Imipenem

TORONTO, Feb. 27, 2024 (GLOBE NEWSWIRE) -- Arch Biopartners Inc. (“Arch” or the “Company”) (TSX Venture: ARCH and OTCQB: ACHFF), announced today that it had a pre-investigational new drug application (PIND) meeting with the U.S. Food and Drug Administration (FDA) Division of Cardiovascular and Renal Products (DCRP) on February 23, 2024 to discuss Arch’s plan to repurpose cilastatin as a new treatment to prevent toxin related acute kidney injury (AKI). Currently, there are no specific treatments for the prevention or treatment of AKI. Arch has the opportunity to sponsor a Phase II trial for cilastatin in toxin-related AKI targeting either nephrotoxic drug and/or rhabdomyolysis-associated AKI (explained further below). The PIND meeting provided the Arch team with guidance from the FDA for the content of a future IND application for cilastatin. An IND application is a request to the FDA for authorization to administer a new drug to patients in a human trial. The Arch team received clarity on several items including cilastatin pharmacology; manufacturing of a cilastatin drug product; design of phase II study protocol targeting toxin-related AKI; and the regulatory path that would lead to a New Drug Application (NDA). Arch is acting as an industry partner with clinical researchers in Canada and the United States who are planning to conduct two separate phase II clinical studies respectively for toxin-related AKI in late 2024. Arch management does not have plans to raise funds during 2024 in the capital markets for cilastatin trials. The Company will support these studies by acting as a partner for grant funding opportunities, providing cilastatin drug product, scientific advice, and pursuing regulatory approvals. Arch management is overseeing the development and manufacturing of a first-ever, stand-alone cilastatin drug product. Arch has arranged for the production of the first lot of a cilastatin to occur during the summer of 2024. Arch has method of use patents in several jurisdictions for repurposing cilastatin as a treatment for AKI. The patents are either proprietary or exclusively licensed to Arch. Quote from Richard Muruve, CEO of Arch Biopartners Inc: “The PIND meeting was the first major milestone in the effort to commercialize cilastatin, Arch’s second drug targeting DPEP-1. Third-party research and clinical interest to test cilastatin as a first ever treatment for both rhabdomyolysis-associated AKI and drug toxin-related AKI have provided the catalyst for Arch to advance this technology toward an NDA in parallel with the LSALT peptide program. We look forward to working with our research and clinical collaborators to establish cilastatin and DPEP-1 inhibition as a new treatment to prevent toxin-related AKI.” About Cilastatin Cilastatin is an enzymatic dipeptidase-1 (DPEP-1) inhibitor originally developed in the early 80´s by Merck Sharp & Dohme Research Laboratories (MSDRL) to limit the renal metabolism of imipenem, a β-lactam antibiotic used for the treatment of systemic infections. Cilastatin was approved for use as fixed combination with imipenem for IV administration to treat different types of bacterial infections. This fixed combination is currently marketed under different names, including Primaxin® (USA, UK, Australia, Italy), Tienam® (Spain, Belgium) or Zienam® (Germany). The combination imipenem/cilastatin was approved by the FDA in 1985. Patents for imipenem and cilastatin have expired and the combination drug is currently in a generic phase. There is no commercial history of cilastatin as a stand-alone drug product. Cilastatin has a slightly different mechanism of action compared with Arch’s novel drug candidate, LSALT peptide (Metablok) a non-enzymatic DPEP-1 inhibitor. Whereas LSALT peptide specifically blocks DPEP-1-mediated inflammation in the kidney, lungs and liver, cilastatin also has off target-effects that prevent toxin uptake in the kidneys. Thus, cilastatin is particularly effective for toxin-related AKI, but not suitable for other forms of non-toxin related AKI targeted by the LSALT peptide. Cilastatin as a potential treatment for AKI AKI reflects a broad spectrum of clinical presentations ranging from mild injury to severe injury that may result in permanent and complete loss of renal function. Clinically, the causes of AKI include sepsis, ischemia-reperfusion injury, and various endogenous as well as exogenous toxins. Exogenous toxins include a wide range of pharmaceutical drugs such as antibiotics (vancomycin, aminoglycosides), chemotherapeutic agents and radiographic contrast. The incidence of AKI is approximately 30% of all hospitalized patients