MALT1

NEW YORK--( BUSINESS WIRE )--Schrödinger (Nasdaq: SDGR), whose physics-based computational platform is transforming the way therapeutics and materials are discovered, is providing a detailed review of its proprietary drug discovery and development programs during its Pipeline Day today, December 14, from 10:00 a.m. - 12:30 p.m. ET. “We are excited to share our first clinical data for a proprietary Schrödinger program, SGR-1505, and to outline the opportunities emerging from our broad portfolio of drug discovery programs in multiple therapeutic areas, including oncology, immunology and neurology,” stated Karen Akinsanya, Ph.D., president of R&D, therapeutics at Schrödinger. “Our therapeutics team has been very productive since we started building this portfolio. With two programs in the clinic, multiple programs in late discovery and preclinical development, and our advancing collaborations, we believe the future of our therapeutics portfolio is very promising.” SGR-1505 Clinical Progress and Program Update During Pipeline Day, Schrödinger is presenting new data showing that its novel MALT1 inhibitor, SGR-1505, was well tolerated in a Phase 1 study of 73 healthy volunteers. No drug-related serious adverse events or dose limiting toxicities were observed in the study. In the study, SGR-1505 achieved greater than 90 percent inhibition of IL-2 secretion in activated T cells, confirming target engagement and meeting the pharmacodynamic goals for the study. The data support continued evaluation of SGR-1505 in the ongoing Phase 1 study in patients with relapsed or refractory B-cell malignancies. “The data presented from our successful healthy volunteer study demonstrate that SGR-1505 is well-tolerated with a pharmacokinetic and pharmacodynamic profile that supports continued development,” stated Margaret Dugan, M.D., chief medical officer at Schrödinger. “These data add significantly to our understanding of SGR-1505 and inform our clinical development strategy in hematologic malignancies. The SGR-1505 program is progressing well, and we look forward to continued enrollment in the patient study and reporting initial data in late 2024 or 2025.” Schrödinger is also presenting preclinical data for SGR-1505 demonstrating that SGR-1505 has favorable attributes and the potential for combination activity with standard-of-care agents in B cell malignancies. These data were presented earlier this week at the American Society of Hematology Annual Meeting. Three New Programs: EGFR C797S , PRMT5-MTA and NLRP3 Schrödinger is presenting three new proprietary discovery programs at Pipeline Day, targeting EGFR C797S , PRMT5-MTA and NLRP3. EGFR inhibitors are first-line standard of care agents for advanced non-small cell lung cancer patients with activating EGFR mutations, but relapse often occurs due to the development of resistance mutations, including EGFR C797S . Schrödinger has identified multiple EGFR C797S inhibitors and is advancing wild-type sparing, double mutant CNS-penetrant inhibitors with the potential to address brain metastases in patients whose disease progresses following first-line treatment, and to potentially achieve deeper, more durable responses through new combination regimens. PRMT5-MTA inhibition has demonstrated clinical responses in both hematologic and solid tumors with improved safety versus PRMT5 inhibitors due to a synthetic lethal targeting of cancer cells with MTAP-deletions. Schrödinger has identified selective, potent PRMT5-MTA inhibitors with potential applications in solid tumors, brain metastases and primary CNS tumors. NLRP3 is a validated target, and mutations in the NLRP3 gene are associated with a broad spectrum of inflammatory and auto-immune diseases. Schrödinger has identified structurally distinct, selective, NLRP3 inhibitors with anti-inflammatory activity in preclinical models, and is continuing to optimize peripheral and brain-penetrant leads. Broad Portfolio Addresses Synthetic Lethality and DNA-Damage Repair Schrödinger is advancing multiple oncology programs designed to exploit the intrinsic vulnerabilities of cancer cells through synthetic lethality and inhibition of DNA-damage repair. Today, the company is discussing its synthetic lethality programs, PRMT5-MTA and SGR-3515 (Wee1/Myt1). The company is also reviewing SGR-2921, which targets CDC7, a key regulator of replication stress and DNA-damage repair. Schrödinger is reporting preclinical data showing that SGR-3515 has a differentiated biochemical, biophysical and functional profile, with sustained inhibition of Wee1 and Myt1 in tumor cells. Concurrent loss of function of Wee1 and Myt1 confers selective vulnerability in cancer cells and could offer increased anti-tumor activity. SGR-3515 has potential to treat a broad range of solid tumors, including uterine and ovarian cancers. Schrödinger plans to submit an IND for SGR-3515 in the first half of 2024. Schrödinger is also discussing preclinical data presented at ASH demonstrating that SGR-2921 exhibited better activity compared to other CDC7 inhibitors, and showed anti-proliferative effects in treatment-resistant acute myeloid leukemia (AML) patient-derived samples, as well as reduction of blasts in multiple AML models. A Phase 1 study of SGR-2921 is ongoing