Methods for Treating HIV with Cabotegravir and Rilpivirine

Abstract

A method is invented for treating HIV in a human in need thereof, comprising administering to such human a therapeutically effective amount of a combination of cabotegravir, or a pharmaceutically acceptable salt thereof, and rilpivirine, or a pharmaceutically acceptable salt thereof.

Description

[Technical Field]

[0001] The present invention relates to a combination of cabotegravir or a pharmaceutically acceptable salt thereof and rilpivirine or a pharmaceutically acceptable salt thereof. in vivo The present invention relates to a method of treating HIV in a human by administering [Background technology]

[0002] The current standard of care for first-line treatment of HIV-1 infection in antiretroviral therapy (ART)-naive adults is a regimen of three or more antiretroviral drugs, including two nucleoside reverse transcriptase inhibitors (NRTIs) and one other drug from either the boosted protease inhibitor (PI), integrase strand transfer inhibitor (INSTI), or non-nucleoside reverse transcriptase inhibitor (NNRTI) classes. However, concerns remain about the need for lifelong therapy with drugs with diverse safety and tolerability profiles. Therefore, a two-drug regimen (2DR) that can induce and / or maintain virologic suppression while reducing lifetime cumulative drug exposure and potential long-term toxicity would offer an alternative treatment option for people living with HIV-1 infection.

[0003] Early (2000–2014) clinical trials evaluating 2DRs yielded inconclusive results, likely due in part to small sample sizes, short treatment durations, and limited available treatments. The AIDS Clinical Trials Group study A5142 team found that the virologic efficacy of a 2DR (n=250) comprising efavirenz and ritonavir-boosted lopinavir was similar to that of efavirenz and two NRTIs (n=250) over 96 weeks of treatment in ART-naive participants. However, this 2DR was associated with an increased incidence of drug resistance. Similarly, the PROGRESS study demonstrated that 2-drug ritonavir-boosted lopinavir and raltegravir (n = 101) had similar antiviral activity to the 3-drug regimen (3-drug) ritonavir-boosted lopinavir and tenofovir disoproxil fumarate / emtricitabine (n = 105) in ART-naive participants at 96 weeks, although this study primarily enrolled participants with viral loads <100,000 copies / mL and CD4+ cell counts ≥200 cells / mm. The GARDEL study demonstrated non-inferior virologic efficacy of open-label ritonavir-boosted lopinavir and lamivudine (n = 214) compared with ritonavir-boosted lopinavir and 2 NRTIs (n = 202) in ART-naive participants after 48 weeks of treatment. However, these 2DRs include ritonavir-boosted protease inhibitors, which are associated with various metabolic syndrome and cardiovascular-related diseases, potentially negating the expected benefits in terms of reduced drug exposure and cumulative toxicity. These studies demonstrate both the potential of 2DRs as ART options and the importance of selecting agents with appropriate and complementary virologic and clinical properties.

[0004] Cabotegravir (GSK1265744) is an analog of the integrase strand transfer inhibitor (INSTI) dolutegravir and exhibits subnanomolar potency and antiviral activity against a broad range of HIV-1 strains. Once-daily oral administration of cabotegravir has demonstrated an acceptable safety and tolerability profile, a long half-life (40 hours), and few drug-drug interactions. Rilpivirine (TMC278), a non-nucleoside reverse transcriptase inhibitor (NNRTI), is approved as a once-daily oral 25 mg dose for the treatment of HIV-1.

[0005] In the LATTE-2 trial, patients initially received a 20-week regimen of oral cabotegravir and abacavir / lamivudine. After a run-in period, suppressed patients were randomized 2:2:1 to receive long-acting injectable cabotegravir and rilpivirine every 4 weeks or every 8 weeks, or to continue the three-drug oral regimen. Patients on the long-acting regimen were extended to 160 weeks, and patients on the oral regimen were given the option to transition to either the every 4-weekly or every 8-weekly regimen at week 96. At week 160, 104 (90%) of 115 participants and 95 (83%) of 115 participants receiving the every 8-weekly and every 4-weekly injectable regimens, respectively, maintained viral suppression. Summary of the Invention

[0006] The present invention comprises a method of treating HIV in a human in need thereof, comprising administering a therapeutically effective amount of a combination of cabotegravir, or a pharmaceutically acceptable salt thereof, and rilpivirine, or a pharmaceutically acceptable salt thereof. Alternatively, an aspect of this embodiment comprises the use of cabotegravir, or a salt thereof, and rilpivirine, or a salt thereof, in the manufacture of a medicament for use in treating HIV infection. Alternatively, an aspect of this embodiment comprises cabotegravir, or a salt thereof, and rilpivirine, or a salt thereof, for use in treating HIV infection.

