Sarilumab at the ACR 2015 Meeting in San Francisco

There have been a couple of publications on sarilumab at the ACR 2015 Annual Meeting in San Francisco. I guess that the proliferation of studies hints at Sanofi thinks to bring sarilumab to the market. I think, it’s still too soon to apply for FDA approval. But let’s look at some of the studies; I’ll quote all studies under references with a link to the ACR Meeting Abstracts.

Vibeke Strand and colleagues presented: “Impact of Sarilumab on Fatigue, Pain, Morning Stiffness, Productivity, and Health Related Quality of Life (HRQoL) in Patients with Active Rheumatoid Arthritis Who Were Inadequate Responders or Intolerant of Anti-TNF-α Therapy: Results from a Phase 3 Study (RCT)” This Phase 3 RCT [randomized controlled trial] showed statistically significant and clinically meaningful changes from baseline in fatigue, morning stiffness, pain, productivity and participation, rheumatoid arthritis impact scores and health related quality of life at Week 24.

There were several studies that looked at different dosages and combinations like the one presented by Roy Fleischmann et al. (Abstract No. 970 / Sarilumab in combination with CsDMARDs in patients with active RA and inadequate responders or intolerant of Anti–TNF-alpha Therapy), Arthur Kavanaugh et al. ( ABSTRACT No. 2760 / Efficacy and safety of sarilumab plus MTX in patients with RA), Mark C. Genovese et al. (ABSTRACT No. 2770 / Efficacy of sarilumab plus methotrexate in achieving clinical Remission in patients with active, moderate-to-severe RA), Maxime Dougados et al. (ABSTRACT No. 2761 / IL-6R blockade with sarilumab plus methotrexate results in changes in clinical and laboratory parameters associated with chronic inflammation), or another evalution by Vibeke Strand et al. (ABSTRACT No. 2313 / Responder rates and numbers needed to treat).

Paul Emery and colleagues presented: “Safety and Tolerability of Subcutaneous Sarilumab Compared to Intravenous Tocilizumab in Patients with RA”. Conclusion: “Overall, there was no clinically meaningful difference between the treatment groups with regards to clinical adverse events. Laboratory changes noted in the sarilumab groups were within the same range as those noted in the tocilizumab groups. […]”.

Gerd Burmester and colleagues looked at: “Sarilumab Dose Reduction to Manage Laboratory Abnormalities in an Open-Label Extension Study in RA Patients”. Conclusions: “In this study, reducing the dose from 200 mg q2w to 150 mg q2w to manage laboratory abnormalities allowed the majority of patients to continue in the study for a mean duration of >1.5 years. For patients continuing in the study, these laboratory abnormalities improved during the 6 months following dose reduction, and efficacy was maintained.” Two points: 1. necessity to reduce dose at all makes me uneasy, 2. if efficacy is maintained, why use a higher dosage at all? There might be at least a subgroup of patients, in whom a lower dosage could be possible.

Now, we come to Anita Boyapati and colleagues, who presented: “Evaluation of Bone and Joint Proteins for Prognostic Association with Radiographic Progression and Disease Activity in Methotrexate Inadequate Responder Rheumatoid Arthritis Patients in a Sarilumab Phase 3 Study”. Methods: “Serum markers [RANKL, MMP-3 and MMP-cleaved fragments of collagen types 1 and 3 (C1M and C3M)] were measured at baseline and posttreatment in patients receiving Pbo +MTX (n=128) or subcutaneous SAR 200 mg q2w + MTX (n=131).” Conclusion: “Analysis of markers […] showed correlation in MOBILITY patients. These data suggest that multivariate analysis of markers may be necessary to identify increased risk of joint destruction and elevated disease activity in patients with established RA.” And it shows, what isn’ seen – the necessity of results on radiographic progression. But it isn’t a shortcoming of this study.

I’m following the development around sarilumab for a couple of years now. I still hope that the drug comes to the market. But … do we need sarilumab? What could sarilumab give us, which we can’t get from tocilizumab? Will I split up my IL-6 inhibitor patients in two groups? Right now I can’t answer these questions. And still we need data on radiographic progression.

References:

Strand V, Kosinski M, Graham N, Chen CI, Joseph GJ, Bauer D, Lin Y, Pacheco-Tena C, Fleischmann R. Impact of Sarilumab on Fatigue, Pain, Morning Stiffness, Productivity, and Health Related Quality of Life (HRQoL) in Patients with Active Rheumatoid Arthritis Who Were Inadequate Responders or Intolerant of Anti-TNF-α Therapy: Results from a Phase 3 Study (RCT) [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/impact-of-sarilumab-on-fatigue-pain-morning-stiffness-productivity-and-health-related-quality-of-life-hrqol-in-patients-with-active-rheumatoid-arthritis-who-were-inadequate-responders-or-intoler/. Accessed November 17, 2015.

