# Presentation: 680234

## Antiviral Drugs Advisory Committee Meeting

**Raltegravir**
**NDA 22-145**** **
**September 5, 2007**

## NDA 22-145: 	IsentressTM (raltegravir potassium)

Applicant: 		Merck & Co., Inc.

Formulation: 	400 mg tablets

Indication: 	HIV-1 treatment-experienced 			adult patients

**Applicant**: 		Merck & Co., Inc.
**Formulation**: 	400 mg tablets
**Indication**: 	HIV-1 treatment-experienced 			adult patients

## Antiretroviral ArmamentariumFive Approved Classes 

- 3 NNRTIs
- 7 NRTIs
- 9 PIs
- 1 Fusion inhibitor
- 1 CCR5 receptor antagonist
- ___________________________________
- > 20 approved agents

## Approved Antiretrovirals

**Approved Antiretrovirals**

**87**

**91**

**92**

**94**

**95**

**96**

**97**

**98**

**99**

**00**

**88**

**89**

**90**

**01**

**04**

**03**

**02**

**NNRTI**

**PI**

**FI**

**93**

**NRTI**

**ddC**

**3TC/ZDV**

**ddI**

**ZDV**

**d4T**

**3TC**

**TDF**

**ABC**

**ABC/3TC/ZDV**

**T-20**

**3TC/ABC**

**FTC/TDF**

**TPV**

**FTC**

**05**

- slide courtesy of C. Fletcher

**DRV**

**06**

**TDF/FTC/EFV**

**07**

**MVC**

**CCR5**

- Courtesy of C. Fletcher

## Antiretroviral Armamentarium: Novel Agents in Clinical Development

**clinicaloptions.com/hiv**

**Notes:**
This slide reviews some of the steps in the viral life cycle and highlights the steps targeted by novel antiretrovirals currently in development. 

Entry inhibitors block HIV entry into CD4+ cells. Enfuvirtide is a fusion inhibitor and is the only approved member of this entry inhibitor class. Drugs currently in development include TNX-355, an antibody that binds to the CD4+ cell receptor to block virus entry; CCR5 inhibitors that block binding to the CCR5 chemokine coreceptor; and CXCR4 inhibitors that block binding to the CXCR4 chemokine coreceptor. 

Once a virus enters a cell, it has to uncoat. Uncoating of the virus may involve a host protein called cyclophilin A, for which inhibitors are being developed. Presumably, these inhibitors block the interaction between cyclophilin A and the virus thereby preventing uncoating. 

Reverse transcription of the viral RNA genome into double-stranded DNA is the next step in the viral life cycle. There are currently several approved reverse transcriptase inhibitors and these are, obviously, not considered novel agents.

The next step is integration of the double-stranded viral DNA into the host chromosome. This process is accomplished via the viral integrase enzyme. Clinical data on 2 integrase inhibitors, MK-0518 and GS-9137, will be discussed later. 

The viral genome is then transcribed and translated into proteins. These viral proteins are cleaved by proteases, including the proteases carried by the virus itself. The process of protein cleavage followed by assembly of the virus is termed maturation. A new drug, PA-457, inhibits this process of maturation or assembly of the virus core without specifically interfering with protease activity. PA-457 is not a protease inhibitor it is a maturation inhibitor. 

## Antiretroviral Armamentarium: Integrase Inhibitor

- Integrase is one of three HIV-1 enzymes required for viral replication
- Results in integration of HIV-1 DNA into host cell genome
- Raltegravir targets viral integrase
- blocks strand transfer step, thus inhibiting viral replication

**Notes:**
Integrase is 1 of 3 enzymes necessary for HIV-1 viral replication. Integrase allows for the integration of HIV-1 DNA into the genome of the host cell. Raltegravir targets this enzyme and blocks strand transfer that is necessary for viral replication.

## Raltegravir: Clinical Development Program

_**Protocols 004/005**_: Phase 2 dose-finding trials in naïve/treatment-experienced patients, respectively
_**Protocols 018/019**_: Identical double-blind, placebo-controlled Phase 3 trials in HIV-1 treatment-experienced patients
- Week 16 primary endpoint because Phase 2 trials demonstrated robust activity
- Allowed to submit NDA with 100% of Week 16 data and about 60% of Week 24 data

**Notes:**
Phase 2 and 3 data provide evidence of the safety and efficacy of Raltegravir . Specifically, trials 18 and 19 were designed identically and differed by geographic location only. Studies 4 and 5 were phase 2 dose-finding trials in naïve and treatment experienced patients respectively.

## Agenda

- Merck
- Introduction
- Background
- Clinical Development Program
- Efficacy
- Resistance
- Safety
- Drug interactions
- Risk Management Plan
- Conclusions
- FDA
- Summary of clinical efficacy, resistance and clinical safety
- Concluding remarks

## Issues for Committee Discussion

- Adequacy of evidence of safety and efficacy
- Any gaps in data or other needed information?
- Safety areas of interest
- Risk of malignancies
- Others
- Impact of raltegravir on design of future antiretroviral Phase 3 clinical trials for treatment-experienced subjects

## NDA 22-145 Review Team

- _Clinical_
- Sarah Connelly
- Kendall Marcus
- Jeff Murray
- Debra Birnkrant
- _Statistical_
- Karen Qi
- Fraser Smith
- Greg Soon
- _Virology_
- Sung Rhee
- Jules O’Rear
- _Project Management_
- Monica Zeballos
- _Pharmacology/Toxicology_
- Ita Yuen
- Hanan Ghantous

- _Clinical Pharmacology_
- Derek Zhang
- Pravin Jadhav
- Shashi Amur
- Jogarao Gobburu
- Kellie Reynolds
- John Lazor
- _Chemistry_
- George Lunn
- Ted Chang
- Stephen Miller
- _Office of Safety and Epidemiology_
- Melissa Truffa
- Paula Gish
- Mary Willy
- Catherine Dormitzer