Application for Inclusion of Emtricitabine On WHO Model List of Essential Medicines. Submitted By. Gilead Sciences, Inc. Foster City, California, USA

Transcription

1 Application for Inclusion of Emtricitabine On Submitted By Foster City, California, USA 28 October 2004 Contact Person: Daniel E. Kates, M.D. Director Medical Communications 333 Lakeside Drive Foster City, CA USA Phone: Fax: dkates@gilead.com

2 2 Application for Inclusion of Emtricitabine on Drug is a member of the therapeutic class of HIV nucleoside analogue reverse transcriptase inhibitors 1. Summary statement of the proposal for inclusion, change or deletion: Emtricitabine is proposed for inclusion in the WHO Model list of essential medicines in combination with other antiretroviral agents for the treatment of HIV-1 infection. 2. Name of the focal point in WHO submitting the application: Jos Perriëns MD Director Care HIV/AIDS Department World Health Organisation 3. Name of the organisation(s) consulted and/or supporting the application: Not applicable. 4. International Nonproprietary Name: emtricitabine 5. Listing type requested: Listing is requested on the Model List of Essential Medicines as an example of the therapeutic class of HIV nucleoside analogue reverse transcriptase inhibitors. Other members of this class of drugs may serve as alternatives, depending on quality, price and local availability. 6. Information supporting the public health relevance of the submission: 6.1. Epidemiological information on disease burden The impact of HIV continues to erode economies, devastate communities, and exhaust already fragile healthcare systems in the developing world. In developing countries, about one third of the population billion people - live on incomes of less than USD 1.00 a day. Almost 1 in 3 children is malnourished, and 1 in 5 is not fully immunized by their first birthday. In addition, over one third of the world's population lacks access to essential

3 3 drugs. 1 As a result, most deaths from infectious diseases occur in developing countries - countries with the least money to spend on health care. Since the first clinical evidence of AIDS was reported over 20 years ago, an estimated 25 million people have died as a result of HIV infection. Current estimates suggest that approximately 40 million people worldwide are infected with HIV and more than 90% of all HIV-infected people live in the developing world. 2 In 2001, 5 million individuals worldwide became infected with HIV, and 3 million others died from HIV/AIDS-related causes. The worst affected area is Sub-Saharan Africa. In some countries, up to 1 in 4 of the adult population is now living with HIV/AIDS. In some areas of Zimbabwe, 20%-50% of pregnant women are infected with HIV and risk infecting their newborns. In addition, an increasing number of maternal deaths are now due to infections contracted by HIVpositive women during delivery. In many countries, life expectancy and child survival rates have plummeted. For example, in Botswana life expectancy at birth has fallen from 70 to around 50 years. 3 Eastern Europe particularly the Russian Federation continues to experience the fastest-growing epidemic in the world. In 2001, there were an estimated 250,000 new infections in this region, bringing the total number of people living with HIV to 1 million. In Asia and the Pacific, approximately 1 million people became infected in 2001; about 7.1 million individuals in this region are now living with HIV/AIDS. 4 Even more staggering, is the fact that 1.8 million people in Latin America and the Caribbean are living with HIV/AIDS. This number includes 190,000 adults and children who were diagnosed in In countries already burdened by huge socio-economic challenges, HIV/AIDS threatens human social welfare, developmental progress and social stability on an unprecedented scale. HIV/AIDS continues to cripple the economic development of entire countries, because it often strikes people during their most productive period of life. 3 For example, of the 14,000 persons who became infected each day in 2001, about 12,000 (86%) were aged 15 to 49 years. 5 The introduction of potent antiretroviral agents and the combined use of these drugs have markedly reduced the replication of HIV in many patients, and improved survival rates. Highly active antiretroviral therapy (HAART) is now the standard of care in the treatment of HIV infection. It is successful in reducing viral load and extending the asymptomatic phase of infection and improving the quality of life for many infected individuals Assessment of current use The primary goals of antiretroviral therapy are maximal and durable suppression of viral load, restoration and/or preservation of immunologic function, improvement of quality of life, and reduction of HIV-related morbidity and mortality. 7 Suppression of viral load as much as possible for as long as possible is an important and achievable goal of antiretroviral therapy. However, this goal must be balanced against the need to preserve effective treatment options. The presence of breakthrough resistant (virus) mutations in

4 4 treatment-experienced patients is a strong predictor of virologic failure and disease progression. An emerging challenge in regard to the successful long-term management of HIV/AIDS is the increasing prevalence of drug resistance. Recently, it has been reported that the development of drug resistance to any class of antiretroviral drug may be as high as 50% in certain cohorts. Moreover, it has also been shown that in the presence of detectable viremia, resistance to the nucleoside analog reverse transcriptase inhibitors (NRTIs) could be detected in up to 70% of patients. 8 The development of resistance leads to decreased susceptibility to other NRTIs through cross-resistance, which limits viable treatment options. This is an increasing problem as patients stay on therapy longer. This problem is further complicated by the fact that resistant virus can be transmitted to others. 9 The development and transmission of resistance-conferring mutations is also associated with a sub-optimal virologic response to initial antiretroviral therapy. 10 This may contribute to increased levels of cross-resistance within NRTIs, which are the backbone of HIV therapy. Cross-resistance also compromises the availability of future treatment options for subsequent courses of therapy in the aftermath of drug resistance. Furthermore, the extent of cross-resistance has also been shown to increase commensurate with the accumulation of additional drug resistance mutations. 11 Taken together, these findings point to the urgent need for novel and improved antiretroviral agents. These agents should have a more robust genetic barriers for the development of drug resistance and a broader spectrum of antiviral activity against HIV-1 strains, harboring resistance mutations in reverse transcriptase that confer diminished susceptibility to several of the currently licensed NRTIs. Current treatment strategies and guidelines recommend selecting potent regimens from all currently available classes of ARVs to maximize suppression of viral load and to minimize the replication and emergence of drug-resistant virus. Despite the improvements in morbidity and mortality, a substantial number of patients do not achieve adequate suppression of HIV-1 viral load Target population In contrast to earlier examples regarding developing countries, an estimated 1.5 million people are living with HIV in high income countries. In the US, the introduction of triple drug therapy in 1996 led to a decline of 42% in deaths attributable to HIV/AIDS in Therefore, new ARVs are needed in order to individualize therapy for patients who cannot tolerate, adhere to, or who are currently failing, antiretroviral therapy. As patients remain on effective therapies for longer periods of time, there is an urgent need for drugs with simpler dosing regimens, improved adverse event profiles, and potent and durable antiviral effects with a decreased propensity for the development of drug resistance The viability, efficacy and tolerability associated with antiretroviral therapy have been adequately demonstrated in a number of clinical programs worldwide. For example, in

