can recombinant zoster vaccine administration decrease ......lal et al. n engl j med...

Can Recombinant Zoster Vaccine Administration Decrease the Use of Herpes Zoster-Related Pain Medication across

Randomized Controlled Studies?

Joon Hyung Kim,1 Robert Johnson,2 Martina Kovac,1a Anthony L. Cunningham,3,4 Srikanth Emmadi,5 Keith Sullivan,6 Alemnew F. Dagnew,1b

Desmond Curran,5 Anne Schuind1c

1GSK, Rockville, MD, United States; 2University of Bristol, Faculty of Health Sciences, Bristol, United Kingdom; 3The Westmead Institute for Medical Research, Westmead, NSW, Australia; 4University of Sydney,

Sydney, NSW, Australia; 5GSK, Wavre, Belgium; 6Duke University Medical Center, Durham, NC, United States

Current affiliations: aPPD, Bethesda, MD, United States; bBill & Melinda Gates Medical Research Institute, Cambridge, MA, United States; cPATH, Washington, DC, United States

IDWeek 2020 Virtual meeting, 21–25 October 2020 1

• Joon Hyung Kim, Martina Kovac, Srikanth Emmadi, Alemnew F. Dagnew, Desmond Curranand Anne Schuind were employed by the GSK group of companies at the time the studies were designed, initiated and/or conducted and declare financial and non-financial relationships and activities. MK, AD, and AS are currently employed by PPD, the Bill & Melinda Gates Medical Research Institute, and PATH, respectively. JHK, MK, AD, DC and AS hold/held shares/stock options in GSK as part of their remuneration. Robert Johnson reports personal and consulting fees from GSK both during the conduct of the study and outside the submitted work. Anthony L. Cunningham received honoraria paid to his institution from GSK, Merck Sharp & Dohme (Merck), and BioCSL/Sequirus outside the submitted work. Keith Sullivan receives consulting fees from Magenta, Kiadis, GSK, Talaris, and Xenikos outside the submitted work.

• Funding: GlaxoSmithKline Biologicals SA

• Medical writing and editorial support were provided by Kristel Vercauteren and Sander Hulsmans(Modis c/o GSK)

Disclosures

Acknowledgments

2

Background

1. Yawn and Gilden. Neurology. 2013;81:928–30; 2. Drolet et al. Clin J Pain. 2010;26:656–66; 3. Johnson et al. BMC Med 2010;8:37; 4. Johnson and Rice. N Engl J Med 2014; 371:1526–33.

Herpes zoster (HZ) or shingles

3

Background



Older adults or theimmunocompromised are at

increased risk of HZ infection, severe disease and

complications1,2

RISK

4

Background



Has a major impact on patients’ quality of life3



complications1,2

RISK

5

Background




~1 OF 6patients with HZ still

have some pain 2 years afteronset4



complications1,2

RISK

6

Background



~1 OF 6patients with HZ still

have some pain 2 years afteronset4

Opioids and other analgesics may be prescribed for pain relief

but there are concerns about long-term effects and potential

misuse4




complications1,2

RISK

7

Background: 3 randomized, placebo-controlled, phase 3 clinical efficacy trials of RZV in older and immunocompromised adults

RZV, adjuvanted recombinant zoster vaccine; HSCT, autologous hematopoietic stem cell transplantation; CI, confidence interval; n, number of participants in the modified Total vaccinated cohort (primary cohort for efficacyanalysis).*at the time of primary endpoint analysis. 1. Lal et al. N Engl J Med 2015;372:2087–96; 2. Cunningham et al. N Engl J Med 2016;375:1019–32; 3. Bastidas et al. JAMA 2019;322:123–33.

Age

% Efficacy against HZ(95% CI)

HZ cases in RZV group (n)HZ cases in placebo group (n)

50+

ZOE-50(NCT01165177)1

70+

ZOE-70(NCT01165229)2

ZOE-HSCT(NCT01610414)3

8



Age



50+

ZOE-50(NCT01165177)1

s

%*3.7; 99.0)

≥50 year

97.2(9

9 (7,340)254 (7,413)

70+

ZOE-70(NCT01165229)2


9



Age



50+

ZOE-50(NCT01165177)1

s

%*3.7; 99.0)

≥50 year

97.2(9

9 (7,340)254 (7,413)

70+

ZOE-70(NCT01165229)2

≥70 years

89.8%(84.2; 93.7)23 (6,541)

