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Upgrades to CareDx's AlloSure Test Enable Earlier Detection of Transplant Rejection

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NEW YORK – Transplant diagnostics company CareDx has released a new version of its signature organ transplant diagnostic AlloSure, which can now detect if patients are showing signs of borderline, subclinical T-cell mediated rejection (TCMR).

AlloSure 3.0, the latest iteration of the company's donor-derived cell-free DNA (dd-cfDNA) test, is specifically meant to enable doctors to detect the earliest and most "ambiguous" signs of rejection that are often undetectable through other means," according to CareDx Chief Commercial Officer Sasha King.

Renal transplant biopsy reporting and treatment is guided by the Banff meetings, which are held every two years to determine international consensus on kidney transplantation metrics. Banff lesion scores assess the presence and the degree of histopathological changes in kidney transplant biopsies. But these lesion scores must also be supplemented by additional diagnostic parameters such as histopathology.

TCMR is another parameter that can be used to determine rejection, but it's not always easy to find at subclinical levels. Three categories are currently used to describe TCMR histology: actual TCMR; borderline, which is characterized by less inflammation than a diagnosis of TCMR; and others, which are neither TCMR nor borderline. This histology also has subclasses, which can provide greater stratification of patients: IA, IB, IIA, IIB, and III.

Because borderline, or IA TCMR, can be ambiguous to detect in biopsies from patients, interoperator variability in biopsy diagnosis has been shown to be as high as 50 percent, CareDx noted. And when there is disagreement between molecular and histology scores for TCMR IA, it can make it harder for doctors to determine whether it's benign or a sign of active rejection.

This also makes treatment more difficult as doctors have to weigh the possibilities of undertreating and risking worsening rejection or overtreating and risking the associated toxicities to the patient.

At the American Society of Nephrology's recent Kidney Week meeting, the company presented new data from an as-yet unpublished study on TCMR detection. According to Dhiren Kumar — an assistant professor and transplant nephrologist at Virginia Commonwealth University and coauthor of the paper — clinicians currently have three options to assess patients. In addition to histology, they can also look at clinical markers such as creatinine and urine proteins, and at donor-specific antibodies in the transplant patient to determine possible rejection.

The problem with all three of these markers, however, is that by the time they're detectable, it may already be too late.

"They are what we call trailing indicators of injury, because the first thing that happens is injury, then the organ responds to this injury, and then histological changes happen. And after histological changes happen, then the creatinine goes up," Kumar said. "Essentially, as of right now, we don't have any marker that detects injury to the allograft as it's going on."

In their paper, Kumar and his colleagues aimed to find a way to detect the degree of injury to a transplanted organ at the time of histology. They also sought to determine whether the addition of a test like AlloSure could help doctors use TCMR IA to distinguish between actual injury to the transplant and benign infiltration of T lymphocytes.

They analyzed data from 79 patients with TCMR IA, dividing them into two groups, those at high risk of allograft injury versus those at low risk, as assessed by the degree of dd-cfDNA in their blood measured by AlloSure. They found that patients with a histological diagnosis of TCMR IA who had a high AlloSure score had poorer outcomes compared to patients who had a TCMR IA histology but had a low AlloSure score.

Of the 37 patients in the study with a low AlloSure score, defined as dd-cfDNA of 0.5 percent or less, only one (2.7 percent) exhibited the presence of donor-specific antibodies, and none experienced recurrent rejection. Of the 42 patients with a high AlloSure score, 17 (40.5 percent) exhibited the presence of donor-specific antibodies and nine patients (21.4 percent) experienced recurrent rejection.

"When you take this from the bench to the bedside, there can be a situation where the patient is doing well, and the allograft is functioning well. But the histology is telling me that they have IA rejection and they may be frail. I might have apprehension in treating them aggressively," he said. "If I have an accurate marker of injury — if, say, they have IA rejection, but the AlloSure [score] is low — I may be more conservative in their treatment as compared to somebody who has IA rejection but a higher injury marker. It prevents me from using a bazooka to kill a mouse."

And regardless of what therapy a doctor chooses to use, he added, better outcomes are more likely the earlier treatment starts.

Further, Kumar said, patients don't jump from one subclass of TCMR to the next — they progress from IA to III in a linear fashion. But anti-rejection therapies have evolved with histology, leading to specific treatments for TCMR I, II, or III. This can also lead to over- or undertreatment.

Having a more accurate injury marker, on the other hand, can tell a clinician where a patient is on the rejection continuum. "Is the patient at I and almost to II, or is he just beginning at I?" Kumar asked, noting that a greater degree of stratification can allow for more accurate treatment.

He also said that AlloSure can be used not only to detect rejection but also to monitor a patient's response to therapy. If a patient's AlloSure score is measured serially, the results can help to determine whether anti-rejection therapy is working or not.

"[We have] a multitude of examples where a patient comes in with a high AlloSure [score], we detect rejection, we treat rejection, and then we follow with AlloSure and see if it's trending down," Kumar said. "So, it's a marker of resolution and something that can be checked more frequently than a biopsy."

Now, Kumar and his colleagues are running additional follow-up studies to determine what the degree in change in AlloSure score means for patients. They're looking at what it might mean if an AlloSure score goes up incrementally, for example from 0.2 percent to 0.3 percent, or what it might mean if it jumps significantly, such as from 0.2 percent to 1 percent.

"The plan is to get more information and get papers out that would further refine the applicability of this test," he said.

CareDx also pointed to certain technical refinements that are available with the new version of the test. AlloSure 3.0 can be run with one tube of blood, King noted. While providing two tubes of blood is not a problem for many patients, for some, it is. " We wanted to make sure our test was something that would work for the full range of transplant recipients, whether it's a pediatric patient or those with dehydration, or other issues that may mean that they don't have as much sample to give."

AlloSure 3.0 has been rolled out for use in all of CareDx's AlloSure-based diagnostics, including kidney, heart, lung, and all of its compassionate-use programs in other organs, King said. AlloSure 3.0 also has a lower level of detection than the test's previous iterations.

The test is regulated under CLIA and College of American Pathologists guidelines, allowing the company to make constant improvements without needing to start the regulatory approval process over again with each new version, she added.

The company declined to name the journal that will be publishing its upcoming study, but King said the paper has been submitted for publication.

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