Ultomiris at lower doses just as safe, effective for children with aHUS: Study
New dosing strategy could cut costs by over $80K per patient annually
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The safety and effectiveness of Ultomiris (ravulizumab-cwvz) as a maintenance therapy for children and adolescents with atypical hemolytic uremic syndrome (aHUS) remained unchanged even when the drug was administered at lower doses, not using the patient’s weight as a guide.
That’s according to a new, small study that sought to determine the differences between using current drug-dosing guidelines and TDM, or therapeutic drug monitoring.
Under those guidelines, a patient’s Ultomiris dose is based on body weight. But TDM dosing relies on measuring what’s known as trough concentration: the drug’s lowest levels in the bloodstream between doses, and/or the treatment’s impact on complement activity, the part of the immune system that drives aHUS.
“Individualized maintenance regimens of [Ultomiris] based on trough and complement monitoring appear safe and effective while reducing drug costs,” the researchers wrote.
Indeed, a cost estimate showed that TDM-guided dosing strategies may reduce the annual cost of Ultomiris treatment by more than $80,000 per patient, according to the researchers.
Still, the team noted that “further study is needed to define the optimal [Ultomiris] maintenance dosing strategy.”
The study, “Evaluation of ravulizumab trough levels in pediatric complement‑mediated hemolytic uremic syndrome in remission,” was published in the journal Pediatric Nephrology.
Ultomiris is a widely approved treatment for adults and children with aHUS. It works by suppressing the abnormal activation of the complement cascade that drives the formation of tiny blood clots in small blood vessels in aHUS. Its dosage, in milligrams, is based on patients’ body weight; the therapy is infused directly into the bloodstream once every four or eight weeks.
Ultomiris levels found to be 3 times higher than needed
While the therapy has been proven effective, reports nonetheless suggest that Ultomiris’ trough concentration — usually measured immediately before a patient’s next scheduled dose — is nearly three times the threshold needed to suppress complement activation.
As a result, “patients could be at increased risk for dose-dependent adverse events and may be able to maintain adequate drug coverage with lower doses,” the researchers wrote.
To learn more, a team led by scientists at Texas Children’s Hospital measured Ultomiris’ trough levels and corresponding complement activity in a group of nine children with aHUS who were in remission.
At the start of treatment, the median patient age was 4.3 years. Five were on a standard regimen with weight-based doses matching those in the package insert.
Four patients received Ultomiris under a modified regimen, with doses or dosing intervals differing from the package insert. Dosing was not based on weight, which had increased, but on Ultomiris trough levels, clinical stability, and concerns about side effects.
“Individualized anticomplement dosing regimens based on [TDM], markers of complement activity, or a combination of both have been suggested in response to high medication costs and serious safety concerns associated with a higher degree of complement suppression,” the team wrote.
Drug’s current wholesale cost is over $21 per milligram
According to blood tests, Ultomiris’s mean trough level across all patients was 399.1 micrograms (mcg)/mL, which was more than twice the threshold for complete complement blockade (175 mcg/mL or higher). The variability in trough levels across multiple tests was low, at less than 25%.
The researchers noted that there was no significant difference in trough levels between patients receiving the standard or TDM-guided modified regimens.
In all patients, there were no signs of complement activation, as indicated by AH50 values below 10%. AH50, fully, Alternative Pathway Hemolytic 50, is a blood test that measures the activity of the alternative complement pathway, the part of the complement system that drives aHUS.
One patient discontinued Ultomiris after additional tests revealed she had so-called typical HUS, caused by E. coli bacteria that produce a toxic protein called Shiga toxin. Still, the drug’s blood levels exceeded the 175 mcg/mL threshold for eight weeks after discontinuation, while AH50 values remained lower than 10%.
A second patient, who had no known aHUS-related genetic mutations, was weaned off Ultomiris after 12 months of remission. Again, trough levels stayed higher than 175 mcg/mL at eight weeks after the last dose, falling below this threshold at 10 weeks. At the same time, AH50 levels remained undetectable.
Reported side effects after starting Ultomiris included infections, affecting 67% of patients, fatigue, experienced by 56%, and headaches, affecting 33%. Diarrhea was a side effect for one-third of patients. The researchers noted that there were no significant differences in side effects between the standard and modified regimens. Also, no meningococcal infections, a potentially life-threatening side effect of Ultomiris, were observed.
Individualized maintenance regimens of [Ultomiris] … are a promising area for further investigation. … Patients on [the modified regimen] were able to maintain disease control while also minimizing drug exposure and drug costs.
The team noted that, based on the current wholesale cost of $21.30 per milligram of Ultomiris, the average annual cost savings for patients who received TDM-guided modified regimens was $81,183 per patient.
“Individualized maintenance regimens of [Ultomiris] based on TDM parameters, such as trough and/or AH50 levels, are a promising area for further investigation,” the researchers concluded, noting that “patients on [the modified regimen] were able to maintain disease control while also minimizing drug exposure and drug costs.”
These results set the stage for advancements in treating children with aHUS, the researchers noted.
“With more studies evaluating the use of TDM with [Ultomiris], a more streamlined approach can be formulated to generalize dosing regimen modifications,” the team wrote.
