RUKOBIA Prolonged-release tablet Ref.[115041] Active ingredients: Fostemsavir

Pharmacotherapeutic group: Antivirals for systemic use, other antivirals
ATC code: J05AX29

Mechanism of action

Fostemsavir is a prodrug without significant antiviral activity that is hydrolysed to the active moiety, temsavir, upon cleavage of a phosphonooxymethyl group in vivo (see section 5.2). Temsavir binds directly to the gp120 subunit within the HIV-1 envelope glycoprotein gp160 and selectively inhibits the interaction between the virus and cellular CD4 receptor, thereby preventing viral entry into, and infection of, host cells.

Pharmacodynamic effects

Antiviral activity in cell culture

Temsavir exhibited variable activity across HIV-1 subtypes. Temsavir IC₅₀ value ranged from 0.01 to >2000 nM against clinical isolates of subtypes A, B, B', C, D, F, G and CRF01_AE in PBMCs. Temsavir was not active against HIV-2. Due to high frequencies of polymorphism S375H (98%) and S375M/M426L/M434I (100%) temsavir is not active against Group O and Group N (see section 4.4).

Against a panel of 1337 clinical isolates tested with the PhenoSense Entry assay, the mean IC₅₀ value was 1.73 nM (range 0.018 to >5000 nM). Isolates tested included subtype B (n=881), C (n=156), F1 (n=48), A (n=43), BF1 (n=29), BF (n=19), A1 (n=17) and CRF01_AE (n=5). Subtype CRF01_AE was associated with higher IC₅₀ values (5/5 isolates with temsavir IC₅₀ values >100 nM). CRF01_AE is considered naturally resistant to temsavir on the basis of available data, due to the presence of polymorphisms at positions S375H and M475I (see below).

Antiviral activity in combination with other antiviral agents

When tested with temsavir in vitro, no antagonism was seen with abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir disoproxil, zidovudine, efavirenz, nevirapine, atazanavir, indinavir, lopinavir, ritonavir, saquinavir, enfuvirtide, maraviroc, ibalizumab, delavirdine, rilpivirine, darunavir, dolutegravir or raltegravir. In addition, antivirals without inherent anti-HIV activity (entecavir, ribavirin) have no apparent effect on temsavir activity.

Resistance in vitro

Serial passage of lab-strains LAI, NL4-3, or Bal, in increasing concentrations of temsavir (TMR) over 14 to 49 days resulted in gp120 substitutions at L116, A204, M426, M434 and M475. Phenotypes of recombinant LAI viruses containing TMR-selected substitutions were investigated. Additionally, phenotypes of viruses with substitutions at position S375 that were identified in pre-treatment samples in fostemsavir clinical studies were evaluated. The phenotypes of those considered clinically relevant are tabulated below (Table 3).

Table 3. Phenotypes of recombinant LAI viruses containing clinically relevant gp120 substitutions:

Note: The phenotype of substitutions at L116 and A204 have been excluded from the table as they are not considered clinically relevant.

Temsavir remained active against laboratory derived CD4-independent viruses.

Cross-Resistance

There was no evidence of cross-resistance to representative agents from other antiretroviral (ARV) classes. Temsavir retained wild-type activity against viruses resistant to the INSTI raltegravir; the NNRTIs rilpivirine and efavirenz; the NRTIs abacavir, lamivudine, tenofovir, zidovudine and the PIs atazanavir and darunavir. Additionally, abacavir, tenofovir, efavirenz, rilpivirine, atazanavir, darunavir and raltegravir retained activity against site-directed mutant viruses with reduced temsavir susceptibility (S375M, M426L, or M426L plus M475I).

No cross-resistance was observed between temsavir and maraviroc or enfuvirtide. Temsavir was active against viruses with resistance to enfuvirtide. Some CCR5-tropic, maraviroc-resistant, viruses showed reduced susceptibility to temsavir, however, there was no absolute correlation between maraviroc resistance and reduced sensitivity to temsavir. Maraviroc and enfuvirtide retained activity against clinical envelopes from the Phase IIa study (206267) that had reduced susceptibility to temsavir and contained S375H, M426L, or M426L plus M475I substitutions.

Temsavir was active against several ibalizumab-resistant viruses. Ibalizumab retained activity against site-directed mutant viruses that had reduced susceptibility to temsavir (S375M, M426L, or M426L plus M475I). HIV-1 gp120 E202 was identified as a rare treatment-emergent substitution in BRIGHTE that can reduce susceptibility to temsavir, and, depending on the sequence context of the envelope, may also result in reduced susceptibility to ibalizumab.

