2003
by Rob Camp
INTRODUCTION
FTC is a once-daily (QD) thiacytidine nucleoside analogue developed by Triangle Pharmaceuticals, North Carolina. Triangle is now owned by Gilead Sciences. The compound was licensed from Emory University in 1996. It comes in 200 mg capsules and should be stored at room temperature, between 15-30 C (59-86 F). There are no food restrictions with FTC administration.
People with the M184I/V mutation associated with 3TC (lamivudine, Epivir) will not benefit from FTC, given that the M184 mutation confers high-level resistance. FTC, like 3TC, selects for the M184 mutation. It is important that persons with detectable viral load who plan to switch therapy from 3TC to FTC have genotypic testing performed to determine whether the M184V mutation is present. Of course, a patient’s treatment history is also extremely important. If 3TC has failed in the past, the 184 is archived, thus rendering FTC unaffective in this patient population.
FTC is currently under review for approval by the FDA for the treatment of HIV in adults. A New Drug Application was filed in September 2002 and with the EMEA in January 2003. In addition, FTC holds promise as a fixed-combination treatment for HIV co-formulated with Viread®. FTC is also in Phase III clinical studies for the treatment of chronic hepatitis B.
FTC has been developed quite slowly. What may have been the most interesting thing about this drug, i.e., QD dosing, is less interesting now that 3TC is licensed as such.
Based on data from ongoing and completed studies, specifically the 301, 302, 303/350 studies and the two ANRS studies 091 and 099, and the two ACTG studies 5015 and 5073, and the currently enrolling M02-418, TAG and the undersigned organizations believe that the FDA should approve the Gilead Sciences application for full approval of Emtriva® brand FTC (NDA 21-500) to treat HIV infection in combination with other antiretroviral agents in adults.
OVERVIEW
This paper will discuss the following issues:
- Executive Summary
- Pre-Clinical Data
- Pharmacokinetics & Dosing
- Side Effects
- Resistance and the M184V
- Efficacy Studies
- Studies to be Done
- Expanded Access
1. Executive Summary
How effective is FTC for the indication in question? In all studies to date, including the 302 which was stopped due to liver issues, later shown not due to FTC, this drug has been seen as a competent first-line cytidine analog, the main difference being that it is dosed once a day. Interestingly, Triangle/Gilead conducted head to head comparison studies with other nucleoside analogues. Unlike abacavir where the development philosophy was to demonstrate its superiority to a combination of two nucleoside analogues (AZT and 3TC), the FTC development strategy involved comparing it directly with d4T and 3TC, utilizing a non-inferiority design.
What are the real side effects? Again, FTC deserves a thumbs up. Although new and more horrific side effects are discovered over time with most drugs, because FTC is so similar to 3TC, the side effect profile is probably well-characterized. Although neither drug was ever studied in monotherapy for extended lengths of time, 3TC has shown over time that headache, malaise/fatigue, nausea, sleep interference and dizziness are the main side effects, all hovering around 5%. Lab abnormalities do not reach 2% at 24 weeks. FTC side effects should be very similar.
Are things not being said? Possibly Triangle (now Gilead) could have been more imaginative in their trial designs, but there seem to be few if any questions not answered.
- One issue not looked at yet is its effect in pregnant women.
- The pediatrics trials done are being repackaged and resubmitted at a later date. When and why?
- There also was a recent charge from the FDA that the Abbott production facility where FTC was being produced was not maintaining standards of quality. The Abbott facility is no longer producing FTC.
- The dose ranging study is only in press now. Why was it submitted so late?
- Liver toxicity may take longer to see than these registration studies.
- Trials should have been stratified for HBV status.
Who will be able to access this? Although pricing is not relevant to the agency’s evalauation of FTC, it continues to be an important community concern. We urge Gilead to price FTC within the range of 3TC. If Gilead maintains the pricing parity with 3TC, hopefully, anyone who has never failed 3TC and has access to 3TC will also be able to access FTC.
2. Preclinical data
Structure & Mechanism of action
FTC is a reverse transcriptase inhibitor, and is active in vitro both on HIV-1 and HBV. Its activity against HIV-1 is approximately 4-10 fold greater than that of 3TC. Studies in animals demonstrated that FTC had good oral bioavailability and the only adverse event seen was mild anemia in mice at extremely high doses (3 g/kg/day). Phase I/II trials started in September 1997.