5 5 Brazil, the policy of universal access to antiretroviral drugs has reduced the number of AIDS-related deaths by nearly 50% and cut the incidence of opportunistic infections by 60% to 80%. 13 Between 1997 and 2000, Brazil saved approximately USD 677 million in averted hospitalizations and treatment of HIV-related infections. In Argentina a program similar to that of Brazil provides even greater access to ARVs. A special fund has been established to pay for antiretroviral drugs for those not covered by social security (such as street vendors, small business people, the unemployed and lowincome pregnant women). 14 Through the UNAIDS Drug Access Initiative Pilot Program, 6 treatment centres in Abidjan, Côte d Ivoire, offer antiretroviral therapy. Of the patients who received therapy, 72% were heavily symptomatic upon initiation. Nonetheless, the overall survival rate was 93% at 6 months, 90% at 12 months, and 86% at 18 months. When survival rates are recalculated using a worst-case scenario in which patients lost to follow-up are assumed to have died immediately after their last clinic visit, 75% survived at 6 months, 64% at 12 months, and 55% at 18 months. 15 With constantly emerging data from high and mid-income countries supporting the use of ARVs in developing countries, along with the continued evolution of improved funding and delivery mechanism to resource-limited countries, the above factors clearly support the addition of Emtriva to the. 7. Treatment details: Recommended Dosage: Due to a difference in the bioavailability of emtricitabine between the capsule and oral solution, 240 mg emtricitabine administered as the oral solution (24 ml) should provide similar plasma levels to those observed after administration of one 200 mg emtricitabine capsule. Adult: The dose of emtricitabine in adults is 200 mg once daily taken orally in combination with other antiretroviral agents, without regard to food. Infants, children and adolescents up to 18 years of age: The recommended dose of emtricitabine 10 mg/ml oral solution is 6 mg/kg up to a maximum of 240 mg (24 ml) once daily taken orally in combination with other antiretroviral agents, without regard to food. Children who weigh at least 33 kg may either take one emtricitabine 200 mg capsule daily or emtricitabine 10 mg/ml oral solution up to a maximum of 240 mg once daily (QD) in combination with other antiretroviral agents, without regard to food. Elderly: No data are available on which to make a dose recommendation for patients over the age of 65 years. However, no adjustment in the recommended daily dose for adults should be required unless there is evidence of renal insufficiency.

6 6 Renal insufficiency: Emtricitabine exposure may be markedly increased in patients with moderate or severe renal insufficiency (creatinine clearance < 50 ml/min) receiving daily doses of 200 mg emtricitabine capsules or 240 mg as the oral solution. Either a dose interval adjustment using emtricitabine 200 mg capsules or a reduction in the daily dose of emtricitabine 10 mg/ml oral solution is required in all patients with creatinine clearance < 50 ml/min. The safety and efficacy of the dose interval adjustment guidelines provided in Tables 1 and 2 are based on single dose pharmacokinetic data and modelling and have not been clinically evaluated. Therefore, clinical response to treatment and renal function should be closely monitored in patients treated with emtricitabine at prolonged dosing intervals. No data are available on which to make a dosage recommendation in paediatric patients with renal insufficiency. Table 1. Dosing Interval Adjustment in Patients with Renal Impairment Emtricitabine 200 mg Capsule Creatinine Clearance (ml/min) < 15 (including patients requiring haemodialysis)* Recommended 200 mg Dosing Interval Every 24 hours Every 48 hours Every 72 hours Every 96 hours *Assumes a 3h haemodialysis session three times a week commencing at least 12h after administration of the last dose of emtricitabine. Table 2. Dosage Adjustment in Patients with Renal Impairment Emtricitabine 10 mg/ml Oral Solution Creatinine Clearance (ml/min) < 15 (including patients requiring haemodialysis)* Recommended dose of emtricitabine 10 mg/ml oral solution every 24 hours 240 mg (24 ml) 120 mg (12 ml) 80 mg (8 ml) 60 mg (6 ml) * Assumes a 3h haemodialysis session three times a week commencing at least 12h after administration of the last dose of emtricitabine. Formulations: Emtricitabine 200 mg capsules and 10 mg/ml oral solution Concomitant Antiretroviral Therapy: Emtricitabine must be given in combination with other antiretroviral medications. Duration: Antiretroviral treatment is usually regarded as life-long, with the exceptions of post-exposure prophylaxis, and for the prophylaxis of infants of HIV-infected mothers.

