Friday, October 14, 2011

New kids on the block – Emerging therapies in rheumatology

New kids on the block – Emerging therapies in rheumatology
EULAR 2011 Meeting in London

There are new therapies, new strategies, but also new drugs based on existing strategies. The following gives an overview based on the abstracts of the EULAR 2011 Meeting in London.

1. Biosimilars

[SP0062] ADVANTAGES AND DISADVANTAGES OF BIOSIMILARS – ARE THEY GENERIC BIOLOGIC AGENTS? by V. Strand: Targets for ''biosimilars'' include etanercept (ETN), infliximab and rituximab. Disadvantages include that relatively small changes in manufacturing, characterization and/or formulation can significantly alter the efficacy, safety and/or immunogenicity of the biosimilar product.

South Korean based Cetlltrion has at least three products in its pipeline:
CT-P13 TNF (like Infliximab / Phase III)CT-P10 CD-20 (like Rituximab / ?)CT-P17 TNF (probably like Etanercept / ?)

2. Anti-CD-20 Monoclonal Antibody (like Rituximab)

[OP0019] OFATUMUMAB, A FULLY HUMAN ANTI-CD20 MAB, IN THE TREATMENT OF BIOLOGIC-NAÏVE RHEUMATOID ARTHRITIS PATIENTS: A RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED CLINICAL TRIAL by P.C. Taylor1 et al.A phase I/II study1 of OFA at doses of 300mg, 700mg and1000 mg administered as 2 infusions 2 weeks apart, …Conclusions: In this study, OFA treatment significantly improved all clinical outcomes in biologic-naïve, active RA pts without inducing immunogenicity. No unexpected safety findings were identified.

[SAT0288] TOLERABILITY, PHARMACOKINETICS AND PHARMACODYNAMICS OF SUBCUTANEOUSLY ADMINISTERED OFATUMUMAB IN RHEUMATOID ARTHRITIS PATIENTS ON STABLE BACKGROUND METHOTREXATE: A PHASE I/II STUDY by R. Kurrasch1 et al.Conclusions: In this study of RA pts on stable MTX doses, SC OFA doses of 30, 60 or 100mg resulted in profound and sustained peripheral B-cell depletion. Single doses up to 60mg were tolerated. OFA SC may provide a method of achieving B-cell depletion without additional CS premedication.

3. Co-Stimulation-Inhibition goes subcuaneously

[SAT0292] SAFETY OF SUBCUTANEOUS ABATACEPT IN PATIENTS WITH RHEUMATOID ARTHRITIS (RA): INTEGRATED ANALYSIS OF FIVE CLINICAL TRIALS UP TO 4.5 YEARS by R. Alten1 et al.Conclusions: These pooled safety data, from 1879 patients with up to 4.5 years and 3086 p–y of exposure, demonstrate that SC abatacept has acceptable safety and tolerability. The safety profile was generally consistent with that of IV abatacept.1 Few SC injection site reactions were observed, which were mostly mild in intensity.

4. Anti-Interleukin-6 Monoclonal Antibody (like Tocilizumab)

[SAT0304] BMS-945429 (ALD518), A HIGH-AFFINITY ANTI-INTERLEUKIN-6 MONOCLONAL ANTIBODY, IS ASSOCIATED WITH IMPROVEMENTS IN HEALTH-RELATED QUALITY OF LIFE IN PATIENTS WITH RHEUMATOID ARTHRITIS AND AN INADEQUATE RESPONSE TO METHOTREXATE by V. Strand1 et al.Objectives: Here, we report health-related quality of life (HRQoL) outcomes from a Phase II randomized controlled trial of intravenous BMS945429 in patients ...Conclusions: Treatment with the IL-6 inhibitor BMS945429 resulted in statistically significant and clinically meaningful improvements in physical and mental aspects of HRQoL.

5. Anti-BAFF Monoclonal Antibody

[OP0017] A PHASE 2 STUDY OF MONTHLY SUBCUTANEOUS LY2127399 (AN ANTI-BAFF MONOCLONAL ANTIBODY) IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS by M. Genovese1, et al.Conclusions: The LY safety profile in this study was similar to available RA therapies and no unexpected safety signals were seen. The 120mg dose group demonstrated significant reductions in the signs and symptoms of RA, and this was not contingent on complete B cell depletion. These results support further exploration of LY to treat RA

6. Anti-Lymphotoxin-alpha Monoclonal Antibody
Etanercept also works against Lymphotoxin-alpha.

[OP0018] ANTI-LYMPHOTOXIN-ALPHA MONOCLONAL ANTIBODY: RESULTS FROM A PHASE I RANDOMIZED, PLACEBO-CONTROLLED CLINICAL TRIAL IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS by B. Emu1 et al.Conclusions: MLTA3698A was generally well tolerated across SD and MD phases in patients with RA. Preliminary evidence of clinical activity was seen in patients with active RA.

7. Secukinumab (an Anti-Il17a Monoclonal Antibody)

FRI0380] SECUKINUMAB (AIN457) SHOWED A RAPID DECREASE OF DISEASE ACTIVITY IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS INCLUDING THOSE WITH HIGH INFLAMMATORY BURDEN by M. Genovese1 et al.Background: Secukinumab has been shown to improve signs and symptoms of patients with active RA in an ongoing phase II trial1 Conclusions: The results indicate that secukinumab provides a rapid reduction of disease activity with the greatest improvements seen in those patients on 150mg or 300mg who had evidence of high inflammatory burden as evidenced by baseline hsCRP levels.