Virologic response at Day 8 by genotype and phenotype in BRIGHTE

The effect of the gp120 resistance-associated polymorphisms (RAPs) on response to fostemsavir functional monotherapy at Day 8 was assessed in the Phase III study (BRIGHTE ²⁰⁵⁸⁸⁸) in heavily treatment-experienced adult subjects. The presence of gp120 RAPs at key sites S375, M426, M434, or M475 was associated with a lower overall decline in HIV-1 RNA and fewer subjects achieving >0.5 log₁₀ decline in HIV-1 RNA compared with subjects with no changes at these sites (Table 4).

The fold change in susceptibility to temsavir for subject isolates at screening was highly variable ranging from 0.06 to 6,651. The effect of screening fostemsavir phenotype on response of >0.5 log₁₀ decline at Day 8 was assessed in the ITT-E population (Table 5). While there does appear to be a trend toward reduced clinical response at higher TMR IC₅₀ values, this baseline variable fails to reliably predict efficacy outcomes in the intended use population.

Table 4. Virologic Response Category at Day 8 (Randomised Cohort) by presence of gp120 resistance-associated polymorphisms (RAPs) at baseline – ITT-E Population:

^a Change in HIV-1 RNA (log₁₀ c/mL) from Day 1 at Day 8, n (%)
^b Subjects with Day 8 Virologic Response Category unevaluable due to missing Day 1 or Day 8 HIV-1 RNA, n (%)
Note: S375Y was not included in the list of substitutions pre-defined for analysis in the phase III study, although. it was subsequently identified as a novel polymorphism and shown to substantially decrease TMR susceptibility in a LAI envelope in vitro.
RAPs = Resistance-associated polymorphisms

Table 5. Virologic Response Category at Day 8 (Randomised Cohort) by Phenotype at baseline – ITT-E Population:

Antiviral activity against subtype AE

Within HIV-1 Group M, temsavir showed considerably reduced antiviral activity against subtype AE isolates. Rukobia is not recommended to be used to treat infections due to HIV-1 Group M subtype CRF01_AE strains. Genotyping of subtype AE viruses identified polymorphisms at amino acid positions S375H and M475I in gp120, which have been associated with reduced susceptibility to fostemsavir. Subtype AE is a predominant subtype in Southeast Asia, but it is not found frequently elsewhere.

Two subjects in the Randomised Cohort had subtype AE virus at screening. One subject (EC₅₀ fold change >4,747-fold and gp120 substitutions at S375H and M475I at baseline) did not respond to fostemsavir at Day 8. The second subject (EC₅₀ fold change 298-fold and gp120 substitution at S375N at baseline) received placebo during functional monotherapy. Both subjects had HIV RNA <40 copies/mL at Week 96 while receiving fostemsavir plus OBT that included dolutegravir.

Emergence of Resistance in vivo

The percentage of subjects who experienced virologic failure through the Week 96 analysis was 25% (69/272) in the randomised cohort (Table 6). Overall, 50% (26/52) of the viruses of evaluable subjects with virologic failure in the Randomised Cohort had treatment-emergent gp120 genotypic substitutions at 4 key sites (S375, M426, M434, and M475).

The median temsavir EC₅₀ fold change at failure in randomised evaluable subject isolates with emergent gp120 substitutions at positions 375, 426, 434, or 475 (n=26) was 1,755-fold compared to 3-fold for isolates with no emergent gp120 substitutions at these positions (n=26).

Of the 25 evaluable subjects in the Randomised Cohort with virologic failure and emergent substitutions S375N and M426L and (less frequently) S375H/M, M434I and M475I, 88% (22/25) had temsavir IC₅₀ FC Ratio >3-fold (FC Ratio is temsavir IC₅₀ FC on-treatment compared to baseline).

Overall, 21/69 (30%) of the virus isolates of patients with virologic failure in the Randomised Cohort had genotypic or phenotypic resistance to at least one drug in the OBT at screening and in 48% (31/64) of the virologic failures with post-baseline data the virus isolates had emergent resistance to at least one drug in the OBT.

In the Non-randomised Cohort virologic failures were observed in 51% (50/99) through Week 96 (Table 6). While the proportion of viruses with gp120 resistance-associated substitutions at screening was similar between patients in the Randomised and Non-randomised Cohorts, the proportion of virus isolates with emergent gp120 resistance-associated substitutions at the time of failure was higher among Non-randomised patients (75% vs. 50%). The median temsavir EC₅₀ fold change at failure in Non-randomised evaluable subject isolates with emergent substitutions at positions 375, 426, 434, or 475 (n=33) was 4,216-fold and compared to 402-fold for isolates without substitutions at these positions (n=11).