Fleischmann R, Castelar-Pinheiro G, Brzezicki J, Hrycaj P, Lin Y, van Adelsberg J, Graham N, van Hoogstraten H, Bauer D, Burmester G. Efficacy and Safety of Sarilumab in Combination with Csdmards in Patients with Active Rheumatoid Arthritis Who Were Inadequate Responders or Intolerant of Anti–TNF-α Therapy: Results from a Phase 3 Study [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/efficacy-and-safety-of-sarilumab-in-combination-with-csdmards-in-patients-with-active-rheumatoid-arthritis-who-were-inadequate-responders-or-intolerant-of-antiaetnf-i%c2%b1-therapy-results-f/. Accessed November 17, 2015.

Kavanaugh A, Kivitz AJ, Miranda P, Fiore S, Fay J, Fan C, van Adelsberg J, Huizinga TWJ. Efficacy and Safety of Sarilumab Plus MTX in Subgroups of Patients with Rheumatoid Arthritis in a Phase 3 Study [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/efficacy-and-safety-of-sarilumab-plus-mtx-in-subgroups-of-patients-with-rheumatoid-arthritis-in-a-phase-3-study/. Accessed November 17, 2015.

Genovese MC, Stanislav M, van Hoogstraten H, Martincova R, Fan C, van Adelsberg J. Efficacy of Sarilumab Plus Methotrexate in Achieving Clinical Remission, Using 4 Different Definitions, in Patients with Active, Moderate-to-Severe Rheumatoid Arthritis in a Phase 3 Study [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/efficacy-of-sarilumab-plus-methotrexate-in-achieving-clinical-remission-using-4-different-definitions-in-patients-with-active-moderate-to-severe-rheumatoid-arthritis-in-a-phase-3-study/. Accessed November 17, 2015.

Dougados M, Choy EH, Kameda H, van Adelsberg J, Fay J, Fiore S, Fan C, Schett G. IL-6R Blockade with Sarilumab Plus Methotrexate Results in Changes in Clinical and Laboratory Parameters Associated with Chronic Inflammation in Patients with Moderate-to-Severe RA in a Phase 3 Study [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/il-6r-blockade-with-sarilumab-plus-methotrexate-results-in-changes-in-clinical-and-laboratory-parameters-associated-with-chronic-inflammation-in-patients-with-moderate-to-severe-ra-in-a-phase-3-study/. Accessed November 17, 2015.

Strand V, Rendas-Baum R, Joseph GJ, Chen CI, van Hoogstraten H, Huizinga TWJ, Genovese MC. Responder Rates and Numbers Needed to Treat Based on Clinically Meaningful Improvements in Patient Reported Outcomes (PROs) Including Health-Related Quality of Life (HRQoL) after Sarilumab Treatment during a Phase III Randomized Controlled Trial (RCT) [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/responder-rates-and-numbers-needed-to-treat-based-on-clinically-meaningful-improvements-in-patient-reported-outcomes-pros-including-health-related-quality-of-life-hrqol-after-sarilumab-treatment-d/. Accessed November 17, 2015.

Emery P, Rondon J, Garg A, van Hoogstraten H, Graham N, Liu M, Parrino J, Spindler AJ, Liu N. Safety and Tolerability of Subcutaneous Sarilumab Compared to Intravenous Tocilizumab in Patients with RA [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/safety-and-tolerability-of-subcutaneous-sarilumab-compared-to-intravenous-tocilizumab-in-patients-with-ra/. Accessed November 17, 2015.

Burmester G, Garg A, van Hoogstraten H, Graham N, Boddy A, Parrino J, Genovese MC. Sarilumab Dose Reduction to Manage Laboratory Abnormalities in an Open-Label Extension Study in RA Patients [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/sarilumab-dose-reduction-to-manage-laboratory-abnormalities-in-an-open-label-extension-study-in-ra-patients/. Accessed November 17, 2015.

Boyapati A, Msihid J, Hamilton JD, Gabay C, Graham N, Fiore S. Evaluation of Bone and Joint Proteins for Prognostic Association with Radiographic Progression and Disease Activity in Methotrexate Inadequate Responder Rheumatoid Arthritis Patients in a Sarilumab Phase 3 Study [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/evaluation-of-bone-and-joint-proteins-for-prognostic-association-with-radiographic-progression-and-disease-activity-in-methotrexate-inadequate-responder-rheumatoid-arthritis-patients-in-a-sarilumab-ph/. Accessed November 17, 2015.

Sarilumab at the EULAR 2014 Meeting in Paris http://rheumatologe.blogspot.de/2014/06/sarilumab-at-eular-2014-meeting-in-paris.html