June 2016 Australian Public Assessment Report for Elvitegravir / Cobicistat / Emtricitabine / Tenofovir alafenamide (as fumarate) Proprietary Product Name: Genvoya Sponsor



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GS-US-292-0102 (Phase II), ART naive and virologically suppressed HIV infected adults

Results for this smaller study of 170 subjects were similar to the pivotal efficacy studies GS-US-292-0104 and GS-US-92-0111 for ART naive patients. For virologically suppressed patients who switched treatment in the extension phase, virologic suppression was maintained and CD4 cell count increased in subjects who switched to EVG/COBI/FTC/TAF. The Delegate notes that the population of virologically suppressed patients for this study was different from GS-US-292-0109, as it included patients switching from Stribild or from a COBI boosted darunavir containing regimen.
Safety

The fundamental advantage with TAF in Genvoya over TDF in Stribild is that by being incorporated into PBMCs much more rapidly, the effects on renal and bone mineral function will be less. Safety data at 48 weeks from the submitted clinical studies were intended to illustrate this. The main sources of safety data for Genvoya were the Phase III studies in ART naive subjects, virologically suppressed subjects, subjects with mild to moderate renal impairment and ART naive adolescents. Supportive safety information was provided by the Phase II Study GS-US-292-0102.

Across the Phase II and III studies, a total of 2,394 subjects received EVG/COBI/FTC/TAF with a median exposure of 48.1 weeks. A total of 97 subjects were ≥ 65 years of age across these studies. The median ages of adult subjects with normal renal function who were ART naive or virologically suppressed were generally similar (range: 33 to 41 years). Subjects with mild to moderate renal impairment in Study GS-US-292-0112 were older with a median age of 58 years in Cohort 1 (ART experienced subjects who switched to EVG/COBI/FTC/TAF).

For the pivotal studies, four key safety endpoints were defined as follows:


  • Percentage change from baseline in hip BMD at Week 48

  • Percentage change from baseline in spine BMD at Week 48

  • Change from baseline in serum creatinine at Week 48

  • Treatment emergent proteinuria by urinalysis (dipstick) through Week 48.
Bone mineral density (hip and spine)

A comparison of bone mineral density loss Genvoya (EVG/COBI/FTC/TAF) versus Stribild (EVG/COBI/FTC/TDF) was performed. The mean and 95% CIs of percentage change from Baseline by visit (observed data) Studies GS-US-292-0104 and GS-US-292-0111 are shown in Figure 7 above.

Fracture probability

For the pivotal Studies GS-US-292-0104, GS-US-292-0111 and GS-US-292-0109 the mean increase from baseline at Week 48 in major osteoporotic fracture risk was numerically smaller for the EVG/COBI/FTC/TAF group compared with the Stribild group in patients ≥ 40 years. Of note, for Study GS-US-292-0109 (switch study from a TDF to a TAF containing regimen), the change from baseline in the 10 year probability of major osteoporotic fracture at Week 48 was 0.10% (0.386) in the EVG/COBI/FTC/TAF group and 0.23% (0.549) in the FTC/TDF + 3rd Agent group (p = 0.002 for the difference between groups).

Renal safety

Change in baseline for serum creatinine.

Results for studies GS-US-292-0104, GS-US-292-0111, GS-US-292-0109 are described in Attachment 2 and include the following:

Overall, increases from baseline in mean values for serum creatinine were smaller in the EVG/COBI/FTC/TAF group compared with the Stribild group for studies GS-US-292-0104 and GS-US-292-0111. The difference between the treatment groups was statistically significant at all time points from Weeks 2 to 48.

For GS-US-292-0109, for subjects who switched to EVG/COBI/FTC/TAF from Stribild, there were decreases from baseline in serum creatinine as compared with increases from baseline observed among subjects who remained on Stribild. For subjects who switched to EVG/COBI/FTC/TAF from atazanavir (ATV)/boosted + TVD regimens (including ATV boosted with COBI or RTV), there were increases or no changes from baseline in serum creatinine at most time points as compared with increases from baseline observed among subjects who remained on ATV/boosted + TVD regimens. There were no significant differences between treatment groups in the changes from baseline in serum creatinine, except at Week 48. In contrast, for subjects who switched to EVG/COBI/FTC/TAF from Atripla, there were increases from baseline in mean values for serum creatinine as compared with either no changes or smaller increases from baseline observed among subjects who remained on Atripla. Increases were observed at Week 2 for the EVG/COBI/FTC/TAF group (consistent with the established COBI effect on serum creatinine) and through to Week 48.



Figure 10. Study GS-US-292-0104: Mean (95% CI) change from baseline in serum creatinine (mg/dL) by visit (observed data; safety analysis sets)



Figure 11. Study GS-US-292-0109: mean (95% CI) change from baseline in serum creatinine (mg/dL) by visit (observed data; safety analysis set, prior treatment regimen = Stribild)

Note: the clinical evaluator explained that this graph illustrates the reverse situation to the previous studies as it is switching from a TDF regimen to a TAF regimen in treatment experienced patients.


