Chemical formula: C₂₅H₂₆N₇O₈P Molecular mass: 583.498 g/mol PubChem compound: 11319217
Fostemsavir is a prodrug without significant antiviral activity that is hydrolysed to the active moiety, temsavir, upon cleavage of a phosphonooxymethyl group in vivo. 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.
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.
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).
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.
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 1).
Table 1. Phenotypes of recombinant LAI viruses containing clinically relevant gp120 substitutions:
Substitutions | Fold-change vs wild type EC50 | Frequency in 2018 LANL database % |
---|---|---|
Wild type | 1 | - |
S375H | 48 | 10.71 |
S375I | 17 | 1.32 |
S375M | 47 | 1.17 |
S375N | 1 | 1.96 |
S375T | 1 | 8.86 |
S375V | 5.5 | - |
S375Y | >10000 | 0.04 |
M426L | 81 | 5.33 |
M426V | 3.3 | 0.31 |
M434I | 11 | 10.19 |
M434T | 15 | 0.55 |
M475I | 4.8 | 8.84 |
M475L | 17 | 0.09 |
M475V | 9.5 | 0.12 |
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.
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.
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 2).
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 3). 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 2. Virologic Response Category at Day 8 (Randomised Cohort) by presence of gp120 resistance-associated polymorphisms (RAPs) at baseline – ITT-E Population:
Randomised Cohort FTR 600 mg BID (N=203) n (%) | |||||
---|---|---|---|---|---|
Response Categorya | Missingb | ||||
n | >1.0 log10 | >0.5 to ≤1.0 log10 | ≤0.5 log10 | ||
n | 203 | 93 | 38 | 64 | 8 |
Sequenced | 194 | ||||
No gp120 RAPs (at pre- defined sites) | 106 | 54 (51) | 25 (24) | 24 (23) | 3 (3) |
Pre-defined gp120 RAPs (S375H/I/M/N/T, M426L, M434I, M475I) | 88 | 36 (41) | 12 (14) | 37 (42) | 3 (3) |
S375 S375H/I/M/N/T S375H S375M S375N | 64 1 5 22 | 29 (45) 0 1 (20) 10 (45) | 9 (14) 0 0 3 (14) | 23 (36) 1 (100) 4 (80) 8 (36) | 3 (5) 0 0 1 (5) |
M426L | 22 | 7 (32) | 3 (14) | 12 (55) | 0 |
M434I | 9 | 5 (56) | 0 | 4 (44) | 0 |
M475I | 1 | 0 | 0 | 1 (100) | 0 |
1 gp120 RAP | 80 | 31 (39) | 12 (15) | 34 (43) | 3 (4) |
2 gp120 RAPs | 8 | 5 (63) | 0 | 3 (38) | 0 |
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 3. Virologic Response Category at Day 8 (Randomised Cohort) by Phenotype at baseline – ITT-E Population:
Baseline Temsavir IC50 Fold Change Category | Virologic Response at Day 8 (>0.5 log10 decline in HIV-1 RNA from Day 1 to Day 8) n=203 |
---|---|
IC50 FC value not reported | 5/9 (56%) |
0-3 | 96/138 (70%) |
>3-10 | 11/13 (85%) |
>10-200 | 12/23 (52%) |
>200 | 7/20 (35%) |
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.
The percentage of subjects who experienced virologic failure through the Week 96 analysis was 25% (69/272) in the randomised cohort (Table 4). 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 4). 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 4. Virologic Failures in BRIGHTE Trial:
Randomised Cohort Total | Non-randomised Cohort Total | |
---|---|---|
Number of virologic failures | 69/272 (25%) | 50/99 (51%) |
Virologic failures with available gp120 data at baseline | 68/272 (25%) | 48/99 (48%) |
With baseline EN RAPs | 42/68 (62%) | 26/48 (54%) |
Virologic failures with post-baseline gp120 data | 52 | 44 |
With Any Emergent EN RASa | 26/52 (50%) | 33/44 (75%) |
With emergent EN RASb | 25/52 (48%) | 32/44 (73%) |
S375H | 1/52 (2%) | 2/44 (5%) |
S375M | 1/52 (2%) | 3/44 (7%) |
S375N | 13/52 (25%) | 17/44 (39%) |
M426L | 17/52 (33%) | 21/44 (48%) |
M434I | 5/52 (10%) | 4/44 (9%) |
M475I | 6/52 (12%) | 5/44 (11%) |
With EN RAS and with temsavir IC50 fold change ratio >3-foldb,c | 22/52 (42%) | 29/44 (66%) |
Without EN RAS and with temsavir IC50 fold change ratio >3-foldc | 3/52 (6%) | 2/44 (5%) |
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.
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 Cmax approximately 4.2-fold lower than the temsavir concentration predicted to increase QTcF interval 10 milliseconds.
