Bibliographic updates

November 2016

Claude MOLINA – Jacques GAYRAUD

For many years, the major Pharmaceutical Companies compete in efforts and activity to seek new monoclonal antibodies and their involvement in Asthma and Allergy with the participation of large departments of Allergy and Lung diseases. There seems to be important to take stock of this topic in the end of year 2016.

1.   New Monoclonal Antibodies (MA)

A. Ligelizumab (L) (QGEO 31) and Mild Asthma:
G.M.Gaudreau et al JACI October 2016 138 4 1051-1059

The Canadian and American researchers have tested in a randomized multicenter study, this fully humanized IgG 1 antibody, which binds with higher affinity to IgE than Omalizumab (O) and provides greater suppression of free IgE and IgE bound to mast cells and basophils.    

3 doses were administered every 2 weeks in 37 patients with mild asthma: 24, 72 or 240mg, during 10 weeks and compared with parallel groups of O. and Placebo. The results confirm the efficacy and safety of this MA, with a greater efficacy than O on inhaled and skin allergen response. Whether these results translate into clinical benefits in severe asthma and chronic spontaneous urticarial need to be evaluated in larger clinical investigations.

B. Reszlizumab ® in poorly controlled and eosinophilic Asthma :
L.Bjermer et al CHEST October 2016 150 4 789-798- and J .Corren et al same review 799-810

Anti-IL 5 MA, humanized, (CINQ air) R was studied by a Canadian group in a randomized phase 3 trial in 179 patients aged 12 to 75 years with non-controlled asthma with inhaled corticosteroids + short-acting β agonists and a blood eosinophil count ≥400 cell/µL. They receive every 4 weeks for 16 weeks a dose of 0.3 or 3.0 mg/kg.
R improved lung function, asthma control, (symptoms) and quality of life. It was well tolerated, in spite of small number and moderate adverse effects: headache, naso-pharyngitis or worsening of asthma. Over all the 3.0 mg/kg dose provided the greatest improvements with comparable safety that the lower dose.

A similar study by an American team, in 492 patients treated at a dose of every 4 weeks for 16 weeks confirmed the efficacy and safety of R. in inadequately controlled asthma, and across a broad range of eosinophil counts.

C. Benralizumab :Add-on treatment for severe eosinophilic Asthma
3 articles devoted to: in Lancet 2016 29 October-4November Vol 388 Issue 10056  
M.Castro 2059-2060.              E.R.Bleeker et al 2115-2127.                 JM.Fitzgerald et al 2128-2141

Anti-interleukin 5 receptor α MA that induces direct, rapid, depletion of eosinophils, B. has been tested in randomized parallel groups placebo-controlled phase3 at 303 sites in 11 countries ( CALIMA) and respectively at 374 sites in 17 countries (SIROCCO) for patients aged 12-75 years with severe asthma uncontrolled by ICS+LABA, as add-on therapy, at the dose of subcutaneous injection of 30mg every 4 weeks or every 8 weeks, the baseline blood eosinophils being 300cells per µL or greater.

Whatever the regimen (every 4 or 8 weeks) the results confirm that B. significantly reduced annual exacerbation rates and was generally well tolerated in this type of patients as additional option.

2.    New therapeutic options for already known MA

A. Dupilumab (D) for Atopic Dermatitis in Adults
E.L.Simpson et al NEJM 2016 October 11 1-13  

Human MA against IL 4 receptor α, D. inhibits signaling of IL4 and IL13 type 2 cytokines and has been assessed in 2 randomized placebo-controlled phase 3 trial of moderate to severe atopic dermatitis in adults, inadequately controlled by topical treatment. The design was identical in the two trials of 671 and 708 enrolled patients: subcutaneous injection of D.300mg or placebo weekly or the same dose every other week alternating with placebo, for 16 weeks. Improvement (symptoms of the disease: pruritus, anxiety, depression and quality of life) occurred in 38% patients who receive D every other week, 37% those who received D weekly, compared with 23% placebo. D was well tolerated except some rare cases of conjunctivitis and injection-site reactions. The 2 trial confirm the efficacy and safety of D. but long term effectiveness must be assessed by trials of longer duration.

B.  Anti-IL5 MA, a possible option for the phenotype Asthma-Obesity :
role of Innate Lymphoid Cells (ILC).                    
(L.Everaere et al JACI 2016 November 138 5 1309-1318).

Obesity is a risk factor for asthma but the mechanism is unclear.

French authors sought to determine the potential involvement of ILC type 2 and 3 in allergic airways disease exacerbation caused by high fat diet-induced obesity.

In experimental studies they show, that compared with a low fat diet, obesity decreased the number of ILC in mouse adipose tissue while increasing it in the lung with parallel to strong eosinophil infiltration. Moreover, in house dust mite allergic airways inflammation by intra-nasal administration, lung ILC, eosinophils, airways hyperresponsiveness and lung Th2 and Th17 profiles were aggravated in obese mice. To confirm the role of ILC, they depleted this population with an anti- CD 90 2 antibody: this ILC depletion led to a profound reduction in all parameters of the allergic reaction. So, ILC type 2 and 3 participate in the aggravation of this house dust mite induced airways inflammation in obesity. The authors suggest that therapies targeting eosinophils such as anti-IL5 antibodies might be of interest in the obese asthma phenotype.

Comments and questions may be sent to:

Claude Molina                                                  
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Jacques Gayraud
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Last updated 27 December 2016