overview of pmr/gca -...

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© Genentech, Inc. All rights reserved.

Overview of PMR/GCA

J. Eugene Huffstutter, M.D.

Clinical Asst. Prof. of Medicine

U of TN at Chattanooga Health Science Center

Arthritis Associates PLLC

Hixson, TN


Disclosures

Speaker Bureau – Janssen, Genentech, UCB, Pfizer

and BMS

Research support – GSK and UAB

Advisor Board - Lilly


Objectives

Understand epidemiology of PMR and GCA

Review diagnostics

Review current therapeutic options

Review data regarding potential new treatments


PMR

Definition: Inflammatory rheumatic condition

characterized by aching and AM stiffness of the

shoulder and hip girdles, usually accompanied by an

elevated ESR


Epidemiology of PMR

Usually occurs in individuals > 50 years old (peak from

70-80)

Female/male ratio of 2.5/1

Second most common inflammatory rheumatic illness

More common in Scandinavian and people of northern

European descent (1 in 1,000 incidence in Norway

compared to 1/10,000 in Italy)

Uncommon in Asian, African and hispanic populations.


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Pathogenesis

Association with HLA DR4 Polymorphism with HLA DrB1 Increased numbers of circulating CD4 + T cells IL-6 is increased in the arteries and peripheral blood Increased Th 17 cells and T reg cells


Aching of shoulder and hip girdles

Morning stiffness

Symmetrical Symptoms

Clinical Manefestations

ROS

Malaise Fever (high values may indicate GCA) Anorexia Fatigue Weight loss

Physical Exam

Temperature Mild synovitis Decreased ROM (more active than passive) Subjective weakness

LAB

ESR (20% < 40, 20% > 100) Elevated CRP Mild anemia Negative serology Mild elevated LFTs (marked increase in alk phos may indicate

GCA)

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Imaging

X-rays are usually normal USG MRI PET

Differential Diagnosis

RA (especially seronegative) FM Malignancy (especially multiple myeloma) Myositis (both idiopathic and drug induced) Hyperparathyroidism Hypothyroidism

Differential Diagnosis (rare)

RS3PE Syndrome (Remitting Symmetrical Synovitis with Pitting

Edema) – also called puffy hand syndrome Vasculitis Endocarditis Crowned Dens Syndrome (calcifications of the periodontal

tissue due to calcium-hydroxyapatite crystals or calcium pyrophosphate crystal deposition) dx. is made by CT since x-rays are usually normal

ACR Diagnostic Criteria for PMR

Required: 1) At least 50 years old 2) Bilateral shoulder aching 3) Elevated ESR/CRP Additional: Must have 4 or more points - AM stiffness of at least 45 minutes (2 points) - pain/limited ROM hip (1 point) - Neg Rf /CCP Ab (2 points) - Absence of peripheral joint pain (1 point)

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Treatment of PMR

Initiate prednisone at 10-15mg/d and try to taper after 3 months No DMARD therapy has been shown to have a steroid sparing

effect, but NSAIDs, MTX and azathioprine have been tried in limited trials.

Treatment of GCA

Initiate prednisone at 40-60mg/d in divided doses Try to taper therapy after 1-3 months MTX has limited value Anti-TNF meds seem to be of limited benefit Small preliminary trial that shows abatacept is effective Large trial with tocilizumab that shows lower rates of relapse

while taking lower doses of steroids – recently approved by FDA

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© 2017 Genentech, Inc. All rights reserved.

© 2017 Genentech, Inc. All rights reserved. © 2017 Genentech, Inc. All rights reserved.


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GiACTA


GiACTA: Eligibility Criteria Modified 1990 ACR Classification Criteria

Age at onset >50 years

ESR >50 mm/h (or CRP ≥2.45 mg/dL)

Unequivocal cranial symptoms of GCA and/or unequivocal symptoms of PMR

Temporal artery biopsy and/or imaging evidence of large-vessel vasculitis

ACR, American College of Rheumatology; ESR, erythrocyte sedimentation rate; GCA, giant cell arteritis; PMR,

polymyalgia rheumatica.

