JULUCA Film-coated tablet Ref.[51355] Active ingredients: Dolutegravir Dolutegravir and Rilpivirine Rilpivirine

Pharmacotherapeutic group: Antivirals for systemic use, antivirals for treatment of HIV infections, combinations
ATC code: J05AR21

Mechanism of action

Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral Deoxyribonucleic acid (DNA) integration which is essential for the HIV replication cycle.

Rilpivirine is a diarylpyrimidine non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1. Rilpivirine activity is mediated by non-competitive inhibition of HIV-1 reverse transcriptase (RT). Rilpivirine does not inhibit the human cellular DNA polymerases α, β and γ.

Pharmacodynamic effects

Antiviral activity in cell culture

The IC₅₀ for dolutegravir against various laboratory strains using PBMC was 0.5 nM, and when using MT-4 cells it ranged from 0.7-2 nM. Similar IC₅₀s were seen for clinical isolates without any major difference between subtypes; in a panel of 24 HIV-1 isolates of clades A, B, C, D, E, F and G and group O the mean IC₅₀ value was 0.2 nM (range 0.02-2.14). The mean IC₅₀ for 3 HIV-2 isolates was 0.18 nM (range 0.09-0.61).

Rilpivirine exhibited activity against laboratory strains of wild-type HIV-1 in an acutely infected T-cell line with a median IC₅₀ value for HIV-1/IIIB of 0.73 nM (0.27 ng/mL). Rilpivirine demonstrated limited in vitro activity against HIV-2 with IC₅₀ values ranging from 2 510 to 10 830 nM.

Rilpivirine also demonstrated antiviral activity against a broad panel of HIV-1 group M (clades A, B, C, D, F, G, H) primary isolates with IC₅₀ values ranging from 0.07 to 1.01 nM and group O primary isolates with EC₅₀ values ranging from 2.88 to 8.45 nM.

Effect of human serum and serum proteins

In 100% human serum, the dolutegravir mean protein fold shift was 75 fold, resulting in protein adjusted IC₉₀ of 0.064 µg/mL.

A reduction in the antiviral activity of rilpivirine was observed in the presence of 1 mg/mL alpha-1-acid glycoprotein, 45 mg/mL human serum albumin, and 50% human serum as demonstrated by median IC₅₀ rates of 1.8, 39.2 and 18.5, respectively.

Resistance

Resistance in vitro

Serial passage is used to study resistance evolution in vitro. For dolutegravir, when using the laboratory strain HIV-1 IIIB during passage over 112 days, mutations selected appeared slowly, with substitutions at positions S153Y and F; these mutations were not selected in patients treated with dolutegravir in the clinical studies. Using strain NL432, integrase mutations E92Q (fold change [FC] 3) and G193E (FC 3) were selected. These mutations have been selected in patients with pre-existing raltegravir resistance and who were then treated with dolutegravir (listed as secondary mutations for dolutegravir).

In further selection experiments using clinical isolates of subtype B, mutation R263K was seen in all five isolates (after 20 weeks and onwards). In subtype C (n=2) and A/G (n=2) isolates the integrase substitution R263K was selected in one isolate, and G118R in two isolates. R263K was reported from two individual patients with subtype B and subtype C in the Phase III clinical program for ART experienced, INI naive subjects, but without effects on dolutegravir susceptibility in vitro. G118R lowers the susceptibility to dolutegravir in site directed mutants (FC 10), but was not detected in patients receiving dolutegravir in the Phase III program.

Primary mutations for raltegravir/elvitegravir (Q148H/R/K, N155H, Y143R/H/C, E92Q, T66I) do not affect the in vitro susceptibility of dolutegravir as single mutations. When mutations listed as secondary integrase inhibitor associated mutations (for raltegravir/elvitegravir) are added to primary mutations (excluding at Q148) in experiments with site directed mutants, dolutegravir susceptibility remains at or near wildtype level. In the case of the Q148-mutation viruses, increasing dolutegravir FC is seen as the number of secondary mutations increase. The effect of the Q148-based mutations (H/R/K) was also consistent with in vitro passage experiments with site directed mutants. In serial passage with strain NL432-based site directed mutants at N155H or E92Q, no further selection of resistance was seen (FC unchanged around 1). In contrast, starting passage with mutants with mutation Q148H (FC 1), a variety of raltegravir associated secondary mutations accumulated with a consequent increase of FC to values >10.

