S/GSK1349572, a new integrase inhibitor for the treatment of HIV: promises and challenges
Johannes Carl Christoph Lenz & Ju¨rgen Kurt Rockstroh
University of Bonn, Medicine I, Bonn, Germany
Introduction: The recent introduction of integrase inhibitors (INIs) into the HIV treatment armentarium has had a significant impact on HIV treatment. How- ever, at present, raltegravir twice daily is the only licensed INI featuring a lower genetic barrier compared with boosted protease inhibitors. S/GSK1349572 represents a new INI in current development. It is a once-daily, unboosted INI with low pharmacokinetic variability and predictable exposure-response relationship. Phase IIb studies in antiretroviral-na¨ıve patients have demon- strated non-inferiority to efavirenz-based HIV therapy. Phase II studies in INI- experienced patients show partially retained activity in vivo. Overall, the safety profile of S/GSK1349572 in all studies completed has been very favorable.
Areas covered: A Pubmed and Medline search was carried out on all articles on S/GSK1349572 from 2005 to 2010, including recent abstract presentations from major HIV conferences (CROI 2010, WAC2010, EACS2009, HIV10 and ICAAC2010). The reader will become acquainted with the unique properties of this new INI and will understand the current promises and challenges of the data available from S/GSK1349572.
Expert opinion: S/GSK1349572 represents a new, unboosted, once-daily INI in development with distinct pharmacokinetics and resistance profile, which has showed promising potency and tolerability in the first clinical studies.
Keywords: antiretroviral therapy, HIV, HIV therapy, integrase, integrase inhibitor, S/GSK1349572
Expert Opin. Investig. Drugs (2011) 20(4):537-548
1. Introduction
S/GSK1349572 is a new integrase inhibitor (INI) for treatment of HIV currently entering the Phase III part of its clinical development (Box 1). Being a once-daily, unboosted INI this compound potentially shows some properties distinct from those of the other currently licensed (raltegravir) or in-development (elvitegravir/
r) INIs. Moreover, this new compound is characterized by a low pharmacokinetic (PK) variability and predictable exposure-response relationship again suggesting possible differences to the currently available INIs in clinical use. Also in vitro data suggest a potentially higher genetic barrier and different resistance profile. In the following review all available preclinical and clinical data of S/GSK1349572 will be presented and critically discussed.
2. Overview of the market
So far only one INI, namely, raltegravir, is licensed for treatment of treatment- na¨ıve as well as treatment-experienced patients. Raltegravir has been developed as a twice-daily drug and is given 400 mg b.i.d. Currently, once-daily raltegravir is being investigated against twice-daily raltegravir in a randomized, controlled Phase III study in therapy-na¨ıve individuals [1]. The first results of this study are
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Box 1. Drug summary.
Drug name Phase
Indication Mechanism of action Route of
administration Chemical structure
Pivotal trials S/GSK1349572
IIa (completed), IIb (24 week data, ongoing)
HIV infection Integrase inhibition
Per os
Na+ O- O
F O
H
N N
F O
Spring-Trial
N H
CH3
O
expected in early 2011. A switch study with once-daily ralte- gravir (ODIS trial) has been presented with inconclusive results and increasing rates of virological failure in patients with previous NRTI resistance, allowing no true assessment of once-daily raltegravir at this point [2]. As all other first- line treatments for HIV (whether 2NRTI + NNRTI or 2NRTI + boosted PI) can be administered once daily clearly the need for a safe once-daily INI remains. As SWITCHMRK and STARTMRK both have led to the emergence of INI associated resistance in virologically failing patients a low- moderate genetic barrier has been postulated for raltegravir [3], clearly suggesting that newer INIs that require more mutation steps for achieving resistance and going hand in hand with an increased genetic barrier may be of some clinical utility. Even- tually, it is hoped that INIs that work even in the presence of prior acquired integrase mutations, allowing the use of new active compounds in patients desperately waiting for new options in salvage therapy after multiple prior treatment fail- ures, can be developed. The other new INI elvitegravir, which is also entering Phase III clinical development at present, has also been designed as a once-daily drug but does require boosting. Instead of ritonavir boosting, which obviously is associated with some short- and long-term toxicities, this compound is studied in combination with cobicistat, a new PK-booster currently under development [4-6].
3. Chemistry
S/GSK1349572 is based on a carbamoyl pyridone scaffold pro- viding a flat planar core [7]. After multiple substitutions and changes to improve in vivo stability, bioavailability, potency and activity against integrase-resistant virus S/GSK1349572 [IUPAC name: (4R,9aS)-5-hydroxy-2-methyl-6,10-dioxo- 3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene- 7-carboxylic acid- 2,4 difluorobenzylamide] was developed. It is a chiral non-racemic (enantiomeric excess > 98%) compound with a molecular mass of 419 g/mol.
