how can the nocebo effect be reduced by switching from ... dokumenter... · this presentation 1....

Prof. dr. Frank van den Hoogen, rheumatologist

Departments of Rheumatology

Sint Maartenskliniek & Radboud University Medical Center

Nijmegen

The Netherlands

How can the nocebo effect be reduced by switching from

reference to biosimilar product –

the importance of a communication strategy

January 7, Oslo

Disclosures

Grants, speakers fee, advisory boards:

AbbVie, Actelion, Amgen, Boehringer Ingelheim, Biogen, BMS, Cellgene,

Corbus, Celltrion, Janssen, Eli Lilly, Mundipharma, Novartis, Pfizer, Roche,

Sandoz, Sanofi.

2

This presentation

1. Background

2. Strategy

3. Biosimilar transitions

4. Concluding remarks

3

1. Background

Radboudumc: academic hospital with all specialties

Sint Maartenskliniek: specialised hospital for - rheumatology

- rehabilitation

- orthopedic surgery

Both located in Nijmegen, distance between hospitals = 3 km

Rheumatologists: 32

Trainees 6

Physician assistants 5

4

Background

Number of patients treated at both departments with:

• Inflammatory rheumatic diseases: 7600

• Treated with biologics: 2900

Total costs in 2015 for biologics: € 30.000.000

Reducing costs for health care: main issue in the Netherlands

Our contributions:

1. dose optimisation biologics*

2. getting the lowest price for biologics

*van Herwaarden et al, BMJ 2015;350:h1389

Background

In the Netherlands:

• Biologics are on the budget of the hospital and distributed by the pharmacy of the hospital

• ‘Hospital’ negotiates directly with pharmaceutical companies about discount

• Subsequently ‘hospital’ negotiates with Health Insurance companies

6

2. Strategy

• Content is leading: rheumatologists decide!

• Rheumatologists must have consensus or at least consent!

• Much effort spent for reaching consensus/consent

• One of the results: preference policy regarding treatment

7

Preference policy for bDMARDs in inflammatory rheumatic diseases

nr Rheumatoid Arthritis Psoariatic Arthritis Ankylosing Spondylitis

1. adalimumab (tocilizumab) adalimumab adalimumab

2. etananercept etanercept etanercept

3. rituximab secukimumab secukimumab

4. abatacept ustekinumab certolizumab

5. tocilizumab tofacitinib golimumab

6. baricitinib apremilast infliximab

7. certolizumab certolizumab

8. golimumab golimumab

9. infliximab infliximab8

3. Biosimilar transitions: discussion at my department

• October 2014: no knowledge about biosimilars

much reluctance to start, let alone to transition: many emotions!

• Education: abstracts

webcasts

visits to symposia

• Consultation of patients

• 1 april 2015: Biosimilars Remsima® / Inflectra® available in the Netherlands

• Remsima® lowest price compared to Remicade® or Inflectra®

• July 2015: transition started

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Guideliness Dutch Association of Rheumatologists

• EMA registered originators and biosimilars are equivalent regarding effectiveness and

side effects

• Patients starting with a biologic can start with a biosimilar

• Costs can be a reason for the choice between originator or biosimilar

Transition a patient from originator to biosimilar is possible, but:

• Non-mandatory

• When transitioned: always offer the possibility to return to originator

10

Logistics transitioning from Remicade® to Remsima®

• Letter to all patients involved, underlining

- biosimilar is ‘similar’ to originator

- free choice to transition

- free choice to restart Remicade® (according to Dutch Ass of Rheum)

• Specialized nurse called patients:

- to answer any questions

- to ask consent for participation in study (bio-switch study)

11

• Open, parallel group, multicentre observational controlled cohort study

• Aim: to evaluate effectivity, safety and immunogenicity of transitioning from

Remicade® to Remsima® in real life

• Primary efficacy endpoint:

- for RA and PsA: difference in mean DAS28-ESR and DAS28-CRP

- for AS: difference in mean BASDAI between baseline and follow-up

(6 and 12 months of treatment)

• Secondary outcomes: - incidence of flares at six and 12 months follow-up

- evaluation of safety and immunogenicity

12

BIO-SWITCH study

Tweehuysen et al, Arthritis Rheumatol 2018;70:60-68

Role of Pharmacist

In the Netherlands: biologics are on the budget of the hospital

distribution biologics is via hospital pharmacy

very close collaboration between rheumatologist, pharmacists and hospital board

pharmacists participated in and facilitated every step of the proces

- Q and A by pharmacist assistants, teaching how to use the injection device etc

- tracking side effects

responsible for pharmacovogilance

13

14

N

Patients eligible 211

Patients transitioned 192 (91%)

Discontinued < 6 months 39 (20%)

