1

UPDATE:Vaccine Candidate Against C. difficile

Shon Anthony Remich, MDSenior Director,

Vaccine Clinical Research & Development

Shon Anthony Remich, MD, is employed by

Pfizer and owns stock in the company

2

Currently, there is no vaccine to prevent initial or recurrent CDI

If Nothing Else, You Should Remember…

CDI=Clostridium difficile infection.

1. Clostridium difficile Infections in Hospital Stays, 2009. https://www.hcup-us.ahrq.gov/reports/statbriefs/sb124.pdf. Accessed May 9, 2019.

2. Lessa FC, et al. N Engl J Med. 2015;372(24):2369-2370.

3. Centers for Disease Control and Prevention: Biggest threats and data. https://www.cdc.gov/drugresistance/biggest_threats.html. Accessed May 9, 2019.

C. difficilebacteria express toxins, causing severe diarrhea1

Antibiotic use causes CDI1

C. difficile at“Hazard Level –Urgent” (CDC)3

>450,000 casesand >29,000

deaths/year in US2

1 in 5 recurrence2

Clostridium (Clostridioides) difficile: A Significant Unmet Medical Need

3

147

24 47

149

628

0

700

All Ages 1-17 yr 45-64 yr18-44 yr ≥65 yr

CD

I in

cid

en

ce p

er

10

0,0

00 p

ers

on

s

100

CDI Incidence in the US by Age Group (2011)1

Typical

recommendation

threshold (100 per 100k)

A Nationwide Surveillance Program by the CDC Demonstrates That the Incidence of C. difficile Increases With Age

1. Lessa FC, et al. N Engl J Med. 2015;372(24):2369-2370.

2. Centers for Disease Control and Prevention: What is C. diff?. https://www.cdc.gov/cdiff/what-is.html. Accessed May 9, 2019.

1 in 11 patients aged

≥65 years died of

healthcare-related CDI

within 1 month of diagnosis2

4

CDC Emerging Infections Program C. difficileUS Surveillance Data: 2011-2016

1. Lessa FC, et al. N Engl J Med. 2015;372(24):2369-2370.

2. Center of Disease Control and Prevention. Data Summary of HAIs in the US: Assessing Progress 2006-2016. Unpublished data (2016) courtesy of Dr. Alice Guh.

No

. o

f c

as

es

per

100

,00

0 p

ers

on

s92.8 92.9

86.0 83.8 82.7

75.4

48.252.9

57.8

65.8 67.2

0

20

40

60

80

100

2011 2012 2013 2014 2015 2016

Associated CDI

Community Associated CDI

Reported Crude Incidence of Community-Associated and Healthcare-Associated

CDI Among the 10 Emerging Infections Program Sites, 2011-20161,2

55.8

Healthcare-

-

Overall 3% decrease in CDI from 2011 to 20162

19% decreasein healthcare-associated

CDI from 2011-20162

39% increasein community-associated

CDI from 2011-20162

In 2011: 453,000 cases,

29,000 deaths1

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Pfizer’s Bivalent Toxoid Vaccine Preserves Important Antigenic Epitopes

APD=autoprotease domain; GTD=glucosyltransferase domain.

1. Donald RG, et al. Microbiology. 2013;159(Pt 7):1254-1266.

2. Gribenko A, et al. Biochem Biophys Rep. 2017;9:193-202.

Key Advantages:

• Safety: Genetically detoxified toxin

• Efficacy: Preservation of neutralizing

epitopes

• Implementation: Ease of manufacturing

Toxin A

Toxin B

Expression in C. difficile

Recipient VPI 11186

SPO-A and Toxin minus

6

C. difficile Vaccine Clinical Development Program

1. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT01706367. Accessed May 9, 2019. 2. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02725437. Accessed May 9, 2019.

3. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02561195. Accessed May 9, 2019. 4. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03090191. Accessed May 9, 2019.

5. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03579459. Accessed May 14, 2019. 6. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03918629. Accessed May 14, 2019.

2015 2016 2017 2018 2019 2020

2012-2013

Phase 1, n=192 (US)First-in-human study at three

dose levels, with or without

adjuvant, to assess safety and

tolerability in adults aged 50 to

85 years1

Phase 1, n=100 (Japan)First-in-Japan study of the safety,

tolerability, and immunogenicity of 2 dose

levels over 2 vaccination schedules of

CDI vaccine in adults aged 65 to 85

years2

Phase 2, n=855 (US)Evaluation of the safety, tolerability, and immunogenicity of CDI vaccine in adults aged 65 to 85 years

on two vaccination schedules, with or without an additional dose 1 year after third dose3

Clover, Phase 3, n~17.5k (Global)Safety, tolerability, and efficacy of CDI vaccine in adults aged ≥50 years4