4. Pharmacodynamics
HIV integrase is one of the key enzymes in the HIV replica- tion cycle. The 288 amino acid protein that is encoded by the pol gene is released from the viral particle by protease- mediated cleavage during viral maturation after fusion of the viral particle with the host cell membrane. It has three struc- turally independent domains [8]. The N-terminal domain promotes protein polymerization by a non-conventional HHCC zinc finger motif. The central catalytic core domain contains a canonical D,D(35)E motif. The catalytic activity requires the presence of a metallic co-factor that binds to the D,D(35)E residues. The C-terminal domain binds DNA non-specifically. The main function of integrase is to catalyze the covalent insertion of the reverse-transcribed viral DNA into the host cells genome [9]. The integration is a two- step process starting with binding of integrase dimers to both ends of viral DNA and catalyzing an endonucleotide cleavage. This first step is known as 3¢-processing and results in the elimination of a dinucleotide generating reactive 3¢-hydroxyls [10]. The second reaction is the strand transfer reaction. During this reaction both viral DNA ends are covalently linked to the cellular genomic DNA of the host cell. Simultaneous binding of both ends of the viral DNA to the cellular DNA is facilitated by formation of an integrase tetramer approaching the cleaved viral 3¢-ends to host cell DNA [11]. After the strand transfer unpaired bases are cleaved and filled by uncharacterized cellular DNA repair mechanisms.
Although targeting of various stages of the integration process could theoretically inhibit viral replication, all drugs available or in clinical trials interact with the second step [12] and are, therefore, defined as integrase strand transfer inhibitors [13].
These inhibitors interact with the integrase when associated with the ends of the viral DNA [14]. The binding of these INIs is mediated by chelating the metal cation or cations present in the active site [15,16]. Integrase strand transfer inhibitors recog- nize a specific site close to the D,D(35)E catalytic motif. This site is exposed following a change in conformation induced by 3¢-processing of the viral DNA [17]. The occupation of this site prevents binding to the target DNA and results in selective inhibition of the strand-transfer reaction [13].
5. Pharmacokinetics
Pharmacokinetics of S/GSK1349572 was assessed in random- ized, double-blind, placebo controlled single-dose and multi- ple-dose, dose escalation studies in healthy volunteers [18]. S/GSK1349572 was delivered as a suspension in these studies.
Administration of a single dose (2, 5, 10, 25, 50, 100 mg or placebo, n = 5 — 8/arm) showed a rapid absorption with a Cmax at 0.5 — 1.25 h post dose. The plasma concentration of S/GSK1349572 declined bi-exponentially. The terminal
elimination half-life (t1/2) ranged from 13 to 15 h. The
AUC increased proportionally from 2 to 100 mg. Cmax was slightly less than dose proportional. In a repeat dose study vol- unteers received 10, 25 and 50 mg of S/GSK1349572 or pla- cebo (n = 8, 10, 8 and 6, respectively) once daily for 10 days. AUC0 — t and Ct showed dose proportional increases over the 10 — 50 mg dose range. The increase in Cmax was slightly less than dose proportional. Steady state was achieved by approx-
imately day 5 of dosing. For the 50 mg cohort the pharmaco- kinetic parameters at steady state were: Cmax 6.16 µg/ml (coefficient of variation [CV] 15%), Tmax 1.00 h (median, range: 0.50 — 2.00), AUC0 — t 76.8 µg*h/ml (CV 19%),
Cmin 1.48 µg/ml (CV 25%) and Ct 1.64 µg/ml (CV 25%).
The intersubject pharmacokinetic variability was low.
To evaluate the effect of the fast/fed status on the pharmaco- kinetics of S/GSK1349572, 12 healthy volunteers received two 10-mg tablets with and without a 30% fat meal [19]. The intake of food had no impact on drug exposure.
6. Metabolism
In an article by Song et al. it is stated that according to unpub- lished data S/GSK1349572 is primarily metabolized via glucuronidation by UGT1A1 although CYP3A4 isoenzymes are also expected to have a minor role [20].
A mass balance study of radioactively labeled S/GSK1349572 has been completed to determine and quan- tify S/GSK1349572-related metabolites in plasma, urine and feces (NCT00828763) [21]. However, the results have not yet been published.
7. Interactions
Modern HIV therapy is a combination therapy usually con- taining three (or more) antiretroviral agents. In the past vast and often unpredictable interactions between different antire- trovirals have been observed. This is often been complicated by other drugs for the treatment of HIV-associated disease and other co-morbidities in an aging population. Therefore, knowledge of corresponding drug interactions is crucial. Var- ious drug-drug interactions with S/GSK1349572 have already been completed. A summary of the drug interaction studies of S/GSK1349572 can be found in Table 1.
In an open-label, randomized, cross-study the effect of co-administration of metal-cation-containing products (ant- acids and multivitamin preparations) and S/GSK1349572 was assessed [22]. The participants received 50 mg of S/GSK1349572 alone, together with a single dose of a multivi- tamin product (One A Day® Maximum, Bayer HealthCare, Morristown, USA), or with a single dose of an aluminum- and magnesium-containing antacid (Maalox® Advanced Maximum Strength, sanofi-aventis, Paris, France), or 2 h before administration of the antacid. Co-administration of S/GSK1349572 with the multivitamin product or the antacid
reduced the exposure by ~ 30 and 70% (AUC0 — t, Cmax,
C24h), respectively. When the participants received the antacid
2 h after S/GSK1349572 the reduction of exposure was attenuated (AUC0 — t 26%, Cmax 18%, C24h 30%).