Reasons for discontination

Experienced ineffectivity 31

Experienced side effects 19

Combination 13

Infusion reaction 2

BIO-SWITCH study


BIO-SWITCH study

Summary of side effects that caused patients to stop Remsima® :

15

Side effect N

Fatigue 8

Headache 3

Malaise 3

Cystitis 2

Erythema face 2

Dyspnea 2

Itch 2

Diarrhoea 2

Candida infection 2

Side effect N

Palpitations 1

Sicca eyes 1

Conjunctivitis 1

Agitation 1

Sombreness 1

Dizziness 1

Myalgia 1


BIO-SWITCH study: 6 months results

Patients who discontinued Remsima®, were next treated with:

16

N = 39

Remicade 31

Adalimumab 2

Etanercept 1

Golimumab 1

Rituximab 1

Not started other treatment 3


Examples of 2 RA patients that ‘reswitched’ to Remicade®

17

26-08-2015 13-11-2015

TJC 2 14

SJC 1 0

VAS 20 90

CRP 1 1

DAS28 CRP 2.98 3.30

14-7-2015 30-3-2016

TJC 3 0

SJC 0 0

VAS 30 70

CRP 1 6

DAS28 CRP 2.60 2.64

Summary

• 91% of patients agreed to transition form Remicade® to Remsima®

• After 6 months: 24% of patients discontinued Remsima®

82% of these patients restarted Remicade®

• Remsima® did not lead to objectively measured increased disease activity or serious side effects

• Most patients experienced subjective complaints

Why did patients dicontinue Remsima®?

Four possible explanations for side effects or increased pain after transitioning:

• Remsima® is less effective than Remicade®

• ‘Normal’ course of the underlying disease

• Incorrect causal attribution

• Nocebo effect of Remsima®

Actions taken

Before every Remicade® infusion disease activity is measured by a trained nurse

We decided:

• If disease activity has not worsened continue Remsima®

• If disease activity is increased - short course of NSAID’s and/or glucocorticoids

- switch to other biologic

From then on:

number of discontinuations decreased to expected levels

rheumatologists and nurses started to understand - incorrect causal attribution

- nocebo-effect

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Transition from Enbrel® to Benepali®

• April 2016: enough knowledge about biosimilars

no reluctance to start or switch

• June 3rd 2016: Benepali® lower price compared to Enbrel®

Project team: rheumatologists, pharmacists, board member, communication/media expert

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• We trained all involved in the ‘biological chain’:

- rheumatologists, pharmacists, phsycian assistants, nurses, pharmacy assistents

- secretaries

• Subjects of the training:

- what is a biosimilar?

- why do we switch?

- how do I communicate with a patient (psycologist)

- what are incorrect attribution and nocebo effect

• We contacted national radio- and television networks

• Tight time schedule (2 weeks)

22


Patients received a short letter: - informing them that they would switch from Enbrel® to Benepali®

- the main reason was reducing costs

- if they did not agree, they had to contact their rheumatologist

The same day: 1. from 6 am until 11 pm every hour on the main radio- and televison channels

2. minister of Health openly supported the transitioning

And what happened?

23

• June 2016:

642 adult patients using Enbrel® 50 mg were asked to transition to Benepali®

7 (1%) patients refused

635 (99%) transitioned from Enbrel® 50 mg to Benepali® 50 mg

• After 6 months 60 patients discontinued Benepali ® :

17 (2.4%) patients ‘retransitioned’ to Enbrel®

32 (4.2%) patients switched to other biologic treatment

11 (1.5%) patients stopped biologic treatment

Open Label Non-Mandatory Transition Enbrel® to Benepali®


Persistence rates Benepali® vs Historical cohort Enbrel®


Beneapali® Enbrel®

Persistence rate 90 % 92 %

N = 60

Lack of efficacy 61 % 43 %

Adverse events 47 % 28 %

Malignancy 4 % 3 %

Pregnancy 4 % 4 %

Other 3 % 3 %

Averse reactions Benepali® ® ® Historic cohort Enbrel®

Total 55 15

Objective AE 9 9

Skin rash 1 1

Injection site reaction 1Upper respiratory tract infection 1 1Total hip replacement infection 1Jaw implant infection 1Elbow replacemènt infectiob 1Wound infection foot 1Salmonella infection 1Hepatitis C 1Aortic aneuyrism surgery 1Retrobulbar neuritis 1

Subjective complaints 46 6

Arthralgia 9

Painful injection 6 1Malaise 5Pruritus 4 1Headache 3Nausea 3Others 16 4

Adverse events leading to discontinuation


Other transitions at our department

• December 2017: 284 patients transitioned from Trackleer® to Rixathon®

4 refused

• November 2018: no switch from Humira® (n=827) to biosimilar adalimumab

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Communication and education/training (1)

- Physicians are at the hearth of decision making: they must agree!