3. Pharmacokinetics & Dosing
A Phase I single dose study evaluated the pharmacokinetics and tolerance of FTC in 12 HIV+ volunteers. The volunteers received six single oral doses of FTC at six-day intervals ranging from 100 to 1,200 milligrams. FTC was well tolerated by all subjects in the doses studied. It was absorbed rapidly into the blood stream following oral administration and was excreted primarily through the kidneys. While food intake slightly decreased the rate of absorption, it did not affect overall oral bioavailability. The absorption, metabolism and excretion of FTC were generally consistent among the
subjects.
Another pharmacokinetic study of FTC in HIV+ individuals demonstrated that a 200 mg daily dose had a plasma half-life of 7.5 to 8 hours and an intracellular half-life for FTC-triphosphate of approximately 39 hours.
The results of a Phase I trial released in February 1998 showed the maximal tolerated dose. Over 14 days, five cohorts of eight patients each received separate escalating doses of FTC (25 mg bid, 100 mg qd, 200 mg qd, 100 mg bid or 200 mg bid). Differences in HIV suppression between cohorts allowed for the initial selection of a dose in trials. Plasma and intracellular drug levels were used to correlate antiviral activity and nucleoside pharmacology. 200 mg QD of FTC appeared to have potent antiviral activity in humans. This dose was chosen in June 1998. The most frequently observed adverse experiences seen were headache, nausea/vomiting, and diarrhea.
Summary of Phase I/II studies
|
Effect in HIV infection |
Experimental model |
Result |
Reference |
| Double-blind, randomised, placebo-controlled PK and oral bioavailability | 18 HIV+ patients receiving six single oral doses of 100 to 1200 mg of FTC at 6 day intervals | Maximum plasma concentration within 3h. Renal excretion, T1/2 < 4h. In the doses studied, there were no reports of adverse reactions. No food effect. | 524W91. Painter GR et al, Drugs Future, 1995 20; 8:761-765. |
| Phase I/II randomised determination of optimal dose of FTC for pivotal combination clinical studies | 80 HIV+ patients receiving 3 doses of FTC, 25, 100 or 200 mg/day or standard dose of lamivudine (150 mg BID) for 10 days | All regimens active. At 200 mg/day, 58% had either a 2log10 drop in viral load or to below detection; 21% had both. | Submitted to JID. In press. |
| Phase I/II, open label, pilot study. Once-a-day HAART regimen of FTC and other antiretroviral agents | 40 HIV+ patients received FTC (200 mg) with ddl (250 to 400 mg) and efavirenz (600 mg) once daily for 24 weeks | ITT NC=F analysis: 98% of patients < 400 copies/mL; 93% < 50 copies/mL at Week 24 | Molina JM, JID 2000; 182:599-602 |
Results of a comparison between FTC and 3TC were presented in Feb ’99. 81 naïve patients with an average of 437 CD4+ cells/mm3 and a mean viral load of 4.4 log10 were randomised between 3 different doses of FTC (25, 100 or 200 mg QD) and one dose of 3TC (150 mg BID). FTC at 200 mg QD had a significantly greater antiviral activity than 3TC as measured by AAUCMB over the study period on slope of RNA decay over the first week of treatment. At the end of the study, HIV RNA decreases from baseline were respectively 1.45, 1.48, 1.60, 1.70 log10 for 3TC 150 mg BID, FTC 25, 100 and 200 mg QD. FTC at both 25 and 100 mg QD had similar antiviral activity to 3TC 150 mg BID.
Phase I/II trials selected HIV strains resistant to the investigational product, because their design consisted of an initial period of monotherapy. According to the researchers, using information on HIV-1 dynamics and observed rates of resistance to other cytidine nucleoside analogues allows rapid assessment of preliminary antiviral efficacy and minimises patient risk.
4. Side effects
Because FTC is a cytidine analogue, the side effects are minimal compared to most antiretroviral drugs, and it can be compared to 3TC, quite possibly the least toxic antiretroviral there is.
