Arch Biopartners' Cilastatin to Join PONTIAC Phase II Trial for Drug-Induced Acute Kidney Injury

Arch Biopartners Inc. is advancing the development of cilastatin, a dipeptidase-1 (DPEP1) inhibitor, as a novel treatment for acute kidney injury (AKI). Cilastatin, originally approved by the FDA in 1985 for use with imipenem to treat bacterial infections, is now being repurposed for AKI due to its unique ability to block toxin uptake into kidney tissue. This characteristic makes cilastatin particularly effective in preventing AKI caused by drug toxins, a significant cause of hospital-related kidney injuries.

The company is participating in the upcoming "Prevention Of NephroToxin Induced Acute kidney injury with Cilastatin" (PONTIAC) trial. This Phase II trial will involve 900 patients and will assess the efficacy of cilastatin in preventing AKI induced by various drugs, including antibiotics, chemotherapeutic agents, and radiographic contrast. The trial is led by investigators from the Universities of Calgary and Alberta, who have secured $1.9 million in funding from the Canadian Institutes of Health Research (CIHR) and the Accelerating Clinical Trials (ACT) initiative.

The PONTIAC clinical team is preparing to submit a Clinical Trial Application (CTA) to Health Canada with plans to initiate the trial by late 2024. Arch Biopartners is collaborating as a study partner, providing cilastatin and offering scientific and regulatory guidance.

Cilastatin operates by inhibiting the enzymatic activity of DPEP1, preventing the uptake of toxins into the kidneys. This sets it apart from Arch's other drug candidate, LSALT peptide (Metablok), which also targets DPEP1 but focuses on blocking inflammation in the kidneys, lungs, and liver. The PONTIAC trial builds on earlier research published by Arch scientists in the Journal of Clinical Investigation, which demonstrated cilastatin's effectiveness in preclinical models at inhibiting leukocyte recruitment and drug toxin uptake in the kidneys, thereby preventing AKI caused by radiographic contrast.

With this announcement, Arch Biopartners is adding a second target indication for preventing acute kidney injury through its drug development program. The company is also conducting an international Phase II trial of LSALT peptide, targeting cardiac surgery-associated AKI (CS-AKI). These efforts are crucial as drug toxins and CS-AKI together account for nearly half of all AKI cases in hospitals, a condition for which there are currently no available preventive treatments.

AKI represents a spectrum of clinical scenarios from mild to severe injury, potentially leading to permanent kidney damage or complete loss of renal function. Causes of AKI are diverse, including sepsis, ischemia-reperfusion injury, and various toxins, both endogenous and exogenous. Severe cases often necessitate dialysis or kidney transplantation.

Drug-induced AKI accounts for around 30% of hospital cases, involving a variety of pharmaceuticals such as antibiotics, chemotherapeutic agents, and radiographic contrast. Cardiac surgery-related AKI represents an additional 20% of in-hospital AKI incidents.

Initially, cilastatin was developed in the early 1980s by Merck Sharp & Dohme Research Laboratories to prevent DPEP1 from breaking down imipenem, a β-lactam antibiotic. This combination was approved by the FDA in 1985 and marketed under various names globally. Although patents have expired and the combination drug has entered the generic phase, cilastatin has no commercial history as a standalone product.

Arch Biopartners Inc. continues to prioritize preventing acute kidney injury through late-stage clinical trials. The company is focusing on developing drugs that mitigate inflammation in the kidneys, lungs, and liver, addressing a significant need in treating organ inflammation in various injuries and diseases.

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