NEW YORK – After a bumpy road to commercialization, Danish diagnostic firm BioPorto has submitted its test for acute kidney injury (AKI) to the US Food and Drug Administration for de novo approval and expects a US launch in 2023.
The test quantitatively measures the presence of neutrophil gelatinase-associated lipocalin (NGAL), a biomarker that correlates to AKI, in a patient's urine or plasma. The biomarker becomes elevated when someone has an AKI, said BioPorto CEO Tony Pare. The firm has exclusive rights to the biomarker, which was discovered by researchers at Cincinnati Children's Hospital and Columbia University. Abbott also has rights to the biomarker and introduced an NGAL test and submitted it to the FDA in 2010, but a representative from the company said the test is currently offered only outside the US.
The assay runs on an automated clinical chemistry analyzer and takes about 10 minutes to return results, Pare said. Although it was validated on a Roche Cobas analyzer during the clinical trial for its FDA submission, he said that the company plans to validate it on other analyzers, including those from Siemens Healthineers and Danaher's Beckman Coulter.
Currently, the standard of care for AKI is serum creatinine testing, but those levels don't elevate in a patient until some kidney damage has already occurred, Pare said. Urine output is also measured, but the "only definitive way" to determine AKI is through an "invasive" biopsy, he said.
NGAL, in contrast to serum creatinine measurements, elevates within two hours of injury, which is important because AKI can be "subclinical," Pare said — there are often no other signs that AKI has occurred. In high-risk patients, such as those who've recently undergone cardiac surgery or transplants, are on a mechanical ventilator, are at risk of sepsis, or who are taking nephrotoxic medications, NGAL can be a useful measurement to catch kidney damage before it's too late.
In a systematic review published in Critical Care earlier this month, a group of Taiwanese researchers analyzed 110 studies to compare the predictive performance of different candidate biomarkers for AKI. The team found that "biomarkers containing NGAL had the best predictive accuracy for the occurrence of AKI, regardless of whether or not the values were adjusted by urinary creatinine." However, the authors noted that the "predictive performance of urinary NGAL was limited in surgical patients" and that all the biomarkers studied had similar predictive performance in patients that were critically ill. The highest performing measurement was the combination of NGAL with serum creatinine, they added.
The authors also said that the limitations of serum creatinine as a measurement include "a lack of steady-state conditions in critically ill patients" and the fact that the "determinants" of the measurement, such as rate of production, apparent volume of distribution, and rate of elimination, are "variable."
Another assay, BioMérieux subsidiary Astute Medical's NephroCheck, measures two other biomarkers — tissue inhibitor of metalloproteinase-2 and insulin-like growth factor binding protein-7 — to determine a patient's risk of developing AKI in the next 12 hours from when the test is administered. The Critical Care review found that urinary NGAL had a higher diagnostic accuracy for the occurrence of AKI than the combination of biomarkers found in the NephroCheck test.
Stuart Goldstein, director of the Center for Acute Care Nephrology at Cincinnati Children's Hospital Medical Center who has been using BioPorto's NGAL test for a number of years, said that the test can be an add-on to determine whether a patient has had a "true injury" or just a functional decrease, such as dehydration, which can help determine the patient's trajectory. The test "helps us discriminate true injury to the kidney tubule from a functional acute kidney injury that is generally not as severe or associated with poor outcomes," he said.
Rather than serving as a replacement for serum creatinine, Goldstein said he sees the NGAL test as a "necessary companion," particularly in critically ill patients, that can give clinicians a sense of the trajectory of the injury and "potentially the duration of injury" for the patient.
Goldstein, who is also a consultant for BioPorto and was the principal investigator for the firm's FDA derivation and validation trials, said that NGAL is the "most studied novel acute kidney injury damage biomarker in humans." Some of that data has shown that the protein comes directly from the injured kidney, rather than other biomarkers that may be elevated throughout the body and filtered through the kidney and thus "tend to be less specific."
It also has "broad applicability" and can help physicians decide whether to de-escalate dialysis care or change a treatment plan, he said. His hospital uses the test in combination with a risk stratification system within the intensive care unit, so if a patient is at potential risk, a NGAL test is automatically performed. The assay is also usually repeated to measure a patient's progress, since the biomarker is "dynamic" and changes over time.
He noted that when a patient is receiving dialysis, serum creatinine "becomes a useless biomarker," so NGAL can indicate renal recovery after an AKI. While Goldstein said he believes "in the science" of the biomarker and test, the "important part" BioPorto must address is demonstrating what clinicians should do with the information provided and how they should best utilize and implement the test. "BioPorto will need to demonstrate how having this information will make you a better clinician."
Goldstein also said he has studied NephroCheck in children after cardiac surgery and that it performs well, but that there are "many many more studies" of NGAL in children.
BioPorto's NGAL test previously received breakthrough device designation from the FDA, which will move it to the front of the line for review, but its de novo status means the agency will have to review not only the test's efficacy but that of the NGAL biomarker as well, which could take longer than a 510(k) clearance, Pare said. The timeline for FDA approval is dependent on the reviewer and a host of other factors, but BioPorto hopes to gain approval in the first half of the year.
The test's road to the FDA hasn't been entirely smooth sailing, Pare noted. It was developed "a number of years ago," but the company had not designed robust trials that would get the test through the FDA process, he said. In 2019, the firm had three pre-submission meetings with the agency and had new trial protocols approved, but the COVID-19 pandemic delayed that trial as research coordinators weren't able to access hospitals during the height of the virus's spread. The firm was only able to start enrolling patients for its trials last year, Pare said.
While some US sites have utilized the test for research-use only, others have adapted and validated the assay for clinical use as a laboratory-developed test, he said. Most hospitals, however, have been waiting on the assay's FDA approval. Cincinnati Children's Hospital's Goldstein also noted that many laboratories are cautious and prefer to await FDA approval before using certain tests, although he knows a "number of pediatric centers" are already using the assay.
The test has received CE marking and has been available through distributors in Europe and Asia for years, but the company put little effort into educating providers or promoting the test abroad and there has been limited use in most countries. It is, Pare noted, being used at sites in South Korea. Clinical education and promotion in both the US and abroad will be the company's main focus in the next year, and the firm is currently hiring its medical affairs team to get the word out about the test and how it can best be used.
BioPorto also has a strategic partnership with Roche and plans to utilize Roche's sales force to sell and distribute the test globally, Pare said.
BioPorto's main product right now is the NGAL test, but the company has other kidney-related assays in its pipeline, although Pare declined to specify further.