aHUS uncertainty is a certainty

Article No. 423

16 March 2021

Update: Seven days after this news blog was published a further report on the ravulizumab trial was published ( see copy here ). 4 more trialists acheived complete TMA sometime between week 26 ,period of first follow up and 77 weeks, latest follow up period reported; bring the total to 34 out of 56 patients who entered the trial  to do so.  
Recently this website featured an article which imagined what it would be like  being a participant  in the trial of the drug Ravulizumab for the treatment of aHUS. ( Article 419
When entering such trials patients are very ill, frequently in a critical and life threatening condition. Getting a drug  may be considered a last chance to survive this terrible disease intact.
So when patients come out of it alive and with their health greatly improved; albeit each taking different times to recover, it can be put down to the efficacy of the drug.
But in the ravulizumab trials not all trialists’ health improved sufficiently. Admittedly more children trialists responded well, but not so the adults. For adults, over a third did not meet the targeted success endpoints after six months of using ravulizumb.
Until the long term follow up results are published it will not be known whether it just took longer for the TMA to subside in these patients , or the drug just did not work for them.
If it did just take longer then could it have made any difference to the patients’ health outcome.
If it did not work for some, was it because of the efficacy of the drug or were they too damaged at diagnosis to be expected to recover. Indeed, would eculizumab have worked for them any better?

This is what trials are for to get such answers.

According to its entry in the ClinicalTrials.gov database the criteria for participating in the adult aHUS ravulizumab trial were:

  1. Male or female ≥ 12 years of age and weighing ≥ 40 kg at the time of consent.
  2. Evidence of thrombotic microangiopathy, including low platelet count, hemolysis (breaking of red blood cells inside of blood vessels), and decreased kidney function.
  3. Documented meningococcal vaccination not more than 3 years prior to, or at the time of, initiating study drug. Participants who received a meningococcal vaccine less than 2 weeks before initiating ravulizumab treatment must have received treatment with appropriate prophylactic antibiotics until 2 weeks after vaccination. Participants who had not been vaccinated prior to initiating ravulizumab treatment should have received prophylactic antibiotics prior to and for at least 2 weeks after meningococcal vaccination. Participants < 18 years of age must have been vaccinated against haemophilus influenzae type b and streptococcus pneumoniae according to national and local vaccination schedule guidelines.
  4. Female participants of childbearing potential and male participants with female partners of childbearing potential had to use highly effective contraception starting at screening and continuing until at least 8 months after the last dose of ravulizumab.

Patients would be excluded if :

  1. A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) deficiency (activity < 5%).  ( i.e. its more likely the patient has  TTP)
  2. Shiga toxin-related hemolytic uremic syndrome. ( the patient has HUS)
  3. Positive direct Coombs test.
  4. Pregnancy or breastfeeding.
  5. Identified drug exposure-related hemolytic uremic syndrome (HUS).
  6. Bone marrow transplant/hematopoietic stem cell transplant within last 6 months prior to start of Screening.
  7. HUS related to known genetic defects of cobalamin C metabolism.
  8. Systemic sclerosis (scleroderma), systemic lupus erythematosus, or antiphospholipid antibody positivity or syndrome.
  9. Chronic dialysis (defined as dialysis on a regular basis as renal replacement therapy for end-stage kidney disease).

There were two HUS patients recruited and they were excluded after one dose of ravulizumab.
It is not known whether there were any patients whose TMA was of a secondary nature. i.e. resulting from something like lupus.
It is also not known for how long the patients had signs and symptoms of an aHUS TMA before  an aHUS diagnosis. They just needed to have evidence of a TMA.
We do know that more than 70% of trialists had reached kidney disease stage 5, which is kidney failure. Their kidney  failure might have been acute, but it  could be chronic by that time.
It is known that patients who are “late presenters” with an aHUS diagnosis can end up with chronic kidney failure despite being treated with eculizumab for a few months. Lateness can affect outcomes.
Complement inhibitors inhibit Complement. They do not repair damage. That is done by the body if it can be done. It is uncertain therefore whether some trialists’ kidneys were beyond help.
So  for some there is still an uncertainty about ravulizumab itself. In a “commentary” for Kidney International, Jan Menne of the Medical School  Hanover, Germany poses the question.
Is ravulizumab the new treatment of choice for atypical hemolytic uremic syndrome (aHUS)?”
Although a payment is needed to read the full commentary (see HERE )  a broad answer is given.
  Ravulizumab, a new long-acting C5 inhibitor, recently received FDA approval for the treatment of aHUS. Rates of complete thrombotic microangiopathy response were similar to those observed in major eculizumab trials; however, fewer patients in the ravulizumab study were able to stop dialysis, probably due to differences in the study populations. Until additional data/analyses are available, eculizumab remains the drug of choice for an acute aHUS episode, whereas ravulizumab has several advantages in maintenance treatment.  
A strategy for retaining eculizumab for use as the starting  treatment of aHUS has  been getting increasing support. Is it to be inferred from Jan Menne’s  commentary that this is because of an uncertainty about the technology’s efficacy? The efficacy of eculizumab being well tested by now.
Or would such a strategy still be considered sensible because of diagnosis uncertainty. Ravulizumab may not be the right treatment for some and to treat for eight weeks may be inappropriate and unnecessarily expensive. Eculizumab has a weekly build up infusion protocol so it  can be stopped sooner if an alternative  diagnosis is confirmed. Ravualizumab has a single two week protocol.
Except, perhaps, where an aHUS diagnosis may be more certain. Say if someone onsets and is known to be predisposed to aHUS  because of prior genetic testing, or has a medical or family history of aHUS. Ravulizumab, if available, could be used. unless overridden by  the technology’s efficacy uncertainty.
There has been no trial directly comparing eculizumab and ravulizumab efficacies for aHUS treatment.  So according to Jan Menne, eculizumab should remain the drug of choice for aHUS acute treatment until experience reveals more data. The ravulizumab trial itself has not yet reported on follow up at nearly four years.
Two comparison trials have been undertaken for the drugs when treating PNH patients.
One is a comparison of two cohorts starting treatment for the first time with either eculizumab or ravulizumab. The other is for PNH eculizumab patients switching to ravulizumab. In PNH trials efficacy is determined primarily  by  the reduction of LDH  from baseline levels at treatment entry.  LDH outcome is one of three primary measures in aHUS trials. Patients with renal problems would be excluded from ravulizumab trials.
In the “starting treatment” trial, 53% of patients treated with ravulizumab returned to LDH normality at six months, compared with 48% on eculizumab treatment.  So ravulizumab  showed it was not inferior for treating PNH.
All which leads to another uncertainty. Whereas PNH patients rarely stop needing a complement inhibitor, it is very unlikely that their bone marrow will stop producing defective red blood cells (i.e. cells which lack surface complement control components), evidence is increasing that some  aHUS patients are  able to withdraw from treatment when their TMA ceases.
If those patients were included in a switch study  and there was no change in their platelet , LDH or EFGR there would still  be an uncertainty about whether that was proof of similar efficacy, or, that neither technology was actually needed to control a TMA that was no longer existed.
As always nothing is straight forward when it comes to aHUS.  Uncertainties are certain!

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