- Communicate with and educate/train all involved: a biosimilar is as effective as an originator

- Create a team spirit

- Speak with one voice

4. How can the nocebo effect be reduced by switching from reference to

biosimilar product – the importance of a communication strategy

Communication and education/training (2)

- Psychological skills: how to deal with a patient’s emotion

- Be direct to patients, they also want to contribute in reducing health care costs

- Keep paying attention for determinants why patients discontinue biosimilar treatment

Future

- biosimilars / originators will be interchangeable?

How can the nocebo effect be reduced by switching from reference to

biosimilar product – the importance of a communication strategy

30

http://www.google.nl/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=2ahUKEwiwseHc1YXeAhXR_aQKHVbtAt0QjRx6BAgBEAU&url=http://edvista.com/claire/tutorial/pp/sld045.htm&psig=AOvVaw3xLXngPnRY6c-QD7VVHCX3&ust=1539597468464404

The Danish experience on switching from originator to biosimilars for

non-medical reasons including subsequent back-switching

Prof Merete L Hetland, MD, DMSc, PHD

Head of the DANBIO steering committee

Rigshospitalet, University of Copenhagen, Denmark

AgendaBackground

Experiences with biosimilars in Denmark

1. Infliximab, the first non-medical switch from originator to biosimilar

2. Etanercept, to switch or not to switch from originator to biosimilar (and back again)

3. Adalimumab – one becomes two

4. Infliximab, multiple switches are here

Concluding remarks

Health care in Denmark

• Biological treatments tax paid

• Provided free of charge to the patient

• Provided through hospitals

• ≈20 hospital departments of rheumatology

• SC treatments are dispensed to the patients every 8 weeks

Expensive drugs, regulation

• Tender based sysem

• Recommendations regarding choice of bDMARD

– Naïve, switchers, non-medical switches

• Audits

– if guidelines are not followed, reasons must be explained by the physician responsible for treatment

• Expert panel, independent of pharmaceutical industry

Non-medical switch

Medical Council for use of expensive drugs, guidelines Nov 2018

Regarding use of biosimilar infliximab, etanercept and adalimumab

Originator bDMARDs and their biosimilars should be considered equal in patients

- who start first line treatment

- who switch bDMARD treatment

- unless specific patient related matters exist, patients on stable treatment with originator should switch to cheapest drug (i.e. the biosimilar)

Originator no longer available

New recommendations

• 1: Biosimilar adalimumab

– In two regions: Hymiroz (Sandoz)

– In three regions: Imraldi (Biogen)

• 2: Biosimilar infliximab (Zessly)

• ... Biosimilar etanercept (Benepali)

• ... Biosimilar rituximab (Rixathon)

• All adult Danish patients with inflammatory diseases (rheumatology, dermatology, gastroenterology)

Non-medical switches in Denmark

May 2015: originator IFX, Remicade biosimilar CT-P13, Remsima

April 2016: originator ETA, Enbrel biosimilar SB4, Benepali

2017: biosimilar CT-P13, Remsima biosimilar CT-P13, Inflectra

Nov 2018: originator ADA, Humira biosimilar Hyrimoz and Imraldi

biosimilar Inflectra biosimilar Zessly (multiple switches)