receiving nephrotoxic medications. Endogenous toxins include heme-pigments such as myoglobin released during severe muscle injury (rhabdomyolysis) due to crush or blunt trauma, prolonged immobilization or drugs. Heme-pigments are avidly taken up by the kidney where they directly damage cells resulting in AKI. The kidney is particularly susceptible to heme-pigment induced injury with AKI occurring in up to 50% of patients experiencing rhabdomyolysis. As stated above, cilastatin is particularly suited to preventing AKI caused by exogenous and endogenous toxins due to a unique off-target effect that blocks their uptake into the kidney tissue. Several in vitro and in vivo studies indicate that cilastatin prevents acute kidney injury (AKI) induced by multiple nephrotoxic drugs (exogenous toxins) and/or heme-pigments (endogenous toxins). About Arch Biopartners Arch Biopartners Inc. is a late-stage clinical trial company focused on preventing inflammation and acute organ injury. The Company is developing new drug candidates that inhibit inflammation in the lungs, kidneys, and liver via the dipeptidase-1 (DPEP-1) pathway and are relevant for common injuries and diseases where organ inflammation is an unmet problem. For more information on Arch Biopartners' science and technologies, please visit: For investor information and other public documents the company has also filed on SEDAR, please visit The Company has 62,755,633 common shares outstanding. Forward-Looking Statements This press release contains forward-looking statements within the meaning of applicable Canadian securities laws regarding expectations of our future performance, liquidity and capital resources, as well as the ongoing clinical development of our drug candidates targeting the dipeptidase-1 (DPEP-1) pathway, including the outcome of our clinical trials relating to LSALT peptide (Metablok), the successful commercialization and marketing of our drug candidates, whether we will receive, and the timing and costs of obtaining, regulatory approvals in Canada, the United States, Europe and other countries, our ability to raise capital to fund our business plans, the efficacy of our drug candidates compared to the drug candidates developed by our competitors, our ability to retain and attract key management personnel, and the breadth of, and our ability to protect, our intellectual property portfolio. These statements are based on management’s current expectations and beliefs, including certain factors and assumptions, as described in our most recent annual audited financial statements and related management discussion and analysis under the heading “Business Risks and Uncertainties”. As a result of these risks and uncertainties, or other unknown risks and uncertainties, our actual results may differ materially from those contained in any forward-looking statements. The words “believe”, “may”, “plan”, “will”, “estimate”, “continue”, “anticipate”, “intend”, “expect” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. We undertake no obligation to update forward-looking statements, except as required by law. Additional information relating to Arch Biopartners Inc., including our most recent annual audited financial statements, is available by accessing the Canadian Securities Administrators’ System for Electronic Document Analysis and Retrieval (“SEDAR”) website at . The science and medical contents of this release have been approved by the Company’s Chief Science Officer Neither TSX Venture Exchange nor its Regulation Services Provider (as that term is defined in the policies of the TSX Venture Exchange) accepts responsibility for the adequacy or accuracy of this release For more information, please contact: Richard Muruve Chief Executive Officer Arch Biopartners, Inc. 647-428-7031 info@archbiopartners.com

About a decade ago, researchers began to observe a recurring challenge in their research: Some of the compounds they were developing to harness energy from bacteria were instead killing the microbes. Not good if the objective of the project was to harness the metabolism of living bacteria to produce electricity. About a decade ago, researchers in UC Santa Barbara chemistry professor Guillermo Bazan's lab began to observe a recurring challenge in their research: Some of the compounds they were developing to harness energy from bacteria were instead killing the microbes. Not good if the objective of the project was to harness the metabolism of living bacteria to produce electricity. "We needed the bacteria to be alive," said Alex Moreland, a Cystic Fibrosis Foundation Postdoctoral Fellow who joined the Bazan research group as