Treatment emergent proteinuria

Results for treatment emergent proteinuria for Studies GS-US-292-0104, GS-US-292-0111 and GS-US-292-0109 are summarised in Attachment 2. Fewer subjects in the EVG/COBI/FTC/TAF group than in the Stribild group had at least 1 recorded, graded proteinuria by dipstick, although differences were modest.
Adverse events; Studies GS-US-292-0104 and GS-US-292-0111

For Studies GS-US-292-0104 and GS-US-292-0111, the proportion of subjects who discontinued study drug due to AEs, regardless of severity, was 0.9% (8 subjects) in the EVG/COBI/FTC/TAF group and 1.5% (13 subjects) in the Stribild group. The only adverse event (AE) (all Grades) considered related to study drug by the investigator that was reported in ≥ 10% of subjects in the EVG/COBI/FTC/TAF group was nausea (10.4%, 90 subjects).

Table 15. GS-US-292-0104 and GS-US-292-0111. Common adverse events (all grades) in ≥ 5% of patients




Elvitegravir, COBI, emtricitabine, tenofovir alafenamide (n=866)

Elvitegravir, COBI, emtricitabine, tenofovir disoproxil fumarate (n=867)

Diarrhoea

147 (17%)

164 (19%)

Nausea

132 (15%)

151 (17%)

Headache

124 (14%)

108 (13%)

Upper respiratory tract infection

99 (11%)

109 (13%)

Nasopharyngitis

78 (9%)

80 (9%)

Fatigue

71 (8%)

71 (8%)

Cough

67 (8%)

60 (7%)

Vomiting

62 (7%)

54 (6%)

Arthralgia

61 (7%)

39 (5%)

Back pain

60 (7%)

57 (7%)

Insomnia

57 (7%)

48 (6%)

Rash

55 (6%)

46 (5%)

Pyrexia

45 (5%)

41 (5%)

Dizziness

44 (5%)

37 (4%)

Results for the other studies are described in Attachment 2
Deaths and SAEs

Seven subjects died during the EVG/COBI/FTC/TAF Phase II and Phase III studies: 5 subjects in Studies GS-US-292-0104 and GS-US-292-0111, and 2 subjects in Study GS‑US‑292-0109 None of the events that resulted in death were considered related to study drug by the investigator.

Serious AEs were reported for a similar percentage of subjects in both treatment groups in the comparative Studies (GS-US-292-0104, GS-US-292-0111 and GS-US-292-0109) and < 10% in the EVG/COBI/FTC/TAF group in each study. No individual SAE occurred in ≥ 1% of subjects in either treatment group.

Among virologically suppressed subjects in Study GS-US-292-0109, subjects who switched to EVG/COBI/FTC/TAF had a higher incidence of any AE considered by the investigator as related to study drug (EVG/COBI/FTC/TAF 19.3%, 185 subjects; FTC/TDF + 3rd Agent 12.8%, 61 subjects). However, SAEs were reported for a similar percentage of subjects in the 2 groups (EVG/COBI/FTC/TAF 4.4%, 42 subjects; FTC/TDF + 3rd Agent 4.4%, 21 subjects).

Serious AEs were reported in Study GS-US-292-0112 (subjects with mild to moderate renal impairment) for 10.7% of Cohort 1 switch subjects (n = 26), with similar percentages reported in subjects with baseline eGFRCG ≥ 50 mL/min (11.3%, n = 9) and eGFRCG < 50 mL/min (10.5%, n = 17). SAEs were reported for 4 subjects (8.3%) in the adolescent study (Study GS-US-292-0106).


Clinical evaluator’s conclusions on clinical safety

The clinical evaluator concluded that there were statistically significant differences favouring EVG/COBI/FTC/TAF over Stribild or TDF containing regimens observed at Week 48 for all key secondary safety endpoints in both ART naive and virologically suppressed subjects. These included mean percentage changes from baseline in hip BMD (p < 0.001 for both ART naive and virologically suppressed subjects) and spine BMD (p < 0.001 for both ART naive and virologically suppressed subjects), mean change from baseline in serum creatinine (p < 0.001 for both ART naive and virologically suppressed subjects), change from baseline in treatment emergent proteinuria (ART naive subjects, p = 0.022), and change from baseline in efavirenz related symptom assessment composite score (for virologically suppressed subjects; p < 0.001).

The evaluator also commented that the clinical relevance of improving BMD was unquestionable in terms of potentially reducing fractures. While it is not possible to determine if the 48 week follow-up period is long enough, it was felt that there was no reason to assume these differences would be reduced following longer-term observation.

Availability of 96 week data for these studies as a future submission to the TGA is therefore requested. This is particularly relevant, given changes in bone mineral density with ART may stabilise 1 to 2 years after initiation of treatment.32

Risk management plan

RMP evaluation

The submission was not presented to ACSOM. The RMP Round 2 advice, dated 16 October 2015 identified the following outstanding issues:

  1. It is recommended that the missing information: ‘Safety in patients with severe renal impairment (estimated creatinine clearance below 30 mL per minute)’ should be included in the summary of safety concerns for Genvoya.

  2. In regards to suicidal ideation and attempt, the RMP evaluator recommended consistency with Stribild in regards to routine risk minimisation, given this safety concern was attributed to the EVG component, which is common to Genvoya.