Stone JH, et al. Oral Presentation at ACR 2016, Washington, DC. Abstract 911.

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GiACTA: Definitions of Newly Diagnosed vs. Relapsing GCA

Newly diagnosed GCA: received diagnosis ≤6 weeks before baseline (diagnosis date was the time of suspected GCA diagnosis and initiation of glucocorticoids).

Relapsing GCA: received diagnosis >6 weeks before baseline and received previous treatment with ≥40 mg/day prednisone for ≥2 consecutive weeks.

− Refractory GCA: those experiencing relapse who never achieved remission during the course of GCA despite treatment with glucocorticoid regimens generally considered adequate to induce remission.

Tuckwell K, et al. Semin Arthritis Rheum. 2016 Nov 15. doi: 10.1016/j.semarthrit.2016.11.002. © 2016 Genentech, Inc. All rights reserved.

GiACTA: Methods

Central hypothesis: TCZ has a powerful steroid-sparing effect

First trial (in any disease): a blinded, variable-dose steroid regimen

− Prednisone doses <20 mg/day were double-blind

Dual-assessor approach

− ALL investigators blinded to CRP

Enrolled 251 patients over 22 months

14 countries, 76 sites (61 Europe, 15 North America)



GiACTA: Presentation of Disease at Baseline

Feature, n (%)

All Patients

n = 251

Newly Diagnosed GCA

n = 119

Relapsing GCA

N = 132

Disease controlled at baseline 145 (57.8%) 84 (70.6%) 61 (46.2%)

Sign or symptoms of GCAa 98 (39.0%) 39 (32.8%) 59 (44.7%)

Symptoms of PMR 49 (19.5%) 9 (7.6%) 40 (30.3%)

Unilateral blindness 4 (1.6%) 0 4 (3.0%)

Bilateral blindness 1 (0.4%) 0 1 (0.8%)

Ischemic optic neuropathy 2 (0.8%) 0 2 (1.5%)

Amaurosis fugax 2 (0.8%) 1 (0.8%) 1 (0.8%)

Blurred vision 14 (5.6%) 4 (3.4%) 10 (7.6%)

Diplopia 0 0 0

Fever 0 0 0

ESR, mm/h,b mean (SD) 24.0 (19.4), n = 246 20.9 (18.8), n = 117 26.8 (19.6), n = 129

CRP, mg/dL,b mean (SD) 7.5 (13.4), n =250 6.5 (10.8), n = 119 8.4 (15.4), n = 131

Tuckwell K, et al. Semin Arthritis Rheum. 2016 Nov 15. doi: 10.1016/j.semarthrit.2016.11.002.

GCA, giant cell arteritis; PMR, polymyalgia rheumatica; SD, standard deviation; TA, temporal artery. aIncludes localized headache, TA, or scalp tenderness, jaw or mouth pain, new or worsened extremity claudication, and

other features judged by both the clinician and the investigator to be consistent with a GCA flare. bPatients were receiving prednisone at the time of the baseline assessment, contributing to acute-phase reactant

measures lower than expected in patients receiving no treatment.


GiACTA: Clinical History and Diagnosis of GCA

Feature

All Patients

n = 251

Newly Diagnosed GCA

n = 119

Relapsing GCA

N = 132

Time since diagnosis, months, mean (SD) 9.1 (16.8) 0.5 (0.5) 16.9 (20.3)

History of ESR > 50 mm/h, n (%) 241 (96.0%) 114 (95.8%) 127 (96.2%)

Cranial GCA symptoms at diagnosis, n (%)

New onset headache 169 (67.3%) 85 (71.4%) 84 (63.6%)

Scalp tenderness 90 (35.9%) 43 (36.1%) 47 (35.6%)

