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

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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

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Otezla® und ein erhöhtes Risiko für Selbstmord

Zu Otezla® (Wirkstoff: Apremilast der Firma Celgene) hat es diesen Monat einen „Rote Hand Brief“ gegeben. In einem „Rote Hand Brief“ bekommen alle Ärzte wichtige Mitteilung zu einem Medikament.

In der Zusammenfassung steht nun:„Gelegentliche Fälle von Suizidgedanken und suizidalem Verhalten (mit oder ohne Depression in der Anamnese) wurden in klinischen Studien und nach Markteinführung berichtet (Häufigkeit ≥1/1.000 bis ≤1/100). Fälle von vollendetem Suizid wurden nach Markteinführung bei Patienten, die mit Apremilast behandelt wurden, berichtet.“

Folgende Hintergrundinformationen wurden u.a. gegeben: „Hinweise bezüglich Suizidgedanken und Suizidverhalten: 
- Die nach Markteinführung bis zum 20. März 2016 erhobenen Daten umfassten 65 gemeldete Fälle mit folgender Verteilung: 5 vollendete Suizide, 4 Suizidversuche, 50 Fälle mit Suizidgedanken, 5 Fälle mit Depression und Suizidgedanken sowie 1 Fall mit suizidalem Verhalten. (…)“

Vielleicht verhalte ich mich gegenüber den small molecules zu skeptisch, aber ich habe schon vor Jahren die Meinung vertreten, dass eine Veränderung der Kommunikation innerhalb der Zelle mehr Probleme in Hinsicht auf unerwünschte Arzneimittelwirkungen nach sich ziehen könnte als die Unterbrechung der Kommunikation der Zellen untereinander (z.B. durch Biologika). Für die die bislang in der Rheumatologie eingesetzten Biologika ist mir eine Erhöhung von Suizid und Suizidgedanken nicht bekannt; allerdings hatte sich Amgen aus der Entwicklung von Brodalumab (anti-IL-17R Autoantikörper) zurückgezogen. Brodalumab wird als Siliq in den USA erhältlich sein, eine Einführung in Europa wird für das 1. Quartal 2017 erwartet. Mehr dazu im Psoriasis-Netz. Für Tofacitinib wurden zwei Suizide im Schreiben „ADVISORY COMMITTEE MEETING TOFACITINIB FOR THE TREATMENT OF RHEUMATOID ARTHRITIS” im Jahr 2012 aufgelistet. Für Baricitinib kann die Zahl der getesteten Patienten für diese Frage noch zu gering sein.

Ich habe Otezla® erst sehr selten eingesetzt, da ich andere Medikamente, die früher zugelassen wurden, durch besseres Wissen und mehr Erfahrung bevorzugt habe. Daran wird sich zunächst auch nichts ändern. Andererseits ist eine Gefahr, die bekannt ist, auch eine geringere Gefahr.
Link:
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

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Baricitinib reaching out for the market

It seems that baricitinib gets ready to come to the market. The annual meetings this year have seen a plethora of studies on baricitinib both at the EULAR meeting in London and the ACR meeting in Washington.

Noteworthy: both meetings received different studies or better different aspects of studies. With other compounds abstracts didn’t differ at both congresses. Not so with baricitinib.

Interestingly the crucial study on radiographic progression only appeared at the EULAR meeting. The FDA approved tofacitinib, but EMEA didn’t a couple of years ago. I think this had an impact on baricitinib. If it had an impact on FDA, let’s wait to see if baricitinib is approved or not. Tofacitinb has applied for approval in Europe (March 2016), so Xeljanz should have an advantage of time.

The study by D. van der Heijde and colleagues showed a robust inhibition of radiographic progression for the 4 mg dose of baricitinib.

N.V. Zamora and colleagues came to the following conclusions: 1. baricitinib with or without MTX had better responses as compared to MTX at 12 and 24 weeks (baricitinib+MTX lower withdrawal rate than MTX alone), 2. baricitinib showed similar effects as adalimumab (with higher rates of SAEs). The authors consider baricitinib to be an additional therapeutic option to treat patients with moderate to severe rheumatoid arthritis, who have an inadequate response to other treatment agents.

There will be a study in a few days by Kevin L. Winthrop and colleagues at the ACR Annual Meeting in Washington: “Herpes Zoster in Patients with moderate to Severe Rheumatoid Arthritis Treated with Baricitinib” [Abstract Number: 3027] – which will have to be discussed at the meeting first.

What can we say today? Lilly is committed to bring baricitinib to the market. Let’s see how quickly. I expect approval or non-approval within half a year both for the US and the EU.

Links:

Radiographic progression – EULAR [THU0168] D. van der Heijde , M. Dougados , Y.-C. Chen, M. Greenwald , E. Drescher , R. Klar , L. Xie , I. de la Torre , T.P. Rooney , S. Witt , D. Schlichting , S. DeBono, P. Emery: Baricitinib Inhibits Radiographic Progression of Structural Joint Damage at 1 Year in Patients with Rheumatoid Arthritis (Ra) and an Inadequate Response to csDMARDS. DOI: 10.1136/annrheumdis-2016-eular.1611

Meta-Analysis - EULAR [SAT0177] N.V. Zamora , J. Tayar , M.A. Lopez-Olivo , R. Christensen , M.E. Suarez-Almazor: Baricitinib for  Rheumatoid Arthritis: A Systematic Review and Meta-Analysis. DOI: 10.1136/annrheumdis-2016-eular.4449