# Presentation: 299361

## Clinical Perspective of Endpoint Selection for HIV Clinical Trials in Treatment-Experienced Populations

**Jeff Murray, M.D., M.P.H.**
- Deputy Director
- Division of Antiviral Products
- CDER/FDA

## Presentation Outline

- Clinical Measures for HIV
- History of Types of Endpoints Used in Clinical Trials
- HIV-RNA Association with Clinical Disease Progression
- Viral Load and Resistance
- Example of Viral Load Changes in Treatment Experienced Patients
- Rationale for Choice of Endpoint

## Clinical Measures

- Two surrogate/laboratory markers
- CD4 cell count/percentage
- HIV-RNA = “viral load”
- Clinical Symptoms and Signs
- CDC Class B events such as oral thrush, oral hairy leukoplakia, weight loss, night sweats
- CDC Class C events = AIDS defining events such as opportunistic infections/malignancies
- Other conditions: renal insufficiency, low platelets

## Assessments in the Clinic

- CD4 cell count
- Absolute number/CD4 percent
- Significant change (2 s.d.) is 30% for number and 3% for suppression
- Major clinical indicator of immune competence
- Most important measure for deciding when to  start HIV treatment (< 350 cells)
- Monitor every 3-6 months
- Initial increase after treatment (in naïve patients) = 100-150 cells, due to redistribution

## Assessments in the Clinic

- Viral Load
- Several assays with lower limit of detection 50-80 copies
- Significant change (2 s.d.) = 3-fold or 0.5 log change
- Most clinicians don’t use viral load to decide when to start treatment (some may for >100,000 when CD4 > 350)
- Prognostic indicator of disease progression, precedes CD4 cell decreases
- Used for assessing response to therapy

##  HIV

** ****HIV**
***infection***

**J. Coffin,  XI International Conf. on AIDS, Vancouver, 1996**

**Development of AIDS is like an impending train wreck**
**Viral Load =  Speed of the train    **
**CD4 count =  Distance from cliff**

## HIV vs CD4 Trajectories

**CD4**

**Viral load**

**1**

**2**

- +100 cells

- - 1 log

- - 2 log

- Detection limit

**3**

## Clinical Endpoints

- Originally a case definition used more for epidemiologic purposes-never validated with mortality endpoint
- Approximately 20 different conditions
- Infections, syndromes (wasting), malignancies
- Infections: viral, fungal, bacterial, parasitic, mycobacterial
- Occur at different levels of immune function, but in clinical trials weighted equally
- Studies counted only first occurrence for most infections

## Clinical Endpoints

**CD4 Count**

- Tuberculosis
- Recurrent Pneumonia
- Kaposi Sarcoma
- Esophageal Candidiasis

- 200

- 100

- 50

- Pneumocystis
- Toxoplasmosis
- Cryptococcus
- Wasting

- CMV retinitis
- PML
- MAC
- Lymphoma

## Clinical Endpoint Studies

- Prior to 1997, Traditional approval required Clinical Endpoints
- CDC criteria for an AIDS defining Event
- death
- all events weighted equally
- Problem: switching prior to endpoint
- viral load monitoring routine part of patient management

## Antivirals AC Meeting July 1997 Conclusions

- HIV RNA is a suitable endpoint for BOTH Accelerated Approval (24 weeks) AND Traditional Approval (48 Weeks)
- Clinical Endpoint Studies Remain an Option (= CDC AIDS defining Events)
- Concordance with other markers (CD4)
- FDA Precedents for “Lab” Endpoints:
- Cholesterol and drugs for D.M.

## HIV RNA and Clinical Benefit                  5 Analyses: >5000 patients

**HIV RNA and Clinical Benefit                  5 Analyses: >5000 patients**

## Risk of Clinical Progression vs. HIV RNA Reduction

**>1.0 log**

**0.5-1.0 log **

**0-0.5 log **

**no reduction**

**ADJ.  RR  (natural log)**

**Stratifying factors**

**study and treatment **
**none****	****	**
**study****	**
**treatment**

**0.0**

**0.5**

**1.0**

**1.5**

**WEEK 24 HIV RNA Reduction**

**Risk of Clinical Progression vs. HIV RNA Reduction**

**POOLED ACTG STUDIES**

**Notes:**
The ACTG analysis found a strong relationship between change from baseline over the first 24 weeks (shown here on the x axis in units of a half a log drop) and the clinical event relative risk on the y axis.  The primary story of this graph and the others to follow is in the slope of the line characterizing the relationship. The particular lines here just represent different ways of analyzing the data.  This relationship was seen after adjustments for baseline RNA, CD4, treatment and study.

