic lymphocytic leukemia, and further reinforce the potential of epcoritamab as a core therapy for the treatment of B-cell malignancies.” Use of epcoritamab in CLL is not approved in the U.S. or in the EU or in any other territory. The safety and efficacy of epcoritamab for use in CLL have not been established. About Chronic Lymphocytic Leukemia (CLL) Chronic lymphocytic leukemia (CLL) is the most prevalent type of leukemia, affecting over 200,000 people in the United States alone. iv Chronic lymphocytic leukemia can be classified as either slow growing (indolent) or fast growing (aggressive). v CLL is incurable, and many patients will likely relapse and progress on frontline therapies. vi Most patients will experience consecutive episodes of disease progression and will require several lines of treatment in their lifetime. vii,viii About the EPCORE ® CLL-1 Trial EPCORE ® CLL-1 is a Phase 1b/2, open-label, multi-center trial to evaluate the safety and preliminary efficacy of epcoritamab as a monotherapy and in combination with standard of care agents in patients with difficult-to-treat relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL), R/R small lymphocytic lymphoma (SLL) and Richter's Syndrome (RS). The trial consists of two parts: a dose-escalation phase (Phase 1b) and an expansion phase (Phase 2). Patients with RS are only included in the expansion phase. The primary objective of Phase 1b is to determine the recommended Phase 2 dose and the maximum tolerated dose as well as establish the safety profile of epcoritamab monotherapy and epcoritamab plus venetoclax in participants with R/R CLL. The purpose of Phase 2 is to assess and evaluate the preliminary efficacy, safety and tolerability profiles of epcoritamab monotherapy and epcoritamab plus venetoclax for patients with R/R CLL and SLL. Additionally, epcoritamab monotherapy and combination therapy will be evaluated in patients with RS to assess their efficacy, safety and tolerability profiles. More information on this trial can be found at https://www.clinicaltrials.gov/ (NCT: 04623541). About Epcoritamab Epcoritamab is an IgG1-bispecific antibody created using Genmab's proprietary DuoBody ® technology and administered subcutaneously. Genmab's DuoBody-CD3 technology is designed to direct cytotoxic T cells selectively to elicit an immune response toward target cell types. Epcoritamab is designed to simultaneously bind to CD3 on T cells and CD20 on B cells and induces T-cell-mediated killing of CD20+ cells. ix Epcoritamab (approved under the brand name EPKINLY ® in the U.S. and Japan, and TEPKINLY ® in the EU) has received regulatory approval in certain lymphoma indications in several territories. Epcoritamab is being co-developed by Genmab and AbbVie as part of the companies' oncology collaboration. The companies will share commercial responsibilities in the U.S. and Japan, with AbbVie responsible for further global commercialization. Both companies will pursue additional international regulatory approvals for the investigational R/R FL indication and additional approvals for the R/R DLBCL indication. Genmab and AbbVie continue to evaluate the use of epcoritamab as a monotherapy, and in combination, across lines of therapy in a range of hematologic malignancies. This includes five ongoing Phase 3, open-label, randomized trials including a trial evaluating epcoritamab as a monotherapy in patients with R/R DLBCL compared to investigator's choice chemotherapy ( NCT04628494 ), a trial evaluating epcoritamab in combination with R-CHOP in adult patients with newly diagnosed DLBCL ( NCT05578976 ), a trial evaluating epcoritamab in combination with rituximab and lenalidomide (R 2 ) in patients with R/R FL ( NCT05409066 ), a trial evaluating epcoritamab in combination with rituximab and lenalidomide (R 2 ) compared to chemoimmunotherapy in patients with previously untreated FL ( NCT06191744 ), and a trial evaluating epcoritamab in combination with lenalidomide compared to chemotherapy infusion in patients with R/R DLBCL ( NCT06508658 ). The safety and efficacy of epcoritamab has not been established for these investigational uses. Please visit www.clinicaltrials.gov for more information. EPKINLY ® (epcoritamab-bysp) U.S. INDICATIONS & IMPORTANT SAFETY INFORMATION What is EPKINLY? EPKINLY is a prescription medicine used to treat adults with certain types of diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma, or follicular lymphoma (FL) that has come back or that did not respond to previous treatment after receiving 2 or more treatments. EPKINLY is approved based on patient response data. Studies are ongoing to confirm the clinical benefit of EPKINLY. It is not known if EPKINLY is safe and effective in children. Important Warnings—EPKINLY can cause serious side effects, including: Cytokine release syndrome (CRS), which is common during treatment with EPKINLY and can be serious or life-threatening. To help reduce your risk of CRS, you will receive EPKINLY on a step-up dosing schedule (when you receive 2 or 3 smaller step-up doses of EPKINLY before your first full dose during your first cycle of treatment), and you may also receive other medicines before and for 3 days after receiving EPKINLY. If your dose of EPKINLY is delayed for any reason, you may need to repeat the step-up dosing schedule. Neurologic problems that can be life-threatening and lead to death. Neurologic problems may happen days or weeks after you receive EPKINLY. People with DLBCL or high-grade B-cell lymphoma should be hospitalized for 24 hours after receiving their first full dose of EPKINLY on day 15 of cycle 1 due to the risk of CRS and neurologic problems. Tell your healthcare provider or get medical help right away if you develop a fever of 100.4°F (38°C) or higher; dizziness or lightheadedness; trouble breathing; chills; fast heartbeat; feeling anxious; headache; confusion; shaking (tremors); problems with balance and movement, such as trouble walking; trouble speaking or writing; confusion and disorientation; drowsiness, tiredness or lack of energy; muscle weakness; seizures; or memory loss. These may be symptoms of CRS or neurologic problems. If you have any symptoms that impair consciousness, do not drive or use heavy machinery or do other dangerous activities until your symptoms go away. EPKINLY can cause other serious side effects, including: Infections that may lead to death. Your healthcare provider will check you for signs and symptoms of infection before and during treatment and treat you as needed if you develop an infection. You should receive medicines from your healthcare provider before you start treatment to help prevent infection. Tell your healthcare provider right away if you develop any symptoms of infection during treatment, including fever of 100.4°F (38°C) or higher, cough, chest pain, tiredness, shortness of breath, painful rash, sore throat, pain during urination, or feeling weak or generally unwell. Low blood cell counts, which can be serious or severe. Your healthcare provider will check your blood cell counts during treatment. EPKINLY may cause low blood cell counts, including low white blood cells (neutropenia), which can increase your risk for infection; low red blood cells (anemia), which can cause tiredness and shortness of breath; and low platelets (thrombocytopenia), which can cause bruising or bleeding problems. Your healthcare provider will monitor you for symptoms of CRS, neurologic problems, infections, and low blood cell counts during treatment with EPKINLY. Your healthcare provider may temporarily stop or completely stop treatment with EPKINLY if you develop certain side effects. Before you receive EPKINLY, tell your healthcare provider about all your medical conditions, including if you have an infection, are pregnant or plan to become pregnant, or are breastfeeding or plan to breastfeed. If you receive EPKINLY while pregnant, it may harm your unborn baby. If you are a female who can become pregnant, your healthcare provider should do a pregnancy test before you start treatment with EPKINLY and you should use effective birth control (contraception) during treatment and for 4 months after your last dose of EPKINLY. Tell your healthcare provider if you become pregnant or think that you may be pregnant during treatment with EPKINLY. Do not breastfeed during treatment with EPKINLY and for 4 months after your last dose of EPKINLY. In DLBCL or high-grade B-cell lymphoma, the most common side effects of EPKINLY include CRS, tiredness, muscle and bone pain, injection site reactions, fever, stomach-area (abdominal) pain, nausea, and diarrhea. The most common severe abnormal laboratory test results include decreased white blood cells, decreased red blood cells, and decreased platelets. In follicular lymphoma the most common side effects of EPKINLY include injection site reactions, CRS, COVID-19, tiredness, upper respiratory tract infections, muscle and bone pain, rash, diarrhea, fever, cough, and headache. The most common severe abnormal laboratory test results include decreased white blood cells and decreased red blood cells. These are not all of the possible side effects of EPKINLY. Call your doctor for medical advice about side effects. You are encouraged to report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch or to Genmab US, Inc. at 1-855-4GENMAB (1-855-443-6622). Please see Full Prescribing Information and Medication Guide , including Important Warnings. Globally, prescribing information varies; refer to the individual country product label for complete information. About Genmab Genmab is an international biotechnology company with a core purpose of guiding