TA tenderness 72 (28.7%) 28 (23.5%) 44 (33.3%)

TA decreased pulsation 29 (11.6%) 12 (10.1%) 17 (12.9%)

Ischemia-related vision loss 25 (10.0%) 7 (5.9%) 18 (13.6%)

Mouth pain/jaw claudication 85 (33.9%) 39 (32.8%) 46 (34.9%)

PMR symptoms alone 51 (20.3%) 27 (22.7%) 24 (18.2%)

Cranial and PMR symptoms 104 (41.4%) 51 (42.9%) 53 (40.2%)

Tuckwell K, et al. Semin Arthritis Rheum. 2016 Nov 15. doi: 10.1016/j.semarthrit.2016.11.002.

GCA, giant cell arteritis; ESR, erythrocyte sedimentation rate; PMR, polymyalgia rheumatica; SD, standard deviation; TA,

temporal artery.


GiACTA: Study Design

SC placebo + 26-week pred taper (PBO + 26; n = 50)

SC placebo + 52-week pred taper (PBO + 52; n = 50)

TCZ 162 mg QW + 26-week pred taper (TCZ QW; n = 100)

TCZ 162 mg Q2W + 26-week pred taper (TCZ Q2W; n = 50)

Primary end point:

sustained remission at

52 weeks

Pts with disease

activity or flare:

Open-label TCZ

162 mg QW

Week

52

Week

156

PBO, placebo; pred, prednisone; Q2W, once every 2 weeks; QW, once a week; SC, subcutaneous; OLE, open-label extension.

Unizony SH et al. Int J Rheumatol. 2013;2013:912562


Pts in remission at

52 weeks: Long-

term followup off

study drug

Part 1: 52 week double blind Part 2: 104 week OLE


GiACTA: Definitions of Flare and Remission

Flare: determined by the investigator and defined as the recurrence of signs or symptoms of GCA and/or ESR ≥30 mm/h attributable to GCA

− An increase in the prednisone dose was required

Remission: absence of flare and normalization of the CRP (<1 mg/dL)

− A single CRP elevation (≥1 mg/dL) not considered absence of remission unless CRP remained elevated (≥1 mg/dL) at the next study visit

Sustained remission: absence of flare following induction of remission within 12 weeks of BL and maintained up to week 52


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GiACTA: Study End Points

Primary end point

− TCZ + 26-week prednisone versus 26-week prednisone only: sustained remission from week 12 to week 52 AND adherence to the protocol-defined prednisone taper

Key secondary end point

− TCZ + 26-week prednisone versus 52-week prednisone: sustained remission from week 12 to week 52 AND adherence to the protocol-defined prednisone taper

Other secondary end points

− Time to flare

− Cumulative glucocorticoid use

− Quality of life

Safety

Stone JH, et al. Oral Presentation at ACR 2016, Washington, DC. Abstract 911. © 2016 Genentech, Inc. All rights reserved.

GiACTA: Statistical Considerations

Estimated effect size: 40%

Alpha set at 0.01

− Primary end point (superiority) tested at 0.005

− All other end points tested at 0.01

− Key secondary end point (noninferiority) tested using a 99.5% CI and a noninferiority margin of ‒22.5

• superiority testing contingent on noninferiority

9 Stone JH, et al. Oral Presentation at ACR 2016, Washington, DC. Abstract 911.


GiACTA: Baseline Characteristics

Baseline Characteristics

All Patients

N = 251

Age, mean (SD) 69.0 (8.2)

Female, % 74.9

Caucasian, % 96.8

Newly diagnosed, % 47.4

Relapsing, % 52.6

Stone JH, et al. Oral Presentation at ACR 2016, Washington, DC. Abstract 911. © 2016 Genentech, Inc. All rights reserved.

