Approved Products for the Treatment of CMV Retinitis in Immunocompromised Patients

William M. Boyd, M.D.Division of Anti-inflammatory, Analgesic, and

Ophthalmologic Drug Products

HFD-550

Approved Products

• Cytovene-IV (ganciclovir)

• Foscavir Injection (foscarnet)

• Cytovene Capsules (ganciclovir)

• Vitrasert Implant (ganciclovir)

• Vistide Injection (cidofovir)

• Vitravene for Injection (fomvirsen)

Cytovene-IV (ganciclovir)

• Approved June 23, 1989

• Clinical Data Source(s) for Approval– Study #1 - randomized, controlled trial,

immediate versus delayed treatment (N = 42)– Study #2 - nonrandomized, retrospective,

immediate versus delayed treatment (N = 41)

Cytovene-IV (ganciclovir)

• Primary Endpoints for Study #1 and #2:– Time to progression of CMV retinitis

• Primary Endpoint Analysis– Study #1 (photos): median time to progression

of 50 days for immediate treatment; 14 days for delayed

– Study #2 (exam): median time to progression of 71 days for immediate treatment; 29 days for delayed

Foscavir Injection (foscarnet)

• Approved September 27, 1991

• Clinical Data Source(s) for Approval– randomized, open label, controlled trial,

immediate versus delayed treatment (N = 24)

• Primary Endpoint– Time to progression of CMV retinitis

Foscavir Injection (foscarnet)

• Primary Endpoint Analysis– median time to progression of 93 days for

immediate treatment; 22 days for delayed (photos)

Cytovene Capsules (ganciclovir)

• Approved December 22, 1994

• Not approved for induction due to poor bioavailability (5% available)

• Study Design for Maintenance Indication– three randomized, open label trials with

Cytovene-IV as comparator (N total = 505)

Vitrasert Implant (ganciclovir)

• Approved March 4, 1996

• Clinical Data Source(s) for Approval– randomized, parallel, ganciclovir implant

versus ganciclovir IV (N =188)

• Primary Endpoint– Time to progression of CMV retinitis

Vitrasert Implant (ganciclovir)

• Primary Endpoint Analysis– median time to progression of 210 days for

immediate treatment; 120 days for delayed (photos)

Vistide Injection (cidofovir)

• Approved June 26, 1996

• Clinical Data Source(s) for Approval– randomized, open label, controlled trial,

immediate versus delayed treatment (N = 48)

• Primary Endpoint– Time to progression of CMV retinitis

Vistide Injection (cidofovir)• Primary Endpoint Analysis

– median time to progression of 120 days for immediate treatment; 22 days for delayed (photos)

Vitravene for Injection (fomvirsen)

• Approved August 26, 1998

• Clinical Data Source(s) for Approval– limited, open label, controlled clinical studies,

immediate versus delayed treatment

(N = 80 eyes)

• Primary Endpoint– Time to progression of CMV retinitis

Vitravene for Injection (fomvirsen)

• Primary Endpoint Analysis– median time to progression of 80 days for

immediate treatment; 14 days for delayed (photos)

Approved Products

Product Administration

Cytovene-IV IVFoscavir Injection IVCytovene Capsules OralVitrasert Implant Intraocular implantVistide Injection IVVitravene for Injection Intravitreal injection

Approved Products for the Treatment of CMV Retinitis in Immunocompromised Patients

William M. Boyd, M.D.Division of Anti-inflammatory, Analgesic, and

Ophthalmologic Drug Products

HFD-550

Valcyt 450 mg Tablets (valganciclovir hydrochloride)

NDA 21-304

valganciclovir tablets

• NDA submitted September 28, 2000

• Clinical Data Source(s) for Approval– randomized, open label, parallel group,

valganciclovir versus ganciclovir IV (N=160)

• Primary Endpoint– proportion of patients with disease progression

at week 4

valganciclovir tablets

• Primary Endpoint Analysis– 7 subjects in valganciclovir arm and 7 subjects

in the ganciclovir treatment arm had CMV progression at week 4 (photos)

valganciclovir tabletsAnalysis of CMV Retinitis Progression by Week 4

Compared to Baseline(Medical Officer’s Masked Photographic Assessment)

GCV/VGCVN=80

VGCV/VGCVN=80

Non-progressor 64 (80%) 64 (80%)Progressor 7 (9%) 7 (9%)

Unevaluable*

*Unevaluable = “missing,” “cannotgrade,” or “no CMV at baseline”

9 (11%) 9 (11%)

valganciclovir tablets

Unevaluable subjects GCV/VGCV VGCV/VGCV

No photographicevidence of CMV

retinitis at Baseline

3 2

Missing photos 4 6

Inadequatephotographic quality

2 1

Total 9 9

valganciclovir tabletsMedical Officer’s Assessment

GCV/VGCVN=80

VGCV/VGCVN=80

Non-progressor 64 (80%) 64 (80%)Progressor 7 (9%) 7 (9%)

Unevaluable 9 (11%) 9 (11%)

Applicant/Reading Center Assessment

GCV/VGCVN=80

VGCV/VGCVN=80

Non-progressor 63 (79%) 64 (80%)Progressor 7 (9%) 7 (9%)

Unevaluable 10 (13%) 9 (11%)