Drugs in development targeting interleukin 13 or its receptors
| Inhibitor | Company | Isotype | Mode of mechanism | Route | Clinical data |
|---|---|---|---|---|---|
| Anti-IL-13 MILR1444A Lebrikizumab | Roche/Genentech | IgG4, κ, with stabilising point mutations | Binds to human IL-13 and inhibits IL-13 induced phosphorylation of STAT6 in TF-1 cells | sc | Positive phase 2 study in patients with adult asthma despite inhaled glucocorticoid therapy (NCT00930163). Monthly treatment with 250 mg improved FEV1 at week 12. Reductions in serum Th2 chemokines (CCL13, CCL17) and IgE were observed.55 Phase 3 studies in patients whose asthma is uncontrolled with inhaled corticosteroids and a second controller medication (LUTE, NCT01545440 and VERSE, NCT01545453) are ongoing, with primary end point being exacerbations during the 52 week placebo controlled period. |
| Anti-IL-13 CAT-354 Tralokinumab | Medimmune/Astra Zeneca | IgG4, λ | Neutralises IL-13 | sc | Phase 2 randomised, double blind, placebo controlled study in moderate to severe asthma (NCT00873860) showed improved FEV1 at week 13, but no improvement in ACQ-6 score.102 A phase IIa, randomised, double blind, placebo controlled, parallel arm, multicentre study to evaluate the efficacy and safety of tralokinumab (every 2 weeks for 12 weeks) as add on therapy, on clinical response in patients with active, moderate to severe, ulcerative colitis is ongoing (NCT01482884). |
| Anti-IL-13 QAX-576 Fully human | Novartis | IgG1, κ | Specific inhibitor of human IL-13 activity | iv | A double blind, placebo controlled study showed reduced IL-13 responses in intranasal grass pollen challenge model, with possible effect on total nasal symptom scores in subgroup with high late phase nasal IL-13 levels at screening (NCT00584584).103 Phase 2 programmes are ongoing in moderate to severe asthma (NCT01130064) and idiopathic pulmonary fibrosis (NCT01266135). A phase 1 study on the sequential administration of a fixed dose of the anti-IL-4 antibody, VAK694, and single ascending doses of QAX576 in patients with well controlled mild to moderate asthma is completed (NCT01568762). In NCT01316601 the efficacy, safety and tolerability of QAX576 in the treatment of perianal fistulas in patients suffering from Crohn's disease is assessed. In patients with eosinophilic oesophagitis, the effects of a 12 week course of iv QAX576 6 mg/kg every 4 weeks is tested to reduce the number of eosinophils in the oesophagus (NCT01022970). The study has been completed, but results are pending |
| Anti-IL-13 ABT-308 | Abbott | Blocks IL-13 interaction with IL-13Rα1/α2104 | sc and iv | Phase 1 in patients with mild to moderate asthma is completed (NCT00986037) | |
| Anti-IL-13 IMA-026 Humanised | Pfizer | IgG1, κ | Specific for IL-13 epitope that binds IL-13Rα1 and IL-13Rα2 | sc | In phase 2 no significant effects on allergen induced late phase asthmatic response or sputum eosinophils could be observed (NCT00725582)56 |
| Anti-IL-13 IMA-638 Anrukinzumab | Pfizer | IgG1, κ | Inhibits formation of a IL-13Rα1 complex with IL-4Rα | sc and iv | In phase 2 (NCT00410280), an attenuated early (19%) and late allergen induced asthmatic response (24%) was described in patients with mild atopic stable asthma.56 A phase 2a study is recruiting patients with active ulcerative colitis and evaluates proof of mechanism of multiple iv doses of anrukinzumab by changes in mechanism based biomarker and pharmacodynamic biomarkers (NCT01284062) |
| Anti-IL-13 CNTO-5825 Fully human | Centocor | IgG1, κ | Neutralising IL-13 | sc and iv | A randomised, placebo controlled, double blind phase I study to assess the safety, tolerability, immune response, pharmacokinetics and pharmacodynamics in healthy volunteers and healthy atopic volunteers is completed (NCT01081691) |
| IL-4 IL-13 targeted | |||||
| Anti-IL-4R SAR231893 (REGN668) | Sanofi/Regeneron | IgG | Binds to IL-4R which blocks the function of IL-4 and IL-13 | sc | A phase 2 study on once weekly injections for 12 weeks vs placebo on reducing the incidence of asthma exacerbations in patients with persistent moderate to severe eosinophilic asthma is ongoing |
| Anti-IL-4Rα antagonist AMG-317 Fully human | Amgen | IgG2a | Binds to IL-4Rα, which competitively blocks the function of IL-4 and IL-13 | iv and sc | In a phase 2, randomised, double blind, placebo controlled study, patients received weekly sc injections of AMG 317 (75–300 mg) for 12 weeks. The primary end point, change from baseline at week 12 in ACQ symptom score, was not met in the total patient population. Patients with highest baseline ACQ were more likely to respond.105 Significant IgE response in population pharmacokinetic model by fitting data from four early phase clinical trials106 |
| IL-4/IL-13 bispecific DvD-Ig SAR156597 | Sanofi | Dvd-Ig (dual variable domain Ig) | Bispecific antibody which simultaneously binds both IL-4 and IL-13 | sc | At Protein Engineering Summit May 2012, presentation on allergen induced airway hyperresponsiveness in monkeys, and on safety, tolerability and pharmacokinetics of single sc doses of SAR156597 in healthy human subjects (phase 1). Randomised, double blind, placebo controlled study of the safety, tolerability, pharmacokinetics and pharmacodynamics of ascending repeated doses in patients with idiopathic pulmonary fibrosis ongoing; orphan drug status granted by FDA |
| IL-4 mutein Pitrakinra | Aerovance/Bayer | Similar to native IL-4 molecule, but with 2 amino acid changes (R121D/Y124D), thus competing for IL-4Rα | Binds to the IL-4Rα subunit and prevents the inflammation induced by IL-4 and IL-13 | Inhaled (sc) | In phase 2a study with inhaled compound diminished late phase asthmatic response to allergen challenge in asthmatic patients.107 Double blind, randomised, placebo controlled, multicentre trial in patients with uncontrolled, moderate to severe asthma did not reveal a difference in incidence of asthma exacerbations vs placebo after 12 week treatment period. Patients with blood eosinophilia > 350 cells/mm3 showed lower incidence of exacerbation.108 109 Better activity in subjects with IL-4R polymorphism110 |
| AIR-645 | ISIS/Altair | IL-4Rα 2′-O-methoxyethyoligonucleotide antisense RNA | Targets the mRNA that encodes the α subunit of the human IL-4R | Inhaled | Positive safety profile, sputum half life ∼ 5 days in sputum.111 Following repeated inhalation, evidence of reductions in serum total IgE, sputum eosinophils in mild asthmatics.112 Not enough activity in ph2 mild atopic asthma to warrant further development |
| (Anti IL-4/Anti IL-13 combo) QBX258 | Novartis | Ab combo | Blocking IL-4 and IL-13 | iv | Anti IL-4 Ab VAK694, in studies of allergic rhinitis. Anti IL-13 Ab QAX576 (see above) |
ACQ, Asthma Control Questionnaire; FEV1, forced expiratory volume in 1 s; IL, interleukin; iv, intravenous; sc, subcutaneous;