its unstoppable team to strive toward improving the lives of patients with innovative and differentiated antibody therapeutics. For 25 years, its passionate, innovative and collaborative team has invented next-generation antibody technology platforms and leveraged translational, quantitative and data sciences, resulting in a proprietary pipeline including bispecific T-cell engagers, antibody-drug conjugates, next-generation immune checkpoint modulators and effector function-enhanced antibodies. By 2030, Genmab’s vision is to transform the lives of people with cancer and other serious diseases with knock-your-socks-off (KYSO ® ) antibody medicines. Established in 1999, Genmab is headquartered in Copenhagen, Denmark, with international presence across North America, Europe and Asia Pacific. For more information, please visit Genmab.com and follow us on LinkedIn and X . This Media Release contains forward looking statements. The words “believe,” “expect,” “anticipate,” “intend” and “plan” and similar expressions identify forward looking statements. Actual results or performance may differ materially from any future results or performance expressed or implied by such statements. The important factors that could cause our actual results or performance to differ materially include, among others, risks associated with preclinical and clinical development of products, uncertainties related to the outcome and conduct of clinical trials including unforeseen safety issues, uncertainties related to product manufacturing, the lack of market acceptance of our products, our inability to manage growth, the competitive environment in relation to our business area and markets, our inability to attract and retain suitably qualified personnel, the unenforceability or lack of protection of our patents and proprietary rights, our relationships with affiliated entities, changes and developments in technology which may render our products or technologies obsolete, and other factors. For a further discussion of these risks, please refer to the risk management sections in Genmab’s most recent financial reports, which are available on www.genmab.com and the risk factors included in Genmab’s most recent Annual Report on Form 20-F and other filings with the U.S. Securities and Exchange Commission (SEC), which are available at www.sec.gov . Genmab does not undertake any obligation to update or revise forward looking statements in this Media Release nor to confirm such statements to reflect subsequent events or circumstances after the date made or in relation to actual results, unless required by law. Genmab A/S and/or its subsidiaries own the following trademarks: Genmab ® ; the Y-shaped Genmab logo ® ; Genmab in combination with the Y-shaped Genmab logo ® ; HuMax ® ; DuoBody ® ; HexaBody ® ; DuoHexaBody ® , HexElect ® and KYSO™. EPCORE ® , EPKINLY ® , TEPKINLY ® and their designs are trademarks of AbbVie Biotechnology Ltd. i Campo, et al. TP53 Aberrations in Chronic Lymphocytic Leukemia: An Overview of the Clinical Implications of Improved Diagnostics. Haematologica . 2018 Nov 15;103(12):1956–1968. https://haematologica.org/article/view/8691 . ii Galieni, et al. Unmutated IGHV at Diagnosis in Patients With Early Stage CLL Independently Predicts for Shorter Follow-Up Time to First Treatment (TTFT). Leukemia Research. 2024. https://doi-org.sutd.idm.oclc.org/10.1016/j.leukres.2024.107541 . iii Zuber, et al. Efficacy and Effectiveness Outcomes of Treatments for Double-Exposed Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma Patients: A Systematic Literature Review. Cancer Medicine . 2024. https://doi-org.sutd.idm.oclc.org/10.1002/cam4.70258 . iv Fedele, et al. Chronic Lymphocytic Leukemia: Time to Care for the Survivors. Journal of Clinical Oncology . 2024. https://ascopubs.org/doi/10.1200/JCO.23.02738 . v Penn Medicine. Chronic Lymphocytic Leukemia (CLL). Accessed November 2024. https://www.pennmedicine.org/cancer/types-of-cancer/leukemia/types-of-leukemia/chronic-lymphocytic-leukemia . vi Odetola, et al. Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL). Curr Hematol Malig Rep . 2023 Jun 6:1–14. doi: 10.1007/s11899-023-00700-z vii Moreno, Carol. Standard Treatment Approaches for Relapsed/Refractory Chronic Lymphocytic Leukemia After Frontline Chemoimmunotherapy. Hematology Am Soc Hematol Educ Program . 2020 Dec 4;2020(1):33-40. doi: 10.1182/hematology.2020000086. viii Leukemia & Lymphoma Society. Relapsed and Refractory CLL. Accessed November 2024. https://www.lls.org/leukemia/chronic-lymphocytic-leukemia/treatment/relapsed-and-refractory . ix Engelberts PJ, et al. DuoBody-CD3xCD20 Induces Potent T-Cell-Mediated Killing of Malignant B Cells in Preclinical Models and Provides Opportunities for Subcutaneous Dosing. EBioMedicine . 2020;52:102625. doi: 10.1016/j.ebiom.2019.102625.

