Nedisertib

Potential best-in-class ATR inhibitor tuvusertib being explored in Phase II combination clinical studies; recently licensed PARP1 inhibitor M9466 to be evaluated in Phase Ib combination dose-finding studies Potential first-in-class anti-CEACAM5 ADC with an exatecan payload, M9140, which entered Phase Ib in colorectal cancer this year, to be explored in other CEACAM5-expressing tumors beginning in 2025 First-in-class anti-GD2 ADC M3554, leveraging company’s novel exatecan-based technology, set to enter first-in-human study in adults in 2024 and in pediatric patients in 2025 Merck KGaA, Darmstadt, Germany, a leading science and technology company that operates its Healthcare business as EMD Serono in the US and Canada, today shared updates on the company’s oncology pipeline and focused approach to the research and development of potential new medicines designed to improve the futures of people with cancer. This year, the company plans to open multiple new Phase Ib and II clinical studies for tuvusertib and M9466, key assets from its broad portfolio of DNA damage response (DDR) inhibitors; has advanced its lead antibody-drug conjugate (ADC), M9140, to Phase Ib based on positive signs of clinical benefit, and plans to expand to additional tumors; and progress M3554, its next ADC based on the company’s proprietary exatecan-payload platform, into clinical development. These and other updates were shared at the company’s Oncology R&D Update Call. “The advancements in our strong early-stage clinical pipeline of ADCs created with our in-house platform and DDR inhibitors are grounded in encouraging data, particularly for M9140 and tuvusertib. The addition of M9466 to our pipeline further supports our focus on synergistic approaches in oncology, with the potential for combination with tuvusertib as well as with multiple other modalities,” said Danny Bar-Zohar, Global Head of Research & Development and Chief Medical Officer for the Healthcare business sector of Merck KGaA, Darmstadt, Germany. "With our preclinical research programs in ADCs, DDR inhibitors, next-generation immuno-oncology compounds and oncogenic signaling assets, we are well-positioned to continue to fuel our clinical development efforts as we work to improve the futures of people touched by cancer.” Realizing the Full Potential of DNA Damage Response Inhibition The company’s leading pipeline of DDR inhibitors is being investigated across core hypotheses including synthetic lethality, activation of immune response, and synergy with cytotoxic drugs, to identify relevant combinations and understand which cancers are most likely to respond to different treatment regimens. Four investigational DDR inhibitor medicines in clinical trials include: Tuvusertib (M1774), a potentially best-in-class small-molecule oral inhibitor of the ataxia telangiectasia and Rad3-related (ATR) kinase; M9466, a next-generation potent and selective PARP1 (poly (ADP-ribose) polymerase 1) inhibitor, recently licensed from Jiangsu Hengrui Pharmaceuticals Co. Ltd. (Hengrui) ; Lartesertib (M4076), an ataxia telangiectasia mutated (ATM) kinase inhibitor; and Peposertib, a DNA-PK inhibitor. Recently presented data lay the foundation for combination Phase II studies with tuvusertib. Data from DDRiver 301 Part B presented today at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting show the ability to combine tuvusertib at a predicted efficacious dose with the PARP inhibitor niraparib, as well as encouraging activity in PARP-pretreated ovarian cancer. These findings complement data for the first-in-class tuvusertib and lartesertib combination first presented at the American Association for Cancer Research (AACR) Annual Meeting 2024 in April. The company is exploring tuvusertib across three Phase II studies: Ongoing Phase Ib/II DDRiver NSCLC 322 study ( NCT05882734 ) in combination with cemiplimab in ICI-resistant advanced non-small cell lung cancer (NSCLC) with biomarker stratification; Recently opened Phase II DDRiver EOC 302 study ( NCT06433219 ) of tuvusertib plus lartesertib or niraparib in biomarker-selected PARP-resistant ovarian cancer; and Recently opened Phase II JAVELIN DDRiver Bladder study ( NCT06424717 ), in combination with BAVENCIO ® (avelumab) in ICI-resistant advanced urothelial cancer. For M9466 (also known as HRS-1167), data presented during the 2024 ASCO Annual Meeting from Hengrui’s first-in-human clinical trial show a favorable safety profile and promising efficacy in PARP-naïve, PARP-sensitive tumors, supporting Merck KGaA, Darmstadt, Germany’s plans to further develop this investigational medicine in various combinations. The recently opened DDRiver 501 study ( NCT06421935 ) will evaluate M9466 in combination with tuvusertib in solid tumors