Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose: ALX-0061 is a 26kD bispecific IL-6R targeting Nanobody® with monovalent binding to IL-6R and serum albumin. It effectively neutralizes IL-6 pathway activity in-vitro and in-vivo. Translational studies (PK/PD modelling) resulted in a novel FIM design combining single ascending dose (SAD), multiple ascending dose (MAD) and clinical POC using PK, biomarker and early clinical read-outs as decision tools.
Methods: Multicentre (6 sites in CEE), randomized, double-blind, placebo (PLC) controlled, dose escalation, Phase I/II study in patients with active RA on stable MTX therapy. Five treatment groups are tested in the SAD part and primary objectives are safety and tolerability of single ascending doses, MTD and/or biological effective doses (BED). Following SAD completion, an interim PK/PD analysis was performed to confirm the adequacy of the anticipated dosing regimen in MAD. Monthly or bi-monthly doses of ALX-0061 up to 12 and 24 weeks are tested in MAD with roll-over of PLC subjects after 12 weeks interim efficacy assessment to enrich the safety and efficacy population of ALX-0061. Biological and clinical efficacy is assessed with PK/PD, radiographic (MRI) and clinical scores at 12 weeks and end of study and correlated with pre-clinical modelling and literature data on IL-6R pathway inhibition.
Results: 28 patients with active RA were included in the SAD part and received single injections of 0.3mg/kg (2 pat), 1mg/kg (6 pat), 3mg/kg (6 pat), 6mg/kg (6 pat) and PLC (8 pat). Average age (52y) and BMI (25.6) were balanced between the groups; compared with PLC group, patients in ALX-0061 arm had higher disease activity (ACR Class II/III 85% vs 62.5%; DAS high disease activity 45% vs 12.5%). Safety: ALX-0061 was well tolerated. One subject reported an acute hypersensitivity event, no further SAEs were reported and no DLT occurred. The MTD was not reached. No clear increase in frequency or severity of AEs with increased doses of ALX-0061 observed. PK: Serum ALX-0061 concentrations and corresponding drug exposure increased with escalated dose. PD: CRP, ESR, fibrinogen and serum amyloid A showed rapid and marked decrease with highest effect observed at highest dose levels (3 and 6mg/kg). IL-6 and sIL-6R plasma concentrations increased with dose, representing a marker to monitor the biological effect of ALX‑0061 on its target. Clinical effect: Following single injection, 16 ALX-0061 subjects (80%) and 3 PLC subjects (37.5%) achieved moderate/good EULAR response at 2 months. 10 ALX-0061 subjects (50%) achieved LDA (6 pat) or DAS28 remission (4 pat), 2 PLC subjects (25%) achieved LDA (1 pat) or DAS28 remission (1pat). Based on PK/PD modelling, three dose levels were selected for the MAD: 1 mg/kg Q4W, 3 mg/kg Q4W and 6 mg/kg Q8W. 36 patients are treated in MAD part and completion is expected before end of 2012.
Conclusion: Single injections of ALX-0061 were well tolerated at BED. The pre-clinical PK/PD modelling was confirmed and dose-dependent changes of early inflammation biomarkers were consistent with inhibition of the IL‑6 pathway. The MAD study part will further assess early effect of ALX-0061 on disease activity with radiographic and clinical disease score evaluations.
Disclosure:
S. De Bruyn,
Ablynx N.V.,
1,
Ablynx N.V.,
3;
B. Gachályi,
None;
B. Rojkovich,
None;
S. Bruk,
None;
P. Sramek,
None;
M. Korkosz,
None;
K. Krause,
None;
P. Schoen,
Ablynx N.V.,
1,
Ablynx N.V.,
3;
L. Sargentini-Maier,
Ablynx N.V.,
1,
Ablynx N.V.,
3;
J. D’Artois,
Ablynx N.V.,
1,
Ablynx N.V.,
3;
K. Verschueren,
Ablynx N.V.,
1,
Ablynx N.V.,
3;
K. De Swert,
Ablynx N.V.,
1,
Ablynx N.V.,
3;
G. Arold,
None;
J. B. Holz,
Ablynx N.V.,
1,
Ablynx N.V.,
3,
Ablynx N.V.,
6.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/anti-il-6-receptor-nanobody-alx-0061-seamless-first-in-human-phase-iii-poc-study-in-patients-with-active-ra-on-stable-mtx-treatment/