originator RTX, MabThera biosimilar Rixathon

Costs, infliximab, Denmark

Thanks to Dorte Klitgaard, Region H Pharmacy

Time period Price per 100 mg, DKK Saving*

Remicade Remsima Inflectra

2015 1/1 - 30/3 4189.21 - - -

1/4 - 30/6 3979.74 1432.00 - 64%

1/7 - 30/7 3665.55 1366.82 - 63%

1/8 - 31/12 3644.60 1366.82 - 63%

2016 1/7- 31/12 2385.75 1322.82 - 45%

2017 1/1-31/3 2385.75 1322.82 - 45%

31/3-1/7 2383.71 1322.82 - 45%

1/7-31/12 2383.71 1195.82 1032.17 57%

2018 1/1-30/6 1074.39 1195.82 1032.17 4%* Biosimilar versus originator

Costs, etanercept, DenmarkTime period Price per 50 mg, DKK Benepali

Saving

Enbrelpen

Enbrelsyringe

Benepalipen/syringe

2016 1/1 - 29/2 8520.37 8520.05 - -

1/3 - 30/4 8520.37 8520.05 4372.44 49%

1/5 - 30/6 8358.35 4453.51 4372.44 2%

1/7 - 30/9 8358.35 4453.51 3772.44 15%

1/10 – 31/12 8358.35 4453.51 3744.83 16%

2017 1/1-31/3 8358.35 4453.51 3744.83 16%

31/3-1/7 8149.39 4449.33 3741.23 16%

1/7-31/12 7266.75 7266.75 3296.23 55%

2018 1/1-30/6 7266.75 7266.75 3296.23 55%

Costs, adalimumab, DenmarkTime period Price per 40 mg, DKK Saving

Humira pen

Humira syringe

Hyrimoz/Imraldi

pen/syringe

2018 ≈8000 ≈8000 -

Nov 2018

6/11-18 to 31/3-19

2339.88 2339.88 1189.251530.01

49%35%

Costs, rituximab, DenmarkTime period Price per 500 mg, DKK Saving

MabThera Rixathon

2018 ≈15000 -

Nov 2018

6/11-18 to 31/3-19

9067.94 4182.31 54%

Information to patients

• Leaflets from The Danish Medicines Agency

‘’You can be completely safe when you use an originator or biosimilar drug’’

‘’The biosimilars and originators work in the same way’’

‘’No differences in treatment effects’’‘’You may be changed to a different pen or syringe’’

https://laegemiddelstyrelsen.dk/da/nyheder/2016/informationsmateriale-om-biosimilaere-laegemidler/~/media/F25626CA269A447A962E5CD01DAE291A.ashx

Monitoring of adverse events

• Mandatory to report all side effects during treatment with biosimilars to The Danish Medicines Agency (by use of online system, DANBIO or safety officers)

• Patients may report (online system)

• Reports available online

RCT vs. observational studies

Observational postmarketing studies may contribute important knowledge regarding the effectiveness of biosimilars‘To facilitate making informed decisions about therapeutic substitution with biosimilars, healthcare providers are encouraged to gather pharmacovigilance data in registries about the outcome of such switches made in the context of clinical practice.’ Kay et al, ARD, Online first 2018

Available data from real-world clinical practice, somewhat conflicting with those of RCTs, seem to suggest that it is premature to formulate recommendations on the switching strategy from the bio-originator to its biosimilar. Cantini et al, ARD, online first 2018

Crucially, the real-world experience that is being proactively gathered through post-marketing studies (including the NOR-SWITCH study) and patient registries will add to our knowledge concerning biosimilars, and may further enhance confidence in the use of these products in clinical practice. Uhlig et at, Rheumatology, online first 2017

Background, DANBIO

• In year 2000, the DANBIO registry was set up by the rheumatological society to monitor patients with inflammatory arthritis receiving biological treatments

• Online data entry in the clinic by patients and physicians

• Nationwide, >95% coverage of biological treatments

• >40,000 patients currently registered in DANBIO

Background, DANBIO

• Approved by authorities as a quality and research database

• Part of the patient file

• Online system, www.danbio-online.dk

• Funding: Hospital owners, pharmaceutical industry, private and public funds

• Pharma: Quarterly aggregated postmarketing data (numbers of pts). No impact on organization, data collection, analysis or publication

DANBIO, Copenhagen

University Hospital at

Dept of rheumatology

Private practitioner

> 400 professionel users>20.000 patients are users

Glintborg B et al. Ann Rheum Dis, 2017;76(8): 1426-31

Remicade-Remsima switch

0

50

100

150

200

250

May June July Aug Sept Oct Nov Dec Jan Feb March April

2015 2016

Number of patients

802 switch patients

Objectives

To investigate the impact of the nationwide non-medical switch from originator infliximab (Remicade) to biosimilar (CT-P13, Remsima) on

1) 3 months’ disease activity and flare rates

2) 1 year retention rates

In adult patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) or axial spondyloarthrits (AxSpA)

Methods

• Observational study as part of routine care

• All patients were monitored prospectively in the DANBIO registry prior to and after the switch

• All Danish departments of rheumatology were invited to validate their data regarding

– Dates for treatment start and stop (Remicade, Remsima)

– Disease activity at baseline (switch) and during follow-up

– Reasons for withdrawal of Remsima

Baseline demographics

Disease activity and flares

During the 3 months prior to the switch compared to the 3 months after the switch

• Disease activity remained largely unchanged

• The proportions of patients with disease flare were similar

Disease activity and flares

Withdrawal

• 132/802 patients (16%) stopped Remsima treatment during 1 year of follow-up

• Prior Remicade treatment duration: 5.9 (2.9-9.2) years

Treatment retention

1 year treatment retention was compared to that of a historic cohort of all patients in DANBIO receiving treatment with Remicade by January 1st 2014

Adjusted* absolute rates:Historic: 86.8% (84.8 - 88.8) Switch: 83.4% (80.8 - 86.2) (p=0.03)corresponding to an absolute difference of 3.4%.