with relevant mutations and/or prior PARP inhibitor exposure, with a focus on castration-resistant prostate and ovarian cancers. The clinical development program will build on the company’s expertise in genitourinary and gastrointestinal cancers and aims to expand the list of indications beyond the tumors shown to be sensitive to first-generation PARP inhibitors. Driving Innovation in Antibody-Drug Conjugates The company has developed a proprietary technology platform for the creation of exatecan-based ADCs, with M9140 the first of these to enter clinical development. M9140 utilizes an antibody specific for CEACAM5, which is highly expressed in several tumor types, and an exatecan payload joined by a β-glucuronide linker that is specifically cleaved in tumors, releasing the cytotoxic agent into the cells. In preclinical research, M9140 has shown high bystander activity, as exatecan released in the target tumor cells can kill these cells and also permeate the cell membrane to induce cell death in neighboring cells. First-in-human data from the PROCEADE-CRC-01 clinical trial presented at the 2024 ASCO Annual Meeting show encouraging clinical activity and a manageable and predictable safety profile for M9140 in this population. Following the completion of the ongoing dose-optimization part, the company plans to assess combinations in colorectal cancer with standard-of-care agents with alternative scheduling options. A basket trial planned to launch in early 2025 will further explore M9140 monotherapy in tumors with high CEACAM5 expression, with the potential for further exploration in various combinations. M3554 is the next ADC based on the company’s platform, linking an exatecan payload with an anti-GD2 antibody. This potentially first-in-class ADC will enter its first-in-human study later in 2024. M3554 will be evaluated in patients with solid tumors with high GD2 prevalence such as neuroblastoma, where GD2 has been validated as a target as a naked antibody, as well as soft tissue sarcoma, glioblastoma and osteosarcoma. ADCs are one of several modalities being explored in preclinical research. By maximizing the exatecan platform, delivering next-generation cytotoxins and targeted payloads, expanding into novel antigens, and discovering immune agonist ADCs, the company anticipates expansion in the organic clinical ADC portfolio over the next several years. Guided Approach to External Innovation Recent agreements continue to support the company’s oncology strategy, guided by focus areas across research, development and commercialization. These collaborations align with the company’s goal of driving over 50% of launches in the coming years with external innovation. In addition to the agreement with Hengrui for M9466, the company has executed agreements with Caris Life Sciences to support target discovery that may accelerate discovery and development of first-in-class ADCs; with Inspirna for ompenaclid, a first-in-class compound being investigated in colorectal cancer, complementing the company’s expertise in this tumor type; and with Abbisko Therapeutics Co. Ltd., for pimicotinib, for which the Phase III study in tenosynovial giant cell tumor recently completed enrollment. Advancing the Future of Cancer Care At Merck KGaA, Darmstadt, Germany, we strive every day to improve the futures of people living with cancer. Our research explores the full potential of promising mechanisms in cancer research, focused on synergistic approaches designed to hit cancer at its core. We are determined to maximize the impact of our standard-of-care treatments and to continue pioneering novel medicines. Our vision is to create a world where more cancer patients will become cancer survivors. Learn more at https://www.emdseronooncology.com/home.html . About Merck KGaA, Darmstadt, Germany Merck KGaA, Darmstadt, Germany, a leading science and technology company, operates across life science, healthcare and electronics. Around 63,000 employees work to make a positive difference to millions of people’s lives every day by creating more joyful and sustainable ways to live. From providing products and services that accelerate drug development and manufacturing as well as discovering unique ways to treat the most challenging diseases to enabling the intelligence of devices – the company is everywhere. In 2023, Merck KGaA, Darmstadt, Germany, generated sales of € 21 billion in 65 countries. The company holds the global rights to the name and trademark “Merck” internationally. The only exceptions are the United States and Canada, where the business sectors of Merck KGaA, Darmstadt, Germany, operate as MilliporeSigma in life science, EMD Serono in healthcare and EMD Electronics in electronics. Since its founding in 1668, scientific exploration and responsible entrepreneurship have been key to the company’s technological and scientific advances. To this day, the founding family remains the majority owner of the publicly listed company. All Merck KGaA, Darmstadt, Germany, press releases are distributed by e-mail at the same time they become available on the EMD Group website. In case you are a resident of the USA or Canada, please go to www.emdgroup.com/subscribe to register for your online, change your selection or discontinue this service.