Mitochondrial toxicity is not an issue with this sub-class. Among the cytidine analogues tested (triphosphate derivatives of zalcitabine, lamivudine, and emtricitabine), FTC, an enantiomer of 3TC, was incorporated 24-fold less readily into the human mitochondrial DNA polymerase than was 3TC, therefore unlikely to react with any human protein. If there is cellular toxicity, it is not through the mitochondrial mechanism.
FTC-301: FTC versus d4T
This randomised double blind, double-dummy trial compared FTC to d4T in treatment-naïve individuals. Background regimen included open label ddI QD and efavirenz (EFV) in both arms. 571 participants were included. Baseline characteristics were similar between the two groups. Overall, 85% of the participants were male, and 52% were caucasian, 26% hispanic, 16% black, 6% other. Median HIV RNA at baseline was 4.9log10 copies/mL, and median CD4 was 288 cells/mm3. 45% lived in the US, 33% in Latin America and 21% in Europe. This was a direct efficacy and tolerability comparison with d4T BID.
Results
|
Table 1: patient disposition at week 48 |
FTC N (%) |
d4T N (%) |
Total N (%) |
P |
| ITT population | 286 | 285 | 571 | |
| Completed week 48 (of ITT population) | 237 (82.9%) | 207 (72.6%) | 444 (77.8%) | < 0.01 |
| Premature discontinuation | 49 (17.1%) | 78 (27.4%) | 127 (22.2%) | < 0.01 |
| Adverse event | 16 (5.6%) | 33 (11.6%) | 49 (8.6%) | < 0.05 |
| Treatment Failure | 8 (2.8%) | 22 (7.7%) | 30 (5.3%) | < 0.01 |
| Lost to follow-up | 9 (3.1%) | 12 (4.2%) | 21 (3.7%) | NS |
| Request for withdrawal | 5 (1.7%) | 4 (1.4%) | 9 (1.6%) | NS |
| Protocol violation | 7 (2.4%) | 2 (<1%) | 9 (1.6%) | NS |
| Study medication on-compliance | 2 (<1%) | 3 (1.1%) | 5 (<1%) | NS |
| Other | 2 (<1%) | 2 (<1%) | 4 (<1%) | NS |
|
Table 2: efficacy results at week 48 |
FTC N=286 |
d4T N=285 |
p |
| % HIV RNA < 400 copies/mL | 80.2 | 67.0 | < 0.001 |
| % HIV RNA < 50 copies/mL | 74.2 | 58.0 | < 0.0001 |
| % virological failure (RNA > 400 at week 12 or after achieving success) | 5.3 | 12.7 | < 0.01 |
| CD4 increase from baseline (cells/mm3) | + 153 | + 119 | < 0.05 |
Triangle defined a composite criteria of virologic failure, death, progression to CDC class C or loss to follow-up, which is not a “standardized” category. This was an endpoint requested by the FDA in one of the earlier FTC protocols and was used as a protocol defined secondary endpoint in FTC study 301.
Through 24 weeks of treatment, both study medications were well tolerated with no difference between treatment arms in the proportion of subjects experiencing serious adverse events. There were 4 adverse events that were observed more frequently in the d4T arm (diarrhea, nausea, paresthesia, and symptomatic hyperlactatemia/lactic acidosis). There was one adverse event that was more commonly seen in the FTC arm (increased cough).
|
Table 3: safety results at week 24 |
FTC N=286 |
d4T N=285 |
P |
|
Clinical |
|||
| Infection | 26% | 28% | NS |
| Diarrhea | 23% | 31% | 0.03 |
| Dizziness | 23% | 25% | NS |
| Headache | 20% | 24% | NS |
| Rash | 20% | 22% | NS |
| Insomnia | 16% | 22% | NS |
| Nausea | 13% | 20% | 0.02 |
| Pain | 13% | 18% | NS |
| Abnormal dreams | 11% | 19% | < 0.01 |
| Abdominal pain | 12% | 15% | NS |
| Asthenia | 11% | 16% | NS |
| Pharyngitis | 13% | 13% | NS |
| Increased cough | 12% | 6% | 0.01 |
| Paresthesia | 4% | 10% | 0.005 |
| Lactic acidosis | 0% | 2% | 0.02 |
|
Metabolic parameters and blood analysis abnormalities |
|||
| Creatine kinase elevation | 10% | 11% | NS |
| Triglycerides | 9% | 6% | NS |
| AST | 5% | 8% | NS |
| ALT | 4% | 6% | NS |
| Neutrophils | 5% | 6% | NS |
| Glycemia | 1% | 2% | NS |
| Serum amylase (pancreatitis) | 3% | 9% | 0.002 |
At the time of the Week 48 analysis, 13% d4T and 4.5% FTC reported neuropathy. This data has not yet been published. The high incidence of dizziness and rash was probably related to efavirenz. There is no hypothesis to explain the significant difference in the incidence of cough.