[0007] According to a first main embodiment, the combination of cabotegravir, a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor (INSTI), and rilpivirine, an HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI), particularly a two-drug co-packaged product (collectively referred to as the "combination"), is indicated as a complete regimen for the treatment of HIV-1 infection in adults to replace the current antiretroviral regimen in virologically suppressed (less than 50 copies of HIV-1 RNA per mL) adults and adults who do not have known or suspected resistance to either cabotegravir or rilpivirine. According to one embodiment, cabotegravir or a salt thereof and rilpivirine or a salt thereof are provided for use in the treatment of HIV infection in adults as a complete regimen to replace the current antiretroviral regimen in virologically suppressed (less than 50 copies of HIV-1 RNA per mL) adults and adults who do not have known or suspected resistance to either cabotegravir or rilpivirine. According to one embodiment, there is provided cabotegravir or a salt thereof and rilpivirine or a salt thereof for use in the treatment of HIV infection in adults as a complete regimen to replace the current antiretroviral regimen in virologically suppressed adults (HIV-1 RNA less than 50 copies per mL) and adults who do not have known or suspected resistance to either cabotegravir or rilpivirine and adults who have not had previous virologic failure with NNRTI and INSTI class drugs. According to one embodiment, there is provided cabotegravir or a salt thereof for use in the treatment of HIV infection in adults as a complete regimen to replace the current antiretroviral regimen in virologically suppressed adults (HIV-1 RNA less than 50 copies per mL) and adults who do not have known or suspected resistance to either cabotegravir or rilpivirine, wherein cabotegravir or a salt thereof is used in combination with rilpivirine or a salt thereof.According to one embodiment, there is provided cabotegravir or a salt thereof for use in the treatment of HIV infection in adults as a complete regimen to replace the current antiretroviral regimen in virologically suppressed (HIV-1 RNA less than 50 copies per mL) adults and adults who have no known or suspected resistance to either cabotegravir or rilpivirine and adults who have no previous virologic failure to drugs of the NNRTI and INSTI class, wherein cabotegravir or a salt thereof is used in combination with rilpivirine or a salt thereof. According to one embodiment, there is provided rilpivirine or a salt thereof for use in the treatment of HIV infection in adults as a complete regimen to replace the current antiretroviral regimen in virologically suppressed (HIV-1 RNA less than 50 copies per mL) adults and adults who have no known or suspected resistance to either cabotegravir or rilpivirine, wherein rilpivirine or a salt thereof is used in combination with cabotegravir or a salt thereof. According to one embodiment, there is provided rilpivirine or a salt thereof for use in the treatment of HIV infection in adults as a complete regimen to replace the current antiretroviral regimen in virologically suppressed (HIV-1 RNA less than 50 copies per mL) adults and in adults who have no known or suspected resistance to either cabotegravir or rilpivirine and who have no prior virologic failure to NNRTI and INSTI class drugs, wherein rilpivirine or a salt thereof is used in combination with cabotegravir or a salt thereof.

[0008] According to a second main embodiment, there is provided a method of treating HIV-1, comprising regularly administering intramuscular injections of cabotegravir or a salt thereof and rilpivirine or a salt thereof, discontinuing one or both of the regularly administered intramuscular injections after at least one intramuscular injection of each of the cabotegravir or a salt thereof and rilpivirine or a salt thereof, and replacing the discontinued intramuscular injection(s) with regularly administered oral therapy. Alternatively, according to one aspect of this embodiment, there is provided cabotegravir or a salt thereof and rilpivirine or a salt thereof for use in therapy, particularly in the treatment of HIV infection, wherein the therapy, particularly the treatment of HIV infection, comprises regularly administering intramuscular injections of cabotegravir or a salt thereof and rilpivirine or a salt thereof, discontinuing one or both of the regularly administered intramuscular injections after at least one intramuscular injection of each of the cabotegravir or a salt thereof and rilpivirine or a salt thereof, and replacing the discontinued intramuscular injection(s) with regularly administered oral therapy.

