# Presentation: 690280

## TENOFOVIR DF

**DIVISION OF ANTIVIRAL DRUG PRODUCTS’ ADVISORY COMMITTEE**
**OCTOBER 3, 2001**

## Advisory Committee Issues

**Treatment indication**
**Nonclinical and clinical assessment of the effects of Tenofovir DF on bone**
**Analysis of resistance data**
**Design of**** ****trials for traditional approval**

## Advisory Committee Issues

**	****Proposed treatment indication:**
***  ******VIREAD******TM****** , in combination with other antiretroviral agents, is indicated for the treatment of HIV-infected adults.  This indication is based on analyses of plasma HIV-1 RNA levels and CD4 counts in two controlled trials of VIREAD******TM****** of 24 and 48 weeks duration in treatment experienced adults with evidence of HIV-1 replication despite ongoing antiretroviral therapy.  At present, there are no results from controlled trials evaluating the effect of tenofovir on clinical progression of HIV.***

## Advisory Committee Issues

**Treatment indication**
**Pivotal studies 902 and 907 were conducted in a treatment experienced adult population**
**on stable ARV therapy for at least 8 weeks**
**median duration of therapy of ~ 4 - 5 years**
**mean baseline viral load = 3.4 log****10**
**mean baseline CD4 counts = 410 cells/mm****3**** **
**baseline resistance mutations - NRTI(94%), PI(58%), NNRTI(~40%)**
**Requesting AC input regarding labeled indication**

## Advisory Committee Issues

**Bone Effects**
**BMD reductions/osteomalacia were observed in 3 species**
**Mechanism not fully defined**
**Clinical trial data limited for BMD**
**Seeking advice regarding:**
**implications of nonclinical and clinical bone data**
**recommendations for additional studies**
**monitoring plans**

## Advisory Committee Issues

**Virology data**
**VIREAD****TM**** NDA contains more virology data than other NDA**
**Many analyses evaluating HIV RNA response by baseline phenotype and genotype**
**Seeking AC comments on:**
**clinical resistance analyses**
**inclusion in product labeling**

## VIREADTM  NDA

**Submitted in May 2001**
**submitted under **_**accelerated approval**_** regulations **
**for serious and life-threatening conditions**
**provide meaningful therapeutic benefit over existing therapies**
**drug has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit or on a clinical endpoint other than survival or irreversible morbidity**
**DAVDP requires 2 adequate and well-controlled trials of 24 weeks duration**

## Advisory Committee Issues

**Traditional approval plans**
**Continued marketing is subject to the need to confirm findings to establish clinical benefit**
**DAVDP requires 2 studies of 48 weeks duration to support traditional approval**
**Study 903 is being conducted in naïve subjects and is fully enrolled**
**Compares tenofovir DF to stavudine on a background of lamivudine and efavirenz**
**Seeking AC advice regarding design of second study in pediatric population**

## Advisory Committee Agenda

- 9:00 a.m.	**Gilead Presentation**
- 9:45 a.m.	**FDA Presentation**
- 10:30 a.m.	**Break**
- 10:45 a.m.	**Discussion**
- 12:00 p.m.	**Lunch**
- 1:00 p.m. 	**Open Public Hearing**
- 2:00 p.m.	**Continue Discussion and Questions to the Committee**
- 5:00 p.m.	**Adjourn**

## NDA 21-356Tenofovir Disoproxil Fumarate

**Kimberly Struble, PharmD**
**Senior Regulatory Review Officer**
**Division of Antiviral Drug Products**

## Presentation Outline

**NDA Submission Overview**
**Efficacy Summary**
**Clinical Virology Results**
**Nonclinical Assessment of Bone Abnormalities - Jim Farrelly, Ph.D.**
**Clinical Assessment of Bone Abnormalities**
**Second Study for Traditional Approval**
**Summary of Regulatory Issues**

## NDA Overview

**Submission Date: May 1, 2001**
**Proposed Dosage: Tenofovir DF 300 mg once daily**
**Indication Sought:  Treatment of HIV infection**