in patients with AML or myelodysplastic syndrome, and the company expects to report initial data from the study in late 2024 or 2025. “CDC7 is a promising therapeutic target for the treatment of myelodysplastic syndromes and acute myeloid leukemia, diseases for which there is a significant unmet need in treating both frontline and relapsed/refractory patients,” stated Elie Traer, M.D., Ph.D., associate professor at the Center for Hematologic Malignancies at Oregon Health & Science University. “Targeting CDC7 with emerging investigational therapeutics, such as SGR-2921, represents an opportunity to expand our armamentarium of treatment options beyond existing targeted therapies.” Anticipated Milestones Today, Schrödinger outlined the anticipated milestones for its proprietary pipeline: Report initial data from the Phase 1 study of SGR-1505 in late 2024 or 2025 Report initial data from the Phase 1 study of SGR-2921 in late 2024 or 2025 Submit IND for SGR-3515 in the first half of 2024 and initiate a Phase 1 study in 2024 Submit an IND from its discovery portfolio in 2025 Event Information Schrödinger’s Pipeline Day will begin at 10:00 a.m. ET and is expected to conclude at approximately 12:30 p.m. ET. The live presentation can be accessed in the “Investors” section of Schrödinger’s website and will be archived for approximately 90 days. To participate in the live webcast, please register for the event here . It is recommended that participants register at least 15 minutes in advance of the event. About Schrödinger Schrödinger is transforming the way therapeutics and materials are discovered. Schrödinger has pioneered a physics-based computational platform that enables discovery of high-quality, novel molecules for drug development and materials applications more rapidly and at lower cost compared to traditional methods. The software platform is licensed by biopharmaceutical and industrial companies, academic institutions, and government laboratories around the world. Schrödinger’s multidisciplinary drug discovery team also leverages the software platform to advance a portfolio of collaborative and proprietary programs to address unmet medical needs. Founded in 1990, Schrödinger has more than 800 employees and is engaged with customers and collaborators in more than 70 countries. To learn more, visit www.schrodinger.com , follow us on LinkedIn and Instagram , or visit our blog, Extrapolations.com . Cautionary Note Regarding Forward-Looking Statements This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995 including, but not limited to those statements regarding the potential advantages of Schrödinger’s computational platform, the clinical potential and favorable properties of its product candidates, including SGR-1505, SGR-2921 and SGR-3515, the potential for SGR-1505 to be used for the treatment of advanced B-cell malignancies, the potential for SGR-2921 to be used for the treatment of AML or myelodysplastic syndrome, the ability to identify any new product candidates, including from the company’s newly announced drug discovery programs, the timing, progress, and results of clinical trials for its product candidates, and the expected timing of additional IND submissions to the FDA for any product candidates the company identifies. Statements including words such as “aim,” “anticipate,” “believe,” “contemplate,” “continue,” “could,” “estimate,” “expect,” “goal,” “intend,” “may,” “might,” “plan,” “potential,” “predict,” “project,” “should,” “target,” “will,” “would” and statements in the future tense are forward-looking statements. These forward-looking statements reflect Schrödinger’s current views about its plans, intentions, expectations, strategies and prospects, which are based on the information currently available to the company and on assumptions the company has made. Actual results may differ materially from those described in these forward-looking statements and are subject to a variety of assumptions, uncertainties, risks and important factors that are beyond Schrödinger’s control, including the uncertainties inherent in drug development and commercialization, such as the conduct of research activities and the timing of and its ability to initiate and complete preclinical studies and clinical trials, whether results from preclinical and clinical studies will be predictive of the results of later preclinical studies and clinical trials, uncertainties associated with the regulatory review of clinical trials and applications for marketing approvals and the ability to retain and hire key personnel on its business and other risks detailed under the caption “Risk Factors” and elsewhere in the company’s Securities and Exchange Commission filings and reports, including its Quarterly Report on Form 10-Q for the fiscal quarter ended September 30, 2023, filed with the Securities and Exchange Commission on November 1, 2023, as well as future filings and reports by the company. Any forward-looking statements contained in this press release speak only as of the date hereof. Except as required by law, Schrödinger undertakes no duty or obligation to update any forward-looking statements contained in this press release as a result of new information, future events, changes in expectations or otherwise.