The interaction of the proton pump inhibitor omeprazole and S/GSK1349752 was studied by measuring pharmacoki- netic parameters of a single 50 mg dose of S/GSK1349752 before and on day 5 of omeprazole 40 mg q.d. therapy in 12 healthy volunteers [23]. The comparison showed no significant effect on S/GSK1349572 pharmacokinetics.
In a sub-study of a pharmacokinetic and safety trial, 10 healthy participants received a midazolam 3 mg q.d. dose
1 day before and on day 10 of S/GSK1349572 25 mg
q.d. [18] to assess CYP3A4 activity changes. There was no difference in midazolam exposure.
A series of studies have been conducted to investigate the interactions of S/GSK1349572 and other antiretroviral agents that are likely to be used in combination therapy.
The effect of the ritonavir-boosted protease inhibitors (PIs) lopinavir (LPV) and darunavir (DRV) on S/GSK1349572 were evaluated in an open-label repeat-dose study in healthy volunteers [20]. A total of 30 participants received S/GSK1349572 30 mg q.d. for 5 days before adding either LPV/ritonavir (LPV/r) 400/100 mg b.i.d. or darunavir/ ritonavir (DRV/r) 600/100 mg b.i.d. for 14 days (15 partici- pants per group). Co-administration of LPV/r did not result in changes of S/GSK1349572 pharmacokinetics. Adding
DRV/r resulted in a modest reduction of AUC0 — t, Cmax
and Ct (22, 11 and 38%, respectively). The pharmacokinetic parameters for LPV/r and DRV/r were comparable to historic data.
In a similar open-label interaction study, 24 healthy volun- teers received S/GSK1349572 30 mg q.d. for 5 days [24]. Then either atazanavir (ATV) 400 mg q.d. or atazanavir/ ritonavir (ATV/r) 300/100 mg q.d. was added for 14 days (n = 14/group). The co-administration with ATV/r increased
plasma S/GSK1349572 AUC0 — t, Cmax and Ct by 62, 34
and 121%, respectively, while unboosted ATV increased plasma S/GSK1349572 AUC0 — t, Cmax and Ct by 91, 50 and 180%, respectively. The observed pharmacokinetic
parameters of ATV/r and ATV were comparable to historic data.
An open-label repeat-dose study evaluated potential inter- actions of co-administration of S/GSK1349572 and tenofovir (TDF) in 15 healthy volunteers [25]. The participants received S/GSK1349572 50 mg q.d. for 5 days followed by a washout period of ‡ 6 days. After the washout TDF 300 mg q.d. was administered for 7 days before S/GSK1349572 50 mg q.d. was added for 5 days. The pharmacokinetic samples were obtained on the last day of each treatment period. There were no significant changes observed in the pharmacokinetics of S/GSK1349572 whether administered alone or in com- bination with TDF. The exposure to TDF was slightly increased when it was co-administered with S/GSK1349572. The pharmacokinetics of S/GSK1349572 (50 mg q.d.) were determined when co-administered with etravirin (ETV)
200 mg b.i.d. alone, ETV and LPV/r 200/400/100 mg
Table 1. Drug interaction of S/GSK1349572.
0.52 nM (range 0.41 — 0.6) for S/GSK1349572. It was concluded that S/GSK1349572 was highly potent in all
Drug Effect on
S/GSK1349572
Effect on other drug
Ref.
assays against HIV, and that S/GSK1349572 activity was independent of HIV subtype.
Midazolam n.a. $ [24]
Multivitamin (#) n.a. [22]
The in vitro potency of S/GSK1349572 against INI resis-
tant HIV-1 and the occurrence of new mutations have been
Metal-cation-containing antacids
# n.a. [22]
studied in serial passage experiments [31-33]. Wild type-,
Q148K-, Q148R-, Q148H-, N155H- and E92Q- HIV-1
Omeprazole $ n.a. [23]
ATV (“) $ [24]
ATV/r (“) $ [24]
DRV/r (#) $ [20]
LPV/r $ $ [20]
TDF $ (“) [25]
ETV # n.a. [26]
ETV and LPV/r $ n.a. [26]
ETV and DRV/r (#) n.a. [26]
(#): Exposure clinically irrelevantly reduced; #: Clinically significantly reduced;
$: Unchanged; (“): Clinically irrelevantly increased; “: Clinically significantly increased.
ATV: Atazanavir; DRV: Darunavir; ETV: Etravirine; LPV: Lopinavir; n.a.: Not available; r: Ritonavir boosted; TDF: Tenofovir.
b.i.d. or ETV and DRV/r 200/600/100 mg b.i.d. to healthy subjects [26]. Co-administration of ETV alone led to a signifi- cant reduction of S/GSK1349572 exposure (AUC0 — t, Cmax and Ct: 71, 52 and 88% reduction, respectively). This effect
was attenuated with co-administration of DRV/r (AUC0 — t, Cmax and Ct: 25, 12 and 37% reduction, respectively).