7 7 Guidelines: Emtricitabine was approved by the US FDA on 02 July 2003 and in the European Union on 24 October The International AIDS Society-USA (IAS) Treatment Recommendations for Adult HIV Infection were updated in July 2004 to include emtricitabine as a component of first line antiretroviral therapy regimens containing double NRTI. 16 The recommended double NRTI backbones in the initial regimen are zidovudine plus emtricitabine or lamivudine; tenofovir plus emtricitabine or lamivudine; or emtricitabine plus didanosine. Of note, it is also recommended that emtricitabine plus didanosine can be used with efavirenz when once daily regimens are necessary. Additionally, as of 10 November 2003, emtricitabine was included in the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents issued by the US Department of Health and Human Services (DHHS). Currently, emtricitabine is recommended as a component of first line alternative regimens for NNRTI-based or PI-based ARV regimens in the US DHHS Guidelines. 7 Alternative regimens refer to regimens for which clinical trial data show efficacy, but are considered alternative due to possible disadvantages compared to the preferred regimens in terms of antiviral activity, demonstrated durable effect, tolerability, or ease of use. In some cases, based on individual patient characteristics, a regimen listed as an alternative regimen in the table may actually be the preferred regimen for a selected patient. Of note, the designation of regimens as preferred or alternative may change as new safety and efficacy data emerge, which, in the opinion of the expert panel, warrants reassignment of regimens in these categories. Special Requirements: Adequate resources for monitoring and specialist oversight are a pre-requisite for the introduction of this class of drugs. Monitoring Parameters: Therapeutic: Periodic determinations of plasma HIV RNA (viral load) and CD4 cell count, hepatitis B prior to initiation of therapy, and periodic determinations of HBV DNA Toxic: Complete blood counts and routine serum chemistry periodically during therapy, signs and symptoms of toxicity (eg, skin rash, gastrointestinal symptoms) 8. Comparative effectiveness in clinical settings: 8.1 Identification of clinical evidence In compiling the evidence for the submission for inclusion of emtricitabine on WHO Model List of Essential Medicines, a search of several databases, including MEDLINE, EMBASE, BIOSIS Previews, and SciSearch, was conducted. Because emtricitabine was recently approved in 2003, we have also included data from trials that provided data and insights that may not normally be available from systematic reviews.

8 Details of literature searches conducted: The databases searched were: o MEDLINE o EMBASE o SciSearch o BIOSIS Previews Search terms included: o Emtricitabine o FTC o BW524 o BW524W91 o 524W91 o Coviracil o Emtriva 8 Study selection: o Randomized, double-blind, multicentre, Phase 3 clinical trials of emtricitabine in HIV-infected adults o Other clinical studies that examined the use of emtricitabine in HIV-infected adults and paediatric patients 8.2 Summary of available data Emtricitabine is indicated, in combination with other antiretroviral agents, for the treatment of human immunodeficiency virus type-1 (HIV-1) infected adults. Emtricitabine is a synthetic analogue of cytidine. As a nucleoside analogue, emtricitabine is efficiently and selectively incorporated into the growing chains of viral DNA with potent activity against HIV-1 and HIV-2 virus. Antiretroviral therapy requires combined potent and sustained efficacy with acceptable tolerability and practical dosing regimens. Emtricitabine exhibits distinct biological characteristics that help meet these requirements. Structurally, emtricitabine is most similar to lamivudine (3TC), which is another analogue of cytidine. Following absorption, emtricitabine is rapidly converted intracellularly to the active triphophate form, which inhibits viral replication by acting as a substrate for HIV-1 RT. Emtricitabine is incorporated into the growing DNA chain; however, it contains structural differences that prevent Reverse Transcriptase (RT) from incorporating any additional deoxynucleotide TriphosPhates (dntps), such as deoxycytosine triphosphate, into HIV DNA. This chain termination prevents DNA synthesis and viral replication. Emtricitabine has demonstrated potent in vitro antiretroviral activity against HIV. The mean IC 50 and IC 90 of emtricitabine are and µm (or and µg/ml),

9 9 respectively, in clinical isolates of HIV Emtricitabine has a much lower IC 50 than does 3TC for most HIV-1 isolates analysed in naturally infected or transfected cells. The most commonly identified mutation that confers resistance to emtricitabine is M184V mutation. The M184V mutation also confers resistance to lamivudine and zalcitabine, but retains sensitivity to tenofovir DF, zidovudine, stavudine (d4t), abacavir, didanosine (ddi), and Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs). However, in vitro, the M184V mutation develops more slowly with emtricitabine than with lamivudine. 18 Additionally, it has been shown that M184V, K103N, and Y181C mutations developed less frequently in patients treated with emtricitabine than in those treated with lamivudine. 19 The M184V mutation occurs in approximately 65% of patients who experience virologic failure following lamivudine therapy and in only approximately 35% patients treated with emtricitabine with virologic failure. 20 Plasma emtricitabine concentrations decline in a multi-exponential manner, with a halflife of approximately 10 hours. At 24 hours post-dose, the plasma concentrations exceed the mean in vitro IC 90 by about 4-fold and remain above in vitro IC 90 for wild-type virus 84 hours after a 200 mg dose at steady state. Furthermore, the intracellular half-life of the active form of emtricitabine is approximately 39 hours. The extended half-life of emtricitabine in plasma, as well as the long intracellular half-life of emtricitabine triphosphate, allows for once daily dosing to provide continued viral suppression with a forgiving dosing regimen. 21 Simplifying HIV treatment regimens using once daily antiretroviral drugs may improve adherence and therapeutic outcomes. The principal clinical studies that demonstrate the clinical efficacy of emtricitabine 200 mg once daily in treatment-naïve and treatment-experienced HIV-infected patients are summarized and described in the following sections. Additional details are provided in Attachment Summary of clinical data Results from the clinical program to date demonstrate that emtricitabine in combination with other antiretroviral agents, including NRTIs, NNRTIs and PIs, is effective in treatment of HIV infection in treatment-naïve and treatment-experienced patients. Treatment-naïve patients treated with emtricitabine 200 mg QD had superior efficacy responses after 48 weeks and after 60 weeks of treatment compared to patients treated with stavudine. Both arms contained a background regimen of once-daily didanosine and efavirenz (Study FTC-301A). Patients on a stable PI-based HAART regimen who simplified their treatment to an entirely QD emtricitabine-based regimen had similar virologic outcomes for HIV-1 RNA < 400 copies/ml and significantly better outcomes for plasma HIV-1 RNA < 50 copies/ml after 48 weeks compared to those who remained on a more complex PIbased regimen (Study ANRS-099 [ALIZE]).