a graduate student in 2014, and currently works at UCSB's Center for Polymers and Organic Solids. "While we were developing new molecules for that application, we found that some of them didn't work because they were killing the bacteria." However, instead of brushing it off as a rather annoying laboratory curiosity, in subsequent research the team leaned into the apparent antimicrobial properties of these compounds, called conjugated oligoelectrolytes (COE). Fast-forward to today, and they now have the basis for a new class of antibiotics, one that not only shows promise against a broad array of bacterial infections but can also evade the dreaded resistance that has been rendering our current generation of first-line antibiotics ineffective. "We realized that the molecular frameworks that we had been working on for some time could, if properly designed, yield a new class of antibiotics; something that is seldom found and that has profound implications for modern medicine," Bazan said. The Bazan Group's proof-of-concept studies for a wide range of bacterial infections appear across multiple papers published in Science Translational Medicine, the Journal of Medicinal Chemistry, and Chemical Communications. A global problem In what has been called an overlooked pandemic, antimicrobial resistance (AMR) is a global problem that affects all walks of life. In 2019, an estimated 1.3 million deaths around the globe could be attributed to AMR. "This figure assumes that if the resistant bacteria was replaced with a non-resistant bacteria of the same type, the patients would have survived," Moreland said. "These are excess deaths specifically related to resistance to antibiotics that were effective in years past." In many cases, he added, the mortality rate for infections with certain resistant bacteria is more than three times higher than that for non-resistant strains. Antibiotic resistance develops when bacteria are exposed to an antibiotic and evolve ways to defeat or bypass the antibiotic. Strategies include using the cell membrane as a barrier, destroying the offending molecule or eliminating it from the cell, or altering the drug's target to render the antibiotic ineffective. These resistance mechanisms can be passed on to progeny bacteria or shared with other bacteria in the environment. "There were 4.95 million deaths associated with antibiotic resistance in 2019, including the 1.3 million deaths that could be directly attributed to AMR, while around 10 million people die every year from cancer," Bazan commented. "However, last time we checked, there were 27 clinical trials for new antibiotics and 1,300 for anticancer treatments. It is worth taking a moment to reflect on these numbers." Broadly effective, yet highly selective COEs appear to hit multiple targets by "remodeling" bacterial membranes, the international team of researchers demonstrate in Science Translational Medicine. Led by Kaixi Zhang, at the time a National University of Singapore (NUS) postdoctoral researcher in the Bazan Lab, the team deployed their compounds against a particularly difficult-to-treat microbe, Mycobacterium abscessus (Mab), infections of which are prevalent in patients with underlying lung diseases, such as cystic fibrosis. Not only does Mab have "an unusually thick and impermeable cell envelope" that repels antibiotics, it also has the ability to hide inside phagocytes, immune cells whose job it is to engulf and kill microorganisms. In the case of Mab, these immune cells do not efficiently kill the bacteria and may unintentionally harbor them against antibiotics. Current treatments often fail despite long bouts with three to four antibiotic combinations for 12 to 18 months -- more than half of the patients are not cured, yet more than 70% of the patients suffer from notable adverse side effects. The COE in this study proved more effective than antibiotic controls amikacin and imipenem at eradicating Mab in both in-vitro and in-vivo experiments. The researchers attribute this effectiveness to the compound's targeting of the physical and functional integrity of the bacteria's cell wall. "If you destroy the membrane, the cell will rupture and of course that's going to kill the bacteria, but that tends not to be a selective mechanism," Zhang said. "However, there are a lot of essential functions that happen in the membrane that can be interrupted by more subtle membrane targeting. Our hypothesis is that our compounds, by inducing membrane remodeling, inhibit multiple essential functions simultaneously." This onslaught of disruption has a multiplicative effect on the bacteria, she added, making it 10 to 1000 