When ETV was co-administered with LPV/r AUC0 — t and Cmax were unchanged and Ct increased by 28%.
Further drug interaction trials are registered at the US NIH website, clinicaltrials.gov. These studies are either ongoing or the results of these trials have not yet been reported. One trial investigating the interaction of S/GSK1349752 and the NNRTI efavirenz in healthy adults (NCT01098526) is marked as completed [27]. Another drug interaction study between S/GSK1349572 and tipranavir/ritonavir in healthy volunteers is recruiting participants (NCT01068925) [28]. A study examining the interaction of S/GSK1349572 and fosamprenavir/ritonavir is currently recruiting healthy volunteers (NCT01209065) [29].
8. Efficacy
8.1 In vitro efficacy
The in vitro activity of S/GSK1349572 across group M (sub- types A — G), group O HIV-1 subtypes and HIV-2 was assessed in peripheral blood mononuclear cells (PBMCs) [30].
The mean IC50 of at least three isolates per subtype/group in group M (subtype A-G), group O and HIV-2 were
0.22 — 0.62 nM, 0.87 nM and 0.29 nM, respectively. Four
HIV-1 subtype B isolates were also evaluated in monocyte- derived-macrophages yielding a mean IC50 of 0.76 nM. In 13 subtype B isolates tested with a PhenoSense™ assay (Virologic, South San Francisco, USA) the IC50 value was
genotype isolates were passaged under increasing concentra- tions of S/GSK1349572 (or raltegravir) for 56 days. Geno- types were obtained at days 14, 28, 42 and 56 of passage. The phenotype expressed as drug susceptibility compared to wild type virus (fold change) was obtained on day 56. At a concentration of 32 nM S/GSK1349572 viral replication was inhibited. With a reduced concentration of 6.4 nM S/GSK1349572 viral replication could be observed. In wild type virus two mutations emerged (E92Q, G193E; 3.1-, 3.2-fold change, respectively). N155H- and E92Q- virus did
not collect further mutations (fold change: 2.0 — 3.9 and
2.9 — 4.1, respectively). In Q148H/R/K virus strains additional mutations occurred, leading to high-level fold changes. Com- pared to raltegravir the mutations emerging in wild type, N155H- and E92Q- virus had a lower level of fold change under S/GSK1349572. The authors conclude that in vitro
experiments support that S/GSK1349572 has a higher genetic barrier when compared to raltegravir. An overview of the mutational pathways and fold changes can be found in Table 2. Fold changes to S/GSK1349572 and raltegravir of 17 HIV-1 isolates harboring INI mutations were determined in vitro [34]. The median (range) fold changes to S/GSK1349572 for N155H-, G140S + Q148H-, G140S +
Q148R- and T97A + Y143R- isolates were 1.37 (1.22 –
1.45), 3.75 (2.05 — 15.0), 13.3 (7.57 — 19.0) and 1.05
(1.04 — 1.06), respectively. The fold changes to raltegravir were considerably higher. The authors concluded that these findings suggest a virologic resistance profile for S/GSK1349572 that is superior to raltegravir.
Wild type HIV-2 clinical isolates showed similar in vitro EC50 values for S/GSK1349572 compared to HIV-1 BRU reference strain [35]. In clinical isolates from HIV-2-infected patients that were treatment-experienced with raltegravir, har- boring the Q148R and one or two other integrase mutations, a high-level fold change was observed. It was concluded that S/GSK1349572 is active against HIV-2 viruses in vitro and that more data is needed to assess the activity in INI-resistant HIV-2.
8.2 Clinical efficacy
In a randomized, placebo-controlled, double-blind, parallel group, 10-day monotherapy, Phase IIa, dose-ranging study in HIV-infected individuals with an HIV viral load
‡ 5,000 copies/ml and a CD4 cell count ‡ 100 cells/µl that were either HIV treatment-na¨ıve or were na¨ıve to INIs and
did not receive HIV-treatment for ‡ 12 weeks three different dosages of S/GSK1349572 were tested [36]. The primary
Table 2. In vitro mutations observed at day 56 of passage with S/GSK1349572 [31].
