Protein Kinase Inhibitors after the ACR 2015 Meeting in San Francisco – how much Hype is left?

I have already written about hype or hope in protein kinase inhibitors. Now, after the ACR 2015 Annual Meeting in San Francisco it’s time to ask: how much hype is left?

Here a chart, I’ve prepared only a year ago:

Xeljanz (tofacitinib) is on the market in the US for the treatment of rheumatoid arthritis, but still lacks approval in Europe.

Otezla (apremilast) has been approved in the US and later in Europe for the treatment of psoriatic arthritis.

One study on fostamatinib came up, but only on bovine cartilage cells – but still unexpected for me; see: links.

Baricitinib had been discussed in several studies, posters, talks at the meeting; I’ll write on the studies in detail, soon.

Addendum: somehow I've left out filgotinib. Filgotinib is still in the race. Please look for more details under links.

This list above is incomplete, I know, but it shows how many hopes we had. I think that too many pharmaceutical companies tried to run for a small molecule, which is easier to produce, but might be sold at a high price. This mass of different molecules with facets of different effects was fuelling the hype, which peaked, when Xeljanz got the FDA approval. But I assure you: the hype is gone. Xeljanz is struggling for EMEA approval. Fostamatinib like most others have been abandoned as potential drugs. Otezla is approved in Germany, but will hardly be used because of failure of obtain a positive GBA ruling. The GBA (Federal Joint Committee) “exerts a direct influence on the healthcare provisions”; for further details look at Wikipedia, you can use the link below. And I think that Baricitinib will reach approval, too.

I hope that the pharmaceutical industry is prudent enough not to overprice small molecules, so that our patient's needs are addressed.

Links:

http://rheumatologe.blogspot.de/2013/06/protein-kinase-inhibitors-hype-or-hope.html

http://rheumatologe.blogspot.de/2014/01/protein-kinase-inhibitors-where-do-we.html

http://rheumatologe.blogspot.de/2014/06/protein-kinase-inhibitors-at-eular-2014.html

http://rheumatologe.blogspot.de/2015/11/fostamatinib-at-acr-2015-meeting-in-san.html

https://en.wikipedia.org/wiki/Federal_Joint_Committee_(Germany)
http://rheumatologe.blogspot.de/2015/11/filgotinib-at-acr-2015-meeting-in-san.html

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Carpe Diem Haiku No. 862 Vistas

  

Snow fallen on peaks

Resting for a while, then melt

Monk is resting, too

Camels are ready

To move down from the mountains

Seasons guide nomads

Sharp ridges on top

Rounded base holds man and rock

Nature is yin-yang

http://chevrefeuillescarpediem.blogspot.de/2015/11/carpe-diem-862-vistas.html

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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ERAP1 at the ACR 2015 Meeting in San Francisco

There has been one publication on ERAP1 at the ACR 2015 Annual Meeting in San Francisco. ERAP1 (endoplasmic reticulum aminopeptidase 1) has a strong genetic association of with ankylosing spondylitis, which is restricted to HLA-B27 positive cases. I’ve become interested while being at the 2014 EULAR Meeting in Paris. And now we have a new tiny piece of evidence that there might be a drug in the far future.

Tri M. Tran and colleagues presented: “ERAP1 Deficiency Protects HLA-B27 Transgenic Rats from Arthritis”. Conclusion: “Complete absence of ERAP1 protected B27-TG rats from arthritis, but led to an increase in gut inflammation, suggesting different effects on pathogenic mechanisms involved in arthritis and colitis. B27-TG rats heterologous for ERAP1 exhibited higher incidence of arthritis concomitant with lower inflammation in the gut as compared to ERAP1-/- .This novel model provides an opportunity to better understand the mechanism(s) by which HLA-B27 contributes to SpA pathogenesis”.

Protection from arthritis, but increase in gut inflammation. What goes through my mind now? Far future, individually tailored therapy, basic science … Yes, and far too early to speculate on a new drug.

References:

Tran TM, Hong S, Gill T, Bennett J, Sikora K, Colbert RA. ERAP1 Deficiency Protects HLA-B27 Transgenic Rats from Arthritis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/erap1-deficiency-protects-hla-b27-transgenic-rats-from-arthritis/. Accessed November 20, 2015.

ERAP1 at the EULAR 2014 Meeting in Paris http://rheumatologe.blogspot.de/2014/07/erap1-at-eular-2014-meeting-in-paris.html

ABT-122 at the ACR 2015 Meeting in San Francisco

There has been one publication on ABT-122 at the ACR 2015 Annual Meeting in San Francisco. ABT-122 is an anti-TNF/IL-17 Dual Variable Domain immunoglobulin (DVD-Ig™). It had been "demonstrated that dual neutralization of TNF and IL-17 provides greater efficacy than blocking either cytokine alone in mouse collagen induced arthritis". But we already know, that for instance secukinumab (an anti-IL-17a MAB) did not achieve the primary endpoint (ACR20) in patients with rheumatoid arthritis. So, from the beginning I’m very sceptical. But let’s look at the study.

