Flotufolastat F-18

− 177Lutetium-labeled radiohybrid Prostate-Specific Membrane Antigen (177Lu-rhPSMA-10.1) is in development as a highly optimized, next generation therapeutic radiopharmaceutical – − Combination of MEK inhibitor cobimetinib with 177Lu-rhPSMA-10.1 radioligand therapy showed enhanced therapeutic effect versus single agents in preclinical models – − Research presented at AACR Annual Meeting 2024 complements Company’s ongoing Phase 1/2 clinical trial of 177Lu-rhPSMA-10.1 in men with metastatic castrate resistant prostate cancer – MONROE TOWNSHIP, N.J. & OXFORD, England--(BUSINESS WIRE)-- Blue Earth Therapeutics, a Bracco company and emerging leader in the development of innovative next generation therapeutic radiopharmaceuticals, today announced results from a series of preclinical analyses designed to identify synergistic combinations of known anticancer drugs with 177Lu-rhPSMA-10.1 radioligand therapy, and from a preclinical efficacy analysis of the lead novel drug combination for the treatment of prostate cancer. Results from a systematic in vitro screen identified MEK inhibitor cobimetinib as a lead candidate with potential for synergistic combination with 177Lu-rhPSMA-10.1, and the preclinical efficacy analysis showed enhanced therapeutic effect of this drug combination when compared to the untreated control and to the single agents alone. The data were presented in a poster presentation at the American Association for Cancer Research (AACR) Annual Meeting 2024 in San Diego, Calif. 177Lu-rhPSMA-10.1, an investigational radiohybrid (rh) Prostate-Specific Membrane Antigen-targeted therapeutic radiopharmaceutical, is the lead candidate in Blue Earth Therapeutics’ oncology development program of next generation therapeutic radiopharmaceuticals. “Radioligand therapy targeting PSMA has been shown to be an effective therapy in men with prostate cancer, and we are pleased to share these promising preclinical results from our study of 177Lu-rhPSMA-10.1 drug combinations with the scientific community at the prestigious AACR Annual Meeting 2024,” said David E. Gauden, D.Phil., Chief Executive Officer of Blue Earth Therapeutics. “Combination approaches are of increasing interest among the medical community, as we know tumors are heterogeneous and some prostate cancer cells do not express PSMA. Importantly, these combinations need to avoid overlapping toxicity. Results from this preclinical study presented at AACR demonstrated a synergistic therapeutic effect between 177Lu-rhPSMA-10.1 and an MEK inhibitor. This may be due to inhibition of the MEK-MAPK pathway during DNA damage response, resulting in radiosensitization of cancer cells to 177Lu-rhPSMA-10.1. Our ongoing Phase 1/2 clinical trial (NCT05413850) is evaluating 177Lu-rhPSMA-10.1 radioligand therapy as a monotherapy in treating men with metastatic castrate resistant prostate cancer, and we may look to evaluate this combination in the clinic in the future.” About the study More than 150 FDA-approved anticancer drugs were screened in a clonogenic survival assay of 22Rv1 cells using the test drug alone, at a range of concentrations <20 µM to determine the IC50. The results were then compared to incubations of the drug plus 15 MBq/mL 177Lu-rhPSMA-10.1 (2-hour incubation) after 10 days. Five lead candidates were then selected for a focused screen where the impact of 177Lu-rhPSMA-10.1 (0–25 MBq/mL) on the drug IC50 was determined. A synergy score was determined using the zero interaction potency (ZIP) reference model and the multi-dimensional synergy of combinations (MuSyc) platform. Therapeutic efficacy of the lead combination, 177Lu-rhPSMA-10.1 (single 30 MBq iv dose) plus cobimetinib (0.25 mg orally per day for 21 days), was then evaluated in 22Rv1 prostate tumor xenograft models and compared to the single agents alone (n = 8 per group, plus untreated controls). Tumor volume was measured 2 times per week for 69 days. Two-way ANOVA and Tukey’s multiple comparisons test (data analyzed until n = 3 remained per group) and Kaplan-Meier Log-rank survival analyses were performed. Results The in vitro screen identified the MEK inhibitor cobimetinib as a lead candidate for synergistic combination with 177Lu-rhPSMA-10.1 across a wide concentration range, with a ZIP synergy score of 13.25% (95% CI ± 2.17) and