223 (6,622)


10



Age



50+

ZOE-50(NCT01165177)1

s

%*3.7; 99.0)

≥50 year

97.2(9

9 (7,340)254 (7,413)

70+

ZOE-70(NCT01165229)2

≥70 years

89.8%(84.2; 93.7)23 (6,541)

223 (6,622)


≥18 years(transplant population)

68.2%(55.6; 77.5)

49 (870)135 (851)

11



Age



50+

ZOE-50(NCT01165177)1

s

%*3.7; 99.0)

≥50 year

97.2(9

9 (7,340)254 (7,413)

70+

ZOE-70(NCT01165229)2

≥70 years

89.8%(84.2; 93.7)23 (6,541)

223 (6,622)


≥18 years(transplant population)

68.2%(55.6; 77.5)

49 (870)135 (851)

12

Aim

Did RZV have an impact in the few people who developed confirmed HZ (“breakthrough cases”) afterRZV vaccination in the ZOE-50, ZOE-70 and ZOE-HSCT studies?

13

Aim


14

Efficacy of RZV vaccination in breakthrough cases on:

Duration of clinically

significant HZ-related

pain

Secondary endpoint (all studies)

Aim


15




pain

Use of HZ-related pain medication

Secondary endpoint (all studies) Secondary endpoint (ZOE-50, ZOE-70) Tertiary endpoint (ZOE-HSCT)

Aim


16




pain

Use of HZ-related pain medication

Duration of HZ-related

pain medication

use

Secondary endpoint (all studies) Secondary endpoint (ZOE-50, ZOE-70) Tertiary endpoint (ZOE-HSCT)

Secondary endpoint (ZOE-50, ZOE-70) Tertiary endpoint (ZOE-HSCT)

Clinically significant pain

Methods

17

Zoster Brief Pain Inventory (ZBPI) questionnaire (only confirmed HZ cases were evaluated)

Least pain in the last 24 hoursWorst pain in the last 24 hoursAverage pain in the last 24 hoursPain right now

0

No PainScore: 0

10

Pain as bad as you canimagine

Score: 10 ZBPI questions:


Methods

18



0

No PainScore: 0

10


Score: 10

103

ZBPI questions:


Methods

19



Medication use for HZ-related pain (only confirmed HZ cases were evaluated)

Manual classification of all HZ-related medications during each episode (post-hoc)

0

No PainScore: 0

10


Score: 10

103

ZBPI questions:

Results: RZV can reduce the duration of clinically significant HZ-related pain

Vaccine efficacy was assessed by COX proportional hazard model. *This analysis excluded pain linked to a confirmed HZ case after the start of relapse treatment. N, number of participants with at least 1confirmed HZ episode; n, number of participants with at least 1 confirmed HZ episode and at least 1 day of clinically significant HZ-related pain; tmed, median duration of clinically significant HZ-related pain; T, sum of the duration of clinically significant HZ-related pain (T=1 for participants without pain).

Efficacy in reducing duration of clinically significant pain (95% CI)

9254

7221

11.015.0

1466705

23223

18198

13.519.0

6289633

49135

37120

14.024.0

8926275

N n tmed (days) T (days)

26.9

28.4

38.5

-80% -60% -40% -20% 0% 20% 40% 60% 80%

RZVPlacebo

RZVPlacebo

RZVPlacebo

ZOE-50

ZOE-70

ZOE-HSCT*

20

Results: RZV can reduce HZ-related pain medication use

Efficacy in reducing pain medication use (95% CI)

9254

6190

13529

23223

10160

31631

49135

3294

65262

N n nmed

RZVPlacebo

RZVPlacebo

RZVPlacebo

ZOE-50

ZOE-70

ZOE-HSCT*

11.7

39.6

6.2

-80% -60% -40% -20% 0% 20% 40% 60% 80%

Vaccine efficacy was assessed by asymptotic standardized unconditional binomial test. *This analysis excluded pain medication linked to a confirmed HZ case after the start of relapse treatment. N, number of participants with at least 1 confirmed HZ episode; n, number of participants with at least 1 confirmed HZ episode who took at least 1 HZ-related pain medication; nmed, number of HZ-related pain medications.

