RUKOBIA 600mg prolonged tablets medication leaflet

Rukobia 600 mg prolonged-release tablets

Each prolonged-release tablet contains fostemsavir tromethamine equivalent to 600 mg fostemsavir.

For the full list of excipients, see section 6.1.

Prolonged-release tablet

Beige, film-coated, biconvex, oval tablets approximately 19 mm in length, 10 mm in width, and 8 mmin thickness and debossed with ‘SV 1V7’ on one side.

Rukobia, in combination with other antiretrovirals, is indicated for the treatment of adults withmultidrug resistant HIV-1 infection for whom it is otherwise not possible to construct a suppressiveanti-viral regimen (see sections 4.4 and 5.1).

Rukobia should be prescribed by physicians experienced in the management of HIV infection.

The recommended dose is 600 mg of fostemsavir twice daily.

If the patient misses a dose of fostemsavir, the patient should take the missed dose as soon as thepatient remembers, unless it is almost time for the next dose. In this case, the missed dose should beskipped and the next dose should be taken according to the regular schedule. The patient should nottake a double dose to make up for the forgotten dose.

No dosage adjustment is required (see sections 4.4 and 5.2).

No dosage adjustment is required for patients with renal impairment or those on haemodialysis (seesection 5.2).

No dosage adjustment is required in patients with hepatic impairment (see section 5.2).

The safety and efficacy of fostemsavir in children and adolescents aged less than 18 years have not yetbeen established. Currently available data are described in section 5.2, but no recommendation on aposology can be made.

Oral use.

Fostemsavir can be taken with or without food (see section 5.2). The prolonged-release tablet shouldbe swallowed whole with water, and not chewed, crushed or split.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Co-administration with strong CYP3A inducers including, but not limited to: carbamazepine,phenytoin, mitotane, enzalutamide, rifampicin and St John’s wort (see section 4.5).

Immune reconstitution inflammatory syndrome

In HIV-infected patients with severe immune deficiency at the time of initiation of anti-retroviraltherapy (ART), an inflammatory reaction to asymptomatic or residual opportunistic infections mayarise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions havebeen observed within the first few weeks or months of initiation of ART. Relevant examples arecytomegalovirus retinitis, generalised and/or focal mycobacterial infections and Pneumocystis jiroveci(formerly P. carinii) pneumonia. Any inflammatory symptoms must be evaluated without delay andtreatment initiated when necessary. Autoimmune disorders (such as Graves’ disease, autoimmunehepatitis, polymyositis and Guillain-Barre syndrome) have also been reported to occur in the setting ofimmune reconstitution, however, the time to onset is more variable, and can occur many months afterinitiation of treatment and sometimes can be an atypical presentation.

QTc prolongation

A supratherapeutic dose (at a Cmax approximately 4.2-fold the therapeutic dose) of fostemsavir hasbeen shown to significantly prolong the QTc interval of the electrocardiogram (see section 5.1).

Fostemsavir should be used with caution in patients with a history of QT interval prolongation, whenco-administered with a medicine with a known risk of Torsade de Pointes (e.g. amiodarone,disopyramide, ibutilide, procainamide, quinidine, or sotalol) or in patients with relevant pre-existingcardiac disease. Elderly patients may be more susceptible to drug-induced QT interval prolongation.

Patients with hepatitis B or C virus co-infection

Monitoring of liver chemistries is recommended in patients with hepatitis B and/or C co-infection.

Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at anincreased risk of severe and potentially fatal hepatic adverse reactions. In case of concomitant antiviraltherapy for hepatitis B or C, please refer also to the relevant product information for these medicinalproducts.

Patients should be advised that fostemsavir or any other antiretroviral therapy does not cure HIVinfection and that they may still develop opportunistic infections and other complications of HIVinfection. Therefore, patients should remain under close clinical observation by physiciansexperienced in the treatment of these associated HIV diseases.

Although the aetiology is considered to be multifactorial (including corticosteroid use,biphosphonates, alcohol consumption, severe immunosuppression, higher body mass index), cases ofosteonecrosis have been reported in patients with advanced HIV-disease and/or long-term exposure tocombination antiretroviral therapy (CART). Patients should be advised to seek medical advice if theyexperience joint aches and pain, joint stiffness or difficulty in movement.

Restricted range of antiviral activity

In vitro data indicate that the antiviral activity of temsavir is restricted to HIV-1 Group M strains.

Rukobia should not be used to treat infections due to HIV-1 strains other than those of Group M (seesection 5.1).

Within HIV-1 group M, there is considerably reduced antiviral activity against CRF01_AE virus.

Available data indicate that this subtype has a natural occurring resistance to temsavir (see section5.1). It is recommended that Rukobia is not used to treat infections due to HIV-1 Group M subtype

CRF01_AE strains.

Co-administration of fostemsavir with elbasvir/grazoprevir is not recommended as increasedgrazoprevir concentrations may increase the risk of ALT elevations (see section 4.5).

Dose modifications and/or careful titration of dose is recommended for certain statins that aresubstrates of OATP1B1/3 or BCRP (rosuvastatin, atorvastatin, pitavastatin, simvastatin andfluvastatin) when co-administered with fostemsavir (see section 4.5).