Roy Fleischmann and colleagues presented: “Safety, Tolerability, and Pharmacodynamics of ABT-122, a Dual TNF- and IL-17-Targeted Dual Variable Domain (DVD)-IgTM in Subjects with Rheumatoid Arthritis”. Background/Purpose: […] ABT-122 is […] is hypothesized to provide greater clinical responses in patients with RA.” Conclusion: “ABT-122 demonstrated a well tolerated safety profile in subjects with RA through 8 weeks of dosing up to 3 mg/kg, […] decreases in these chemokines [CXCL9, CXCL10, and CCL23] indicate that ABT-122 rapidly modulates potential pathophysiologic pathways in RA patients, with evidence for persistent effects after cessation of dosing. These results suggest that dual neutralization of TNF and IL-17 may provide an opportunity to control inflammation and its clinical manifestations in RA subjects and in other immune-mediated inflammatory diseases.” Thin ice!

I think the first step in convincing me would be testing ABT-122 against a TNF-inhibitor. As ABT-122 comes from AbbVie, testing against Humira shouldn’t be a problem. Until then, IL-17 in ABT-122 may be nothing more than a pinch of cinnamon in the coffee, which changes the flavour but not the caffeine content.

References:

Fleischmann R, Wagner F, Kivitz AJ, Mansikka HT, Khan N, Liu J, Gagnon J, Hong F, Ruzek M, Padley RJ. Safety, Tolerability, and Pharmacodynamics of ABT-122, a Dual TNF- and IL-17-Targeted Dual Variable Domain (DVD)-IgTM in Subjects with Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/safety-tolerability-and-pharmacodynamics-of-abt-122-a-dual-tnf-and-il-17-targeted-dual-variable-domain-dvd-igtm-in-subjects-with-rheumatoid-arthritis/. Accessed November 20, 2015.

Brodalumab at the ACR 2015 Meeting in San Francisco

There has been one publication on brodalumab at the ACR 2015 Annual Meeting in San Francisco.

Brodalumab is an anti-IL 17 receptor MAB, which is a promising new drug on the horizon against psoriatic arthritis as it targets IL-17, which plays a role "in the pathogenesis and ongoing inflammation of psoriatic disease". But only one study!

Mark C. Genovese and colleagues presented: “Two-Year Clinical Response to Brodalumab, an Anti-Interleukin-17 Receptor Antibody, in Patients with Psoriatic Arthritis”. Conclusion: “Treatment with brodalumab resulted in a safety profile comparable to the overall safety profile of biologics approved for PsA [psoriatic arthritis] and meaningful clinical benefit that was maintained through week 108 in patients with PsA in this ongoing OLE [open label extension].”

An evaluation of clinical data of phase 2 study isn’t very convincing. Where’s data on radiographic progression after two years? The sponsor doesn’t seem to push the agenda. Still committed or simply keeping it up at low level in case something weird happens to Secukinumab to push it from getting approval as a drug. Else I don’t see a reason, why not recruiting for a phase 3 study.

References:

Genovese MC, Mease PJ, Greenwald M, Ritchlin CT, Beaulieu A, Deodhar AA, Newmark R, Feng J, Erondu N, Nirula A. Two-Year Clinical Response to Brodalumab, an Anti-Interleukin-17 Receptor Antibody, in Patients with Psoriatic Arthritis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/two-year-clinical-response-to-brodalumab-an-anti-interleukin-17-receptor-antibody-in-patients-with-psoriatic-arthritis/. Accessed November 19, 2015.

Sirukumab at the ACR 2015 Meeting in San Francisco

There has been one publication on sirukumab at the ACR 2015 Annual Meeting in San Francisco. Sirukumab is a human MAB that binds to IL-6, designed for the treatment of rheumatoid arthritis. So sirukumab will compete with tocilizumab. I’ve seen the first studies at the EULAR 2012 Meeting in Berlin. So now we have one study. You know, how suspicious I am, and this makes me even more suspicious.

Tsutomu Takeuchi and colleagues presented: “One-Year Safety of Sirukumab Monotherapy: Results from a Randomized, Double-Blind, Parallel-Group, Multicenter Study in Japanese Subjects with Moderate to Severe Rheumatoid Arthritis”. It’s a phase 2 study. Conclusions: “Sirukumab 50mg q4 and 100mg q2 monotherapy dose regimens for 52 weeks were well tolerated in Japanese RA patients. […] The proportions of ACR 20/50/70 responses at Week 24 in the 100mg q2 group were numerically higher than those in the 50mg q4 group; however, the number of subjects was too limited to make conclusions about dose response.”

Why is the sponsor not pushing to get to the market? If he wants to take part of the IL-6 piece of the cake, he should hurry as the cake is cut into more and more pieces. I see a lack of commitment. And actually I don’t see a medical reason to have another IL-6 inhibitor.

References:

Takeuchi T, Yamanaka H, Harigai M, Tamamura R, Kato Y, Ukyo Y, Nakano T, Ota T, Hsu B, Tanaka Y. One-Year Safety of Sirukumab Monotherapy: Results from a Randomized, Double-Blind, Parallel-Group, Multicenter Study in Japanese Subjects with Moderate to Severe Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/one-year-safety-of-sirukumab-monotherapy-results-from-a-randomized-double-blind-parallel-group-multicenter-study-in-japanese-subjects-with-moderate-to-severe-rheumatoid-arthritis/. Accessed November 19, 2015.