BTK(Bruton's tyrosine kinase), is a non-receptor tyrosine kinase of the Tec family that is expressed in B cells, neutrophils, basophils, and platelets. It is also a key kinase in the B-cell receptor (BCR) signaling pathway and is expressed in all hematopoietic cells except T cells and terminally differentiated plasma cells.  BTK inhibitors can regulate the functions of various immune cells that are crucial to innate and adaptive immune responses. They are widely expressed in various types of malignant hematopoietic diseases and participate in the proliferation, differentiation, and apoptosis of B cells. Because of the high specificity of BTK small molecule inhibitors, they have significant advantages in treating B-cell malignancies and some B-cell immune diseases. BTK inhibitors have thus become one of the most promising drugs on the market for hematopoietic tumors. BTK Competitive LandscapeAccording to the data provided by Patsnap Synapse-Global Drug Intelligence Database: the following figure shows that as of 8 Sep 2023, there are a total of 169 BTK drugs worldwide, from 194 organizations, covering 116 indications, and conducting 1243 clinical trials. 👇Please click on the picture link below for free registration or login directly if you have freemium accounts, you can browse the latest research progress on drugs , indications, organizations, clinical trials, clinical results, and drug patents related to this target.The current competitive landscape of target BTK is characterized by the presence of multiple companies actively developing drugs in various stages of development. AbbVie, Inc., Eli Lilly & Co., Johnson & Johnson, Sanofi, and Roche Holding AG are some of the key players with drugs in advanced stages of development.  The approved indications for drugs targeting BTK include B-Cell Chronic Lymphocytic Leukemia, Mantle-Cell Lymphoma, Small Lymphocytic Lymphoma, Waldenstrom Macroglobulinemia, Marginal Zone B-Cell Lymphoma, and others.  Small molecule drugs and PROTACs are the most rapidly progressing drug types, indicating intense competition in the market. China and the United States are leading in terms of drug development under the target BTK, with China showing significant progress.  Overall, the future development of target BTK holds promise with a strong pipeline of drugs and active research and development efforts by various companies and countries/locations. First Generation BTK Inhibitors:IbrutinibIbrutinib is a small molecule drug that targets BTK. It has been approved for various therapeutic areas including neoplasms, digestive system disorders, hemic and lymphatic diseases, respiratory diseases, urogenital diseases, immune system diseases, infectious diseases, nervous system diseases, cardiovascular diseases, and endocrinology and metabolic diseases. 👇Please click on the image below to directly access the latest data (R&D Status | Core Patent | Clinical Trial | Approval status in Global countries) of this drug. The drug has shown efficacy in treating several indications, including lymphoplasmacytic lymphoma, marginal zone B-cell lymphoma, graft vs host disease, chronic graft-versus-host disease, small lymphocytic lymphoma, Waldenstrom macroglobulinemia, mantle-cell lymphoma, mantle cell lymphoma refractory, B-cell chronic lymphocytic leukemia, pancreatic cancer, lymphoma, non-Hodgkin lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, primary central nervous system lymphoma, COVID-19, SARS-CoV-2 acute respiratory disease, T-cell prolymphocytic leukemia, squamous cell carcinoma, B-cell lymphoma, central nervous system neoplasms, acute myeloid leukemia, multiple myeloma, renal cell carcinoma, urogenital neoplasms, gastrointestinal neoplasms, non-small cell lung cancer, myelodysplastic syndromes, neoplasms, and colorectal cancer. The drug was originated by Pharmacyclics LLC and has received approvals in both the global and Chinese markets. It obtained its first approval in the United States in November 2013. Ibrutinib has undergone various regulatory processes, including priority review, accelerated approval, fast track designation, orphan drug status, breakthrough therapy designation, and special review projects. In summary, Ibrutinib is a small molecule drug that targets BTK and has been approved for a wide range of therapeutic areas. It has shown efficacy in treating multiple indications, including various types of lymphomas, leukemias, solid tumors, and viral infections such as COVID-19. The drug was first approved in the United States in 2013 and has received regulatory designations to expedite its development and approval process. Second Generation BTK Inhibitors:AcalabrutinibAcalabrutinib is a small molecule drug that targets BTK. It has been approved for various therapeutic areas including neoplasms, immune system diseases, hemic and lymphatic diseases, infectious diseases, nervous system diseases, cardiovascular diseases, digestive system disorders, endocrinology and metabolic disease, respiratory diseases, and urogenital diseases.  