When fostemsavir was co-administered with oral contraceptives, temsavir increased concentrations ofethinyl oestradiol. Doses of oestrogen-based therapies, including oral contraceptives, should notcontain more than 30 µg of ethinyl oestradiol per day in patients who are receiving fostemsavir (seesection 4.5). Furthermore, caution is advised particularly in patients with additional risk factors forthromboembolic events.

When fostemsavir is co-administered with tenofovir alafenamide (TAF), temsavir is expected toincrease plasma concentrations of TAF via inhibition of OATP1B1/3 and/or BCRP. Therecommended dose of TAF is 10 mg when co-administered with fostemsavir (see section 4.5).

Effect of other medical products on the pharmacokinetics of temsavir

Temsavir is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but notof organic anion transporters OATP1B1 or OATP1B3. Its biotransformation to two circulatingmetabolites, BMS-646915 and BMS-930644, is mediated by unidentified esterases (36.1%) and bycytochrome P450 (CYP)3A4 enzyme (21.2%), respectively.

When fostemsavir was co-administered with the strong CYP3A inducer rifampicin, a significantreduction in temsavir plasma concentrations was observed. Significant decreases in temsavir plasmaconcentrations may also occur when fostemsavir is co-administered with other strong CYP3Ainducers, and may result in loss of virologic response (see section 4.3).

Fostemsavir may be co-administered with strong CYP3A4, BCRP and/or P-gp inhibitors (e.g.,clarithromycin, itraconazole, posaconazole, and voriconazole) without dose adjustment based on theresults of clinical drug interaction studies with cobicistat and ritonavir.

Effect of temsavir on the pharmacokinetics of other medicinal products

In vitro, temsavir inhibited OATP1B1 and OATP1B3 (IC50 = 32 and 16 µM, respectively).

Additionally, temsavir and its two metabolites (BMS-646915 and BMS-930644) inhibited BCRP (IC50= 12, 35, and 3.5 to 6.3 µM, respectively). Based on these data, temsavir is expected to affect thepharmacokinetics of active substances that are substrates of OATP1B1/3 or BCRP (e.g. rosuvastatin,atorvastatin, simvastatin, pitavastatin and fluvastatin). Therefore, dose modifications and/or carefultitration of dose is recommended for certain statins.

Selected drug interactions are presented in Table 1. Recommendations are based on either druginteraction studies or predicted interactions based on the expected magnitude of the interaction andpotential for serious adverse events or loss of efficacy. (Abbreviations: ↑ = Increase; ↓ =decrease; ↔= no significant change; AUC=area under the concentration versus time curve; Cmax=maximumobserved concentration, Cτ=concentration at the end of dosing interval; *= Using cross-studycomparisons to historical pharmacokinetic data).

Table 1: Interactions

Concomitant medicinal Effect on concentration ofproduct by therapeutic temsavir or concomitant Recommendation concerning co-area medicinal product administration

HIV-1 Antiviral Agents

Non-nucleoside Reverse Transcriptase Inhibitor

Efavirenz (EFV) Temsavir ↓ This interaction has not been studied.

(induction of CYP3A Efavirenz is expected to decreaseenzymes)1 temsavir plasma concentrations. Nodose adjustment is necessary.

Etravirine (ETR) without Temsavir ↓ Etravirine decreased temsavir plasmaboosted protease inhibitors AUC ↓ 50% concentrations. No dose adjustment

Cmax ↓ 48% of either medicinal product is

Cτ ↓ 52% necessary.(induction of CYP3Aenzymes)1

ETR ↔

Nevirapine (NVP) Temsavir ↓ This interaction has not been studied.(induction of CYP3A Nevirapine is expected to decreaseenzymes)1 temsavir plasma concentrations. Nodose adjustment is necessary.

Nucleoside Reverse Transcriptase Inhibitor

Tenofovir disoproxil (TDF) Temsavir ↔ No dose adjustment of either

AUC ↔ medicinal product is necessary.

Cmax ↓ 1%

Cτ ↑ 13%

Tenofovir ↑

AUC ↑ 19%

Cmax ↑ 18%

Cτ ↑ 28%

Tenofovir alafenamide TAF ↑ This interaction has not been studied.(TAF) (inhibition of OATP1B1/3 Temsavir is expected to increaseand/or BCRP) tenofovir alafenamide plasmaconcentrations. The recommendeddose of TAF is 10 mg when co-administered with fostemsavir.

Protease Inhibitor

Atazanavir (ATV)/ritonavir Temsavir ↑ Atazanavir/ritonavir increased(RTV) AUC ↑ 54% temsavir concentrations. No dose

Cmax ↑ 68% adjustment of either medicinal

Cτ ↑ 57% product is necessary.(inhibition of CYP3Aenzymes and P-gp)1

ATV ↔

RTV ↔

Darunavir (DRV)/cobicistat Temsavir ↑ Darunavir/cobicistat increased

AUC ↑ 97% temsavir plasma concentrations. No

Cmax ↑ 79% dose adjustment is necessary.