promising results on MuSyc analysis. The 177Lu-rhPSMA-10.1 plus cobimetinib MEK inhibitor combination significantly suppressed tumor growth in vivo versus untreated controls (from day 13–30; p<0.01) and 177Lu-rhPSMA-10.1 alone (from day 17–30; p<0.001). The median survival in the combination group (49 days) was significantly longer versus the untreated group (23 days; p=0.001) and the group treated with 177Lu-rhPSMA-10.1 alone (36 days; p=0.002). The results were discussed in a poster presentation, “Evaluation of a synergistic drug combination with 177Lu-rhPSMA-10.1 for prostate cancer: Results of an in vitro screen and in vivo proof of concept study,” by Caroline Foxton, Ph.D., Blue Earth Group, Oxford, UK, at the AACR Annual Meeting 2024 on April 7, 2024. The abstract is available in the online program here . About Radiohybrid Prostate-Specific Membrane Antigen (rhPSMA) rhPSMA compounds are referred to as radiohybrid (“rh”), as each molecule possesses three distinct domains. The first consists of a Prostate-Specific Membrane Antigen-targeted receptor ligand which attaches to and is internalized by prostate cancer cells. It is attached to two labelling moieties which may be radiolabeled with diagnostic isotopes such as 18F or 68Ga for PET imaging, or with therapeutic isotopes such as 177Lu or 225Ac for radioligand therapy – enabling the potential for a true theranostic technology. They may play an important role in patient management in the future, and offer the potential for precision medicine for men with prostate cancer. Radiohybrid technology and rhPSMA originated from the Technical University of Munich, Germany. Blue Earth Diagnostics acquired exclusive, worldwide rights to rhPSMA diagnostic imaging technology from Scintomics GmbH in 2018, and therapeutic rights in 2020, and has sublicensed the therapeutic application to its sister company Blue Earth Therapeutics. Blue Earth Therapeutics and Blue Earth Diagnostics work closely on the development of 177Lu-rhPSMA-10.1. Currently, Blue Earth Therapeutics’ rhPSMA compounds have not received regulatory approval. About Blue Earth Therapeutics Blue Earth Therapeutics, one of the Bracco family of companies, is a clinical stage company dedicated to advancing next generation targeted radiotherapeutics to treat patients who have cancer. With proven management expertise across the spectrum of radiopharmaceutical and oncology drug development, as well as biotechnology start-up experience, the Company aims to innovate and improve upon current technologies and rapidly advance new targeted therapies for serious diseases. Blue Earth Therapeutics has an emerging pipeline, initially focused on prostate cancer, and with plans to expand into additional disease areas in oncology. Blue Earth Therapeutics is an indirect subsidiary of Bracco Imaging S.p.A, and based in Oxford, UK. For more information, please visit: . About Bracco Imaging Bracco Imaging S.p.A., part of the Bracco Group, is a world-leading diagnostic imaging provider. Headquartered in Milan, Italy, Bracco Imaging develops, manufactures and markets diagnostic imaging agents and solutions. It offers a product and solution portfolio for all key diagnostic imaging modalities: X-ray imaging (including Computed Tomography-CT, Interventional Radiology, and Cardiac Catheterization), Magnetic Resonance Imaging (MRI), Contrast Enhanced Ultrasound (CEUS), and Nuclear Medicine through radioactive tracers and novel PET imaging agents to inform clinical management and guide care for cancer patients in areas of unmet medical need. Our continually evolving portfolio is completed by a range of medical devices, advanced administration systems and dose-management software. In 2019, Bracco Imaging enriched its product portfolio by expanding the range of oncology nuclear imaging solutions in the urology segment and other specialties with the acquisition of Blue Earth Diagnostics. In 2021, Bracco Imaging established Blue Earth Therapeutics as a separate, cutting-edge biotechnology vehicle to develop radiopharmaceutical therapies. Visit: . This press release is for U.S. audiences only