A clinically relevant phenotypic cut-off value (FC vs wild type virus) has not been determined; genotypic resistance was a better predictor for outcome.

Rilpivirine-resistant strains were selected in cell culture starting from wild type HIV-1 of different origins and clades as well as NNRTI-resistant HIV-1. The most commonly observed amino acid substitutions that emerged included: L100I, K101E, V108I, E138K, V179F, Y181C, H221Y, F227C and M230I. Resistance to rilpivirine was considered present when FC in EC₅₀ value was above the biological cut-off (BCO) of the assay.

Resistance in vivo

Through 48 Weeks with comparative data two subjects receiving dolutegravir plus rilpivirine and two subjects continuing their current antiretroviral regimen (CAR) experienced confirmed virologic failure leading to withdrawal (CVW) criteria across the pooled SWORD-1 (201636) and SWORD-2 (201637) studies. Overall eleven subjects receiving dolutegravir plus rilpivirine met CVW through Week 148, see Table 3. The NNRTI-associated substitutions E138E/A and M230M/L were detected in three and two subjects at time of withdrawal.

Table 3. Summary of resistance by drug class for subjects with confirmed virologic withdrawal in early and late switch phases of the SWORD studies:

^* The resistance testing at virologic failure time failed for one subject, therefore, details are not included in this table.
^** CVW was met with 2 consecutive viral loads after Day 1 ≥50 c/mL, with the second one being >200 c/mL.
^*** The baseline assay only provides genotypic data, and not phenotypic data. CAR = current antiretroviral regimen; DTG+RPV = dolutegravir plus rilpivirine SVW = suspected virologic withdrawal criteria; CVW = confirmatory virologic withdrawal criteria; BL = baseline resistance testing results; VW = resistance testing results when CVW criteria have been met; Wk = week; UNS = unscheduled visit; “ND” Baseline testing was not performed as PBMC/Whole blood samples were note collected; “none” indicates no resistance observed; “NR” indicates data are not reported due to assay failure or sample unavailability.

In previously untreated patients receiving dolutegravir + 2 NRTIs in Phase IIb and Phase III, no development of resistance to the integrase class, or to the NRTI class was seen (n=876, follow-up of 48-96 weeks). In patients with prior failed therapies, but naïve to the integrase class (SAILING study), integrase inhibitor substitutions were observed in 4/354 patients (follow-up 48 weeks) treated with dolutegravir, which was given in combination with an investigator selected background regimen (BR). Of these four, two subjects had a unique R263K integrase substitution, with a maximum FC of 1.93, one subject had a polymorphic V151V/I integrase substitution, with maximum FC of 0.92, and one subject had pre-existing integrase mutations and is assumed to have been integrase inhibitor experienced or infected with integrase inhibitor resistant virus by transmission. The R263K mutation was also selected in vitro (see above).

From rilpivirine Phase IIIstudies, in the week 48 pooled resistance analysis conducted with previously untreated patients, 62 (of a total of 72) virologic failures in the rilpivirine arm had resistance data at baseline and time of failure. In this analysis, the resistance-associated mutations (RAMs) associated with NNRTI resistance that developed in at least 2 rilpivirine virologic failures were: V90I, K101E, E138K, E138Q, V179I, Y181C, V189I, H221Y, and F227C. In thestudies, the presence of the mutations V90I and V189I, at baseline, did not affect response. The E138K substitution emerged most frequently during rilpivirine treatment, commonly in combination with the M184I substitution. In the week 48 analysis, 31 out of 62 of rilpivirine virologic failures had concomitant NNRTI and NRTI RAMs; 17 of those 31 had the combination of E138K and M184I. The most common mutations were the same in the week 48 and week 96 analyses. From the week 48 to the week 96 analysis, 24 (3.5%) and 14 (2.1%) additional virologic failures occurred in the rilpivirine and efavirenz arm, respectively.

