Fostamatinib at the ACR 2015 Meeting in San Francisco

There has been one publication on Fostamatinib at the ACR 2015 Annual Meeting in San Francisco. After reading the study by M. Genovese and colleagues last year, I thought I’d never hear anything on fostamatinib again; follow the link below for the whole story. Let’s look at the study, I’ve found in the wake of this year’s ACR Meeting.

Cecilie F. Kjelgaard-Petersen and colleagues presented: “The Active Metabolite of Fostamatinib, R406, Only Decreases the Inflammation-Driven Extracellular Matrix Turnover of the Joint at High Concentrations Ex Vivo”. Background/Purpose: “Osteoarthritis (OA) and rheumatoid arthritis are degenerative diseases of the whole joint. […]” I wouldn’t classify RA as a degenerative disease, though mutilations might lead to further degeneration, also after successful therapy and in the absence of autoimmune inflammation. But let’s move on. “Fostamatinib has been tested in both phase II and phase III clinical trials with mixed results.” Well, I'd call this statement euphemistic, but this view is possible. Methods: ”Cartilage turnover was investigated using a bovine cartilage explant (BEX) model. […]” Conclusion: “These data show that R406 can inhibit pro-inflammatory ECM joint degradation at concentrations higher than 0.5 μM, but at 0.5 μM or lower R406 increased the inflammatory degradation of collagen type III and had no effect on aggrecan degradation. In contrast, the p38 inhibitor SB203580 had no effect on synovial ECM turnover or aggrecan degradation, underlining the importance of understanding the differences between inhibitors of pro-inflammatory mediators and their effect on the joint tissue.”

I think , we best sum it up this way: good study to know more about “differences between inhibitors of pro-inflammatory mediators and their effect on the joint tissue”, but I don’t see anything, that could lead to putting fostamatinib back on the agenda concerning rheumatoid arthritis.

References:

Kjelgaard-Petersen CF, Thudium CS, Siebuhr AS, Christiansen TG, Karsdal MA, Hägglund P, Bay-Jensen AC. The Active Metabolite of Fostamatinib, R406, Only Decreases the Inflammation-Driven Extracellular Matrix Turnover of the Joint at High Concentrations Ex Vivo [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/the-active-metabolite-of-fostamatinib-r406-only-decreases-the-inflammation-driven-extracellular-matrix-turnover-of-the-joint-at-high-concentrations-ex-vivo/. Accessed November 20, 2015.

Fostamatinib in Rheumatoid Arthritis

http://rheumatologe.blogspot.de/2014/10/fostamatinib-in-rheumatoid-arthritis.html

04.12.2015
Today I've read in the "Annals of the Rheumatic Diseases / The EULAR Journal" an article by P.C. Taylor and colleagues: "OSKIRA-4: a phase IIb randomised, placebo-controlled study of the efficacy and safety of fostamatinib monotherapy". Conclusions: "Fostamatinib demonstrated efficacy as monotherapy, showing superior DAS-28(CRP) score changes between baseline and 6 weeks when compared with placebo in treatment arms A and B. However, all fostamatinib regimens demonstrated inferior responses compared with adalimumab at Week 24." "The modest clinical resulta in all of the phase III studies have let to a decision by the companies developing fostamatinib to not submit a regulatoty filing for its use in RA." "The relevance of these findings for other more selective SYK inhibitors remains to be seen.

Link:
http://ard.bmj.com/content/early/2014/07/29/annrheumdis-2014-205361.short?rss=1 

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Fostamatinib in Rheumatoid Arthritis

I was quite surprised reading the title of the following study by M.C. Genovese and colleagues: „ A Phase III, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group Study of 2 Dosing Regimens of Fostamatinib in Patients with Rheumatoid Arthritis with an Inadequate Response to a Tumor Necrosis Factor-α Antagonist.” I thought that fostamatinib had been abandoned as a drug against rheumatoid arthritis. Reading the whole abstract it turned out that I was right: “Because of efficacy and safety results from the phase III clinical program, the companies developing fostamatinib have decided not to study it further in RA at this time.” But let’s look at the first half of the conclusion, too: “Fostamatinib 100 mg bid, but not fostamatinib 100 mg bid for 4 weeks then 150 mg qd, achieved statistical improvements in ACR20 at 24 weeks versus placebo.” In results we find: “Significantly more patients in fostamatinib Group A (36.2%; p = 0.004), but not B (27.8%; p = 0.168), achieved ACR20 at Week 24 versus placebo (21.1%).” Even if the difference between groups is statistically significant, achieving an ACR20 of only 36.2% is too low to continue studies as there are safety concerns as well. Nevertheless, publishing the negative results is most wanted!

Links:

Abstract of the study: http://www.ncbi.nlm.nih.gov/pubmed/25225285

http://rheumatologe.blogspot.de/2013/06/fostamatinib-at-eular-2013.html

Fostamatinib at the EULAR 2013

Concerning fostamatinib I had grown suspicious if it will come to market at all.