Cτ ↑ 124%(inhibition of CYP3Aenzymes, P-gp and/or

BCRP)1

Darunavir (DRV)/ritonavir Temsavir ↑ Darunavir/ritonavir increased

AUC ↑ 63% temsavir plasma concentrations. No

Cmax ↑ 52% dose adjustment is necessary for any

Cτ ↑ 88% medicinal product when co-(inhibition of CYP3A administered.enzymes and P-gp)1

DRV ↔

AUC ↓ 6%

Cmax ↓ 2%

Cτ ↓ 5%

RTV ↔

AUC ↑ 15%

Cmax ↔

Cτ ↑ 19%

Darunavir (DRV)/ritonavir Temsavir ↑ Darunavir/ritonavir co-administered+ Etravirine AUC ↑ 34% with etravirine increased temsavir

Cmax ↑ 53% plasma concentrations. No dose

Cτ ↑ 33% adjustment is necessary for anymedicinal product when co-

Darunavir ↓ administered.

AUC ↓ 6%

Cmax ↓ 5%

Cτ ↓ 12%

Ritonavir ↑

AUC ↑ 9%

Cmax ↑ 14%

Cτ ↑ 7%

Etravirine ↔

AUC ↑ 28%

Cmax ↑ 18%

Cτ ↑ 28%

Pharmacokinetic Enhancer

Cobicistat (COBI) Temsavir ↑ Cobicistat increased temsavir plasma

AUC ↑ 93% concentrations. No dose adjustment is

Cmax ↑ 71% necessary.

Cτ ↑ 136%(inhibition of CYP3Aenzymes, P-gp and/or

BCRP)1

Ritonavir Temsavir ↑ Ritonavir increased temsavir plasma

AUC ↑ 45% concentrations. No dose adjustment

Cmax ↑ 53% of either medicinal product is

Cτ ↑ 44% necessary.(inhibition of CYP3A and

P-gp)1

RTV ↔

Maraviroc (MVC) Temsavir ↔ No dose adjustment of either

Cmax ↑ 13% medicinal product is necessary.

AUC ↑ 10%

Cτ ↓ 10%

MVC ↔

AUC ↑ 25%

Cmax ↑ 1%

Cτ ↑ 37%

Raltegravir (RAL) Temsavir ↔* No dose adjustment of eithermedicinal product is necessary.

RAL ↔*

Other medicinal products

Buprenorphine/naloxone Buprenorphine ↔ No dose adjustment necessary.

AUC ↑ 30%

Cmax ↑ 24%

Norbuprenorphine ↔

AUC ↑ 39%

Cmax ↑ 24%

Methadone Methadone ↔ No dose adjustment necessary.

R-Methadone

AUC ↑ 13%

Cmax ↑ 15%

S-Methadone

AUC ↑ 15%

Cmax ↑ 15%

H2-Receptor Antagonists: Temsavir ↔ No dose adjustment is necessary

Famotidine AUC ↑ 4% when combined with medicinal

Cmax ↑ 1% products that increase gastric pH.

Cτ ↓ 10%

Oral contraceptives: EE ↑ EE should not exceed 30 µg daily.

Ethinyl estradiol (EE) AUC ↑ 39% Caution is advised, particularly in

Cmax ↑ 40% patients with additional risk factors(inhibition of CYP enzymes for thromboembolic events (seeand/or BCRP)1 section 4.4).

Norethindrone acetate (NE) NE ↔ No dose adjustment is necessary

AUC ↑ 8%

Cmax ↑ 8%

Rifabutin Temsavir ↓ Rifabutin decreased temsavir plasma

AUC ↓ 30% concentrations. No dose adjustment is

Cmax ↓ 27% necessary.

Cτ ↓ 41%(induction of CYP3Aenzymes)1

Rifabutin + Ritonavir Temsavir ↑ Rifabutin co-administered with

AUC ↑ 66% ritonavir increased temsavir plasma

Cmax ↑ 50% concentrations. No dose adjustment is

Cτ ↑ 158% necessary.

Rifampicin Temsavir ↓ Rifampicin co-administration may

AUC ↓ 82% lead to loss of virologic response to

Cmax ↓ 76% fostemsavir due to significant(induction of CYP3A decreases in temsavir plasmaenzymes) concentrations caused by strong

CYP3A4 induction. Therefore, theconcomitant use of fostemsavir andrifampicin is contraindicated.

Although not studied, concomitantuse of fostemsavir and other strong

CYP3A4 inducers is contraindicated(see section 4.3).

HMG CO-A Reductase Rosuvastatin ↑ Coadministration of fostemsavir

Inhibitors: AUC ↑ 69% increases rosuvastatin plasma

Rosuvastatin Cmax ↑ 78% concentrations caused by

Atorvastatin (inhibition of OATP1B1/3 OATP1B1/3 and/or BCRP inhibition

Pitavastatin and/or BCRP) by temsavir. Therefore use the lowest

Fluvastatin possible starting dose of rosuvastatin

Simvastatin with careful monitoring.

Although not studied, use the lowestpossible starting dose of other statinsthat are substrates of OATP1B1/3and/or BCRP with careful monitoringfor HMG-CoA reductase inhibitor-associated adverse reactions.

Pravastatin Pravastatin ↑ Although not studied, clinicallyrelevant increases in plasmaconcentrations of pravastatin are notexpected as it is not a substrate of

BCRP. No dose adjustment isrequired.

Hepatitis C virus Direct- Grazoprevir ↑ This interaction has not been studied.

