Ask the Doctors
Physician/Scientists specialized in HAE answer patients’ questions
on the Facebook pages for the US HAEA Angioedema Center at
the University of California San Diego as well as the US HAEA. Here
is one of the most recent questions – and the reply from Dr. Sandra
Christiansen, Dr. Marc Riedl, and Dr. Bruce Zuraw.
“My doctor wants me to go on the Ruconest, which is
a recombinant C1 inhibitor. I recently read a social
media post where someone stated that Ruconest
caused blood clots. I did see, however, that this person
used a port to take the medicine. Another patient
posted that Ruconest causes allergic reactions because
the C1 inhibitor medicine is derived from the milk of
rabbits. Can you provide some expert advice?”
Dr. Christiansen:
This is a very timely question for
multiple reasons. As many of you are aware there
have been recent manufacturing problems at Shire
with Cinryze and resulting shortages. CSL Behring has
also announced that they will not be able to meet the
demand for plasma-derived C1 inhibitor (pdC1INH),
with their available stocks. Patients are rightfully
anxious about running out of medication. Recombinant
C1 inhibitor (rC1INH) is identical to the plasma-derived
C1 inhibitor protein. It is expressed and purified from
the milk of transgenic rabbits. Intravenous rC1INH has
been shown to be safe and effective for the treatment of
acute attacks of angioedema in a pivotal phase III study.
A Phase II study led by Dr. Riedl demonstrating efficacy
for prophylaxis of attacks has also been published this
last year. Fortunately for patients, there is no shortage
of supply of rC1INH and the manufacturer, Pharming,
is dedicated to facilitating availability to patients. As is
the case for pdC1INH there have been no significant
safety concerns. The questioner raises the issue of rabbit
allergy. A warning about rabbit allergy is included in the
package insert in the US, which stems from a single
case of anaphylaxis during the trials in an individual
with rabbit allergy – which had not been disclosed to
the investigators. With the manufacturing process, there
are very low levels of host-related impurities (HRIs) in
the final product and such that the risk is very low of a
reaction even in rabbit allergic patients. A large study in
a rabbit allergic cohort has not been done, however. In
the event that rC1INH is the best option for a patient
with a history of rabbit allergy, everything has a risk-
benefit ratio. I would consider skin testing with rabbit
and the rC1INH to check prior to use. If the testing for
rC1INH is negative and the rabbit positive to err on the
side of caution I would then give a test dose of rC1INH
under observation in the office to see if it is safe to use.
Dr. Riedl:
In order to address the question about allergic
reactions to the recombinant human C1INH (rhC1INH/
Ruconest), let’s quickly review the process by which it’s
manufactured: rhC1INH is produced in rabbits that have
been designed to generate the human C1INH protein
in their milk. The rabbit milk goes through extensive
complex processing to purify the human C1INH protein
and remove all other materials. At the end of the process,
the medication contains less than 0.002% rabbit-related
proteins. So it is an incredibly pure human C1INH
medication. To my knowledge, there has been only one
confirmed case of an allergic reaction to rhC1INH due
to rabbit allergy. This occurred during the early clinical
studies with the drug when a young woman treated
in the study did not mention to study physicians that
she had previously had allergic reactions to rabbits. On
receiving the medication, she developed symptoms of a
serious allergic reaction but was treated and recovered
without complication. Since that time additional studies
have carefully monitored for this potential allergy issue,
but no additional allergic reactions related to rabbit
allergy have been observed. For a while, the European
regulatory agency required that all patients have rabbit
allergy testing performed prior to using rhC1INH, but
this requirement was removed in 2016 due to the fact
no additional issues with such allergic reactions had
been seen. The FDA has never required such testing
though of course warns of the possible risk in the
medication label. Since FDA-approval, an additional
study investigating this issue showed that four of five
individuals with positive allergy tests to rabbit in fact
tolerated rhC1INH treatment without any allergy issues.
The fifth individual was the aforementioned woman
who had an allergic reaction in the study; she also had
the strongest rabbit allergy test of the group. All told,
it appears that rabbit allergy issues related to rhC1INH
are exceedingly rare. If someone has a history of allergic
reactions to rabbit exposure, then it would be important
for them to speak with their physician about rabbit
allergy test (blood or skin test) prior to using rhC1INH.
But for the vast majority of people, this is not going to
be a significant risk or concern, since rabbit allergy is
quite uncommon.
Dr. Christiansen:
As to the thrombosis (clotting) issue
there is no more concern than has been raised for the
pdC1INH. The rC1INH is identical to the pdC1INH with
the exception of a small difference in the carbohydrate
decoration on the plasma human-derived protein. It does
have a shorter half-life then the pdC1INH, however, the
higher dose (50 IU/kg) appears to compensate. There is
really no published data linking rC1INH to thrombosis
and no cases during the trials with the drug. There is
much more data on pdC1INH, all of which is reassuring
and can be extrapolated for the rC1INH. In a study by
Henriette Farkas of 144 patients over 29 years the
incidence of thromboembolism was actually less than
for individuals not treated by pdC1INH. Paula Busse has
also published results from an international registry
on 135 subjects with 3196 infusions of pdC1INH and
found no evidence to suggest that pdC1INH was an
independent causative risk factor for thromboembolism.
Concern about potential thrombogenesis stems from a
report of off-label use in 13 neonates without HAE who
developed thrombus at up to 500 IU/kg in an attempt to
prevent capillary leak during cardiac bypass for severe
congenital heart defects. There have been five reports
of thrombosis on Cinryze in the open-label study, but
all patients had underlying risk factors. Studies in
animals have actually reported that C1INH may be
antithrombogenic rather than prothrombogenic. All this
being said there are still concerns for patients with an
indwelling port which is a risk factor for thrombosis.
Dr. Zuraw:
I can only echo what you've already said.
C1INH inhibits two clotting factors, activated factor
XII and activated factor XI. In C1INH deficient patients,
the clotting times are shorter, possibly indicating an
enhanced tendency to clot – although the relationship
between these lab measurements and the clinical risk
of clotting is far from simple or clear. Replacing C1INH
activity with either pdC1INH or rC1INH should improve
the inhibition of these clotting factors and thus reduce
the risk of thrombosis. My own sense is that it is the
other risk factors, especially indwelling ports, that
increase the risk of clotting and that both plasma-
derived and recombinant C1INH concentrates do not
contribute to this risk.