EULAR 2012: “It looks a bit too good not to cause suspicion, not in the results but in the relevance. I think we should look careful at the results of the studies that are to come in the next two years. Larger numbers of patients in phase 2 studies would make me more confident that fostamatinib may become a useful drug in the treatment of rheumatoid arthritis.”
ACR 2012, after I had to look at a rodent study: “And there has been nothing more at the ACR 2012 meeting! Perhaps asking for a date, when fostamatinib is to be launched, was a bit premature. I ask myself if there really is any drug in sight!”

Any new developments at the EULAR 2013 to get less suspicious?

There has been a study, one study. P. C. Taylor and colleagues presented [OP0048]: “OSKIRA-4: a phase IIb randomised, placebocontrolled study of the efficacy and safety of fostamatinib monotherapy”. Objectives were the efficacy of fostamatinib monotherapy compared with placebo and the assessment of non-inferiority of fostamatinib to Adalimumab. Two study arms of fostamatinib were superior to placebo, but one wasn’t. All three fostamatinib arms were inferior to adalimumab. The authors argue: “However, the performance of ADA monotherapy in this trial was at the upper end of that observed in previous studies. Fosta is being evaluated in combination with DMARDs in the ongoing Phase III programme.” If I choose to run a 100 m sprint against Donovan Bailey and loose, I can’t argue that he was exceptional quick this day.

The suspicion reaches maximum proportions. We must ask the people in charge if it’s still ethical to continue the phase III study as up to 27% diarrhoea as well as other adverse events may harm the patients, who take part in the trial. I don’t think that FDA or EMEA will approve a drug with such a weak effect and side effects nowadays.

PS. OT: I wouldn’t have approved anakinra for the indication rheumatoid arthritis!

Links:
http://rheumatologe.blogspot.de/2012/07/fostamatinib-at-eular-2012.html
http://rheumatologe.blogspot.de/2012/12/fostamatinib-at-acr-2012-in-washington.html

PPS. Just got a post on Twitter by Philip Gardiner ‏@PhilipGardiner : AstraZeneca has already dropped the fostacitinib! http://www.pmlive.com/pharma_news/astrazeneca_drops_arthritis_candidate_fostamatinib_481092

Fostamatinib at the ACR 2012 in Washington

New data from the EULAR 2013 at: http://rheumatologe.blogspot.de/2013/06/fostamatinib-at-eular-2013.html

Concerning fostamatinib (a SYK inhibitor), how far have we come during the time since EULAR 2012? Any date for launching the drug? Look for details already presented at the EULAR 2012: http://rheumatologe.blogspot.de/2012/07/fostamatinib-at-eular-2012.html

I was quite surprised seeing a rat CIA study on fostamatinib by Polly Pine et al. (Abstract No. 329): “The SYK Inhibitor, Fostamatinib, Administered Alone or in Combination with Methotrexate in Rat Collagen-Induced Arthritis, Reduces Bone Erosions, Biomarkers of Cartilage/Bone Destruction, and Synovial Osteoclastogenic Cytokines.” Conclusion: “Fostamatinib significantly reduced the severity of established rat CIA, had modest additional improvement [my italics] with co-administered MTX, and was superior to MTX alone. These results indicate that fostamatinib may have potential therapeutic benefits for both the inflammatory synovitis and bone erosions of CIA. Fostamatinib is currently in Phase III trials for RA.” This doesn’t sound convincing and if it isn’t convincing in rats, what about humans? I had already voiced my suspicions before, though there’s nothing wrong with this study, it doesn’t convince me of the drug.

And there has been nothing more at the ACR 2012 meeting! Perhaps asking for a date, when fostamatinib is to be launched, was a bit premature. I ask myself if there really is any drug in sight!

Fostamatinib at the EULAR 2012

New data from the EULAR 2013 at: http://rheumatologe.blogspot.de/2013/06/fostamatinib-at-eular-2013.html



Concerning fostamatinib (a SYK inhibitor, SYK stand for spleen tyrosine kinase), how far have we come during the past year?

I have already referred to the study of E. Salgado and colleagues, who systematically reviewed the safety of protein kinase inhibitors in clinical trials in rheumatoid arthritis. They found dizziness in 5%, rash in 6%, increased AST/ALT in 15% (!), hypertension in 13% (!),diarrhea in 17% (!),headaches in 8%, and neutropenia in 7% of patients treted with fostamatinib. So adverse events are an issue with this SYK inhibitor. No wonder that the studies presented at the EULAR 2012 meeting are looking at safety issues.

P. Martin and colleagues studied effects on R406 (the active metabolite of fostamatinib) pharmacokinetics in a total of 32 volunteers with hepatic impairment in Child-Pugh Classes A-C and volunteers with normal hepatic function (each group had eight individuals). As hepatic impairment didn´t affect the exposure of the active metabolite R406 to an extent that would be considered clinically relevant, they concluded that there is no need for dose reduction of fostamatinib in patients with impaired hepatic function.

