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RotaTeq®: The of the Story

Beyond the Primary Phase III Efficacy & Safety Results

Penny M. Heaton, MDMerck Research Laboratories

7th International Rotavirus SymposiumJune 12-13, 2006

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Objectives

Rationale for development of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine

Characteristics of RotaTeq®

Design of Rotavirus Efficacy and Safety Trial (REST) and other Phase III studies

Results of Phase III studies– Efficacy– Safety

Current environment and future studies of RotaTeq®

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Basis for Developing a Pentavalent Rotavirus Vaccine

Infants and young children have multiple rotavirus infections in the first few years of life

Wild-type rotavirus infection induces immunity against subsequent rotavirus (RV) gastroenteritis

Natural immunity is largely serotype-specific, particularly with a child’s first infection

– A second illness caused by the same G-serotype is uncommon

Velazquez et al, N Engl J Med 1996;335:1022-8.

Any

77 (60, 88)

83 (64, 92)

92 (44, 99)

Mod. to severe

87 (55, 96)

100

---

# of previousRV infections

1

2

3

% efficacy (95% CI) by disease severity

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Basis for Developing a Pentavalent Rotavirus Vaccine (Cont.)

Antibody responses broaden with repeated infections – Broadening of immune response to different G types most likely due

to common P type

Homotypic response to VP7 (G) typically of greater magnitude than heterotypic response mediated by VP4 (P)

Merck Phase II Study*

We developed a pentavalent vaccine containing the most prevalent G serotypes for comprehensive protection of young infants

– Included P1[8] for protection against non G1-4 strains

*Vesikari et al, Vaccine 2006; 24:4821-9.

Quad (G1-4)270

74 (40, 90)

100 (25, 100)

Mono (P1[8])327

43 (-2, 63)

88 (11, 100)

RV disease severityN

Any severity

Severe disease

% efficacy (95% CI)

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Development of the Human-Bovine (WC3) Reassortants

RotaTeq® contains 5 human-bovine (WC3) reassortants

WC3 bovine rotavirus strain isolated in 1981

Animal studies showed that WC3 was naturally attenuated for non-bovine species (e.g., poor replication in mice and rabbits)

Clinical trials indicated WC3 was naturally attenuated for human infants

– Well tolerated in >700 infants who received at least one dose– Efficacy was variable

Human-bovine reassortants were developed to improve efficacy

– Human surface VP7/VP4 (G/P) induce immunity– WC3 strain preserves tolerability

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Bovine Rotavirus

WC3

Human-Bovine Reassortant Rotavirus Vaccine Strains

G1 (P7) G2 (P7) G3 (P7) G4 (P7) P1 (G6)

Human Rotaviruses G1-4, P1[8]

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Characteristics of RotaTeq®Oral vaccine suspended in a liquid buffer/stabilizer

– Protected from gastric acid– Stored refrigerated with 24-month shelf life

Ready-to-use, administered directly from tube– No reconstitution required

3-dose regimen: First dose at age 6 to 12 weeks and subsequent doses at 1- to 2-month intervals

– Integrates into existing immunization schedules• 2-, 3-, 4-month• 2-, 4-, 6-month• 6-, 10-, 14-week

– Provides coverage before peak age of rotavirus hospitalizations

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RotaTeq® Packaging and Container

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Developmentof RotaTeq®

Proof-of-concept study (G1-3,

P1) (002)

Study to establish dose

and reassortant composition

(pentavalent; G1-4, P1) (005)

1993 1997 1998 2001 2002 200320001999

Reports ofIS with RRV-TV

Large-Scale Trial(Rotavirus Efficacy and

Safety Trial ; REST) (006)

Dose Confirmation

Efficacy(007)

2004 2005

Consist-ency Lots

Study (009)

Phase III (RotaTeq™)

Clinical study ofdifferent buffers (G1-2) (003)

FDA ACMfor REST

2006

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Analyses of Data from REST and Other Phase III Studies

Efficacy – Rotavirus acute gastroenteritis (RV AGE) caused by

serotypes in the vaccine (G1-4, P1[8])• First and second RV seasons postvaccination

– Reduction in health care encounters for RV AGE• Hospitalizations, emergency department visits, and

office visits• First and second years of life• Serotype-specific• By region (EU, US, Latin American/Caribbean)

Safety– Serious adverse events including intussusception (IS)– Other adverse events (AEs) including AEs of special

clinical interest

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Design of REST and Other Phase III Studies