10 10 In patients on a stable lamivudine-containing HAART regimen, switching to emtricitabine 200 mg QD demonstrated comparable efficacy compared to continuing lamivudine 150 mg BID through 48 weeks of treatment. Both medications were given in combination with a NRTI and a PI or NNRTI (Study FTC-303). Long-term data (4 years) have demonstrated that emtricitabine-treated patients have durable suppression of plasma HIV RNA levels with a Kaplan-Meier probability of virologic failure equal to 11% through the fourth year of follow-up (Study FTC-350) Summary of comparative effectiveness in HIV-infected Adults Treatment-naïve patients Clinical efficacy in antiretroviral treatment-naïve HIV-infected patients has been demonstrated based on significant changes in established and validated surrogate markers for HIV-1 disease (plasma HIV-1 RNA levels) and immune competence (CD4 cell count), following up to 3 years of treatment with emtricitabine in combination with didanosine (ddi) and efavirenz. Study FTC-301A (Pivotal Trial) Study FTC-301A was a 48-week, randomised, double-blind, double-dummy, multicenter study comparing emtricitabine 200 mg QD to stavudine 40 mg BID with a background regimen of didanosine (400 mg QD if 60 kg, 250 mg QD if < 60 kg) and efavirenz (600 mg QD) in antiretroviral-naïve HIV-infected adults with plasma HIV RNA levels > 5,000 copies/ml and Karnofsky score > ,22,23 Patients were excluded if they had severe hepatic, hematologic, or pancreatic abnormalities at screening. Randomization was stratified based on plasma HIV-1 RNA levels < or 100,000 copies/ml. The primary endpoint was persistent virological response, which was analyzed as the percentage of subjects with plasma HIV-1 RNA levels below the lower limit of quantification of the assay used (< 50 copies/ml for the Roche Amplicor Untrasensitive Test). This end point followed the US Food and Drug Administration (FDA) time to loss of virologic response (TLOVR) algorithm, which considered a patient as a nonresponder at the earliest time point of the following events: death (all reasons), permanent discontinuation of study drug, loss to follow-up, having 2 consecutive viral load values above the limit of assay quantification after having achieved the limit of assay quantification (loss of response), or never achieving suppression of viral load at the lower limit of assay quantification (lack of response). Secondary endpoints were the percentages of patients experiencing confirmed virologic failure (viral load > 400 copies/ml at Week 12 or thereafter), efficacy failure (defined as virologic failure, death, progression of disease [defined as a development of a new clinical event included in Category C of the 1993 classification of the US Centres for Disease Control and Prevention, 24 or death due to any cause], or loss to follow-up), and tolerability failure (defined as permanent discontinuation of the blinded medication due to an adverse event).

11 11 A total of 580 patients were randomized between August 21, 2000 and November 22, Nine patients never received study drug because they did not return for the baseline visit; therefore, the remaining 571 patients were included in the intent-to-treat analysis. No statistically significant difference was found in any patient characteristics at baseline shown in Table 3. Twenty-nine patients (5%) were missing baseline measurements of viral load and 15 patients (3%) were missing baseline CD4 cell counts. Table 3. Baseline Patient Characteristics 22 * Characteristic Emtricitabine (n = 286) Stavudine (n = 285) Age, Mean (SD)[range], years 35.8 (9.3)[18-67] 36.5 (9.6)[18-69] Plasma HIV RNA, Mean (SD)[range], 4.8 (0.67)[ ] 4.8 (0.67)[ ] log 10 copies/ml CD4 cell count, Mean (SD)[range], 312 (203)[5-1156] 324 (203)[6-1317] cells/µl History of CDC class C events, n (%) 7 (2.4%) 9 (3.2%) *SD: standard deviation; n: number of patients no statistically significant difference between groups in baseline characteristics for any characteristic baseline plasma HIV RNA 2.6 log 10 copies/ml in 3 patients randomized to emtricitabine and 2 randomized to stavudine A protocol-planned interim analysis was conducted using all data available after the last patient randomized completed Week 24 and was provided to Data and Safety Monitoring Board (DSMB) while maintaining the study blinding. Based on review of the interim analysis, the DSMB recommended on 19 July 2002 that the double-blind comparative phase be terminated and offered all patients open-label access to the emtricitabine treatment regimen. 23 When the amended protocol received its final approval, the last randomized patient completed the Week 48 visit and the median duration of double-blind follow-up was 60 weeks. Efficacy results at Weeks 24, 48, and 60 demonstrated that patients treated with emtricitabine had a superior antiviral response than those treated with stavudine. Results are shown in Tables 4-6. Table 4. Efficacy Results at Week * Parameter Emtricitabine Stavudine P-Value KM probability of persistent virologic response 88% 81% 0.03 < 400 copies/ml (n) (n=251) (n=231) KM probability of persistent virologic response 85% 76% < 50 copies/ml (n) (n=244) (n=217) Mean Change in CD4 Cell Count (cells/µl) *n: number of patients at risk; KM: Kaplan-Meier number of patients were missing data on viral load: 7 in the emtricitabine group and 8 in the stavudine group number of patients were missing CD4 cell counts: 9 in the emtricitabine group and 19 in the stavudine group