Acting Antivirals (HCV (inhibition of OATP1B1/3) Temsavir may increase grazoprevir

DAAs): plasma concentrations to a clinically

Elbasvir/Grazoprevir relevant extent caused by

OATP1B1/3 inhibition by temsavir.

Co-administration of fostemsavir withelbasvir/grazoprevir is notrecommended as increasedgrazoprevir concentrations mayincrease the risk of ALT elevations.

Sofosbuvir HCV-DAA ↑ Although not studied, temsavir may

Ledipasvir increase plasma concentrations of

Velpatasvir other HCV DAAs. No dose

Voxilaprevir adjustment is necessary.

Ombitasvir

Paritaprevir

Dasabuvir

Daclatasvir1Potential mechanism(s) of drug interactions

QT prolonging medicinal products

There is no information available on the potential for a pharmacodynamic interaction betweenfostemsavir and medicinal products that prolong the QTc interval of the ECG. However, based on astudy of healthy subjects, in which a supratherapeutic dose of fostemsavir prolonged the QTc interval,fostemsavir should be used with caution when co-administered with a medicinal product with a knownrisk of Torsade de Pointes (see sections 4.4).

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use offostemsavir in pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity atexposure levels of temsavir in the range of the recommended human dose (RHD) (see section 5.3). Inpregnant rats fostemsavir and/or its metabolites cross the placenta and are distributed to all foetaltissues.

As a precautionary measure, it is preferable to avoid the use of Rukobia during pregnancy.

It is recommended that women living with HIV do not breast-feed their infants in order to avoidtransmission of HIV.

It is unknown whether fostemsavir/temsavir are excreted in human milk. Available toxicokinetic datain lactating rats have shown excretion of fostemsavir/temsavir in milk (see section 5.3).

There are no data on the effects of fostemsavir on human male or female fertility. Animal studiesindicate no effects of fostemsavir on male or female fertility at clinically relevant doses (see section5.3).

Fostemsavir has a minor influence on the ability to drive and use machines. Patients should beinformed that headache, dizziness and somnolence have been reported during treatment withfostemsavir (see section 4.8). The clinical status of the patient and the adverse reaction profile offostemsavir should be borne in mind when considering the patient's ability to drive or operatemachinery.

The most serious adverse reaction was immune reconstitution inflammatory syndrome (see section4.4). The most commonly seen treatment emergent adverse reactions were diarrhoea (24%), headache(17%), nausea (15%), rash (12%), abdominal pain (12%), and vomiting (11%).

The adverse reactions identified in clinical trials are listed in Table 2 by body system, organ class andfrequency. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon(≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000).

Table 2: Tabulated list of adverse reactions

System Organ Class Frequency1 Adverse Reactions

Immune system Common Immune reconstitution inflammatory syndrome2 (seedisorders section 4.4)

Psychiatric disorders Common Insomnia

Nervous system Very Headachedisorders common

Common Dizziness, Somnolence, Dysgeusia

Cardiac disorders Common Electrocardiogram QT prolonged (see section 4.4)

Gastrointestinal Very Diarrhoea, Nausea, Abdominal pain3, Vomitingdisorders common

Common Dyspepsia, Flatulence

Hepatobiliary Common Transaminases increased4disorders

Skin and Very Rash5subcutaneous tissue commondisorders Common Pruritus6

Musculoskeletal and Common Myalgiaconnective tissuedisorders

General disorders Common Fatigueand administrationsite conditions

Investigations Common Blood creatinine increased, Blood creatinephosphokinase increased1 Calculated based on safety data from 570 subjects (n=370 from phase III [BRIGHTE] study at 144weeks, and n=200 from phase IIb study with mean duration 174 weeks).2Includes central nervous system immune reconstitution inflammatory response and immunereconstitution inflammatory syndrome.3Includes abdominal discomfort, abdominal pain and abdominal pain upper.4Includes increases in ALT, AST, hepatic enzymes and transaminases.5Includes rash, rash erythematous, rash generalised, rash macular, rash maculo-papular, rash papular,rash pruritic and rash vesicular.6Includes pruritus and pruritus generalised.

Increases in creatine phosphokinase (CPK) were observed following treatment with fostemsavir,which were mainly mild or moderate. These changes were rarely associated with musculoskeletalcomplaints and are not considered clinically relevant.

Clinically relevant increases in serum creatinine have primarily occurred in patients with identifiablerisk factors for reduced renal function, including pre-existing medical history of renal disease and/orconcomitant medications known to cause increases in creatinine. A causal association betweenfostemsavir and elevation in serum creatinine has not been established.

Asymptomatic elevations in creatinine, creatine phosphokinase and liver enzymes were mainly grade1 or 2 and did not require interruption of treatment

Increases in direct (conjugated) bilirubin have been observed following treatment with fostemsavir.

Cases of clinical significance were uncommon and were confounded by the presence of intercurrentserious comorbid events not related to dosing with study medication (e.g. sepsis, cholangiocarcinomaor other complications of viral hepatitis co-infection). In the remaining reports, elevations in directbilirubin (without clinical jaundice) were typically transient, occurred without increases in livertransaminases and resolved on continued fostemsavir.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is no specific treatment for overdose with fostemsavir. In case of overdose, it is recommendedthat the patient be monitored for any signs or symptoms of adverse reactions and given appropriatesymptomatic treatment. Standard supportive measures should be applied as required, includingmonitoring of vital signs as well as observation of the clinical status of the patient. As temsavir ishighly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis.