Sample size: 71,799 (36,203 RotaTeq® : 35,596 Placebo)

Age: 6 to 12 weeks at first dose

Regimen: 3 oral doses, 1 every 4 to 10 wks

Sites: Areas with good standard of care for intussusception

Duration: January 2001 to October 2005

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71,799 Subjects in 11 Countries 36,203 in RotaTeq® Group35,596 in Placebo Group

GermanyGermanyBelgiumBelgium

FinlandFinland

USUSPuerto RicoPuerto RicoJamaicaJamaica

Native Native American American NationsNations

SwedenSweden

TaiwanTaiwanMMééxicoxico

GuatemalaGuatemalaCosta RicaCosta Rica

ItalyItaly

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71,799 Subjects in 11 Countries 36,203 in RotaTeq® Group35,596 in Placebo Group

US ~35,100US ~35,100

Latin America/Latin America/CaribbeanCaribbean

~5300~5300

EU ~31,100EU ~31,100

Asia: ~200Asia: ~200

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Efficacy Evaluations in the Phase IIIStudies

All Subjects in REST• Efficacy against hospitalizations and emergency department visits for rotavirus acute gastroenteritis (RV AGE)

• Efficacy against all RV AGE (severity classified by scoring system)

• Efficacy against office visitsfor RV AGE (REST only)

Substudy in REST and All Subjects

in 007

REST, Protocol 007

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Efficacy EvaluationCase definition for RV AGE

– >3 loose stools and/or vomiting– RV-positive stool by EIA; serotype by PCR

In efficacy substudy, severity of cases designated with a 24-pt scoring system

– Based on intensity and duration of vomiting, diarrhea, fever, and behavioral changes (parent reported)

Scoring system validated in a Phase II study– Strongly correlates with physician assessment of severity– Also correlates with intensity of care required for RV AGE

MildModerate-and-Severe

Severe

Severity1 – 8

>8 and ≤16>16

Score

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Surveillance for Acute Gastroenteritis (AGE)

Monitoring for hospitalizations and emergency visits for AGE

– Parents contacted wks 1, 2, and 6 after each dose– After dose 3, contacts continued every 6 weeks for up to 2

years

Monitoring for all AGE– Parents contacted every 2 weeks during rotavirus season

Subjects were enrolled year-round– If enrolled during the RV season, followed for the rest of that

season and another RV season

A subset of infants in REST were followed for a second rotavirus season postvaccination

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14 days PD 3

Duration of Efficacy Follow-up For Subjects Who Received Dose 3 Before

Start of Rotavirus Season

* If enrolled early enough into the study, surveillance was also conducted for a second season.

Subject A*Completes

1st Full RV Season 2nd Full RV Season

SeasonBegins

SeasonEnds

SeasonBegins

SeasonEnds

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Duration of Efficacy Follow-up For Subjects Who Received Dose 3 After

Start of Rotavirus Season

SeasonBegins

1st Partial RV Season

14 days PD 3

1st Full RV Season

Subject B*Completes

SeasonEnds

SeasonBegins

SeasonEnds

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Efficacy Results

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Cumulative Number of G1-4 RV AGE Cases by Day of Follow-up and Treatment Group

Integrated Data – REST and Protocol 007

1 50 100 150 200 250 300 350 400 450 Day of Follow-up

0

50

100

150

200

250

300

350

Cum

ulat

ive

Num

ber o

f Cas

es RotaTeq™Placebo

Days of Follow-up

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REST Efficacy Substudy and Protocol 007(For the First Rotavirus Season Postvaccination)

Efficacy of RotaTeq® Against G1-4 RV AGE

N=number vaccinated.

DiseaseSeverityAnySevere

% Efficacy7498

95% CI67,7990,100

Number of Cases

971

Vaccine(N=3484)

36957

Placebo(N=3499)

22* Adjusted for multiplicity.