12 12 Table 5. Efficacy Results at Week 48 22* Parameter Emtricitabine Stavudine P- KM probability of persistent virologic response < 400 copies/ml (n) HIV RNA 100,000 copies/ml HIV RNA < 100,000 copies/ml KM probability of persistent virologic response < 50 copies/ml (n) HIV RNA 100,000 copies/ml HIV RNA > 100,000 copies/ml Mean Change in CD4 Cell Count (ITT, LOCF) 81% (n=232) 82% 80% 78% (n=233) 68% (n=193) 73% 61% 59% (n=167) Value < <0.001 < % 76% 65% 50% <0.001 (cells/µl) (0.02) +168 (+153) +134 (+120) 0.15 *n: number of patients at risk; KM: Kaplan-Meier; ITT, LOCF: intent-to-treat population with the last observation carried forward number of patients were missing CD4 cell counts: 15 in the emtricitabine group and 16 in the stavudine group Table 6. Efficacy Results at Week 60 22* Parameter Emtricitabine Stavudine P- KM probability of persistent virologic response (< 400 copies/ml) Patients with HIV RNA 100,000 copies/ml Patients with HIV RNA > 100,000 copies/ml KM probability of persistent virologic response (< 50 copies/ml) Patients with HIV RNA 100,000 copies/ml Patients with HIV RNA > 100,000 copies/ml Virologic Failure Patients with HIV RNA 100,000 copies/ml Patients with HIV RNA > 100,000 copies/ml 79% (n=157) 80% 78% 76% (n=153) 63% (n=121) 69% 56% 54% (n=107) 79% 65% 76% 50% 4% 12% 3% 7% 7% 19% *n: number of patients at risk; KM: Kaplan-Meier; ITT, LOCF: intent-to-treat population with the last observation carried forward number of patients were missing data on viral load: 7 in the emtricitabine group and 5 in the stavudine group Overall, 5 patients (1.7%) in the emtricitabine group experienced progression of clnical disease, compared to 10 patients (3.5%) in the stavudine group. 22 These included the events shown in Table 7. Value < <0.001 < <0.001 <

13 13 Table 7. Events of Clinical Disease Progression 22* Event Emtricitabine Stavudine Kaposi sarcoma (n) 1 2 Esophageal candidiasis (n) 1 1 Wasting syndrome (n) 0 4 Diarrhea due to Isospora belli (n) 1 0 Diarrhea due to Cryptosporidium (n) 0 1 Mycobacterium tuberculosis (n) 1 0 Herpes simplex virus infection (n) 1 0 Pneumocystis pneumonia with herpes simplex proctitis (n) 0 1 Death (n) 0 2 *n: number of patients Study FTC-301A demonstrated that antiretroviral-naïve patients who begin therapy with a FTC-based entirely once-a-day regimen achieved and maintained superior efficacy and safety responses compared to patients treated with d4t twice daily in combination with once-daily ddi and efavirenz. Many HAART regimens contain thymidine analogues, such as d4t. Resistance to d4t develops when mutations occur in various sites in the gene encoding RT. Emtricitabine is not cross-resistant with d4t. Study FTC-301A showed that patients treated with emtricitabine develop fewer resistance mutations than patients treated with stavudine. Genotypic analysis was performed retrospectively on the plasma HIV-RNA obtained from 48 of the 50 patients who experienced protocol defined virologic failure, which was defined as never achieving < 400 copies/ml or rebound > 400 copies/ml on 2 consecutive measurements (n=13 in the FTC group; n=37 in the d4tgroup). 22 Overall, the prevalence of mutations in patients experiencing virologic failure was significantly lower in the emtricitabine arm than the stavudine arm (p < 0.01). Resistance mutations were observed at baseline in 38% (5/13) of the patients in the FTC group and 34% (12/35) of the patients in the d4t group with mutations associated with NNRTI resistance being most prevalent. Virologic failure with at least one new genotypic mutation was significantly greater in the stavudine arm (11%) than the emtricitabine arm (4%) (p = 0.005). The M184V/I mutations occurred significantly more frequently in the emtricitabine arm than the stavudine arm (p < 0.001). Results are shown in Table 8.

14 14 Table 8. New Genotypic Mutations in Patients at Time of Virologic Failure 22 * Mutation Emtricitabine Arm (N= 286) Stavudine Arm (N= 285) Any NNRTI TAM 0 7 ddi 1 3 M184V/I 6 0 Wild-type virus 1 4 *defined as never achieving < 400 copies/ml or rebound > 400 copies/ml on 2 consecutive measurements n: number of patients; NNRTI mutations: K103N, L100I, G190A/E/S, Y188C/Y, K101E/N, V106I/M, Y181, V108I, P225H; TAM mutations: T215F/I/S/Y, D67G, K219N, ddi mutations: L74V, K65N; NNRTI: non-nucleoside reverse transcriptase inhibitor; TAM: thymidine analogue mutations; ddi: didanosine Two patients in the d4t group were missing genotypic results at the time of virologic failure. Study M This was a randomized, open-label, multicenter study designed to compare lopinavir 800 mg/ritonavir 200 mg QD vs. lopinavir 400 mg/ritonavir 100 mg BID with the background regimen of FTC 200 mg and TDF 300 mg QD in antiretroviral-naïve patients with HIV RNA >1,000 copies/ml A total of 190 patients between the ages of years were enrolled; 115 to the QD arm and 75 to the BID arm. At baseline, the median HIV RNA levels for patients in the QD and BID arms were 4.8 and 4.6 log 10 copies/ml and the median CD4 cell counts were 214 and 232 cells/mm 3, respectively. Overall, approximately 45% of patients had CD4 cell count < 200 cells/mm 3 and 38% had HIV RNA > 100,000 copies/ml. Results at Weeks 24 and 48 revealed that a similar proportion of patients achieved HIV RNA < 50 copies/ml (95% confidence interval at Week 48 [ITT missing = failure analysis: 7%; 20%]). In addition, increase in CD4 cell counts was similar between the 2 groups. Detailed data are presented in Table 9 below.