Superior efficacy of TCZ + 26-week prednisone vs. 26-week and 52-week prednisone alone

GiACTA: Primary and Key Secondary End Points

Patients

in S

usta

ined R

em

issio

n,

%

2° endpoint: p < 0.0001

1° endpoint: p < 0.0001

1° endpoint p < 0.0001

2° endpoint p = 0.0002

PBO + 26 PBO + 52 TCZ QW TCZ Q2W

QW, weekly; Q2W, every 2 weeks; PBO, placebo; TCZ, tocilizumab


n = 50 51 100 49


Excluding CRP from the definition of sustained remission did not alter the conclusion of the primary analysis

GiACTA: Primary and Key Secondary End Points - Sensitivity Analysis

Patients

in S

usta

ined R

em

issio

n,

%

PBO + 26 PBO + 52 TCZ QW TCZ Q2W

2° endpoint: p = 0.003

1° endpoint: p < 0.0001

QW, weekly; Q2W, every 2 weeks; PBO, placebo; TCZ, tocilizumab




n = 50 51 100 49


GiACTA: Time to First Flare Following Clinical Remission

Zone

where 26-

week

prednisone

taper

reaches

0 mg/day

100

80

60

40

20

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Time, weeks

Patients

Without G

CA

Fla

re,

%

PBO QW + 26 week (n = 50)


TCZ QW + 26 week (n = 100)

TCZ Q2W + 26 week (n = 49)

+ Censored


Primary Clinical Study Report GiACTA, p104.

No of Patients

PBO QW + 26 week

PBO QW + 52 week

TCZ QW + 26 week

TCZ Q2W + 26 week

50

51

100

49

44

48

93

47

40

44

88

45

36

41

85

40

34

38

85

40

29

35

81

39

23

32

77

35

19

30

74

32

18

28

71

30

16

25

69

30

14

22

67

29

13

17

64

26

13

15

63

24

3

5

2

Note: the low number of patients at risk at Week 52 is due to the method used to calculate the Week 52 time window. The major ity of patients completed their Week 52 visit in the few days prior to

the end of the window and are therefore censored at the very end of the Week 52 window. This does not impact the results in any way and is applied consistently across all patients and groups.

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GiACTA: Time to First Flare, New-Onset vs. Relapsing Disease

Pa

tie

nts

With

ou

t G

CA

Fla

re, %

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Time, weeks

0

20

40

60

80

100

PBO QW + 26 wk (n = 23) PBO QW + 52 wk (n = 23) TCZ QW + 26 wk (n = 47) TCZ Q2W + 26 wk (n = 26) Censored +

Stone JH, et al. Oral Presentation at International Vasculitis and ANCA Workshop, 2017,

Tokyo, Japan. Abstract SY4-6.

New Onset Disease

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Time, weeks

0

20

40

60

80

100

PBO QW + 26 wk (n = 27) PBO QW + 52 wk (n = 28) TCZ QW + 26 wk (n = 53) TCZ Q2W + 26 wk (n = 23) Censored +

Relapsing Disease


GiACTA: Cumulative Steroid Exposure

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Time, weeks

Cum

ula

tive G

lucocort

icoid

Dose,

mg



TCZ QW + 26 week (n = 100)

TCZ Q2W + 26 week (n = 49)

4000

3000

2000

1000

0

Actual Cumulative Dose

to Week 52, mg

PBO + 26

n = 50

PBO + 52

n = 51

TCZ QW

n = 100

TCZ Q2W

n = 49

Median 3296 3818 1862 1862

Includes prednisone received as part of the taper, escape prednisone, and concomitant steroids.

p ≤ 0.0003 for all comparisons of TCZ to PBO.


Zone

where 26-

week

prednisone

taper

reaches

0 mg/day


GiACTA: Safety Overview

AEs balanced across groups

No new safety signals/laboratory abnormalities observed

No deaths

No bowel perforations

2 malignancies (both in prednisone-only groups)

PBO + 26

n = 50

PBO + 52

n = 51

TCZ QW

n = 100

TCZ Q2W

n = 49

Pts with ≥1 AE, % 96.0 92.2 98.0 95.9

Total AEs, n 470 486 810 432

Pts with ≥1 SAE, % 22.0 25.5 15.0 14.3

Pts with ≥1 SI, % 4.0 11.8 7.0 4.1

AE, adverse event; pts, patients; SAE, serious adverse event; SI, serious infection.