## NDA Submission:Four Clinical Studies

**Supportive:**
**901: Phase 2 dose finding (35 days)**
**908: Compassionate Use Safety**
**Principal**
**902 and 907: Randomized, Double-blind Placebo Controlled (24 weeks)**

## Principal Studies: 902 and 907

**Similar Study Designs**
**Safety and Efficacy of TNV vs PBO when added to stable ARV regimen in treatment experienced patients**
**Similar baseline characteristics**
**Differences in baseline HIV RNA**
**902: Baseline HIV RNA 400-100,000 copies/mL**
**907: Baseline HIV RNA 400-10,000 copies/mL**

## Primary Efficacy Endpoint

**Primary endpoint = Time weighted change in log****10 ****HIV RNA over 24 weeks (DAVG****24****)**
**DAVG is an acceptable endpoint for evaluating virologic responses in treatment experienced patients, such as those enrolled in 902 and 907**
**Secondary endpoints = Proportion < 400 and 50 copies/mL**

## HIV RNA Results:Placebo vs Tenofovir 300 mg

## Mean Change From Baseline: HIV RNA

-  **2**

-  **4**

-  **8**

-  **12**

-  **24**

**WEEKS**

-  **16**

-  **20**

-  **0**

**DAVG****24****= - 0.58 **

**DAVG****24****= - 0.61**

## Proportion < 400 and < 50 copies/mL

**Study 902**

**Study 907**

**Weeks**

**Weeks**

## CD4 Cell Count Results:Placebo vs Tenofovir 300 mg

## CD4 Response: Study 902

**4**

**8**

**12**

**24**

**Weeks**

**DAVG****24****= -3.6**

**DAVG****24****= -10.5**

## CD4 Response: Study 907

**4**

**8**

**12**

**16**

**20**

**24**

**Weeks**

**DAVG****24****= +12.6**

**DAVG****24****= -10.6**

## CD4 Response by Baseline CD4: Studies 902 and 907

## Efficacy Summary

**Mean viral load reductions similar for 902 and 907 (Mean DAVG 0.5 - 0.6)**
**< 400 and < 50 copies/mL**
**numerical differences: 902**
**statistically significant differences: 907**
**Modest CD4 increases in study 907**
**No differences for CD4 in study 902 over 24 weeks**

## Efficacy Summary (cont.)

**Study population in 902 and 907 may not be optimal for observing large increases in CD4, given only one new drug added to stable regimen**
**Addition of one new agent did not produce substantial increases in CD4 over time**
**Further evaluations of CD4 in studies with different designs are needed**

## Clinical Virology Results

## Clinical Virology

**Applicant: HIV RNA response by prospectively defined baseline mutation subgroups**
**FDA: Exploratory analyses to further investigate HIV RNA response according to presence or absence of specific NRTI mutations**
**Determine if specific mutations or mutational patterns affected response****	****to tenofovir**

## Clinical Virology: Limitations of FDA Analyses

**Large number of potential comparisons limits ability to test for statistical significance**
**Limited # of patients for some primary NRTI and multi-drug resistant mutations to determine clinical significance**
**Given these limitations FDA is soliciting feedback on the types of exploratory analyses conducted and recommendations for labeling**

## Genotypic Results

## Genotypic Results

**HIV RNA response by presence or absence of thymidine analogue mutations (TAMs)**
**TAMs are defined as **
**M41L**
**D67N**
**K70R**
**L210W**
**T215Y/F**
**K219Q/E/N**