Initial viruses Mutations Fold change
The time to HIV-RNA < 50 copies/ml was significantly shorter in S/GSK1349572 arms than in the efavirenz arm (each p < 0.001 vs efavirenz) [38]. CD4 cell count increased by 159, 206, 167 and 110 cells/µl in the 10, 25, 50 mg
Wild type E92Q G193E
3.1
3.2
S/GSK1349572 and efavirenz groups, respectively. The
CD4 cell count in the pooled S/GSK1349572 groups
N155H N155H 2.0 -- 3.9
E92Q E92Q 2.9 -- 4.1
(CD4 cell increase 176 cells/µl) was significantly higher com-
pared to efavirenz (p = 0.008) [39]. Three protocol-defined
Q148H G140S/Q148H
T97A/G140S/Q148H V75I/E138K/G140S/ Q148H/M154I
Q148R G140S/Q148R E138K/G140S/Q148R G140S/Q148R/V201I
4.8 -- 8.0
44
46
16
13
39
virological failures were noted. One occurred in the control arm (efavirenz and TDF/FTC) with a slow HIV-RNA decline achieving < 50 copies/ml at week 20. One subject in the 10 mg S/GSK1349572 group with TDF/FTC as back- bone showed a rebound at week 4. In this participant non-adherence was suspected. In the on-treatment geno-
Q148K E138K/Q148K 47 -- 190
endpoint in this proof-of-concept trial was change from baseline HIV-RNA. Secondary endpoints were percentage of HIV-RNA < 400 and < 50 copies/ml, and change of CD4 cell count from baseline. The 35 participants received 2, 10, 50 mg q.d. of S/GSK1349572, or placebo (n = 9, 9, 10, 7, respectively). In all treatment groups a rapid decline in HIV-RNA was detected. A mean decrease from baseline to day 11 in plasma HIV-RNA of 1.51 -- 2.46 log10 copies/
ml was observed across the S/GSK1349572 doses tested compared with placebo (+0.05 log10 copies/ml). The percen- tages of HIV-RNA < 50 copies/ml on day 11 were 11, 0 and
70% in the 2, 10 and 50 mg dose groups, respectively (Figure 1). During the 10-day monotherapy study no integrase mutations were detected.
In an analysis of this trial the pharmacokinetic- pharmacodynamic relationship of S/GSK1349572 was assessed [37]. A clear exposure-response relation was identified and the best description was by a simple Emax model with Emax fixed to 2.6 log10 and a Hill coefficient s = 1: E = Emax
* Cs/(Cs + ECs ). Ct was the best predictor of antiretroviral efficacy in this short-term treatment.
The SPRING-1 trial is a Phase IIb, randomized, con- trolled, dose-ranging, partially blind trial in n = 205 therapy-na¨ıve HIV-infected subjects with HIV-RNA ‡ 1,000 copies/ml and a CD4 cell count ‡ 200 cells/µl [38]. Primary outcome measure was percentage of HIV-RNA
< 50 copies/ml at week 16, 24, 48 and 96. Patients enrolled were randomized (1:1:1:1) to received one of three blinded dosages of S/GSK1349572 (10, 25, 50 mg q.d.) or as an open-label control efavirenz 600 mg q.d. The backbone therapy of two NRTI is either co-formulated tenofovir/ emtricitabine (TDF/FTC) 300/200 mg or co-formulated abacavir/lamivudine (ABC/3TC) 600/300 mg depending on the investigators’ choice (Figure 2). Baseline characteristics were comparable for all therapy arms and the control arm. In the planned 24-week interim analysis 96, 90, 92 and 78% in the 10 mg, 25 mg, 50 mg and control arm, respectively, had a HIV-RNA < 50 copies/ml (Figure 3) [39].
type of this individual the only mutation detected was M184M/V [38]. There were no INI-associated mutations pres- ent and the phenotype showed unchanged susceptibility to S/GSK1349572. The third subject with virological failure received 25 mg of S/GSK1349572 and ABC/3TC. In this patient HIV-RNA was < 50 copies/ml week 4 through week 20 before rebounding at week 24. A geno- or phenotype could not be obtained. In this participant non-compliance was documented.
The VIKING Study, a Phase IIb, multicenter, open- label study enrolled n = 27 HIV treatment-experienced HIV-infected individuals with an HIV-viral load > 1,000 copies/ml and a CD4 cell count of > 200 cells/µl and current or historic virological failure to the INI raltegravir with evi- dence of raltegravir resistance and resistance to two or more other ART [40]. The participants were allocated to two expected sensitivity groups based on genotype at screening (Q148H/K/R + one or more associated mutations and all other genotypes). Subjects discontinued raltegravir and received S/GSK1349572 50 mg q.d. while continuing their failing regimen (functional monotherapy) to day 11. Then the background regimen was optimized, and S/GSK1349572 continued for 24 weeks (Figure 4). Primary endpoint was HIV-RNA < 400 copies/ml or ‡ 0.7 log10 reduction below baseline values at day 11. Initial data of 27 patients that were heavily pre-treated (median duration of ART 14 years, median number of prior antiretrovirals
17) showed that 21/27 (78%) met primary endpoint criteria. The mean reduction of HIV-RNA was 1.45 (SD 0.76) log10 copies/ml. Analysis of the two subgroups showed that all individuals that failed the primary endpoint were in the group with Q148H/K/R + associated mutations (6/9) (Table 3). In this group the mean reduction of HIV- RNA was 0.72 (SD 0.63) log10 copies/ml. Indeed none of the subjects with Q148 + two or more mutations was sup- pressed through week 24, whereas suppression was achieved in 4/4 patients with the G140S + Q148 mutation pattern only [41]. Enrollment to this group was halted early due to less robust virologic responses. In the other group HIV- RNA dropped 1.82 (SD 0.53) log10 copies/ml. Week 24 response rate in G140S + Q148 was 100% (4/4), though
100
80
60
40
20
0
0
-0.5
-1
-1.5
-2
-2.5
2 mg n = 9 10 mg n = 9 50 mg n = 10
none of the subjects with Q148 + two or more mutations was suppressed through week 24 (in discussion as well). G140S + Q148 was most commonly described in the BENCHMRK failures. The week 24 response was strongly dependent of the phenotypic sensitivity score (PSS) of the optimized background regimen (OBR) [41]. The overall pro- portion of patients with an HIV-RNA < 50 copies/ml at week 24 was 41%. The response rate at week 24 (HIV- RNA < 50 copies/ml) for a PSS of 0, 1 and > 2 were 8,
57 and 75%, respectively (Figure 5).