15 15 Table 9: Results at Week 24 and 48: Intent-to-Treat Analysis (Observed Analysis) * Parameter Week 24 Week 48 QD BID QD BID % with HIV RNA < 50 copies/ml 57% (68%) (n=97) 57% (78%) (n=61) 70% (90%) (n=89) 64% (85%) (n=55) Mean Change in CD4 Cell Count (cells/mm 3 ) +128 (n=99) +103 (n=62) +185 (n=88) +188 (n=55) *Intent-to-treat analysis: missing=failure; observed analysis: missing=exclusion QD: once daily; BID: twice daily; n: number of patients Study ANRS 091 (Montana) This was a phase 2, open-label study of a QD regimen containing emtricitabine (200 mg), efavirenz (600 mg), and didanosine (400 mg if 60 kg; 250 mg if < 60 kg). Patients (N = 40) were treatment-naive adults with CD4 cell counts > 100 cells/mm 3 (median: 373 cells/mm 3 ) and HIV RNA levels > 5,000 copies/ml (median: 4.77 log 10 copies/ml). 27,28 Using an intent-to-treat (missing = failure) analysis at 96 weeks, 85% and 80% of the patients had HIV RNA < 400 and < 50 copies/ml, respectively. In addition, CD4 cell counts increased by a mean of 259 cells/mm 3. At 3 years, 75% of patients maintained HIV RNA < 400 copies/ml. 29 The Montana Study shows that a FTC-based entirely once-daily regimen was well tolerated and provided durable suppression of plasma HIV-1 RNA through 96 weeks of follow-up. Thus, this study shows that an initiation of antiretroviral therapy with a oncedaily dosing regimen provides effective, long-term viral suppression. Treatment-experienced patients Study ANRS-099 (ALIZE) This was a randomised, open-label, multicenter study comparing the continued treatment of a stable protease inhibitor (PI)-based regimen (2 nucleoside reverse transcriptase inhibitors [NRTIs] + 1 PI) versus switching to a QD regimen containing emtricitabine (200 mg), didanosine (400 mg if 60 kg, 250 mg if < 60 kg), and efavirenz (600 mg). 30 Patients (N = 355) enrolled in this study were naïve to non-nrti (NNRTI) and didanosine and had HIV RNA levels < 400 copies/ml for at least 6 months and CD4 cell counts 100 cells/mm 3 at screening. At entry, patients had been on their PI-based regimen for a median of 35 months, and 46% had used an NRTI prior to HAART. The mean CD4 cell count at baseline was 533 cells/mm 3. At Week 48, 94% of patients in the QD arm and 92% of patients in the continued PI arm had plasma HIV RNA < 400 copies/ml (intent-to-treat). However, the proportion of patients with plasma HIV RNA < 50 copies/ml was significantly higher in the QD arm than the continued PI arm (95% vs. 87%; p = 0.01). Virologic failure, defined as a

16 16 confirmed plasma HIV-RNA 400 copies/ml from baseline to Week 48, was observed in 18 patients (10%) enrolled in the QD arm compared to 22 patients (12%) in the continued arm (NS). The median increase in CD4 cell count was 13 cells/mm 3 for the QD arm and 21 cells/mm 3 for the continue arm. 30 Study FTC-303 (Pivotal Trial) Study FTC-303 was a 48-week, randomised, open-label, multicenter non-inferiority study comparing emtricitabine (200 mg QD) to lamivudine (150 mg BID), in combination with stavudine (40 mg BID) or zidovudine (300 mg BID) and a PI or NNRTI in 440 patients who were on a lamivudine-containing triple-antiretroviral regimen for at least 12 weeks prior to study entry and had HIV-1 RNA < 400 copies/ml. 17,31 Patients were randomised 1:2 to either continue therapy with lamivudine or to switch to emtricitabine; the stable background regimen was maintained. The primary endpoint was the percentage of patients with plasma HIV-1 RNA levels 50 copies/ml and those with levels 400 copies/ml after 48 weeks using the Roche Amplicor Ultrasensitive Test. The secondary endpoint was the percentage of patients experiencing confirmed virologic failure due to loss of response, which was defined as a rebound of viral load to levels > 400 copies/ml from previously reduced levels on 2 consecutive visits during the study. At study entry, the median duration of prior antiretroviral and lamivudine therapies were 27.6 and 18 months, respectively, the median plasma HIV RNA was 1.7 log 10 copies/ml, and the mean CD4 cell count was 527 cells/mm 3. Results at Week 48 are shown in Table 10. An Intent-To-Treat (ITT) analysis was used, with patients who did not complete the study counted as treatment failures. There were no statistically significant differences between emtricitabine and lamivudine treatment arms. Table 10. Results at Week 48 17,31* Parameters Emtricitabine (n = 294) Lamivudine (n = 146) Responder* 77% (67%) 82% (72%) Virologic Failure (> 400 copies/ml) Rebound Never Suppressed through Week 48 7% 5% 2% 8% 5% 3% Study Discontinuation Due to Adverse Events For Other Reasons Death 4% 12% 0% 0% 10% < 1% *patients achieved and maintained confirmed HIV RNA < 400 copies/ml (< 50 copies/ml) through Week 48; n: number of patients includes patients who failed to achieve virologic suppression or rebounded after achieving virologic suppression includes lost to follow up, patient s withdrawal, non-compliance, protocol violation and other reason The mean change increase from baseline in CD4 cell count was 29 cells/mm 3 for the emtricitabine arm and 61 cells/mm 3 for the lamivudine arm. Through Week 48, 2 patients

