BTK-Inhibitors at the 2019 EULAR Meeting in Madrid

Again there is a hype on small molecules as JAK-inhibitors are on the market and the drug are sold at exorbitant prices – for a small, less complex molecules as compared to large, complex molecules like MABs with much higher production costs. So it is understandable that companies try to come to the market with such drugs. Filgotinib is presented in 10 studies at the 2019 EULAR Meeting in Madrid; as tofacitinib and as baricitinib.

Bruton’s tyrosine kinase (BTK) plays an essential role in B cell development and is thought to be involved in the pathogenesis of RA. There are 5 studies on different BTK-inhibitors at the 2019 EULAR Meeting.

I’ve had a discussion on twitter with friend and colleague Dr Irwin Lim (@_connectedcare) on Twitter yesterday [1]. So I looked deeper into BTK-inhibitors.

Acalabrutinib (Calquence®)

Acalabrutinib (Calquence®) by AstraZeneca: study completed, but no published data on outcome (DAS28) in April 2015. Nothing at the 2019 EULAR Meeting. Calquence® has been approved by the FDA and the EMA for the treatment of mantle cell lymphoma (MCL).

AC0058

AC0058 by ACEA has an ungoing study on systemic lupus erythematodes (NCT03878303), which is still recruiting. I haven't found a study on rheumatoid arthritis.

BMS-986142

BMS-986142 by Bristol-Myers Squibb: study completed, but no published data on outcome (ACR20, ACR70) in Feb. 2016. Nothing at the 2019 EULAR Meeting.

Evobrutinib

Evobrutinib by Merck: study ongoing (ACR20) in Jul. 2017. Nothing at the 2019 EULAR Meeting.

Fenebrutinib

Fenebrutinib by Roche/Genentech: study completed (ACR50) in Sep. 2016. There are two studies. St. Cohen and colleagues concluded in phase 2 study: “FEN [Fenebrutinib] demonstrated higher efficacy rates than PBO [placebo] for ACR50 at W12 in both MTX-IR and TNF-IR [inadequate response] populations, and was similar to ADA [adalimumab] in MTX-IR pts. The overall safety profile of FEN was acceptable.“ [2] The other study is a cell study (THE BTK INHIBITOR, FENEBRUTINIB, EFFECTIVELY MODULATES B AND MYELOID CELL BIOLOGY IN RHEUMATOID ARTHRITIS PATIENTS).

Poseltinib

Poseltinib (LY3337641) by Eli Lilly: study terminated because of lack of efficacy (ACR20) in Aug. 2016. Early in 2018 Eli Lilly has halted a phase 2 trial on rheumatoid arthritis after looking at the mid-study data. Probably the efficacy goal wasn’t likely to be met (ACR20). [3] These study results will be discussed at the 2019 EULAR Meeting on Saturday.

Spebrutinib

Spebrutinib by Celgene failed to meet primary outcome (ACR20) in Oct. 2013. Nothing at the 2019 EULAR Meeting.

TAS 5315

TAS 5315 is a BTK inhibitor by Taiho. There are two animal studies at the 2019 EULAR Meeting.

Tirabrutinib

Tirabrutinib (ONO-4059) by Ono Pharmaceutical/Gilead Sciences: there had been some efficacy in a CIA study, but nothing more than a phase 1 study for rheumatoid arthritis so far.

Irwin, you’ve written: Fenebrutinib in RA - some promise #eular2019, and I have to admit, I come to the same conclusion. I had answered: BTK inhibitor? There have been posters for a long time. Is the small molecule hype back? #EULAR2019 #Fenebrutinib. There is some promise as fenebrutinib showed a similar response like adalimumab. Now, we’ll have to wait for a phase 3 study and of course the approval by FDA, EMA and other countries’ boards. Hopefully, the price level will be lower than it is now with other small molecules.

Links:

[1] Orininal Tweet by Dr Lim: https://twitter.com/_connectedcare/status/1138821551229493250

[2] St. Cohen and colleagues: Ann Rheum Dis, volume 78, supplement 2, year 2019, page A80 http://scientific.sparx-ip.net/archiveeular/?view=1&c=a&searchfor=Bruton%E2%80%99s%20tyrosine%20kinase%20&item=2019OP0025

[3] https://www.fiercebiotech.com/biotech/lilly-scraps-rheumatoid-arthritis-trial-after-interim-review

.

High Hopes and Aspirations or how ASP015K / Peficitinib brings back the Small Molecule Hype

ASP015K, now called peficitinib is an oral Janus kinase (JAK) inhibitor with selectivity for JAK1/3, developed by Astellas Pharma for treatment of rheumatoid arthritis (RA) and other autoimmune diseases [1]. A year later, as the hype about JAK and small molecules were cooling down, I’ve written: “Could ASP015K keep up with its’ aspirations at the EULAR 2013 meeting?” And: “My positive impression dwindles considerably! I hope we’ll see results from a phase 2b study later this year.” [2] So we already had a Phase 2b study presented at the EULAR 2013 Meeting.