Further geno- and phenotypical analysis of day 1 and day 11 data (functional monotherapy period) of the VIKING- trial showed that higher fold change to S/GSK1349572 was associated with more evolved INI mutations (Q148 + associ- ated mutations), while N155 and Y143 pathway mutations were not associated with a significant increase in fold- change [42,43]. During the 10-day functional monotherapy only few additional raltegravir-associated mutations were detected and minimal changes in S/GSK1349572 fold-change were noted.
Currently, an evaluation of S/GSK1349572 50 mg b.i.d. is in progress with cohort II (NCT00950859), which might help to overcome the decreased susceptibility of raltegravir-resistant viruses with 140/148 mutations.
9. Safety and tolerability
Figure 1. Day 11 response of monotherapy with once- daily S/GSK1349572 [36]. Upper panel: Percentage of participants with HIV-RNA < 400 copies/ml (white bar) and < 50 copies/ml (black bar). Lower panel: mean log10 reduction of HIV-RNA.
In the study reported by Min et al. where 47 healthy volun- teers were administered a single dose of S/GSK1349752 (2, 5, 10, 25, 100 mg) or placebo, the investigational drug was generally well tolerated and no serious or severe adverse events (AEs) were reported [18]. Two AEs were reported by more than one participant (headache 2 and 10 mg dose, som- nolence both 50 mg dose). Of 16 reported AEs, 8 were con- sidered drug related. One volunteer had an asymptomatic grade 3 lipase elevation 3 days after administration of SGSK1349752 2 mg, which resolved 4 days later. In a second study with repeated doses of S/GSK1349752 10, 25 or 50 mg
q.d. or placebo for 10 days in 32 healthy volunteers the study medication was generally well tolerated. Serious or severe AEs did not occur. Most commonly reported AEs were headache, pharyngo-laryngeal pain and pruritus. Although most AEs occurred in the 50 mg dose group, the authors state that this was not dose related. One subject had a treatment- emergent grade 3 triglyceride elevation and grade 2 alanine aminotransferase and aspartate transaminase elevation on day 10 that resolved within 1 week.
In a randomized, placebo-controlled, double-blind, parallel group, 10-day monotherapy Phase IIa dose-ranging
study in 35 INI-na¨ıve HIV-infected individuals, where
Figure 2. Study-design of the Spring-Trial in HIV therapy- nay¨ ve patients [38]. S/GSK1349752 10, 25 and 50 mg q.d. are compared to efavirenz 600 mg q.d. with a backbone therapy of either ABC/3TC or TDF/FTC depending of the investigators choice.
S/GSK1349572 2, 10 and 50 mg or placebo were adminis- tered, the study medication was generally well tolerated [34]. The most common AEs were diarrhoea (14%), fatigue (7%) and headache (7%). Four grade 3 AEs were reported: migraine headache (50 mg), asymptomatic elevation of lipase
100
80
60
40
20
0
200
150
100
50
0
10 mg 25 mg 50 mg EFV 600 mg
10 mg 25 mg 50 mg EFV 600 mg
observed in all S/GSK1349572 groups (0.02, 0.09 and
0.11 mg/dl in the S/GSK1349572 10, 25 and 50 mg groups, respectively). However, no grade 2 or higher changes in serum creatinine were observed. As a putative mechanism for serum creatinine increase the blockade of tubular secretion of creati- nine by inhibition of the organic cation transporter 2 was stated. Triglycerides, cholesterol, LDL and HDL were unchanged in the S/GSK1349572 treatment arms.
In the week 24 safety analysis of the VIKING trial with 27 treatment-experienced HIV-infected subjects drug-related AEs (n = 2) were grade 2 fatigue with insomnia and grade 2 diarrhea [40]. Four SAEs were reported (neurosyphilis, brain mass, immunoblastic lymphoma, dyspnea). None of these were considered drug related. Asymptomatic grade 3 labora- tory abnormalities were observed in 6 (22%) subjects: lipase increase (n = 2), phosphorous decrease (n = 2), amylase increase (n = 1), and total cholesterol increase (n = 1). Grade 4 laboratory toxicities did not occur.
To assess the effect of S/GSK1349572 on cardiac repolari- zation 42 healthy volunteers received a supra-therapeutic dose of S/GSK1349572 250 mg, moxifloxacin 400 mg and pla-
cebo with a 10 -- 14 day washout period between the different
treatments. Over the following 24 h administration of 250 mg
Figure 3. Week 16 [38] and 24 [39] response in the Spring-
Trial. Upper panel: Primary outcome measure HIV-RNA
< 50 copies/ml at week 16 (grey bar) and week 24 (black bar). Lower panel: Median CD4 cell count change from baseline at week 16 (grey bar) and week 24 (black bar).