Phase 3, n=1316 (US)Study to evaluate the lot consistency, safety, tolerability, and

immunogenicity of CDI vaccine in adults aged 65 to 85 years5

Phase 3, n=500 (US)Study to evaluate the immuno-

genicity, safety, and tolerability of

a 2-dose CDI vaccine regimen

compared to a 3-dose regimen in

adults aged ≥50 years6

7

CDI vaccine 100 µg (n=183)

CDI vaccine 200 µg (n=183)

Placebo (n=61)

Month 0, 1, 6

Schedule:

Vaccination period Follow-up period

M0 M1 M6 M7 M12 M18

Extension stage

Randomization

Proof of Concept Phase 2 Study to Evaluate the Safety, Tolerability, and Immunogenicity of CDI Vaccine in Adults Aged 65 to 85 Years (NCT02561195)

67.2

3.3Sero-Status

Sero-negative

A+/B-

B+/A-

A+/B+

Sero-

positive

97 86:

Sex Ratio

Patient Demographics | (200 μg – Month 0, 1, 6)

Range: 65-85

Mean: 71.3

65 85

Age (y)

Remich S, et al. A phase-2, placebo-controlled, randomized, observer-blinded study to evaluate the safety, tolerability and immunogenicity of two 3-dose regimens of a Clostridium difficile vaccine in

healthy adults 65 to 85 years of age. Poster presented at: ECCMID; April 21-24, 2018; Madrid, Spain.

9.8

19.7

8

Month Regimen Geometric Mean Concentration (GMC) Levels(200 μg vs Placebo)

0 30 60 90 120 150 180 210 240 270 300 330 360 390 420 450 480 510 54010

100

1000

GMC levels - Month Regimen (Toxin A)

Days

GM

C

(ne

utr

ali

za

tio

n u

nit

s/m

L)

Placebo

200 g

0 30 60 90 120 150 180 210 240 270 300 330 360 390 420 450 480 510 540100

1000

10000

GMC levels - Month Regimen (Toxin B)

Days

GM

C

(ne

utr

ali

za

tio

n u

nit

s/m

L)

200 g

Placebo

Month 0, 1, 6 Schedule:

Month 0, 1, 6 Schedule:

Remich S, et al. A phase-2, placebo-controlled, randomized, observer-blinded study to evaluate the safety, tolerability and immunogenicity of two 3-dose regimens of a Clostridium difficile vaccine in

healthy adults 65 to 85 years of age. Poster presented at: ECCMID; April 21-24, 2018; Madrid, Spain.

9

E-diary Reported Events: Month 0, 1, 6 Regimen(Follow-up 14 Days After Each Dose)

0%10%20%30%40%50%

Pla

cebo

200 μ

g

Pla

cebo

200 μ

g

Pla

cebo

200 μ

g

Pain Redness Swelling

Post dose 1

Local

Reactions 0%10%20%30%40%50%

Pla

cebo

200 μ

g

Pla

cebo

200 μ

g

Pla

cebo

200 μ

g

Pain Redness Swelling

Post dose 2

0%10%20%30%40%50%

Pla

cebo

200 μ

g

Pla

cebo

200 μ

g

Pla

cebo

200 μ

g

Pain Redness Swelling

Post dose 3

Grade 1 (mild) Grade 2 (moderate) Grade 3 (severe) Grade 4

0%10%20%30%40%

Pla

cebo

200 μ

g

Pla

cebo

200 μ

g

Fatigue Headache

Post dose 1

0%10%20%30%40%

Pla

cebo

200 μ

g

Pla

cebo

200 μ

g

Fatigue Headache

Post dose 2

0%10%20%30%40%

Pla

cebo

200 μ

g

Pla

cebo

200 μ

g

Fatigue Headache

Post dose 3

Fatigue and

Headache

Remich S, et al. A phase-2, placebo-controlled, randomized, observer-blinded study to evaluate the safety, tolerability and immunogenicity of two 3-dose regimens of a Clostridium difficile vaccine in

healthy adults 65 to 85 years of age. Poster presented at: ECCMID; April 21-24, 2018; Madrid, Spain.

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E-diary Reported Fever: Month 0, 1, 6 Regimen(Follow-up 14 Days After Each Dose)

0%

1%

2%

3%

4%

5%

Pla

cebo

200 μ

g

Post dose 1

0%

1%

2%

3%

4%

5%

Pla

cebo

200 μ

g

Post dose 2

0%

1%

2%

3%

4%

5%

Pla

cebo

200 μ

g

Post dose 3

38.0-38.4 ºC 38.5-38.9 ºC 39.0-40.0 ºC >40.0 ºC

Remich S, et al. A phase-2, placebo-controlled, randomized, observer-blinded study to evaluate the safety, tolerability and immunogenicity of two 3-dose regimens of a Clostridium difficile vaccine in

healthy adults 65 to 85 years of age. Poster presented at: ECCMID; April 21-24, 2018; Madrid, Spain.