[FRI0174] THE ANTI-IL17A MONOCLONAL ANTIBODY SECUKINUMAB (AIN457) SHOWED GOOD SAFETY AND EFFICACY IN THE TREATMENT OF ACTIVE ANKYLOSING SPONDYLITIS by D. Baeten1 et al.Conclusions: The primary endpoint of this study was met, as AIN457 induced significantly higher ASAS20 responses than placebo at w6. No early safety signals were noted in this study population. Interim data presented here suggest that AIN457 may be useful for the treatment of active ankylosing spondylitis and thereby warrant larger long term studies on safety and efficacy.

8. Oral JAK-Inhibitor, “small molecules”, SYK-Inhibitor and others

[SAT0243] ORAL SOLO (A3921045): A PHASE 3 STUDY OF ORAL JAK INHIBITOR TOFACITINIB (CP-690,550) MONOTHERAPY IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS: SUBGROUP ANALYSIS OF EFFICACY - POSTER TOURS by R. Fleischmann1 et al.Results: The Mo 3 ACR20 response rate was 59.8% (CP 5 mg) and 65.7% (CP 10 mg) vs 26.7% (PBO), p<0.0001. Conclusions: In this first Phase 3 study in pts with RA, clinically significant efficacy and acceptable safety vs PBO was demonstrated with CP 5 and 10 mg BID monotherapy at Mo 3 and in the majority of major demographic subgroups investigated.

[SAT0240] TASOCITINIB MONOTHERAPY CAN PREVENT RADIOGRAPHIC PROGRESSION IN RHEUMATOID ARTHRITIS by J.W. Kim et al.Conclusions: In this pilot study, we found that a novel JAK inhibitor, tasocitinib can prevent structural damage of RA in respect of joint erosion and JSN. A large-scale randomized prospective study is warranted to confirm our result.
Tasocitinib is the older name for Tofacitinib.

[SAT0249] SAFETY AND PHARMACOKINETIC PROFILE IN HEALTHY VOLUNTEERS OF GLPG0259, A SMALL MOLECULE MAPKAPK5 INHIBITOR CURRENTLY IN A PHASE II RA STUDY by F. Vanhoutte1 Conclusions: GLPG0259 showed good safety and a PK profile supporting once daily dosing. Based on these promising results, a randomized, placebo-controlled multi-center Phase II dose-finding study was initiated in October 2010, where three dose levels of GLPG0259 will be evaluated in 180 active RA patients with an inadequate response to MTX.

[OP0292] IDENTIFICATION OF GLPG0259, AN ORALLY BIOAVAILABLE INHIBITOR OF MAPKAPK5, AS A CLINICAL CANDIDATE FOR THE TREATMENT OF RHEUMATOID ARTHRITIS by M. Andrews1 et al.Conclusions: Compound screening and rational drug design were applied to generate a series of potent inhibitors of the novel RA target MAPKAPK5. Of these promising molecules, ... GLPG0259 is currently being evaluated in a Phase II trial in RA patients.

[OP0292] IDENTIFICATION OF GLPG0259, AN ORALLY BIOAVAILABLE INHIBITOR OF MAPKAPK5, AS A CLINICAL CANDIDATE FOR THE TREATMENT OF RHEUMATOID ARTHRITIS by M. Andrews1 et al.Conclusions: Compound screening and rational drug design were applied to generate a series of potent inhibitors of the novel RA target MAPKAPK5. Of these promising molecules, ... GLPG0259 is currently being evaluated in a Phase II trial in RA patients.
These Phase II Study has already been stopped because of lack of efficacy.

[SAT0246] AMAP102, AN ORALLY AVAILABLE 5-HT2 RECEPTOR ANTAGONIST DEVELOPED FOR THE TREATMENT OF RA, IS SAFE AND WELL TOLERATED IN HEALTHY SUBJECTS by A.-C. Ryde1Background: The 5-HT2 antagonism leads to a reduction of IL-6 and TNF-α, two important mediators of joint inflammation and cartilage/bone destruction. Conclusions: In this single and multiple oral dose Phase I study, AMAP102 was safe and well tolerated. The safety and pharmacokinetic profile of AMAP102 supports its further development. A Phase II study in patients with RA is planned.

[OP0057] IMPROVED HEALTH-RELATED QUALITY OF LIFE IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS RECEIVING FOSTAMATINIB (R788) by M.E. Weinblatt1 et al.Conclusions: In this phase II study involving RA patients, 100 mg bid fostamatinib was associated with significant improvements in HRQoL outcomes including physical functioning, pain, fatigue, and overall physical health status.

[SAT0247] PHARMACOKINETICS OF FOSTAMATINIB, A NOVEL SYK INHIBITOR, IN HEALTHY HUMAN SUBJECTS FOLLOWING SINGLE AND MULTIPLE ORAL DOSING by M. Baluom1 et al.Conclusions: … and is currently being evaluated in phase 3 clinical studies (OSKIRA trials) in RA.

The oral JAK-Inhibitor Tofacitinib seems to be the most promising agent. And also the one, which might be available soon.

Let’s see, what new developments will be shown at the ACR 2011 Meeting in Chicago during November. As for rheumatology we’re living in a very interesting time.

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