MEMORANDUM
DATE: April
2218,
2005
TO: FDA
Antiviral Advisory Committee Members/Guests
FROM: Tipranavir
Review Team (HFD-530)
THROUGH: Mark
Goldberger, MD, MPH
Director,
Office of Drug Evaluation IV
Debra
Birnkrant, MD
Director,
Division of Antiviral Products
DRUG: APTIVUS®
(tipranavir) 250 mg Capsules
APPLICANT’s
PROPOSED INDICATION: APTIVUS
(tipranavir), co-administered with low-dose ritonavir, is indicated
for combination antiretroviral treatment
of HIV-1 infected patients who are protease inhibitor
treatment-experienced.
This briefing document
provides background information for the May 19, 2005 Antiviral Drugs Advisory Committee meeting on
tipranavir
(TPV). On
this day, the committee will be asked to consider efficacy and safety data
submitted to support the accelerated approval of TPV administered with low dose
ritonavir (RTV,
r) and
provide comments on the risk-benefit analysis of the use of this drug product
given the following challenging issues:
1) Design/analyses of efficacy in studies of “heavily
pretreated,” HIV-infected individuals
2)
Impact of
resistance on treatment response
3) Management
of known and potential TPV/r drug-drug interactions
4) TPV/r safety concerns including liver
toxicity, lipid abnormalities, rash (particularly in women) and HIV clinical
events and mortality
1)Design/analyses of the efficacy in studies of
“heavily pretreated” populations
1)Impact of resistance information
3) Management of known and potential drug-drug
interactions
4) Safety concerns
including liver and lipid monitoring/management, rash and gender differences, and clinical events on study
including mortality
TPV is a non-peptidic
inhibitor of the HIV protease that inhibits viral replication by preventing the
maturation of viral particles. The Applicant submitted NDA 21-814
(tipranavir) 250 mg Capsules on December 22, 2005 seeking approval for
marketing under accelerated approval regulations: 21 CFR 314.510 Subpart
H. Under the current guidance for HIV
treatment, the basis for approval will be based upon surrogate endpoint
analyses of plasma HIV RNA levels for primary efficacy balanced with safety
analyses in controlled studies up to 24 weeks duration.
I. SUMMARY
OF EFFICACY AND SAFETY DATA
Efficacy: Two
open-label, multi-center Phase 3 trials (RESIST 1 and 2) submitted in support
of this NDA provide evidence of the antiviral effect of TPV over currently
available antiretroviral regimens in a population which are “heavily
pretreated” (3 class antiretroviral
experienced with a median number of 12
prior antiretroviral drugs), and infected with a high level of resistant virus
at baseline (97% of the isolates were resistant to at least one PI, 95% to at
least one NRTI, and >75% to at least one NNRTI). The Applicant submitted 24-week
efficacy data on all 620 subjects in RESIST 1 and 539 out of 863 subjects in the RESIST 2. In both RESIST trials combined,
87% of the subjects were
possibly/definitely resistant to the assigned comparator protease inhibitor
(CPI). Thus, although these pivotal trials are presented
as TPV/r + optimized background regimen (OBR) versus CPI/r + OBR, in actuality,
the results should be interpreted more as TPV/r versus a partially active
control with both arms utilizing a large variety of OBR (n = 161 different drug
combinations as per FDA statistical analysis) necessitating a superiority efficacy anaylsis.
Thus, although these pivotal trials are presented
as TPV/r + optimized background regimen (OBR) versus CPI/r + OBR, in actuality,
the results should be interpreted more as TPV/r versus suboptimal control with
both arms utilizing a large variety of OBR (n = 161 different drug combinations
as per FDA statistical analysis)
necessitating a superiority efficacy analysis.
The primary efficacy
endpoint was the proportion of subjects with confirmed 1 log10
RNA drop from baseline at week 24 without evidence of treatment failure. The trial was designed with an escape clause to allow
subjects in the comparator arm with a lack
of initial virologic response at week 8 to discontinue the RESIST trials
and receive TPV in a rollover safety trial. Lack of initial virologic response was
defined as no drop in viral load >
0.5 log10 and failure to achieve a viral load of
<100,000 copies/mL during the first 8 weeks of treatment despite a >
0.5 log10 drop. Subjects who discontinued treatment due to lack of
initial virologic response in the comparator arm were considered as treatment
failures at week 24, which largely accounted for the treatment difference
between the two arms in the primary efficacy endpoint. The initial virologic treatment difference
(24%) between the two arms at week 8
explains the virologic treatment difference (20%) between the two arms at week
24.
These same discontinued
subjects in the comparator arm were considered as treatment failures at week 24
largely accounting for the treatment difference in the primary efficacy
endpoint. The initial virologic treatment
difference (24%) between the two arms (95% CI for the difference in proportions of 18%, 29%) shown at week 8 explains the virologic treatment
difference (20%, 95% CI of
15%, 24%) between the two arms at week
24.
For all-cause mortality the numbers of on-treatment deaths (15 TPV/r versus 13
CPI/r) were similar between the two arms. The added virologic benefit (as measured by the surrogate of
plasma HIV RNA) did not translate into any reduction in mortality at the 24
week time-point. . These
results may be explained by the fact thatHowever, these studies were not
powered for mortality, the 24 week time-point ismay be too premature to see any clinical endpoint
differences, and/or
the comparator arm’s escape clauseoption option at week 8 may have salvaged subjects prior to
prolonged virologic failure. The
relationship of plasma HIV RNA as surrogate endpoints to the actual clinical
outcomes may be less well understood in studies of heavily pretreated
populations. In addition, the
open-label design of the RESIST trials
as well as the comparator arm’s escape clause for lack of initial
virologic response by 8 weeks make it somewhat difficult to discern treatment
differences in some efficacy and safety parameters beyond 8 weeks of treatment.
Lastly, In addition, due to the open-label design of these
RESIST trials with the inherent bias as well as the built in escape clause for
the comparator arm at 8 weeks after lack of initial virologic response, it is
difficult to discern meaningful comparative efficacy data (both virologic and
clinical) beyond 8 weeks of treatment. AIDS defining or AIDS progression events were
captured in RESIST trials as adverse events only and not specifically
abstracted or adjudicated.
Resistance: Genotypes
from 1482 isolates and 454 phenotypes from both studies were submitted for
review for the combined RESIST 1 and 2 studies. The FDA analyses of virologic outcome by baseline genotype resistance showed
consistently greater response rates for the TPV/r arm over CPI/r arm across multiple
sensitivity analyses. Both the number
and type of baseline PI mutations affected response rates to TPV/r in RESIST 1
and 2. Virologic response rates in TPV/r-treated
subjects were reduced when isolates with substitutions at positions I13, V32,
M36, I47, Q58, D60 or I84 and substitutions V82S/F/I/L were present at
baseline. Virologic responses to TPV/r
at week 24 decreased when the number of baseline PI mutation was 5 or more. Subjects taking TPV/r with ENF were able to achieve
>1.5 log10 reductions in viral load from baseline out to 24 weeks
even if they had 5 or more baseline PI mutations. Virologic responses to TPV/r decreased in Resist 1 and 2 when the
baseline phenotype for TPV was >3.
The most common protease mutations that developed in >20% of isolates
from treatment- experienced subjects who failed on TPV/r treatment were
L10I/V/S, I13V, L33V/I/F, M36V/I/L V82T, V82L, and I84V. The resistance profile
in treatment-naive subjects has not yet been characterized.
Drug-drug interaction: The drug-drug interaction potential of 500 mg of TPV in
combination with 200 mg of ritonavir is extensive. TPV/r can alter
plasma exposure of other drugs and other drugs can alter plasma exposure of
TPV/r. The known and potential
interactions between TPV/r and other HIV medications are listed in Table 12 on Page 21-23. The table also describes the potential for
interactions with other classes of drugs.
· Administration of TPV/r can increase plasma
concentrations of agents that are primarily metabolized by CYP3A, because TPV/r
is a net inhibitor of CYP3A.
· The applicant did not evaluate the effect of
TPV/r on substrates for enzymes other than CYP3A. In vitro studies indicate TPV is an inhibitor of CYP1A2, CYP2C9,
CYP2C19 and CYP2D6. Due to the known
effect of RTV on CYP2D6, the potential net effect of TPV/r is CYP2D6 is
inhibition. The net effect of TPV/r on CYP1A2, CYP2C9 and CYP2C19 is not known.