(10 mg), asymptomatic triglyceride elevation (10 mg) and night sweats (placebo). Clinically relevant trends in AEs, lab- oratory parameters, vital signs or electrocardiogram values were not observed.
In a meta-analysis of six healthy subject trials and one HIV subject study with short-term administration of S/GSK1349572 the safety data of 183 subjects (S/GSK1349572 n = 166 and placebo n = 17) was included [44]. In this analysis no trends for AEs, serious AEs (SAEs), laboratory abnormalities or changes in electrocardio- gram values could be identified. It was concluded that no clin- ically significant safety signals were found after short-term dosing of S/GSK1349752.
In the 24 week data safety analysis of the spring trial with 205 therapy-na¨ıve participants (S/GSK1349572 10, 25, 50 mg vs efavirenz 600 mg and NRTI backbone) no SAEs attributed to the investigational drug were reported [39]. One AE of dyspepsia and another of Burkitt’s lymphoma in the S/GSK1349572 group led to discontinuation. In the efa- virenz group four subjects were discontinued (two due to CNS AEs, two due to drug intolerance/hypersensitivity).
Overall the incidence of AEs (grade 2 -- 4) was lower across
all S/GSK1349572 arms (6%) compared to the efavirenz con- trol arm (20%) (Table 4). Grade 3 or 4 laboratory abnormal- ities were rare in all treatment groups (8% S/GSK1349572, 10% efavirenz). A light increase in serum creatinine was
had no effect on cardiac repolarization [45].
A trial to study the mechanism of serum creatinine increase has been registered (NCT01214993) [46]. This study aims to determine the effect of S/GSK1349752 50 mg over 14 days on glomerular filtration rate and effective renal plasma flow measured by iohexol plasma clearance (primary outcome measure) and plasma clearance of para-aminohippurate.
10. Regulatory affairs
GlaxoSmithKline and Shionogi developed S/GSK1349572 in a joint venture [47]. In 2009 GlaxoSmithKline and Pfizer announced the formation of a new company focused on HIV medicine and both companies marketed the pipeline products (including S/GSK1349572) for HIV treatment in a combined manner [48]. This new company ViiV Healthcare is continuing to work together with Shionogi [49] in the devel- opment of S/GSK1349572. As Phase III clinical trials have not yet been conducted approval by regulatory bodies has not been filed.
11. Conclusion
S/GSK1349572 represents a new INI with promising distinct features. In vitro work has identified this new compound as a once daily, unboosted INI with low pharmacokinetic variabil- ity and predictable exposure-response relationship. The over- all potential for drug interactions is low; co-administration with proton pump inhibitors appears feasible. No relevant impact of food intake on pharmacokinetic parameters has been noted. First studies in HIV-infected individuals showed considerable antiretroviral potency. At 24 weeks > 90% of
HIV-RNA > 1000
copies/ml, present or historic failure to RAL, resistance to 2 or more other ART classes Q148H/K/R + one or more secondary resistance mutations
N ~ 15
All other mutations (including codon 148 single mutation)
N ~ 15
S/GSK1349752 50 mg
once daily + failing back ground therapy S/GSK1349752 50 mg
once daily + optimized back ground therapy
Day 1 to 11 Through week 24
Figure 4. Study-design of the VIKING trial in HIV treatment-experienced HIV-infected individuals with current or historic virological failure to raltegravir with evidence of raltegravir resistance and resistance to two or more other ART classes [40]. The participants were allocated to two expected sensitivity groups based on genotype at screening.
Table 3. Day 11 response in the VIKING
study: HIV-infected subjects with virological failure to raltegravir after 10 days of functional monotherapy with 50 mg of S/GSK1349572 [40].
patients initiating S/GSK1349572 in combination with fixed- dose combination 2 NRTI (ABC/3TC or TDF/FTC) achieve undetectable HIV viral loads (< 50 copies/ml). Overall, non- inferiority is reached with regard to virological endpoints in comparison to an efavirenz-based antiretroviral therapy.
HIV-RNA
< 400 copies/ml or $ 0.7 log10 copies/ml decline in HIV-RNA
HIV-RNA
log10 copies/ml change from baseline
CD4 cell count increases, however, are significantly higher in the S/GSK1349572 treated subjects with an improved tol- erability profile in parallel. The 50 mg q.d. dose has been identified as the optimal one for further clinical development, which has now entered clinical Phase III studies. In vitro
All subjects 21/27 (78%) -1.45 (SD 0.76)
S/GSK1349572 has been associated with a higher genetic bar-
Q148H/K/R and
‡ 1 of L74, E138,
G140 mutations
All other genotypes from N155H or Y143H pathways
3/9* (33%) -0.72 (SD 0.63)
18/18 (100%) -1.82 (SD 0.53)
rier to resistance and some retained activity in the presence of
INI-associated mutations. Phase II studies in treatment- experienced patients with previous INI exposure show that higher fold-change to S/GSK1349572 was associated with more evolved INI mutations (Q148 + associated mutations),
while N155 and Y143 pathway mutations were not yet asso-
*Enrollment to this group was halted early.
