CONS: BIOLOGICALS DO NOT PREVENT OR MODIFY PROGRESSION OF ALLERGIC
DISEASES UPON DISCONTINUATION
A positive disease-modifying immunological effect would indicate that
biologicals prevent the onset or the progression of the disease, the
development of associated co-morbidities, support tolerance development
by allergen immunotherapy (AIT) or create a persistent beneficial effect
after cessation of the treatment.
- Few datasets address the issue of revision or sustainability of a
biological-related remission upon discontinuation. Discontinuation of
dupilumab resulted in a risk of re-initiation of AD in almost 80% of
patients.10 Omalizumab cessation after one year of
asthma treatment led to 68% relapse rate in omalizumab
responders.11 For mepolizumab, one randomized,
placebo-controlled trial on subcutaneous mepolizumab against placebo
after long term mepolizumab treatment in asthmatics (COMET trial)
described a 59% asthma relapse and a 4-5 fold increase in blood
eosinophil counts.12
- Few datasets on synergies of biologicals with AIT have been reported.
Omalizumab in addition to peanut, milk, multi-food or hymenoptera
immunotherapy significantly reduced the time to maintenance dose and
the rate of side effects. However, it does not enhance long term
clinical outcomes or increases the rate of tolerance or sustained
unresponsiveness of food AIT.13
- Thus, novel approaches to mediate the dose reduction process in
omalizumab facilitated OIT are needed.14, 15 One
double-blind placebo-controlled study investigated a non-marketed
anti-IL-4 antibody (VAK694) in the context of a suboptimal
subcutaneous grass pollen AIT. Despite some promising mechanistic
findings, no additional clinical benefit to the AIT was observed.
- Dupilumab, approved for T2 asthma, CRSwNP and AD addresses both the
IL-4 and IL-13 axis, thus potentially affecting disease progression
through interfering with isotype switching and IL-13 dependent
T-follicular helper cell function. However, human data from controlled
trials are missing.
- Once omalizumab therapy is ceased if used as a monotherapy for food
allergy, symptoms re-occur.
- Eosinophilia or eosinophil infiltration of the lung or the GI-tract is
a common phenomenon observed in patients with atopic diseases.
Anti-IL5 or IL-5R targeting antibodies could have synergistic effects
by abolishing this eosinophil driven inflammation on the one hand and
increase safety by controlling asthma during AIT. No controlled trials
are available until now.
- Recently increased infectious events have been reported for
benralizumab in severe asthma patients, which has been linked to the
presence of auto-antibodies.16 This is very
interesting as this signal was absent in phase III benralizumab trials
and require further consideration for future applications in
vulnerable populations.
- Even less clinical evidence is available for a preventive or
disease-modifying effect of biologicals. It is tempting to speculate
on disease-modifying or preventive effects of biologicals addressing
IL-4/IL-13 pathway or upstream like anti-IL-33 on very young children
or even in pregnancy. However, more safety data from controlled trials
are required before approaches interfering with immune pathways in
childhood and very early in life (<2 years) can be
considered in such vulnerable populations.
In conclusion, there is no evidence that biologicals can sustainably
break vicious cycles of inflammation and thereby rescind or stop the
progression of the disease. Moreover, we do not have sufficient evidence
to suggest a role of T2 immunity targeting biologicals to promote
tolerance development to allergens when applied with or without AIT.