Response from the Argenica team:Regarding the pharmacology of...

Response from the Argenica team:

Regarding the pharmacology of ARG-007 there is one key point to make regarding its composition that is important. In the scientific literature ARG-007 is referred to as R18D. The “D” denotes the fact that the polyarginine is made up of the D isomer form of arginine, as opposed to being made up of the L isomer of arginine, which in fact is what we refer to as R18 in the scientific literature. The synthesis of ARG-007 as the D isomer of arginine means that our drug is resistant to proteolytic degradation (as published here - https://pubmed.ncbi.nlm.nih.gov/35305237/). This is because D-amino acids have a different stereochemistry and therefore are not recognised as substrates by most proteases (the molecules in the body that degrade L-peptides). The reason we changed our drug from R18 (ARG-006 made up of L-arginine) to R18D (ARG-007 made up of D-arginine) is twofold, but both relate to proteolytic degradation.

Firstly, given we are delivering the drug IV in our stroke clinical trials, and there are a range of proteases that circulate in the blood stream, we needed to ensure that our drug was not going to be degraded as soon as it entered the blood stream. We proved this by showing in our Phase 1 trial that the half-life of ARG-007 in humans is 12-15 hours (ASX Announcement dated 15 May 2023 – Final Phase 1 Clinical Trial Report Confirms Argenica Successfully Passes Critical Milestone).

Secondly, given some stroke patients receive a standard of care drug that dissolves the clot (tPA or alteplase), and this drug activates the protease plasmin, we needed to ensure ARG-007 was not going to be degraded by the plasmin that is activated by tPA. Our CSO has shown that R18D, but not R18, retains its neuroprotective properties in the glutamic acid excitotoxicity injury model when pre-incubated with plasmin, the protease that arises from conversion of plasminogen activated by tPA (https://pubmed.ncbi.nlm.nih.gov/33523394/). NA-1, or nerinetide, (a competitive peptide drug owned by NoNo Inc) was found to be degraded by plasmin, therefore it is not surprising that NoNo found no efficacy in patients that received tPA in their phase 3 trial. Our CSO has shown that the proteolytic stability of R18D when incubated with trypsin-like enzyme, is superior to both R18 and NA-1 (https://pubmed.ncbi.nlm.nih.gov/35305237/).

We understand that a number of neuroprotective drugs have failed in the past. In saying this though, I would like to point out that NA-1 (or nerinetide), a peptide drug with a cell penetrating TAT conjugate, is the first drug to in fact show neuroprotective efficacy in a Phase 3 clinical trial with thrombectomy, a trial was designed to assess the drug’s potential to protect against secondary reperfusion injury following thrombectomy in acute ischaemic stroke patients. However, (as noted above) because the drug is an L-isomer, it did not work in the tPA cohort of patients, as it was being degraded by the plasmin that was generated by the administration of tPA (https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30258-0/abstract). This meant that the trial was neutral, and they needed to repeat it. In the second Phase 3 trial, where they only included patients that didn’t receive tPA, however one of the key differences in this trial was the time from drug administration to reperfusion doubled. The lack of effect seen could have been because there was likely not enough circulating drug in the body to exert an effect against reperfusion injury given the short 10-minute half-life of NA-1 (data presented at World Stroke Conference 2023). Given ARG-007’s half-life is 12-15 hours it enables the drug to be resident in the brain for a considerably longer amount of time to exert protection of the neurons and avert re-perfusion injury.

Whilst it is well documented in the scientific literature that a lot of neuroprotective trials have failed in the past across all classes of drugs, including small molecules and peptides, a lot of work has been undertaken by the scientific, clinical and regulatory community to understand why, in particular through the Stroke Treatment Academic Industry Roundtable (STAIR) consortia and conferences (https://www.thestair.com/). Through STAIR, we now have a deeper understanding of why these trials have failed, and it relates less to the class of drug, and more to the mechanism of the drug, design of clinical trials and adequacy of preclinical studies. We now have a different standard of care, being thrombectomy, which allows us to design better clinical trials because neuroprotective drugs can work on the reperfusion injury (secondary injury) sustained after thrombectomy when the blood rushes back into the brain, therefore hopefully showing efficacy. We also know that we need agents that have multiple mechanisms of action, such as ARG-007, that don’t just block a single ion channel receptor or subunit on the receptor, we know we need to perform preclinical studies on more relevant animal models, such as work in primates, as previously conducted by our CSO, and we need to design clinical trials in which neuroprotective agents can be given reliably in a clinical setting with current standard of care procedures and drugs. To this point, one of ARG-007’s benefits over other drugs in clinical trials is that it only requires a single 10-minute IV infusion. Anything longer than this can potentially disrupt thrombectomy clinical workflows in emergency departments.

Whilst we are confident that we have designed the right drug to overcome the issues that NA-1 faced, have designed a robust Phase 2 clinical trial with the input of world leading stroke clinicians, and undertaken the required preclinical studies over the past 10+ years as recommended by STAIR, we understand there is always risk when you test a drug in a human patient population for the first time. However, we are confident in the preclinical data, and results of our Phase 1 pharmacology.

Apologies for this length and technical detail in this email, but I hope this has alleviated any concerns you and other investors have. There is a huge amount of scientific literature in the public domain on ARG-007 (R18D) which I encourage anyone to review this information if there are any further concerns on the pharmacology of ARG-007, and of course all our previous ASX Announcements have further detail.

Thank you again for your support of Argenica.

Kind regards,

The Argenica Team