80
60
40
20
0
Overall 0 1 2
Phenotypic sensitivity score
Figure 5. Week 24 response in the VIKING trial in HIV treatment-experienced HIV-infected individuals overall and according to the phenotypic sensitivity score (PSS) of the optimized background regimen [41].
ciated with a significant increase in fold-change. Overall, the safety profile of S/GSK1349572 in all studies completed so far has been very favorable. In conclusion S/GSK1349572 represents a promising new INI under current development, which seems to offer distinct drug properties making this drug clearly worthwhile to develop.
12. Expert opinion
S/GSK1349572 offers some interesting properties that may differentiate this compound from the other INIs in clinical use or in current development. By being an upfront once- daily antiretroviral without need of boosting, it is already is different from the twice-daily administered raltegravir and the boosted elvitegravir. Nevertheless this potential advantage may become less relevant when the ongoing raltegravir once- daily versus twice-daily study shows similar efficacy results and if the new pharmacokinetic booster cobicistat proves to have less side effects than observed under the traditional rito- navir boosting. Yet, the prerequisite of requiring a pharmaco- kinetic booster suggests significant drug-drug interactions that so far have not been described to a greater extent with
Table 4. AEs reported twice or more in the SPRING-1 trial in therapy-naı¨ve HIV-infected subjects in the week 24 safety analysis [39].
S/GSK1349572 Efavirenz
10 mg
(n = 53) (%) 25 mg
(n = 51) (%) 50 mg
(n = 51) (%) All doses
(n = 155) (%) 600 mg
(n = 50) (%)
Grade 2 -- 3 AEs, drug related (all) 4 (8) 2 (4) 4 (8) 10 (6) 10 (20)
Gastrointestinal 1 (2) 1 (2) 1 (2) 3 (2) 2 (4)
Psychiatric disorders 0 0 0 0 3 (6)
Skin disorders 0 0 0 0 2 (4)
Infections 2 (4) 0 0 2 (1) 0
General disorders 1 (2) 0 1 (2) 2 (1) 1 (2)
Serious adverse events 3 (6) 1 (2) 3 (6) 7 (5) 4 (8)
AEs leading to discontinuation 0 1 (2) 1 (2) 2(1) 4 (8)
AE: Adverse event.
S/GSK1349572. Moreover, the low pharmacokinetic vari- ability and predictable exposure-response relationship of S/GSK1349572 makes this compound better understandable and interpretable with regard to pharmacokinetics whereas no clear exposure-response was found for raltegravir.
From a clinical perspective the introduction of INIs (ralte- gravir) into the HIV armentarium has been highly welcomed due to the overall excellent safety profile and the potential use of an INI as a fully active compound in a newly composed antiretroviral regimen in a patient experiencing virological failure and drug resistance. The detection of raltegravir- associated drug resistance conferring mutations in patients failing virologically under a raltegravir-based first-line therapy as well as the emergence of INI specific mutations in patients who were switched from a boosted PI and previously had completely suppressed viral replication has initiated an ongo- ing discussion about the genetic barrier of raltegravir. In addi- tion the cross-resistance between raltegravir and elvitegravir has prompted the quest for the development of new INIs with potentially retained activity even in the presence of raltegravir-specific mutations. First clinical trials indeed sug- gest that at least in the presence of genotypes from the N155H and Y143H pathway S/GSK1348572 still shows considerable antiviral activity. Yet, patients harboring the Q148H/K/R + associated mutations showed a clear decrease in S/GSK1349572 activity. This implies that the longer a virologically failing patient under raltegravir treatment remains on raltegravir-based therapy, the more likely the
emergence of unfavorable mutations for the later use of S/GSK1349572 becomes. Moreover, large-scale studies have shown that the 148 pathway is the most frequently observed of the two pathways in RAL treatment failure [50]. Also at least one study indicates that the N155 pathway may shift to the Q148 pathway over time again underlining the concern of cross-resistance to the 140/148 raltegravir resistance pathway [51]. Nevertheless, the in vivo demonstrated higher genetic barrier and the observation that so far in the na¨ıve Phase IIb trial no INI mutations have occurred remains promising. The safety profile from all studies with S/GSK1349572 to date underlines the excellent tolerability of this class and adds further to the attractiveness of this compound. In summary S/GSK1349572 is a very attractive once-daily INI with some potential for unique features among the INI class, clearly warranting further clinical development. Yet, the results from the Phase III program evaluating S/GSK1349572 in much larger patient popu- lations will eventually drive its position in the HIV drug armentarium.
Declaration of interest
J Rockstroh has received consulting fees from Abbott, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck, Pfizer, Roche, Tibotec and ViiV, and has carried out contracted research for Abbott, Merck and Roche. JCC Lenz declares no conflict of interest.
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