RESTORE - Development of a novel broad-spectrum antibiotic resistant inhibitor product

In the RESTORE project, Adjutec will prepare and carry out the first clinical phase 1 study in humans with our new antibiotic product (APC301). Bacteria develop antibiotic resistance by producing enzymes that destroy antibiotics. These bacteria are now spreading rapidly throughout the world and there are no modern antibiotics that are effective against bacteria that produce the most advanced of these enzymes. APC301 contains a well-known and effective broad-spectrum antibiotic (meropenem), a known enzyme inhibitor and our new enzyme inhibitor APC148. This product has already shown good effect in the laboratory against the most important bacterial enzymes that cause resistance. The work will continue with testing of resistant bacterial infections in mice to confirm the results in the laboratory. The combination product must be tested for possible side effects in an animal model before it can be administered to humans in a clinical trial. Our product contains three medicinal substances and two of them are ready to be administered to humans. The company will develop the third substance itself through this project. When these activities are finished, the company will submit an application to start the phase 1 study in healthy volunteers to document safety after intravenous administration of the medicinal substances. APC301 is a product for the treatment of serious infections such as complicated urinary tract- and lung infections. The product will be administered as an infusion, probably three times a day for 7-14 days. In this phase 1 study, the product will first be administered as a single dose to a group of eight subjects. The subjects will be monitored at all times with blood tests, ECG, blood pressure and other tests to ensure safety. Once safety has been documented, a new group of subjects will be tested with higher doses until a safe and effective dose is defined for further testing with multiple doses over several days.

RESTORE: An increasing number of bacteria develop resistance to last-resort antibiotics (e.g. meropenem). They do so by producing enzymes that destroy antibiotics. This can be compensated for by increasing the dose of the antibiotic, but results in side effects to the patient. Eventually, the antibiotic becomes ineffective. The objective of this research project is to develop a antibiotic product combining meropenem with enzyme inhibitors. Meropenem will then become effective in meropenem-resistant bacteria. Our meropenem product includes our novel enzyme inhibitor APC148 (MBL-inhibitor) that has shown to be very effective in experiments with bacteria and animals, together with another well-known enzyme inhibitor (SBL-inhibitor). The two enzyme inhibitor targets different enzymes and will together cover the most significant enzymes. We will first investigate the safety of APC148 alone in healthy volunteers in a dose-escalating phase 1a clinical study. In the next phase 1b study we will investigate the combination of meropenem, APC148 and another enzyme inhibitor. To prepare for the phase 1b study we need to investigate the safety of the combination in an animal model and formulate drug products of all substances. The main challenge is to define a safe and effective dose of all compounds in the combination product. This includes measurement of a multiple of safety parameters and analysis of pharmacokinetics (drug distribution and elimination) data from blood and urine that also reaches an effective plasma level. Before starting the phase 1b combination study in healthy volunteers, the combination of APC148+meropenem+SBL-inhibitor will be tested in an animal model to investigate potential interactions and further microbiology studies are needed to validate previous findings. This will require blood and urine sampling and safety biochemistry.