The pharmacokinetics of temsavir following administration of fostemsavir are similar between healthy and HIV-1 infected subjects. In HIV-1 infected subjects, the between-subject variability (CV) in plasma temsavir Cmax and AUC ranged from 20.5 to 63 and Cτ from 20 to 165%. Between-subject variability in oral clearance and oral central volume of distribution estimated from population pharmacokinetic analysis of healthy subjects from selected Phase I studies and HIV-1 infected patients were 43% and 48%, respectively.
Fostemsavir is a prodrug that is metabolised to temsavir by alkaline phosphatase at the luminal surface of the small intestine and is generally not detectable in plasma following oral administration. The active moiety, temsavir, is readily absorbed with the median time to maximal plasma concentrations (Tmax) at 2 hours post dose (fasted). Temsavir is absorbed across the small intestine and caecum/proximal ascending colon. Pharmacokinetic parameters following multiple oral doses of fostemsavir 600 mg twice daily in HIV-1 infected, adult subjects are shown in the following table.
Multiple-Dose Pharmacokinetic Parameters of Temsavir following oral administration of Fostemsavir 600 mg twice daily:
Pharmacokinetic Parameters | Geometric Mean (CV%)a |
---|---|
Cmax (μg/mL) | 1.77 (39.9) |
AUC (μg*hr/mL) | 12.90 (46.4) |
C12 (μg/mL) | 0.478 (81.5) |
a Based on population pharmacokinetic analyses with or without food, in combination with other antiretroviral drugs.
CV = Coefficient of Variation.
The absolute bioavailability of temsavir was 26.9% following oral administration of a single 600 mg dose of fostemsavir.
Temsavir bioavailability (AUC) was not impacted by a standard meal (approximately 423 kcal, 36% fat) but increased 81% with a high-fat meal (approximately 985 kcal, 60% fat) and is not considered clinically significant. Regardless of calorie and fat content, food had no impact on plasma temsavir Cmax.
Temsavir is approximately 88% bound to human plasma proteins based on in vivo data. Human serum albumin is the major contributor to plasma protein binding of temsavir in humans. The volume of distribution of temsavir at steady state (Vss) following intravenous administration is estimated at 29.5 L. The blood-to-plasma total radiocarbon Cmax ratio was approximately 0.74, indicating minimal association of temsavir or its metabolites with red blood cells. Free fraction of temsavir in plasma was approximately 12 to 18% in healthy subjects, 23% in subjects with severe hepatic impairment, and 19% in subjects with severe renal impairment, and 12% in HIV-1 infected patients.
In vivo<.em>, temsavir is primarily metabolised via esterase hydrolysis (36.1% of administered dose) and secondarily by CYP3A4-mediated oxidative (21.2% of administered dose) pathways. Other non- CYP3A4 metabolites account for 7.2% of the administered dose. Glucuronidation is a minor metabolic pathway (<1% of administered dose).
Temsavir is extensively metabolised, accounting for the fact that only 3% of the administered dose is recovered in human urine and faeces. Temsavir is biotransformed into two predominant circulating inactive metabolites, BMS-646915 (a product of hydrolysis) and BMS-930644 (a product of N-dealkylation).
Significant interactions are not expected when fostemsavir is co-administered with substrates of CYPs, uridine diphosphate glucuronosyl transferases (UGTs), P-gp, multidrug resistance protein (MRP)2, bile salt export pump (BSEP), sodium taurocholate co-transporting polypeptide (NTCP), OAT1, OAT3, organic cation transporters (OCT)1, and OCT2 based on in vitro and clinical drug interaction data. Based on in vitro data, temsavir and its two metabolites (BMS-646915 and BMS-930644) inhibited multidrug and toxin extrusion protein (MATE)1/2K; this interaction is unlikely to be of clinical significance.
Temsavir has a terminal half-life of approximately 11 hours. Plasma temsavir clearance following intravenous administration was 17.9 L/hr, and the apparent clearance (CL/F) following oral administration was 66.4 L/hr. After oral administration of a single 300 mg dose of 14C-labelled fostemsavir in a human mass balance study, 51% and 33% of the radioactivity was retrieved in the urine and faeces, respectively. Based on limited bile collection in this study (3 to 8 hours post dose), biliary clearance accounted for 5% of the radioactive dose, suggesting that a fraction of the faecal excretion is from biliary excretion.
Following single and repeat administration of fostemsavir ER tablets, increases in plasma temsavir exposure (Cmax and AUC) appeared dose proportional, or slightly greater than dose proportional, in HIV-1 infected subjects.
The pharmacokinetics of temsavir have not been evaluated in children and adolescents younger than 18 years.
Population pharmacokinetic analysis of temsavir using data in HIV-1 infected adults showed that there was no clinically relevant effect of age on temsavir exposure.
