GLP & Non-GLP: What's the Difference?GLP & Non-GLP: What's the Difference? 2021: Theralase launches Anti-Cancer Therapy Research Centre – Theralase Technologies Michael Jewett MD, FRCSC, FACS, CM, Departments of Surgery (Urology), University of Toronto and Chair, Theralase Medical and Scientific Advisory Board, stated “I am delighted by the research and clinical milestones that the Theralase® team has been able to achieve in advancing its PDC technology, including, launching a Phase II Non-Muscle Invasive Bladder Cancer (“NMIBC”) pivotal clinical study in Canada and the US. In 2021, Theralase® plans to complete the non-Good Laboratory Practice (“GLP”) and GLP toxicology of Rutherrin® (TLD-1433 combined with transferrin) to be used as a radiosensitizer in the treatment of multiple solid tumor types: including Glio-Blastoma Muliforme (“GBM”) and Non-Small Cell Lung Cancer (“NSCLC”) among others. As Theralase® advances in its research with Rutherrin® it makes sense for the Company to launch its own independent research centre focused on this evolving technology.” From the August 2022 MD&A: Once Rutherrin®’s Maximum Tolerated Dose (“MTD”) and hence Human Equivalent Dose (“HED”) limits have been determined through non-Good Laboratory Practices (“GLP”) and GLP toxicology studies, Theralase®, subject to regulatory approval, plans to inject Rutherrin® systemically into patients via a Phase Ib clinical study, to allow localization to various cancer cells, including GBM and NSCLC and then activate Rutherrin® with radiation with the intent of safely and effectively destroying the cancer of interest. Rutherrin®, if proven successful, would thus be able to “hunt” and “localize” into cancer cells and when activated by radiation “destroy” them; wherever, they may reside in the body.
Now, lets go back to 2015, as a refresher, to see what was needed back then for TLD1433 in order to know what has to be delivered this time for Rutherrin:
2015:
Theralase Successfully Completes GLP Toxicology Analysis of Lead Drug – Theralase Technologies announced today that it has successfully completed the toxicology analysis of its lead Photo Dynamic Compound (“PDC”), TLD-1433, in compliance with Good Laboratory Practice (“GLP”) standards. This milestone is critical for a Clinical Trial Application (“CTA”) submission to Health Canada.
Pending Health Canada approval of the CTA, Theralase would commence enrolling patients inflicted with Non-Muscle Invasive Bladder Cancer (“NMIBC”) into a Phase Ib clinical trial aimed at proving the primary objective of safety and tolerability with an exploratory objective of efficacy.
Completion of the GLP toxicology analysis of TLD-1433 has now achieved the second major milestone for the Company to complete its submission of a CTA application to Health Canada for NMIBC.
Key components required to submit a CTA to Health Canada for a new drug / device combination include:
– GMP manufacture including CMC information for the drug (Complete);
– Good Laboratory Practice (“GLP”) Toxicology Analysis of the drug (Complete);
– Completion of the Clinical Protocol and Investigator’s Brochure;
– Completion of detailed information regarding the device used in conjunction with the drug.
Conclusions of the GLP toxicology analysis demonstrate success in both the rat and dog models evaluated. The rat model successfully determined toxicity levels after an intravenous (“IV”) injection, while the dog model successfully determined toxicity levels after an intravesical bladder installation followed by Photo Dynamic Therapy (“PDT”) laser light activation.
In the rat toxicology study, the No Observed Adverse Events Level (“NOAEL”) IV limit was determined to be 1.2 mg/mL (6 mg/kg).
In the dog toxicology study, NOAEL was determined to be 6 mg/ml (30 mg/kg) for dog bladder infusion. Within 24 hours after instillation, the maximum level of TLD-1433 detected in blood was 0.03 ug/mL. This value is 200,000 times less than the instilled dose, indicating an ultra-low level of seepage into the blood stream supporting an extremely high safety margin. 7 days after infusion, the maximum level of TLD-1433 detected in blood was 0.002 ug/mL. This value is 3 million times less than the instilled dose, indicating a barely detectable level of TLD-1433 in the blood stream. This supports the conclusion that an infusion of 6 mg/ml of TLD-1433 (high human dose) into the bladder will be almost completely removed from the blood stream within 7 days. Thus the patient may be light sensitive for up to 7 days, which is significantly less than 30 to 90 days for Photofrin®.
In summary, the maximum detected dose in the blood stream within 24 hours after Beagle bladder infusion is 40,000 times lower than the IV NOAEL and 600,000 lower in 7 days, making bladder infusion an extremely safe route of administration for patients presenting with NMIBC.