· In vivo data suggest that the net effect of
TPV/r on P-glycoprotein is induction.
Based on current data, it is difficult to predict the net effect of
TPV/r on oral bioavailability and plasma exposure of drugs that are dual
substrates of CYP3A and P-gp.
· TPV is a CYP3A substrate as well as a P-gp
substrate. Therefore, co-administration of TPV/r and drugs that induce CYP3A
and/or P-gp may decrease TPV plasma concentrations and reduce its therapeutic
effect. Conversely, co-administration of TPV/r and drugs that inhibit P-gp may
increase TPV plasma concentrations and increase or prolong its therapeutic and
adverse effects. Co-administration of
TPV/r and drugs that inhibit CYP3A may not further increase TPV plasma
concentrations, based on the results of a submitted mass balance study.
Administration of TPV/r can increase
plasma concentrations of agents that are primarily metabolized by CYP3A,
because TPV/r is a net inhibitor of CYP3A. The Applicant did not evaluate the effect of TPV/r on substrates
for enzymes other than CYP3A. In vitro
studies indicate TPV is also an inhibitor of CYP1A2, CYP2C9, CYP2C19 and
CYP2D6. Due to the known effect of RTV
on CYP2D6, the potential net effect of TPV/r is CYP2D6 is inhibition. The net
effect of TPV/r on CYP1A2, CYP2C9 and CYP2C19 is not known. In vivo data suggest that the net effect of TPV/r on
P-glycoprotein is induction. Based on
current data, it is difficult to predict the net effect of TPV/r on oral
bioavailability and plasma exposure of drugs that are dual substrates of CYP3A
and P-gp. TPV is a CYP3A substrate as
well as a P-gp substrate. Therefore, co-administration of TPV/r and drugs that
induce CYP3A and/or P-gp may decrease TPV plasma concentrations and reduce its
therapeutic effect. Conversely, co-administration of TPV/r and drugs that
inhibit P-gp may increase TPV plasma concentrations and increase or prolong its
therapeutic and adverse effects.
Co-administration of TPV/r and drugs that inhibit CYP3A may not further
increase TPV plasma concentrations, based on the results of a submitted mass
balance study.
Safety Issues: A safety concern throughout the TPV drug
development program has been hepatotoxicity. Initial signals were observed throughout the 18 Phase 1 studies
in healthy volunteers. A total of 36
(5.5%) healthy HIV-negative subjects experienced treatment emergent grade 3 or
4 liver abnormalities (rise in ALT) in the Phase 1 studies. The Phase 2 dose-finding study 1182.52
showed that ALT increases were TPV dose dependent. The proportions of patients
who had grade 3/4 ALT increases in three treatment arms, TPV/r 500/100 mg ,
TPV/r 500/200mg, and TPV/r 750/200mg , were 4%, 11%, and 23%,
respectively. The higher proportion of
ALT abnormalities on the TPV/r 750 /200 mg arm compared to the TPV/r 500/200 mg
arm probably resulted from increased TPV concentrations because RTV exposure
was actually lower in the TPV/r 750/200 mg arm than in the TPV 750/200 mg
arm. In addition, detailed
exposure-response analyses on Study 1182.52 indicate that ALT increases are
associated with increased TPV exposures.Initial hepatotoxicity signals were
observed throughout the 18 Phase 1 studies in healthy volunteers. A total of 36 (5.5%) healthy HIV-negative
subjects experienced treatment emergent grade 3 or 4 liver abnormalities (rise
in ALT) in the Phase 1 studies.
Results from the Phase 2 dose-finding study 1182.52 indicated that the ALT
increases were TPV dose dependent. The proportions of subjects who had
grade 3/4 ALT increases in three treatments, TPV/r 500/100 mg , TPV/r 500/200mg
, and TPV/r 750/200mg , were 4.3%, 11.1%, and 23%, respectively. The ALT
abnormality comparison between treatment of TPV/r 500/200 mg and TPV/r 750 /200 mg suggested that the increased transaminase
elevations in the TPV/r 750/200 mg arm most likely resulted from increased TPV
exposures instead of RTV, because RTV exposure
was lower in the TPV/r 750/250 mg. Further exposure-response analyses on study 1182.52
indicated that the ALT increases were associated
with increased TPV exposures and not RTV exposures.
In the RESIST trials, 10% of subjects on the TPV/r arm compared to 3% on the
CPI/r arm developed treatment emergent grade 3 or 4 ALT or AST elevations. For RESIST 1, time to first DAIDS Grade 3 or 4 ALT elevation
(p=0.0028) was significantly different between the two arms with subjects in
the TPV/r arm more likely to develop Grade 3 or 4 elevations in ALT and at a
significantly faster rate than those in the CPI/r arm. For RESIST 2, time to first Grade 3 or 4 ALT
elevation (p=0.0255) was significantly shorter for subjects in the TPV/r arm
compared those for subjects in the CPI/r arm. Very few subjects had documented concurrent symptoms; however, at the time
of data submission, a substantial number of subjects (~50%) had not resolved their LFT elevations, and
therefore, no conclusions can be made about the acute clinical impact of these
laboratory abnormalities. At this time, FDA exploratory analyses examining the
possible baseline risk factors for hepatotoxicity (i.e. baseline CD4 counts,
hepatitis co-infection, gender, or race) are ongoing.
More subjects in the
TPV/r arm developed Grade 3 or 4 laboratory lipid abnormalities than
those in the CPI/r arm and at a significantly faster rate. For combined RESIST 1 and 2 datasets, 21% of
subjects developed treatment emergent grade 3 or 4 triglycerides compared to
11% of subjects on the CPI/r arm. Analyses of RESIST 1 laboratory data showed
that the time to first Grade 3 or 4 in total cholesterol (p=0.0007) or
triglycerides (p=0.0186) were significantly different between the two
arms. Analyses of RESIST 2 laboratory
data showed that the time to first Grade 3 or 4 elevation in total cholesterol
(p=0.0255) or triglycerides (p<0.0001) were shorter for subjects in the
TPV/r arm.
The
significant differences in the frequency of Grade 3 or 4 lipid or transaminase
elevations between the TPV/r and CPI/r
arms may be due to differences in follow-up between the two arms. The escape
clause in these studies resulted in a differential duration of randomized
treatment exposure and laboratory monitoring between the two arms. On the other
hand, it is important to keep in mind many subjects randomized to the CPI/r
arms (13%) already had a long duration of exposure to the CPI drug because they
entered the study and continued on their current PI.
The significant differences in developing DAIDS
Grade 3 or 4 elevations in liver or lipid laboratory between TPV/r and CPI/r
regimens may be due at least in part to the differences in the lengths of
follow-up between the two arms. For example in RESIST 1, a
median of 24.1 weeks in laboratory tests for triglycerides was obtained for
subjects in the TPV/r arm, significantly greater than a median of 19.8 weeks in
the CPI/r arm. Again, the RESIST trials’ open-label trial design with
an escape clause resulted in differential drug exposure duration between TPV/r
versus CPI/r study arms. On the other hand, it is important to keep in mind
that there were subjects enrolled into the CPI/r arms (13%) who already had a
large exposure to the CPI drug because they entered the trial and
continued on their current PI.
Cutaneous reaction (adverse event of “rash”)
was another safety event of special interest in this review due to a
substantial Phase 1 signal from an oral contraceptive study in healthy HIV
negative women (Study 1182.22).
Seventeen subjects (33%) developed a rash while receiving TPV. This high and unexplained incidence of rash in
healthy, female volunteers raised the possibility that gender and immune status
may have an impact on the frequency and types of adverse events (AEs) observed with TPV/r use.
Other phase
1 trials in healthy HIV-negative volunteers showed that rash was seen in 14/390
(3.6%) males as compared to 34/265 (13%) females. In Phase 2 trials of HIV infected subjects, one large study (1182.51)
showed a rash rate of 10.2% (32/315).
Rash was only reported in males but the study population was 93%
male. In another large phase 2 study
(1182.52), 8.6% (18/216) of subjects in the study developed treatment-emergent
rash. Dose relation was suggested
because there were 10 subjects who developed rash in TPV/r 750/200 mg group,
including one discontinuation, whereas there were 5 subjects in the TPV/r
500/200 mg group and 3 subjects in the TPV/r 500/100 mg group. Relationship of the development of rash to
an intact immune system (as indicated by preserved CD4 cell counts) could not
be examined in these two large Phase 2 studies because these subjects were
heavily pretreated and advanced in HIV disease with median CD4 cell count of 133
(1182.51) and 178 (1182.52). Phase 2
trials enrolled predominantly males: however of the limited data available,
females on the TPV/r in phase 2 trials had higher incidence of rash (15/114 or
13.2%) as compared to males (59/745 or 7.9%).
