High blood levels of Soliris seen in patients, may be needed for full efficacy
Scientists in Spain favor work allowing for personalized treatment
Blood concentrations of Soliris (eculizumab) needed to fully suppress the immune complement cascade may be higher than previously thought in people with atypical hemolytic uremic syndrome (aHUS), according to a study from Spain.
Most patients were found to have concentrations above estimated therapeutic levels in their bloodstream before a next Soliris dose, with levels associated with complement blockade higher than those reported in the therapy’s European Union label. Safety at these levels did not appear to be a concern.
Taken together, the findings encourage work leading to “the personalization of treatment with [Soliris],” the researchers wrote.
Soliris, an aHUS treatment, works to prevent complement overactivation
In aHUS, abnormal activation of the immune complement cascade triggers inflammation and blood clotting in small blood vessels. Patients experience cardinal disease symptoms of red blood cell destruction (hemolysis), low platelet counts, and kidney failure.
Soliris is an antibody therapy that targets C5, a critical protein in the complement signaling cascade to prevent complement overactivation. It is approved to treat adults with aHUS in the U.S., and both pediatric and adult aHUS patients in the European Union.
The treatment is given as into-the-vein (intravenous) infusions once weekly for four weeks at a dose of 900 mg, followed by a single 1,200 mg dose a week later (induction phase). Patients then receive a 1,200 mg dose every two weeks as maintenance treatment.
Doctors can monitor the efficacy of this Soliris dosing through blood tests, looking for markers of hemolysis, kidney function markers, platelet counts, circulating levels of complement proteins, or levels of CH50, an indicator of the hemolytic activities of the complement cascade.
Its European prescribing label indicates that a target range of 50-100 micrograms/milliliter (mcg/mL) of Soliris in the blood just prior to receiving a new infusion — i.e. at its lowest, or trough, level between doses — is optimal to achieve full complement suppression.
Still, there is some controversy relative to this therapeutic range, with some studies suggesting it may be higher than reported. Previous research has shown that certain factors, such as body weight and levels of specific complement proteins, can influence Soliris’ pharmacokinetics, or its movement into, through, and out the body.
A team of researchers set out to better understand the blood concentrations of Soliris likely to be effective in people with aHUS or C3 glomerulopathy, a type of complement-mediated kidney disease.
A total of 22 aHUS patients and three with C3 glomerulopathy, all treated at five hospitals in Spain between 2020 and 2022, were included in the study. Of them, 19 were adults with a median age of 43.4 and six were children with a median age of 10.1. All received Soliris at its recommended regimen.
Blood samples taken just before and after next Soliris dose given
Blood samples were collected just before administering the next scheduled dose of Soliris (trough or pre-dose levels) and again one hour after dosing (post-dose levels). For some patients, samples were collected from the start of Soliris treatment and included the induction and maintenance phase; for others, measures were obtained only during maintenance treatment.
Results showed that in the induction phase, mean pre-dose Soliris blood levels were 115.6 mcg/mL and post-dose concentrations were 474.9 mcg/mL. Drug concentrations gradually increased by an average of 90.5 mcg/mL every two weeks.
In the maintenance phase, pre- and post-dose Soliris levels were 243.8 mcg/mL and 747.4 mcg/mL, respectively.
Higher pre-dose concentrations significantly associated with lower CH50 concentrations, reflecting better complement blockade, as well as lower red blood cell counts, lower blood levels of creatinine — a marker of kidney dysfunction — and lower body weight.
Higher post-dose Soliris levels significantly associated with lower blood creatinine levels and higher platelet counts, although this difference wasn’t observed at concentrations above 800 mcg/mL.
Researchers then conducted analyses to assess which pre-dose Soliris blood concentration was associated with complete complement blockade, defined as undetectable CH50 values (which in the case of the technique used, corresponded to values up to 13.49%).
Blood samples collected from all 25 study patients at any time during their Soliris treatment were included in this analysis.
A total of 15 aHUS patients and the three C3 glomerulopathy patients exhibited complete complement blockade, while the other seven with aHUS had ineffective suppression.
Compared with those showing complete suppression, aHUS patients without it were generally older (median age of 47.2 vs. 29), were more likely to need dialysis (57.1% vs. 27.8%), and were on Soliris treatment for a shorter time (median of 8.4 months vs. about 3.5 years).
The frequency of certain complement mutations also differed between the two groups.
Reasonable safety seen at the higher blood levels found
Importantly, a pre-dose blood concentration of more than 149 mcg/mL was found to be optimal for achieving complete complement blockade. This cutoff value was able to identify patients with such complement suppression with an accuracy of 87%.
Researchers also found that time to clearance of Soliris from the bloodstream varied considerably among patients, but not within the same patient.
Reasonable safety also was seen, with an infusion-related side effect reported in one patient, and no one stopping treatment due to adverse events, the scientists wrote.
Overall, study findings indicate that most patients exceeded reported therapeutic concentrations of Soliris in the bloodstream, and that the optimal concentration may be higher than what’s listed for the medication, the team noted.
“To fully determine the efficacy of treatment with [Soliris], population pharmacokinetic models or algorithms must be developed to customize the treatment,” the researchers wrote.
“The optimization of the dosage of [Soliris] based on pharmacokinetic monitoring must be accompanied by close clinical follow-up, thus guaranteeing the efficacy and safety of the treatment,” they concluded.