These two figures show time to loss of virological response (above) and time to permanent discontinuation of medication due to adverse event (below). They both indicate less failures and less AEs in the FTC containing arm.
Of note, because this was a placebo-controlled study vs a BID drug, it was not a QD vs BID protocol. The protocol required 3 pills QD + 4 pills BID.
5. Resistance and cross resistance
FTC-302: FTC versus 3TC
FTC-302 was conducted at 16 sites in South Africa. In April 2000 the trial was put on hold by the FDA due to a higher than expected incidence of liver toxicity (two deaths). Further evaluation determined that the deaths resulted from the coadministered
nevirapine, and the trial resumed in October 2000. Gilead is requesting that this data not be used in the FDA’s final analysis. In any case, 302 is a good trial to analyze resistance and cross resistance due to its head-to-head character with 3TC, hepatic
issues notwithstanding.
The Kaplan-Meier probability of virological failure with genotypic mutation through Week 48 in Study FTC-302 was identical (10%) in both treatment groups (FTC and 3TC).
The incidence of drug resistant mutations with HIV-1 genotype corresponding to the NRTI and the NNRTI study medications in subjects who were confirmed virological failures was evaluated and compared between treatment arms and are shown in the
Table below.
|
Table: Results of Genotypic Analysis |
|||||
|
Mutation Position |
FTC (N=33) |
3TC (N=23) |
P-Value* |
||
| At Least 1 | 24 | (73%) | 20 | (87%) | 0.32 |
| None | 9 | (27%) | 3 | (13%) | 0.03 |
| M184 | 10 | (30%) | 15 | (65%) | 0.01 |
| G190 | 9 | (27%) | 7 | (30%) | 1.00 |
| E138 | 1 | (3%) | 0 | (0%) | 1.00 |
| K101 | 2 | (6%) | 2 | (9%) | 1.00 |
| K103 | 12 | (36%) | 13 | (51%) | 0.18 |
| Y181 | 5 | (15%) | 6 | (26%) | 0.33 |
| Y188 | 1 | (3%) | 1 | (4%) | 1.00 |
| V106 | 2 | (6%) | 3 | (13%) | 0.39 |
| V108 | 1 | (3%) | 2 | (9%) | 0.56 |
| TAMS** | 1 | (3%) | 1 | (4%) | 1.00 |
| NNRTI + M184 | 10 | (30%) | 15 | (65%) | 0.01 |
| * Fisher’s exact test ** Includes M41, D67, K70, T215, K219 and V75. |
|||||
Of the virologic failures in the FTC treatment arm, 30% had developed the M184V mutation, while 65% of the failures in the 3TC treatment arm developed a mutation at M184V. The difference was statistically significant (p=0.01). The frequency of mutations associated with resistance to the NNRTIs was somewhat higher, although not statistically significant, in the FTC arm. Overall, 73% of confirmed virologic failures in the FTC arm and 87% of the failures in the 3TC arm developed mutations to at least one study drug.
By comparing the ratio of M184V mutations to NNRTI mutations within the virologic failures of each treatment arm, one is able to use the incidence of NNRTI mutations as an internal control for exposure to treatment regimens. Differences in the potency of the study medications as manifested by the selection of HIV-1 mutations may be compared between treatment arms after adjusting for exposure. The table below presents the M184V/NNRTI ratios for each treatment arm, as well as the 3TC/FTC Odds Ratio.
|
Table: Odds Ratio Between Treatment Groups in the Incidence of M184V to NNRTI Mutations |
||
|
Treatment Group |
||
|
3TC (N=23) |
FTC (N=33) |
|
| M184V mutation | 15 | 10 |
| NNRTI mutation | 20 | 24 |
| Ratio M184V/NNRTI | 0.75 | 0.42 |
| Odds Ratio (95% CI) 3TC/FTC |
1.79 |
|
The 3TC/FTC Odds Ratio was 1.79 and suggests that people failing the 3TC regimen were 1.79 times more likely to acquire the M184V mutation than were those who failed the FTC regimen.