[0009] According to a third main embodiment, there is provided a method of treating HIV, the method comprising: administering regularly scheduled intramuscular injections of cabotegravir or a salt thereof and rilpivirine or a salt thereof; discontinuing one or both of the regularly administered intramuscular injections after at least one intramuscular injection of each of said cabotegravir or a salt thereof and rilpivirine or a salt thereof; and re-establishing intramuscular administration of one or both of cabotegravir or a salt thereof and rilpivirine or a salt thereof by first administering a loading dose of the discontinued cabotegravir or a salt thereof and / or rilpivirine or a salt thereof, and thereafter continuing the regularly administered intramuscular injections. Alternatively, according to one aspect of this embodiment, there is provided cabotegravir or a salt thereof and rilpivirine or a salt thereof for use in therapy, particularly in the treatment of HIV infection, said therapy, particularly the treatment of HIV infection, comprising regularly administering intramuscular injections thereof, discontinuing one or both of said regularly administered intramuscular injections after at least one intramuscular injection of each of said cabotegravir or a salt thereof and rilpivirine or a salt thereof, and re-establishing intramuscular administration of one or both of cabotegravir or a salt thereof and rilpivirine or a salt thereof by first administering a loading dose of the discontinued cabotegravir or a salt thereof and / or rilpivirine or a salt thereof, and thereafter continuing the regularly administered intramuscular injections. [Brief explanation of the drawings]

[0010] [Figure 1] Specific Description of the Invention

[0011] First Main Embodiment According to a first principal embodiment, the combination of cabotegravir, a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor (INSTI), and rilpivirine, an HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI), particularly a two-drug co-packaged product (collectively referred to as the "combination"), is indicated as a complete regimen for the treatment of HIV-1 infection in adults to replace current antiretroviral regimens in virologically suppressed (less than 50 copies of HIV-1 RNA per mL) adults and who do not have known or suspected resistance to either cabotegravir or rilpivirine. In one embodiment, the combination consists of a cabotegravir long-acting formulation and a rilpivirine long-acting formulation. In one embodiment, the combination consists of a cabotegravir long-acting intramuscular injection and a rilpivirine long-acting intramuscular injection.

[0012] The combination is indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults to replace the current antiretroviral regimen in virologically suppressed (HIV-1 RNA less than 50 copies per mL) adults and adults with no known or suspected resistance to either cabotegravir or rilpivirine. In one embodiment, the combination is indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults to replace the current antiretroviral regimen in virologically suppressed (HIV-1 RNA less than 50 copies per mL) adults and adults with no known or suspected resistance to either cabotegravir or rilpivirine and adults with no prior virologic failure to NNRTI and INSTI class agents.

[0013] According to one aspect of the main embodiment, an oral induction dose to assess the tolerability of the combination, wherein oral induction (one 30 mg tablet of cabotegravir and one 25 mg tablet of rilpivirine once daily, e.g., one tablet comprising 31.62 mg of cabotegravir sodium and one tablet comprising 27.5 mg of rilpivirine hydrochloride) is used approximately one month (at least 28 days) prior to initiation of the combination to assess the tolerability of cabotegravir and rilpivirine.

[0014] According to another aspect of the main embodiment, the combination is administered by intramuscular injection. Starting injection (3mL administration kit) Injections begin on the last day of oral induction. The recommended starting injection dose for this combination in adults is a single 3 mL (600 mg) intramuscular injection of cabotegravir and a single 3 mL (900 mg) intramuscular injection of rilpivirine. Cabotegravir and rilpivirine should be administered at the same visit at separate gluteal injection sites. Continuous injection (2mL administration kit) After the initiation injection, the recommended continuation dose of this combination in adults is a single 2 mL (400 mg) intramuscular injection of cabotegravir and a single 2 mL (600 mg) intramuscular injection of rilpivirine monthly. Cabotegravir and rilpivirine should be administered at separate buttock injection sites during the same visit. Patients may receive this combination up to 7 days before or after the scheduled monthly 2 mL injection.

[0015] [Table 1]

[0016] According to another aspect of the primary embodiment, adherence to the monthly injection administration schedule is strongly recommended. Patients who miss a scheduled injection visit should be clinically reevaluated to ensure that resumption of treatment remains appropriate. See Table 2 for recommended doses after a missed injection.

[0017] [Table 2]

[0018] According to another aspect of the main embodiment, the injections must be administered by a medical professional. The full dose requires two injections: one injection of cabotegravir and one injection of rilpivirine. This combination injection is intended for intramuscular use only. The patient's body mass index (BMI) is taken into consideration to ensure that the needle length is sufficient to reach the gluteal muscle. Each injection is administered at a separate gluteal injection site during the same visit. A ventral cavity site is recommended.