*Age, gender, diagnosis, methotrexate (yes–no), comorbidities(number), patient’s global score

Health care resources

Glintborg B et al, RMD Open 2018

Conclusion

In this observational nationwide study of 802 patients with RA, PsA or AxSpA treated with Remicade for >6 years who conducted a non-medical switch to biosimilar Remsima:

– Disease activity and flare rates 3 months after the switch were comparable to those 3 months prior to switch

– 16% stopped treatment during 1 year of follow-up mainly due to lack of effect or adverse events

– Withdrawal rate was similar to a historic cohort of Remicade treated patients

– No evidence of increased use of health care resources

Glintborg et al, ARD Nov 5th 2018

Baseline characteristics

• Compared to non-switchers, switchers had

– More often received conc MTX (in RA and PSA)

– Longer ETA treatment history

– Received fewer previous bDMARD

– Lower disease activity

Date of Enbrel-Benepali switch

Number of patients

2016

1621 switchers

Treatment retention

Backswitchers (LOE)

Backswitchers (AE)

• Arthralgia (1)

• Bladder dysfunction (1)

• Blurred vision (1)

• Diarrhoea (4)

• Dizziness (2)

• Dyspnoea (2)

• Erectile dysfunction (1)

• Hair loss (1)

• Headache/migraine (4)

• Hyperhidrosis (2)

• Hypertension (1)

• Hypotension (1)

• Infections (2)

• Leg cramps (1)

• Local injection problems (3)

• Myalgia (1)

• Nausea (2)

• Neuropathies (1)

• Psoriasis worsening (1)

• Rash/itching (9)

• Not stated (21)

Conclusion

In this observational nationwide study of 2061 patients switching from Enbrel to Benepali

- The outcomes (retention, remission) were influenced by patients’ and physicians’ choice to comply with the guideline (i.e. switch) or not (i.e. not switch), which was reflected in differences in baseline characteristics

- Other factors than the switching alone may have influenced the outcome

- Withdrawal was most common in patients not in remission

- Switch outcome in routine care is affected by non-specific drug effects and patient-related factors

Overall conclusion

• A tender based system that rates bsDMARD equal to boDMARD have resulted in significant reductions of drug costs

• Mandatory switching from originator to biosimilar drugs is associated with increased drug withdrawal

• This may in part be explained by non-specific and patient-related factors

• For infliximab and etanercept no major safety concerns have been raised

• Future non-medical switches (bs adalimumab, bs rituximab and multiple switching of bs infliximab) stress the importance of continued monitoring of biosimilars in real-world registries

Current recommandationsBio-naive Switch

Rheumatoid arthritis + csDMARD

1. Biosimilar IFX (50%)2. Biosimilar ETA (30%)

1. Biosimilar IFX (50%)2. Biosimilar ETA (30%)3. Rituximab4. s.c. Abatacept--

Rheumatoid arthritis mono Biosimilar ETA 1. Biosimilar ETA2. Tocilizumab s.c3. Tocilizumab i.v.4. Certolizumab5. Adalimumab

Psoriatic arthritis and mild PsO

1. Biosimilar IFX (60%)2. Biosimilar ETA (30%)

1. Biosimilar IFX2. Biosimilar ETA3. Secukinumab4. Golimumab--

Psoriatic artrhitis and severe PsO

1. Biosimilar IFX (60%)2. Secukinumab (30%)

1. Biosimilar IFX2. Secukinumab3. Adalimumab--

Current recommandationsBio naive Switch

Ankylosing spondylitis* 1. Biosimilar IFX (50%)2. Biosimilar ETA (30%)

1. Biosimilar IFX 2. Biosimilar ETA 3. Secukinumab4. Golimumab---

Nr-AxSpA* 1. Biosimilar IFX (50%)2. Biosimilar ETA (30%)

1. Biosimilar IFX 2. Biosimilar ETA 3. Golimumab4. Certolizumab5. Adalimumab

*Specific recommandations for uveitis, IBDhttp://www.medicinraadet.dk/media/5816/rev-lmr_aspa_32.pdf

Kaplan-Meier plots of crude treatment retention rates among SB4 switch patients.

Bente Glintborg et al. Ann Rheum Dis doi:10.1136/annrheumdis-2018-213474

©2018 by BMJ Publishing Group Ltd and European League Against Rheumatism

Infliximab, 2015The Nordic countries

T Kvien

Switching between biologicals;

exemplified by the Leuven

infliximab - adalimumab switch study

Jørgen Jahnsen

Switch to Adalimumab in Patients with Crohn’s Disease Controlled by Maintenance Infliximab:Prospective Randomized SWITCH Trial

Gert A. Van Assche, Severine Vermeire, Vera Ballet, Frederik Gabriels, Maja Noman, Geert D’Haens, Christophe Claessens, Evelien Humblet, Niels Vande Casteele, Ann Gils, Paul Rutgeerts

Background & Aim

• Elective switching between anti-TNF agents based on

patients’ preference or budgetary reasons has entered

clinical practice

- No prospective controlled trials exist comparing efficacy of

infliximab (IFX) and adalimumab (ADA) in Crohn’s Disease (CD)

or in other indications

• IFX and ADA differ in mode of administration, dosing

frequency and degree of humanization

• Aim:

- To prospectively assess the impact of elective switching of

patients with CD well controlled with intravenous infliximab to

subcutaneous adalimumab in a controlled trial

SWITCH

Van Assche G. et al. Gut. 2012 Feb;61(2):229-34.