Further management should be as clinically indicated or as recommended by the national poisonscentre, where available.

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

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 bindsdirectly to the gp120 subunit within the HIV-1 envelope glycoprotein gp160 and selectively inhibitsthe interaction between the virus and cellular CD4 receptor, thereby preventing viral entry into, andinfection 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 (see section 4.4).

Against a panel of 1337 clinical isolates tested with the PhenoSense Entry assay, the mean IC50 valuewas 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_AEwas associated with higher IC50 values (5/5 isolates with temsavir IC50 values >100 nM). CRF01_AEis considered naturally resistant to temsavir on the basis of available data, due to the presence ofpolymorphisms 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) over14 to 49 days resulted in gp120 substitutions at L116, A204, M426, M434 and M475. Phenotypes ofrecombinant LAI viruses containing TMR-selected substitutions were investigated. Additionally,phenotypes of viruses with substitutions at position S375 that were identified in pre-treatment samplesin fostemsavir clinical studies were evaluated. The phenotypes of those considered clinically relevantare tabulated below (Table 3).

Table 3: Phenotypes of recombinant LAI viruses containing clinically relevant gp120substitutions

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 arenot 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 PIsatazanavir and darunavir. Additionally, abacavir, tenofovir, efavirenz, rilpivirine, atazanavir, darunavirand raltegravir retained activity against site-directed mutant viruses with reduced temsavirsusceptibility (S375M, M426L, or M426L plus M475I).

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

Temsavir was active against several ibalizumab-resistant viruses. Ibalizumab retained activity againstsite-directed mutant viruses that had reduced susceptibility to temsavir (S375M, M426L, or M426Lplus 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 theenvelope, 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 fostemsavirfunctional monotherapy at Day 8 was assessed in the Phase III study (BRIGHTE [205888]) in heavilytreatment-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 >0.5log10 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 variableranging from 0.06 to 6,651. The effect of screening fostemsavir phenotype on response of >0.5 log10decline at Day 8 was assessed in the ITT-E population (Table 5). While there does appear to be a trendtoward reduced clinical response at higher TMR IC50 values, this baseline variable fails to reliablypredict efficacy outcomes in the intended use population.

Table 4: Virologic Response Category at Day 8 (Randomised Cohort) by presence of gp120resistance-associated polymorphisms (RAPs) at baseline - ITT-E Population

Randomised Cohort FTR600 mg BID(N=203)n (%)

Response Categorya>1.0 log10 >0.5 to ≤1.0 ≤0.5 log b10 Missingn log10n 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, 88 36 (41) 12 (14) 37 (42) 3 (3)

M434I, M475I)

S375

S375H/I/M/N/T 64 29 (45) 9 (14) 23 (36) 3 (5)

S375H 1 0 0 1 (100) 0

S375M 5 1 (20) 0 4 (80) 0

S375N 22 10 (45) 3 (14) 8 (36) 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) 01 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 wassubsequently identified as a novel polymorphism and shown to substantially decrease TMR susceptibility in a LAIenvelope in vitro.

RAPs = Resistance-associated polymorphisms

Table 5: Virologic Response Category at Day 8 (Randomised Cohort) by Phenotype at baseline -

ITT-E Population

Baseline Temsavir IC50 Fold Change Virologic Response at Day 8

Category (>0.5 log10 decline in HIV-1 RNA from Day 1to 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%)

Antiviral activity against subtype AE

Within HIV-1 Group M, temsavir showed considerably reduced antiviral activity against subtype AEisolates. 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 acidpositions S375H and M475I in gp120, which have been associated with reduced susceptibility tofostemsavir. Subtype AE is a predominant subtype in Southeast Asia, but it is not found frequentlyelsewhere.

Two subjects in the Randomised Cohort had subtype AE virus at screening. One subject (EC50 foldchange >4,747-fold and gp120 substitutions at S375H and M475I at baseline) did not respond tofostemsavir at Day 8. The second subject (EC50 fold change 298-fold and gp120 substitution at S375Nat baseline) received placebo during functional monotherapy. Both subjects had HIV RNA <40copies/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 subjectswith virologic failure in the Randomised Cohort had treatment-emergent gp120 genotypicsubstitutions at 4 key sites (S375, M426, M434, and M475).

The median temsavir EC50 fold change at failure in randomised evaluable subject isolates withemergent gp120 substitutions at positions 375, 426, 434, or 475 (n = 26) was 1,755-fold compared to3-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 emergentsubstitutions S375N and M426L and (less frequently) S375H/M, M434I and M475I, 88% (22/25) hadtemsavir 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 Cohorthad 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 atleast 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 screeningwas similar between patients in the Randomised and Non-randomised Cohorts, the proportion of virusisolates with emergent gp120 resistance-associated substitutions at the time of failure was higheramong 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, or475 (n = 33) was 4,216-fold and compared to 402-fold for isolates without substitutions at thesepositions (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 Cohorthad 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 atleast one drug in the OBT.