👇Please click on the image below to directly access the latest data (R&D Status | Core Patent | Clinical Trial | Approval status in Global countries) of this drug. The drug has shown efficacy in treating small lymphocytic lymphoma, B-cell chronic lymphocytic leukemia, mantle-cell lymphoma, diffuse large B-cell lymphoma, chronic graft-versus-host disease, Richter's syndrome, glioblastoma, ovarian cancer, B-cell lymphoma, non-small cell lung cancer, head and neck neoplasms, bladder cancer, pancreatic cancer, Burkitt lymphoma, multiple myeloma, Waldenstrom macroglobulinemia, prolymphocytic leukemia, follicular lymphoma, and B-cell prolymphocytic leukemia. Acalabrutinib was developed by AstraZeneca PLC and has received approval in multiple countries, including the United States. Its highest phase of development is approved, indicating that it has successfully completed clinical trials and demonstrated safety and efficacy. The drug has also received priority review, conditional marketing approval, accelerated approval, orphan drug designation, and breakthrough therapy designation. These regulatory designations highlight the potential of acalabrutinib to address unmet medical needs and expedite its development and availability to patients. The approval of acalabrutinib in various therapeutic areas underscores its versatility and potential to treat a wide range of diseases. Its mechanism of action, targeting BTK, suggests that it may be particularly effective in diseases involving abnormal B-cell signaling, such as lymphomas and leukemias. Additionally, its approval for neoplasms and various other disease areas indicates its potential to modulate the immune system and impact multiple disease pathways. Overall, acalabrutinib represents a significant advancement in the field of biomedicine, offering a targeted therapeutic option for patients with various diseases. Its approval in multiple countries and regulatory designations further validate its potential and highlight the importance of continued research and development in the pharmaceutical industry. Third Generation BTK Inhibitor:PirtobrutinibPirtobrutinib is a small molecule drug that targets BTK C481S. It falls under the therapeutic areas of neoplasms, immune system diseases, cardiovascular diseases, and hemic and lymphatic diseases. The drug is indicated for various conditions including mantle cell lymphoma recurrent, mantle cell lymphoma refractory, lymphoplasmacytic lymphoma, small lymphocytic lymphoma, mantle-cell lymphoma, B-cell chronic lymphocytic leukemia, diffuse large B-cell lymphoma, marginal zone B-cell lymphoma, Waldenstrom macroglobulinemia, hematologic neoplasms, and multiple myeloma. 👇Please click on the image below to directly access the latest data (R&D Status | Core Patent | Clinical Trial | Approval status in Global countries) of this drug. The originator organization of Pirtobrutinib is Redx Pharma Plc. The drug has reached the highest phase of approval globally, indicating that it has successfully completed clinical trials and has been approved for use. However, in China, it is currently in phase 3 of development, suggesting that it is still undergoing clinical trials in that country. Pirtobrutinib received its first approval in the United States in January 2023. The drug has undergone priority review and accelerated approval, indicating that it has demonstrated significant benefits over existing treatments and has the potential to address unmet medical needs. Based on the available information, Pirtobrutinib appears to be a promising drug in the field of biomedicine. Its approval for various indications related to lymphomas and other hematologic neoplasms suggests that it may have a broad therapeutic potential. The fact that it specifically targets BTK C481S, a protein associated with certain cancers and immune system disorders, further highlights its potential efficacy in treating these conditions. The approval of Pirtobrutinib in the United States and its ongoing phase 3 development in China indicate that it has gained recognition and interest from regulatory authorities in these countries. This suggests that the drug may have significant market potential and could potentially become a valuable treatment option for patients in need. In conclusion, Pirtobrutinib is a small molecule drug developed by Redx Pharma Plc that targets BTK C481S. It has received approval for various indications related to lymphomas and hematologic neoplasms, and its first approval was in the United States in January 2023. The drug has undergone priority review and accelerated approval, indicating its potential to address unmet medical needs. With ongoing phase 3 development in China, Pirtobrutinib shows promise as a valuable treatment option in the field of biomedicine.