Methods• Adult CD patients on scheduled IFX treatment with durable complete

response for at least 6 months

- Complete response = physician’s global assessment of signs and symptoms and CDAI < 200

- 5 mg/kg IFX q6-8 weeks scheduled therapy

- ADA-experienced pts and pts receiving IFX doses > 5 mg/kg wereexcluded

• Patients in complete response with scheduled IFX treatment were randomized to:

A) ADA 80 mg followed by 40 mg EOW

B) Remain on IFX with same interval (q6-q8 weeks)

• Clinical response (CDAI), adverse events and tolerability including patient preference (only group A) were assessed every 8 weeks until week 56

• Patients with a disease flare were allowed dose intensification with the same agent they were on and/or short (4-week) course of steroids

SWITCH


Study design

weeks 0

80mg sc 40mg sc EOW

R

Group A

ADA

(n=36)

Group B

IFX

(n=37)

54

73 CD pts on IFX

maintenance with

≥ 6 months

symptom control

5mg/kg q6-q8 weeks

LOR Interval decrease (EW)

LOR Interval decrease/

dose increase (10mg/kg)

INTOLERANCE

or

COMPLETE LOR

SWITCH


Patient eligibility

• Inclusion criteria

- Men or women >18 yrs with informed consent

- Patients in clinical remission and/or complete response (as judged by the investigator (CDAI < 200)) on IFX scheduled maintenance therapy for at least 6 months

• Exclusion criteria

- Patients receiving IFX doses > 5 mg/kg

- Patients with previous exposure to ADA

- Patients with a medical condition or laboratory abnormalities that preclude further administration of anti-TNF agents

- Patients with an imminent need for surgery

- Patients with a draining abdominal enterocutaneous fistula

SWITCH


Major endpoints

• Proportion of patients preferring ADA over IFX

• Proportion of patients

- needing rescue therapy with anti-TNF dose escalation or short courses of oral corticosteroids

- stopping the assigned anti-TNF agent

• Proportion of patients experiencing disease flare as defined by a CDAI increase of >100 points above baseline

• Proportion of patients who develop injection site or infusion related reactions

SWITCH


Baseline characteristicsAdalimumab (n=36) Infliximab (n=37) p-value

Age, median (IQR), years 38 (27-47) 37 (29-42) 0.82

Sex (F/M, % 50/50 46/54 0.91

Weight, kg 69 (61-73) 66 (61-71) 0.38

Disease duration, months 167 (76-213) 146 (116-218) 0.66

Time on infliximab, months 32 (20-65) 63 (33-85) 0.07

Concomitant

immunosuppressives6 (AZA), 0 (MTX) 0 (AZA), 2 (MTX) 0.15

Disease location

(ileal/colonic/ileocolonic)3/7/26 7/11/19

Infliximab every 8 wks at

entry83% (30/36) 76% (28/37) 0.60

Current smoker 25% (9/36) 30% (11/37) 0.79

CDAI baseline, median

(IQR)48 (24-110) 58 (34-122) 0.51

CRP baseline, median (IQR) 3.3 (2.0-3.9) 5.7 (1.8-6.9) 0.53

SWITCH


Results

Independent Data Safety and Monitoring Board (DSMB) advised to stop further

recruitment based on large difference in discontinuation of assigned treatment between

groups

GROUP A

ADA

N=36

Dose escalation or

early termination

n=17 (47%)

Early termination

N=10 (28%)

GROUP B

IFX

N=37

Dose escalation or

early termination

n=6 (16%)

Early termination

N=1 (2%)

p = 0.003

p<0.01

1/1 8/10

Due to loss of

tolerance in 6

pts and loss of

efficacy in 4

pts

Due to

loss of

tolerance

SWITCH


Results

• Dose intensification or early termination in 17/36 (47%) in the ADA group vs. 6/37 (16%) in the IFX group (p=0.003)

- 10/36 stopped ADA due to LOR (4 patients) or intolerance (6 patients) vs 1/37 in the IFX group (28% vs 2%, p<0.01)

- An additional 7/36 (19%) of ADA patients required dose escalation and/or steroids to maintain response compared with 5/37 (14%) with IFX (p=0.22)

• An increase in CDAI ≥ 100 points was observed in 10/36 (28%) patients in the ADA group and in 7/37 (19%) patients in the IFX group while on the initially assigned treatment

• All 8 patients that crossed back to IFX responded and tolerated the infusions

- But 4 patients needed IFX dose intensification within 1 year of restarting

SWITCH


84%

14%

2%

Group B IFX

53%

19%

28%

Group A ADA

Stable

Dose escalation

Early termination

Results overview

p=0.003

p=0.006

p=0.22

• 47% (17/36) ADA patients required dose adjustments for LOR or stopped therapy for complete LOR or intolerance vs. 16% (6/37) IFX patients (p=0.003).