In the phase 3 RESIST trials, the overall incidence
of rash was similar in both arms (11% TPV/r versus 10% CPI/r). The severity and need for treatment were
also similar between the two arms.
Since the RESIST trial population was immunologically depleted, adequate
exploration of the
immune-mediated rash was limited. An exploratory analysis of females in the RESIST
trials (n=118 TPV/r; n=90 CPI/r) showed that the females on the TPV/r arm had a
higher incidence of rash (14%) as compared to the females on the CPI/r arm
(9%). However, the small
number of women in these trials made it impossible to draw any definitive
conclusions. Although BI is currently
conducting a study in antiretroviral naïve subjects, the study is already fully
enrolled with
only about 20% of female subjects (similar to the RESIST trials) and based on
baseline CD4+ count, viral load and AIDS defining illnesses, these naïve
subjects have advanced HIV disease.
Therefore, it appears unlikely that the current naïve trial will provide definitive
answers to whether or not TPV/r
affects women
and/or
immunocompetent subjects differently than the remainder of the HIV+
population.
Mortality: One
hundred and two subjects died during the entire TPV clinical development
program up through the database lock on June 11, 2004. In total, 12 subjects died during the
pretreatment phase and 90 subjects died after being exposed to at least one
dose of drug (post-drug exposure). For most deaths,
subjects had advanced HIV disease and multiple concomitant medications. Three of the 90 post-drug exposure subject deaths
were considered to be possibly TPV/r treatment related by the Applicant. However, FDA could not rule out relatedness
or a possible contribution of the effects of TPV in most death cases. This unclear ascertainment of study drug’s
relationship to mortality (and to morbidity) is due to the nature of the
population under study, and in many cases, was due to the lack of available
information surrounding the death cases.
Overall, there were more
deaths in RESIST 1 than in RESIST 2 (22 versus 11), and there were more deaths
on the TPV/r arms compared to the CPI/r arms (19 versus 14). The observed virologic benefit of the TPV/r
over CPI/r did not translate to better mortality outcome at the 24 week
time-point. However, the RESIST trials
were not designed to assess clinical endpoints. The escape clause at 8 weeks precluded optimal evaluation of
longer term clinical efficacy and safety.
In order to
place the numbers of deaths in the TPV program in perspective, mortality rates were
examined from the in the NDA databases of all “treatment-experienced” trials
which led to approval of an antiretrovirals. The population enrolled in the enfuvirtide (ENF)
phase 3 studies most closely approximated the TPV phase 3 studies. Comparison of the frequency of deaths and
mortality rates (MR, #death/100 patient years) between the test and control
arms were relatively similar for both the TPV and ENF NDAs at 24 weeks as
summarized below:
·
TPV vs. CPI: 2%
(4.5 MR) vs. 1.2% (2.6 MR)
·
ENF vs no
treatment: 1.5% (3.3 MR) vs.1.5%
(3.3 MR)
Based on the information as summarized above
summary, we would like the committee’s feedback on the issues outlined in
section II. The remaining sections of
this background document provides greater detail on the efficacy, safety,
resistance profile, and clinical pharmacology of TPV/r.
From the archives of DAVDP, these analyses showed
that the population enrolled (http://www.fda.gov/cder/foi/nda/2003/021481_fuzeon_review.htm) in the enfuvirtide (ENF) phase 3 studies most closely approximated the TPV phase 3
studies. Comparison of % frequency of deaths or mortality rates (MR,
#death/100 subject years) between the test and control arms were
relatively similar for both the TPV (2% vs. 1.2% or 4.5 MR vs. 2.6 MR) and ENF
(1.5% vs. 1.5% or 3.3 MR vs. 3.3 MR) NDAs at 24 weeks.
II. ISSUES
FOR COMMITTEE DISCUSSION
·
The risk/benefit
assessment of TPV/r given the data provided for safety and efficacy in the
treatment of “heavily pretreated” HIV-infected individuals.
·
Appropriate
safeguards for the use of TPV/r given the limited inclusion criteria of the
RESIST trials, TPV/r drug-drug interactions, the impact of resistance on
response and the safety considerations outlined above.
·
Display of TPV/r
resistance data/analyses in the TPV package insert that would be useful to clinicians.
·
Monitoring and
management of hepatotoxicity during clinical use of TPV/r given the
transaminase elevations data in healthy volunteers and HIV-infected patients in
the development program.
·
Further
investigation and characterization of the safety signal of rash in females in
the TPV program given the limited available data in HIV-infected females.
·
Lessons learned
from the TPV drug development program regarding the study of heavily pretreated
HIV-infected individuals including:
o
Need for drug-drug
interaction and resistance data
o
Use of open-label
study designs
o
Use of escape
clauses resulting in a diminishing comparator arm
o
Need for better
adjudication of clinical events (i.e. treatment-emergent AIDS progression
events) and need for comprehensive data collection for serious adverse events
including death
o
Increasing female
participation in HIV drug trials
II. ISSUES FOR
THE COMMITTEE DISCUSSION
·The risk/benefit assessment of TPV/r given the data
provided for safety and efficacy in the treatment of previously “heavily
pretreated” HIV infected population.
·Appropriate safeguards for the use of TPV/r given
the limited inclusion criteria of the RESIST trials, the drug-drug
interactions, the resistance information and the safety considerations.
·Display of TPV/r resistance data/analyses in the
TPV package insert that would be useful to the clinician.
·Monitoring and management of hepatotoxicity during
clinical use of TPV/r given the transaminase elevations data in healthy
volunteer studies, dose-response/dose-exposure studies, and both RESIST trials.
·Further investigation and characterization of the
safety signal of rash in females in the TPV program given the limited available
data in HIV-infected females.
·Discussion of increasing female participation in
HIV drug trials in general.
·Lessons learned from the TPV drug program regarding
the study of heavily pretreated HIV population which includes the
oNeed for drug-drug interaction and resistance data
oOpen-label study design with inherent bias
oEscape clause with loss of comparator arm
oNeed for better adjudication of clinical events
(i.e. treatment-emergent AIDS progression events) and need for comprehensive
data collection for serious adverse events including death
This
briefing document provides background information for the May 19, 2005
Antiviral Drugs Advisory committee meeting on tipranavir. On this day, the
committee will be asked to consider efficacy and safety data submitted to
support the accelerated approval of tipranavir for the treatment of HIV
infection in the “heavily pretreated” HIV-infected adult population.
Tipranavir
(TPV) is a
non-peptidic inhibitor of the HIV protease that inhibits viral replication by
preventing the maturation of viral particles.
The applicant submitted NDA 21-814 (tipranavir) 250 mg Capsules on
December 22, 2005 seeking approval for marketing under accelerated approval
regulations: 21 CFR 314.510 Subpart H.
Under the current guidance for HIV treatment, the basis for approval
will be based upon surrogate endpoint analyses of plasma HIV RNA levels for
primary efficacy balanced with safety analyses in controlled studies up to 24
weeks duration.
I. SUMMARY OF
EFFICACY AND SAFETY DATA
The
FDA analyses of the submitted NDA data thus far are consistent with the applicant’s
overall findings. Two
open-label, multi-center Phase 3 trials (RESIST 1 and 2) submitted in support
of this NDA provide evidence of the additional antiviral
effect of TPV over currently available antiretroviral regimens in a population
which are “heavily pretreated” ( 3
class antiretroviral experience with median number of prior therapy at 12
drugs). Overall at baseline, 97% of the isolates
were resistant to at least one PI, 95% of the isolates were resistant to at
least one NRTI, and >75% of the isolates were resistant to at least one
NNRTI. It is important to note that close
to 90% of comparator protease inhibitors (CPI) exhibited resistance at baseline
to the clinical isolates. Thus,
although these pivotal trials are being presented
as TPV/r + Optimized background
regimen (OBR) versus CPI/r + OBR, in actuality, the results should be
interpreted more as TPV/r versus placebo with
both arms utilizing a large variety of OBR (n = 161 different drug combinations
as per FDA statistical analysis). TPV/r
showed significantly greater treatment effect than CPI/r when subjects were
already possibly or definitely resistant
to their treatment CPIs. There was no significant effect of TPV/r
over CPI/r if the subjects were sensitive to their CPI.