Four lead programs on track to deliver clinical data and to inform future development plans Recent equity financing extends cash runway into 2026, enabling advancement of Prelude’s pipeline through critical milestones WILMINGTON, Del., Aug. 03, 2023 (GLOBE NEWSWIRE) -- Prelude Therapeutics Incorporated (Nasdaq: PRLD), a clinical-stage precision oncology company, today reported financial results for the second quarter ended June 30, 2023, and provided a corporate update. Kris Vaddi, Ph.D., Chief Executive Officer of Prelude stated, “With the recent financing that extended our cash runway into 2026, we are in a strong position to advance our diverse pipeline of potentially best and/or first-in-class compounds to address the needs of patients with certain underserved cancers. Our focus remains on generating critical data for each of our molecules to make key strategic decisions. As disclosed recently, and based on additional data generated in this quarter, PRT2527 (CDK9 inhibitor) and PRT1419 (MCL1 inhibitor) demonstrated differentiated clinical safety profiles and strong target inhibition and are continuing to enroll patients with hematological malignancies, which is where we see the best opportunities for these molecules.” “Our first-in-class selective SMARCA2 degrader, PRT3789, and next generation CDK4/6 inhibitor, PRT3645, are progressing well in Phase 1 and are on track to reach confirmation doses in the first half of 2024 and by year end 2023, respectively,” added Dr. Vaddi. “Based on meaningful progress made in the first half of the year, we look forward to sharing updates and clarity around strategic prioritization of our pipeline in the coming months.” Pipeline Updates PRT2527- CDK9 Inhibitor Program The Company believes its highly selective CDK9 inhibitor, PRT2527, has the potential to avoid off-target toxicities, achieve substantial clinical activity and become the best-in-class CDK9 inhibitor, making it amenable for combination with other therapies. PRT2527 has completed a Phase 1 multi-dose escalation study (NCT05159518) in patients with solid tumors. In this trial, PRT2527 was shown to achieve high levels of target inhibition and the potential to be better tolerated than existing CDK9 inhibitors, specifically, manageable neutropenia and an absence of meaningful gastrointestinal events or hepatotoxicity. * *AACR2023 Poster Presentation A Phase 1 multi-dose escalation study (NCT05665530) is currently ongoing in hematologic malignancies. Patient recruitment for hematological clinical trials in the US is highly competitive and this trial has recently been expanded to include global sites to support patient recruitment. The Company’s objective is to establish a biologically active confirmation dose by Q1 2024. As part of this Phase 1 multi-dose escalation trial, the Company intends to expand the Phase 1 clinical trial and evaluate PRT2527 in combination with zanubrutinib. Potential indications for PRT2527 include aggressive B-cell lymphoma subtypes, mantle cell lymphoma (MCL), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) including Richter syndrome, and T-cell lymphoma subtypes. The Company intends to provide a program update by year end on the CDK9 inhibitor program and present initial results at a future scientific meeting. PRT1419- MCL1 Inhibitor ProgramPRT1419 is a potent and selective MCL1 inhibitor. With its optimized PK/PD profile, the Company believes PRT1419 has the potential to achieve greater target engagement and provide patients with better clinical outcomes as well as improved safety and tolerability, as compared to other MCL1 inhibitors in development. PRT1419 has completed a Phase 1 multi-dose escalation study (NCT04837677) in patients with solid tumors. In this study, PRT1419 demonstrated an acceptable safety and tolerability profile in patients with advanced and metastatic solid tumors. No cardiac toxicity was observed. Pharmacokinetics/pharmacodynamics and safety data in the 80 mg/m2 QW dose cohort support further evaluation of this dose in future studies. A Phase 1 multi-dose escalation clinical trial of PRT1419 in patients with hematologic malignancies is ongoing (NCT05107856). In this trial, PRT1419 is being evaluated as monotherapy for myeloid malignancies and in combination with azacitidine or venetoclax for patients with relapsed/refractory myeloid or B-cell malignancies. The Company will provide a clinical update on PRT1419 by year end. PRT3645- Next Generation CDK4/6 Inhibitor ProgramPRT3645 is a highly potent and selective next generation CDK4/6 inhibitor with the potential to provide improved safety and tolerability outcomes and higher, more effective brain and tissue penetration than current CDK4/6 