The Delegate acknowledges the sponsor’s response to the consolidated request for information which summarises the data for 2,394 patients receiving at least 1 dose of EVG/COBI/FTC/TAF (Genvoya) across several different patient populations (naive, switch, adolescents and renal impairment) and notes that there was no evidence suggesting causality from an assessment of the individual reports, which all involved patients with a pre-existing history of depression or psychiatric illness. However, given the concerns raised by the RMP evaluator, it is suggested that this information be included in the Adverse Effects section of the proposed PI for Genvoya and that the ASA be revised accordingly.

Risk-benefit analysis

Delegate’s considerations

Discussion

The submission includes sufficient data in regards to efficacy and safety to recommend registration. Non-inferiority to Stribild in ART naive and virologically suppressed HIV infected patients has been demonstrated. This is expected, given the active metabolite TFV-DP is common to both products and that dose finding studies have demonstrated comparable exposure and anti-viral activity of TDF 300 mg (for Stribild) and TAF 10 mg boosted with COBI (for Genvoya).

Discussion of the wording of the proposed indication is warranted, noting that the sponsor is proposing an indication for Genvoya that was not accepted by ACPM for Stribild (PM-2014-01079-1-2) at ACPM in June 2015. Justification of this was based on the amended indication providing a more accurate reflection of the submitted data. While the current application for Genvoya and the application for Stribild (PM-2014-01079-1-2) are distinct, both submissions included virologically suppressed patients on a stable ART regimen (switch strategy trials) rather than salvage therapy in patients failing other regimens. Study GS-US-292-0109 included patients with plasma HIV-1 RNA concentrations at undetectable levels for at least 6 consecutive months prior to the screening visit and HIV RNA < 50 copies/mL at screening. For this reason, the Delegate proposes that the indication for Genvoya be amended to reflect the actual populations studied. With respect to adolescents, data are sufficient to extend use to patients age 12 to 18 years, however given the EU has approved use in adolescents with body weight at least 35 kg, and that Genvoya is a fixed dose combination, the Delegate proposes to following wording for the indication:



Genvoya is indicated as a single tablet regimen for the treatment of HIV-1 infection in treatment naive adults and adolescents aged 12 years and older with body weight at least 35 kg. Genvoya is also indicated in certain virologically suppressed (HIV1 RNA < 50 copies/mL) adult patients on a stable antiretroviral regimen at start of therapy in order to replace their current antiretroviral treatment regimen (see Clinical Trials). Patients must not have a history of treatment failure or known mutations associated with resistance to the antiretroviral components of Genvoya (tenofovir alafenamide, emtricitabine or elvitegravir).

Genvoya is a fixed dose combination of one integrase inhibitor, one pharmacokinetic enhancer and two nucleos(t)ide HIV-1 reverse transcriptase inhibitors.

Safety and efficacy data were limited to 48 week results, and this is relevant particularly for safety data including BMD, given the majority of BMD decreases for all ARV regimens occur within the first year of therapy and may stabilise with time. While BMD changes are more prominent with TFV, other risk factors for BMD in the HIV population need to be considered including viral load, age, co-morbidities and body mass index.29,33 The 96 week data for the submitted studies is therefore very relevant and fracture risk will require long-term follow-up in the post-marketing period. There appears to be a positive benefit of Genvoya in terms of significantly reduced parameters of renal toxicity, compared with Stribild and when switching to Genvoya from a tenofovir containing regimen. This is relevant for all TAF based antiretroviral therapies currently under development.


Delegate’s issues for the sponsor

  1. Please provide an update of the overseas regulatory status.

  2. Results (including efficacy and safety data) were available up to 48 weeks for studies GS-US-292-0104, GS-US-292-0111, GS-US-292-0109 and GS-US-292-0112 and for 24 weeks for GS-US-292-0106. Please provide the 96 week data for these studies to the TGA as a future submission when available. With respect to the indication in children, please also submit Study GS-US-292-1515 in virologically suppressed, HIV-infected adolescents 12 to < 18 years of age and the final report for study GS-US-292-0106 which will include children age 6 to < 12 years when available.

  3. Please submit a revised ASA noting the RMP second round recommendations for risk minimisation in relation to severe renal impairment and suicidal ideation and attempt.

  4. With regards to the evaluation, please provide a reference for the chosen non-inferiority level of < 12% for studies GS-US-292-0104, GS-US-292-0111 and GS-US-292-0109.

  5. With respect to the proposed indication in adolescents for Genvoya, it is noted that for Stribild, its use in children or adolescents under the age of 18 years is contra indicated in the PI. Is this based on the suitability of the fixed combination product for administration to younger children (and those of low weight) together with a lack of any data in adolescents rather than a specific adolescent issue?

Summary of issues

Genvoya contains the same individual components as Stribild, with the exception of TAF. TAF replaces TDF in Genvoya and is a newer oral prodrug of TFV. There is the potential for less toxicity (nephrotoxicity and reduced bone mineral density) with TAF.


Proposed action


The Delegate had no reason to say, at this time, that the application for Genvoya should not be approved for registration.

Approval is subject to resolution of the RMP second round recommendations, PI and outstanding quality issues.


Request for ACPM advice


The ACPM is requested to provide advice on the following specific issues:

  1. What is the committee’s view with regards to the sponsor’s proposed indication? Does the committee consider the indication should be amended as suggested, given the submitted data? With respect to the indication in adolescents, does the committee agree with proposed wording, noting the EU recommendation?