The added antiviral benefit of the TPV arm over the
comparator arm was mainly the effect of the lack of initial virologic response* in
the comparator arm measured at week
8. This measured benefit of the TPV arm
over the comparator arm at week 8 was sustained at week 24
based upon the composite endpoint** largely
due to those same comparator subjects with initial lack of virologic response
being discontinued from study (rolling over to a TPV
safety study) and being considered treatment failures at week 24. The initial virologic treatment difference
(24%) between the two arms shown at week 8 explains the virologic treatment
difference (20%) between the two arms at week 24. Again,
this virologic treatment
difference was only measured over comparator
PI regimens which were possibly/definitely resistant. TPV/r did not offer added antiviral benefit over CPI/r for
subjects in the comparator arm who were sensitive to their PIs. Moreover, using all-cause
mortality as a definitive clinical event in these trials
(AIDS-defining events were captured in these trials as adverse events only and
not separately captured or adjudicated), it is worthy of note that the
number of on-treatment
deaths (15 TPV/r versus 13 CPI/r) were similar between the two arms. The added virologic benefit
(as measured by the surrogate of plasma HIV RNA) did not translate into any
reduction in mortality at the 24 week time-point. These results may be explained by the fact that these studies
were not powered for mortality and the 24
week time-point is too premature to see any clinical endpoint differences. It is worthy of note however that the use of plasma
HIV RNA as a surrogate endpoint in clinical trials of antiretrovirals was
examined in populations who were treatment-naïve or early experienced. The use of viral
surrogates in studies of the
current heavily pretreated population is an extrapolation with unmeasured
harms or benefits not yet well understood. Moreover, due to
the open-label nature of these RESIST trials with all the inherent bias as well
as the built in escape clause for the comparator arm at 8 weeks after lack of
initial virologic response, it is difficult to discern meaningful comparative
efficacy data (both virologic and clinical) beyond 8 weeks of treatment.
* defined as Lack of Initial Virologic Response by Week 8:
proportion of subjects with
1) Viral load has not dropped 0.5 log10
during the first 8 weeks of treatment
and 2) Failure to achieve a viral load of <100,000 copies/mL during
the first 8 weeks of treatment, despite a 0.5 log10 drop
after 8 weeks of treatment.
**defined as Composite endpoint at 24 weeks: proportion of subjects with 1) confirmed 1
log RNA drop from baseline and 2) without evidence of treatment failure
One
important subgroup analyses was virologic response in subjects with concomitant
enfurvitide (T-20) use which improved
virologic response for both arms. When T-20 was
added to TPV/r, the treatment effect was greater than if T-20 was
not used (net treatment effect of 29.4% vs 15.6%, respectively, for T-20 users
versus non-use of T-20). The concomitant use of T-20 in
the RESIST trials also illustrates an example of how post-randomization bias
enters into open-label trials. For
TPV/r randomized subjects, 9 additional
subjects who did not have T-20
pre-specified in their OBR received T-20
post-randomization. Conversely for
CPI/r randomized subjects who did have T-20
pre-specified in their OBR, 9
subjects did not ultimately receive their specified T-20.
Genotypes
from 1482 isolates and 454 phenotypes from both studies were submitted for
review for the combined RESIST 1 and 2 studies. The FDA analyses of virologic outcome by baseline resistance showed
consistently greater response rates for TPV/r arm over control across multiple
sensitivity analyses. The most common protease mutations that developed in
>20% of isolates from treatment- experience subjects who failed on TPV/r
treatment were L10I/V/S, I13V, L33V/I/F, M36V/I/L V82T, V82L, and I84V. The
resistance profile in treatment-naive subjects has not yet been
characterized. Both the number and type
of baseline PI mutations affected response rates to TPV/r in RESIST 1 and
2. Virologic response rates in TPV/RTV-treated
subjects were reduced when isolates with substitutions at positions I13, V32,
M36, I47, Q58, D60 or I84 and substitutions V82S/F/I/L were present at
baseline. Virologic responses to TPV/r
at week 24 decreased when the number of baseline PI mutation was 5 or
more. Subjects taking enfuvirtide with
TPV/r were able to achieve >1.5 log10 reductions
in viral load from baseline out to 24 weeks even if they had 5 or more baseline
PI mutations. Virologic responses to
TPV/r decreased in Resist 1 and 2 when the baseline phenotype for TPV was
>3.
The drug-drug interaction potential of 500 mg of
TPV in combination with 200 mg of ritonavir is extensive. TPV/r can affect other
drugs and other drugs can affect TPV/r. TPV is a CYP 3A inhibitor, as well as a
CYP3A inducer. TPV/r is a net inhibitor of the CYP3A. TPV/r may therefore increase plasma concentrations of agents that
are primarily metabolized by CYP3A and could increase or prolong their
therapeutic and adverse effects. Studies in human liver microsomes indicated
TPV is an inhibitor of CYP1A2, CYP2C9, CYP2C19 and CYP2D6. The potential net effect of TPV/r is CYP2D6
is inhibition. The net effect of TPV/r on CYP1A2 and CYP2C9 is not known. Data
are not available to indicate whether TPV inhibits or induces glucuronosyl
transferases. Tipranavir is a
P-glycoprotein (P-gp) substrate, a weak P-gp inhibitor, and likely a potent
P-gp inducer as well. Data suggest that the net effect of TPV/r is P-gp
induction at steady-state. Based on the
current limited data, it is difficult to predict the net effect of TPV/r on
oral bioavailability of drugs that are dual substrates of CYP3A4 and P-gp. TPV is a CYP3A substrate as well as a P-gp
substrate. Therefore, co-administration of TPV/r and drugs that induce CYP3A
and/or P-gp may decrease TPV plasma concentrations and reduce its therapeutic
effect. Conversely, co-administration of TPV/r and drugs that inhibit P-gp may
increase TPV plasma concentrations and increase or prolong its therapeutic and
adverse effects. Co-administration of
TPV/r and drugs that inhibit CYP3A may not
further increase TPV plasma concentrations based on the results of a submitted
mass balance study.
TPV/r has established or
potential drug-drug interactions with multiple antiretroviral drugs including
zidovudine, didanosine, abacavir, delavirdine, amprenavir, lopinavir, and
saquinavir as well as the other protease inhibitors (indinavir, nelfinavir,
atazanavir). In addition,
antiarrhythmics, antihistamines, antimycobacterials (rifampin), ergot
derivatives, GI motility agents (cisapride), herbal products (St. John’s wort),
HMG CoA reductase inhibitors (lovastatin, simbastatin),
neuroleptics, and sedatives/hypnotics are contraindicated and not recommended
for co-administration with TPV/r. Other
drugs which may be used concomitantly in
the HIV population and exhibit established or potential important drug-drug
interactions are antacids, antidepressants (SSRIs, atypicals), antifungals
(fluconazole, itraconazole, ketoconazole, voriconazole), anticoagulant
(warfarin),
anti-diabetic agents, antimycobacterials (rifabutin), macrolides
(clarithromycin, azithromycin), calcium channel blockers (felodipine,
nifedipine, nicardipine), corticosteroid (dexamethasone), HMG-CoA reductase
inhibitors (atorvastatin), narcotic analgesics (methadone, meperidine), oral
contraceptives/Estrogens (ethinyl-estradiol), despiramine, theophylline, and
disulfiram/ methronidazole,
A safety concern
throughout the TPV drug development program has been hepatotoxicity. Initial signals were observed throughout the
18 Phase 1 studies in healthy volunteers.
A total of 36 (5.5%) healthy HIV-negative subjects experienced treatment
emergent grade 3 or 4 liver abnormalities (rise in SGPT) in
the Phase 1 studies. Results from the Phase
2 dose-finding study 052
indicate that the SGPT abnormality
was TPV dose dependent. The
proportion of patients who had grade 3/4 SGPT abnormality
in three treatments: 500mg /100mg
tipranavir/ritonovir
(TPV/RTV), 500mg /200mg
TPV/RTV, and 750mg /200mg
TPV/RTV, was 4.3%,
11.1%, and 23%, respectively. The SGPT
abnormality comparison between treatment of 500mg/200
mg TPV/RTV and
750 mg/200 mg TPV/RTV
suggested that the increased liver
toxicity in the higher TPV
arm most likely resulted from increased TPV exposure instead of RTV,
because RTV exposure was lower in
the arm with higher liver toxicity. Logistic regression
analysis also suggested that when
TPV trough concentration doubles, the odds of having grade
3/4 SGPT abnormality was increased
by 96%. Detailed
exposure response analysis on this Study 052
indicated that the SGPT abnormality
was associated with TPV exposure. The likelihood that
RTV contributes to the SGPT
abnormality was small.