[0019] According to another aspect of the primary embodiment, cabotegravir and rilpivirine are in a suspension for intramuscular injection that requires no further dilution or reconstitution. The order of administration of cabotegravir and rilpivirine injection is not important. Before preparing for injection, remove the combination from the refrigerator and wait at least 15 minutes to allow the medication to reach room temperature. Shake each vial of the combination vigorously to ensure a uniformly appearing suspension before injection. Small air bubbles are expected but acceptable. Parenteral medications should be visually inspected for particulate matter and discoloration before administration, whenever the solution and container permit. Cabotegravir vials have brown-colored glass, which may limit visual inspection. If either medication exhibits particulate matter or discoloration, discard the combination.

[0020] In one aspect, oral administration is provided by cabotegravir sodium, particularly 30 mg base equivalent. In one aspect, oral administration is provided by rilpivirine hydrochloride, particularly 25 mg base equivalent. In one aspect, cabotegravir injection, particularly intramuscular injection, is provided by cabotegravir base. In one aspect, rilpivirine injection, particularly intramuscular injection, is provided by rilpivirine base.

[0021] According to another aspect of the main embodiment, the combination contains cabotegravir 200 mg / mL as a white to pale pink, free-flowing, sustained-release injectable suspension and rilpivirine 300 mg / mL as a white to off-white, sustained-release injectable suspension, co-packaged as follows: 2mL administration kit A single-dose vial of 400 mg cabotegravir 600 mg single-dose vial of rilpivirine 3mL administration kit A single-dose vial of 600 mg cabotegravir 900 mg single-dose vial of rilpivirine

[0022] In one embodiment, the above-mentioned vials of cabotegravir and rilpivirine are not co-packaged, but are packaged separately.

[0023] According to another aspect of the main embodiment, the combination is contraindicated in patients with: Previous hypersensitivity reaction to cabotegravir or rilpivirine. Receiving the following concomitant medications that may cause a significant decrease in cabotegravir and / or rilpivirine plasma concentrations due to induction of uridine diphosphate (UDP)-glucuronosyltransferase (UGT) 1A1 and / or cytochrome P450 (CYP) 3A enzymes, which may result in loss of virologic response: Anticonvulsants: carbamazepine, oxcarbazepine, phenobarbital, phenytoin Antimycobacterial drugs: rifabutin, rifampin, rifapentine Glucocorticoids (systemic): dexamethasone (more than a single dose of treatment) Herbal product: St. John's wort (Hypericum perforatum)

[0024] According to another aspect of the lead embodiment, precautions are taken before and during treatment with the combination. Severe skin and hypersensitivity reactions, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been reported during postmarketing experience with oral rilpivirine-containing regimens. Some skin reactions were accompanied by systemic symptoms such as fever, while others were associated with organ dysfunction, including elevated liver serum biochemistry. During phase 3 clinical trials of oral rilpivirine, treatment-related rashes of at least Grade 2 severity were reported in 3% of subjects, but no Grade 4 rashes were reported.

[0025] According to another aspect of the main embodiment, the combination is administered by intramuscular injection only. Specifically, the intramuscular injection is administered without oral induction. In one embodiment, proceeding to intramuscular injection without oral induction shows similar efficacy to treatment including oral induction before intramuscular injection. Following randomization and administration (1:1), ART-naive participants who achieved virologic suppression (HIV-1 RNA <50 c / mL) with daily oral dolutegravir / abacavir / lamivudine during the 20-week induction period either continued daily oral dolutegravir / abacavir / lamivudine or switched to LA. Participants randomized to monthly combination therapy received a once-daily oral induction of the combination for at least four weeks before receiving the monthly injectable combination. After completing the maintenance phase at week 100 (W), participants in the dolutegravir / abacavir / lamivudine group switched to either direct (direct injection [DTI] group) or a four-week oral loading dose combination (extension switch group). Endpoints evaluated in W124 for the expanded switch population included viral load (HIV-1 RNA ≥ 50 c / mL and < 50 c / mL), confirmed virologic failure (CVF; HIV-1 RNA ≥ 200 c / mL on two consecutive doses), and safety and tolerability profiles. Switching to combination therapy without oral challenge demonstrated similar efficacy to treatment with oral challenge in W124. Safety and tolerability were comparable between treatment groups. This suggests that this combination with optional oral challenge is a well-tolerated, effective maintenance therapy for virologically suppressed patients living with HIV-1.