Stone JH, et al. Oral Presentation at ACR 2016, Washington, DC. Abstract 911. © 2010 Genentech, Inc. All rights reserved

Important Safety Information Laboratory Values

• Laboratory monitoring is recommended due to potential consequences of treatment-related changes in neutrophils, platelets, lipids, and liver function tests. Dosage modifications may be required.

• It is recommended that Actemra not be initiated in patients with an ANC<2000/mm3, platelet count below 100,000/mm3, or who have ALT or AST above 1.5xULN.

• Infections have been uncommonly reported in association with treatment-related neutropenia in long-term extension studies and postmarketing clinical experience. Please see full prescribing information for more information.

© 2010 Genentech, Inc. All rights reserved

Important Safety Information

• Treatment with Actemra is not recommended in patients with active hepatic disease or hepatic impairment.

• Avoid use of live vaccines concurrently with Actemra. It is recommended that all patients, particularly PJIA and SJIA patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating Actemra therapy. The interval between live vaccinations and initiation of Actemra therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.


Important Safety Information Risk of GI Perforation

• Events of gastrointestinal (GI) perforation have been reported in clinical trials, primarily as complications of diverticulitis in RA patients.

• Use Actemra with caution in patients who may be at increased risk for GI perforation. .

• Promptly evaluate patients presenting with new onset abdominal symptoms for early identification of GI perforation.

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Important Safety Information Demyelinating Disorders

• The impact of treatment with Actemra on demyelinating disorders is not known, but multiple sclerosis and chronic inflammatory demyelinating polyneuropathy were reported rarely in clinical studies.

• Monitor patients for signs and symptoms potentially indicative of demyelinating disorders. Prescribers should exercise caution in considering the use of Actemra in patients with preexisting or recent onset demyelinating disorders.


Additional Important Safety Information Effect on CYP450 Enzyme Activity

• Inhibition of IL-6 signaling in RA patients treated with Actemra may restore CYP450 activities to higher levels than those in the absence of Actemra leading to increased metabolism of drugs that are CYP450 substrates.

• The effect of Actemra on CYP enzymes may be clinically relevant for CYP450 substrates with narrow therapeutic index, where the dose is individually adjusted. Upon initiation or discontinuation of Actemra in patients being treated with these types of medicinal products, perform therapeutic monitoring of effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) and the individual dose of the medicinal product adjusted as needed.

• Exercise caution when coadministering Actemra with CYP3A4 substrate drugs where decrease in effectiveness is undesirable, e.g., oral contraceptives, lovastatin, atorvastatin, etc.


Important Safety Information Boxed Warning Serious Infections (continued)

• Perform test for latent TB; if positive, start treatment for TB prior to starting Actemra. Monitor all patients for active TB during treatment, even if initial latent TB test is negative.

• The risks and benefits of treatment should be considered prior to initiating Actemra in patients with chronic or recurrent infection; who have been exposed to TB; with a history of serious or an opportunistic infection; who have resided or traveled in areas of endemic TB or endemic mycoses; or with underlying conditions that may predispose them to infection.

• Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with Actemra.


GiACTA: Summary

This was the first trial to utilize a blinded, variable-dose steroid regimen

Significantly more patients treated with TCZ + 26-week prednisone taper achieved sustained remission at Week 52 than those treated with placebo with either a 26-week or 52-week prednisone taper.

Patients treated with TCZ remained in clinical remission longer, and had significantly lower cumulative glucocorticoid dose compared to placebo-treated patients.

No new safety signals or laboratory abnormalities were seen with TCZ



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