Of the 32 evaluable virologic failures in the Non-randomised Cohort with emergent substitutions S375N and M426L and (less frequently) S375H/M, M434I and M475I, 91% (29/32) had temsavir IC₅₀ FC Ratio >3-fold.

Overall, 45/50 (90%) of the viruses of patients with virologic failure in the Non-randomised Cohort had genotypic or phenotypic resistance to at least one drug in the OBT at screening and in 55% (27/49) of the virologic failures with post-baseline data the virus isolates had emergent resistance to at least one drug in the OBT.

Table 6. Virologic Failures in BRIGHTE Trial:

EN RAPs = Envelope resistance-associated polymorphisms; EN RAS = Envelope resistance-associated substitutions.
^a Substitutions at positions: S375, M426, M434, M475.
^b Substitutions: S375H, S375M, S375N, M426L, M434I, M475I.
^c Temsavir IC₅₀ fold change ratio >3-fold is outside of the usual variability observed in the PhenoSense Entry assay.

Effects on electrocardiogram

In a randomised, placebo- and active-controlled, double-blind, cross-over thorough QT study, 60 healthy subjects received oral administration of placebo, fostemsavir 1 200 mg once daily, fostemsavir 2 400 mg twice daily and moxifloxacin 400 mg (active control) in random sequence. Fostemsavir administered at 1 200 mg once daily did not have a clinically meaningful effect on the QTc interval as the maximum mean time-matched (2-sided 90% upper confidence bound) placebo-adjusted QTc change from baseline based on Fridericia’s correction method (QTcF) was 4.3 (6.3) milliseconds (below the clinically important threshold of 10 milliseconds). However, fostemsavir administered at 2 400 mg twice daily for 7 days was associated with a clinically meaningful prolongation of the QTc interval as the maximum mean time-matched (2-sided 90% upper confidence bound) for the placebo- adjusted change from baseline in QTcF interval was 11.2 (13.3) milliseconds. Steady-state administration of fostemsavir 600 mg twice daily resulted in a mean temsavir C_max approximately 4.2-fold lower than the temsavir concentration predicted to increase QTcF interval 10 milliseconds (see section 4.4).

Clinical efficacy

The efficacy of fostemsavir in HIV-infected, heavily treatment-experienced adult subjects is based on data from a Phase III, partially-randomised, international, double-blind, placebo-controlled trial 17 BRIGHTE (205888), conducted in 371 heavily-treatment experienced HIV-1 infected subjects with multi-class resistance. All subjects were required to have a viral load greater than or equal to 400 copies/mL and ≤2 antiretroviral (ARV) classes remaining at baseline due to resistance, intolerability, contraindication, or other safety concerns.

At Screening, subjects from the Randomised Cohort had one but no more than two fully active and available ARVs which could be combined as part of an efficacious background regimen. 272 subjects received either blinded fostemsavir, 600 mg twice daily (n= 203), or placebo (n= 69), in addition to their current failing regimen, for 8 days of functional monotherapy. Beyond Day 8, Randomised subjects received open-label fostemsavir, 600 mg twice daily, plus an optimised background therapy (OBT). The Randomised Cohort provides primary evidence of efficacy of fostemsavir.

Within the Non-randomised Cohort, 99 subjects with no fully active, approved ARVs available at Screening, were treated with open-label fostemsavir, 600 mg twice daily, plus OBT from Day 1 onward. The use of an investigational drug(s) as a component of the OBT was permitted.

Table 7. Summary of Demographic and Baseline Characteristics in BRIGHTE trial-ITT-E Population:

^a Subjects randomised to the placebo group received fostemsavir 600 mg BID during the open-label phase.
^b Age is imputed when full date of birth is not provided.
^c History of AIDS = Yes if a subject has Nadir CD4+ count <200 cells/mm³, or if response to “Does subject have AIDS?” on Disease History CRF is Yes.
^d N=15 (15%) received ibalizumab, which was an investigational agent at the start of BRIGHTE

The primary endpoint analysis, based on the adjusted mean decline in HIV-1 RNA from Day 1 at Day 8 in the Randomised Cohort, demonstrated superiority of fostemsavir to placebo (0.79 vs. 0.17 log₁₀ decline, respectively; p<0.0001, Intent To Treat-Exposed [ITT-E] population) (Table 8).