In the
RESIST trials, 10% of
subjects on the TPV/r arm compared to 3% on the CPI/r arm developed treatment
emergent grade 3 or 4 ALT or AST elevations.
For
RESIST 1, time to first DAIDS Grade 3 or 4 in ALT
(p=0.0028) and Gamma GT (p=0.0002) were
significantly different between the two arms with subjects in the TPV/r arm more
likely to develop Grade 3 or 4 elevations in ALT and
Gamma GT as well as at a
significantly faster pace than
those in the CPI/r arm. For RESIST 2, time
to first Grade 3 or 4 in ALT
(p=0.0255) and Gamma GT (p<0.0001) were
significantly shorter for subjects in the TPV/r arm compared those for subjects
in the CPI/r arm. Again,
subjects in the TPV/r arm were more likely to develop DAIDS Grade 3 or 4 in
liver enzymes and at a faster pace than those in the CPI/r arm.
The significant
differences in developing Grade 3 or 4 toxicity
and in change from baseline laboratory test measurements between CPI/r and
TPV/r regimens may be due at least in part to the
significant difference in lengths of follow-up period between the two arms. For
example for RESIST 1, a mean
of 21.8 weeks (std=5.7 weeks) and a median of 24.1 weeks in
laboratory tests for triglycerides were obtained for subjects in the TPV/r arm,
significantly greater than a mean of 18.9 weeks
(std=6.8 weeks) and a median of 19.8 weeks in the CPI/r arm. Again, the current open-label study design
with an escape clause for this highly pretreated population resulted in
differential drug exposure duration between TPV/r versus CPI/r study arms from
the start of the trial to the cut-off time-point of safety comparisons at 24
weeks and beyond. On the other hand, it
is important to keep in mind that there were subjects enrolled into the CPI/r
arms (13%) who already had a large exposure to the CPI drug because they
entered the study with an
already failing regimen.
The relationship (and
time-course) of these liver enzyme elevations
with symptomatic clinical disease manifestation was difficult to
ascertain. For
possible baseline risk factors of outcome, Grade
3 or 4 transaminase elevations on the TPV/r arm were associated with higher
baseline median CD4+ counts (238.5 cells/mm3 versus
175 cells/mm3) as compared to the
general TPV/r population. The numbers
of subjects were too small to draw any conclusions about the risk factors of
viral hepatitis co-infection, gender, or race.
In regards to lipid abnormalities
measured in the RESIST trials, TPV/r is consistent with what has been generally
observed as an important safety concern regarding
the PI class. Analyses
of RESIST 1 laboratory data showed that the time to first Grade 3 or 4 in total
cholesterol (p=0.0007) and
triglycerides (p=0.0186) were significantly different between the two
arms. Analyses of RESIST 2 laboratory
data showed that the time to first Grade 3 or 4 in total cholesterol (p=0.0255)
and triglycerides
(p<0.0001) were significantly shorter
for subjects in the TPV/r arm. More subjects in the TPV/r arm developed Grade 3
or 4 total cholesterol and triglycerides than those in the CPI/r arm and at a
significantly faster pace. For combined RESIST 1
and 2 datasets, 21% of subjects developed treatment emergent grade 3 or 4
triglycerides compared to 11% of subjects on the CPI/r arm. Clinically at the
24 week time-point, none of the subjects
with grade 3 or 4 triglycerides on either arm went on to have documented clinical pancreatitis.
Cutaneous reactions (adverse event
incidence of “rash”) was another
safety event of special interest in this review due to a substantial Phase 1
signal from an oral contraceptive study in healthy HIV negative women (study 022). Seventeen subjects (33%)
developed a rash while receiving TPV and 20% had musculoskeletal pain. Three subjects had both skin and
musculoskeletal findings. An additional
three subjects reported symptoms that can be
associated with drug hypersensitivity while receiving TPV; one had generalized
pruritis and conjunctivitis on day 11, one had conjunctivitis on day 11, and
the other had intermittent numbness and tingling in the leg on day 11. Therefore in the most conservative analysis,
51% of these healthy subjects had possible drug hypersensitivity. FDA’s review
of other supportive studies as well as the RESIST studies for this safety
signal was focused on examining possible gender differences, immunologically based
skin reactions, and/or sulfa-related effect (TPV is a sulfonamide).
Other
phase 1 trials in healthy HIV-negative volunteers showed that rash was seen in
14/390 (3.6%) males as compared to 34/265 females (13%). In Phase 2 trials of HIV infected subjects, one
large study (051) showed a rash rate
of 10.2% (32/315). These subjects were
all males since the study population was 93% male. In the subset of subjects identified with a history of sulfa rash
(n=58), a higher % of subjects (17%) developed a hypersensitivity-like rash
within the first 6 weeks. In another
large phase 2 study (052),
8.6% (18/216) of subjects in the study developed treatment-emergent rash. Dose relation was suggested because there
were 10 subjects who developed rash in 750TPV/200 RTV mg
group, including one discontinuation, whereas there were 5 subjects in the
500/200 mg group and 3 subjects in the 500/100 mg group. Relationship of the development of rash to
an intact immune system (as indicated by preserved CD4 cell counts) could not
be examined in these two large Phase 2 studies because these subjects were
heavily pretreated and advanced in HIV disease with median CD4 cell count of 133 (study
051) and 178 (052). Phase 2 trials enrolled predominantly males:
however of the limited data available, females on the TPV/r in phase 2 trials
had higher incidence of rash ( 15/114
or 13.2%) as compared to males (59/745 or 7.9%).
In the phase 3 RESIST
trials, the overall incidence of rash was similar on both arms (11% TPV/r
versus 10% CPI/r). The severity and
need for treatment were also similar between the two arms. Three subjects on the TPV/r arm compared to
zero on the CPI/r arm ended up discontinuing study treatment due to their
rash. Since the RESIST trial population
was a clinically advanced and immunologically depleted, examination of
immunologically-mediated rash (or drug hypersensitivity) adverse reactions was
limited. Sulfa-allergic subjects were
not excluded in these trials and
------------------------- A
subgroup analysis of the females in the Resist trials (n=118 TPV/r; n=90 CPI/r)
revealed that the females on the
TPV/r arm had a higher incidence of rash (14%) as compared to the females on
the CPI/r arm (9%). Seven of the
17 subjects on the TPV/r had no baseline CD4+ count recorded, so FDA
can not make an accurate assessment of the immunologic
status of these women.
A
total of 103 death cases
representing 102 patients died during the entire TPV clinical
development program up through the database locking of pivotal
studies 1182.12 and 1182.48 on June
11, 2004. In total,12 subjects died
during the pretreatment phase and 90 subjects died after being exposed to at
least one dose of drug (post-drug exposure).
Three of the 90 post-drug exposure subject deaths were considered to be
possibly TPV/r treatment related by the applicant. Subject
521394 from the rollover study 1182.17 died of acute renal failure, but the
subject had a history of chronic renal disease and was on a number of
potentially nephrotoxic agents. Subject
121025 from the rollover study 1182.17 died of multi-system organ failure
including hepatic failure. The
subject had a history of fatty live disease and was taking other potentially
hepatotoxic medications at the time of death.
Subject 215 in study
1182.6 died from respiratory failure and brain stem infarction subsequent to developing elevated liver enzymes and
lactic acidosis. For
most death cases, subjects had advanced
HIV disease and multiple concomitant medications. Although only these three cases are described here,
relatedness or possible
contribution of the effects of TPV to the death events
could not be ruled out by the FDA reviewers for almost all death
cases. This unclear ascertainment of
study drug’s relationship to mortality (and to morbidity) is due to the nature
of the population under study, and in many cases, was due to the lack of
available information surrounding the death cases.
