InfanDx AG, a privately held diagnostics company focusing on the development and commercialization of novel diagnostic solutions for newborns, has completed the validation of metabolic biomarker panels for the early detection of hypoxic ischemic encephalopathy (HIE) in newborns.
The validated biomarkers of such panels will be the target of the company’s HypoxE blood test for the early detection of HIE.
Achim Plum, CEO of InfanDx, told Labiotech.eu: “HIE, is a brain injury that is caused by oxygen-deprivation around the time of birth (perinatal asphyxia). If not treated early, it can lead to life-long disabilities including cerebral palsy (CP), cognitive disabilities, epilepsy, or hearing and vision impairments.
“Currently, the only guideline-recommended therapy is therapeutic hypothermia or “cooling.” The core body temperature of the babies is lowered by 3-4°C for three days to slow down brain metabolism and hence give the brain a chance to recover. However, to be effective cooling needs to be initiated within 6 hours of birth, which provides a diagnostic dilemma: Current early diagnosis relies on clinical assessment at the time of birth, e.g. APGAR scores, and blood parameters that indicate low oxygen supply like blood pH. Unfortunately, these parameters are not very specific and do not allow objective decision making in HIE cases that do not have a very obvious clinical manifestation. MRI and aEEGs can provide a better diagnosis at a later stage – which is too late to initiate therapy.”
InfanDx, in collaboration with the groups of Hans-Peter Deigner and Matthias Kohl at Furtwangen University, had previously identified metabolites associated with HIE by comparing metabolite profiles in the blood of newborns with and without HIE in a multicenter AAMBI study with 155 study subjects.
Many of these individual metabolic biomarkers have now independently been confirmed to distinguish between children with and without HIE enrolled in the BANON study using blood samples taken at birth or shortly thereafter.
The multicenter BANON study with 553 study subjects enrolled at 13 sites predominantly in Germany was closed in May 2022 and focused on studying the population of newborns that are at high risk to develop HIE as indicated by clinical and/or routine blood parameters. The newborns enrolled in BANON were confirmed to either suffer from HIE or not.
Based on the validated biomarkers, InfanDx’s designed panels combining top performing biomarkers with the APGAR score at five minutes after birth, means a quick test done on every newborn can assess the need for extra medical care.
These panels and their interpretive algorithms were optimized by InfanDx on a set of data not part of the validation data set of the BANON study. Algorithms were designed for either umbilical cord blood samples taken at birth or peripheral blood samples taken about two hours after birth in combination with short- and long-term outcome, respectively. In a blinded evaluation, the optimized panels were then validated by Axel Franz, principal investigator and coordinator of the BANON study, and his group at the University Hospital of Tübingen in collaboration with Kohl in the independent validation data set of the BANON cohort.
In the blinded validation,the best performing panel demonstrated a sensitivity of 89% at a specificity of 93% for detecting HIE cases as defined by short-term outcome using umbilical cord blood samples.
When using long-term outcome as an endpoint, the same algorithm detected HIE cases with a sensitivity of 74% at a specificity of 93%. In both settings, the biomarkers added significantly to the performance of the combined algorithm including the APGAR score. This, on the one hand, reflects the consensus among clinicians that the APGAR score alone is inadequate for detecting HIE, and, on the other hand, confirms research by other groups that it can nevertheless complement biomarker for HIE.
On the back of these results InfanDx will now enter the formal development phase of its HypoxE Test. The test will be intended as an aid in the early detection and diagnosis of HIE in newborns supporting clinicians in the timely decision to initiate neuroprotective therapies.
To this end, prototype assays for most of the panel biomarkers have already been developed for the Selectra proM Clinical Chemistry Analyzer commercialized by InfanDx’ strategic partner ELITechGroup.
Once developed, the HypoxE Test for Selectra proM will be subjected to a performance evaluation as required by European IVD Regulations (IVD-R) and submitted to a notified body for clearance. The company expects such submission for the end of 2023.
In parallel, InfanDx will work on a version of the HypoxE Test for point-of-care testing and progress its preparations to perform a study in the U.S. as a basis for a submission for clearance by the US FDA.
“With these data of the BANON study, our efforts to identify novel early biomarkers for HIE yielded first top-line results,” said Franz.
“It confirms the concept that clinical parameters such as the APGAR score and biomarker information are complementary in a complex condition like HIE. This observation has also been made by other research groups. We expect that the wealth of data provided by AAMBI and BANON will provide us with further important insights into the molecular pathology and clinical dynamics of HIE.”
“I would like to thank our tremendously committed collaborators in Tübingen and Furtwangen and at all the clinical study sites that made these strong results possible,” said Plum.
“We will continue working with the scientific and clinical community in HIE to turn these results into a diagnostic product that can aid clinicians in the timely and accurate diagnosis of HIE in newborns that may benefit from neuroprotective therapies.”
“With the biomarkers validated in the BANON cohort, there is now a clear path forward turning these significant results into an IVD product in 2023,” said Gunter Weiss, COO of InfanDx.
“We have the technical expertise in the team, have implemented the required quality management system, and with the ELITechGroup a very supportive partner on board to reach this goal in the original timeframe we communicated in early 2021.”
Based on this, InfanDx intends to leverage its biomarker and IVD development work to broaden its pipeline of diagnostic products with the aim of ultimately improving outcomes in neonatal acute and critical care.
Plum told us the HypoxE Test will greatly assist with early diagnosis.
“Our aim is to develop a blood test for metabolic biomarkers that are associated with HIE that can be applied at the time of birth and supports more objective early diagnosis of HIE within the critical time-window of six hours after birth,” Plum said.
As for what the test will mean for newborns and their parents, Plum said more certainty is very important in a situation where babies show adaptation problems at birth.
“On one hand, you do not want to treat this lightly as it can affect mother-child bonding for which the first hours after birth are very important. Also, cooling is a severe and very expensive critical care intervention with sedation and ventilation of the babies. On the other hand, no baby should be missed that could potentially benefit from cooling in order to prevent or mitigate life-long impairments. With the HypoxE Test, we aim to contribute to more certainty in the timely and accurate diagnosis of HIE.”
Sometimes, symptoms of HIE aren’t noted until a child reaches the teenage years. Will this help identify cases earlier? And will that mean that children will be able to receive appropriate treatment earlier?
Plum said: “Yes. There is a subgroup of HIE that is wrongly termed “mild HIE” because their clinical symptoms at birth are mild. Guidelines currently do not recommend cooling for these babies. However, in recent studies the clinical community came to realize that within this group there are children that do have severe outcomes later in life and therefore could potentially benefit from cooling as newborns. We hope that the HypoxE® Test will eventually help to identify such children at birth.”
There are also many different outcomes for children diagnosed with HIE. When asked if the company’s work in the field will help, Plum said: “In our dialogues with neonatologists, we learned that beyond the actual decision to treat with cooling or not, long-term outcome prognosis is very important for parents as it helps them to understand what the the family may have to face and how they can support the development of the child in the best possible way. In our studies, we also looked at whether our biomarkers can predict long-term neurological outcomes at about two years of life and could show a solid performance in these particular studies.”