Article No. 446
14 July 2021
Eculizumab effectiveness and safety in the treatment of aHUS was established in five clinical trials involving 130 aHUS patients of all ages.
The trials took place in 2009 and 2010. Based on the the results, eculizumab became a licenced marketable drug for aHUS treatment.
Those who participated in the trials were invited to join a long term follow up study to observe what happened to the them in the next five years.
37 patients declined to participate. The remaining 93 were observed until 2017.
Focus of the follow up would be on whether there were any further manifestations of TMA Also whether there were changes to renal function and/or any serious adverse events from treatment.
Commencing in 2012, the study concluded on March 30th 2017. A report on the outcome was published in April 2019. The Menne et al article can be read at this link HERE.
Of the 93 eculizumab patients 42 (17 children, 25 adults) withdrew from eculizumab treatment at some point,and half of them eventually returned to treatment.
Only 11 of the 21 returned to eculizumab treatment because of recurrent TMA. Five returned to treatment when they had a kidney transplant; four either missed a single treatment or their withdrawal was down to administration issues. One of them died after a serious adverse event.
The other 21 patients , 24% of all patients in the study, remained off treatment. Compared with those returning to treatment, those remaining off treatment were:
-older at first treatment, median 30 years versus 21 years ,
-female, 76% v 52%,
-treated longer since the last TMA event, median o.6 years v 0.4,
-diagnosed for a shorter time before entry to study,
-having fewer TMA manifestations , 24% v 38% who had 2 or more TMAs,
– less likely to have genetic mutations, 48% v 67%.
Information is provided in the table below about the genetic status of the three cohorts of patients after five years of follow up observation
|Never discontinued||Discontinued returned||Discontinued remained|
|High risk mutations||25||8||6|
|Low/Medium risk mutations||6||6||3|
The data shows that those that have no identifiable genetic mutation are more likely to withdraw from treatment successfully 11/21. But those with high risk CFH, CFH autoantibodies ,CFB and C3 can also withdraw without return. So more needs to be known about specific mutations and not rely on the complement component only. Something which more recent research is beginning to suggest.
Applying the relative results of returned and remained , while ignoring that half of the returned did not do so because of recurrent TMA, perhaps 10 of the high risk “never discontinued”, 2 of the medium/low risk and 12 of the no genetic cause identified may also have had a successful withdrawal if attempted. So as many as 45 patients could have withdrawn and remain discontinued. Almost half of the patients in the study.
The long term kidney function results of 63 of the 93 patients who had sufficient follow up results were based on the eGFR measure. The baseline average eGFR when eculizumab was first given was similar for those who discontinued as well as those who continued on treatment their eGFR was around 30.
The 24 , of the 63, who had discontinued treatment had an eGFR of 92 at discontinuation.
At time of their last follow up test, discontinued treatment patients had an eFGR of 85.9 and continued treatment patients a score of 65.2.
18 out of those 51 who continued on treatment had been on dialysis before treatment and only 2 remained on dialysis at last follow up. The figures for those who had discontinued were 17 and 5 respectively. Relatively more of those who had discontinued had been on dialysis prior to treatment( 17/35)
Kidney function and reliance on dialysis by last follow up had improved for all upon the baseline levels. Overall both were at normal levels.
Although remaining higher than those who had continued, there had been some reduction in the kidney function of the discontinued patients from the time of discontinuation. 77% of those who had stayed on treatment had “stable or improved” kidney function, the figure for those who remained was 90%. Those who were reinstated after discontinuation did not fare as well, 100% were “stable or had declined”.
7 of the 93 patients in the follow up study had serious adverse events. 3 had died. 4 reported meningococcal infections ( 2 serotype B, 1 serotype W , 1 suspected but not found) . All were vaccinated but not against serotype B. 2 were on prophylactic antibiotics, 2 were not.
None of the deaths were due to aHUS, nor eculizumab treatment, All of those with an infection recovered with antibiotic treatment within 6 to 17days and remain on eculizumab treatment.
130 aHUS patients around the world entered eculizumab trials more than 11 years ago. 37 dropped out from follow up after the 26 week monitoring period. More is known about 93 who remained. By 2017, 3 had died, 4 had a serious infection, 21 had successfully withdrawn from treatment. That is the value of long term studies such as these. They build on the knowledge needed not only to approve a treatment but to help with long term prognosis.
It is now a further four years on from the end of the extended trial follow up and there may well have been other changes.
Eculizumab is now an established and approved treatment of aHUS, which the aHUS 130 would not have known when entering the original clinical trials.
If any of those original trialists view this article perhaps they could let us know what their latest status is. ( firstname.lastname@example.org or via the website “comments” tab)