11

E-diary Reported Events: Month 0, 1, 6 Regimen(Follow-up 14 Days After Each Dose)

0%

10%

20%

30%

Pla

cebo

200 μ

g

Pla

cebo

200 μ

g

Diarrhea Vomiting

Post dose 1

0%

10%

20%

30%

Pla

cebo

200 μ

g

Pla

cebo

200 μ

g

Diarrhea Vomiting

Post dose 2

0%

10%

20%

30%

Pla

cebo

200 μ

g

Pla

cebo

200 μ

g

Diarrhea Vomiting

Post dose 3

0%

10%

20%

Pla

cebo

200 μ

g

Pla

cebo

200 μ

g

Muscle pain Joint pain

Post dose 1

0%

10%

20%

Pla

cebo

200 μ

g

Pla

cebo

200 μ

g

Muscle pain Joint pain

Post dose 2

0%

10%

20%

Pla

cebo

200 μ

g

Pla

cebo

200 μ

g

Muscle pain Joint pain

Post dose 3

Grade 1 (mild) Grade 2 (moderate) Grade 3 (severe) Grade 4

Diarrhea and

vomiting

Muscle pain and

joint pain

Remich S, et al. A phase-2, placebo-controlled, randomized, observer-blinded study to evaluate the safety, tolerability and immunogenicity of two 3-dose regimens of a Clostridium difficile vaccine in

healthy adults 65 to 85 years of age. Poster presented at: ECCMID; April 21-24, 2018; Madrid, Spain.

12

0

20

40

60

80

Any AE Related AE Any SAE Related SAE Withdrawal dueto AE

Withdrawal dueto AE (related)

Death

Pro

po

rtio

n o

f su

bje

cts

(%

)

200 μg CDI vaccine

Placebo

Safety Profile: Adverse Events and Serious Adverse Events

Safety profile of 200 μg dose at 0, 1, and 6 months in this phase 2 study is consistent with previous studies

AE=adverse event; SAE=serious adverse event.

Remich S, et al. A phase-2, placebo-controlled, randomized, observer-blinded study to evaluate the safety, tolerability and immunogenicity of two 3-dose regimens of a Clostridium difficile vaccine in

healthy adults 65 to 85 years of age. Poster presented at: ECCMID; April 21-24, 2018; Madrid, Spain.

14

Subjects meeting all inclusion

and no exclusion criteria

~17.5k subjects

Month 0 61

Follow-up Period

Up to 3 years

Vaccination

Period

3 or more

unformed stools

(Bristol stool

chart types 5-7)

within 24 hours

Interim

analysis:

63 cases

Enrollment

Final

analysis:

106 cases

Kentucky

Brussels

Singapore

Diagnostic Assays

382 sites in 23 countries

Clostridium Difficile Vaccine Efficacy Trial (Clover)

15

≥3 diarrheal

episodes in 24 hrs

Stool Collection:

Home, Nursing Home,

Clinic / Urgent Care,

Hospital

NanoCool Shipper

2-10 °C 96 hrs

PPD Processing Lab

Kentucky

Belgium

Singapore

Central Testing Lab

Pearl River, NY

From Sample Collection to Diagnostic Testing

Maintenance of Sample Cold Chain Custody

Stool Sample

PCRCepheid GeneXpert ® STEP 1

No Case

- +Positive Case

- +

No Case

STEP 2Perform CCNA

PCR

Xpert® C. difficile/Epi

Two-Step Testing AlgorithmEndorsed by KOLs, ESCMID, ISDA, SHEA, CHMP, and the FDA

Diagnostic Testing

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Conclusions

• CDI causes significant disease in adults >50 years of age in communityand hospital settings

• Pfizer’s vaccine was produced using a novel detoxification processthat preserves critical epitopes maximizing production ofneutralizing antibodies

• The vaccine induces polyclonal antibodies that neutralize diverse toxinsand shows protection in preclinical models

• Vaccine program has progressed through proof of concept to phase 3demonstrating robust immune responses with a strong safety profile

• Status: phase 3 Clover trial is fully enrolled and awaiting case accrual

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Acknowledgments

We thank all of the study participants and the investigators for their substantial contributions to the enrollment of subjects and collection of data

Pfizer Contributors

Chris Webber

Nick Kitchin

Shon Remich

Catia Ferreira

Jody Lawrence

Ping Li

Stephen Lockhart

Bill Gruber

Michael Pride

Kathrin Jansen