Pharmacokinetic data for temsavir in subjects greater than 65 years old are limited. Elderly patients may be more susceptible to drug-induced QT interval prolongation.
The effect of renal impairment on the exposure of temsavir after a single 600 mg dose of fostemsavir was evaluated in an open-label study in 30 adult subjects with normal renal function, mild, moderate, and severe renal impairment, and subjects with ESRD on haemodialysis (n=6 per group). Based on creatinine clearance (CLcr), as follows: 60 ≤ CLcr ≤89 (mild), 30 ≤ CLcr <60 (moderate), CLcr <30 (severe, and ESRD on haemodialysis) mL/min, there was no clinically relevant effect of renal impairment on pharmacokinetic exposure parameters (Cmax and AUCs) of temsavir (total and unbound). The mean fraction unbound (fu) TMR for the severe renal impairment group was approximately 58% higher compared with the normal renal function group. The regression model- predicted average increases in plasma TMR (unbound fraction) Cmax and AUC were ≤15% and for AUC ≤30% for the mild, moderate, and severe RI groups. Cmax (bound and unbound) was lower than the Cmax threshold of an approximate 4.2-fold increase (7500 ng/ml) established based on temsavir exposure-response. Temsavir was not readily cleared by haemodialysis, with approximately 12.3% of the administered dose removed during the 4-hour haemodialysis session. Haemodialysis initiated 4 24 hours after temsavir dosing was associated with an average 46% increase in plasma total temsavir Cmax and an average 11% decrease in AUC relative to pharmacokinetics off haemodialysis.
The effect of hepatic impairment on the exposure of temsavir after a single 600 mg dose of fostemsavir was evaluated in an open-label study in 30 adult subjects with normal (n=12), mild (Child-Pugh Score A, n=6), moderate (Child-Pugh Score B, n=6), and severe (Child-Pugh Score C, n=6) hepatic impairment. In patients with mild to severe hepatic impairment, the increased exposure to both unbound and total Cmax and AUC was in the range of 1.2- to 2.2-fold. However, the upper bounds of the 2-sided 90% CI for the impact of hepatic impairment on plasma total and unbound temsavir Cmax are lower than the Cmax threshold of an approximate 4.2-fold increase (7500 ng/ml) established based on temsavir exposure-response.
Population pharmacokinetic analyses indicated no clinically relevant effect of gender on the exposure of temsavir. Of the 764 subjects included in the analysis, 216 (28%) were female.
Population pharmacokinetic analyses indicated no clinically relevant effect of race on the exposure of temsavir.
Neither fostemsavir nor temsavir were mutagenic or clastogenic using in vitro tests in bacteria and cultured mammalian cells and an in vivo rat micronucleus assay. Fostemsavir was not carcinogenic in long term studies in the mouse and rat following oral gavage administration up to 26 and 100 weeks, respectively.
In rats, male fertility was not affected at TMR exposures up to 125 times the human exposure at the RHD despite testicular and epididymal toxicity. Female fertility and early pregnancy were also not adversely affected at exposures up to 186 times the human exposure at the RHD. While embryofetal exposure was demonstrated in a separate distribution study in pregnant rats with oral administration of 14C-FTR, no effects on embryofetal development were noted in this species at exposures up to 200 times the human exposure at the RHD. In rabbits embryofetal development was also not affected at exposures up to 30 times the human exposure at the RHD. Prenatal and postnatal development including the attainment of puberty and learning memory in offspring was not influenced in rats at exposures up to 50 times the human exposure at the RHD. At maternal exposures that are up to 130 times the human AUC at the RHD, reduced postnatal viability probably due to an increased lactational exposure to TMR was noted in the offspring. TMR is present in the milk of lactating rats and in the blood of the rat pups exposed through lactation.
Fostemsavir has been evaluated in repeat dose toxicity studies in rats (up to 26 weeks) and in dogs (up to 39 weeks). Cardiovascular telemetry studies indicated that both FTR and TMR minimally prolonged the QT interval in dogs (approximately 8 to 18 msec) at plasma concentrations of TMR >2x RHD Cmax. Principle findings were testicular toxicity (degeneration of seminiferous epithelium, decreases in sperm motility and sperm morphologic alterations), renal toxicity (decreases in urine pH, renal tubular dilatation, increase kidney weight and urine volume), adrenal toxicity (angiectasis, increased gland size and weight), and liver toxicity (hepatic canalicular bile pigment deposits and lipofuscin pigment deposits in Kupffer cells). These findings were observed in rats only (at systemic exposures ≥30 times the 600 mg twice daily human clinical exposure based on AUC), except liver toxicity reported in dogs (at exposure multiples ≥3). The majority of these effects were duration-dependent and reversible upon cessation of treatment.
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