Biosimilars und Biologika auf dem DGRh Kongress 2017 in Stuttgart

Warum ist die Politik so daran interessiert, warum Krankenkassen, Patientenverbände, Fachgesellschaften? Weil sie zuvor ihre Hausaufgaben nicht gemacht haben. Denn sie haben der Preisexplosion nicht Einhalt geboten. Das fing schon vor den Biologika an, aber hierbei ist es doch besonders offensichtlich – und ein Ende ist da nicht in Sicht, wenn wir an die small molecules wie Tofacitinib oder Baricitinib denken. So steigen die Preise weiter an. Der Markt wird immer unüberschaubarer.

Biosimilars kommen wie Innovationen daher, als hätte die Welt darauf gewartet, aber es sind schließlich nur  Imitate; die entscheidenden Ideen haben andere gehabt und in Studien die Wirksamkeit nachgewiesen. Die  Patienten jedenfalls werden damit überfordert. Insbesondere wo es neben Biosimilars auch schon Bioidenticals gibt. Auch wenn ich nicht auf Biosimilars gewartet habe, werde ich sie denooch anwenden, besser anwenden müssen.

Welche Biosimilars haben wir denn? Welche Biologika wurden denn vorgestellt? Gab es funkelnagelneue Bio***s? In dieser Übersicht werde ich mich auf den Einsatz dieser Medikamentengruppe in der Therapie der rheumatoiden Arthritis, der Psoriasisarthritis und den seronegatiben Spondyloarthritiden beschränken.

Biosimilar-Kandidaten zu Humira® (Adalimumab) BI 695501 von Boehringer Ingelheim - ENCORE.42 (Encore sind Poster, die bereits anderswo gezeigt wurden) - das Poster beschäftigt sich mit dem Autoinjektor. Encore.47 beschäftigt sich mit Wirksamkeit und Nebenwirkung und findet keinen wesentlichen Unterschied.

Ansonsten fanden sich viele Poster zu Secukinumab, aber auch Daten zu Tocilizumab, Certolizumab, Canakinumab, Sarilumab, Abatacept, Golimumab, Rituximab, Ixekizumab und Infliximab.

H. Kellner präsentierte Daten aus seiner Schwerpunktpraxis (EV.13): " Hohe Patientenakzeptanz bei Neueinstellung oder Umstellung von Originalabiologika (Enbrel, Remicade) auf Biosimilar-TNF Ak". Die Arbeit hat nur geringe Fallzahlen. In der Schlussfolgerung lesen wir: "Den angesprochenen Patienten ist die Möglichkeit einer substanziellen Kostenersparnis bei Einsatz von Biosimilar durchaus bewußt und ein wesentliches Element der Bereitschaft selbst Biosimilars zu verwenden." Das kann ich so aus den Ergebnissen nicht herauslesen. Ob eine Kostenersparnis dauerhaft gegenüber den Originalherstellern bestehen bleibt, muss die Zukunft zeigen, denn es wird wahrscheinlich zu Festpreisen kommen.

Zusammenfassend spielen die Biosimilars in der Wissenschaft eine untergeordnete Rolle. Das liegt in der Natur der gesetzlichen Bestimmungen, denn es muss nur der Nachweis von gleicher Effektivität und Nebenwirkung zum Orinalpräparat in einer Indikation nachgewiesen werden. Das sollte auch leicht möglich sein, wenn die Strukturgleichheit gegeben ist - und davon ist auszugehen. Für Infliximab haben wir die Biosimilars Remsima®, Inflectra® und Flixabi®, wovon Remsima® und Inflectra® bioidentisch sind, d.h. sie haben einen Hersteller und zwei Vertreiber. Für Etanercept haben wir die Biosimilars Benepali® und Erelzi™. Für Rituximab ist das Biosimilar Truxima® zugelassen. Für Adalimumab ist das Biosimilar Amjevita™ in den USA zugelassen und wird neben anderen hier in der nahen Zulunft erwartet [1].

Für die o.g. Originalpräparate ist eine Fülle von neuen Daten veröffentlicht worden. Allerdings habe ich nichts zu Mavrilimumab und Vobarilizumab gefunden.