## Clinical Hazard by Duration of ReductionDLV studies

## Clinical Endpoint/Viral Load Studies

- VA Study (ZDV)
- 	+ clinical effect (subset)
- ACTG 116B/117 (ddI)
- 	+ clinical effect
- ACTG 175 (dual Nucs.)
- 	+ clinical effect
- Delta (dual Nucs.)
- 	+ clinical effect
- NV14256 (saquinavir)
- 	+ clinical effect
- CAESAR (lamivudine)
- 	+ clinical effect
- ACTG 300 (lamivudine)
- 	+ clinical effect

- ACTG 300 (LMV):
- 	+ clinical effect
- SV14604 (saquinavir)
- 	+ clinical effect
- PU-0017 (delavirdine)
- 	no clinical effect
- M94-247 (ritonavir)
- 	+ clinical effect
- ACTG 320 (indinavir)
- 	+ clinical effect
- Study 028 (indinavir)
- 	+ clinical effect
- ACTG 193 (nevirapine)
- 	no significant clinical effect

## Correlation of HIV RNA Reduction and Clinical Progression

- HIV RNA decreases (> 0.5 log) are associated with lower risks of disease progression
- Greater Reduction associated with lower risk of progression
- More Sustained Reductions (> 8-12 weeks) in HIV RNA are associated with lower risks of disease progression

## HIV RNA

- Greater Suppression Associated with Durability of Suppression
- Rebound or inability to suppress generally means RESISTANCE
- Full suppression means low mutation rate and less likelihood of resistance
- Continued viral replication in the presence of drug results in step-wise resistance

## Viral Load and Resistance

**Accumulation of Mutations: Loss of Drugs**

**No mutations**

- - 1 log

- - 2 log

- Detection limit

- 184-3TC

- 103-EFV

- 65-TDF

## EndpointLoss of Virologic Response

- < LOQ (below assay limit) for naïve population
- Other definitions may be appropriate for other populations (e.g., drug resistant)
- A rigorous hurdle: patients with limited options may not be able to achieve assay detection limit, but lesser degrees of suppression possible

## Advantages of Proportion Endpoints

- Endpoint captured before Rx switches
- Less confounding due to treatment switches
- Coincides with clinical management
- Benefits for sample size

**Log****10 ****HIV RNA**

**Weeks of Treatment**

- Endpoint Reached

- LoQ

## Enfuvirtide (T-20): Pivotal Studies

**T20-301 (US) and T20-302 (Europe)**
**Open-label, randomized, active controlled **
**Randomized 2:1 to T-20/ OB vs OB alone**
**Dose: 90 mg SC twice daily**
**“****Switch” option (less than 0.5 log drop by 8 weeks)**
**Patients with prior ARV experience and/or resistance to all 3 classes of antiretroviral drugs**

**Notes:**
Bill Taylor will briefly touch on the preclinical data in a minute.  The NDA for T-20 contains the results from 9 PK and safety studies, 3 Phase 2 studies, 2 pediatric studies, and 2 Phase 3 clinical trials. 

The 2 Phase 3 studies, T20-301 and 302, are almost identical - except for minor differences in inclusion criteria.  T20-301 was a multicenter study in North America and Brazil and T20-302 was in Western Europe and Australia. Both studies were open-label, randomized studies with an active control.  1,013 subjects were randomized in a 2 to 1 ratio to receive either T-20 plus an optimized antiretroviral background versus optimized background (OB) only.  
The optimized background regimen was chosen by the individual investigators and was based on the subject’s past treatment and  the resistance patterns of the subject’s viral isolate on randomization.  Subjects in the OB arm who met the criteria for virologic failure could switch to a T-20 containing regimen any time after 8 weeks.  However, subjects on the T-20/OB arm who reached virologic failure could choose to remain on study.
The patient population was unusual in that subjects were heavily pretreated with either previous experience will all 3 currently approved classes of antiretroviral drugs and/or resistance to all 3 classes.  This population is very difficult to treat and salvage studies in this population were discussed in a DAVDP advisory committee several years ago.
One last important piece of information - T-20 is a peptide that must be administered by SC injection twice daily. (Point to Jeff O’Neill....)

## Example of Viral Load Changes in Treatment Experienced Patients

Enfuvirtide Trials

- Enfuvirtide Trials

## Demographics

## Enfuvirtide Efficacy Results

**Primary endpoint: mean change in plasma HIV RNA from baseline to wk 24**

|  | T-20/OB | OB | p value |
| --- | --- | --- | --- |
| T20-301 | -1.696 | -0.764 | <.0001 |
| T20-302 | -1.429 | -0.648 | <.0001 |

**Notes:**
I want to briefly show the efficacy results.  
The primary efficacy endpoint was the change in viral load at 24 weeks.  In both studies, the subjects receiving T-20+ OB had a greater decrease in viral load than subjects receiving OB alone which was statistically significant.
No matter how the results were examined - different subpopulations and secondary efficacy endpoints were analyzed - the T-20/OB group did better.  

## Enfuvirtide Efficacy (cont’d)

## Clinical Endpoint Trials:  2006

- Registrational Trials: Infeasible
- Virologic monitoring routine
- Patients switch treatment at time of viral rebound prior to clinical endpoint
- Clinical Endpoint studies best if subjects continue regimen until clinical endpoint occurs
- Strategy Trials: Feasible
- Example: SMART Study
- Patients stopped/restarted therapy based on CD4 criteria

## Conclusions

- Viral Load is a dynamic endpoint
- Quick virologic changes with onset or withdrawal of therapy
- Rebound is an early indicator of resistance
- Full suppression strategy preserves drugs
- HIV RNA reductions from baseline correlated with disease progression
- Proportion reaching specific goals (<400, > 1 log drop)—feasible in treatment experienced, AND is more convenient from a statistical analysis perspective