Cross-resistance

Site-directed INI mutant virus

Dolutegravir activity was determined against a panel of 60 INI-resistant site-directed mutant HIV-1 viruses (28 with single substitutions and 32 with 2 or more substitutions). The single INI-resistance substitutions T66K, I151L, and S153Y conferred a greater than 2-fold decrease in dolutegravir susceptibility (range: 2.3- fold to 3.6-fold from reference). Combinations of multiple substitutions T66K/L74M, E92Q/N155H, G140C/Q148R, G140S/Q148H, R or K, Q148R/N155H, T97A/G140S/Q148, and substitutions at E138/G140/Q148 showed a greater than 2-fold decrease in dolutegravir susceptibility (range: 2.5-fold to 21- fold from reference).

Site-directed NNRTI mutant virus

In a panel of 67 HIV-1 recombinant laboratory strains with one amino acid substitution at RT positions associated with NNRTI resistance, including the most commonly found K103N and Y181C, rilpivirine showed antiviral activity (FC≤BCO) against 64 (96%) of these strains. The single amino acid substitutions associated with a loss of susceptibility to rilpivirine were: K101P, Y181I and Y181V. The K103N substitution did not result in reduced susceptibility to rilpivirine by itself, but the combination of K103N and L100I resulted in a 7-fold reduced susceptibility to rilpivirine.

Considering all of the available in vitro and in vivo data, the following amino acid substitutions, when present at baseline, are likely to affect the activity of rilpivirine: K101E, K101P, E138A, E138G, E138K, E138R, E138Q, V179L, Y181C, Y181I, Y181V, Y188L, H221Y, F227C, M230I or M230L.

Recombinant clinical isolates

Seven hundred and five raltegravir resistant isolates from raltegravir experienced patients were analysed for susceptibility to dolutegravir. Dolutegravir had a <10 FC against 94% of the 705 clinical isolates.

Rilpivirine retained sensitivity (FC ≤ BCO) against 62% of 4786 HIV-1 recombinant clinical isolates resistant to efavirenz and/or nevirapine.

Previously untreated HIV-1 infected adult patients

In a Week 96 pooled analyses of virologic failures with baseline viral load ≤100,000 copies/mL and resistance to rilpivirine (n = 5), subjects had cross-resistance to efavirenz (n = 3), etravirine (n = 4), and nevirapine (n = 1).

Effects on electrocardiogram

The effect of rilpivirine at the recommended dose of 25 mg once daily on the QTcF interval was evaluated in a randomised, placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 60 healthy adults, with 13 measurements over 24 hours at steady-state. Rilpivirine at the recommended dose of 25 mg once daily is not associated with a clinically relevant effect on QTc.

When supratherapeutic doses of 75 mg once daily and 300 mg once daily of rilpivirine were studied in healthy adults, the maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline correction were 10.7 (15.3) and 23.3 (28.4) ms, respectively. Steadystate administration of rilpivirine 75 mg once daily and 300 mg once daily resulted in a mean C_max approximately 2.6-fold and 6.7-fold, respectively, higher than the mean steady-state C_max observed with the recommended 25 mg once daily dose of rilpivirine (see section 4.4).

No relevant effects were seen with dolutegravir on the QTc interval, with doses exceeding the clinical dose by approximately three fold.

Clinical efficacy and safety

The efficacy and safety of switching from an antiretroviral regimen (containing 2 NRTIs plus either an INI, an NNRTI, or a PI) to a dual regimen of dolutegravir 50 mg and rilpivirine 25 mg was evaluated in 2 identical 148-week, randomised, open-label, multicentre, parallel-group, non-inferiority studies SWORD-1 (201636) and SWORD-2 (201637). Subjects were enrolled if they were on their first or second antiretroviral regimen with no history of virological failure, had no suspected or known resistance to any antiretroviral and had been stably suppressed (HIV-1 RNA < 50 copies/mL) for at least 6 months prior to screening. Subjects were randomised 1:1 to continue their CAR or be switched to a two-agent regimen dolutegravir plus rilpivirine administered once daily. The primary efficacy endpoint for the SWORD studies was the proportion of subjects with plasma HIV-1 RNA <50 copies/mL at Week 48 (Snapshot algorithm for the ITTE population).