Table 8. Plasma HIV-1 RNA log₁₀ (copies/mL) Change from Day 1 at Day 8 (Randomised Cohort) in BRIGHTE trial – ITT-E Population:

^a Mean adjusted by Day 1 log₁₀ HIV-1 RNA.
^b Difference: Fostemsavir – Placebo.
^c Mean value of viral load change from baseline (Fostemsavir = Placebo).
Note: p-value from Levene’s Test of Homogeneity of variance 0.2082.
^d Two subjects (both in the fostemsavir arm) who had missing Day 1 HIV-1 RNA values were not included in the analysis.

At Day 8, 65% (131/203) and 46% (93/203) of subjects had a reduction in viral load from baseline >0.5 log₁₀ c/mL and >1 log₁₀ c/mL, respectively, in the fostemsavir group, compared with 19% (13/69) and 10% (7/69) of subjects, respectively, in the placebo group. By subgroup analysis, fostemsavir-treated Randomised subjects with baseline HIV-1 RNA >1, 000 c/mL achieved a median decline in viral load of 1.02 log₁₀ c/mL at Day 8, compared with 0.00 log₁₀ c/mL decline in subjects treated with blinded placebo.

Median change in HIV-1 RNA log₁₀ c/mL from Day 1 to Day 8 of FTR functional monotherapy was similar in subjects with subtype B and non-B subtype virus (F1, BF1 and C). There was a reduced median response at Day 8 observed in subtypes A1 (n=2) and AE (n=1) but sample size was limited (Table 9).

Table 9. HIV-1 RNA (log₁₀ c/mL) Change from Day 1 at Day 8 by HIV subtype at Baseline:

Note: FTR Monotherapy refers to functional monotherapy where FTR is given on a background of failing ARV therapy.
^a Number of subjects with both Day 1 and Day 8 data available
^b Other includes (n): Non-analysable/Not reported (1), G (2); Recombinant virus/Mixtures (4).

Virologic outcomes by ITT-E Snapshot Analysis at Weeks 24, 48 and 96 are shown in Tables 10 and 11 for the Randomised and Non-randomised Cohorts, respectively.

Table 10. Virologic Outcomes (HIV-1 RNA <40 copies/mL) at Weeks 24, 48 and 96 with Fostemsavir (600 mg twice daily) plus Optimised Background Treatment (Randomised Cohort) in BRIGHTE trial (ITT-E Population, Snapshot Algorithm):

N = Number of subjects in the Randomised Cohort.
OBT = Optimised Background Therapy; DRV = Darunavir; DTG = Dolutegravir
^* Includes subjects who never initiated OBT, were incorrectly assigned to the Randomised Cohort or had one or more active ARV agents available at screening but did not use these as part of the initial OBT.

In the Randomised Cohort, viral load <200 HIV-1 RNA copies/mL was achieved in 68%, 69% and 64% of subjects at Weeks 24, 48 and 96, respectively. At these timepoints, the proportion of subjects with viral load <400 HIV-1 RNA copies/mL was 75%, 70% and 64%, respectively (ITT-E, Snapshot algorithm). Mean changes in CD4+ T-cell count from baseline continued to increase over time (i.e. 90 cells/mm³ at Week 24, 139 cells/mm³ at Week 48 and 205 cells/mm³ at Week 96). Based on a sub-analysis in the Randomised Cohort, subjects with the lowest baseline CD4+ T-cell counts (<20 cells/mm³) had a similar increase in CD4+ count over time compared with subjects with higher baseline CD4+ T-cell count (>50, >100, >200 cells/mm³).

Table 11. Virologic Outcomes (HIV-1 RNA <40 copies/mL) at Weeks 24, 48 and 96 with Fostemsavir (600 mg twice daily) plus Optimised Background Treatment (Non-Randomised Cohort) in BRIGHTE trial (ITT-E Population, Snapshot Algorithm):

In the Non-randomised Cohort (subjects with no fully active and approved ARVs available at Screening), the proportion of subjects with HIV-1 RNA <200 copies/mL was 42%, 43% and 39%, and the proportion of subjects with HIV-1 RNA <400 copies/mL was 44%, 44% and 40%, at Weeks 24, 48 and 96, respectively (ITT-E, Snapshot algorithm). Mean changes in CD4+ cell count from baseline increased over time: 41 cells/mm³ at Week 24, 64 cells/mm³ at Week 48 and 119 cells/mm³ at Week 96.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Rukobia in one or more subsets of the paediatric population in HIV infection (see section 4.2 for information on paediatric use).