Highlights Clarity recently reported that in its diagnostic Phase 1/2 trial, COBRA, 64Cu-SAR-bisPSMA was found to be safe and highly effective in detecting prostate cancer (PC) lesions in patients with biochemical recurrence (BCR). In trial participants where standard of care (SOC) imaging was unable to detect any lesions, up to approximately 60% had lesions identified by same-day imaging with 64Cu-SAR-bisPSMA and up to 80% on next-day imaging, with high specificity on both days. The number of lesions identified by 64Cu-SAR-bisPSMA almost doubled from same-day (up to 80) to next-day imaging (up to 153). One of the reasons for the higher detection of lesions on next-day imaging was due to the ability of 64Cu-SAR-bisPSMA to detect much smaller lesions compared to other prostate specific membrane antigen (PSMA) agents, including a lesion with a diameter of less than 2 mm. For all lesions, regardless of their size, 64Cu-SAR-bisPSMA lesion uptake increased by more than 80% and lesion contrast increased almost 5 times when comparing same-day to next-day imaging. A key observation was the high uptake and contrast observed in lesions of less than 5 mm. More lesions and smaller lesions detected on next-day imaging could have a substantial impact on how patients are treated. The detection of lesions that are less than 5 mm in size by current PSMA positron emission tomography (PET) imaging agents (including PYLARIFY® and the generic product 68Ga-PSMA-11) is challenging, which possibly contributes to the low sensitivity of these agents. The information gathered from the Phase 1/2 COBRA trial, including the size of lesions that are detected by 64Cu-SAR-bisPSMA, will be used to inform the design of the registrational Phase 3 trial in patients with BCR of PC. SYDNEY, March 8, 2024 /PRNewswire/ -- Clarity Pharmaceuticals (ASX: CU6) ("Clarity"), a clinical-stage radiopharmaceutical company with a mission to develop next-generation products that improve treatment outcomes for children and adults with cancer, is pleased to share additional data from its diagnostic 64Cu-SAR-bisPSMA trial, COBRA (NCT05249127)[1]. COBRA was a multi-centre, single-arm, non-randomised, Phase 1/2 diagnostic imaging study of 64Cu-SAR-bisPSMA administered to participants with BCR of PC following definitive therapy and who had a negative or equivocal SOC scan at screening. The primary objectives of the trial were to investigate the safety and tolerability of 64Cu-SAR-bisPSMA as well as its ability to correctly detect recurrence of PC. Patients underwent PET/computed tomography (CT) scans with 64Cu-SAR-bisPSMA on Day 0 and Day 1 (1-4h and 24±6h post-dose, respectively), which were interpreted by three blinded central readers. Following the recent announcement of positive results from the COBRA trial[2], which began showcasing the many benefits of 64Cu-SAR-bisPSMA, further analysis of the data reveals additional advantages of this optimised PSMA product. 64Cu-SAR-bisPSMA was able to detect much smaller lesions than anticipated, including a lesion with a diameter of less than 2 mm. This compares favourably against the current SOC PSMA PET imaging agents, including PYLARIFY® and the generic product 68Ga-PSMA-11, with which the detection of lesions smaller than 5 mm is challenging. Sensitivity is a known challenge for the existing PSMA PET agents, particularly for lesions <5 mm[3]-[6]. This suggests that lesions are missed by current SOC imaging, which can have significant implications on accurate staging and subsequent treatment decisions. For those undergoing initial staging of their disease, missing lesions may lead to unnecessary surgery resulting in long-lasting side effects (e.g. impotence and/or incontinence following the removal of the prostate)[7]. In patients with BCR of PC, it is also crucial to identify their cancer early to avoid disease progression and the side effects of systemic treatments that accompany such therapies[8]. Clarity's Executive Chairperson, Dr Alan Taylor, commented, "The cornerstone of better therapy is better diagnosis, and we are incredibly excited about the substantial degree of improvement in detection of lesions with our bisPSMA product compared to SOC imaging. This difference is similar to comparing the old Hubble telescope to the new James Webb telescope, allowing us to visualise with much greater clarity, and to effectively change the paradigm of treatment to considerably improve the outcomes for patients with PC. Innovative products like 64Cu-SAR-bisPSMA may prevent