HDP-101 clinical trial in Europe and US continues with adjusted protocol and larger number of study sites in Europe; fifth patient cohort initiated at 100 µg/kg dosing Patient from third cohort continues to be dosed and shows stable disease Divestment of minority stake in Emergence leads to higher other income and additional cash inflows Sales and other income above plan, other financials in line with plan Ladenburg, Germany, 12 October 2023 – Heidelberg Pharma AG (FSE: HPHA) reported today on its course of business as well as on the Group's financial figures for the first nine months of fiscal year 2023 (1 December 2022 – 31 August 2023). Dr. Jan Schmidt-Brand, CEO of Heidelberg Pharma AG, commented: “After a turbulent start to the year at former partner Magenta and their strategic realignment, we were able to clarify issues regarding the ATAC technology platform and continue our study with HDP-101. Based on the experience at Magenta, additional safety measures were included in the study protocol. The good safety profile to date and the increase in the number of study sites have led to an accelerated recruitment of study participants, so that the fourth dose cohort has now been completed. The Safety Review Committee confirmed in early September that HDP-101 is safe and well tolerated at 80 ug/kg. The Committee recommended to escalate the dose for the next cohort. Our financials performed in line with plan, with an exceptional income recorded. As part of the acquisition by an US pharmaceutical company, we sold our minority stake in Emergence Therapeutics. As a result of the transaction, we recorded a cash inflow of USD 7.4 million, which we mainly used for a partial loan repayment of EUR 5 million to the shareholder loan extended by dievini." HDP-101 development program: HDP-101, an Antibody Targeted Amanitin Conjugate directed against the antigen BCMA, is being tested in a Phase I/IIa open-label, multicenter study for the treatment of relapsed or refractory multiple myeloma, a cancer of the bone marrow. The first part of the study is a Phase I dose escalation study to find the safe and optimal dosing of HDP-101 for the Phase IIa portion of the study. The first four patient cohorts and dose levels were completed with no evidence of dose limiting toxicities. Heidelberg Pharma had added additional safety measures to the clinical trial as a precautionary measure following the events at former partner Magenta. In order to accelerate the recruitment of the study, Heidelberg Pharma opened additional study centers, mainly in Poland and Hungary. This enabled rapid patient recruitment and the opening of the fourth cohort as early as June 2023, following adjustment of the study's protocol and receipt of all regulatory approvals. Further information can be found under "Events after the end of the reporting period". In the Phase IIa dose expansion portion, the recommended dose of HDP-101 will be administered to at least 30 patients. The primary objective of this second phase of the study is to provide an initial assessment of the anti-tumor activity of HDP-101 and to further evaluate the safety of the therapy. Developments at partner Magenta: Magenta reported earlier this year that a serious adverse event of grade 5 occurred that deemed to be possibly related to MGTA-117. For safety reasons, Magenta subsequently paused dosing in the clinical trial until further notice. Shortly thereafter, Magenta announced a change in strategy combined with the discontinuation of all current development programs and supply contracts. This resulted in Heidelberg Pharma losing sales revenue in the low single-digit million range for the financial year 2023. In April 2023, Heidelberg Pharma signed a termination agreement with Magenta under which all licensed ATAC rights and some MGTA patents were taken over by Heidelberg Pharma. New preclinical data from ATAC technology platform presented at AACR Annual Meeting 2023: At the American Association for Cancer Research (AACR) 2023 Annual Meeting in April, Heidelberg Pharma presented preclinical results from its ATAC technology. The first poster showed that in preclinical models, subcutaneous dosing of the ATACs used resulted in prolonged half-life and lower maximum serum levels