Overall there are more
deaths in Resist 1 than in Resist 2 (22
versus 11), and there are more
deaths on the TPV/r arms compared to the CPI/r arms (19 versus 14). In Resist 1 there are two
major differences between the two arms: 1. The number of deaths on the TPV/r
arm over the CPI/r arm (14 versus 8, p-value = 0.19), and
2. the TPV/r arm had a lower median baseline and last CD4+ count as compared to
the CPI/r arm (baseline CD4: 13.75 versus 149; last CD4: 13 versus 158). Certainly,
the observed virologic benefit of the TPV/r over
CPI/r did not translate to better mortality outcome at the 24 week
time-point. The
importance of examining the relationship between the virologic effect and
clinical outcome in this evolving heavily pretreated population is
paramount. Unfortunately for the RESIST
trials as currently designed, the comparative efficacy or safety
database is less than optimal after 8 weeks of study and the limitations worsen
over time due to the large discontinuations of subjects in the comparator arm.
In
order to place the numbers of deaths in the TPV program in perspective, mortality
rates in the NDA database of all “treatment-experienced” trials which led to
approval of an antiretroviral from
the archives of DAVDP was
examined. This analyses
showed that the population enrolled in the T-20 phase
3 studies most closely approximated the TPV phase 3 studies. Comparison of % frequency of deaths or
mortality rates (MR, #death/100 patient years) between the test and control
arms were relatively similar for both the TPV (2% vs. 1.2% or 4.5 MR vs. 2.6 MR)
and T-20 (1.5% vs. 1.5% of 3.3
MR vs. 3.3 MR) NDAs at 24 weeks.
The Division is
convening this meeting to solicit the committee’s comments on the breadth of the proposed
treatment indication and the risk-benefit analysis of
the use of tipranavir administered with low
dose ritonavir given the following challenging issues:
1)Design/analyses of the efficacy in studies of
“heavily pretreated” population
1)Impact of resistance information
3) Management
of known and potential drug-drug interactions
4) Safety
concerns including liver and lipid monitoring/management, rash and gender differences, and clinical events on study
including mortality.
III. DESIGN/ANALYSES
OF THE EFFICACY IN STUDIES OF “HEAVILY PRETREATED”
POPULATION
A.
Study Design of
Phase 3 Trials
Please see Appendix I
for discussion of dose selection for RESIST trials..
RESIST 1 (1182.12) and
RESIST 2 (1182.48), were multi-center, multi-national, randomized and controlled,
open-label studies in highly treatment-experienced HIV-infected subjects with triple
antiretroviral class (NRTI, NNRTI, and PI) experience and with at least two failed PI-based regimens. The two major differences between the RESIST
trials was 1)
RESIST 1 was conducted in the United States, Canada and Australia, while RESIST 2 was conducted in Europe and Latin America; and 2) RESIST 1
performed 24 week interim analyses while RESIST 2 performed 16 week interim
analyses. For the accelerated
approval application, the Applicant submitted 24-week efficacy data on all 620 subjects in RESIST 1 study and
539 out of 863 subjects in the RESIST 2 study who were able to reach
24 weeks. The safety and efficacy of TPV/r 500 mg/200 mg was compared through 24
weeks of treatment against a control group of other protease inhibitors boosted
with RTV (comparator PI/r or
CPI/r) where the control PIs were genotypically determined. The studies were designed to continue
through 96 weeks. Genotypic resistance
testing was done at screening, and as protocol defined, subjects were required
to have at least one primary PI mutation(s) at codons 30N, 46I/L, 48V, 50V,
82A/F/L/T, 84V, or 90M and have no more than two protease mutations at codons 33,
82, 84, or 90.
Subjects were randomized 1:1 to either TPV/r or the
comparator PI/r group and stratified with respect to pre-selected protease
inhibitor (PI) as well as use of ENF. Both
treatment groups (TPV/r versus CPI/r) were designed to receive OBR regimen based on
genotypic resistance testing prior to randomization. Due to the complex comparator treatment group containing various
protease inhibitors, the studies had to be designed as open-label trials. Furthermore, the FDA review team strongly
recommended that the studies be designed to test for superiority of efficacy of
TPV/r versus CPI/r, since testing for non-inferiority against multiple control
groups in such an experienced population would be uninterpretable. A schematic of the RESIST trials shows the
complexity of the study design of these trials (Appendix II). As shown in the schema,
the subjects who had a lack of
initial virologic response by Week 8 in the control arm of comparator protease
inhibitors were allowed to enroll into the roll-over Study 1182.17 where all subjects would receive TPV/r. This escape clause for subjects in the control group
has complicated our ability to interpret the efficacy of TPV/r in a controlled fashion
beyond 8 weeks of treatment.
B.
Baseline demographics and disease characteristics
in RESIST trials
Baseline characteristics of subjects enrolled in
these studies are summarized below.
Table 1:
Baseline Characteristics: Studies 1182.12 and 1182.48
|
|
RESIST 1 (012) |
RESIST 2 (048) |
|
# of Subjects
Randomized |
630 |
880 |
|
# of Subjects Treated |
620 |
863 |
|
Age (Years) Mean Median Range |
45 44 24, 80 |
43 42 17, 76 |
|
Sex (%) Male Female |
91 9 |
84 16 |
|
Race (%)
Caucasian Black Asian Missing |
77 22 1 0 |
68 5 1 26 |
|
Weight (kilograms) Mean Median Range |
76 75 35, 151 |
69 68 32, 118 |
|
CD4 Cell Count
(cells/mm3) Mean Median Range |
164 123 0.5, 1183.5 |
224 189 1.5, 1893 |
|
HIV RNA (log10
copies/mL) Mean Median Range Proportions w/ HIV RNA (copies/mL) < 10,000 >=10,000 to <100,000 ≥ 100,000 |
4.7 4.8 2.0, 6.3 16% 43% 41% |
4.8 4.8 2.9, 6.8 15% 49% 36% |
|
Stage of HIV Infection (CDC Class) Class A Class B Class C |
24% 73% 3% |
17% 80% 3% |
|
Protease Inhibitor
Stratum APV IDV LPV SQV |
14% 4% 61% 21% |
40% 3% 38% 20% |
|
Genotypic Resistance
to Pre-selected Protease Inhibitor Not
Resistant
Possible Resistance Resistant |
8% 35% 57% |
20% 6% 74% |
|
Actual use of ENF Yes No |
36% 64% |
12% 88% |
C.
Primary Efficacy Endpoints
The primary efficacy
endpoint in the RESIST trials is the proportion
of subjects with a treatment
response at 48 weeks (≥ 1 log10 reduction from baseline
HIV RNA in two consecutive measurements without prior evidence of treatment failure). The efficacy endpoint for the 24-week data
submitted in this application is the proportion
of subjects with a treatment
response at 24 weeks. Multiple
secondary analyses were performed for each study.
This efficacy analysis is models the FDA analysis of
time to loss of virologic response (TLOVR) analysis which is an intent-to-treat
analysis that examines endpoints using the following definitions of treatment
response and treatment failure for subjects who have achieved a confirmed 1 log10
drop in HIV RNA from baseline.
Treatment response is
defined by confirmed virologic response (two consecutive viral load
measurements ≥1 log10 below baseline) without prior treatment
failure, i.e., occurrence of any of the following events: death, permanent discontinuation
of the study drug, loss to follow-up, introduction of a new ARV
drug to the regimen for reasons other than toxicity or intolerance to a
background ARV drug, and confirmed virologic failure (defined as 1) viral load of <1 log10
below baseline confirmed at two consecutive visits >2 weeks apart, following
a confirmed virologic response of two consecutive viral load measurements
≥1 log10 below baseline, or 2) one viral load of <1 log10 below
baseline followed by permanent discontinuation of the study drug or loss to
follow up, following a confirmed virologic response of two consecutive viral
loads ≥1 log10 below baseline.)
According to the study design, investigators were
allowed to switch subjects in the control arm of boosted CPI/r after 8 weeks of
treatment if they had initial lack of virologic response (defined as 1) viral load has not dropped
0.5 log10 during the first 8 weeks of treatment and 2) failure to achieve a
viral load of <100,000 copies/mL during the first 8 weeks of treatment,
despite a 0.5 log10 drop after 8 weeks of treatment.
D.
Study Design Issues
The open-label design of
the RESIST trials was unavoidable because of the choice of various CPIs in the control arm
(LPV, IDV, SQV, APV—boosted with low-dose ritonavir). Additionally, due to the choice of the control group, the studies
must be evaluated for superiority of TPV/r over the CPIs to which the majority
of the subjects have documented drug
resistance at baseline.