Links:

[1] http://rheumatologe.blogspot.de/2016/12/possible-problems-with-piosimilars.html

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Gout (Part 2) at the ACR 2015 Meeting in San Francisco

There has been a multitude of publications on Gout at the ACR 2015 Annual Meeting in San Francisco. I’ve select my personal highlights and updates. The second part in on studies concerning drugs to reduce inflammation or to lower uric acid.

Let’s first look at what’s new on febuxostat.

Nicola Dalbeth and colleagues presented: “Imaging and Safety Assessments Following Treatment with Febuxostat and Placebo for 2 Years in Subjects with Early Gout”. Conclusion: “This first clinical trial in early gout subjects demonstrated that treatment with febuxostat can achieve a significant reduction in synovitis compared to placebo.” They didn’t see any difference in the RAMRIS erosion and bone edema scores, which might be due to the fact of having restricted the study to patients with early gout.

Pierre-Antoine Juge and colleagues looked at: “Efficacy and Safety of Febuxostat in 55 Gouty Patients with Stage 4/5 Chronic Kidney Disease: Results from a Retrospective Multicenter Study”. Conclusion: “Febuxostat appears efficient in gouty patients with stage 4/5 CKD or renal transplants. However, safety data is not yet validated with respect to renal function. Further studies with larger samples are warranted for assessing this issue.” That leaves us much at the point, where we’ve been before.

The next study is on arhalofenate, a novel urate lowering anti flare therapy in gout. “It lowers serum uric acid (sUA) by blocking URAT1, a tubular UA transporter, and reduces gout flares by blocking the local release of IL-1β.”

Alexandra Steinberg and colleagues presented: “A Study to Evaluate the Efficacy and Safety of Arhalofenate for Preventing Flares and Reducing Serum Uric Acid in Gout Patients”. “Subjects [N=239] were randomized 1:2:2:2:2 to placebo, arhalofenate 600 mg or 800 mg, allopurinol 300 mg or allopurinol 300 mg combined with colchicine 0.6 mg.“ Conclusion: “Arhalofenate at 800 mg significantly decreases gout flares when compared to allopurinol 300 mg. There was no statistical difference in flares between arhalofenate 800 mg and allopurinol 300 mg combined with colchicine. Arhalofenate 800 mg also significantly decreased flares when compared to placebo. These results indicate that Arhalofenate has intrinsic anti-inflammatory activities clinically associated with improvement in gout flares. Arhalofenate sUA lowering activity, while significant compared to placebo, was lower than in the allopurinol 300 mg groups. Arhalofenate was well tolerated and appeared safe. Arhalofenate is currently in development for the treatment of gout as a combination therapy with ULT, both to lower serum uric acid and prevent flares.” The idea might be to suggest a single therapy for flares and lowering uric acid, and achieving this with a single drug. It looks more like a marketing stunt, no matter how much effect there is on IL-1β. Maybe arhalofenate is aiming at too much at the same time. Just a thought. It’s much too early to evaluate this. Arhalofenate might be useful in the time after the first / a flare.

There were two studies on adding lesinurad either to febuxostat or the allopurinol. I guess, you’re not too surprised that these combinations work.

Let’s close this 2nd part with a study on canakinumab.

Naomi Schlesinger and colleagues presented: “A 3-Year Follow-up Study of Canakinumab in Frequently Flaring Gouty Arthritis Patients, Contraindicated, Intolerant, or Unresponsive to Nonsteroidal Anti-Inflammatory Drugs and/or Colchicine”. The authors looked at patients, who were radomized in the two phase 3 studies (N=456), of these 272 patients were followed up in extension studies, where re-treatment was initiated after a flare. Conclusion: “Over 3 years, a mean “on demand” dosing of CAN was 2.68 per pt. Efficacy of CAN was demonstrated […]”.

I think both flares and urate lowering therapies were addressed in the studies. Gout still is a challenge. I hope that studies will also look at the problem of adherence to drugs.

References:

Dalbeth N, Saag KG, Palmer W, Choi H, Hunt B, MacDonald P, Thienel U, Gunawardhana L. Imaging and Safety Assessments Following Treatment with Febuxostat and Placebo for 2 Years in Subjects with Early Gout [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/imaging-and-safety-assessments-following-treatment-with-febuxostat-and-placebo-for-2-years-in-subjects-with-early-gout/. Accessed November 16, 2015.