17 17 (0.7%) in the emtricitabine group experienced a new CDC Class C event, compared to 2 patients (1.4%) in the lamivudine group. 17 A total of 7% (n = 21) of patients in the emtricitabine arm and 8% (n = 11) of patients the lamivudine arm had virologic failure (rebound > 400 copies/ml on 2 consecutive 17, 32 measurements) at Week 48. Genotypic analysis was attempted retrospectively on these patients; however, due to the low plasma HIV RNA level at baseline, M184 sequence was only obtained for 23 patients. Of these patients, 20 (87%) had the M184V mutation at baseline. Patients with HIV RNA 50 copies/ml at baseline failed more frequently than those with HIV RNA < 50 copies/ml at baseline (39% vs. 5%, p < ). Among patients with HIV RNA 50 copies/ml at baseline, those with the M184V mutation at baseline were significantly more likely to fail than those without the mutation (50% vs. 9%; p = ). These findings were similar between both treatment arms. 32 This study demonstrated that simplifying a regimen from lamivudine 150 mg twice daily to emtricitabine 200 mg once daily, while keeping all other medications the same, is equally safe and effective after 48 weeks of follow-up. Patients with viral loads < 400 copies/ml at Week 48 were invited to participate in Study 350, a long-term study of Study FTC-303. Study 350 (Study 303 Extension) This is an open-label extension of Study FTC-303. Patients participating in this study are those with plasma HIV RNA < 400 copies/ml at Week 48 who continued emtricitabine (n = 215) or switched from lamivudine to emtricitabine (n = 74). 33 Patients are currently in the fourth year of emtricitabine treatment, with a median duration of follow-up of 140 weeks. Through 4 years of follow-up, the Kaplan-Meier probability of virologic failure was 11%. 33 Thus, even after 4 years of therapy, the majority of patients continued to have viral suppression less than 400 copies/ml without treatmentlimiting adverse events Summary of data in HIV-infected paediatric patients FTC-203 is an ongoing, Phase 2, open-label, multicenter study conducted to assess the pharmacokinetics, antiviral activity, and safety of emtricitabine in combination with other antiretroviral agents in treatment-naïve (HIV RNA 5,000 but 500,000 copies/ml) and experienced (on stable lamivudine-containing regimen for 3 months, median prior ART 5 years, and HIV RNA 400 copies/ml) HIV-infected children aged 3 months to 17 years old. 34,35,36 Treatment-naïve patients were given emtricitabine (6 mg/kg QD, up to a maximum of 200 mg QD, either as solution or capsules), stavudine (1 mg/kg BID if < 30 kg; 30 mg BID if between kg; 40 mg BID if 60 kg), and lopinavir/ritonavir (12/3 mg/kg BID if 7 to < 15 kg; 10/2.5 mg/kg BID if 15 to 40 kg; 400/100 mg BID if > 40 kg). Treatment-experienced patients were switched from lamivudine to

18 18 emtricitabine and their background ART could be changed at the investigator's discretion. Please refer to Table 11 for detailed characteristics at baseline. Parameter Ethnic Origin (n) Black Caucasian Other Table 11. Study FTC Baseline Characteristics 36* Treatment-Naïve Treatment-Experienced (n=71) (n=45) Total (N=116) 63 (89%) 0 8 (11%) 17 (37%) 4 (8.7%) 24 (52.2%) 80 (69%) 4 (3%) 32 (28%) Mean Age (years) 5 (0.3-12) 7 (1-16) 6 (0.3-16) Median HIV RNA (log 10 copies/ml) Median CD4 Cell Count (cells/mm 3 ) CDC Disease Category (n) B C 5 ( ) 1.7 ( ) 4.5 ( ) 719 ( ) 1045 ( ) 826 ( ) 35 (50%) 13 (19%) *n: number of patients; ART: antiretroviral therapy; NA: not applicable 28 (62%) 9 (20%) 63 (54%) 22 (19%) PACTG P1021 is an ongoing, Phase 1/2 open-label study designed to evaluate the pharmacokinetics, safety, and efficacy of a once daily regimen of emtricitabine (6 mg/kg QD, maximum of 200 mg QD), didanosine (240 mg/m 2, maximum of 400 mg QD) and efavirenz (adjusted by body weight to a maximum of 600 mg QD as capsules or 720 mg QD as oral liquid), in treatment-naive or minimally-treated paediatric patients infected with HIV. 35 A total of 37 children and young adults between the ages of 3-21 years were enrolled (median 10.5 years). At baseline, median HIV RNA level and CD4 cell count were 47,775 copies/ml and 310 cells/µl, respectively. Efficacy data were obtained from studies FTC-203 and PACTG-P1021. The primary efficacy parameters in both studies were the proportion of patients with plasma HIV RNA < 400 and < 50 copies/ml. Results are shown in Tables 12 and 13. Table 12. Study FTC-203 Efficacy at Week 48 36* Parameter Treatment-Naïve (n=50) Treatment-Experienced (n=31) HIV RNA 400 copies/ml (n) 45 (90%) 25 (81%) HIV RNA 50 copies/ml (n) 37 (74%) 2 1(68%) Virologic Failure (%) 9% 7% *n: number of patients Virologic failure defined as HIV RNA > 400 copies/ml

19 19 Table 13. PACTG-P1021 Study Efficacy at Weeks 24, 48, 72, 84 33* Parameter Week 24 Week 48 Week 72 Week 84 HIV RNA < 400 copies/ml (n) 30/37 (81%) 19/24 (79%) 7/13 (54%) 2/9 (22%) HIV RNA < 50 copies/ml (n) 29/37 (78%) 19/24 (79%) 7/13 (54%) 2/9 (22%) Median Change in CD4 Cell +254 (n=33) +263 (n=20) +586 (n=6) +521 (n=2) Count (cells/µl) *n: number of patients Intent-to-treat: discontinued = failure Results are as treated because no measurements were made after the cessation of study drug Overall, in virologically stable treatment-experienced and treatment-naïve infants and children ranging from 4 months to 18 years of age, the majority of patients achieved or maintained complete suppression of plasma HIV-1 RNA through 48 weeks Summary of overall efficacy Results from the clinical program to date demonstrate that emtricitabine (200 mg QD) in combination with other antiretroviral agents, including NRTIs, NNRTIs and PIs, is effective for the treatment of HIV infection in both treatment-naïve and treatmentexperienced patients on a stable triple therapy regimen. 9. Comparative evidence on safety: 9.1 Estimate of total patient exposure to date Clinical trials It is estimated that approximately 1,246 patients were exposed to emtricitabine in clinical trials during the reporting period 03 January July 2004 (Table 14). Table 14. Estimated Patient Exposure to Emtricitabine in Clinical Trials in the Reporting Period of 03 January July 2004 Number of Patients Corporate-sponsored studies 469 Expanded Access Program (Romania) 15 Collaborative Studies 762* TOTAL 1,246 patients * Patient exposure estimates from collaborative studies are less likely to be accurate compared to estimates from company-sponsored trials Post-marketing Patient exposure to marketed emtricitabine was estimated from sales data, using the total number of tablets sold in the period and dividing by 365 to provide patient-years of treatment. Patient exposure to emtricitabine in the period 01 January June 2004 is estimated to be 10,395 patient-years of treatment (Table 15). The cumulative exposure