The open-label design poses a number of challenges
in evaluation of efficacy. Both RESIST
trials were conducted in subjects with very limited treatment options for whom TPV represented a potential
and possibly the only option. Therefore
subjects who met the same
failure criteria or experienced similar toxicity or safety events may act
differently depending on the treatments they received: TPV subjects will be more likely to
elect to remain in the same treatment group despite problems whereas control
group subjects will be more likely to
switch to TPV through the roll-over
trial 1182.17. This creates a potential bias in
efficacy assessments if we regard all switches or discontinuations as failures.
To address this
open-label bias issue, we used the protocol-defined failure criteria—of initial
lack of virologic response—at Week 8 to supplement the analysis. In other words, all subjects who met the failure
criteria at Week 8, regardless of whether they switched treatments, were
considered failures for the Week 24 evaluation in the FDA analysis.
Another bias that was introduced by the open-label
design of RESIST trials was the ability to change the pre-determined OBR. Subjects were required to have a pre-determined background
regimen at the time of randomization based on their genotypic resistance test
results and background ARV medication history.
In RESIST 1 and RESIST 2 trials, there were a total of 11% and 14%,
respectively
of subjects
whose pre-determined OBR was different from the actual background regimen
received. One example of this bias is
the number of subjects who had ENF predetermined as part of their OBR (TPV/r
165 versus CPI/r 159) differed from the number of subjects who actually took
ENF (TPV/r 166 versus CPI/r 134). The
TPV/r arms had a net gain of 1 subject using ENF although it was not
predetermined, while the CPI/r arm had a net loss of 25 subjects who did not
actually use ENF although it was part of their predetermined background. The Applicant believes, and DAVDP concurs, that the RESIST
Investigators likely wanted to save ENF for use with a known active PI, and
therefore, once subjects were randomized to the CPI/r the Investigator changed
the OBR to exclude ENF. In addition, due to the high total
number of combinations of ARVs in the OBRs (161), it was also difficult to
examine the treatment effect by ARV regimen.
This analysis might have helped determine the clinical effect of TPV
drug-drug interactions.
The Applicant had difficulty
enrolling the RESIST trials as designed to compare TPV/r to an active CPI/r, so they
amended the protocol to allow subjects with no available sensitive PI, as per their genotype, to enroll. This amendment resulted in complete enrollment of the RESIST trials; however, most of the
CPI/r subjects entered the trial already genotypically resistant to their
assigned PI (92% of subjects in RESIST 1 and 80% of subjects in
RESIST 2 had possible or full resistance to the pre-selected PIs). Therefore, the CPI/r arm is not truly an active
control arm,
but a suboptimal control arm. The
results of the RESIST studies should be interpreted as TPV/r versus suboptimal control, and the studies must
be evaluated for superiority of TPV/r over the CPIs.
E. HIV RNA Results
Tables 2 and 3 show the
primary efficacy results for TPV on the proportion of subjects with treatment
response (confirmed 1 log10 reduction in HIV RNA from baseline
without prior evidence of treatment failure).
This was based on the time-to-loss of virologic response (TLOVR)
algorithm as defined in the primary efficacy endpoint.
In each RESIST trial, the proportion of treatment
responders were significantly higher in the TPV/r treated group versus the subjects in the CPI/r treated
group (RESIST 1: 36% TPV/r versus 16%
CPI/r; RESIST 2: 32% TPV/r versus 13%
CPI/r.
As explained above, in order to address the bias
due to an open-label study design, the FDA analysis treated all subjects who
showed an initial lack of virologic response by Week 8 (that is no 0.5 log10
drop in HIV RNA during first 8 weeks of treatment and failure to achieve viral
load <100,000 copies/mL) as treatment failures. We believe that the FDA analysis differs from the Applicant’s results primarily due
to this group of subjects who had initial lack of virologic response during
first 8 weeks. These subjects would be most likely
to discontinue the study drug later, roll-over to Study 1182.17 to receive TPV,
or add additional background ARV drugs.
Table 2: RESIST Outcome at Week 24: FDA Analysis (TLOVR)
|
|
RESIST 1 Trial 1182.12 |
RESIST 2 Trial 1182.48 |
Total |
|||
|
|
TPV/r |
CPI/r |
TPV/r |
CPI/r |
TPV/r |
CPI/r |
|
|
n (%) |
n (%) |
n (%) |
n (%) |
n (%) |
n (%) |
|
Total treated |
311 (100) |
309 (100) |
271 (100) |
268 (100) |
582 (100) |
577 (100) |
|
Treatment
response at Week 24 |
112 (36) |
49 (16) |
86 (32) |
34 (13) |
198 (34) |
83 (14) |
|
No
confirmed 1 log10 drop from baseline |
172 (55) |
234 (76) |
143 (53) |
223 (83) |
315 (54) |
457 (79) |
|
Initial Lack of
Virologic Response by Week 8 |
109 (35) |
166 (54) |
97 (36) |
176 (66) |
206 (35) |
342 (59) |
|
Rebound |
40 (13) |
40 (13) |
28 (10) |
26 (10) |
68 (12) |
66 (11) |
|
Never suppressed
through Week 24 |
23 (7) |
28 (9) |
18 (7) |
21 (8) |
41 (7) |
49 (8) |
|
Added ARV
drug |
20 (6) |
21 (7) |
35 (13) |
8 (3) |
55 (9) |
29 (5) |
|
Discontinued
while suppressed |
1 (<1) |
2 (1) |
4 (1) |
1 (<1) |
5 (1) |
3 (1) |
|
Discontinued
due to adverse events |
3 (1) |
1 (0) |
3 (1) |
2 (1) |
6 (1) |
3 (1) |
|
Discontinued
due to other reasons |
3 (1) |
2 (1) |
0 (0) |
0 (0) |
3 (1) |
2 (0) |
|
Consent withdrawn |
1 (<1) |
0 (0) |
0 (0) |
0 (0) |
1 (<1) |
0 (0) |
|
Lost to follow-up |
1 (<1) |
1 (<1) |
0 (0) |
0 (0) |
1 (<1) |
1 (<1) |
|
Non-compliant |
0 (0) |
1 (<1) |
0 (0) |
0 (0) |
0 (0) |
1 (<1) |
|
Protocol violation |
1 (<1) |
0 (0) |
0 (0) |
0 (0) |
1 (<1) |
0 (0) |
|
Source: FDA Statistical Reviewer’s Analysis |
||||||
Table 3:
Proportion of Subjects with Treatment Response
|
|
RESIST 1 – 24 weeks |
RESIST 2 – 24 weeks |
||
HIV RNA
|
TPV/r + OBR n/N (%) |
CPI/r + OBR n/N (%) |
TPV/r + OBR n/N (%) |
CPI/r + OBR n/N (%) |
|
Response Rate (confirmed 1 log10 drop
in HIV RNA) |
112/311 (36) |
49/309 (16) |
86/271 (32) |
34/268 (13) |
|
Difference in proportions (TPV/r – CPI/r) (95%
Confidence Interval) |
20.2% (13.4%, 26.9%) |
19.0% (12.2%, 25.9%) |
||
|
p-value |
<0.001 |
<0.001 |
||
|
Source: FDA Statistical Reviewer’s Analysis |
||||
In the RESIST trials,
randomizations were stratified according to the pre-selected protease
inhibitors (APV, IDV, LPV, SQV) based on genotypic resistance testing and according
to the use of ENF or not. FDA conducted
subgroup analyses based on these stratification factors which are summarized in
the tables 4 and 5 below
Treatment difference
between the TPV/r 500 mg/ 200 mg group and the CPI/r group was statistically
significant in both subgroups of the ENF-use strata (used ENF or did not use ENF). These results were consistent between RESIST
1 and RESIST 2 studies. In addition,
FDA conducted statistical tests to examine interaction between the subgroups on
ENF use and treatment group. A
statistically significant treatment interaction was observed for the subgroup
of subjects who actually used ENF versus did not use ENF (p-value = 0.02
significant at a=0.15 level).
In other words, in this highly
treatment-experienced subject population, the net proportion of subjects with confirmed 1 log10
reduction in HIV-RNA using TPV/r in combination with ENF would be likely to be
significantly greater than if TPV/r was used alone without ENF (net treatment
effect of 29.4% vs 15.6%, respectively, for ENF users versus non-use of ENF).