times more difficult for them to develop resistance compared to conventional antibiotics. The unique mechanism of COEs also figures heavily in another facet of antibiotic resistance or tolerance: the production of a biofilm, a state in which a community of microbes band together and produce a polymeric substance, creating a shield of sorts. In the Journal of Medicinal Chemistry, led by UCSB/NUS postdoctoral researcher Jakkarin Limwongyut, the team demonstrated another COE compound's efficacy against Pseudomonas aeruginosa, a biofilm-forming drug-resistant bacteria that is considered an urgent threat by World Health Organization and the Centers for Disease Control and Prevention, and is among the pathogens more traditionally associated with AMR. It causes a variety of diseases from ear infections to life-threatening pneumonia, and is especially prevalent in hospital settings. "Some antibiotics can't penetrate into a biofilm, but also when bacteria form biofilms, their metabolism changes because they have less access to nutrients," said Limwongyut, explaining that the slower metabolism can render the effects of an antibiotic more tolerable to the pathogens and therefore less effective. "Recalcitrant and recurring infections, be that UTIs, pneumonia, endocarditis, or diabetic foot ulcer infections, are often associated with biofilms," he said. The team proved that their COE compound was capable of killing bacteria in established biofilms while also inhibiting the formation of biofilms. It's a rare one-two punch in the world of antibiotics. "There are a couple of antibiotics that do have anti-biofilm activity, but they either aren't used systemically or they are used systemically but really shouldn't be," Moreland said, alluding to the high toxicity of some of these antibiotics. For example, polymyxins in a topical form are effective against biofilms, but are toxic to kidneys at the doses used systemically (intravenous injection). Polymyxins accumulate in patients' kidneys, causing damage to the cells and tissue, and in severe cases, leading to kidney transplants. In contrast, the Bazan Lab has developed COEs to be highly selective for bacteria. In Chemical Communications, Moreland and team investigated how structural features of these molecules could drive their affinity for bacterial membranes and their antibiotic activity without "detergent-like" effects. In detergents, the antibacterial action relies on the indiscriminate destruction of cell membranes. "Your skin cells are pretty good at tolerating soaps and detergents but other cells in your body, and especially red blood cells, are very sensitive," he said, which is why these compounds are used only externally or to decontaminate surfaces and not as therapeutic agents. For COEs, they found, membrane permeability and antibiotic action are not inherently linked, suggesting a novel mechanism behind the COEs' activity, and critically, a mechanism that can be highly selective for bacterial membranes over mammalian ones. In fact, the molecules in the Mab experiment were able to reach inside of the phagocytes to kill the bacteria without damaging the mammalian cells. "We don't yet know the exact mechanisms, but we can definitively show that COEs kill bacteria and don't kill mammalian cells," Moreland said. He added, "this was not necessarily the case with the original molecules that we discovered early on, but with a lot of chemistry, and the help of tools such as machine learning, we were able to determine which molecular structures appear to strike the balance between efficacy against bacteria and safety for mammals." In various infection models, mice also appeared to tolerate COE treatments fairly easily. Looking ahead It's still early days for the Bazan research group, now mostly based in Singapore, as they continue to investigate mechanisms of action, search for additional novel properties and design and refine their molecules. Ideally, COE antibiotics would someday serve as safe and effective treatments, effective in cases of even the most resistant bacterial infections. Still, the road to clinical trials is a long one, albeit with interest and support from a variety of institutes and research collaborations around the globe, from the Singapore Centre for Environmental Life Sciences to the Cystic Fibrosis Foundation and Walter Reed Army Institute of Research in the U.S. "So far, so good. COEs have worked well in the experiments that we've done to-date," said Moreland, adding that the molecules in the studies need further refinement before advancing into clinical trials. "There's obviously more development required but we're up to it."