[THU0139] PHARMACOKINETICS OF FOSTAMATINIB IN PATIENTS WITH IMPAIRED HEPATIC FUNCTION: A PHASE I STUDY
P. Martin1, S. Oliver1, M. Gillen1, T. Marbury2, D. Millson1. 1AstraZeneca Pharmaceuticals, Macclesfield, United Kingdom; 2Orlando Clinical Research Center, Orlando, United States
Conclusions: Hepatic impairment did not affect the exposure of the active metabolite R406 to an extent that would be considered clinically relevant. Consequently, there is no expectation of a need for fostamatinib dose reduction in hepatically impaired subjects.

The same group looked at 24 subjects with normal, moderately and severly impaired renal function. As rrenal impairment didn´t affect the exposure of the active metabolite R406 to an extent that would be considered clinically relevant, they concluded that there is no need for dose reduction of fostamatinib in patients with impaired renal function.

[THU0138] PHARMACOKINETICS OF FOSTAMATINIB IN PATIENTS WITH IMPAIRED RENAL FUNCTION: A PHASE I STUDY
P. Martin1, S. Oliver1, M. Gillen1, T. Marbury2, D. Millson1. 1AstraZeneca Pharmaceuticals, Macclesfield, United Kingdom; 2Orlando Clinical Research Center, Orlando, United States
Conclusions: Renal impairment did not affect the exposure of the active metabolite R406 to an extent that would be considered clinically relevant. Consequently, there is no expectation of a need for fostamatinib dose reduction in renally impaired subjects.

It looks a bit too good not to cause suspicion, not in the results but in the relevance. I think we should look careful at the results of the studies that are to come in the next two years. Larger numbers of patients in phase 2 studies would make me more confident that fostmatinib may become a useful drug in the treatment of rheumatoid arthritis.

Fostamatinib

New data from the EULAR 2013 at: http://rheumatologe.blogspot.de/2013/06/fostamatinib-at-eular-2013.html



Fostamatinib is an oral spleen tyrosine kinase inhibitor, but there hadn’t been as much new data as there had been on Tofacitinib during the 2011 ACR Meeting in Chicago. There are ongoing phase 3 studies, but we have to wait for next year’s EULAR and ACR meetings for results that might lead to marketing and availability.


Effects Fostamatinib on Health-Related Quality of Life in Active Rheumatoid Arthritis

Michael E. Weinblatt and colleagues looked into effects of the oral SYK inhibitor, Fostamatinib, in patients with rheumatoid arthritis, who failed to respond to methotrexate The analysis of this phase II study assessed the impact of fostamatinib on health-related quality of life. Fostamatinib significantly improved health-related quality of life outcomes including physical function, pain, fatigue, and overall physical health status.
[SUN] 420
Effects of the Oral SYK Inhibitor, Fostamatinib (R788), on Health-Related Quality of Life in a Phase II Study of Active Rheumatoid Arthritis.
Michael E. Weinblatt1, Arthur Kavanaugh2, Mark C. Genovese3, David A. Jones4, Theresa K. Musser5, Elliott B. Grossbard5 and Daniel B. Magilavy5.
1Brigham and Women’s Hospital, Boston, MA, 2University of California San Diego, San Diego, CA, 3Stanford University, Palo Alto, CA, 4AstraZeneca, Macclesfield, United Kingdom, 5Rigel Pharmaceuticals, South San Francisco, CAConclusion: In this phase II study, 100 mg bid fostamatinib significantly improved HRQL outcomes including physical function, pain, fatigue, and overall physical health status. Phase III clinical trials of fostamatinib in RA are in progress.


Safety of Fostamatinib (R788) in Patients with Rheumatoid Arthritis From up to 2 Years of Exposure

Arthur Kavanaugh and colleagues presented data on longer-term safety and tolerability for fostamatinib. Data came from randomized, placebo-controlled, fostamatinib phase II trials (TASKi1, 2, and 3), the TASKi1 extension study and from an ongoing open-label study (C-935788-012). Thie analysis included 803 patients with 1,038 patien-years of fostamatinib exposure (mean exposure 1.3 years).
[WED] 2594
Longer-Term Safety of Fostamatinib (R788) in Patients with Rheumatoid Arthritis—Analysis of Clinical Trial Data From up to 2 Years of Exposure.
Arthur Kavanaugh1, Michael E. Weinblatt2, Mark C. Genovese3, Theresa K. Musser4, Elliott B. Grossbard4, Daniel B. Magilavy4, Sally Hollis5, Eveline Wesby van-Sway5 and David Millson5.
1University of California San Diego, San Diego, CA, 2Brigham and Women’s Hospital, Boston, MA, 3Stanford University, Palo Alto, CA, 4Rigel Pharmaceuticals, South San Francisco, CA, 5AstraZeneca, Macclesfield, United KingdomConclusion: No new significant safety signals were identified with longer-term dosing of fostamatinib. Biologic refractory patients on a background of mixed DMARDs had a higher incidence rate of AEs, SAEs, and SIEs compared to MTX inadequate responders on background MTX; further confounding factors may play a role. This will be explored in ongoing phase III studies.