PI3Kβ

OXFORD, England--(BUSINESS WIRE)--Karus Therapeutics (‘Karus’), a leader in the development of innovative, orally-active medicines with breakthrough potential in the treatment of cancer, today announced that the first patients have been dosed in a Phase I study for its lead candidate, KA2237. This is the Company’s first product to enter clinical trials. KA2237 is a dual-selective inhibitor of two PI3K isoforms, p110ß and p110d. Inhibiting these two isoforms combines an immunotherapeutic response and a direct effect on tumor growth, through selective, targeting of the PI3K pathway. Karus believes that KA2237 has broad therapeutic applicability in the treatment of hematological and solid tumors, as a single agent and in combination with other drugs. This study forms part of the pre-clinical and clinical collaboration between Karus and the University of Texas MD Anderson Cancer Center, the world’s leading cancer research and care center. The first part of the trial has been designed to assess the safety of KA2237 alone in relapsed, treatment-resistant B cell lymphoma patients. An expansion cohort study will follow and is scheduled to start in 2017. Karus anticipates that up to 40 patients will be treated over the entire study. Dr. Simon Kerry, CEO of Karus Therapeutics, commented: “Our first clinical trial is a major milestone for the company. Karus has made exceptional progress and our collaboration with MD Anderson will help us to accelerate this clinical program. We believe that as an orally-active dual p110ß/d inhibitor, KA2237 has significant potential in the treatment of hematological and solid tumors in areas of high, unmet medical need.” Professor Stephen Shuttleworth, CSO, added: “Our R&D programs are built on many years’ investment in research that have given us a deep understanding of PI3K medicinal chemistry and tumor biology. To take a scientific concept through rational de novo-design to create KA2237, a dual-selective, small molecule PI3K inhibitor that has been designed specifically to address areas of unmet medical need, is a very rewarding moment in our journey towards developing new cancer treatments for patients with few remaining therapeutic options.” The agreement with MD Anderson covers a number of preclinical studies of Karus’s two cancer programs, KA2237 and KA2507, with a focus on identifying optimal drug combinations and the appropriate patient populations for further clinical development. The second program, KA2507, a selective-HDAC6 inhibitor, also has both a targeted therapy and immunotherapeutic action and has potential in the treatment of multiple myeloma, B- and T-cell lymphomas and PD-L1 expressing hematological and solid tumors. -Ends- About Karus Therapeutics Karus Therapeutics is a leader in the development of innovative medicines that have breakthrough potential in the treatment of cancer. The Company’s scientific excellence is reflected in its proprietary PI3K and HDAC6 inhibitor programs, from which innovative small molecule drugs with significant clinical and commercial potential have been developed. The UK-based Company is privately-held with a strong financial track record and experienced investors, including SV Life Sciences, New Leaf Ventures, Novo A/S and IP Group. For further information please visit www.karustherapeutics.com About MD Anderson The University of Texas MD Anderson Cancer Center in Houston ranks as one of the world's most respected centers focused on cancer patient care, research, education and prevention. MD Anderson is one of only 41 comprehensive cancer centers designated by the National Cancer Institute (NCI). For the past 25 years, MD Anderson has ranked as one of the nation's top two cancer centers in U.S. News & World Report's annual "Best Hospitals" survey. MD Anderson receives a cancer center support grant from the NCI of the National Institutes of Health (P30 CA016672).