Oral presentation describes distinct preclinical profile for potent, selective MALT1 scaffolding inhibitor that is highly differentiated from MALT1 protease inhibitors BOSTON, Dec. 11, 2023 /PRNewswire/ -- HotSpot Therapeutics, Inc., a biotechnology company pioneering the discovery and development of oral, small molecule allosteric therapies targeting regulatory sites on proteins referred to as "natural hotspots," today announced the presentation of preclinical data from the Company's highly differentiated mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) program in an oral presentation at the 2023 American Society of Hematology (ASH) Annual Meeting. MALT1 is a component of the CARD11-BCL10-MALT1 (CBM) protein complex, which serves as a key regulator of NFkB signaling in cells, including B and T cells. MALT1 is implicated in a range of hematological malignancies, including Non-Hodgkin's lymphoma, as well as other lymphomas and selected solid tumors. Leveraging our proprietary Smart Allostery™ platform, HotSpot has developed potential first-in-class small molecules designed to selectively inhibit the scaffolding function of MALT1, a dominant driver of the NFkB pathway, while sparing MALT1's protease function. "MALT1's therapeutic potential rests in the role of its scaffolding function to regulate the NFkB pathway, which is implicated in a broad range of hematological and solid tumors," said Geraldine Harriman, Co-Founder and Chief Scientific Officer of HotSpot. "Using our Smart Allostery™ platform, HotSpot has delivered a potential first-in-class allosteric inhibitor, HST-1021, that is designed to potently and selectively inhibit MALT1's scaffolding function. HST-1021's pharmacological attributes suggest therapeutic potential, as these preclinical data demonstrated in vivo tumor growth inhibition without any observed negative impact on other immune functions. We look forward to providing additional updates as we advance our program, as we plan to file an Investigational New Drug (IND) application for HST-1021 in 2024." The presentation describes preclinical data for HST-1021, HotSpot's MALT1 inhibitor development candidate: Using the Smart Allostery™ platform, HotSpot elucidated and drugged a natural hotspot on MALT1 that potently and selectively inhibited MALT1's scaffolding function, while sparing MALT1's protease function. In several B-cell lymphoma xenograft models, HST-1021 demonstrated robust, dose-dependent tumor growth inhibition (TGI), including in both MALT1 protease-inhibitor sensitive ABC-DLBCL and MALT1 protease-resistant NFkB-driven DLBCL models. In contrast to MALT1 protease inhibitors, HotSpot's scaffolding inhibitor did not deplete Treg cells or suppress T-cell activation in vivo, which HotSpot believes supports the potential for clinical mitigation of the risk of autoimmune disease resulting from chronic MALT1 protease function inhibition and would allow for broad combination use. About HotSpot Therapeutics, Inc. HotSpot Therapeutics, Inc. is pioneering a new class of allosteric drugs that target certain naturally occurring pockets on proteins called "natural hotspots." These pockets are decisive in controlling a protein's cellular function and have significant potential for new drug discovery by enabling the systematic design of potent and selective small molecules with novel pharmacology. The Company's proprietary Smart Allostery™ platform combines computational approaches and AI-driven data mining of large and diverse data sets to uncover hotspots with tailored pharmacology toolkits and bespoke chemistry to drive the rapid discovery of novel hotspot-targeted small molecules. Leveraging this approach, HotSpot is building a broad pipeline of novel allosteric therapies for the treatment of cancer and autoimmune diseases. To learn more, visit . Investor & Media Contact: Natalie Wildenradt [email protected] SOURCE HotSpot Therapeutics