  2. Please comment on the data submitted for patients with renal impairment (studies GS-US-120-0108, GS-US-292-0112) and whether these findings are adequately reflected in the PI. Please also comment on the renal safety data for the pivotal studies GS-US-292-0104, GS-US-292-0111, GS-US-292-0109.

  3. Please comment on the clarity of the Drug Interactions and Precautions sections of the PI, given the potential for drug-drug interactions with other components of Genvoya (COBI and EVG).

The committee is also requested to provide advice on any other issues that it thinks may be relevant to a decision on whether or not to approve this application.

Response from sponsor

Summary

With introduction of highly active antiretroviral therapy and the consequential large decrease in AIDS related mortality, clinical attention has become more focused on the optimisation of tolerability, long-term safety, and adherence to potent ART regimens. There remains a significant medical need for new, effective therapies that take into consideration the non HIV co-morbidities, demographics of the aging HIV infected population, ART resistance, and regimen simplification.

Genvoya has demonstrated both potent antiviral efficacy and a safety and tolerability profile that offer advantages over existing recommended ART regimens, meeting important unmet medical needs. Genvoya represents a favourable new therapeutic once daily option for HIV infected adults, including those with mild to moderate renal impairment, and paediatric patients 12 years of age and older. The benefits provided by Genvoya also meet an important unmet need for optimised treatment in the context of an aging cohort of HIV infected individuals with a life expectancy close to that observed in the general population who are exposed to ART for long periods of time.

It was concluded by the TGA clinical evaluator that the overall safety profile of Genvoya is a ‘significant improvement over the safety profile of Stribild’, ‘the clinical relevance of improving BMD is unquestionable in terms of potentially reducing fractures’, and ‘there appears to be a positive benefit of Genvoya in terms of renal toxicity, compared with Stribild and also when patients were switch to Genvoya from a TDF containing regimen’.

Discussion of Delegate’s comments
Delegate’s questions for the sponsor

  1. Please provide an update of the overseas regulatory status

Sponsor’s response:

An update of the overseas regulatory status is provided.



  1. Results (including efficacy and safety data) were available up to 48 weeks for studies GS‐US‐292‐0104, GS‐US‐292‐0111, GS‐US‐292‐0109 and GS‐US‐292‐0112 and for 24 weeks for GS‐US‐292‐0106. Please provide the 96 week data for these studies to the TGA as a future submission when available. With respect to the indication in children, please also submit Study GS‐US‐292‐1515 in virologically suppressed, HIV‐infected adolescents 12 to < 18 years of age and the final report for study GS‐US‐292‐0106 which will include children age 6 to < 12 years when available.

Sponsor’s response:

As per the response to Q2 of Delegate’s request for ACPM advice, all available longer term data for the included clinical trials (GS-US-292-0104, GS-US-292-0111 (Week 96), GS-US-292-0109, GS-US-292-0106 (Week 48), GS-US-292-0112 (Week 72) has been included in the updated PI. Gilead also provides assurance that Study GS‐US‐292‐1515 will be provided when available.



  1. Please submit a revised ASA noting the RMP Round 2 recommendations for risk minimisation in relation to severe renal impairment and suicidal ideation and attempt.

Sponsor’s response:

A revised ASA was submitted to the TGA on 29 October in response to the second round RMP evaluation report. The ASA was updated to include safety in patients with severe renal impairment as missing information in the summary of safety concerns as per the RMP evaluator’s request.

Major depression is a common comorbidity among HIV infected persons; therefore suicidal ideation/suicide attempt would not be unexpected in this population. For instance, in a systemic literature review of articles involving HIV infected patients, the crude mean prevalence of committed suicide was 2.4% (range 1.5 to 5.6%) and the crude mean prevalence of suicidal ideation was 26.9% (3.9 to 78%)34. Furthermore, suicide events were reported in the medical history of 1.6% of the ART naive patients in Studies GS-US-292-0104 and GS-US-292-0111 prior to ART initiation. Suicidal ideation/suicide attempt is currently classed as an important potential risk within the summary of safety concerns in the EU-RMP and ASA. No further risk minimization measures are considered necessary as there is currently insufficient evidence to support a causal association between suicidal ideation/suicide attempt and Genvoya use. Across the Genvoya study program, no suicide AE was considered related to study drug by the investigator and all patients who experienced a suicide related AE when receiving Genvoya had a pre-existing history of depression or psychiatric illness.

Incidences of suicidal ideation and suicide attempt for patients treated with Genvoya at Week 48 were 0.4% (9 out of 2,396 patients) and 0.3% (6 out of 2,396 patients) respectively. These are equivalent or lower than the randomised comparator, as shown in Table 16 below. One patient had AEs of both suicidal ideation and suicide attempt and one additional subject had an AE of intentional self-injury such that the incidence of any suicide related AE was 0.6% (15 out of 2396 patients). Over 96 weeks in Studies GS-US-292-0104 and GS-US-292-0111, the incidences of suicidal ideation and suicide attempt for patients treated with Genvoya were 0.8% (7 out of 866 patients) and 0.3% (3 out of 866 patients), respectively, with an overall incidence of any suicide-related AE of 1.2% (10 out of 866 patients). (Studies; GS-US-292-0102, GS-US-292-0104, GS-US-292-0111, GS-US-292-0109, GS-US-292-0112, GS-US-292-0106).