inhibitors. In preclinical models in vivo, PRT3645 has been shown to be efficacious in multiple cancers as monotherapy as well as when combined with KRAS inhibitors, MEK inhibitors and with a brain penetrant HER2 receptor kinase inhibitor. Additionally, oral administration of PRT3645 has been shown to induce tumor regressions in preclinical models that are resistant to currently approved CDK4/6 inhibitors. Together, these data suggest that PRT3645 may extend the benefit of CDK4/6 inhibition beyond HR+ breast cancer. A Phase 1 multi-dose escalation clinical trial of PRT3645 (NCT05538572) is underway and the Company expects to reach a biologically active dose confirmation in Q4 2023. Potential indications for PRT3645 in combination with other therapies, in addition to breast cancer with or without brain metastases, include endometrial, sarcomas, glioblastomas, non-small cell lung cancer, head and neck cancers. The Company intends to provide a program update by year end and present initial results at a future scientific meeting. PRT3789- SMARCA2 Targeted Protein Degrader ProgramPRT3789 is a first-in-class highly selective degrader of SMARCA2 protein, which along with SMARCA4 controls gene regulation through chromatin remodeling. Cancer cells with SMARCA4 mutations are dependent on SMARCA2 for their growth and survival and selectively degrading SMARCA2 induces cell death in cancer cells while sparing normal cells. PRT3789 is efficacious and well tolerated in preclinical models of SMARCA4 deleted/mutated cancers as monotherapy and in combination with standards of care. The Company believes a selective SMARCA2 degrader has the potential to be of benefit in up to 70,000 US/EU cancer patients with the SMARCA4 mutation. Patients with SMARCA4 mutations or deletions may have poor clinical outcomes and limited treatment options. Therefore, mutated, or deleted SMARCA4 cancers provides a potential biomarker to select those patients most likely to respond to treatment with a highly selective SMARCA2 degrader. A Phase 1 multi-dose escalation clinical trial of PRT3789 is ongoing (NCT05639751) in biomarker selected SMARCA4 mutated cancers. The Company intends to evaluate PRT3789 as monotherapy as well as in combination. The Company intends to provide a program update by year end and expects to reach confirmation dose in the first half of 2024. SMARCA2- Oral ProgramThe Company has also recently nominated a new chemical entity as a potent, orally bioavailable and highly selective SMARCA2 degrader candidate (>1000x over SMARCA4) and intends to file an IND early in 2024. Second Quarter 2023 Financial Results Cash, Cash Equivalents and Marketable Securities: In May 2023, the Company completed a public offering of common stock, raising gross proceeds of $113.0 million before deducting underwriting discounts, commissions and offering expenses. Net proceeds received, $110.4 million, will be focused on the continued development and expansion of the Company’s product pipeline. Cash, cash equivalents, and marketable securities as of June 30, 2023, were $255.0 million. Prelude anticipates that its existing cash, cash equivalents and marketable securities will fund the Company’s operations into 2026. Research and Development (R&D) Expenses: For the second quarter of 2023, R&D expense increased to $25.0 million from $21.3 million for the prior year period. Research and development expenses increased primarily due to the timing of our clinical research programs. We expect our R&D expenses to vary from quarter to quarter, primarily due to the timing of our clinical development activities. General and Administrative (G&A) Expenses: For the second quarter of 2023, G&A expenses decreased to $7.4 million from $8.2 million for the prior year period. General and administrative expenses decreased reflecting the Company’s careful management of its G&A expenses. Net Loss: For the three months ended June 30, 2023, net loss was $30.4 million, or $0.54 per share compared to $27.4 million, or $0.58 per share, for the prior year period. Included in the net loss for the quarter ended June 30, 2023, was $6.7 million of non-cash expense related to the impact of expensing share-based payments, including employee stock options, as compared to $6.0 million for the same period in 2022. About Prelude Therapeutics Prelude Therapeutics is a clinical-stage precision oncology company developing innovative drug candidates targeting critical cancer cell pathways. The Company’s diverse pipeline is comprised of highly differentiated, potentially best-in-class proprietary small molecule compounds aimed at addressing clinically validated pathways for cancers with selectable underserved patients. Prelude’s pipeline includes four candidates currently in clinical development: PRT1419, a potent, selective inhibitor of MCL1, PRT2527, a