compared with intravenous administration. This resulted in better tolerability while maintaining antitumor efficacy. Based on these preclinical models, subcutaneous administration could be a promising route of administration for ATACs in humans as well. A corresponding patent application for subcutaneous administration of ATACs has been filed by the company. A second poster presented preclinical data on ATACs targeting the protein GCC (Guanylyl Cyclase C). GCC is overexpressed in many gastrointestinal tumors, particularly in colorectal, esophageal, gastric and pancreatic cancers. In preclinical models, ATACs targeting GCC demonstrated high antitumor activity and inhibit tumor growth in preclinical models even at low concentrations after single or multiple dose treatment. These ATACs also showed a favorable safety profile and good tolerability and may represent a promising new therapeutic option against colorectal cancer. The posters are available on the website.[1] New CFO appointed: Walter Miller was appointed to the Executive Board with effect from 1 May 2023 and is responsible for the financial area as Chief Financial Officer. Dr. Jan Schmidt-Brand, who has served in a dual function since 2014, remains Spokesman of the Executive Board/CEO and handed over his duties as CFO to him. Walter Miller holds a degree in business administration and has many years of experience in corporate finance, M&A, strategic controlling as well as accounting and corporate development. He was most recently CFO of Optimapharm Group, headquartered in Zagreb, Croatia, a clinical research organisation (CRO), where he was responsible for finance, M&A and administration. Prior to that, Mr Miller was CFO at Mologen AG, Berlin and CFO at Nuvisan Group, headquartered in Neu-Ulm, Germany, and spent more than ten years in senior financial positions at Santhera Pharmaceuticals, Pratteln, Switzerland. Minority interest in Emergence sold: At the end of June, Heidelberg Pharma sold its minority stake in Emergence Therapeutics AG, Duisburg, (Emergence). The pharmaceutical company Eli Lilly and Company acquired all shares in Emergence. As a result of the transaction, Heidelberg Pharma received USD 7.4 million (EUR 6.8 million), the full amount of which was recognized in profit or loss. The cash was mainly used for a loan repayment of EUR 5 million on the shareholder loan extended by dievini. If defined guarantees are fulfilled and depending on clinical and regulatory milestones further inflows of up to USD 5 million (EUR 4.6 million) are possible. Partner Takeda reaches development milestone: Partner Takeda reached a development milestone in August for starting a GLP (Good Laboratory Practice) toxicology study for an Antibody Targeted Amanitin Conjugate. Upon achievement of the milestone, Heidelberg Pharma received a milestone payment. The payment was already budgeted for in Heidelberg Pharma's financial forecast for financial year 2023. Takeda exclusively licensed the worldwide development and commercialization rights for the use of the ATAC technology with an antibody directed against a defined target and the resulting product candidates in 2022. Expansion of ADC technology into a "toolbox": Heidelberg Pharma is expanding its own ADC technology to include suitable active substances in order to develop the best possible ADCs for further targets and areas of application. This includes an ADC technology for a topoisomerase inhibitor, immunostimulatory agents and other new approaches. The first ADC candidate HDP-201 with a new payload is in the early development phase. Progress with partner Telix: TLX250-CDx, the Zirconium-89 radiolabeled antibody girentuximab (89Zr-DFO-girentuximab), is a diagnostic imaging agent. It was developed at Heidelberg Pharma AG up to a first Phase III trial and out-licensed to the Australian company Telix Pharmaceuticals Limited, Melbourne, Australia, (Telix) in 2017. Accumulation of this antibody in tumor tissue can be visualized by positron emission tomography (PET) scans. This could fundamentally change therapy planning for renal cancer patients and avoid potentially unnecessary surgery. TLX250-CDx was tested in a phase III trial (ZIRCON) with 300 patients for imaging diagnosis of kidney cancer using PET. In November 2022, Telix reported positive data and plans to submit applications for marketing approval as a diagnostic in ccRCC with the FDA and other regulatory authorities worldwide. According to Telix the submission of the application is planned for the fourth quarter of 2023. Potential future benefits could include active surveillance, surgical staging and treatment response monitoring for renal cancer. Telix is conducting further clinical trials to expand the indication. The first patient in the Phase II STARBURST study with TLX250-CDx was dosed in June. STARBURST is a prospective, open-label Phase II "basket" study to investigate CAIX expression in patients across a broad range of solid tumors for potential diagnostic and therapeutic use. Tumor types being studied include breast, cervical, colorectal, gastric, and esophageal cancers.