Cross Resistance
FTC-resistant isolates of HIV have been selected in vitro. Genotypic analysis of these isolates showed that the reduced susceptibility to FTC was associated with a mutation in the HIV reverse transcriptase gene at codon 184 which resulted in an amino acid substitution of methionine by valine or isoleucine (M184V/I).
FTC-resistant isolates of HIV have also been recovered from patients treated with FTC alone or in combination with other antiretroviral agents. Genotypic analysis of these isolates showed that the resistance was due to the M184V/I mutation in the reverse transcriptase gene. These isolates are cross-resistant to lamivudine and zalcitabine
(ddC).
An unanswered question is: What is the efficacy of being on a regimen aiming at maintaining selective pressure on the 184V?
6. Efficacy studies
In FTC-301, antiretroviral-naive HIV+ people with viral loads > 5000 copies/mL were randomized to receive FTC QD or d4T BID and matching placebo, as well as open-label Videx EC (ddI) and efavirenz (EFV). Study endpoints included measurement of viral failure, the frequency of genotypic mutations at time of failure and the CD4+ change from baseline between the two arms. The primary measure of analysis for this study was the % of patients with plasma HIV-1 RNA < 50 copies/mL at Week 48. The study was powered to be able to demonstrate equivalence between FTC and d4T within 12.5% as well as to detect differences between treatment arms of 15%.
571 people were randomized and received at least one dose of randomized study medication. At baseline, the median viral load was 4.9 log copies/mL and the median CD4+ count was 288 cells/mm3. The proportion of people having viral failure through Week 48 was 5.3% in the FTC arm and 12.7% in the d4T arm (p < 0.01). The mean increase from baseline to Week 48 in CD4+ was significantly greater in the FTC arm (+153 cells/mm3) than the d4T arm (+120 cells) (p < 0.05). Also measured wasefficacy
failure-defined as virologic failure, death, progression to CDC class C event, or loss to follow-up-which occurred in 18% of people in the d4T group and 9% of people in the FTC group through Week 48 (p < 0.01). In terms of the proportion of people with undetectable viral loads at Week 48 using an intent-to-treat, non-completer equals failure analysis: 80% in the FTC group and 67% in the d4T group had viral loads below 400 copies/mL (p < 0.001), and for plasma viral load < 50 copies/mL, 74% FTC, compared to 58% d4T, got there after 48 weeks of treatment (p < 0.0001).
Genotypic analysis was performed on all of the 49 confirmed VFs through Week 48 (35 d4T, 14 FTC). Of the 35 genotypic evaluables failing d4T, 34 (97%) had mutations in the HIV polymerase gene as compared to 71% (10/14) from the FTC subgroup (p=0.019). The M184V mutation was observed only in the FTC subset, 43% (6/14), while TAMs were observed in 7% (1/14) of the FTC arm and 20% (7/35) of the d4T group.
Although these results show that FTC was statistically superior to d4T, it is worth note that the combination ddI + d4T is not regularly recommended now in 2003.
In another non-inferiority study, the French ANRS 099 or ALIZE, people receiving a PI-based regimen with plasma HIV-RNA levels < 400 copies/mL were randomized to continue their regimen (C arm) or to switch to once-daily combination (5 pills per day) of FTC, ddI, and efavirenz (QD). Intent-to-treat on available data (ITT), on treatment on available data (OTT) and intent-to-treat with missing = failure (M=F) analyses were conducted.
A total of 355 people were randomized; 86% were male with a median age of 41, a median duration of PI use of 35 months, and a median CD4 count of 540 cells/mm3. Of course, today, at 540 CD4s, these people would probably be offered a treatment interruption of some sort instead of rolled into another new treatment protocol of 48 weeks. The proportion (98%) of people with virologic success at Week 48 is shown below.
|
Analysis |
C arm |
QD arm |
Difference C-QD |
ULC |
| ITT | 92% | 94% | -1.6 | 3.0 |
| M=F | 88% | 89% | -1.8 | 3.8 |
There was a statistically significant difference in the proportion of people having plasma HIV-1 RNA < 50 at Week 48 (95% on QD vs. 87% on C, p=0.01). The median CD4 count increase was similar between arms. Rates of treatment discontinuations were “low” and not statistically different, 12.4% and 10.1%. A significant increase in median fasting HDL cholesterol levels was observed in the QD arm as compared to the C arm. Other metabolic parameters remained similar between arms throughout the 48 weeks of the study. People who simplified to this once daily regimen had an improved outcome compared to subjects reamaining on the more complex PI-based regimens.