potent and highly selective CDK9 inhibitor, PRT3645 a next generation CDK4/6 inhibitor, PRT3789 an IV administered, potent and highly selective SMARCA2 degrader, and a preclinical oral candidate targeting SMARCA2. For more information, visit our website and follow us on LinkedIn and Twitter. Cautionary Note Regarding Forward-Looking Statements This press release contains forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995, including, but not limited to, anticipated discovery, preclinical and clinical development activities, the timing and/or announcements relating to the reporting of expected findings for PRT1419, PRT2527, PRT3645, PRT3789, and its preclinical oral SMARCA2 degrader, the potential benefits of Prelude’s product candidates and platform, and the sufficiency of cash and cash equivalents to fund operating expenses and capital expenditures into 2026. All statements other than statements of historical fact are statements that could be deemed forward-looking statements. Although Prelude believes that the expectations reflected in such forward-looking statements are reasonable, Prelude cannot guarantee future events, results, actions, levels of activity, performance or achievements, and the timing and results of biotechnology development and potential regulatory approval is inherently uncertain. Forward-looking statements are subject to risks and uncertainties that may cause Prelude's actual activities or results to differ significantly from those expressed in any forward-looking statement, including risks and uncertainties related to Prelude's ability to advance its product candidates, the receipt and timing of potential regulatory designations, approvals and commercialization of product candidates, clinical trial sites and our ability to enroll eligible patients, supply chain and manufacturing facilities, Prelude’s ability to maintain and recognize the benefits of certain designations received by product candidates, the timing and results of preclinical and clinical trials, Prelude's ability to fund development activities and achieve development goals, Prelude's ability to protect intellectual property, and other risks and uncertainties described under the heading "Risk Factors" in documents Prelude files from time to time with the Securities and Exchange Commission. These forward-looking statements speak only as of the date of this press release, and Prelude undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date hereof. PRELUDE THERAPEUTICS INCORPORATED STATEMENTS OF OPERATIONS AND COMPREHENSIVE LOSS(UNAUDITED) Three Months Ended June 30, (in thousands, except share and per share data) 2023 2022 Operating expenses: Research and development $24,966 $21,310 General and administrative 7,432 8,151 Total operating expenses 32,398 29,461 Loss from operations (32,398) (29,461)Other income, net 1,967 2,087 Net loss $(30,431) $(27,374)Per share information: Net loss per share of common stock, basic and diluted $(0.54) $(0.58)Weighted average common shares outstanding, basic and diluted 56,240,491 47,276,684 Comprehensive loss Net loss $(30,431) $(27,374)Unrealized (loss) gain on marketable securities, net of tax (313) 19 Comprehensive loss $(30,744) $(27,355) PRELUDE THERAPEUTICS INCORPORATED BALANCE SHEETS(UNAUDITED) (in thousands, except share data) June 30,2023 December 31,2022 Assets Current assets: Cash and cash equivalents $26,446 $30,605 Marketable securities 228,543 171,123 Prepaid expenses and other current assets 5,221 2,652 Total current assets 260,210 204,380 Restricted cash 4,044 4,044 Property and equipment, net 6,082 4,908 Right-of-use asset 918 1,792 Prepaid expenses and other non-current assets 9,357 5,376 Total assets $280,611 $220,500 Liabilities and stockholders’ equity Current liabilities: Accounts payable $5,585 $6,777 Accrued expenses and other current liabilities 8,667 13,093 Operating lease liability 938 1,832 Total current liabilities 15,190 21,702 Other liabilities 3,361 3,361 Total liabilities 18,551 25,063 Commitments (Note 8) Stockholders’ equity: Voting common stock, $0.0001 par value: 487,149,741 shares authorized; 41,958,456 and 36,496,994 shares issued and outstanding at June 30, 2023 and December 31, 2022, respectively 4 4 Non-voting common stock, $0.0001 par value: 12,850,259 shares authorized; 12,850,259 and 11,402,037 shares issued and outstanding at June 30, 2023 and December 31, 2022, respectively 1 1 Additional paid-in capital 655,473 531,682 Accumulated other comprehensive loss (711) (1,692)Accumulated deficit (392,707) (334,558)Total stockholders’ equity 262,060 195,437 Total liabilities and stockholders’ equity $280,611 $220,500 Investor Contact:Lindsey TrickettVice President, Investor Relations240.543.7970ltrickett@preludetx.com Media Contact:Helen ShikShik Communications 617.510.4373Helen@ShikCommuncations.com