many millions of men from receiving inappropriate treatments and suffering substantial debilitating side effects from surgery or other therapies. "When combining the optimised dual PSMA targeting agent with the ideal half-life of copper-64 (64Cu), we continue to observe higher uptake and retention of 64Cu-SAR-bisPSMA in PC lesions. We believe the ability of 64Cu-SAR-bisPSMA to detect such small lesions is due to the higher uptake and retention of the product over time with high contrast (parameters measured by mean standardised uptake value [SUVmean], maximum standardised uptake value [SUVmax] and tumour-to-background ratio [TBR]). Small lesions become more readily detectable if the uptake of the product in the lesion is high and the background noise on the image is low. This effect enhances the contrast, making the lesion easier to detect, providing clinicians with valuable information on how to best treat their patients." The size of the PC lesions detected by 64Cu-SAR-bisPSMA was recorded on the same-day (Day 0) and next-day (Day 1) imaging. Lesions with less than 5 mm in size were identified across readers among 14% (7/50) of patients (Figures 1 and 2). These lesions were located in the bone, pelvic and extra-pelvic lymph node regions. The smallest lesion (pelvic lymph node) identified in the study was 2.6 x 1.9 mm (Figure 3). The SUVmax, SUVmean and TBR were assessed in up to 25 lesions per patient on the same-day and next-day 64Cu-SAR-bisPSMA PET imaging. Mean SUVmean and SUVmax increased more than 80% (82% and 87% average increase across all readers, respectively) and TBR increased almost 5 times (4.8x average increase across all readers) comparing same-day with next-day imaging (ranges among readers, Day 0 and Day 1, respectively: SUVmean 6.6-9.9 and 14.7-15.8; SUVmax 13.9-14.0 and 22.2-33.4; TBR 23.2-25.4 and 118.1-181.7) (Graphs 1 and 2). Lesions of less than 5 mm in size had SUVmean, SUVmax and TBR value of 16.3, 16.8 and 90.1, respectively (mean values across all readers). The ability of 64Cu-SAR-bisPSMA to detect lesions less than 5 mm is a result of a few factors unique to the product. 64Cu has a longer half-life (12.7 h) than the isotopes used in currently approved PSMA PET agents, such as gallium-68 (68Ga) and fluorine-18 (18F) (<2 h), enabling next-day imaging, which is impossible with 18F- and 68Ga-based agents. Clarity's SAR Technology holds isotopes of copper securely inside a cage, preventing their leakage when administered to patients. Pre-clinical and clinical evidence has demonstrated that the optimised dual targeting molecule connected to the cage, bisPSMA, ensures increased targeting and retention of the product in PC tumours compared to its single targeting molecule counterpart and approved PSMA agents[9],[10]. Results from Clarity's Phase I PROPELLER trial substantiated this hypothesis as 64Cu-SAR-bisPSMA showed detection of additional lesions and 2-3 times greater uptake within the same PC lesions compared to the generic SOC imaging agent, 68Ga-PSMA-11. Furthermore, the initial positive results from the COBRA study, announced on the 15th of February 2024[2], showed that delayed imaging with 64Cu-SAR-bisPSMA is able to detect PC lesions in up to 80% of patients with BCR of PC, who demonstrated negative or equivocal SOC imaging at screening. It also showed that the number of lesions detected by 64Cu-SAR-bisPSMA almost doubled on delayed imaging compared to same-day imaging. "The COBRA trial was designed to showcase the true benefits of bisPSMA compared to current SOC imaging, implementing a high standard of study design to validate our findings and utilise an unbiased view of assessment. The results are nothing short of extraordinary, and as we continue to adhere to best practice in clinical development, our science at Clarity is clearly differentiating us from our competitors. Combined with our clinical and pre-clinical evidence to date, this data further validates SAR-bisPSMA as a potential best-in-class PSMA agent for the diagnosis (with 64Cu) and subsequent treatment (with copper-67 [67Cu]) of PC. The benefits of 64Cu-SAR-bisPSMA are now even more evident, given the highest scientific rigour applied to the COBRA study design, and confirmed by clinicians who reported that they would change their treatment plan in response to the 