[2] In parallel, Telix is preparing to launch an Expanded Access Program (EAP) in the US to provide patients with pre-approval access to TLX250-CDx. In Europe, the first study sites have been enrolled in the Early Access Program.[3] In addition to the development of the diagnostic antibody, Telix also plans to develop a therapeutic radioimmune conjugate (177Lu-DOTA-girentuximab, TLX250) program based on the lutetium-177-labeled girentuximab antibody. TLX250 will be tested in two Phase II combination studies (STARLITE 1 and 2) with immunotherapies. The first patients will be treated with TLX250 in combination with the anti-PD-1 immunotherapy Opdivo® in the STARLITE 2 trial at Memorial Sloan Kettering Cancer Center in New York. The STARLITE 1 study is testing TLX250 in combination with Cabometyx® and Opdivo® for the treatment of advanced renal cancer. Preparations are currently underway to enroll patients in the trial. In collaboration with Merck KGaA, Telix is also testing TLX250 in an open-label, single-arm, multicenter Phase Ib dose escalation and dose expansion study in combination with the DNA protein kinase inhibitor peposertib, a DNA damage response inhibitor (DDRi). The first patient in this STARSTRUCK study was dosed in July. Progress at partner RedHill: Redhill Biopharma Ltd (RedHill; NASDAQ: RDHL) is developing the out-licensed serine protease inhibitor upamostat (RHB-107 at RedHill) for the treatment of COVID-19, among other diseases. RHB-107 has shown both antiviral and potential tissue-protective activity, with RHB-107 strongly inhibiting SARS-CoV-2 replication in a preclinical human bronchial tissue study. At the end of July, the company announced that RHB-107 was included in the US government-supported “Austere environments Consortium for Enhanced Sepsis Outcomes” (ACESO) multinational PROTECT platform trial for early outpatient treatment of COVID-19, to be conducted in the US, Thailand, Ivory Coast and South Africa. In addition, it was announced that the Phase II study, predominantly funded by the US Government Department of Defense's Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense (JPEO-CBRND), has received FDA clearance to start and is estimated to be completed by end of 2024. Events after the end of the reporting period Phase I/IIa clinical update with HDP-101: After the end of the reporting period, Heidelberg Pharma announced that recruitment of patients for the fifth patient cohort at a dose of 100 µg/kg has started. The evaluation of the patient data of the fourth cohort by the Safety Review Committee (SRC) showed that no dose-limiting toxicities have occurred to date. The first four dose levels have shown to be safe and well tolerated. So far 12 patients have been treated in the trial. Study participant with "stable disease": A study participant who received the first dose (60 µg/kg) of HDP-101 in January 2023 has shown no progression of the disease for nine months (stable disease). The patient receives monotherapy with HDP-101 and was treated so far with twelve doses. With the approval of the fourth cohort by the Safety Review Committee this patient is now being offered a higher dose of 80 µg/kg. The Heidelberg Pharma Group, consisting of Heidelberg Pharma AG and its subsidiary Heidelberg Pharma Research GmbH reports consolidated figures as at the balance sheet date. The reporting period referred to below relates to the period from 1 December 2022 to 31 August 2023 (9M 2023). In the first nine months of the 2023 business year, the Group generated sales revenues and income totaling EUR 13.9 million (previous year: EUR 16.8 million), which is above plan. The sales revenues included in this figure amounted to EUR 6.6 million, a significant decrease compared to the previous year's total of EUR 15.7 million, which was exceptionally high caused by a payment for a license taken by the partner Huadong. Due to the unplanned sale of the Emergence shares, other income increased to EUR 7.3 million and was thus significantly above the previous year's level of EUR 1.1 million. Operating expenses, including depreciation, amounted to EUR 30.0 million in the reporting period (previous year: EUR 27.6 million) and break down as follows: Cost of sales decreased significantly to EUR 3.1 million (previous year: EUR 5.2 million) and correspond to 10% of total costs. Research and development costs of EUR 22.1 million increased compared to the same period last