Steinberg A, Chera H, Choi YJ, Martin R, McWherter C, Zhang Y, Boudes P. A Study to Evaluate the Efficacy and Safety of Arhalofenate for Preventing Flares and Reducing Serum Uric Acid in Gout Patients [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/a-study-to-evaluate-the-efficacy-and-safety-of-arhalofenate-for-preventing-flares-and-reducing-serum-uric-acid-in-gout-patients/. Accessed November 16, 2015.

Juge PA, Truchetet ME, Ottaviani S, Vigneau C, Loustau C, Cornec D, Pascart T, Cornec-Legall E, Florien M, Bailly F, Schaeverbeke T, Saraux A, Dieude P, Flipo RM, Jean-Baptiste G, Richette P, Lioté F, Bardin T, Chales GH, Ea HK. Efficacy and Safety of Febuxostat in 55 Gouty Patients with Stage 4/5 Chronic Kidney Disease: Results from a Retrospective Multicenter Study [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/efficacy-and-safety-of-febuxostat-in-55-gouty-patients-with-stage-45-chronic-kidney-disease-results-from-a-retrospective-multicenter-study/. Accessed November 16, 2015.

Saag KG, Bardin T, So A, Khanna P, Storgard C, Baumgartner S, Fung M, Bhakta N, Adler S, Kopicko J, Becker MA. Analysis of Gout Subjects Receiving Lesinurad and Allopurinol Combination Therapy By Baseline Renal Function [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/analysis-of-gout-subjects-receiving-lesinurad-and-allopurinol-combination-therapy-by-baseline-renal-function/. Accessed November 16, 2015.

Dalbeth N, Jones G, Terkeltaub R, Khanna D, Kopicko J, Adler S, Bhakta N, Fung M, Storgard C, Baumgartner S, Perez-Ruiz F. Efficacy and Safety in Patients with Tophaceous Gout Receiving Lesinurad and Febuxostat Combination Therapy: Interim Analysis of an Extension Study [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/efficacy-and-safety-in-patients-with-tophaceous-gout-receiving-lesinurad-and-febuxostat-combination-therapy-interim-analysis-of-an-extension-study/. Accessed November 16, 2015.

Schlesinger N, Bardin T, Bloch M, Lheritier K, Machein U, Junge G, So A, Alten R. A 3-Year Follow-up Study of Canakinumab in Frequently Flaring Gouty Arthritis Patients, Contraindicated, Intolerant, or Unresponsive to Nonsteroidal Anti-Inflammatory Drugs and/or Colchicine [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/a-3-year-follow-up-study-of-canakinumab-in-frequently-flaring-gouty-arthritis-patients-contraindicated-intolerant-or-unresponsive-to-nonsteroidal-anti-inflammatory-drugs-andor-colchicine/. Accessed November 16, 2015.

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Gout and other crystal diseases at the EULAR 2012

Gout and other crystal diseases have been a hot topic at the EULAR meeting 2012 in Berlin.


M. Doherty has given a superb lecture on gout and other crystal diseases. Gout is well understood in pathogeneis and can even be cured. The pathogenesis of calcium pyrophosphate (CPP) or basic calcium phosphate (BCP) crystal associated diseases is less well understood. For acut gout or pseudo-gout (CPP) best practice "is to aspirate and inject the joint with corticosteroid (this is safe, quickly effective and allows confirmation of diagnosis) and then apply ice-packs." Alternatives are: " oral steroid; intramuscular injection of steroid or ACTH; oral colchicine (0.5mg 2-4 times daily); oral NSAID/coxib (with PPI); or IL-1 inhibition using a biologic (e.g. anakinra, canakinumab - though currently not licensed for gout)." I must say, I don´t use intramuscular steroids. Without constructing the prerequisites of a patient, who would be considered for intramuscular steroids, I´d say it´s obsolete. I´ll come back to it later. And I don´t see "many" patients, who would not tolerate low dose colchicine. And M. Doherty mentioned colchicine useful: "Low dose colchicine may be helpful for patients with frequently recurring acute CPP crystal synovitis, with or without OA, but there is no long-term treatment to eliminate CPP crystals." If we can lower urate levels, we can "cure" gout. We can do so with: " allopurinol, febuxostat, sulphinpyrazone and benzbromarone - each has its own advantages and disadvantages." Gout has a lower profile than other forms of arthritis, which is to be addressed. " Successful management requires full patient discussion and explanation concerning gout and its treatment". " The key challenge therefore is to raise the profile of gout and to improve training, interest and knowledge of doctors so they can impart correct information to their patients." All in all time spent on this lecture has been time well spent!