## HIV RNA Response by Baseline TAMs

**67 +**

**67 -**

**70 +**

**70 -**

**219 +**

**219 -**

**HIV RNA Response by Baseline TAMs**

**Mean DAVG****24**** (N)**

**-0.53 (79)**

**-0.62 (143)**

**-0.71 (67)**

**-0.54 (155)**

**-0.60 (57)**

**-0.58 (165)**

## HIV RNA Response by Baseline TAMs

**Mean DAVG****24**** (N)**

**-0.80 (116)**

**-0.35 (106)**

**-0.70 (176)**

**-0.17 (46)**

**-0.78 (141)**

**-0.26 (81)**

**215 -**

**215 +**

**210 -**

**210 +**

**41 -**

**41 +**

**HIV RNA Response by Baseline TAMs**

## Impact of 215 Mutation on HIV RNA Response

**No           41 or 210**

** ****41 or  210**

** ****215 -**

**Impact of ****215 Mutation**** on HIV RNA Response**

**Mean DAVG****24**** (N)**

**-0.25 (82)**

**-0.70 (25)**

**-0.80 (116)**

## Impact of 41 or 210 Mutation on HIV RNA Response

**No           41 or 210**

** ****41 or  210**

**Mean DAVG****24**** (N)**

**-0.79 (139)**

**-0.26 (93)**

**Impact of ****41 or 210 Mutation**** on HIV RNA Response**

## HIV RNA Response by # of Baseline TAMs: Mean DAVG24 (N)

## Other NRTI Mutations and HIV RNA Response

**L74V/I affects tenofovir efficacy**
**DAVG****24 ****= -0.17 (n=18)**
**Rates similar regardless if 41 or 210 mutation present with 74 (-0.12 to -0.19)**
**K65R mutation reduces susceptibility to tenofovir in vitro**
**DAVG****24 ****= 0 (N=6)**
**More data needed to make any definitive conclusions**

## Phenotypic Results

## Phenotypic Analyses

**To determine if tenofovir or other NRTI baseline susceptibility affected  response**
**Baseline TNF susceptibility:**
**TNF  **_**<**_** 4 fold **
**DAVG****24  ****= -0.61 (n=91)**
**TNF > 4 fold**
**DAVG****24 ****= -0.12 (N=9)**

## Resistance Summary

**Genotypic data suggest potential for some cross resistance between tenofovir and specific NRTI mutations or patterns of mutations**
**However too few patients expressing some primary NRTI or multi-drug resistant NRTI mutations to determine clinical significance**
**No cross resistance between tenofovir and lamivudine**

## Resistance Summary

**41 or 210 mutation diminished responses, whereas 67, 70, 215 and 219 did not**
**Number and types of TAMs affect tenofovir efficacy**
**Efficacy reduced for **_**>**_** 3 TAMs which include M41L or L210W**
**K65R and L74V/I mutation may affect tenofovir efficacy**
**Reduced susceptibility to TNF (> 4 fold) at baseline diminishes tenofovir efficacy**

## Safety Summary

## Safety Summary

**Treatment with TNF appears to be well tolerated**
**Most common AEs: ****asthenia (19%), headache (14%), diarrhea (22%), nausea (20%) and pharyngitis (18%)**
**GI events greater in TNF group vs PBO **
**diarrhea (22% vs 17%) **
**flatulence (6% vs 2%) **
**nausea (20% vs 15%) **
**vomiting (12% vs 6%)**

## Nonclinical Assessment of Bone Abnormalities

**James G. Farrelly, Ph.D.**
**Pharmacology Supervisor**

## Toxicity in Rat and Dog Four Week Gavage Studies

**Doses up to 500 mg/kg/day in rats**
**Little toxicity seen**
**Doses up to 30 mg/kg/day in dogs**
**Minor toxicity in kidney but no bone toxicity**

## Toxicity in Rat 42 Week Gavage Study

**Doses @ 0, 30, 100, 300, 1000 mg/kg/d for 42 wks with 13 wk recovery and a 13 week interim evaluation**
**Bone Effects:****	**
****** ****Bone mineral content and density**
****** ****Cortical thickness of femur**
****** ****Deoxypyridinoline at three highest doses **
****** ****Osteocalcin at the two highest doses **
****** ****Plasma phosphorus **
****** ****Urinary calcium and phosphorus **
****** ****PTH **