Table 4: Proportion of Subjects with Treatment
Response through 24 weeks by ENF use
|
Both RESIST Trials combined (confirmed 1 log10
drop in HIV RNA from baseline) |
|||||
|
Enfuvirtide
(ENF) used? |
TPV/r N=311 |
CPI/r N=309 |
Difference
in proportions (TPV/r – CPI/r) |
Test for treatment effect |
Test for treatment by subgroup interaction |
|
Yes (25%) |
76/158 (48%) |
24/128 (19%) |
29.4% |
<0.0001 |
0.02** |
|
No (75%) |
122/424 (29%) |
59/449 (13%) |
15.6% |
<0.0001 |
|
|
† Asymptotic confidence intervals based on
normal distribution. ‡ p-value
is based on the Mantel-Haenszel chi-square test. § p-value
based on t-test ** Treatment
by subgroup interaction is statistically significant at a 0.15 level. |
|||||
|
Source: FDA Statistical Reviewer’s Analysis. |
|||||
With regard to the
pre-selected comparator protease inhibitor stratum, FDA also conducted analyses
to see the treatment effect of TPV/r in the PI strata if subjects were not-resistant to
the PI versus possibly/definitely resistant to the comparator PI. In both RESIST trials combined, only 13% were not
resistant to the pre-selected PI stratum, and remaining 87% were possibly/definitely
resistant to the comparator PIs. In the
subgroup of subjects for whom the
pre-selected PI was not resistant to the HIV, the treatment difference between
TPV/r and CPI/r was not consistent between RESIST 1 (US, Canada, Australia)
study versus RESIST 2 (the non-US study). The treatment difference between
TPV/r and CPI/r (-4.8%) among subjects not resistant to PIs was not statistically
significant in RESIST 1 (-4.8%) or in RESIST 2, (15.4%). Additionally, in RESIST 1, there was a
strong treatment by subgroup interaction (p-value = 0.03) between the
non-resistant group versus possibly/definitely resistant group, indicating that
the treatment effect in non-resistant group was not significant (-4.8%) and in
resistant group was significant (~20%).
For both RESIST studies combined, among the subgroup of
possibly/definitely resistant comparator PIs, the treatment difference was
statistically significant in favor of TPV/r versus CPI/r (treatment effect of
~21%). The result of this subgroup of subjects with possible/definite
resistance to PIs was consistent with the overall results on the primary
efficacy endpoint (treatment effect of 19% to 20%).
In summary, TPV/r showed
significantly greater treatment effect than CPIs/r only when subjects were possibly or
definitely resistant to their CPI/r. When ENF
was added to TPV/r, the treatment effect was even more significantly greater
than if ENF was not used.
Table 5: Proportion with
Treatment Response through 24 weeks by resistance CPI stratum
|
RESIST 1 |
|
|
|
|
|
|
Resistance
in PI stratum |
TPV/r N=311 |
CPI/r N=309 |
Difference
in proportions (TPV/r – CPI/r) |
Test for treatment effect |
Test for treatment by subgroup interaction |
|
Not Resistant |
5/21 (24%) |
8/28 (29%) |
-4.8% |
0.711 |
0.03** |
|
Possibly Resistant |
47/120 (39%) |
18/94 (19%) |
20% |
0.002 |
|
|
Resistant |
60/169 (35%) |
23/187 (12%) |
23.2% |
<0.0001 |
|
|
RESIST 2 |
|
|
|
|
|
|
Not Resistant |
18/55 (33%) |
9/52 (17%) |
15.4% |
0.0677 |
0.61 |
|
Possibly Resistant |
9/15 (60%) |
5/18 (28%) |
32.2% |
0.066 |
|
|
Resistant |
59/200 (29%) |
20/198 (10%) |
19.4% |
<0.0001 |
|
|
† Asymptotic confidence intervals based on
normal distribution. ‡ p-value
is based on the Mantel-Haenszel chi-square test. § p-value
based on t-test ** Treatment
by subgroup interaction is statistically significant at a 0.15 level. |
|||||
|
Source: FDA Statistical Reviewer’s Analysis. |
|||||
F. CD4 Cell Counts
At baseline the mean CD4 cell counts in RESIST 1
and RESIST 2 trials were 164 cells/mm3 and 224 cells/mm3,
respectively. FDA conducted an
on-treatment analysis to compare the change from baseline in CD4 cell counts
between TPV/r and CPI/r groups and determine whether the results would be
significantly different if subjects in the CPI/r group were to continue beyond Week 8
rather than discontinue in the CPI/r arm at Week 8. In general, the CD4 cell counts increased in the TPV/r group
through Weeks 2, 4, 8 and 16, and remained stable at Week 24. The mean increase in CD4 cell counts in the
TPV/r group at Weeks 8 and 24 were +50 and +58 cells/ mm3,
respectively, for both RESIST studies combined. The mean increases in CD4 cell counts from baseline in the CPI/r group were modest
through Week 8 and were around +20 cells/mm3. Recall that there were greater numbers of subjects with initial lack of
virologic response during the first 8 weeks in the CPI/r group who may have
influenced the mean increase in CD4 cell counts.
At Weeks 16 and 24, among the subjects who remained in the
RESIST 1 trial with the assigned treatment, the differences between TPV/r group
and CPI/r group were no longer statistically significant. However, in RESIST 2, the difference in mean
increase in CD4 cell count at Week 24 was statististically significant, but this difference may not
have clinical significance due to the small magnitude of differences. For both studies combined, the Week 24 mean
increase in CD4 cell counts in TPV/r group and CPI/r groups were +58 and +40
cells/mm3, respectively.
II. DESIGN/ANALYSES
OF THE EFFICACY IN STUDIES OF “HEAVILY PRETREATED”
POPULATION
A.Study
Design of Phase 3 Trials
The two identically
designed RESIST trials, namely, RESIST 1 (1182.12) and RESIST 2 (1182.48) were
multi-center, multi-national, randomized and controlled, open-label studies in
highly treatment-experienced HIV-infected patients with triple antiretroviral
class and dual protease inhibitor (dual PI)–drug regimen experience. The difference between the two studies was that RESIST 1 was
conducted in the United States, Canada and Australia, while RESIST 2 was conducted in Europe and Latin
America. Tipranavir boosted with
ritonavir (TPV/r 500
mg/200 mg) was compared with respect to safety and efficacy through 24 weeks of
treatment against a control group of other protease inhibitors boosted with
ritonavir (comparator PI/r or CPI/r) where the control PIs were genotytpically
determined. The studies are designed to
continue through 96weeks.
Patients were highly antiretroviral
treatment-experienced HIV-infected with triple ARV class (NRTI, NNRTI, and PI)
experience and dual-PI regimen experience.
Genotypic resistance testing was done at screening in which patients
must have at least one primary PI mutation(s) at codons 30N, 46I/L, 48V, 50V,
82A/F/L/T, 84V, or 90M and have no more than two protease mutations 33, 82, 84,
or 90.
Patients were randomized
equally to either TPV/r or comparator PI/r group and stratified with respect to
pre-selected protease inhibitor (PI) as well as use of enfuvirtide (T-20). Both treatment groups (TPV/r versus CPI/r)
were designed to receive optimized background regimen based on genotypic
resistance testing prior to randomization.
Due to the complex comparator treatment group containing various
protease inhibitors with varying degrees of resistance profiles of the drugs,
the studies had to be designed as open-label trials. Furthermore, the FDA review team strongly recommended the
Applicant that the studies be tested for superiority of efficacy of TPV/r
versus CPI/r, since testing for non-inferiority against multiple control groups
in such an experienced population will be uninterpretable. A schematic of the RESIST shows the
complexity of the study design of these trials. As shown in the schema, the patients
who had a lack of initial virologic response by Week 8 (viral load did not drop
0.5 log10 from baseline during
the first 8 weeks of treatment and failed to achieve viral load <100,000
copies/mL despite a 0.5 log10 drop)
in the control arm of comparator protease inhibitors were allowed to enroll
into the roll-over Study 1182.17 where all patients would receive tipranavir
(TPV/r). This escape clause for
patients in the control group has complicated our ability to interpret the
efficacy of tipranavir beyond 8 weeks of treatment.
Figure 1: Schematic of RESIST Trials—Study Design
Figure 1 Continued:
Source: FDA
Statistical Reviewer’s depiction of study design and Protocols 1182.12 (RESIST
1) and 1182.48 (RESIST 2), Volume 1.6 of Module 5
A.Baseline
demographics and disease characteristics in resist
trials
Baseline
characteristics of subjects enrolled in these studies are summarized below.
Table 1: Baseline Characteristics: Studies 1182.12
and 1182.48
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
A.Primary
Efficacy Endpoints
<