Table 6: Virologic Failures in BRIGHTE Trial

Randomised Cohort Non-randomised

Total Cohort Total

Number of virologic failures 69/272 (25%) 50/99 (51%)

Virologic failures with available gp120 data at 68/272 (25%) 48/99 (48%)baseline

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 22/52 (42%) 29/44 (66%)change ratio >3-foldb,c

Without EN RAS and with temsavir IC50 fold 3/52 (6%) 2/44 (5%)change ratio >3-foldc

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, 60healthy subjects received oral administration of placebo, fostemsavir 1 200 mg once daily, fostemsavir2 400 mg twice daily and moxifloxacin 400 mg (active control) in random sequence. Fostemsaviradministered at 1 200 mg once daily did not have a clinically meaningful effect on the QTc interval asthe maximum mean time-matched (2-sided 90% upper confidence bound) placebo-adjusted QTcchange 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 at2 400 mg twice daily for 7 days was associated with a clinically meaningful prolongation of the QTcinterval 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-stateadministration 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 (seesection 4.4).

The efficacy of fostemsavir in HIV-infected, heavily treatment-experienced adult subjects is based ondata from a Phase III, partially-randomised, international, double-blind, placebo-controlled trial

BRIGHTE (205888), conducted in 371 heavily-treatment experienced HIV-1 infected subjects withmulti-class resistance. All subjects were required to have a viral load greater than or equal to 400copies/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 andavailable ARVs which could be combined as part of an efficacious background regimen. 272 subjectsreceived either blinded fostemsavir, 600 mg twice daily (n= 203), or placebo (n= 69), in addition totheir current failing regimen, for 8 days of functional monotherapy. Beyond Day 8, Randomisedsubjects 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 1onward. 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

Randomised Cohort Non-

FTR Randomised

Placeboa TOTAL(N=69) 600 mg BID Total Cohort(N=203) (N=272) FTR 600 mg BID (N=371)(N=99)

Sex, n (%)

Male 57 (83) 143 (70) 200 (74) 89 (90) 289 (78)

Age (yrsb)

Median 45.0 48.0 48.0 50.0 49.0≥ 65, n (%) 1(1) 9(4) 10(4) 2(2) 12(3)

Race, n (%)

White 48 (70) 137 (67) 185 (68) 74 (75) 259 (70)

Baseline HIV-1 RNA (log10 c/mL)

Median 4.6 4.7 4.7 4.3 4.6

Baseline CD4+ (cells/mm3)

Median 100.0 99.0 99.5 41.0 80.0

Baseline CD4+ (cells/mm3), n (%)<20 17 (25) 55 (27) 72 (26) 40 (40) 112 (30)<200 49(71) 150(73) 199(72) 79(79) 278(75)

AIDS History, n (%)c

Yes 61 (88) 170 (84) 231 (85) 89 (90) 320 (86)

Number of Years Treated for HIV Infection, n (%)>15 40 (58) 142 (69) 182 (67) 80 (81) 262 (70)

Number of Prior ART Regimens (including current failing regimen) n (%)5 or more 57 (83) 169 (83) 226 (83) 90 (91) 316 (85)

Number fully active agents in their original OBT n (%)0 1 (1) 15 (7) 16 (6) 80 (81) 96 (26)1 34 (49) 108 (53) 142 (52) 19 (19)d 161 (43)2 34 (49) 80 (39) 114 (42) 0 114 (31)

Number with history of hepatitis B and/or C co-infectionn (%) 6 (9) 15 (7) 21 (8) 8 (9) 29 (8)

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 Day8 in the Randomised Cohort, demonstrated superiority of fostemsavir to placebo (0.79 vs. 0.17 log10decline, 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

Randomised n Adjusted Meana Differenceb p-valuec

Treatment (95% CI) (95% CI)

Placebo 69 -0.166 - -(-0.326, -0.007)

Fostemsavir 600 mg 201d -0.791 -0.625 <0.0001twice daily (-0.885, -0.698) (-0.810, -0.441)

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, 000c/mL achieved a median decline in viral load of 1.02 log10 c/mL at Day 8, compared with 0.00 log10c/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 wassimilar in subjects with subtype B and non-B subtype virus (F1, BF1 and C). There was a reducedmedian 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

Randomised Cohort FTR 600 mg BID (N=203)

Plasma HIV-1 RNA (log10 copies/mL) Change from Day 1 at Day 8

HIVsubtype at n Mean SD Median Q1 Q3 Min. Max.

Baselinen 199a -0.815 0.7164 -0.877 -1.324 -0.317 -2.70 1.25

B 159a -0.836 0.7173 -0.923 -1.360 -0.321 -2.70 1.25

F1 14 -0.770 0.6478 -0.760 -1.287 -0.417 -1.61 0.28

BF1 10 -0.780 0.5515 -0.873 -1.074 -0.284 -1.75 -0.01

C 6 -0.888 0.6861 -0.823 -1.155 -0.558 -2.02 0.05

A1 2 -0.095 0.3155 -0.095 -0.318 0.128 -0.32 0.13

AE 1 0.473 0.473 0.473 0.473 0.47 0.47

Otherb 7 -0.787 1.0674 -1.082 -1.529 -0.034 -2.11 1.16

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

a. 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 and11 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)

Fostemsavir 600 mg twice daily

Week 24 Week 48 Week 96(N = 272) (N = 272) (N = 272)