SWITCH


Serum levels


Infliximab Adalimumab

Weeks Weeks

µg

/ml

µg

/ml

Adverse events

• No SAE occurred in the IFX group

ADA (n=36) IFX (n=37) P-value

Injection site/infusion reactions 22.2% (8/36) 2.7% (1/37) <0.01

5 SAE in ADA group

- Terminal ileitis and secondary ileus ADA dose escalation

- Anal abscess IFX restarted

- CD flare with perforation and ileal abscess resection

- Anal abscess and stenosis, complex fistula IFX restarted

- Anastomotic stenosis IFX restarted

SWITCH


Conclusions

• Elective switching from IFX to ADA is associated with loss of tolerance and loss of efficacy within 1 year

• Intolerance to ADA was the main reason for discontinuation

• Patients returning to IFX responded and tolerated the infusions

• Adherence to the first anti-TNF is recommended

SWITCH


Takk for oppmerksomheten!

SWITCH

NOR-DMARD medikamentoverlevelse (drug

survival, adherence)

Tore K. Kvien

Dept of Rheumatology

Diakonhjemmet Hospital

Oslo, Norway

bDMARDs – targets in RA• TNF-alpha (5 different (etanercept,

adalimumab, infliximab, golimumab,

certolizumab + biosimilar infliximab,

etancercept, and adalimumab)

• IL-6 (tocilizumab)

• B-cells (rituximab and biosimilar

rituximab)

• T-cells (abatacept)

….and more to come

Targeted synthetic DMARDS

(tsDMARDs)

• Janus kinas (JAK) inhibitors

(«Jakinibs»)– Tofacitinib

– Baricitinib

Types of Treatments for RA: Nomenclature

Disease Modifying Antirheumatic Drugs (DMARDs)

Synthetic DMARDs

(sDMARDs)

Biological DMARDs

(bDMARDs)

Conventional

synthetic

(csDMARDs

Targeted

synthetic

(tsDMARDs)

Biological

originator

(boDMARDs)

Biosimilar

(bsDMARDs)

MTX, SSZ, LEF,

OH-Chl

Tofacitinib,

Baricitinib

Adalimumab, Certoli-

zumab, etanercept,

golimumab, infliximab;

Abatacept, rituximab,

tocilizumab,

Etanercept,

infliximab,…

After Smolen JS, et al. Ann Rheum Dis 2014 Jan;73(1):3-5.

Time frame: Jan 2007-July 2016

NOR-DMARD

2000-2002 2003-2004 2005-20062007-

2008

2009-

2010p-value

n=351 n=463 n=394 n=358 n=300

Disease dur.

months*10.0 4.8

1.80.5 0.3 <0.001

DAS28† 5.17 5.06 4.85 4.62 4.75 <0.001

MHAQ† 0.625 0.625 0.625 0.625 0.50 <0.001

28-SJC* 7 7 5 4 5 <0.001

28-TJC* 7 7 7 6 6 <0.001

ESR* 27 22 18 19 23 0.001

CRP* 18 13 10 8 8 <0.001

Physician’s global VAS†

44.3 40.1 39.9 36.2 34.8 <0.001

Patient’s global VAS†

51.2 49.0 46.8 47.2 46.1 0.003

Means (†) or medians (*).

Time trends 2000-2010

Baseline characteristics RA MTX mono (n=1866)

Aga et al. ARD 2015


Response- and remission rates MTX mono

Aga et al. ARD 2015

2000-2002 2003-20042005-

20062007-2008

2009-

2010p-value

n=85 n=184 n=143 n=160 n=135

Dis.dur, yr* 8.0 6.5 6.3 4.2 3.8 <0.001

DAS28† 5.88 5.25 5.21 4.87 4.64 <0.001

MHAQ† 1.00 0.75 0.71 0.625 0.625 <0.001

28-SJC* 10 8 7 5 5 <0.001

28-TJC* 10 7 8 7 6 <0.001

ESR* 34 24 20 19 20 <0.001

CRP* 27 19 12 9 7 <0.001

Physician’s global VAS†

58.6 47.2 43.9 40.0 36.4 <0.001

Patient’s global VAS†

63.0 55.1 55.4 55.5 47.8 <0.001


Baseline characteristics RA TNFi + MTX

Means (†) or medians (*). Aga et al. ARD 2015


Response- and remission rates TNFi + MTX

Aga et al. ARD 2015

RA biologic startersNOR-DMARD 2009-2015

2009 2010 2011 2012 2013 2014 2015p-

value

N 113 116 200 112 99 117 82

Mean age (years) 51.4 53.4 54.2 54.7 53.0 53.8 56.1 0.47

% Female 65.5 77.6 80.8 65.2 76.8 67.5 63.4

Median (IQR)

disease duration

(years)