EMERYVILLE, Calif., April 10, 2023 /PRNewswire/ -- Totus Medicines, a clinical stage biotechnology company fueled by its breakthrough Accel™ platform, announced it will be presenting four posters at the American Association for Cancer Research (AACR) Annual Meeting, regarding its lead program, TOS-358, the first highly specific, covalent PI3Kα inhibitor. Totus has created the Accel™ Platform that, for the first time ever, can search, map, and decode billions of drug molecules across multiple cellular targets in a single experiment. This has allowed Totus to identify candidate molecules in months, not years, and rapidly advance these molecules toward the clinic. Notably, the Accel™ Platform enabled discovery of TOS-358 at an unprecedented pace. TOS-358 was discovered in under 4 months and received IND approval in ~2 years from original screening. TOS-358 represents the first highly specific covalent inhibitor of PI3Kα, which is mutated in ~15% of all cancers (Breast, Colorectal, Lung, Bladder, etc.). However, the therapeutic benefit of current molecules is limited by two key problems. Firstly, current non-covalent PI3Kα inhibitors cannot achieve continuous >95% target pathway inhibition, which is required for anti-tumor efficacy. Secondly, high doses of current non-covalent PI3Kα inhibitors are non-specific and inhibit other PI3K isoforms at effective doses. This leads to toxicity such as hyperglycemia and GI toxicity. TOS-358 represents the first ever highly specific covalent molecule targeting PI3Kα that can achieve durable, near 100% inhibition of PI3Kα activity and avoid these safety issues in preclinical studies. Totus will outline three key points at AACR to support TOS-358 as the best-in-class PI3Kα inhibitor: Despite claims indicating 80% inhibition is sufficient, PI3Kα-mutant tumors consistently require >95% inhibition to induce significant anti-tumor effects, and TOS-358 can uniquely achieve this level of inhibition. Common pathway feedback mechanisms re-activate PI3Kα in most cell lines and render non-covalent approaches ineffective. TOS-358 can uniquely block these feedback mechanisms and retain >95% inhibition over time. PI3Kα-WT inhibition alone does not induce significant hyperglycemia or metabolic dysfunction. Previous non-covalent molecules (Alpelisib) inhibit both PI3Kα and other off-target (PI3Kβ) leading to significant toxicities. TOS-358 does not cause significant metabolic dysfunction due to its highly specific ability to target PI3Kα. Based on these studies, we outline the best-in-class status of TOS-358 due to its unique ability to achieve >95% inhibition of PI3Kα with limited side effects leading to unprecedented monotherapy efficacy in preclinical models. "We're thrilled to be presenting several posters at AACR that demonstrate the preclinical efficacy, safety, and differentiation of TOS-358, the world's first covalent inhibitor of PI3Kα in clinical development," said Neil Dhawan, CEO and co-founder of Totus Medicines. "We've come a long way, fast, and are looking forward to sharing our findings with the broader cancer research community, which we believe will redefine the cancer community's understanding of PI3Kα targeting." The poster presentations are listed below and the full abstracts will be available on the AACR and Totus Website. A study to evaluate the safety and tolerability of the covalent phosphoinositide-3-kinase (PI3K)-alpha Inhibitor, TOS-358, in adult subjects with select solid tumors Abstract number: CT249 Date and Time: Tuesday April 18 at 1:30 PM - 5:00 PM ET Development and validation of a pharmacodynamic (PD) assay for TOS-358, the first covalent inhibitor of PI3Kα in clinical development Abstract number: 2249 Date and Time: Monday, April 17 at 9:00 AM - 12:30 PM ET Inhibition of wild-type PI3Kα signaling is required for durable efficacy in PI3Kα mutant cancer cells due to robust re-activation of wild-type PI3Kα signaling Abstract number: 4946 Date and Time: Tuesday, April 18 at 1:30 PM - 5:00 PM ET TOS-358, a first-in-class covalent PI3Kα inhibitor, demonstrates superior efficacy and does not induce significant hyperglycemia at efficacious doses in multiple animal models Abstract number: 4945 Date and Time: Tuesday, April 18 at 1:30 PM - 5:00 PM ET About Totus Medicines Founded in 2019, Totus Medicines has developed the next generation of cellular analysis to create life-changing therapies to treat previously untreatable diseases. Totus' platform uses proprietary molecular tags that track drug binding in individual cells to enable the screening of billions of molecules across any drug target. Totus is based in the Bay Area. For more information, please visit totusmedicines.com and follow Totus on LinkedIn and Twitter. MEDIA CONTACT [email protected] SOURCE Totus Medicines