NEW YORK--(BUSINESS WIRE)-- Schrödinger (Nasdaq: SDGR), whose physics-based computational platform is transforming the way therapeutics and materials are discovered, today announced new preclinical data on SGR-1505, its investigational MALT1 inhibitor, and SGR-2921, its investigational CDC7 inhibitor, in a poster session at the American Society of Hematology (ASH) 65th Annual Meeting taking place virtually and in San Diego, California. The preclinical data reported show that both SGR-1505 and SGR-2921 have multiple favorable attributes and the potential for combination activity with standard-of-care agents. Schrödinger also reported preliminary pharmacodynamic data from the Phase 1 study of SGR-1505 in healthy subjects, which showed that SGR-1505 inhibited cytokine release in human whole blood and demonstrated evidence of MALT1 inhibition in humans. The company will report additional data from the healthy subject study at its Pipeline Day on December 14, 2023. “The pharmacological data for SGR-1505 and SGR-2921 demonstrate that our development candidates have favorable, differentiated profiles with best-in-class potential,” stated Karen Akinsanya, Ph.D., president of R&D therapeutics at Schrödinger. “Our progress within these programs further validates our computational approach to designing therapies with the potential to address the limitations of current treatments. SGR-1505 and SGR-2921 are now being evaluated in Phase 1 clinical studies, and we look forward to seeing these programs advance.” A Phase 1 dose-escalation study of SGR-1505 in relapsed or refractory B-cell malignancy patients is ongoing in the U.S. and Europe. Additionally, a Phase 1 clinical study of SGR-2921 was recently initiated in patients with acute myeloid leukemia or myelodysplastic syndrome. Both studies are designed to evaluate the safety, pharmacokinetics, pharmacodynamics, and determine the recommended dose for further development. SGR-1505 Data at ASH The presentation (Abstract # 2997), “SGR-1505 is a Potent MALT1 Protease Inhibitor with a Potential Best-in-Class Profile,” includes preclinical data demonstrating the potency of SGR-1505 and the potential for combination activity with standard of care agents. Preclinical data showed that SGR-1505 is more potent than JNJ-6633, which has previously provided clinical validation for MALT1 inhibition as a potential therapeutic strategy for treating both chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphomas (NHL). In a preclinical model of diffuse large B-cell lymphoma, SGR-1505, in combination with venetoclax, demonstrated a stronger combination impact on cell viability compared to JNJ-633 plus venetoclax. Gene expression analysis showed that SGR-1505 provides greater modulation of NF-ΚΒ and related pathway genes compared to JNJ-6633. Signaling of the NF-ΚΒ pathway is known to play a critical role in the initiation and progression of many types of cancers, particularly B cell malignancies. Preliminary clinical biomarker data from the Phase 1 study in healthy subjects showed that SGR-1505 inhibited cytokine release in ex vivo stimulation of human whole blood. The inhibition of certain cytokines in whole blood from human subjects dosed with SGR-1505 provides pharmacodynamic evidence of MALT1 inhibition. These data are consistent with prior preclinical observations in an in vitro whole blood assay from healthy human subjects, where approximately a 50-fold lower concentration of SGR-1505 was needed to achieve 90 percent inhibition of cytokine release compared to JNJ-6633. The data support continued evaluation of SGR-1505 in the ongoing Phase 1 study in patients with advanced B-cell malignancies. SGR-2921 Data at ASH The presentation (Abstract #2801), “SGR-2921, a Potent CDC7 Inhibitor, Demonstrates Significant Anti-Leukemic Responses in Patient-Derived AML Models Representing Difficult-to-Treat Disease,” includes preclinical data for SGR-2921 which demonstrate the potency, breadth of activity and synergistic effects of SGR-2921 in combination with standard-of-care therapies. In vitro, SGR-2921 exhibited greater potency compared to other clinical-stage CDC7 inhibitors and showed anti-proliferative activity in AML patient-derived samples regardless of driver mutations. In vivo, SGR-2921 showed dose-dependent reduction of AML blasts in multiple AML models representing difficult-to-treat disease. SGR-2921 also showed synergistic activity in combination with decitabine in p53-mutated AML models in vivo. Together, these data support the ongoing evaluation of SGR-2921 as a potential treatment for AML, with particular utility in patients with high-risk mutations and relapsed and refractory AML. Schrödinger Pipeline Day Webcast Information Schrödinger will review the company's proprietary research and