[SP0096] GOUT AND OTHER CRYSTAL DISEASES
M. Doherty. Academic Rheumatology, University of Nottingham, Nottingham, United Kingdom
Citation: Ann Rheum Dis 2012;71(Suppl3):24
Session: How to manage 5




In the next study K. Reiter and colleagues looked at "comparative effectiveness and health economic evaluation of systemic anti-inflammatory therapies for acute gout flares". See for yourself at conclusions and limitations. I see a problem for canakinumab as it is extreme expensive compared to other alternative and moreover it´s off-label.



[FRI0430] COMPARATIVE EFFECTIVENESS AND HEALTH ECONOMIC EVALUATION OF SYSTEMIC ANTI-INFLAMMATORY THERAPIES FOR ACUTE GOUT FLARES
K. Reiter1, E. Krishnan1, J. Goldhaber-Fiebert2. 1Deapartment of Medicine; 2Health Policy, Stanford University, Palo Alto, United States
Conclusions: When priced as an unbranded product, colchicine is cost effective for the treatment of acute gout flare. In the US, where colchicine is sold as a branded product, systemic corticosteroids provide a more cost effective alternative. At current prices, biologic therapy does not provide additional benefits commensurate with the cost.
Limitations: These results apply to patients with gout who do not have absolute contraindications to any of the treatment options, such as allergies to the drugs, advanced liver or renal disease, or heart failure. Our models did not take into account the drug half-life of parenteral corticosteroids. Our assessment of biologic therapy may not be applicable to non-canakinumab therapies currently in development.


The next studies all come from the same set or nearly the same set of authors. The first is by R. Alten and colleagues, who compared canakimumab to intramuscular triamcinolone. Serious adverse events occurred more often in the group of patients treated with canakinumab (8.5% vs. 3.4%). Look for yourself!


[AB1081] EFFICACY AND SAFETY OF CANAKINUMAB VS TRIAMCINOLONE ACETONIDE IN PERSISTENT OR ELDERLY GOUTY ARTHRITIS PATIENTS
R. Alten1, M. Bloch2, T. Bardin3, A. So4, A. Shpilsky5, J.M. Nebesky6, T. Kiechle6, N. Schlesinger7. 1Charité Univ Medicine, Berlin, Germany; 2Holdsworth House Medical Practice, Sydney, Australia; 3Hôpital Lariboisière, Paris, France; 4CHUV, University of Lausanne, Lausanne, Switzerland; 5Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States; 6Novartis Pharma AG, Basel, Switzerland; 7Umdnj-Rwjms, NJ, United States
Conclusions: Canakinumab provided superior pain relief and reduced the risk of a new flare vs TA in this subgroup of pts with persistent GA or elderly pts with GA. Thus it may represent a treatment alternative given that these pts are at a higher risk of comorbidities and may have more limitations to currently available treatments.


In the next study N. Schlesinger and colleagues studied the "effect of canakinumab vs triamcinolone acetonide for treatment of gouty arthritis in patients who are unable to use NSAIDs and colchicine or with severe gouty arthritis". I wondered where they recruited 312 of 454 patients, who are unable to use NSAIDs and colchicine, but severity does the trick. The authors conclude that canakinumab "may represent a potential treatment alternative for this subpopulation." That would be a large subgroup if defined like the authors did.

[FRI0369] EFFECT OF CANAKINUMAB VS TRIAMCINOLONE ACETONIDE FOR TREATMENT OF GOUTY ARTHRITIS IN PATIENTS WHO ARE UNABLE TO USE NSAIDS AND COLCHICINE OR WITH SEVERE GOUTY ARTHRITIS - POSTER TOURS
N. Schlesinger1, R. Alten2, T. Bardin3, M. Bloch4, A. Shpilsky5, G. Krammer6, T. Kiechle6, A. So7. 1Umdnj-Rwjms, NJ, United States; 2Charité Univ Medicine, Berlin, Germany; 3Hôpital Lariboisière, Paris, France; 4Holdsworth House Medical Practice, Sydney, Australia; 5Novartis Pharmaceuticals Corporation, East Hanover NJ, United States; 6Novartis Pharma AG, Basel; 7CHUV, Univ of Lausanne, Lausanne, Switzerland
Conclusions: Pts unable to use NSAIDs and colchicine or with severe GA when treated with CAN had significantly reduced risk of new flare and better pain relief compared to pts treated with TA. CAN may represent a potential treatment alternative for this subpopulation.