20 20 since first marketing approval in the US on 02 July 2003 to 30 June 2004 is estimated to be 14,292 patient-years of treatment. It should be noted that the use of sales data for patient exposure calculations will generally overestimate patient exposure, due to the accumulation of drug stocks at distributors. Table 15. Estimated Patient Exposure to Marketed Emtricitabine Geographic Area Patient-Years of Exposure Europe Distributor Region EU 55 France 467 Germany 308 Portugal 30 United Kingdom 115 USA 9395 Latin America 25 TOTAL 10, Description of adverse effects/reactions Warnings and precautions for use Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination with other antiretrovirals. Treatment with emtricitabine should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity. Emtricitabine is principally eliminated by the kidney by both glomerular filtration and active tubular secretion. It is recommended that the dosing interval (emtricitabine 200mg capsule) or dosage (emtricitabine 10 mg/ml oral solution) be modified in patients with impaired renal function. There may be competition for other compounds that are also renally eliminated. Emtricitabine has not been evaluated in patients with hepatic impairment; however, emtricitabine is not metabolised by liver enzymes, so the impact of liver impairment should be limited. Limited data are available on the efficacy and safety of 200 mg emtricitabine per day in chronic hepatitis B patients and in HIV patients co-infected with chronic hepatitis B. In clinical trials of non-hiv-infected patients treated with emtricitabine for chronic hepatitis B, clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of emtricitabine. These exacerbations have been detected primarily by serum ALT elevations in addition to re-emergence of HBV DNA. Patients co-infected with HIV and HBV should be closely monitored with both clinical and laboratory followup for at least several months after stopping treatment. There is insufficient evidence to

21 21 determine whether reinitiation of emtricitabine alters the course of post-treatment exacerbations of hepatitis. Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and cushingoid appearance have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are unknown. A causal relationship has not been established. Emtricitabine has not been studied in patients over the age of 65. Elderly patients are more likely to have decreased renal function; therefore, caution should be exercised when treating elderly patients with emtricitabine. Emtricitabine has not been studied in children younger than 4 months of age Drug interactions At concentrations up to 14 fold higher than those observed in vivo, emtricitabine did not inhibit in vivo drug metabolism mediated by any of the following human CYP 450 isoforms: CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Emtricitabine did not inhibit the enzyme responsible for glucuronidation. Based on the results of these in vitro experiences, and the known elimination pathways of emtricitabine, the potential for CYP450 mediated interactions involving emtricitabine with other medicinal products is low. There are no clinically significant drug interactions when emtricitabine is co-administered with either indinavir, zidovudine, stavudine, famciclovir, or tenofovir disoproxil fumarate Pregnancy and lactation Reproductive studies were conducted in rats, mice, and rabbits. Animal studies (performed at fold human exposure) did not indicate harmful effects of emtricitabine with respect to fertility, pregnancy, fetal development, parturition or postnatal development. Emtricitabine should be used during pregnancy only if clearly needed. It is not known whether emtricitabine is secreted into human milk. Therefore, it is recommended that mothers being treated with emtricitabine do not breastfeed their infants. Heath care providers are encouraged to monitor pregnancies and to provide information on pregnancy outcomes to Gilead or the company's agents. Gilead or its agent will provide the reporter with the choice of communicating pregnancy details directly to an Antiretroviral Pregnancy Registry or will communicate the information on behalf of the reporter to the relevant agency Effects on ability to drive and use machines

22 22 No studies of the effect of emtricitabine on the ability to drive or use machines have been performed. However, patients should be informed that dizziness has been reported during treatment with emtricitabine. 9.3 Overdose Administration of up to 1,200 mg emtricitabine has been associated with the adverse reactions listed above. If overdose occurs, the patient should be monitored for signs of toxicity, and standard supportive treatment applied as necessary. Emtricitabine can be removed by haemodialysis, which removes approximately 30% of the emtricitabine dose over a 3-hour dialysis period starting within 1.5 hours of emtricitabine dosing. It is not known whether emtricitabine can be removed by peritoneal dialysis. 9.4 Undesirable effects: Experience from controlled clinical studies Assessment of adverse reactions is based on pooled data from three controlled clinical studies (301A, 302, 303) in which 1,039 treatment naïve and 440 treatment experienced patients received emtricitabine (n = 814) or comparator drug (n = 665) for at least 48 weeks. The adverse reactions with suspected (possible, probable, remote or missing) relationship to treatment are listed below by body system organ class and incidence, which are defined as very common (> 1/10) or common (> 1/100, < 1/10). NERVOUS SYSTEM DISORDERS Very common: headache Common: dizziness, asthenia, insomnia, abnormal dreams GASTROINTESTINAL SYSTEM DISORDERS Very common: diarrhea, nausea Common: vomiting, dyspepsia, abdominal pain SKIN AND SUBCUTANEOUS TISSUE DISORDERS Common: rash event (rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, pustular rash, and allergic reaction), skin discoloration GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Common: pain