The incidence of all suicide related AEs to Week 48 from Genvoya Phase III studies of ART naive patients (GS-US-292-0104, GS-US-292-0111) and virologically suppressed patients (GS-US-292-0109) is provided in the table below. In Genvoya Phase II Study GS‑US‑292‑0102 to Week 144, 1 patient (0.9%) had a suicide event (suicidal ideation) reported.

Table 16. The incidence of all suicide-related AEs to Week 48 from Genvoya Phase III studies of ART naive patients (GS-US-292-0104, GS-US-292-0111) and virologically suppressed patients (GS-US-292-0109)

In summary, no further risk minimization measures are considered necessary as the robust long-term data do not support a causal association between suicidal ideation/suicide attempt and Genvoya use. As such Gilead does not propose to include any further risk minimisation recommendations regarding suicidal ideation and attempt within the ASA or proposed PI at this time.



  1. With regards to the evaluation, please provide a reference for the chosen non‐inferiority level of < 12% for studies GS‐US‐292‐0104, GS‐US‐292‐0111 and GS‐US‐292‐0109.

Sponsor’s response:

The chosen non-inferiority margin level of < 12% is the most commonly used margin in HIV clinical trials35 and is consistent with US regulatory guidance.36



  1. With respect to the proposed indication in adolescents for Genvoya, it is noted that for Stribild, its use in children or adolescents under the age of 18 years is contra‐indicated in the PI. Is this based on the suitability of the fixed combination product for administration to younger children (and those of low weight) together with a lack of any data in adolescents rather than a specific adolescent issue?

Use of Stribild in children or adolescents under the age of 18 years is contra indicated due to the lack of sufficient data in this population.
Delegate’s request for ACPM advice

  1. What is the committee’s view with regards to the sponsor’s proposed indication? Does the committee consider the indication should be amended as suggested, given the submitted data? With respect to the indication in adolescents, does the committee agree with proposed wording, noting the EU recommendation?

Sponsor’s response:

Of most concern, the TGA proposed indication restricts the paediatric population to naive patients only and defines virologically suppressed (< 50 copies per mL) which are considered unnecessary. Apart from this, Gilead does not have strong objections to the proposed indication but would suggest to the Delegate and ACPM that a more succinct indication would be considered:



Genvoya is indicated for the treatment of HIV-1 infection in adults and adolescents aged 12 years of age and older with body weight at least 35 kg (see Clinical Trials). Patients must not have a history of treatment failure or known mutations associated with resistance to the antiretroviral components of Genvoya.

Genvoya is a fixed dose combination of one integrase inhibitor, one pharmacokinetic enhancer and two nucleos(t)ide HIV‐1 reverse transcriptase inhibitors.

This simplified indication captures the concerns of the Delegate in that it excludes non-stable treatment experienced patients that are outside the patient populations investigated by Gilead. Inclusion of the definition virologically suppressed (HIV1 RNA < 50 copies/mL) in the indication is unnecessary. The European AIDS Clinical Society (EACS) HIV treatment guideline version 8.0 now recommends ART for all HIV positive persons, irrespective of CD4 cell count. Retaining this limit of detection in the clinical trials section suitably discloses how the pivotal trials were conducted.

Genvoya has demonstrated potent antiviral efficacy in ART naive adults and adolescents and treatment experienced adults. The safety profile of Genvoya in adolescents is similar to that in adults, and the PK data shows equivalent exposures between adults and adolescents. This strongly supports that there is no reason to expect that treatment experienced virologically suppressed adolescent patients on a stable regimen would behave any differently to adults. Conducting clinical research on children is a difficult and challenging expectation; it would be unreasonable to expect clinical research in children in different sub-populations when there is such strong evidence that there is no age associated difference in humans infected with the same virus treated with Genvoya.

Current approved therapies for the treatment of HIV-1 in adolescents include older products and complicated regimens (e.g., twice daily or with different dosage forms) that are difficult to tolerate. Genvoya will represent a treatment simplification that can reduce these patients’ pill burden and promote adherence. Gilead believes the inclusion of adolescent patients in the indication is important due to the specific and complex challenges for the treatment of adolescents, who also represent the population that will require ART for the longest time. As such Gilead would like the Delegate and ACPM to consider an indication statement that includes a broader adolescent indication.

The indication statement proposed by the Delegate may be viewed as unnecessarily restrictive in this important population, and may exclude patients who can benefit from a treatment option that has been demonstrated to be efficacious, safe, and well tolerated. The indication statement is critical in defining patient access, especially in a constantly evolving reimbursement environment and in providing patients who are in need of antiviral treatments with the best therapeutic options available.


  1. Please comment on the data submitted for patients with renal impairment (studies GS‐US‐120‐ 0108, GS‐US‐292‐0112) and whether these findings are adequately reflected in the PI. Please also comment on the renal safety data for the pivotal studies GS‐US‐292‐0104, GS‐US‐292‐0111, GS‐US‐292‐0109.

