Arch Biopartners Has Pre-IND Meeting With FDA to Discuss Repurposing Cilastatin as a New Treatment to Prevent Acute Kidney Injury

Arch Biopartners Inc. recently announced it had a pre-investigational new drug application (PIND) meeting with the US 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 2 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 US who are planning to conduct two separate Phase 2 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.

“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,” said Richard Muruve, CEO of Arch Biopartners Inc.

Cilastatin is an enzymatic dipeptidase-1 (DPEP-1) inhibitor originally developed in the early 80s 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 (US, 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.

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).

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, visit www.archbiopartners.com/our-science.