21

Results: RZV can reduce the duration of HZ-related pain medication use

Vaccine efficacy was assessed by COX proportional hazard model. *This analysis excluded pain medication linked to a confirmed HZ case after the start of relapse treatment. N, number of participants with at least 1confirmed HZ episode; n, number of participants with at least 1 confirmed HZ episode and at least 1 day of HZ-related pain medication use; tmed, median duration of HZ-related pain medication use; T, sum of theduration of HZ-related pain medication use (T=1 for participants without pain medication).

Efficacy in reducing duration of pain medication use (95% CI)

9254

6190

21.022.0

15914,524

23223

10160

30.038.0

110831,949

49135

3294

21.547.5

191715,465

N n tmed (days) T (days)

RZVPlacebo

RZVPlacebo

RZVPlacebo

ZOE-50

ZOE-70

ZOE-HSCT*

24.7

49.3

22.5

-80% -60% -40% -20% 0% 20% 40% 60% 80%

22

Results: Proportion of participants with confirmed HZ by medicine type in ZOE-50

N, number of participants with at least 1 confirmed HZ episode; n, number of participants with at least 1 confirmed HZ episode taking at least 1 of the specified HZ-related medications; † Based on the World Health Organization’s pain relief ladder [www.who.int/cancer/palliative/painladder/en/].

ZOE-50

Participants taking at least 1 HZ-related medication

6

3

1

1

3

155

49

21

21

17

55

15

10

24

37

1

54

0% 10% 20% 30% 40% 50% 60% 70%

Non-opioids†

Weak opioids†

Strong opioids†

Corticosteroids

Antidepressants

Psychiatric medications

Anesthetics

Antihistamines

Gastro-intestinal medications

Antibiotics

Muscle relaxants

Other medications

RZV (N=9)

Placebo (N=254)

n

23

Results: Proportion of participants with confirmed HZ by medicine type in ZOE-70

ZOE-70


RZV (N=23)

Placebo (N=223)

6

2

1

1

3

1

2

3

103

30

5

10

18

35

11

9

6

32

2

42

0% 10% 20% 30% 40% 50% 60% 70%

Non-opioids†

Weak opioids†

Strong opioids†

Corticosteroids

Antidepressants


Anesthetics

Antihistamines

Gastro-intestinal medications

Antibiotics

Muscle relaxants

Other medications

N, number of participants with at least 1 confirmed HZ episode; n, number of participants with at least 1 confirmed HZ episode taking at least 1 of the specified HZ-related medications; † Based on the World Health Organization’s pain relief ladder [www.who.int/cancer/palliative/painladder/en/].

n

24

Results: Proportion of participants with confirmed HZ by medicine type in ZOE-HSCT

ZOE-HSCT


RZV (N=49)

Placebo (N=135)

22

6

5

2

3

8

0

1

2

5

0

6

62

34

12

14

13

42

7

11

2

14

0

19

0% 10% 20% 30% 40% 50% 60% 70%

Non-opioids†

Weak opioids†

Strong opioids†

Corticosteroids

Antidepressants


Anesthetics

Antihistamines

Gastro-intestinaI medications

Antibiotics

Muscle relaxants

Other medications

This analysis excluded medication linked to a confirmed HZ case after the start of relapse treatment. N, number of participants with at least 1 confirmed HZ episode; n, number of participants with at least 1 confirmed HZ episode taking at least 1 of the specified HZ-related medications; † Based on the World Health Organization’s pain relief ladder [www.who.int/cancer/palliative/painladder/en/].

n

25

Conclusions

26

Conclusions

In addition to the high efficacy of RZV in preventing HZ, data from these 3 large clinical efficacy trials indicates that RZV may shorten the duration of HZ-related pain and therefore shorten the duration of pain medication use in breakthrough cases in older adults and HSCT recipients.

27

Conclusions


The results from these preplanned secondary and tertiary study endpoints should be interpreted withcaution due to the low number of breakthrough HZ cases (high vaccine efficacy).

28

Conclusions



By preventing HZ through vaccination, RZV could potentially reduce exposure to opioids and othermedication (see also abstract 902651).

29

Conclusions



Even in cases when shingles develops in vaccinated people, RZV may reduce its severity and the need for pain relief. These additional benefits of vaccination improve the patient’s quality of life and might mitigate the risk of overmedication.

By preventing HZ through vaccination, RZV could potentially reduce exposure to opioids and othermedication (see also abstract 902651).

30

Thank you

31

can recombinant zoster vaccine administration decrease ......lal et al. n engl j med...

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