As tofacitinib and baricitinib are approved in the EU right now, hype and hopes in protein kinase inhibitors return. Last year I’ve speculated: “I guess that the pharmaceutical industry isn’t prudent enough not to overprice small molecules, so that our patient's needs are addressed.” [3] And I’ve proven right. [4]

Recently Gregory M. Weiss, M.D. has published an article [5]: “JAK Inhibitor Peficitinib Reduces RA Symptoms”. He refers to a phase 2b study. So, it seemed to me nothing new under the sun. I stumbled over the sentence: “The authors suggest that rheumatoid arthritis patients with elevated C-reactive protein levels may respond better to higher doses of peficitinib than those with elevated sedimentation rates.” Most of my patients, who have elevated sedimentation rates also have elevated C-reactive protein levels, and vice versa.

There is already a phase 3 study on Peficitinib under way [6]. I’ve checked the abstracts for the 2017 EULAR Meeting (still under embargo), but there isn’t any study mentioned, so that I expect news on this study could be published at the ACR 2017 Meeting later this year.

There will be an open extension phase 2b study on filgotinib being presented at the EULAR 2017 Meeting. No study on decernotinib expected at the EULAR 2017 Meeting.

The race for the high end price level small molecules is open again. Let’s hope that besides the hype there’ll be some benefit for our patients.

Links:

[1] http://rheumatologe.blogspot.de/2012/12/asp015k-at-acr-2012-in-washington.html

[2] http://rheumatologe.blogspot.de/2013/06/asp015k-at-eular-2013-meeting.html

[3] http://rheumatologe.blogspot.de/2016/08/protein-kinase-inhibitors-small.html

[4] http://rheumatologe.blogspot.de/2017/05/tofacitinib-xeljanz-kommt-gerade-an.html Text in German.

[5] http://www.rheumatologynetwork.com/rheumatoid-arthritis/jak-inhibitor-peficitinib-reduces-ra-symptoms?GUID=71CAAEF6-94A2-4616-B379-17C18CF13750&rememberme=1&ts=30052017

[6] http://adisinsight.springer.com/drugs/800028907

.

Otezla® and an increased risk of suicide

Otezla® (active ingredient: Apremilast from Celgene) has been given a "Red Hand Letter" this month. In a "red hand letter" all physicians in Germany get important communications about a drug (e.g. new discovered side effects of a drug).

In the summary the letter reads: "Occasional cases of suicidal thoughts and suicidal behavior (with or without history of depression) have been reported in clinical trials and after market introduction (frequency ≥1/1,000 to ≤1/100). Cases of successful suicide have been reported after market introduction in patients treated with Apremilast."

The following background information has been given: "Notes on suicide thoughts and suicide behaviors: - The data collected after market launch by 20^th March 2016 included 65 reported cases with 5 suicides completed, 4 suicide trials, 50 cases with suicide thoughts, 5 cases with depression and suicide thoughts, and 1 case with suicidal behavior. (...)"

Perhaps I’m too skeptical about small molecules, but I had argued already years ago that a change in communication within the cell could lead to more problems in regard to side effects than the interruption of communication between cells (e.g. by biologics). For the biologics used up to date in rheumatology, I do not know an increase in suicide and suicidal ideation; however, Amgen had withdrawn from the development of brodalumab (anti-IL-17R autoantibody). Brodalumab will be available in the US as Siliq, an introduction to Europe is expected for the first quarter of 2017. More about this has been discussed in the psoriasis network (in German!). For Tofacitinib, two suicides were listed in 2012, "ADVISORY COMMITTEE MEETING TOFACITINIB FOR THE TREATMENT OF RHEUMATOID ARTHRITIS". For baricitinib the number of patients tested may still be too low to answer this question.

I have used Otezla® very rarely since I have preferred other drugs, which were approved earlier, because of better knowledge and more experience. I won’t change this attitude. On the other hand, a danger that is known is also a lesser danger. 

Links (some texts in German):
Psoriasis-Netz zu Brodalumab http://www.psoriasis-netz.de/lexikon/brodalumab-siliq 
ADVISORY COMMITTEE MEETING TOFACITINIB FOR THE TREATMENT OF RHEUMATOID ARTHRITIS im Jahr 2012 - http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM302960 http://rheumatologe.blogspot.de/2015/11/brodalumab-at-acr-2015-meeting-in-san.html 
http://rheumatologe.blogspot.de/2013/01/neue-therapien-bei-rheumatoider.html 
http://rheumatologe.blogspot.de/2016/08/protein-kinase-inhibitors-small.html

.