## Toxicity in Dog 42 Week Gavage Study

**Doses @ 0, 3, 10, and 30 mg/kg/d for 42 wks with 13 wk recovery and a 13 week interim evaluation**
**Bone Effects**
****** ****Bone mineral content and density **
****** ****Urinary N-telopeptide **
****** ****Urinary calcium and phosphorus **
****** ****Bone specific ALP **
****** ****1,25-dihydroxy vitamin D****3**

## Toxicity in Mouse 13 Week Gavage Study

**Range-finding study to determine the maximum tolerated dose for a two year carcinogenicity study**
**Doses studied =  0, 100, 300, 600 mg/kg/d**
**Toxicity was seen in the kidney and duodenum**
**Carcinogenicity study is still ongoing**

## Intravenous Study in Cynomolgus Monkeys

**Monkeys were dosed for 14 days by the intravenous route at doses up to 25 mg/kg/day with tenofovir**
**No bone toxicities were seen in this study**
**There were treatment findings in the kidneys**

## Rhesus Monkey Efficacy Studies

**Studies designed to assess efficacy against SIV**
**Doses Studied = 10 and 30 mg/kg/day**
**Bone toxicities seen after 10 months dosing**
**Newborn**** ****monkeys showed earlier bone toxicity when dosed at 30 mg/kg/day**
**At 10 mg/kg/day, no bone toxicity was seen in newborns dosed for two years**

## Rhesus Monkey Efficacy Studies, Cont.

**Bone Toxicity**
**Seen as abnormal growth plates and trabecula of femurs and ribs**
**Also seen were bone deformities and displacements, rib fractures and reduced bone density with bone loss**
**Reduction in serum phosphorus**
**Elevated ALP**
**Non-hyperglycemic glucosuria and proteinuria**
**Serum calcium unchanged****  **

## Rhesus Monkey Efficacy Studies, Cont.

**It was concluded that treatment of rhesus monkeys at 30 mg/kg/day results in a mineralization defect in developing and growing cortical bone**
**The defect  was considered to be osteomalacia**
**The defect was reversed by reducing the dose to 10 mg/kg/day or stopping treatment**

## Reproductive Toxicology Studies

**No bone toxicity was seen in reproductive toxicology studies**
**Rats dosed to 600 mg/kg/day**
**Rabbits dosed to 300 mg/kg/day**

## Conclusions

**Tenofovir and tenofovir DF induce     bone toxicities in three animal species consistent with a diagnosis of osteomalacia**
**The mechanism is unknown**

## Conclusions, Cont.

**The evidence from toxicology studies in three species as well as from a number of in vivo and in vitro studies is consistent with the hypothesis that the bone effects are secondary to a negative phosphate balance associated with drug-related impairment of intestinal phosphate absorption and/or renal reabsorption of phosphate and not a direct effect on bone**

## Clinical Assessment of Bone Abnormalities

## Animal Exposures in Relation to Human Exposures

**Margin of safety**
**BMD reduction in rats and dogs 6-10 times higher than human exposures (AUC)**
**Osteomalacia in monkeys 12 times higher than human exposures (AUC)**

## Clinical Assessment of Bone Abnormalities

**No clinically significant changes in phosphate, calcium, PTH or BMD observed over time**
**PTH and BMD only available for a small subset of patients**

## Incidence of Clinical Fractures: 

**5.5% in study 902**
**Proportion of patients with fracture in study 902 is higher than that seen in FDA meta-analysis of 13 trials**
**2% (202/10166)**
**Observation may be due to small sample size but further investigation of potential safety signal warranted**

## Slide 58

## Clinical Assessment of Bone Abnormalities

**Review of entire non clinical and clinical safety and PK data, it is unlikely TNF-related fractures will occur over 48 weeks**
**Assuming mechanism is mediated by renal phosphate wasting or decreases in intestinal absorption of phosphate**
**No significant changes in renal parameters, in particular phosphate**
**Rate of fractures does not increase over 6 month time intervals**

## Clinical Assessment of Bone Abnormalities

**Insufficient numbers of patients receiving prolonged TNF treatment and lack of control arm past 24 weeks **
**Therefore difficult to conclude whether or not TNF will cause clinical fractures over time or if the risk will increase over time**

