# Presentation: 135467

## FDA Analyses of Maraviroc Safety Data

- Scott Proestel, M.D.
- Division of Antiviral Products
- Food and Drug Administration
- April 24, 2007

## Presentation Outline

- Overall Summary of AEs
- Mortality
- Malignancies
- Hepatic AEs
- Infections
- Additional AEs
- Selected Laboratory Data

## Summary of AEs During Double-Blind PhaseStudies 1027 and 1028

## Duration of Therapy During Double-Blind PeriodStudies 1027 and 1028

- Median Treatment Days
- MVC QD		236
- MVC BID		239
- Placebo		145

## Days to Individual AEs During Double-Blind PeriodPlacebo Arms, Studies 1027 and 1028

- Study Day

## Days to Subject Discontinuation From the Double-Blind PeriodPlacebo Arms, Studies 1027 and 1028

- Study Day

## Mortality Data

## 1026

- 1027

- 1028

- 1029

## Mortality Data

- Numerical increase in mortality in MVC arms overall, however:
- Imbalance occurred in only 1 of 4 trials
- Degree of imbalance extremely small (for double-blind phase, p-value 0.60, Barnard's unconditional exact test)
- No clustering of death causes
- Types of deaths were consistent with the population studied
- Sick population at baseline (there were 11 additional deaths between screening and randomization)

## Malignancies

## All Lymphomas by Treatment ArmStudies 1027 and 1028

- 1 Received placebo during double-blind period, but subsequently received MVC during open-label period prior to malignancy diagnosis
- 2 Presumed diagnosis as no biopsy was performed

## Non-Hematologic Malignancies During Double-Blind Phase*Studies 1027 and 1028

| 

Malignancy | Numbers of Subjects with an AE |  |  |
| --- | --- | --- | --- |
|  | MVC QD
(n=414) | MVC BID
(n=426) | Placebo
(n=209) |
| Anal cancer | 3 | 3 | 3 |
| Kaposi’s sarcoma | 1 | 2 | 3 |
| Squamous cell carcinoma | 3 | 1 | 1 |
| Basal cell carcinoma | 1 | 1 | 0 |
| Oesophageal carcinoma | 1 | 0 | 0 |
| Liver metastases | 1 | 0 | 0 |
| Skin cancer | 0 | 1 | 0 |
| Bowen’s disease | 0 | 1 | 0 |
| TOTAL | 10 | 9 | 7 |

- * A subject could have more than one type of adverse event.

## Hepatic Adverse Events

## Hepatic AEs

## Hy’s Law Summary

- Hy’s Law
- AST or ALT >= 3x ULN
- TB >= 2x ULN
- No marked increase in alkaline phosphatase
- No evidence of another cause
- Predicts a 10-50% likelihood of death or liver transplant
- No Hy’s Law cases were observed

## Case History

- 	The subject is a 43 year-old woman with history of injection drug use, alcoholism, and hepatitis C who received MVC for 203 days.  On enrollment, she was HBsAg negative, HBcAb negative, HCV RNA positive, and reported drinking 5 alcoholic beverages per week.  Her baseline AST and ALT were elevated at 101 and 43 IU/L.  There were no substantive increases from these baseline LFT values through Day 169.  Her baseline total bilirubin was normal at 1.1 mg/dL, but peaked at 5.2 mg/dL on Day 15.  The bilirubin subsequently decreased from the peak level and was normal at the last measurement on Day 169.  Of note, her total bilirubin was 2.3 mg/dL 41 days prior to starting MVC (peak direct and indirect bilirubin levels were abnormal at 3.3 and 1.9 mg/dL, respectively).  She started atazanavir 537 days prior to MVC, and stopped on the day that MVC was started.  She had 3 reported liver AEs during her study participation (grade 3 increase in bilirubin on two occasions, and grade 1 hepatosplenomegaly once).

## AST and/or ALT Elevation During Double-Blind PeriodStudies 1027 and 1028

| 
AST and/or ALT | MVC QD
(n=414) | MVC BID
(n=426) | Placebo
(n=209) |
| --- | --- | --- | --- |
| > ULN | 249 (60%) | 269 (63%) | 139 (67%) |
| > 3 x ULN | 43 (10%) | 56 (13%) | 21 (10%) |
| > 5 x ULN | 21 (5%) | 21 (5%) | 10 (5%) |
| > 10 x ULN | 3 (1%) | 6 (1%) | 1 (<1%) |

## Total Bilirubin During Double-Blind PeriodStudies 1027 and 1028

## Infectious Adverse Events

## Most Common Infection-Related AEs During Double-Blind Period (Studies 1027 and 1028)

## Category C AEs During Double-Blind PeriodStudies 1027 and 1028

## Herpes Virus Infections During Double-Blind PeriodStudies 1027 and 1028

- 65 Herpes AEs
- MVC QD	25 AEs in 18 (4.3%) subjects
- MVC BID	32 AEs in 29 (6.8%) subjects
- Placebo	8 AEs in 8 (3.8%) subjects
- 19 Category C Herpes-related AEs
- MVC QD	11 AEs in 10 (2.4%) subjects
- MVC BID	6 AEs in 6 (1.4%) subjects
- Placebo	2 AEs in 2 (1.0%) subjects