Sponsor’s response:

The totality of results from renal assessments in HIV-1 infected adult and adolescent patients across the clinical development program demonstrated that treatment with Genvoya is associated with a preferential renal safety profile compared with Stribild or with TDF containing regimens, with statistically significant differences in multiple tests of renal function. This positive benefit of Genvoya in terms of renal toxicity, compared with Stribild and also when patients were switch to Genvoya from a TDF containing regimen was also noted by the TGA clinical evaluator.

Study GS-US-292-0112 is extensively presented in the clinical trials section of the proposed PI. In the submission, 24 week data were presented. Since that time, all patients (N = 248) in Study GS-US-292-0112 have received 72 weeks of treatment, including the 80 patients with baseline eGFRCG < 50 mL/min. Results from the longer term data confirmed that, after once daily administration of Genvoya without dose adjustment, the safety profile in patients with baseline eGFRCG < 50 mL/min was similar to that in patients with baseline eGFRCG ≥ 50 mL/min.

Following discussions with the Delegate, it has been agreed that all available longer term data for the included clinical trials (GS-US-292-0104, GS-US-292-0111 (Week 96), GS-US-292-0109, GS-US-292-0106 (Week 48) and GS-US-292-0112 (Week 72) can be included in the updated PI.

Renal safety data is also presented throughout the proposed PI within the pharmacokinetics, precautions and dosage and administration sections, and is consistent with the data as presented within the EU SmPC.


  1. Please comment on the clarity of the drug interactions and precautions sections of the PI, given the potential for drug-drug interactions with other components of Genvoya (COBI and EVG).

Sponsor’s response:

The drug interactions and precautions section of the proposed PI is presented in an identical manner to the approved PI for Stribild, and other TGA approved HIV products registered by Gilead. The drug interactions section has been updated in line with the Delegate’s comments to include all recommendations in the ‘Drug interactions and other forms of interaction’ table are consistent with the EU SmPC. Annotated and clean copies of the current proposed PI and CMI are provided.


Advisory committee considerations


The Advisory Committee on Prescription Medicines (ACPM), having considered the evaluations and the Delegate’s overview, as well as the sponsor’s response to these documents, advised the following:

The ACPM, taking into account the submitted evidence of efficacy, safety and quality, agreed with the Delegate and considered Genvoya tablet containing 150 mg EVG (EVG), 150 mg of cobicistat (COBI), 200 mg of emtricitabine (FTC) and 10 mg of tenofovir alafenamide fumarate (TAF) of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide fumarate to have an overall positive benefit–risk profile for the amended indication:



Genvoya is indicated as a single tablet regimen for the treatment of HIV-1 infection adults and adolescents aged 12 years and older with body weight at least 35 kg who are either:

  • treatment naive; or

  • virologically suppressed (HIV-1 RNA < 50 copies/mL) on a stable antiretroviral regimen at start of therapy in order to replace their current antiretroviral treatment regimen (see CLINICAL TRIALS)

Patients must not have a history of treatment failure or known mutations associated with resistance to the antiretroviral components of Genvoya.

Genvoya is a fixed dose combination of one integrase inhibitor, one pharmacokinetic enhancer and two nucleos(t)ide HIV-1 reverse transcriptase inhibitors.

In making this recommendation the ACPM



  • Was of the view that the indication proposed by the Delegate was appropriate and reflected the data presented in the application.

  • Advised that the indication for virologically suppressed patients should not be limited to adults only and that the restriction aged 12 years and older with a body weight of at least 35 kg was appropriate.
Proposed conditions of registration

The ACPM agreed with the Delegate on the proposed conditions of registration.
Proposed PI/CMI amendments

The ACPM agreed with the Delegate to the proposed amendments to the PI and CMI and specifically advised on the inclusion of the following:

  • Under precautions –general - removal of the wording ‘Patients should be advised that antiretroviral therapies, including Genvoya, have not been proven to prevent the risk of transmission of HIV to others through sexual contact or blood contamination.’ The ACPM advised that there is now extensive evidence that effective treatment of HIV decreases the risk of transmission by more than 90% and that similar wording included in the EU SmPC should be used ‘While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of HIV transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines’.

  • Under precautions- use with other anti-retroviral products- the statement ‘Genvoya should not be used in conjunction with protease inhibitors’ should clarify that it is Hepatitis C protease inhibitors due to potential reduced activity with a number of these and that no evidence exists of efficacy or safety with HIV protease inhibitors. In addition, the following could be added ‘there are no data on interactions of Genvoya with HIV protease inhibitors and/or NNRTIs, but as a fixed dose combination for HIV, it is not expected that co-administration with other anti retrovirals would be required’.

  • The percentage of each of the ethnicities in the pivotal trials should be reflected in the PI rather than just the current statement in the PI ‘No clinically relevant pharmacokinetic differences due to gender or ethnicity’, to further inform clinicians. The ACPM agreed that study GS-US-292-0108 was too small to demonstrate a difference in pharmacokinetics due to race and that the PI should state that pharmacokinetic differences due to ethnicity are unclear.

  • The addition in the CMI of the following regarding commencing other medicines if taking Genvoya: ‘there are complex interactions with many different medications, so you should consult your doctor or pharmacist before starting any new medication’.
Specific advice

The ACPM advised the following in response to the Delegate’s specific questions on this submission:

  1. What is the committee’s view with regards to the sponsor’s proposed indication? Does the committee consider the indication should be amended as suggested, given the submitted data? With respect to the indication in adolescents, does the committee agree with proposed wording, noting the EU recommendation?