development programs, including updates on SGR-1505 and SGR-2921, at its Pipeline Day taking place in-person and virtually on December 14, 2023. Pipeline Day will be a hybrid event, with a webcast and limited in-person attendance available to members of the investment community. The presentation can be accessed in the “Investors” section of Schrödinger’s website and will be archived for approximately 90 days. To participate in the live webcast, please register for the event here. It is recommended that participants register at least 15 minutes in advance of the event. About Schrödinger Schrödinger is transforming the way therapeutics and materials are discovered. Schrödinger has pioneered a physics-based computational platform that enables discovery of high-quality, novel molecules for drug development and materials applications more rapidly and at lower cost compared to traditional methods. The software platform is licensed by biopharmaceutical and industrial companies, academic institutions, and government laboratories around the world. Schrödinger’s multidisciplinary drug discovery team also leverages the software platform to advance a portfolio of collaborative and proprietary programs to address unmet medical needs. Founded in 1990, Schrödinger has approximately 800 employees and is engaged with customers and collaborators in more than 70 countries. To learn more, visit , follow us on LinkedIn and Instagram, or visit our blog, Extrapolations.com. Cautionary Note Regarding Forward-Looking Statements This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995 including, but not limited to those statements regarding the potential advantages of Schrödinger’s computational platform, the clinical potential and favorable properties of its product candidates, including SGR-1505 and SGR-2921, the potential for SGR-1505 to be used for the treatment of advanced B-cell malignancies, the potential for SGR-2921 to be used for the treatment of AML or myelodysplastic syndrome, and the timing, progress, and results of clinical trials for its product candidates. Statements including words such as “aim,” “anticipate,” “believe,” “contemplate,” “continue,” “could,” “estimate,” “expect,” “goal,” “intend,” “may,” “might,” “plan,” “potential,” “predict,” “project,” “should,” “target,” “will,” “would” and statements in the future tense are forward-looking statements. These forward-looking statements reflect Schrödinger’s current views about its plans, intentions, expectations, strategies and prospects, which are based on the information currently available to the company and on assumptions the company has made. Actual results may differ materially from those described in these forward-looking statements and are subject to a variety of assumptions, uncertainties, risks and important factors that are beyond Schrödinger’s control, including the uncertainties inherent in drug development and commercialization, such as the conduct of research activities and the timing of and its ability to initiate and complete preclinical studies and clinical trials, whether results from preclinical and early clinical studies will be predictive of the results of later preclinical studies and clinical trials, uncertainties associated with the regulatory review of clinical trials and applications for marketing approvals and the ability to retain and hire key personnel on its business and other risks detailed under the caption “Risk Factors” and elsewhere in the company’s Securities and Exchange Commission filings and reports, including its Quarterly Report on Form 10-Q for the fiscal quarter ended September 30, 2023, filed with the Securities and Exchange Commission on November 1, 2023, as well as future filings and reports by the company. Any forward-looking statements contained in this press release speak only as of the date hereof. Except as required by law, Schrödinger undertakes no duty or obligation to update any forward-looking statements contained in this press release as a result of new information, future events, changes in expectations or otherwise. View source version on businesswire.com: Contacts Matthew Luchini (Investors) Schrödinger, Inc. matthew.luchini@schrodinger.com 917-719-0636 Allie Nicodemo (Media) Schrödinger, Inc. allie.nicodemo@schrodinger.com 617-356-2325 Source: Schrödinger View this news release online at: