Abatacept Biosimilars at the 2017 EULAR Annual Meeting in Madrid

The patents on abatacept (Orencia) will expire in Europe in December 2017 and in the US in October 2019 [1]. So I guess the idea isn’t farfetched to look for a biosimilar of abatacept at the 2017 EULAR Annual Meeting in Madrid. I could shorten the story and tell you that hasn’t been any data on abatacept biosimilars EULAR 2017 meeting (I've at every abstract concerning abatacept). But …

In 2014 I found a possible abatacept biosimilar in China [2]: “Leining, a novel cytotoxic T-lymphocyte antigen-4 fusion protein”. Leining had been developed by Shanghai CP Guojian Pharmaceutical. Leining looked like a biosimilar to abatacept (Orencia) to me. In abatacept the extracellular domain of CTLA-4 and the Fc region of the immunoglobulin IgG1 are fused together. As I couldn’t find anything on it, I’ve contacted W. Fan and colleagues to tell us, whether Leining is a biosimilar to abatacept or what else it is. I’ve never received an answer. Leining could well be a biomimic [3]. Adisinsight shows as most recent events [4]:” 5 Mar 2016 - Biomarkers information updated / 24 Mar 2014 - No development reported - Preregistration for Rheumatoid arthritis in China (Parenteral)”. I think we won’t hear more from Leining.

Generics and Biosimilars Initiative (GaBI) reported, that BioXpress Therapeutics (Switzerland) and Momenta Pharmaceuticals/Mylan (USA) are working on abatacept biosimilars [1]. In November 2016 Momentapharm initiated a phase 1 clinical trial to compare the pharmacokinetics, safety and immunogenicity of M834, their on abatacept biosimilar, to US- and EU-sourced Orencia in normal healthy volunteers [5].

So it means that Orencia will have a reprieve without biosimilar competitors.

Links and References: 
[1] http://www.gabionline.net/Biosimilars/General/Biosimilars-of-abatacept 
[2] http://rheumatologe.blogspot.de/2014/11/leining-novel-cytotoxic-t-lymphocyte.html 
[3] http://rheumatologe.blogspot.de/2016/08/bioidenticals-biosimilars-biologics.html 
[4] http://adisinsight.springer.com/drugs/800039891 
[5] http://www.momentapharma.com/pipeline/development-programs.php

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Bioidenticals - Biosimilars - Biologics - Biomimics

In rheumatology, there are lots of new concepts to learn nowadays.

Most people already know, what biologics are. Biologics are biopharmaceutical products that have been in use for about two decades in rheumatology. These are for instance Remicade (infliximab), Enbrel (etanercept), Humira® (adalimumab), Kineret® (anakinra), Orencia® (abatacept), Mabthera® (rituximab), Actemra® (tocilizumab), Simponi® (golimumab), Cimzia® (certolizumab) Benlysta® (belimumab), Prolia® (Denusomab) Ilaris® (canakinumab), Stelara® (ustekinumab), Cosentyx® (Secukinumab).

Biosimilars are generic biologics that may be approved after patent expiry of the original drug. Biosimilars are not completely identical to the original products. Biosimilars must demonstrate bioequivalence in studies. In Germany currently we have infliximab biosimilars and a etanercept biosimilar.

Infliximab Biosimilars: Remsima®, Inflectra®, Flixabi®.

Etanercept biosimilar: Benepali®.

Biomimics are generic biologics like biosimilars, but they do not meet the requirements for bisosimilars. Another term for these biomimics is "intended copies". More here: http://rheumatologe.blogspot.de/2016/01/biomimics.html (English text). At the recent European rheumatology annual meeting (EULAR 2016 in London), I saw a poster by M. Scheinberg and colleagues under the title: "Variability of Intended Copies for etanercept in 5 Countries". They showed significant differences. These Biomimics do not have approval in Germany.

What are bioidenticals? Bioidenticals are generic biologics of the same production. So these are identical to each other. One can imagine this: a production is bottled in vials, but have different labels. Currently this applies only to infliximab in Germany. Remsima® and Inflectra® come from one production (Celltrion in South Korea).

If a biologic (in this example: Remsima®, Inflectra®, Flixabi®) is prescribed by trade name (for example Remicade), an exchange by a biosimilar (Remsima®, Inflectra®, Flixabi®) is not possible. A prescription under the generic name (in this example: infliximab) is rated as "unclear prescription", so that the pharmacist is not allowed to give out any drug. Bioidenticals are an exception; these can be exchanged according to discount agreements. Remsima® and Inflectra® could therefore be used interchangeably.

In summary, it looks more complicated than it is.

(Translation of a German text on this blog)

Bioidenticals – Biosimilars – Biologika – Biomimics

In der Rheumatologie gibt es derzeit viele neue Begriffe zu lernen.

Was Biologika sind, wissen die meisten. Biologika sind biopharmazeutische Arzneimittel, die bereits seit ca. zwei Jahrzehnten in der Rheumatologie angewendet werden. Es sind dies z.B. Remicade^® (Infliximab), Enbrel^® (Etanercept), Humira^® (Adalimumab), Kineret^® (Anakinra), Orencia^® (Abatacept), Mabthera^® (Rituximab), RoActemra^® (Tocilizumab), Simponi^® (Golimumab), Cimzia^® (Certolizumab), Benlysta^® (Belimumab), Prolia^® (Denusomab), Ilaris^® (Canakinumab), Stelara^® (Ustekinumab), Cosentyx^® (Secukinumab).

Biosimilars sind Nachahmerprodukte von Biologika, die nach Ablauf der Patentzeit des Originalwirkstoffs zugelassen werden können. Biosimilars sind nicht völlig identisch mit dem Originalprodukt. Sie müssen die Bioäquivalenz in Studien nachweisen. Zur Zeit sind in Deutschland zugelassen: Infliximab-Biosimilars und ein Etanercept-Biosimilar.

Infliximab-Biosimilars: Remsima^®, Inflektra^®, Flixabi^®.

Etanercept-Biosimilar: Benepali^®.

Biomimics sind wie Biosimilars Nachahmerprodukte von Biologika, aber sie erfüllen nicht die Anforderungen für Bisosimilars. Ein anderer Begriff dafür ist „Intended Copies“. Mehr dazu hier: http://rheumatologe.blogspot.de/2016/01/biomimics.html (englischer Text).  Auf dem letzten europäischen Kongress (EULAR 2016 in London) sah ich ein Poster dazu. M. Scheinberg und Kollegen berichteten unter dem Titel: „Variability of Intended Copies for Etanercept in 5 Countries“. Sie wiesen erhebliche Unterschiede nach. Diese Biomimics sind bei uns nicht zugelassen.

Was sind nun Bioidenticals? Bioidenticals sind Nachahmerprodukte von Biologika aus derselben Herstellung. Sie sind also untereinander identisch. Man kann sich das so vorstellen: eine Produktion wird in Fläschchen abgefüllt, aber es werden verschiedene Etiketten aufgeklebt. Aktuell gibt es dies nur für Infliximab. Remsima^® und Inflektra^® stammen aus einer Produktion (Celltrion in Süd Korea).

Wird ein Biologikum mit Handelsnamen (z.B. Remicade^®) verordnet, ist ein Austausch durch ein Biosimilar (in diesem Beispiel: Remsima^®, Inflektra^®, Flixabi^®) nicht möglich. Eine Verordnung unter dem Wirkstoffnamen (in diesem Beispiel: Infliximab), wird als „unklare Verordnung“ gewertet, so dass der Apotheker kein Arzneimittel abgeben darf. Bioidenticals bilden eine Ausnahme, sie können entsprechend von Rabattverträgen ausgetauscht werden. Remsima^® und Inflektra^® könnten also untereinander ausgetauscht werden.

Zusammenfassend sieht es komplizierter aus, als es ist.

Biomimics

What are biomimics, you might ask. I did the same thing. Well, with the proliferation of biosimilars, we should be able to tell the one from the other.

Dr.Martínez (@MtzReuma) already has tweeted about a year ago: “… Biosimilars are NOT "biomimics" (AKA intended copies) …” (https://twitter.com/mtzreuma/status/569270634057871360). I won’t leave you with this statement though it already tells you what biomimcs are, but I’ll try to go a little deeper in the subject. “Biomimics, also known as intended copies, are non-originator biologicals that have received marketing approval before biosimilar regulations were put in place. They are currently available in some Asian and Latin American countries.” Link: http://www.gabionline.net/layout/set/print/Biosimilars/Research/Approval-of-biosimilars-in-rheumatology.

Yisaipu (益赛普) is an etanercept biomimic from China which is also sold as Etanar/Etart/Etacept in Colombia, Mexico, and India. Yisaipu wasn’t compared to innovator Etanercept. Infinitam is another etanercept biomimic, manufactured and marketed by Probiomed, a Mexican company.

Reditux® is biomimic marketed by Dr Reddy's Laboratories in Bolivia, Chile, India, Iran, and Peru; Wikipedia uses the classification as a “non-comparable biologic (NCB) version of rituximab”; link: https://en.wikipedia.org/wiki/Reditux. Also marketed in Paraguay by Farmasa as Tidecron®. Kikuzubam®, another biomimic of rituximab, is marketed by Probiomed in Bolivia, Chile, Mexico, and Peru.

A biosimilars must demonstrate equivalent efficacy and safety in head-to-head clinical studies with the originator biological. Biomimics fail to prove biosimilarity. Maybe Reditux® could prove to be a biosimilar to originator rituximab, but hasn’t done so as it has been approved in 2007 in India and won’t try to go to European or Northern American markets; until then it should be called a biomimic (I wouldn’t use the term “non-comparable biologic (NCB)”).

Take away message: Biomimics, also known as intended copies, are non-originator biologicals, that failed to prove biosimilarity.

Link:

Gilberto Castañeda-Hernández and colleagues: Biosimilars in rheumatology: what the clinician should know. http://rmdopen.bmj.com/content/1/1/e000010.full