upamostat (formerly MESUPRON®) – Oral uPA Inhibitor
upamostat is an oral uPA/serine protease inhibitor, which has been developed by Heidelberg Pharma until Phase II. It is designed to block the activity of tumor-relevant serine proteases such as uPA, plasmin and thrombin to prevent tumor growth and metastasis.
In 2014, the development and commercialization rights for upamostat were out-licensed to Link Health Co., Guangzhou, China (Link Health) for China, Hong Kong, Taiwan and Macao, and RedHill Biopharma Ltd., Tel Aviv, Israel (RedHill) for the rest of the world.
Heidelberg Pharma’s partner RedHill is also developing RHB-107 for treating COVID-19. RHB-107 has demonstrated both antiviral and potential tissue-protective effects, with RHB-107 strongly inhibiting SARS-CoV-2 replication in a preclinical human bronchial tissue study. The candidate targets human serine proteases that are involved the virus’s entry into target cells. Because RHB-107 targets human cell factors and not the virus itself, RHB-107 is expected to be effective against emerging virus variants. RedHill started a Phase II/III trial with non-hospitalized patients in the USA in early 2021, dosing the first patient in February 2021. RedHill announced receipt in May 2021 of a Notice of Allowance from the US Patent and Trademark Office (USPTO) covering RHB-107 as a method for the treatment of COVID-19. Recruitment for Part A of the study has been completed and initial positive data from it were announced in March 2022.
RHB-107 is also planned to be tested in combination with RedHill’s other development candidate opaganib for the treatment of advanced cholangiocarcinoma, subject to approval from the FDA. RBased on preclinical results showing strong anti-tumor activity of the combination of RHB-107 with opaganib, RedHill plans to enroll a third cohort in its ongoing Phase IIa study in cholangiocarcinoma to evaluate this combination therapy. In addition, RedHill announced a U.S. patent grant in 2020 for the combination of RHB-107 and opaganib for the oral treatment of solid tumors.
girentuximab (TLX250-CDx) – Diagnostic Antibody
TLX250-CDx is a radiolabeled form of the antibody Girentuximab, which binds to the tumor-specifc antigen CAIX on clear cell renal cell carcinoma. Accumulation of this antibody in tumor tissue can be visualized by positron emission tomography scans (PET). This could fundamentally change therapy planning for renal cancer patients and avoid potentially unnecessary surgery. The diagnostic agent may also prove suitable for monitoring response to treatment, detecting metastases and diagnosing other kinds of tumors.
Under the name REDECTANE®, the project was developed up to an initial Phase III trial (REDECT) at Heidelberg Pharma AG and licensed in 2017 to the Australian firm Telix Pharmaceuticals Limited, Melbourne, Australia, (Telix). The license agreement also covers the development of a therapeutic radioimmunoconjugate program. Last year Telix developed a modernized production process for the manufacture of the antibody Girentuximab.
The TLX250-CDx (89Zr-DFO-girentuximab) is radioactively labeled with zirconium-89 and has been tested in a Phase III study (ZIRCON) for imaging diagnostics of renal cancer using PET since August 2019. The study is being carried out as a global multicenter Phase III trial at sites in Europe, Turkey, Australia, Canada and the USA, enrolling around 250 renal cancer patients who are to undergo kidney surgery. It will determine the sensitivity and specificity of TLX250-CDx PET imaging to detect clear cell renal cell cancer (ccRCC) in comparison with histology as standard of truth determined from surgical resection specimens. The target enrollment of 252 patients was reached in March 2022. Recruitment into the study will continue for up to three additional months, with a data read out expected in the second half of 2022. The project has been classified as a “breakthrough” by the FDA and therefore has the chance of an accelerated submission in the so-called rolling procedure
Under Telix’s guidance a number of investigator-led studies of TLX250-CDx have been initiated, supporting the goal of indication expansion. In mid-2021, a Phase I study (ZiP-UP) of TLX250-CDx was launched to evaluate the feasibility of using it in detecting urothelial carcinoma or bladder cancer. ZiP-UP is the first in a series of studies that will harness TLX250-CDx to evaluate CAIX expression in cancers other than renal cancer. In October, Telix announced that a first patient had been dosed in a Phase II study of TLX250-CDx in patients with triple-negative breast cancer (OPALESCENCE); further collaborative studies are in the pipeline for ovarian, colorectal, head and neck, lung and pancreatic cancers.
girentuximab (TLX250) – Therapeutic Antibody
Telix is also planning the further development of a therapeutic radioimmunoconjugate (177Lu-DOTA-girentuximab, TLX250) program based on the lutetium-177-labeled girentuximab antibody.
The IND application to conduct a Phase II (STARLITE 2) study was accepted by the FDA in September 2021. TLX250 is to be tested in the STARLITE 2 study as therapy for an estimated 29 patients with advanced clear cell renal cell carcinoma (ccRCC). The study will evaluate TLX250 in combination with the immunotherapy Opdivo® (nivolumab). The efficacy of combining immunotherapy with TLX250, as assessed by the number of tumors responding to the Telix therapy versus the current standard of care, will be tested. The first patient has been dosed in May 2022.