## Herpes Virus Infections During Double-Blind Period*Studies 1027 and 1028

| 

Adverse Event
 | Numbers of Subjects with an AE |  |  |  |
| --- | --- | --- | --- | --- |
|  | MVC QD
(n=414) | MVC BID
(n=426) | Placebo
(n=209) | Time-Adjusted Placebo
(Placebo x 2.6) |
| Herpes simplex | 10 | 8 | 2 | 5 |
| Herpes virus | 3 | 2 | 2 | 5 |
| Anal/rectal herpes | 3 | 8 | 1 | 3 |
| Labial herpes | 3 | 8 | 0 | 0 |
| Oral herpes | 0 | 3 | 0 | 0 |
| Genital herpes | 1 | 2 | 3 | 8 |
| TOTAL | 20 | 31 | 8 | 21 |

- * A subject could have more than one type of adverse event.

## Candidiasis Infections During Double-Blind PeriodStudies 1027 and 1028

- 70 Candidiasis AEs
- MVC QD	41 AEs in 26 (6.2%) subjects
- MVC BID	18 AEs in 17 (4.0%) subjects
- Placebo	11 AEs in 11 (5.3%) subjects
- 19 Category C Candidiasis AEs
- MVC QD	14 AEs in 12 (2.9%) subjects
- MVC BID	3 AEs in 3 (0.7%) subjects
- Placebo	2 AEs in 2 (1.0%) subjects

## Candidiasis Infections During Double-Blind Period*Studies 1027 and 1028

| 

Adverse Event | Numbers of Subjects with an AE
 |  |  |  |
| --- | --- | --- | --- | --- |
|  | MVC QD
(n=414) | MVC BID
(n=426) | Placebo
(n=209) | Time-Adjusted Placebo
(Placebo x 2.6) |
| Oral candidiasis | 16 | 13 | 8 | 21 |
| Oesophageal candidiasis | 12 | 2 | 2 | 5 |
| Oropharyngeal candidiasis | 2 | 0 | 1 | 3 |
| Pharyngeal candidiasis | 1 | 0 | 0 | 0 |
| Vaginal candidiasis | 2 | 0 | 0 | 0 |
| Worsening candidiasis | 1 | 0 | 0 | 0 |
| Candidiasis | 1 | 2 | 0 | 0 |
| Balanitis candida | 1 | 0 | 0 | 0 |
| Nail candida | 0 | 1 | 0 | 0 |
| TOTAL | 36 | 18 | 11 | 29 |

- * A subject could have more than one type of adverse event.

## Additional Adverse Events

## Cardiovascular AEs During Double-Blind PeriodStudies 1027 and 1028

## Cardiovascular Disorders at Baseline

- 95 patients with any cardiovascular disorder
- MVC QD	40 (10%)
- MVC BID	40 (9%)
- Placebo	15 (7%)
- 45 patients with any ischemic cardiac disorder
- MVC QD	21 (5%)
- MVC BID	17 (4%)
- Placebo	7 (3%)

## Thrombotic AEs During Double-Blind Period*Studies 1027 and 1028

| 
Adverse Event | Numbers of Subjects with an AE |  |  |
| --- | --- | --- | --- |
|  | MVC QD
(n=414) | MVC BID
(n=426) | Placebo
(n=209) |
| Transient ischemic attack | 0 | 0 | 3 |
| Angina pectoris | 2 | 1 | 0 |
| Unstable angina | 1 | 1 | 0 |
| Myocardial ischemia | 0 | 2 | 0 |
| Myocardial infarction | 2 | 0 | 0 |
| Coronary artery disease | 3 | 1 | 0 |
| Antiphospholipid syndrome | 1 | 0 | 0 |
| Mesenteric artery thrombosis | 0 | 0 | 1 |
| Peripheral embolism | 0 | 1 | 0 |
| Portal vein thrombosis | 0 | 1 | 0 |
| Pulmonary embolism | 0 | 1 | 0 |
| Venous thrombosis | 0 | 1 | 0 |
| Thrombophlebitis | 0 | 0 | 1 |
| Cavernous sinus thrombosis | 1 | 0 | 0 |
| Iliac artery stenosis | 0 | 0 | 1 |
| Intermittent claudication | 1 | 0 | 0 |
| TOTAL | 11 | 9 | 6 |

- * A subject could have more than one type of adverse event.

## Postural Hypotension During Double-Blind PeriodStudies 1027 and 1028

- Dose-limiting AE during phase 1 at doses of 600-1200 mg
- MedDRA terms: Hypotension, orthostatic hypotension, dizziness, syncope
- 109 Patients:
- MVC QD 	51 (12%)
- MVC BID 	39 (9%)
- Placebo 		19 (9%)

## AEs Potentially Associated with QT Prolongation During Double-Blind Period (Studies 1027 and 1028)

- Preclinical testing revealed potential for QT prolongation
- A previous CCR5 antagonist (“Schering C”) found to cause QT prolongation
- Thorough QT study for MVC determined to be inadequate
- No significant prolongation with MVC, but control arm was not interpretable
- Attempts to resolve this issue are underway
- MedDRA terms: Arrhythmia, Palpitations, Syncope, Tachycardia
- 14 patients with potential ventricular events:
- MVC QD	4 (1.0%)
- MVC BID 	7 (1.6%)
- Placebo 	3 (1.4%)

## CPK Elevation AEs During Double-Blind PeriodStudies 1027 and 1028

- MedDRA terms: Blood creatine phosphokinase increased, myositis, rhabdomyolysis
- 19 Subjects with AEs
- MVC QD	7 (1.7%)
- MVC BID	11 (2.6%)
- Placebo	1 (0.5%)

## CPK Elevation by Treatment Group During Double-Blind Period (Studies 1027 and 1028)

## Fasting Total Cholesterol During Double-Blind PeriodStudies 1027 and 1028

## Fasting Total Cholesterol at Week 24 (+/- 2 Weeks)Studies 1027 and 1028

## Fasting Total Cholesterol During Double-Blind PeriodStudies 1027 and 1028

## LDL Cholesterol During Double-Blind PhaseStudies 1027 and 1028

## LDL Cholesterol During Double-Blind PhaseStudies 1027 and 1028

## Summary

- No increase in mortality or malignancy observed
- No clear evidence of hepatotoxicity, but this was a complicated patient population with a high rate of liver abnormalities at baseline.
- Infections
- No evidence of increase overall
- Possible increase in Candida, Herpes, and influenza infections
- Possible increase in cardiac ischemic events
- Possible increase in myositis
- Mild increase in total cholesterol and LDL levels

## FDA Analyses of Maraviroc Efficacy Data 

**Susan Zhou, Ph.D.**
**Division of Biometrics IV, FDA**
**Scott Proestel, M.D.**
**Division of Antiviral Products, FDA**
- April 24, 2007

## Primary Efficacy Endpoint (Studies 1027 and 1028)

| Summary of Change from Baseline in HIV-1 RNA to Week 24
Sensitivity Analysis for All Missing Data (Treatment Failure Classification, No Change) |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- |
| Treatment Group |             Change from Baseline to Week 24 |  |  |  | Treatment Difference
Maraviroc - Placebo |
|  | N | Raw
Mean (se) | Raw
Median | Adjusted Mean (se) | Estimate (se)

-0.872 (0.119)

-0.988 (0.118)

N/A |
| Maraviroc QD | 414 | -1.825 (0.070) | -2.229 | -1.833 (0.069) |  |
| Maraviroc BID | 426 | -1.946 (0.069) | -2.409 | -1.950 (0.068) |  |
| Placebo | 209 | -0.960 (0.091) | 0.000 | -0.962 (0.097) |  |

**Primary Efficacy Endpoint (Studies 1027 and 1028)**
**Mean Change from Baseline to Week 24 in HIV-1 RNA (log****10**** copies/mL)**

- Mean Treatment Difference & 99.95% CI for (Adjusted Data)
-   Maraviroc QD-Placebo	-0.872 (-1.335, -0.409)
-   Maraviroc BID-Placebo	-0.988 (-1.447, -0.529)

## Primary Efficacy Endpoint (Week 24)Sensitivity Analyses 

- Analysis 1: Using both on- and off- treatment HIV-1 VL data
- MVC-QD -Placebo: -0.50 (-0.90,-0.10)
- MVC-BID-Placebo: -0.49 (-0.90,-0.09)
- Analysis 2: Completers through Week 24
- MVC-QD-Placebo: -0.48 (-0.93,-0.02)
- MVC-BID-Placebo: -0.54 (-0.99,-0.09)
- Analysis 3: Imputing a single value (-0.4 to 0.3 by 0.1) to missing
- Results are similar to the sponsor’s sensitivity analyses
- The imputed value is the median for the placebo
- MVC-QD-Placebo: -0.79~0.97
- MVC-BID-Placebo: -0.88~1.06
- All 99.95% CIs support the superiority of MVC

## Efficacy at Week 24 by Baseline DemographicsStudies 1027 and 1028

## Efficacy at Week 24 by Disease CharacteristicsStudies 1027 and 1028

## Change in CD4+ Cell Counts (Studies 1027 and 1028)   

- Completers through Week 24 (n=672)
-                         **n          Mean (se)      Treatment Effect (99.95% CI)**
- MVC QD   283	137.8 (7.7)          41.1 (-5.0,87.3)
- MVC BID  296	123.6 (6.2)          26.9 (-18.9,66.3)
- Placebo	  93	96.7 (10.8)
- LOCF through Week 24 (n=1033)
-                         **n          Mean (se)      Treatment Effect (99.95% CI)**
- MVC QD	408	113.5 (6.1)          58.8 (26.5,91.1)
- MVC BID	418	105.9 (5.1)          51.2 (21.0,81.4)
- Placebo	207	54.7 (7.0)
- Treatment effects are robust

## Conclusions

- Evidence of Superiority Over Placebo Convincing
- Efficacy reduced by the most conservative analyses
- At least of 0.5 log10 copies/mL
- Increase in CD4+ cell count observed
- Patients with OSS >= 3 without apparent benefit