64Cu-SAR-bisPSMA scan results in approximately half of their trial patients. Our COBRA trial was an exploratory first-in-human Phase 1/2 trial in BCR to generate information to allow us to meticulously design a Phase 3 registrational trial. Now that we know what we are looking for, including lesions in the 2 mm range, we can structure a Phase 3 trial in the BCR of PC indication to clearly differentiate ourselves from the first-generation PSMA agents as we head towards our ultimate goal of improving treatment outcomes for people with cancer," Dr Taylor said. About SAR-bisPSMA SAR-bisPSMA derives its name from the word "bis", which reflects a novel approach of connecting two PSMA-targeting agents to Clarity's proprietary sarcophagine (SAR) Technology that securely holds copper isotopes inside a cage-like structure, called a chelator. Unlike other commercially available chelators, the SAR Technology prevents copper leakage into the body. SAR-bisPSMA is a Targeted Copper Theranostic that can be used with isotopes of copper-64 (Cu-64 or 64Cu) for imaging and copper-67 (Cu-67 or 67Cu) for therapy. 64Cu-SAR-bisPSMA and 67Cu-SAR-bisPSMA are unregistered products. The data outlined in this announcement has not been assessed by health authorities such as the US Food and Drug Administration (FDA). A clinical development program is currently underway to assess the efficacy and safety of these products. There is no guarantee that these products will become commercially available. About Prostate Cancer Prostate cancer is the second most common cancer diagnosed in men globally and the fifth leading cause of cancer death worldwide[11]. The American Cancer Institute estimates in 2024 there will be 299,310 new cases of prostate cancer in the US and around 35,250 deaths from the disease[12]. About Clarity Pharmaceuticals Clarity is a clinical stage radiopharmaceutical company focused on the treatment of serious disease. The Company is a leader in innovative radiopharmaceuticals, developing Targeted Copper Theranostics based on its SAR Technology Platform for the treatment of cancer in children and adults. References Clinicaltrials.gov Identifier: NCT05249127. clinicaltrials.gov/ct2/show/NCT05249127 Initial COBRA results announcement. 15 Feb 2024. claritypharmaceuticals.com/news/cobra_results/ Pienta et al. A Phase 2/3 Prospective Multicenter Study of the Diagnostic Accuracy of Prostate Specific Membrane Antigen PET/CT with 18F-DCFPyL in Prostate Cancer Patients (OSPREY). Journal of Urology, 2021. Hope et al. Diagnostic Accuracy of 68Ga-PSMA-11 PET for Pelvic Nodal Metastasis Detection Prior to Radical Prostatectomy and Pelvic Lymph Node Dissection. JAMA Oncol, 2021. Petersen et al. 68Ga-PSMA PET/CT compared with MRI/CT and diffusion-weighted MRI for primary lymph node staging prior to definitive radiotherapy in prostate cancer: a prospective diagnostic test accuracy study. World Journal of Urology, 2019. Surasi et al. Diagnostic Performance and Safety of Positron Emission Tomography with 18F-rhPSMA-7.3 in Patients with Newly Diagnosed Unfavourable Intermediate- to Very-high-risk Prostate Cancer: Results from a Phase 3, Prospective, Multicentre Study (LIGHTHOUSE). European Urology, 2023. Stanford et al. Urinary and Sexual Function After Radical Prostatectomy for Clinically Localized Prostate Cancer. The Prostate Cancer Outcomes Study. JAMA, 2000. Shore et al. Biochemical recurrence in patients with prostate cancer after primary definitive therapy: treatment based on risk stratification. Prostate Cancer and Prostatic Diseases, 2023. Zia et al. A Bivalent Inhibitor of Prostate Specific Membrane Antigen Radiolabeled with Copper-64 with High Tumor Uptake and Retention. Angew Chem Int Ed Engl. 2019. Lengyelova et al. 64Cu-SAR-bisPSMA (PROPELLER) positron emission tomography (PET) imaging in patients with confirmed prostate cancer. ASCO, 2023. Global Cancer Statistics 2020. GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. acsjournals.onlinelibrary.wiley.com/doi/10.3322/caac.21660 American Cancer Society Key Statistics for Prostate Cancer. cancer.org/cancer/prostate-cancer/about/key-statistics.html This announcement has been authorised for release by the Executive Chairperson. View original content to download multimedia: SOURCE Clarity Pharmaceuticals Company Codes: Australia:CU6