The multinational Phase III study is evaluating leniolisib tablets in children aged 4 to 11 years with APDS, a rare primary immunodeficiency LEIDEN, Netherlands, Feb. 21, 2023 /PRNewswire/ -- Pharming Group N.V. ("Pharming" or "the Company") (EURONEXT Amsterdam: PHARM)/(Nasdaq: PHAR) announces that the first patient has been enrolled in its Phase III clinical trial (NCT05438407) evaluating the investigational drug leniolisib, an oral, selective phosphoinositide 3-kinase delta (PI3Kδ) inhibitor, in children with activated phosphoinositide 3-kinase delta syndrome (APDS). There is currently no approved treatment for this complex and progressive disease caused by genetic variants. At sites in the United States, Europe, and Japan, the single-arm, open-label, multinational clinical trial will evaluate the safety, tolerability, and efficacy of leniolisib in approximately 15 children aged 4 to 11 years who have a confirmed APDS diagnosis. The study's primary efficacy endpoints are a reduction in index lymph node size and an increased proportion of naïve B cells out of total B cells from baseline at 12 weeks. Secondary endpoints include an assessment of the ability of leniolisib to modify health-related quality of life based on measures of physical, social, emotional, and school functioning using a validated patient questionnaire. Pharming plans to initiate a similar clinical trial in the third quarter of 2023 that will include children aged 1 to 6 years, with APDS, to evaluate a new pediatric formulation of leniolisib. Eligible patients enrolled in either of the pediatric trials will continue to receive leniolisib for a year after the initial 12-week treatment period through an open-label extension trial. Manish Butte, MD, PhD, E. Richard Stiehm Endowed Chair, Professor with tenure in the Department of Pediatrics, and Division Chief of Immunology, Allergy, and Rheumatology at UCLA, commented: "In treating APDS, the current standard of care is to use an array of supportive therapies. While these therapies can treat some of the manifestations of APDS, they do not target the underlying cause of the disease. Pharming's studies of leniolisib in children with APDS are important for evaluating the possibility of minimizing symptoms earlier in the disease progression." Pharming's program for the clinical development of leniolisib in pediatric APDS is supported by positive data from a Phase II/III clinical trial that investigated the drug as a treatment for patients with the disease aged 12 years and older. As announced on February 2, 2022, and recently detailed in Blood1, the international medical journal of the American Society of Hematology, the trial met both its co-primary endpoints, with patients who took leniolisib versus placebo achieving significant reductions in lymphoproliferation as measured by index lymph node size and increases in immunophenotype corrections as measured by the percentage of naïve B cells in peripheral blood. During the first half of 2022, positive opinions were received from the European Medicines Agency (EMA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA) on the Pediatric Investigation Plan (PIP) for leniolisib as a treatment for APDS in children. The PIP(s) included the plans for both pediatric clinical trials. Anurag Relan, MD, MPH, Chief Medical Officer of Pharming, commented: "I am pleased we have initiated the first trial in our Phase III pediatric clinical program evaluating leniolisib in children with APDS, and I look forward to our second pediatric trial getting underway. Building on the encouraging findings from our successful Phase II/III study in patients aged 12 years and older with APDS, we are committed to bringing leniolisib to even younger patients with the goal of intervening before they develop immune-related symptoms likely to progress throughout their lives. While continuing to focus on patients of all ages with APDS, we are dedicated to collaborating with regulatory authorities with the goal of generating regulatory filings to gain approval that could support the treatment of children under 12 years of age who are living with this disease." Based on the Phase II/III trial results and long-term open-label extension data, the U.S. Food and Drug Administration (FDA) is conducting a priority review of Pharming's New Drug Application for leniolisib as a treatment for adolescents and adults with APDS and has assigned a Prescription Drug User Fee Act (PDUFA) goal date of March 29, 2023. In addition, Pharming's Marketing Authorisation Application (MAA) for leniolisib in the same patient population is under evaluation by the European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP). Pharming expects that the CHMP will issue its opinion on the leniolisib MAA in 2H 2023. About Activated Phosphoinositide 3-Kinase δ Syndrome (APDS) APDS is a rare primary immunodeficiency that affects approximately 1 to 2 people per million. APDS is caused by variants in either of two genes, PIK3CD or PIK3R1, that regulate maturation of white blood cells. Variants of these genes lead to hyperactivity of the PI3Kδ (phosphoinositide 3-kinase delta) pathway.2,3 Balanced signaling in the PI3Kδ pathway is essential for physiological immune function. When this pathway is hyperactive, immune cells fail to mature and function properly, leading to immunodeficiency and dysregulation.2,4 APDS is characterized by severe, recurrent sinopulmonary infections, lymphoproliferation, autoimmunity, and enteropathy.5,6 Because these symptoms can be associated with a variety of conditions, including other primary immunodeficiencies, people with APDS are frequently misdiagnosed and suffer a median 7-year diagnostic delay.7 As APDS is a progressive disease, this delay may lead to an accumulation of damage over time, including permanent lung damage and lymphoma.5-8 A definitive diagnosis can be made through genetic testing. About leniolisib Leniolisib is a small-molecule inhibitor of the delta isoform of the 110 kDa catalytic subunit of class IA PI3K. PI3Kδ is expressed predominately in hematopoietic cells and is essential to normal immune system function through conversion of phosphatidylinositol-4-5-trisphosphate (PIP2) to phosphatidylinositol-3-4-5-trisphosphate (PIP3). Leniolisib inhibits the production of PIP3 and PIP3 serves as an important cellular messenger activating AKT (via PDK1) and regulates a multitude of cell functions