aHUS patients and carers raised the research topic :
“Can the side effects of treatment using a complement inhibitor be distinguished from those temporary and permanent ongoing ailments which follow initial onset?”
A long awaited report on the safety of eculizumab , when patients with PNH and aHUS are “exposed to it” , is finally in the public domain.
It goes some way to answering the aHUS community’s question at least as far as eculizumab is concerned.
Without much fanfare despite its importance to those on eculizumab , it appeared in the British Journal of Haematology in February. In that journal , rather than a renal one, because the bulk of the use of eculizumab so far has been for treating PNH . This is because it has been available for PNH for four years longer than it has for aHUS ( i.e. from 2007 PNH, and 2011 for aHUS).
The article’s title is “Eculizumab in paroxysmal nocturnal haemoglobinuria and atypical haemolytic uraemic syndrome : 10 year pharmacovigilance analysis.”
A copy of the 14 page long article can be found here.
Alexion were obligated to produce a safety report as a condition of eculizumab’s licence and so most of the publication’s authors are Alexion employees, both past and present. The lead author however is a clinician from a hospital in Paris, France- Gerard Socie.
The group also included Prof. Peter Hillman, an Haematologist from England, who was key to the translational research which linked eculizumab to PNH, and then ultimately to aHUS. Prof. Johan Vande Wall from Belgium an eminent aHUS researcher involved in the early trials is also listed as an author.
The 10 year period covered is from 2007 to 2016 and pharmacovigilence is doctorspeak for studying the adverse events (AE) reported from the use of a drug.
PNH and aHUS are different diseases. The former is a bone marrow disorder whilst aHUS is the result of a mal-functioning innate immune system Complement . Both however benefit from eculizumab.
The conclusion of the study was that “the overall safety profile of eculizumab is consistent with that reported from clinical trials” .
So AEs reported by those participating in the initial trials of the drug continued to happen during the routine use in the 10 years since the drug was approved. The study, however, gives more insight into the likelihood of those AEs happening and what their impact has been.
The records kept in Alexion’s databases covered just over 21,000 years of use by PNH patients ( say roughly 4250 or more patients for an average of 5 years) and 7,500 years of use by aHUS patients ( roughly 2500 patients for an average of 3 years) . 28,500 years in total.
Whilst the total number of AEs is not explicitly stated, such incidents are reported as “so many per 100 patient years” ( how many times a patient could expect to experience it if they lived 100 years on the drug!)
Cumulatively over the period there were a total of 283.2 AEs per 100 PY So that means roughly 285 x 283 incidents actually reported overall. Just less than 3 per patient per year on average.
These AEs were either volunteered through clinical management ( 25%) or offered by patients in response to surveys (75%). It is the biggest amount of data about the safety of eculizumab ever.
Some of the most frequent AEs reported were common to both PNH and aHUS Patients, haemoglobin decreased , fatigue , pyrexia (raised temperature), headache, dyspnoea (breathlessness) , platelet count decrease.
aHUS patients, however ,reported more incidence of vomiting , nausea, death and un-evaluable events(?).
Table 1 (PNH) Table 2 (aHUS) of the study displays the relative incidence of AEs spit between how they were reported, and whether they were considered serious or not. The aHUS deaths were not eculizumab related.
Overall most of the AEs were seen as not serious.
Perhaps not surprisingly, although not the most common AE, the serious adverse event of “special interest” that of meningococcal infection gets a specific mention ( see previous website article about meningococcal infection by clicking here).
76 cases of meningococcal infection were reported. Almost all in those patients previously vaccinated, but not always for all serotypes. Serotype B was the main cause of infections and relatively more infections were reported by aHUS patients than those with PNH.
Of the 24 aHUS patients infected
- most were female,
- all but 3 were confirmed as vaccinated.
- infection was most likely to occur in the second year following commencement of treatment ( although the earliest was 44 days and the longest was more than 4 years after)
- Almost 90% of incidents were known to be caused by just 3 serotypes B, Y and W , of which B was the most common.
- Two thirds of the incidents were experienced by patients aged 16 to 44. and a quarter were by children.
- Half of incidents resulted in either Sepsis and/or Meningitis, which was less than that experienced by 75% of infected PNH patients
There was a notable reduction in infection incidences for all eculizumab users over the 10 years studied. There was almost 4 times more incidents in 2007 than there were in 2016. By 2016 only 0.16 per 100 PY were reported , so roughly one incident every 600 years and very unlikely to happen to patients.
There were 8 deaths caused by meningococcal infections , all were PNH patients. No deaths were reported in the period 2012-2016. It was reported that 39 of the 76 were known to have fully recovered or were improving with some ill effects from the event. There is no information on the other 29.
So it seems that there are not as many incidents and each has better outcomes as time goes by.
Vaccination against A ,C, W Y and B strains is encouraged when taking eculizumab. Consideration should be given to have prophylaxis antibiotics too.
Along with close monitoring, it makes sense to do so and stay protected.
Although there is less risk there is no room for complacency.
Other serious infections reported included
Bacterial- Enterococcus, Streptococcus, Pseudomonas, Tuberculosis, Haemophilus.
Viral- Influenza, Herpes, Cytomegalovirus, BK or JC virus
Fungal- Aspergillus, Candida
The study also looked at eculizumab use during pregnancy. Of 434 pregnant women who were exposed to eculizumab , 99 were aHUS patients. Of those, 54 had reported outcomes ( 38 were still pregnant at study cut off). Just under 60% had live births, others had miscarriages or induced abortions (35%). There were 3 still births .
Around a third of all births were by C-section.
Only 1 related AE ( mastitis) being reported among the 20 PNH/ 11 aHUS mothers who were breast feeding.
Although it is not something that is frequently raised in the aHUS community , cancers were reported in both PNH and aHUS patients whilst on eculizumab.
PNH patients, unsurprisingly as PNH is a benign bone marrow disorder, experienced more haematological tumours but these were not due to eculizumab. Whilst more solid organ tumours were experienced by aHUS patients , but more likely due to the higher risk from immunosupression following renal transplant. The incidence of tumours in adults and children exposed to eculizumab was reported as little different from the general population.
Whilst acknowledging the limitations of data and its sources , the overall impression of the authors was that reported AEs were more the result of the underlying illness than triggered by eculizumab. It is also likely that some events could have been double counted and so the actual incidence of AEs is maybe less in reality.
To briefly summarise:
- most AEs reported when exposed to eculizumab are not serious,
- no additional safety concerns following the early trials is emerging,
- It is the immunosuppression effect of eculizumab that raises risks to patients,
- meningococcal infection is the most likely serious AE but apparently is becoming less so with good clinical management and patient vigilance,
- the use of eculizumab during pregnancy appears to be risk beneficial,
- most AEs are probably due to underlying illness.