FTC-303 was a randomized, 48-week, open label equivalence trial in which people with HIV-1 RNA = 400 copies/mL either continued their 3TC regimen or switched 3TC 150 mg BID to FTC 200 mg QD while continuing the other medications in their regimen. People with plasma HIV-1 RNA = 400 copies/mL at Week 48 were offered FTC as part of their HAART regimen in protocol FTC-350.
Out of 294 people originally randomized to FTC in study 303, 227 (77%) had HIV-1 RNA = 400 copies/mL at Week 48. Of these, 215 continued in rollover study FTC-350; 152 of 294 (51%) maintained suppression of HIV-1 RNA = 400 copies/mL and 139 (47%) = 50 copies/mL through Week 120 (2.3 yrs). Through a median follow-up of 4 years, the probability of virologic failure (>400 copies/mL) was 11% while prescribed FTC. FTC was well tolerated throughout the study. The probability of treatment limiting adverse events was < 13% at year 4 of follow-up. The annualized rate of the most common treatment-emergent Grade 3 or Grade 4 laborabory abnormalities was 7% for creatine kinase and 5% for hypertriglyceridemia, with the annualized rate of all other laboratory abnormalities < 2% after 4 years of follow-up. Asymptomatic and transient elevations in CPK accounted for more than 2/3 of the overall Grade 4 adverse events. Everyone continued on the background regimen that was part of the stable 3TC regimen at the start of FTC-303. This regimen included AZT or d4T as well as an
NNRTI or a PI.
7. Studies to be done
• A PK assessment in people with different stages of hepatic impairment should be
done.
• Is there a clinical benefit to keeping the 184V active?
• Because the half-life is so long, should FTC be stopped before the other drugs,
not unlike the NNRTIs? In time-sensitive STIs (rather than clinically-sensitive), what
is the role for FTC or any long half-life drug?
ACTG studies 5015 (accelerated disease and aging) and 5073 (a DOT study) are fully enrolled and should be reporting results soon.
8. Expanded access
There has been no expanded access with this drug. We would like to express our sadness at the sponsor’s not having taken the opportunity of using this drug in real life before approval. Even open-label pseudo-expanded access (where the issue is not the life and death of patients) would have been helpful in better defining some of the few outstanding questions found in section 7 of this paper, i.e., is maintenance of the 184V clinically helpful? If so, in what circumstances?
The author would like to thank Francois Houyez for his help on this paper.
The following organizations and individuals have signed on to this paper along with Treatment Action Group:
[list in formation]• AAPNW (AIDS Action Project Northwest), Portland, Oregon
• AAPNW (AIDS Action Project Northwest), Portland, Oregon
• AIDS Action Baltimore
• AIDS ACTION, Washington DC
• AIDS Treatment Activists Coalition, USA
• AIDS Treatment Data Network, New York, New York
• The Center for AIDS, Hope & Remembrance Project, Dallas, Texas
• CHAMP (Community HIV/AIDS Mobilization for Power), Philadelphia, Pennsylvania
• Gay Men’s Health Crisis (GMHC), New York, New York
• HIV Advocacy Council of Oregon and SW Washington, Portland, Oregon
• IFARA (International Foundation for Alternative Research in AIDS), Portland, Oregon
• Positives For Positives, Cheyenne, Wyoming
• Program for Wellness Restoration, PoWeR, Texas
• Project Inform, San Francisco, California
• Search for a Cure, Boston, Massachusetts
• Test Positively Aware Network, Chicago, Illinois
• Ken Formataro, New York, New York
• Carlton Hogan, University of Minnesota
• Melvin Littles, New York, New York
• Robert J. Munk, Arroyo Seco, New Mexico
• Tracy Swan, New York, New York
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