Summary of Efficacy ResultsFrom Phase II and III Studies

N Vaccinated

Any Severity% Efficacy (95% CI)

Severe% Efficacy (95% CI)

Severity of RV AGE(G1-G4)

Phase II

439

75 (50,88)

100 (44,100)

002

G1-3, P1~5.9×107

PFU/dose650

74 (38,91)*

100 (35,100)

005(Middle-dose)

G1-4, P1~7.9×106

PFU/dose

Phase III

1310

73 (51,86)

100 (13,100)

007(Expiry)

G1-4, P1~1.1×107

IU/dose5673

74 (67,80)

98 (88,100)

REST(Release)

G1-4, P1~6.7 to 12.4×107

IU/dose

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Efficacy of RotaTeq® During the Second Rotavirus Season Postvaccination

REST

First Season Second Season0

20

40

60

80

100

Effi

cacy

(%)

(36V:88P) (2V:17P)(1V:51P)(82V:315P)

AnySevere

(74%)

(98%)

(63%)

(88%)

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Efficacy of RotaTeq® Against Hospitalizations, Emergency Department

Visits & Office Visits for G1-4 RV AGE

† N=34,035 vaccinated in vaccine group and 34,003 vaccinated in placebo group.‡ N=2834 vaccinated in vaccine group and 2839 vaccinated in placebo group.

Type of HealthCare Encounter

Hospitalizations†

Emerg. Dept. Visits†

Office Visits‡

% RateReduction

969486

95% CI91, 98 89, 9774, 93

Number of Cases

61313

Vaccine138191

98

Placebo

REST

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Efficacy of RotaTeq® Against Hospitalizations and Emergency

Department Visits for G1-4 RV AGE by Year of Age

Age StrataLess than 1 Yr Old*1-2 Years of Age†

% RateReduction

9497

95% CI91,9782,100

Number of Cases

191

Vaccine33732

Placebo

REST

*N=34,035 RotaTeq®/ 34,003 Placebo†N=1219 RotaTeq®/ 1283 Placebo

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Serotype-Specific Efficacy of RotaTeq®Against Hospitalizations and Emergency

Department Visits for RV AGEREST

Serotype % Efficacy95889389

100

Number of Cases

161120

Vaccine(N=34,035)

3288

151813

Placebo(N=34,003) 95% CI

92,97<0,9949,9952,9867,100

G1P1a*G2P1bG3P1aG4P1aG9P1a

* Representative subset of samples with VP4 testing.N=number vaccinated.

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Serotype-Specific Efficacy of RotaTeq® Against Hospitalizations and Emergency Department

Visits for RV AGE:ITT Population (Subjects Who Received At Least One Dose)

Serotype % Efficacy9292859092

Number of Cases

321322

Vaccine(N=34,035)

41412202025

Placebo(N=34,003) 95% CI

88,9535,9950,9657,9866,98

G1P1a*G2P1bG3P1aG4P1aG9P1a

* Representative subset of samples with VP4 testing.N=number vaccinated.

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Efficacy of RotaTeq® Against Hospitalizations and Emergency Department Visits for G1-4 RV

AGE by Region

RegionEurope*

US¶

Native AmericanNations†

Latin America/Caribbean‡

% RateReduction

95

96

93

90

95% CI91,97

77,100

76,99

29,100

Number of Cases

16

1

2

1

Vaccine301

27

31

10

Placebo

REST

*N = 14,018 RotaTeq®/ 13,984 Placebo¶N = 11,990 RotaTeq®/ 11,892 Placebo†N = 294 RotaTeq®/ 287 Placebo‡N = 2252 RotaTeq®/ 2237 Placebo.

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Efficacy of RotaTeq® Against Hospitalizations and Emergency Department Visits for RV AGE

Regardless of Serotype by Region ITT Population (Subjects Who Received At Least One Dose)

Region% Rate

Reduction92

77

82

80

95% CI88,95

51,89

63,92

29,96

Number of Cases

31

15

9

3

Vaccine387

66

54

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PlaceboEurope*

US¶

Native AmericanNations†

Latin America/Caribbean‡

*N = 14,831 RotaTeq®/ 14,734 Placebo¶N = 15,261 RotaTeq®/ 15,218 Placebo†N = 326 RotaTeq®/ 343 Placebo‡N = 2651 RotaTeq®/ 2630 Placebo.

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Safety Evaluationsin Phase III Studies

Substudy in RESTand All Subjects in

Protocol 007 andProtocol 009

All serious adverse events (SAEs) including intussusception (IS)

All adverse events (AEs)

All Subjects in REST,Protocol 007, and

Protocol 009

• Fecal vaccine-strain shedding was evaluated in 2 ways– Pre-specified time interval– All rotavirus-positive potential acute gastroenteritis cases

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Safety Monitoring

Case definition for intussusception (IS) required radiographic, surgical, autopsy diagnosis

Contacted parents of all subjects and asked about SAEs including IS weeks 1, 2, and 6 after each dose

– Continued every 6 weeks after the third dose for up to one year after the first dose