The ACPM recalled that in June 2015 consideration of prior combination Stribild where clinical trials were also undertaken in treatment naive patients and as a ‘switch study’ in patients virologically suppressed on treatment, and did not include use as salvage in treatment experienced patients with virologic failure. The ACPM agreed that the sponsor’s amended indication for Genvoya in its pre-ACPM response, was generally acceptable but should specify the two study populations, naive and switch/currently virologically suppressed, explicitly. The ACPM advised that the Delegates proposed indication in adults and adolescents aged 12 years and over is appropriate based on the data provided. The ACPM advised that the indication for virologically suppressed patients should not be restricted to adults, as Genvoya should be useful in the same way for adolescents as adults. The ACPM advised that weight above 35 kilograms was an appropriate restriction.

  1. Please comment on the data submitted for patients with renal impairment (studies GS-US-120-0108, GS-US-292-0112) and whether these findings are adequately reflected in the PI. Please also comment on the renal safety data for the pivotal studies GS-US-292-0104, GS-US-292-0111, GS-US-292-0109.

The ACPM noted that the creatinine increased at least in part due to COBI; however, potential toxicity appears to be less than TDF over the 48 weeks studied. The ACPM advised that monitoring of markers of proximal renal damage should be recommended and specified in the PI. The ACPM noted that the sponsor, in its pre-ACPM response, agreed to include all available longer term data including data at week 96, in the PI.

The ACPM noted that the effects on serum creatinine were expressed as eGFR, which is consistent with current terminology and clinical practice. The ACPM advised that Genvoya should not be used in patients with severe renal impairment. The ACPM noted that dosage advice had been provided on use in patients with a creatinine clearance of less than 30 mL/min and that Genvoya should not be used in these patients. The PI also stated that there are no pharmacokinetic data on EVG, COBI, or tenofovir alafenamide in subjects with estimated creatinine clearance less than 15 mL/min. The ACPM was of the view that stating there were ‘no data’ was not adequate and that the wording in the US PI which states ‘Genvoya is not recommended in patients with estimated creatinine clearance below 30 mL per minute because data in this population is insufficient’ was more appropriate pending more data.



  1. Please comment on the clarity of the drug interactions and precautions sections of the PI, given the potential for drug-drug interactions with other components of Genvoya (cobicistat and elvitegravir).

The ACPM was of the view that the list of drugs which interact with Genvoya was extensive but did not include explanatory information by specific drug as did the US PI. The ACPM advised that a list of drugs which don’t interact might also be helpful if included in the PI and the CMI, similar to the US PI or EU SmPC. The ACPM considered that the CMI needed to emphasise that it is imperative that patients discuss with their treating physician the addition of any therapy, including over the counter or natural therapies due to drug interactions with Genvoya and suggested the following wording: ‘there are complex interactions with many different medications, so you should consult your doctor or pharmacist before starting any new medication’.

The ACPM advised that implementation by the sponsor of the recommendations outlined above to the satisfaction of the TGA, in addition to the evidence of efficacy and safety provided would support the safe and effective use of this product.


Outcome


Based on a review of quality, safety and efficacy, TGA approved the registration of Genvoya elvitegravir (150 mg), cobicistat (150 mg), emtricitabine (200 mg) and tenofovir alafenamide (as fumarate) 10 mg) fixed dose combination tablets for oral administration, indicated for:

Genvoya is indicated as a single tablet regimen for the treatment of HIV-1 infection in adults and adolescents aged 12 years of age and older with body weight at least 35 kg who are either treatment, naive; or virologically suppressed (HIV-1 RNA < 50 copies/mL) on a stable antiretroviral regimen at start of therapy in order to replace their current antiretroviral treatment regimen (see clinical trials). Patients must not have a history of treatment failure or known mutations associated with resistance to the antiretroviral components of Genvoya.

Genvoya is a fixed dose combination of one integrase inhibitor, one pharmacokinetic enhancer and two nucleos(t)ide HIV‐1 reverse transcriptase inhibitors.

Specific conditions of registration applying to these goods


The Genvoya (elvitegravir (150mg), cobicistat (150 mg), emtricitabine (200 mg) and tenofovir alafenamide fumarate (10 mg)) Fixed Dose Combination Tablets Risk Management Plan (RMP): "The European Risk Management Plan for Genvoya (Version: 0.1, dated 10 November 2014), as qualified by the Australian Specific Annex as Annex 13 (Version: 1.0, dated December 2015), and any subsequent revisions, as agreed with the TGA will be implemented in Australia.

Attachment 1. Product Information


The PI approved for Genvoya at the time this AusPAR was published is at Attachment 1. For the most recent PI, please refer to the TGA website at .

Attachment 2. Extract from the Clinical Evaluation Report


Therapeutic Goods Administration

PO Box 100 Woden ACT 2606 Australia

Email: info@tga.gov.au Phone: 1800 020 653 Fax: 02 6232 8605



https://www.tga.gov.au



1 Markowitz M, et al. Phase I/II study of the pharmacokinetics, safety and antiretroviral activity of tenofovir alafenamide, a new prodrug of the HIV reverse transcriptase inhibitor tenofovir, in HIV-infected adults. J Antimicrob Chemother 2014; 69: 1362–1369.