At baseline, in the pooled analysis, characteristics were similar between treatment arms with the median age of subjects of 43 years (28%, 50 years of age or older; 3%, 65 years of age or older), 22% female, 20% nonwhite and 77% were CDC Class A. Median CD+cell count was about 600 cells per mm³ with 11% having CD4+ cell count less than 350 cells per mm³. In the pooled analysis, 54%, 26%, and 20% of subjects were receiving an NNRTI, PI, or INI (respectively) as their baseline third treatment agent class prior to randomisation.

The pooled primary analysis demonstrated that dolutegravir plus rilpivirine is non-inferior to CAR, with 95% of subjects in both arms achieving the primary endpoint of <50 copies/mL plasma HIV-1 RNA at Week 48 based on the Snapshot algorithm (Table 4).

The primary endpoint and other outcomes (including outcomes by key baseline covariates) for the pooled SWORD-1 and SWORD-2 studies are shown in Table 4.

Table 4. Virologic outcomes of randomised treatment at week 48 (Snapshot algorithm):

^* Adjusted for baseline stratification factors and assessed using a non-inferiority margin of -8%.
^** Non-inferiority of dolutegravir plus rilpivirine to CAR, in the proportion of subjects classified as virologic non-responders, was demonstrated using a non-inferiority margin of 4%. Adjusted difference (95% CI) -0.6 (-1.7, 0.6).
^*** The results of the pooled analysis are in line with those of the individual studies, for which differences in proportions meeting the primary endpoint of <50 copies/mL plasma HIV-1 RNA at Week 48 (based on the Snapshot algorithm) for DTG+RPV versus CAR were -0.6 (95% CI: -4.3; 3.0) for SWORD-1 and 0.2 (95% CI: -3.9; 4.2) for SWORD-2 with a preset noninferiority margin of -10%.
N = Number of subjects in each treatment arm
CAR = current antiretroviral regimen; DTG+RPV = dolutegravir plus rilpivirine;
INI = Integrase inhibitor; NNRTI = Non-nucleoside reverse transcriptase inhibitor;
PI = Protease Inhibitor

At Week 148 in the pooled SWORD-1 and SWORD-2 studies, 84% of subjects who received dolutegravir plus rilpivirine as of study start had plasma HIV-1 RNA <50 copies/mL based on the Snapshot algorithm. In subjects who initially remained on their CAR and switched to dolutegravir plus rilpivirine at Week 52, 90% had plasma HIV-1 RNA <50 copies/mL at Week 148 based on the Snapshot algorithm, which was comparable to the response rate (89%) observed at Week 100 (similar exposure duration) in subjects receiving dolutegravir plus rilpivirine as of study start.

Effects on bone

In a DEXA substudy mean bone mineral density (BMD) increased from Baseline to Week 48 in subjects who switched to dolutegravir plus rilpivirine (1.34% total hip and 1.46% lumbar spine) compared with those who continued on treatment with a TDF-containing antiretroviral regimen (0.05% total hip and 0.15% lumbar spine. Any beneficial effect on fracture rate was not studied.

Pregnancy

No efficacy and safety data are available for the combination of dolutegravir and rilpivirine in pregnancy. Rilpivirine in combination with a background regimen was evaluated in a clinical study of 19 pregnant women during the second and third trimesters, and postpartum. The pharmacokinetic data demonstrate that total exposure (AUC) to rilpivirine as a part of an antiretroviral regimen was approximately 30% lower during pregnancy compared with postpartum (6-12 weeks). Of the 12 subjects that completed the study, 10 subjects were suppressed at the end of the study; in the other 2 subjects an increase in viral load was observed postpartum, for 1 subject due to suspected suboptimal adherence. No mother to child transmission occurred in all 10 infants born to the mothers who completed the study and for whom the HIV status was available. There were no new safety findings compared with the known safety profile of rilpivirine in HIV-1 infected adults.

In limited data from small numbers of women who received dolutegravir 50 mg once daily in combination with a background regimen, the total exposure (AUC) to dolutegravir was 37% lower during the 2nd trimester of pregnancy, and 29% lower during the 3rd trimester of pregnancy, compared with postpartum (6-12 weeks). Of the 29 subjects that completed the study, 27 subjects were suppressed at the end of the study. No mother to child transmission was identified. While 24 infants were confirmed to be uninfected, 5 were indeterminate due to incomplete testing, see section 5.2.

Paediatric population

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