HIV-1 RNA <40 copies/mL 53% 54% 60%

HIV-1 RNA ≥40 copies/mL 40% 38% 30%

Data in window not <40 copies/mL 32% 26% 12%

Discontinued for lack of efficacy <1% 2% 4%

Discontinued for other reasons while not 1% 3% 6%suppressed

Change in ART regimen 6% 7% 8%

No virologic data 7% 8% 10%

Reasons

Discontinued study/study drug due to 4% 5% 6%adverse event or death

Discontinued study/study drug for other 2% 3% 3%reasons

Missing data during window but on study 1% <1% 2%

HIV-1 RNA <40 copies/mL by Baseline Covariates n/N (%)

Baseline Plasma viral load (copies/mL)<100,000 116/192 (60%) 118/192 (61%) 124/192 (65%)≥100,000 28/80 (35%) 28/80 (35%) 39/80 (49%)

Baseline CD4+ (cells/ mm3)<20 23/72 (32%) 25/72 (35%) 33/72 (46%)20 to <50 12/25 (48%) 12/25 (48%) 14/25 (56%)50 to <200 59/102 (58%) 59/102 (58%) 62/102 (61%)≥200 50/73 (68%) 50/73 (68%) 54/73 (74%)

Number of Fully Active and Available

Antiretroviral (ARV) Classes in initial

OBT0* 5/16 (31%) 5/16 (31%) 3/16 (19%)1 80/142 (56%) 82/142 (58%) 92/142 (65%)2 59/114 (52%) 59/114 (52%) 68/114 (60%)

Response by DTG as a component of OBT

DTG 129/229 (56%) 127/229(55%) 146/229 (64%)

DTG (once daily) 35/58 (60%) 34/58 (59%) 40/58 (69%)

DTG (twice daily) 94/171 (55%) 93/171 (54%) 106/171 (62%)

No DTG 15/43 (35%) 19/43 (44%) 17/43 (40%)

Response by DTG and DRV as acomponent of OBT

DTG and DRV 68/117 (58%) 60/117 (51%) 75/117 (64%)

With DTG, without DRV 61/112 (54%) 67/112 (60%) 71/112 (63%)

Without DTG, with DRV 5/17 (29%) 8/17 (47%) 8/17 (47%)

Without DTG, without DRV 10/26 (38%) 11/26 (42%) 9/26 (35%)

Male 104/200 (52%) 102/200 (51%) 118/200 (59%)

Female 40/72 (56%) 44/72 (61%) 45/72 (63%)

White 90/185 (49%) 92/185 (50%) 103/185 (56%)

Black or African-American/Others 54/87 (62%) 54/87 (62%) 60/87 (69%)

Age (years)<50 81/162 (50%) 81/162 (50%) 96/162 (59%)≥50 63/110 (57%) 65/110 (59%) 67/110 (61%)

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% and64% of subjects at Weeks 24, 48 and 96, respectively. At these timepoints, the proportion of subjectswith viral load <400 HIV-1 RNA copies/mL was 75%, 70% and 64%, respectively (ITT-E, Snapshotalgorithm). 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 (<20cells/mm3) had a similar increase in CD4+ count over time compared with subjects with higherbaseline 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)

Fostemsavir 600 mg twice daily

Week 24 Week 48 Week 96(N = 99) (N = 99) (N = 99)

HIV-1 RNA <40 copies/mL 37% 38% 37%

HIV-1 RNA ≥40 copies/mL 55% 53% 43%

Data in window not <40 copies/mL 44% 33% 15%

Discontinued for lack of efficacy 0% 2% 3%

Discontinued for other reasons while not 2% 3% 6%suppressed

Change in ART regimen 8% 14% 19%

No virologic data 8% 9% 19%

Reasons

Discontinued study/study drug due to 4% 7% 14%adverse event or death

Discontinued study/study drug for other 0% 2% 4%reasons

Missing data during window but on study 4% 0% 1%

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%, andthe proportion of subjects with HIV-1 RNA <400 copies/mL was 44%, 44% and 40%, at Weeks 24, 48and 96, respectively (ITT-E, Snapshot algorithm). Mean changes in CD4+ cell count from baselineincreased over time: 41 cells/mm3 at Week 24, 64 cells/mm3 at Week 48 and 119 cells/mm3 at Week96.

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 forinformation on paediatric use).

The pharmacokinetics of temsavir following administration of fostemsavir are similar between healthyand HIV-1 infected subjects. In HIV-1 infected subjects, the between-subject variability (%CV) inplasma temsavir Cmax and AUC ranged from 20.5 to 63% and Cτ from 20 to 165%. Between-subjectvariability in oral clearance and oral central volume of distribution estimated from populationpharmacokinetic analysis of healthy subjects from selected Phase I studies and HIV-1 infected patientswere 43% and 48%, respectively.

Fostemsavir is a prodrug that is metabolised to temsavir by alkaline phosphatase at the luminal surfaceof the small intestine and is generally not detectable in plasma following oral administration. Theactive 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 andcaecum/proximal ascending colon.

Pharmacokinetic parameters following multiple oral doses of fostemsavir 600 mg twice daily in HIV-1infected, adult subjects are shown in Table 12.

Table 12: Multiple-Dose Pharmacokinetic Parameters of Temsavir following oral administrationof Fostemsavir 600 mg twice daily

Pharmacokinetic Geometric Mean (CV%)a

Parameters

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 mgdose of fostemsavir.