year (EUR 17.7 million) due to the ongoing clinical trial with HDP-101 and the expansion of cost-intensive external manufacturing for the ATAC projects. R&D costs continue to be the largest cost block, accounting for 74% of operating expenses. Administrative costs, which include the costs of holding activities and the stock exchange listing, were lower at EUR 3.6 million compared to the same period last year (EUR 4.1 million), which showed increased legal and consulting costs due to the Huadong transaction. Other expenses for business development, marketing and commercial market supply activities, which mainly include personnel and travel expenses, increased year-on-year to EUR 1.2 million (previous year EUR 0.6 million) and represented 4% of operating expenses. The financial result, which mainly consists of net interest income amounts to EUR 0.5 million (previous year: EUR -0.6 million). The net loss for the first nine months of the financial year increased to EUR 15.8 million compared to the previous year's figure of EUR 13.2 million. The increase is due to lower sales revenues and higher expenses. Earnings per share improved from EUR 0.39 in the previous year to EUR 0.34, considering the significantly higher number of shares. Cash amounted to EUR 50.7 million at the end of the third quarter (30 November 2022: EUR 81.3 million; 31 August 2022: EUR 10.5 million). In the first nine months of the financial year, Heidelberg Pharma had an average cash outflow of EUR 2.3 million per month (previous year: EUR 0.1 million), excluding the loan repayment of EUR 10 million. If the one-time inflows from the sale of the Emergence investment are excluded, the monthly cash consumption without financing activities amounts to EUR 3.0 million. Total assets as of 31 August 2023 amounted to EUR 74.3 million and were thus below the value of the comparative reporting date of 30 November 2022 (EUR 100.6 million). Equity (EUR 51.5 million) also decreased as a result of the loss for the period compared to the end of the 2022 financial year (EUR 66.6 million). For the 2023 financial year, the Executive Board planned revenues and other income totaling between EUR 7.0 million and EUR 10.0 million (2022: EUR 19.9 million). Due to the emergence transaction, other income could be increased significantly; accordingly, the annual planning will be exceeded. Operating expenses will develop in line with the planning between EUR 37.0 million and EUR 41.0 million and thus at a comparable level to the 2022 financial year (EUR 37.0 million). For 2023, an operating result (EBIT) of between EUR -28.5 million and EUR -32.5 million is expected (2022: EUR -17.2 million), which should, however, improve due to the volume of the Emergence transaction. Cash consumption for the business operations of the Heidelberg Pharma Group will also increase in line with the operating business and range between EUR 32.5 million and EUR 36.5 million. This corresponds to an average cash consumption per month of EUR 2.7 million to EUR 3.1 million (2022: EUR 0.7 million). Based on the current planning, the Group is financed until mid-2025. The complete set of figures for the interim financial statements is available at http://www.heidelberg-pharma.com/ "Press & Investors > Announcements and Reports > Financial Reports > Interim announcement of 12 October 2023. A conference call on this interim announcement will not be offered. Key figures for the Heidelberg Pharma Group In EUR thsd. 9M 2023 1 EUR thsd. 9M 2022 1 EUR thsd. Earnings Sales revenue 6,635 15,695 Other income 7,259 1,149 Operating expenses (29,985) (27,611) of which research and development costs (22,065) (17,676) Operating result (16,091) (10,767) Earnings before tax (15,561) (11,347) Net loss for the period (15,838) (13,224) Basic earnings per share in EUR (0.34) (0.39) Balance sheet as of the end of the period Total assets 74,328 29,805 Cash 50,675 10,523 Equity 51,488 (6,073) Equity ratio2 in % 69.3 (20.4) Cash flow statement Cash flow from operating activities (26,494) (1,201) Cash flow from investing activities 5,871 (282) Cash flow from financing activities (10,024) 4,932 Employees (number) Employees as of the end of the period3 111 104 Full-time equivalents as of the end of the period3 101 97 1 The reporting period begins on 1 December and ends on 31 August. 2 Equity / total assets 3 Including members of the Executive Management Board Rounding of exact figures may result in differences. [1] https://heidelberg-pharma.com/de/forschung-entwicklung/wissenschaftliche-poster [2] https://telixpharma.com/news-views/first-patient-dosed-in-phase-ii-starburst-study-of-tlx250-cdx-exploring-indication-expansion/ [3] https://telixpharma.com/wp-content/uploads/2023/08/20230823-H1-2023-Results-Deck-vFINAL.pdf