Initial COBRA results: Clarity’s SAR-bisPSMA is safe and highly effective in detecting tumours in prostate cancer patients. Phase 3 planning underway.

On February 14, 2024 Clarity Pharmaceuticals (ASX: CU6) ("Clarity", "the Company"), a clinical stage radiopharmaceutical company with a mission to develop next-generation products that improve treatment outcomes for children and adults with cancer, reported positive results from its diagnostic 64Cu-SAR-bisPSMA trial, COBRA (NCT05249127) (Press release, Clarity Pharmaceuticals, FEB 15, 2024, View Source [SID1234640087]).

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Dr Neal Shore MD, FACS Lead Principal Investigator in the COBRA trial, Medical Director of Carolina Urologic Research Centre, commented, "We are very enthusiastic regarding the data from the early phase COBRA trial as 64Cu-SAR-bisPSMA was confirmed to be safe and effective in detecting PC lesions in patients with BCR who came into the study with negative or equivocal scans using SOC imaging. The trial demonstrates a clinical advantage of same-day and next-day imaging in detecting additional lesions as well as for potentially detecting low prostate-specific membrane antigen (PSMA) expressing or smaller lesions. When detecting recurrence of PC, it is important to visualise small lesions, as reliable imaging of low volume tumor burden can affect treatment decision making. In the COBRA trial, we saw that 64Cu-SAR-bisPSMA positron emission tomography (PET) informed potential changes in the treatment plan in approximately half of the patients. This makes a difference for patients who may then have insight into the location of their disease recurrence and thereby proceed to treatment of their cancer. We look forward to additional data readouts from the trial and presenting the results at future international medical conferences. If the data from the COBRA trial can be substantiated in a registrational Phase 3 study, and if approved by the United States Food and Drug Administration (US FDA), this PET PSMA modality will impact care for patients with PC."

Clarity’s Executive Chairperson, Dr Alan Taylor, commented, "We are extremely excited with the initial findings from the COBRA trial as it further substantiates the many benefits of copper-64 (64Cu) and our optimised bisPSMA product in the diagnosis of PC. Combined with our clinical and pre-clinical trial data to date, this 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. We have also seen the performance of 64Cu-SAR-bisPSMA in the real-world setting through our compassionate use program, which demonstrated the ability of 64Cu-SAR-bisPSMA to detect lesions in patients with BCR and a negative or equivocal SOC imaging (including 18F-DCFPyL and 68Ga-PSMA-11). These cases also showed a higher number of lesions and lesions with higher maximum standardised uptake values (SUVmax) on next-day imaging. Therefore, we were already aware of the benefits of later-timepoint imaging, but the high number of lesions detected on same-day imaging that were negative or equivocal on SOC imaging (e.g. bone scan, CT or PSMA PET), and the almost doubling of the number of lesions with next-day imaging, is remarkable. The COBRA study now validates previous observations in a larger group of patients under trial conditions.

"Most importantly, the high rate of detection of PC in up to 80% of patients that were negative or equivocal on SOC imaging further brings to light the low sensitivity issues of current SOC imaging. We adhere to the highest standards and methods of clinical development as we pride ourselves on high quality science at Clarity. As such, the COBRA trial design was built to reflect the gold standard in clinical research and took a very conservative approach. Given we identified a large number of lesions with 64Cu-SAR-bisPSMA that were not visible with SOC scans, a number that was not anticipated when the protocol was prepared, it was not feasible nor ethical to verify all of these lesions with biopsy when caring for the patient. Therefore, our investigators were not able to confirm the true positivity of a very large number of lesions. Furthermore, among the patients that were excluded from the assessment of the efficacy endpoints because they had initiated systemic therapy while on study (which is not allowed according to the trial protocol), the majority had positive 64Cu-SAR-bisPSMA scans. As this was a first-in-human study in BCR PC patients, we have learnt significantly more about our product relative to current SOC imaging and will consider this potentially much higher level of detection and sensitivity of 64Cu-SAR-bisPSMA when structuring the Phase 3 trial design in this patient group.

"As can be seen from this study, and the clinicians reporting that they would change their treatment plan in response to this data, the increase in sensitivity with bisPSMA is incredibly important when assessing the return of PC in BCR patients. It is equally important for patients at initial staging of their disease, when they are considering their first course of definitive therapy, in order to understand whether their PC has metastasised or not from the primary lesion prior to prostatectomy. This is an immediate unmet medical need, which we are addressing with our Phase 3 CLARIFY trial2. Current SOC imaging fails to do this for a large percentage of men who eventually experience BCR of their PC. As such, there is an immediate opportunity for bisPSMA to address the entire market of PSMA imaging as we move closer to our ultimate goal of improving treatment outcomes of people with cancer.