2 Gilead. Press Releases. http://www.gilead.com/news/press-releases/2015/9/gileads-investigational-fixeddose-combination-of-emtricitabinetenofovir-alafenamide-ftaf-meets-primary-48week-objective-in-phase-3-study (accessed 7 October 2015)

3 Approval has since been granted in the EU on 19 November 2015.

4 Approved in Canada on 27 November 2015.

5 https://www.tga.gov.au/therapeutic-goods-orders

6 This issue was resolved prior to registration with the sponsor appropriately tightening the limit.

7 AUCtau = Area under the concentration versus time curve to the end of the dosing period

8 Cmax = Peak plasma concentration

9 Ctau = Plasma concentration at the end of the dosing period

10 ICH M3(R2) Guidance on nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals. Questions & answers (R2). Combination drug toxicity testing, March 2012.

11 TgRasH2 mice is a transgenic mouse carrying the three copies of human prototype c-Ha-ras oncogenes with endogenous promoter and enhancer in tandem. Tg-rasH2 mice are sensitive to both genotoxic and non-genotoxic human carcinogens and show no response to non-carcinogens.

12 Birkus G et al. Cathepsin A is a major hydrolase catalysing the intracellular hydrolysis of the antiretroviral nucleotide phosphnoamidate prodrugs GS-7340 and GS-9131. Antimicrob Agents Chemoth 2007; 51: 1-7.

13 The approved PI has been amended to ‘Genvoya should not be used in conjunction with protease inhibitors that are inhibitors of cathepsin A (such as anti-Hepatitis C agents telaprevir and boceprevir) due to potential drug-drug interactions including altered and/or suboptimal pharmacokinetics of tenofovir alafenamide.’

14 EMA CHMP (2007). Reflection paper on in vitro investigation of mitochondrial toxicity of anti-HIV nucleoside reverse transcriptase inhibitors (EMEA/CHMP/SWP/8212/2007).

15 Cherrington JM et al. Kinetic interaction of the diphosphates of 9-(2-phosphonylmethoxyethyl) adenine and human DNA polymerases a, b, and g. Antivir. Chem. Chemotherap. 1995; 6: 217-221.

16 Cihlar T et al. Incorporation of selected nucleoside phosphonates and anti-human immunodeficiency virus nucleotide analogues into DNA by human DNA polymerases a, b and g. Antivir Chem Chemotherap 1997; 8: 187-195.

17 Hep G2 is a perpetual cell line which was derived from the liver tissue of a 15-year-old Caucasian American male with a well-differentiated hepatocellular carcinoma.

18 In electrocardiography, the PR interval is the period, measured in milliseconds, that extends from the beginning of the P wave (the onset of atrial depolarization) until the beginning of the QRS complex (the onset of ventricular depolarization); it is normally between 120 and 200ms in duration.

19 The Caco-2 cell line is a continuous cell line of heterogeneous human epithelial colorectal adenocarcinoma cells.

20 ICH M3 (R2) Guidance on nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals M3(R2)

21 EMA (2012) ICH guideline M3 (R2) –questions and answers (EMA/CHMP/ICH/507008/2011).

22 CPMP/ICH/299/95 Note for guidance on carcinogenicity: testing for carcinogenicity of pharmaceuticals

23 ICH Topic S 5 (R2); Note for guidance on the detection of toxicity to reproduction for medicinal products & toxicity to male fertility (CPMP/ICH/386/95).

24 FDA Reference ID: 3244145,

25 EMA/CHMP/SAWP/214541/2013, EMEA H/SA/2410/FU/1/2013/1

26 Pregnancy category B2 Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals are inadequate or may be lacking, but available data show no evidence of an increased occurrence of fetal damage.

27 Pregnancy category B1 Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have not shown evidence of an increased occurrence of fetal damage.

28 Pregnancy category B3 Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans.

29 These issues were resolved to the satisfaction of the TGA prior to registration.

30 EMA (2012) ICH guideline M3 (R2) –questions and answers (EMA/CHMP/ICH/507008/2011).

31 eGFRCG: estimated glomerular filtration rate(GFR) calculated using the Cockcroft-Gault equation, aGFR,:actual GFR, eGFR CKD-EPI, cys C:Chronic Kidney Disease Epidemiology Collaboration cystatin C method for calculating GFR, eGFR CKD-EPI, creatinine:eGFR calculated using the CKD-EPI serum creatinine method

32 Yin, MT et al. Increasing clarity on bone loss associated with antiretroviral initiation. JID 2011:203;1705-1707

33 Huang JS et al. Bone mineral density effects of randomised regimen and nucleoside reverse transcriptase inhibitor selection from ACTG A5142. HIV Clin Trials. 2013 ; 14: 224–234

34 Catalan J, et al. HIV infection and mental health: suicidal behaviour--systematic review. Psychology, health & medicine 2011; 16: 588-611.

35 Hill A, Sabin C. Designing and interpreting HIV non-inferiority trials in naive and experienced patients. AIDS 2008;22:913-921.

36 U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER). Guidance for Industry Human Immunodeficiency Virus-1 Infection: Developing Antiretroviral Drugs for Treatment. November 2015
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