A New Treatment for Toxin Related Acute Kidney Injury
Cilastatin
Repurposing cilastatin to target acute kidney injury (AKI) via dipeptidase-1 (DPEP1).
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.
Originally developed in the early 1980´s by Merck Sharp & Dohme Research Laboratories (MSDRL), cilastatin was shown to protect the drug imipenem from being destroyed by DPEP1. Several in vitro and in vivo studies indicate that cilastatin prevents AKI induced by multiple nephrotoxic drugs (exogenous toxins) and/or heme-pigments (endogenous toxins).
- Whereas Arch’s lead drug candidate LSALT peptide specifically blocks DPEP1 mediated inflammation in the kidney, lungs and liver, cilastatin has off target effects that prevent toxin uptake in the kidneys.
- Cilastatin is particularly effective for toxin-related AKI, but not suitable for other forms of non-toxin related AKI that are targeted by LSALT peptide.
- 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 August 2024, Arch announced that cilastatin, the Company’s second drug candidate for preventing AKI, would be the focus of an upcoming investigator led trial entitled “Prevention Of NephroToxin Induced Acute kidney injury with Cilastatin” (PONTIAC). PONTIAC is a 900 patient Phase II trial that will evaluate the efficacy of the dipeptidase-1 inhibitor cilastatin for preventing AKI caused by drugs such as antibiotics, chemotherapeutic agents and radiographic contrast.
The PONTIAC trial builds on research published by lead Arch scientists and their colleagues in JCI (The Journal of Clinical Investigation) in 2018, when cilastatin was shown in pre-clinical models to effectively inhibit leukocyte recruitment and drug toxin uptake in the kidney, thereby preventing AKI caused by radiographic contrast.
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.
- Now off-patent, cilastatin is being produced by Arch for the first time ever as a standalone drug product for approval and commercialization.
Cilastatin was originally approved for use as a 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.
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.