such as proliferation, differentiation, cytokine production, cell survival, angiogenesis, and metabolism. Unlike PI3Kα and PI3Kβ, which are ubiquitously expressed, PI3Kẟ and PI3Kγ are expressed primarily in cells of hematopoietic origin. The central role of PI3Kẟ in regulating numerous cellular functions of the adaptive immune system (B-cells and, to a lesser extent, T cells) as well as the innate immune system (neutrophils, mast cells, and macrophages) strongly indicates that PI3Kẟ is a valid and potentially effective therapeutic target for immune diseases such as APDS. To date, leniolisib has been well tolerated during both the Phase 1 first-in-human trial in healthy subjects and the Phase II/III registration-enabling study in patients with APDS. About Pharming Group N.V. Pharming Group N.V. (EURONEXT Amsterdam: PHARM/Nasdaq: PHAR) is a global biopharmaceutical company dedicated to transforming the lives of patients with rare, debilitating, and life-threatening diseases. Pharming is commercializing and developing an innovative portfolio of protein replacement therapies and precision medicines, including small molecules, biologics, and gene therapies that are in early to late-stage development. Pharming is headquartered in Leiden, Netherlands, and has employees around the globe who serve patients in over 30 markets in North America, Europe, the Middle East, Africa, and Asia-Pacific. For more information, visit and find us on LinkedIn. Forward-looking Statements This press release may contain forward-looking statements. Forward-looking statements are statements of future expectations that are based on management's current expectations and assumptions and involve known and unknown risks and uncertainties that could cause actual results, performance, or events to differ materially from those expressed or implied in these statements. These forward-looking statements are identified by their use of terms and phrases such as "aim", "ambition", ''anticipate'', ''believe'', ''could'', ''estimate'', ''expect'', ''goals'', ''intend'', ''may'', "milestones", ''objectives'', ''outlook'', ''plan'', ''probably'', ''project'', ''risks'', "schedule", ''seek'', ''should'', ''target'', ''will'' and similar terms and phrases. Examples of forward-looking statements may include statements with respect to timing and progress of Pharming's preclinical studies and clinical trials of its product candidates, Pharming's clinical and commercial prospects, and Pharming's expectations regarding its projected working capital requirements and cash resources, which statements are subject to a number of risks, uncertainties and assumptions, including, but not limited to the scope, progress and expansion of Pharming's clinical trials and ramifications for the cost thereof; and clinical, scientific, regulatory and technical developments. In light of these risks and uncertainties, and other risks and uncertainties that are described in Pharming's 2021 Annual Report and the Annual Report on Form 20-F for the year ended December 31, 2021, filed with the U.S. Securities and Exchange Commission, the events and circumstances discussed in such forward-looking statements may not occur, and Pharming's actual results could differ materially and adversely from those anticipated or implied thereby. All forward-looking statements contained in this press release are expressly qualified in their entirety by the cautionary statements contained or referred to in this section. Readers should not place undue reliance on forward-looking statements. Any forward-looking statements speak only as of the date of this press release and are based on information available to Pharming as of the date of this release. Pharming does not undertake any obligation to publicly update or revise any. Inside Information This press release relates to the disclosure of information that qualifies, or may have qualified, as inside information within the meaning of Article 7(1) of the EU Market Abuse Regulation. References Rao VK, et al. Blood. 2022. . Lucas CL, et al. Nat Immunol. 2014;15:88-97. Elkaim E, et al. J Allergy Clin Immunol. 2016;138(1):210-218. Nunes-Santos C, Uzel G, Rosenzweig SD. J Allergy Clin Immunol. 2019;143(5):1676-1687. Coulter TI, et al. J Allergy Clin Immunol. 2017;139(2):597-606. Maccari ME, et al. Front Immunol. 2018;9:543. Jamee M, et al. Clin Rev Allergy Immunol. 2019;May 21. Condliffe AM, Chandra A. Front Immunol. 2018;9:338. For further public information, contact: Pharming Group, Leiden, The Netherlands Michael Levitan, VP Investor Relations & Corporate Communications T: +1 (908) 705 1696 Heather Robertson, Investor Relations & Corporate Communications Manager E: [email protected] FTI Consulting, London, UK Victoria Foster Mitchell/Alex Shaw/Amy Byrne T: +44 203 727 1000 LifeSpring Life Sciences Communication, Amsterdam, The Netherlands Leon Melens T: +31 6 53 81 64 27 E: [email protected] US PR Ethan Metelenis E: [email protected] T: +1 (917) 882 9038 EU PR Dan Caley E: [email protected] T: +44 (0) 787 546 8942 Logo - The content and accuracy of news releases published on this site and/or distributed by PR Newswire or its partners are the sole responsibility of the originating company or organisation. Whilst every effort is made to ensure the accuracy of our services, such releases are not actively monitored or reviewed by PR Newswire or its partners and under no circumstances shall PR Newswire or its partners be liable for any loss or damage resulting from the use of such information. All information should be checked prior to publication. SOURCE Pharming Group N.V.