"In addition to the clinical benefits, 64Cu-SAR-bisPSMA has a number of logistical and manufacturing advantages in comparison to other currently used PSMA agents. The ready-to-use product has been shipped to the trial sites in the US from a central manufacturing facility on-demand and on time, providing flexibility and reliability to the patients and their treating staff. This facilitates expanding the radiopharmaceutical field into the large oncology market, minimising logistical hindrances associated with the current generation of radio-diagnostics, and helping to focus on the needs of patients and their clinicians. Furthermore, the longer shelf-life of 64Cu-based products, coupled with the advantages of the SAR Technology, could offer access to PSMA PET for PC patients in underserved and broad geographical areas, which is one of the limitations of the approved PSMA agents due to their short half-life."

COBRA trial design & quality

The US-based COBRA study (Copper-64 SAR-bisPSMA in Biochemically Recurrent prostAte cancer) was a first-in-human trial of 64Cu-SAR-bisPSMA in patients with BCR of PC. It was a multi-centre, single-arm, non-randomised, Phase 1/2 diagnostic imaging study of 64Cu-labelled SAR-bisPSMA (64Cu-SAR-bisPSMA) administered to participants with BCR of PC following definitive therapy. 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 on Day 0 and Day 1 (1-4h and 24±6h post-dose, respectively), which were interpreted by three blinded central readers. To determine the efficacy of 64Cu-SAR-bisPSMA imaging, the Day 0 and Day 1 PET/CT results of the central readers were assessed against a composite reference standard that was determined by an independent, blinded, central expert panel. The reference standard consisted of histopathology, follow-up SOC imaging and/or confirmed prostate specific antigen (PSA) response to focal therapy.

The design of the COBRA study followed advice from regulators to achieve the highest standards in clinical research in the BCR setting, in contrast to trials with other PSMA agents. Based on this guidance, the expert panel, who determined the reference standard, was blinded to the results of the 64Cu-SAR-bisPSMA scans and distinct from the central readers assessing the 64Cu-SAR-bisPSMA scans. This approach removed any potential biases in the assessment of the reference standard, which was not the case with previously approved PSMA tracers, where the reference standard was determined by readers having access to the PSMA scans investigated in the study, aiming to anatomically correlate the findings across the scans. Furthermore, a conservative approach was taken for the analysis of both co-primary endpoints. If a lesion identified on the 64Cu-SAR-bisPSMA scan was not biopsied and it was also not present on follow-up SOC imaging (a suboptimal reference standard with known low sensitivity), it was considered as false positive in the analysis by default. The higher standards in study design for COBRA compared to that used for other PSMA agents’ trials, along with various benefits intrinsic to 64Cu-SAR-bisPSMA not seen with currently approved products (e.g. higher uptake/retention and delayed imaging), make comparisons among other PSMA tracers and 64Cu-SAR-bisPSMA not viable. The methodology used in the COBRA trial underscores the ability of 64Cu-SAR-bisPSMA to correctly identify PC recurrence even when a higher level of rigour in study design is applied, making the transition of data to real world scenarios more probable.

Initial results from the COBRA trial

This study was the first-in-human trial of 64Cu-SAR-bisPSMA in patients with BCR of PC. Fifty-two patients with negative or equivocal SOC scans were enrolled and imaged, of whom 42 were included in the calculation of the efficacy endpoints. The median PSA at study entry was 0.9 ng/mL (range 0.25 – 17.60). This PSA range was considerably lower than in the registrational studies for the approved PSMA PET agents in BCR. Among the patients who did not complete the study as they proceeded to systemic therapy (which was not allowed according to the trial protocol), the majority had lesions identified on the 64Cu-SAR-bisPSMA scan, but they did not contribute towards the assessment of the efficacy endpoints. Results from COBRA showed for the first time that 64Cu-SAR-bisPSMA is safe and effective in detecting lesions in patients with BCR of PC who were negative or equivocal on SOC imaging (e.g. bone scan, CT or PET with approved PSMA imaging agents) at screening.

Next-day imaging – a key advantage

The possibility of performing next-day imaging is a feature not available to currently approved PSMA-targeted PET products and unique to 64Cu-based SAR diagnostics due to the optimal half-life of 64Cu and the ability of the SAR Technology to prevent leakage of copper isotopes from the radiopharmaceutical in-vivo. The COBRA trial confirmed the benefits of delayed imaging in this patient group as more lesions and more patients with a positive scan were identified on next-day imaging.

64Cu-SAR-bisPSMA was able to identify approximately 91% more lesions (median increase) on next-day imaging compared to same-day imaging (ranges across the readers for the total number of lesions: 53–80 on Day 0 vs. 82–153 on Day 1). The number of lesions in the pelvic LN region more than doubled on next-day imaging compared to same-day imaging (median increase of 108.3% across all readers comparing Day 0 vs. Day 1) (Figures 4 and 5). The ranges of CDR and patient-level detection rate (DR, defined as the proportion of participants with a positive 64Cu-SAR-bisPSMA PET/CT scan out of all scanned participants) were both higher on Day 1 compared to Day 0. The DR range on Day 0 was 44–58% (95% CI 30–71.8), increasing on Day 1 to 58–80% (95% CI 43.2–90).

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 TCT 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 worldwide3. 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.