There have been more studies:


[AB1080] EFFECT OF SERUM URATE LEVEL ON PREVENTION OF FLARE IN ACUTE GOUTY ARTHRITIS PATIENTS WITH CANAKINUMAB
P. Sunkureddi1, N. Schlesinger2, T. Kiechle3, A. Shpilsky4, A. So5. 1Clear Lake Rheumatology Center, Texas; 2Umdnj-Rwjms, New Jersey, United States; 3Novartis Pharma AG, Basel, Switzerland; 4Novartis Pharmaceuticals Corporation, East Hanover NJ, United States; 5CHUV, University of Lausanne, Lausanne, Switzerland
Conclusions: Results of this retrospective exploratory analysis show that baseline SU level was not a predictor of new flares in patients receiving anti-inflammatory therapy for acute GA, suggesting that GA severity may be more closely related to the prevention of flare than the baseline SU level.


[FRI0377] EARLY RESPONSE TO TREATMENT IS A SURROGATE MARKER OF FLARE RECURRENCE IN ACUTE GOUTY ARTHRITIS
A. So1, T. Bardin2, M. Bloch3, A. Shpilsky4, T. Kiechle5, N. Schlesinger6. 1CHUV, University of Lausanne, Lausanne, Switzerland; 2Hôpital Lariboisière, Paris, France; 3Holdsworth House Medical Practice, Sydney, Australia; 4Novartis Pharmaceuticals Corporation, New Jersey, United States; 5Novartis Pharma AG, Basel, Switzerland; 6Umdnj-Rwjms, New Jersey, United States
Conclusions: These results demonstrate that a 50% pain reduction by VAS within 7 days of treatment in acute GA pts is associated with delay of new flare and can be used as a surrogate marker of time to new flare.


[FRI0402] TOPHI SPREAD, ACUTE JOINTS AND FLARE FREQUENCY PREDICT REFLARE IN GOUTY ARTHRITIS: A SPATIO-TEMPORAL MODEL
T. Bardin1, R. Alten2, N. Schlesinger3, A. Shpilsky4, T. Kiechle5, A. So6. 1Hôpital Lariboisière, Paris, France; 2Charité Teaching Hospital–Schlosspark-Klinik, Berlin, Germany; 3Umdnj-Rwjms; 4Novartis Pharmaceuticals Corporation, NJ, United States; 5Novartis Pharma AG, Basel; 6CHUV-University of Lausanne, Lausanne, Switzerland
Conclusions: Based on this spatio-temporal model the number of tophi locations, number of joints affected by acute GA, along with the number of flares is predictive of subsequent reflaring in this population of GA patients. Thus, the phenomenon of repeated acute GA is impacted mainly by the extent of advanced GA, i.e. the degree of systemic disease and frequency of flares, and not by factors immediately preceding an inflammation (CRP, urate level, etc.) thought to be contributing to the reflaring.


[AB1077] THE SPREAD OF TOPHACEOUS DISEASE STRONGLY PREDICTS TIME TO NEW FLARE IN GOUTY ARTHRITIS
N. Schlesinger1, P. Sunkureddi2, R. Alten3, T. Bardin4, A. Shpilsky5, T. Kiechle6, A. So7. 1Umdnj-Rwjms, NJ; 2Clear Lake Rheumatology Center, Texas, United States; 3Charité Teaching Hospital–Schlosspark-Klinik, Berlin, Germany; 4Hôpital Lariboisière, Paris, France; 5Novartis Pharmaceuticals Corporation, NJ, United States; 6Novartis Pharma AG, Basel; 7CHUV, University of Lausanne, Lausanne, Switzerland
Conclusions: Our results suggest that the number of locations to which tophaceous formations have spread throughout the body leading to systemic disease is an indicator of disease severity in GA. This quantitative measure is a strong predictor of delay of new flare (the higher the number of locations the less delay in reflares).


To me it looks like a massive attack to push forward the use of canakinumab in gouty attacks. Let´s stay alerted if our definitions of intolerability of certrain drugs or disease severity change!