Effect of Food

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 consideredclinically 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 serumalbumin is the major contributor to plasma protein binding of temsavir in humans. The volume ofdistribution of temsavir at steady state (Vss) following intravenous administration is estimated at29.5 L. The blood-to-plasma total radiocarbon Cmax ratio was approximately 0.74, indicating minimalassociation of temsavir or its metabolites with red blood cells. Free fraction of temsavir in plasma wasapproximately 12 to 18% in healthy subjects, 23% in subjects with severe hepatic impairment, and19% in subjects with severe renal impairment, and 12% in HIV-1 infected patients.

In vivo, temsavir is primarily metabolised via esterase hydrolysis (36.1% of administered dose) andsecondarily 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 metabolicpathway (<1% of administered dose).

Temsavir is extensively metabolised, accounting for the fact that only 3% of the administered dose isrecovered in human urine and faeces. Temsavir is biotransformed into two predominant circulatinginactive 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 interactiondata. 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 ofclinical significance.

Temsavir has a terminal half-life of approximately 11 hours. Plasma temsavir clearance followingintravenous administration was 17.9 L/hr, and the apparent clearance (CL/F) following oraladministration was 66.4 L/hr. After oral administration of a single 300 mg dose of 14C-labelledfostemsavir in a human mass balance study, 51% and 33% of the radioactivity was retrieved in theurine 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 faecalexcretion is from biliary excretion.

Following single and repeat administration of fostemsavir ER tablets, increases in plasma temsavirexposure (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 than18 years.

Population pharmacokinetic analysis of temsavir using data in HIV-1 infected adults showed that therewas no clinically relevant effect of age on temsavir exposure.

Pharmacokinetic data for temsavir in subjects greater than 65 years old are limited. Elderly patientsmay be more susceptible to drug-induced QT interval prolongation (see section 4.4).

The effect of renal impairment on the exposure of temsavir after a single 600 mg dose of fostemsavirwas 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 oncreatinine 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 renalimpairment on pharmacokinetic exposure parameters (Cmax and AUCs) of temsavir (total andunbound). The mean fraction unbound (fu) TMR for the severe renal impairment group wasapproximately 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 thanthe Cmax threshold of an approximate 4.2-fold increase (7500 ng/ml) established based on temsavirexposure-response. Temsavir was not readily cleared by haemodialysis, with approximately 12.3% ofthe administered dose removed during the 4-hour haemodialysis session. Haemodialysis initiated 4hours after temsavir dosing was associated with an average 46% increase in plasma total temsavir Cmaxand 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 offostemsavir 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 bothunbound and total Cmax and AUC was in the range of 1.2- to 2.2-fold. However, the upper bounds ofthe 2-sided 90% CI for the impact of hepatic impairment on plasma total and unbound temsavir Cmaxare lower than the Cmax threshold of an approximate 4.2-fold increase (7500 ng/ml) established basedon temsavir exposure-response (see section 5.1- Effects on electrocardiogram).

Population pharmacokinetic analyses indicated no clinically relevant effect of gender on the exposureof 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 oftemsavir.

Carcinogenesis and mutagenesis

Neither fostemsavir nor temsavir were mutagenic or clastogenic using in vitro tests in bacteria andcultured mammalian cells and an in vivo rat micronucleus assay. Fostemsavir was not carcinogenic inlong 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 notadversely affected at exposures up to 186 times the human exposure at the RHD. While embryofetalexposure was demonstrated in a separate distribution study in pregnant rats with oral administration of14C-FTR, no effects on embryofetal development were noted in this species at exposures up to 200times the human exposure at the RHD. In rabbits embryofetal development was also not affected atexposures up to 30 times the human exposure at the RHD. Prenatal and postnatal developmentincluding the attainment of puberty and learning memory in offspring was not influenced in rats atexposures up to 50 times the human exposure at the RHD. At maternal exposures that are up to 130times the human AUC at the RHD, reduced postnatal viability probably due to an increased lactationalexposure to TMR was noted in the offspring. TMR is present in the milk of lactating rats and in theblood 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 (upto 39 weeks). Cardiovascular telemetry studies indicated that both FTR and TMR minimallyprolonged 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 andlipofuscin pigment deposits in Kupffer cells). These findings were observed in rats only (at systemicexposures ≥ 30 times the 600 mg twice daily human clinical exposure based on AUC), except livertoxicity reported in dogs (at exposure multiples ≥ 3). The majority of these effects were duration-dependent and reversible upon cessation of treatment.

Hydroxypropylcellulose

Hypromellose

Colloidal anhydrous Silica

Magnesium stearate

Poly(vinyl alcohol)

Titanium dioxide (E171)

Macrogol 3350

Talc

Iron oxide yellow (E172)

Iron oxide red (E172)

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

White high density polyethylene (HDPE) bottles with polypropylene child resistant closures thatinclude a polyethylene faced induction heat seal liner. Each pack consists of one or three bottles, eachcontaining 60 prolonged-release tablets.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

ViiV Healthcare BV

Van Asch van Wijckstraat 55H3811 LP Amersfoort

Netherlands

EU/1/20/1518/001

EU/1/20/1518/002

Date of first authorisation: 04 February 2021

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.