JAKs could offer convenience advantages over other biologics
As a once-daily oral treatment, JAK inhibitors offer potential convenience advantages
over competitor biologics which often require physician visits for intravenous
administration. A subcutaneous formulation of Entyvio for maintenance
treatment has been filed with regulators, with US FDA issuing a Complete Response
Letter in December but European approval likely after a positive CHMP decision.
As small molecules, an added advantage of JAK inhibitors is the lack of anti-drug
antibodies, which may increase the likelihood of sustained responses, versus the loss
of response which can occur with biologics, as well as enabling intermittent treatment
for disease flares, which is generally not advisable for biologics.
Safety in focus
Safety will be a key focus for the SELECTION trial, given the concerns related to the
JAK inhibitor class overall, but could potentially act as confirmation of filgotinib's
differentiated safety profile. In July 2019 FDA issued new warnings about an
increased risk of blood clots and death with the 10mg twice daily (bid) dose of Xeljanz,
and recommended reserving use for patients who have failed or are intolerant of antiTNFs,
avoiding use in patients at high risk of thrombosis and limiting the use of the 10mg
bid dosage to the shortest duration needed. Europe's EMA followed suit in November
2019, advising that Xeljanz should be used with caution in patients at high risk of blood
clots and limiting use in patients >65 years.
Potentially differentiated safety profile
Other JAK inhibitors have been shown to produce a range of side effects, including
abnormalities in platelets, low density lipoprotein (LDL), cholesterol, red blood cell count
and NK (natural killer) cell count, raising concerns about risk of serious infections and
venous thromboembolism (VTE). Filgotinib has more JAK1 selectivity than
any other JAK inhibitor, which could result in an improved safety profile.
In keeping with this, the Phase II DARWIN and Phase III FINCH RA programmes
confirmed filgotinib's potentially best-in-class safety profile with
rates of VTE, serious infection, opportunistic infection, malignancy, major adverse
cardiovascular events and death broadly in-line or below placebo rates.
An added potential benefit of filgotinib for inflammatory bowel disease (IBD) is the
lack of adverse effect on haemoglobin levels demonstrated in trials to-date, with an
actual increase in levels of up to 4% in the DARWIN trial. This compares favourably
to Xeljanz, which carries a warning requiring haemoglobin monitoring and doseadjustment
depending on levels. This is particularly important for IBD, with up to
one-third of patients suffering from recurrent anaemia, and could potentially be a
differentiating factor for filgotinib.
MANTA studies ongoing
FDA has previously had issues regarding use of the highest 200mg/day filgotinib
dose in male patients, based on concerns over toxicity to the male reproductive system
relating to rat/dog toxicology studies. Consequently, despite the fact the Phase II
DARWIN trials confirmed no clinically meaningful changes in male hormone levels, US
males taking part in the Phase III SELECTION UC and Phase III DIVERSITY Crohn's
disease studies are only eligible to receive the higher 200mg/day dose if they have failed
at least one prior biologic.
In contrast, the FINCH RA programme, approved by a different FDA division, allowed
inclusion of the 200mg/day dose, but included a dedicated male UC patient testicular
safety study, MANTA, which could finally lay safety concerns to rest. During
2019, a second study, MANTA-RAy was initiated, with more relaxed inclusion criteria
and including patients with other rheumatic diseases, in order to speed up recruitment,
albeit enrolment into both studies has now been paused due to the COVID-19 outbreak.
Unblinded data from these male safety studies will be made available to FDA as part of
the RA filing.
Broad applicability means multi-blockbuster potential
It remains unclear when Gilead/Galapagos will share the topline MANTA data, given Gilead expects patient recruitment to finish in "H2:20". Initially assumed the partners would unblind the
data in 2020 to support the RA filing (PDUFA expected in Aug 2020), but Galapagos has recently said MANTA is not required for approval, and that the company would share the data in an