4.89

(1.63,

12.73)

3.17

(1.30,

8.81)

5.28

(1.95,

14.93)

6.69

(2.26,

12.21)

5.36

(1.34,

11.21)

4.44

(1.21,

13.78)

1.63

(0.85,

8.72)

0.02

DAS 28 (with ESR),

mean (SD)

4.68

(1.45)

4.57

(1.43)

4.34

(1.33)

3.88

(1.45)

4.05

(1.14)

4.07

(1.45)

3.88

(1.25)<0.001

CDAI, mean (SD)21.92

(12.17)

20.56

(11.43)

18.35

(11.38)

17.21

(12.14)

16.22

(9.56)

17.44

(12.47)

17.05

(11.02)0.006

SDAI, mean (SD)24.13

(13.13)

22.40

(12.16)

19.70

(12.26)

18.07

(13.05)

17.25

(9.90)

18.74

(13.43)

18.03

(11.46)<0.001

Kristianslund EK (unpublished data)

The ARCTIC trial

Aiming for Remission in rheumatoid arthritis:

a randomized trial examining the benefit of

ultrasonography in a Clinical TIght Control regimen

Treatment strategyUltrasound tight control Conventional tight control

Treatment response Treatment responseBased on DAS, and Based on DAS

change in ultrasound score

Treatment target Treatment target

Clinical remission Clinical remission

DAS<1.6 and no swollen joints, and DAS<1.6 and no swollenjoints

Imaging remission

No ultrasound PD signal in any joint

Intra-articular injections Intra-articular injections

Ultrasound guided Palpation guided

Treat-to-target DMARD regimen

• Treatment was

escalated

according to a

predefined

algorithm if target

was not reached,

or in case of no

response

Step Treatment

1Methotrexate 15-20 mg/daily

+ Prednisolone for 7 weeks as bridging therapy

2Optimize monotherapy Increase Methotrexate to 25-30 mg/week

3Triple combination therapy*Methotrexate, sulfasalazine and

hydroxychloroquine

4Optimize triple combination therapy Add Prednisolone 7,5 mg 1 x 1

51st biologic** + Comedication with synthetic DMARD if

tolerated

62nd biologic + Comedication with synthetic DMARD if

tolerated

73rd biologic + Comedication with synthetic DMARD if

tolerated

* Escape option available if risk factors present

** This step requires signs of ongoing inflammatory activity

Primary endpoint

Ultrasound(n=118)

No Ultrasound(n=112)

Difference(95 % CI)

P-value

Primary endpoint 26 (22.03 %)

21 (18.75 %)

3.28 % (-7.1% - 13.7%)

0.537

113

Components of the primary endpoint

Sustained DAS remission

64 (54.2 %) 58 (51.8 %)2.45 %

(-10.4% - 15.4%)0.71

No radiographicprogression

49 (41.5%) 39 (34.8%)6.7 %

(-19.2% - 5.8%)0.296

No swollen joints 62 (52.5%) 61 (54.5 %)1.9 %

(-14.8% - 11.7%)0.77

Treatment at end of study

6,9

5,1

0

1

2

3

4

5

6

7

8

Ultrasound Conventional

Total number of i.a. injections

Biologic treatment at end of study (24 months, n(%))

Ultrasoundtight controln=118

Conventionaltight controln=112

P-value

Biologic treatment 34 (29) 19 (17) 0.03

1st bDMARD 27 (23) 10(9) 0.003

2nd bDMARD 5 (4) 9 (8) 0.23

Third bDMARD 2 (2) 0 (0) 0.50

Are different TNF-inhibitors interchangeable (faglig

likeverdige?)

Efficacy of Various Agents

Smolen JS, Aletaha D & McInnes I. Lancet 2016; 388:2023-2038

CONCLUSIONS - RA

• Withrawal rates of TNFi are higher in real life

than in RCTs (NOR-DMARD)

• Response rates are also lower (NOR-DMARD)

• Earlier treatment leads to better responses

(NOR-DMARD)

• Stringent T2T strategy leads to better results

and less switching from csDMARDs to

bDMARDs (ARCTIC)

• Failure of one TNFi does not exclude efficacy

of a second TNFi (GO-AFTER and

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