Elonva (corifollitrophin alfa) has been shown to be a very effective rFSH stimulant for
Controlled Ovarian Hyperstimulation (COH) in the setting of IVF treatment. Its long duration
of action (7 days) results in a significant reduction in the number of COH stimulation
injections (average of 3 injections v 9 injections in the traditional "short acting" r FSH
COH), with 30% of patients requiring only a single Elonva injection for their COH (Engage
study, Devroey et al 2009). It is assumed that a reduction in the number of required COH
injections will have the advantages of improved patient acceptability and better compliance
due to a reduction in room for error. Despite these advantages the clinical uptake of Elonva
has been slow due to 2 principal concerns among clinicians:
A tendency for Elonva COH to result in a higher ovarian response with increased risk of
Ovarian Hyper-Stimulation Syndrome (OHSS). While this risk of OHSS was not statistically
significant in the pivotal Engage study, there was still a numerically greater chance of
OHSS and a greater chance of the IVF cycle being cancelled due to OHSS risk in the
Elonva arm compared to the traditional Puregon arm. Since women at high risk of OHSS
were excluded from the Engage study, clinicians perceive that the risk of OHSS is likely
to be significantly greater in the more heterogeneous general clinical population.
Whether this is a correct assumption is still up for debate, but it is a perceived issue
with the existing Elonva protocol that must be addressed if Elonva is to become used
widely as a COH stimulant.
According to the Engage and Ensure studies, the majority (70%) of women using Elonva
require "top up"short acting Puregon rFSH, with an average of 2 doses being required
before the patients reach the criteria for triggering and oocyte retrieval. As a result
clinics are required to teach two different injection protocols, increasing the time
required to educate the patient and possibly increasing the risk of confusion. The
ability to deliver a solitary COH stimulant without the need for any "top up" Puregon
would be a major advantage.
Rationale We would like to propose that it may be possible to use a solitary dose of Elonva
as the sole COS rFSH stimulant for the vast majority of women undergoing IVF, assuming that
it is possible that "coasting" (withholding short acting rFSH) from day 8 of the stimulation
until trigger/ oocyte retrieval will still result in a significant number of mature oocytes
being produced.
In the setting of OHSS it is common practice to withhold any further rFSH stimulant towards
the end of the COS process. It is generally accepted that medium size follicles of 14 mm or
greater will continue to develop to maturity in the absence of rFSH stimulation, while
smaller follicles will regress. This has the therapeutic advantage of reducing estradiol
levels and OHSS risk in women at high risk of OHSS. With this coasting physiology in mind, we
propose that provided a single injection of Elonva can result in a significant number of
follicles being 14 mm or greater by day 8 of stimulation, further rFSH will not be required.
Results from the Engage study (Doody et al 2011) reveal that by day 8 of stimulation on
average there were 5.1 follicles of 15 mm or greater. Therefore even if no further "top up"
rFSH was given from day 8, one could expect to get at least 5 mature oocytes from an oocyte
retrieval triggered by hCG in the next 2 days. While 5 mature oocytes is significantly less
than what was produced by the traditional Elonva protocol using additional rFSH (average 10.8
in the Engage study, 10.7 in the Ensure study), this could be perceived as a significant
advantage since it will likely result in a significant reduction in OHSS risk, a perceived
problem with the traditional Elonva protocol. If we assume a 70% fertilization rate and that
approximately half of all embryos are of good quality by day 4/5 of culture, the production
of > 3 mature oocytes should ensure the generation of at least one good quality embryo for
transfer with a good chance of pregnancy. This type of low impact stimulation is likely to be
very popular in Europe and Australia where clinicians already accept the benefits of mild
COS.
In summary, if we are able to provide evidence in this pilot study that a single injection of
Elonva can result in the majority of women reaching oocyte retrieval with the production of
at least 3 mature oocytes, while giving good fresh embryo transfer pregnancy rates and no
OHSS, the coasting Elonva protocol may become a significant clinical protocol for low impact
COS in the future.