Continuous monitoring by independent DSMB as each case occurred

Of 71,799 subjects enrolled in the Phase III studies, follow-up for 6 weeks after the last dose was completed in:

– 99.8% in the RotaTeq® group– 99.7% in the placebo group

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REST Intussusception Results

No intussusception cases in Protocols 007 and 009

35 Investigator-DiagnosedIntussusception Cases

0V:2P

11 caseswithin

42 daysof a dose

4 casesreported after studycompleted

17 cases>42 daysof a doseand ≤1 yrof dose 1

0V:4P6V:5P 7V:10P

32 positively-adjudicatedcases

2 negatively-adjudicated

cases

1 unadjudicatedcase

0V:1P

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AEs Occurring at a Statistically Significant Different Rate in the RotaTeq® vs. Placebo Groups for All 3

Phase III StudiesDifferences are only evident when data are combined across the 3 Phase III studies

– N=11,722 [6143 RotaTeq®/5579 Placebo]

AE of crying was reported at a higher rate in placebo recipients than vaccine recipients (3.6% vs. 4.4%)

AEs within 42 days after any dose reported at a higher rate among vaccine recipients than placebo recipients:

– Diarrhea (24% vs. 21%)– Vomiting (15% vs. 14%)– Nasopharyngitis (7% vs. 6%)– Otitis media (15% vs. 13%)– Bronchospasm (1.1% vs. 0.7%)

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Fecal Shedding of Vaccine-Virus Strains in REST and Protocol 007

OneTwoThree

Dose Number32/360 (8.9)0/249 (0)1/385 (0.3)

RotaTeq®

Number of Shedders/Number Tested (%)

• Shedding peaks 4 to 6 days postvaccination (Phase II)• Latest shedding in Phase III was 15 days from dose 1• One subject shed 4 days from dose 3• Low quantities (5×101 to 1.88×104 PFU/mL)

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Percent of Infants with Fever Within Week of First Dose by Day after Dose and

Vaccination Group

0

5

10

15

20

25

1 2 3 4 5 6 7Days Postdose 1

% o

f Sub

ject

s

RotaTeq™ Placebo

N=11,722 (6143 RotaTeq®/5579 Placebo)

Fever = temperatures ≥100.5°F, rectal equivalent

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0

5

10

15

20

25

1 2 3 4 5 6 7

Percent of Infants with Vomiting and/or Diarrhea Within Week of First Dose by Day after Dose

and Vaccination Group

0

5

10

15

20

25

1 2 3 4 5 6 7Days Postdose 1

RotaTeq™ Placebo

Percent of Subjects

Vomiting

Diarrhea

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Overall Assessment and Conclusions

RotaTeq® was well tolerated with respect to all adverse events including IS

RotaTeq® prevented RV AGE– 74% efficacy against any severity– 98% efficacy against severe disease– 95% reduction in RV-related hospitalizations

RotaTeq® reduced RV-related hospitalizations and emergency department visits caused by strains G1P[8], G2P[4], G3P[8], G4[P8], and G9[P8]

The reduction in RV-related hospitalizations and emergency department visits appeared similar by region (EU, US, Native American Nations, Latin America/Caribbean)

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Study to establish dose

and reassortant composition

(pentavalent; G1-4, P1) (005)

1997 1998 2001 2002 200320001999

Reports ofIS with RRV-TV

Large-Scale Trial(Rotavirus Efficacy and

Safety Trial ; REST) (006)

Dose Confirmation

Efficacy(007)

2004 2005

Consist-ency Lots

Study (009)

Filed for licensure

Phase III (RotaTeq™)

Clinical study ofdifferent buffers (G1-2) (003)

FDA ACMfor REST

2006

FDA ACM US

Approval

Positive CHMP

Opinion

ACIPUniversal

Recommendation

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Current EnvironmentSince February, over half a million doses of RotaTeq®distributed in the US

Intussusception is a naturally-occurring illness; therefore, cases are expected to occur

Post-licensure studies in place to monitor safety– Prospective population-based study to assess IS

and general safety– Enhanced passive surveillance

Coordinating with regulatory and public health agencies

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Developing World Program for RotaTeq®

Ongoing study of concomitant use of OPV and RotaTeq® in Latin America

Rotavirus disease surveillance and an effectiveness study of RotaTeq® in Latin America

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Developing World Program for RotaTeq®

Efficacy and safety studies in Africa and Asia

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Thank You