## Traditional Approval:

## Traditional Approval Plans

**Two studies required assessing HIV RNA over 48+ weeks**
**First study: Treatment Naïve Patients **
**Study 903**
**TNF + 3TC + EFV vs D4T + 3TC + EFV**
**Second study:**
**proposed in treatment experienced children**

## Two - Part Hybrid (N=100)

**Stable ARV **
_**>**_** 8 weeks **
**randomized **
**1:1**

**TNF**

**PBO**

**TNF**

**PBO**

**OBR wk 2**

**2 wks**

**46 wks**

**Endpoint: DAVG****2**** and DAVG****48**

**Patient Population:**
**HIV RNA > 30,000 copies/mL**
**CD4% < 20% or <30% with OI in last 90 days**
**TX Experienced with at least 1 member of         each drug class**

## Summary of Regulatory Issues

## Summary of Regulatory Issues:Indication

**Study population in studies 902 and 907 quite select**
**antiretroviral experienced**
**mean baseline values 3.4 log and 410 cells**

## Summary of Regulatory Issues:Indication

**Committee discussion regarding most appropriate indication**
**For the treatment of HIV infection**
**includes both treatment naïve or treatment experienced patients**
**For the treatment of HIV infection in patients who have received prior antiretroviral therapy**

## Summary of Regulatory Issues: Bone Abnormalities

**Non clinical bone toxicity**
**Reductions in bone mineral density seen in 3 animal species**
**Exact mechanism(s) unknown but may be due to renal phosphate wasting or decrease in intestinal absorption of phosphate**

## Summary of Regulatory Issues:Bone Abnormalities

**Clinical bone toxicity**
**No clinically significant changes in phosphate, calcium , PTH or BMD observed over time**
**PTH and BMD only available for a small subset of patients**
**Rates of fractures does not increase over 6 month intervals**
**Controlled safety data in more patients for longer duration needed**

## Summary of Regulatory Issues:Bone Abnormalities

**Please provide your assessment of the nonclinical and clinical data with regard to bone effects.**
**Are there additional non clinical or clinical studies that the applicant should conduct to further evaluate tenofovir associated bone abnormalities?**

## Summary of Regulatory Issues:Clinical Virology

**Prospective and Exploratory Analyses**
**Limitations of exploratory analyses include:**
**Limited # of patients for some primary NRTI and multi-drug resistant mutations to determine clinical significance**
**Large number of potential comparisons limit ability to conduct tests for statistical significance**

## 
Please provide comments on the clinical resistance analyses conducted during the development of tenofovir.  
Please provide recommendations for the types of clinical virology analyses that should be conducted for future antiretroviral drug development and suggestions for type of resistance data/analyses warranting display in package inserts

**Please provide comments on the clinical resistance analyses conducted during the development of tenofovir.  **
**Please provide recommendations for the types of clinical virology analyses that should be conducted for future antiretroviral drug development and suggestions for type of resistance data/analyses warranting display in package inserts**

**Summary of Regulatory Issues:****Clinical Virology**

## Summary of Regulatory Issues: Accelerated Approval and Phase 4 Commitments

**   **
**Please provide comments on the  proposed second study for traditional approval**
**Please provide comments for other study designs or patient populations that should be studied as phase 4 commitments**

## Tenofovir Review Team

**Clinical:**** Kimberly Struble, Pharm.D., Jeff Murray, M.D., M.P.H., and Bruce Schneider, M.D.**
**Stats:**** Rafia Bhore, Ph.D., and Greg Soon, Ph.D.**
**Micro: ****Nara Battula, Ph.D.**
**Clin Pharm:**** Jooran Kim, Pharm.D., and Kellie Reynolds, Pharm.D.**
**Pharm/tox****: Pete Verma, Ph.D., and Jim Farrelly, Ph.D.**
**Chemistry:**** Rao Kambhampati, Ph.D and Steve Miller, Ph.D.**
**Project Management:**** Marsha Holloman, BS Pharm, J.D.**