[0026] According to another aspect of the main embodiment, the combination is used to treat hepatitis C. In one embodiment, the combination is used to treat hepatitis C-HIV coinfection. An open-label, international, Phase 3 study evaluated switching to monthly intramuscular injections of a combination formulation of CAB (CAB LA) and RPV (RPV LA) versus continued oral standard-of-care ART in adult participants with HIV-1 RNA <50 c / mL. In the combination group, participants initially received oral CAB 30 mg + RPV 25 mg once daily for 4 weeks, and after safety and tolerability assessments, monthly injection therapy was initiated. Participants with chronic HCV infection without cirrhosis not requiring HCV treatment were analyzed for the proportion with plasma HIV-1 RNA >50 c / mL and <50 c / mL (Snapshot algorithm), change from baseline in CD4+ cell count, systemic and hepatic safety, and PK parameters. The combination demonstrated efficacy and safety similar to oral standard-of-care therapy in participants co-infected with HIV and HCV.

[0027] Hypersensitivity reactions have been reported in association with other integrase inhibitors. These reactions were characterized by rash, systemic findings, and occasionally organ dysfunction, including hepatic dysfunction. Although no such reactions have been observed in phase 2 and 3 clinical trials involving cabotegravir, caution should be exercised and the combination discontinued if a hypersensitivity reaction is suspected.

[0028] Immediately discontinue this combination if signs or symptoms of a severe skin or hypersensitivity reaction occur (including, but not limited to, severe rash or rash accompanied by fever, general malaise, malaise, muscle or joint pain, blisters, mucosal lesions [oral blisters or lesions], conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema). Clinical status, including hepatic transaminases, should be monitored and appropriate treatment initiated. Administer an oral induction dose prior to administration of this combination to help identify patients who may be at risk for a hypersensitivity reaction.

[0029] Hepatotoxicity has been reported in a limited number of patients receiving cabotegravir, with or without known pre-existing liver disease. Hepatic adverse events have been reported in patients receiving rilpivirine-containing tablet regimens. Patients with underlying hepatitis B or C virus infection or significantly elevated transaminases prior to treatment may be at higher risk for worsening or development of transaminase elevations. A small number of cases of hepatotoxicity have been reported in adult patients receiving rilpivirine-containing regimens without pre-existing liver disease or other identifiable risk factors. Liver chemistry monitoring is recommended, and treatment with the combination should be discontinued if hepatotoxicity is suspected.

[0030] Depressive disorders (including depressed mood, depression, dysthymia, major depression, dysthymia, negative ideation, suicide attempt, and suicidal ideation or attempt) have been reported with rilpivirine. Promptly evaluate patients with severe depressive symptoms to assess whether the symptoms are related to the combination and to determine whether the risks of continued treatment outweigh the benefits.

[0031] Concomitant use of the present combination with other drugs may result in known or potentially important drug interactions, some of which may lead to loss of therapeutic efficacy of the combination and the possible development of viral resistance.

[0032] Rilpivirine at the recommended dose of 25 mg once daily is not associated with clinically relevant effects on QTc. Rilpivirine plasma concentrations after rilpivirine injection are comparable to therapeutic concentrations, which do not prolong the QTc interval. In healthy subjects, oral rilpivirine at doses of 75 mg once daily and 300 mg once daily has been shown to prolong the QTc interval on the electrocardiogram. This combination should be used with caution when combined with drugs known to have a risk of torsades de pointes.

[0033] See Table 5 for steps to prevent or manage these potential and known important drug interactions, including dosing recommendations. Consider the possibility of drug interactions before and during therapy with this combination, and review concomitant medications during therapy with this combination.

[0034] Residual concentrations of cabotegravir and rilpivirine may remain in the patient's systemic circulation for extended periods (up to 12 months or more). Consider the long-acting properties of cabotegravir and rilpivirine when discontinuing this combination.

[0035] To minimize the risk of developing viral resistance, it is essential to adopt an alternative fully suppressive antiretroviral regimen within one month of the final infusion of this combination. If virologic failure is suspected, prescribe an alternative regimen as soon as possible.

[0036] In accordance with another aspect of the main embodiment, because clinical trials are conducted under widely varying conditions, the side effect rates observed in clinical trials of one drug cannot be directly compared to rates in clinical trials of another drug and do not reflect the rates observed in practice.

[0037] The safety assessment of this combination is based on an analysis of pooled 48-week data from 1,182 virologically suppressed subjects with HIV-1 infection in two international, multicenter, open-label pivotal trials, FLAIR and ATLAS. Additional safety information from earlier clinical trials of the cabotegravir and rilpivirine programs was considered when evaluating the overall safety profile of this combination.

[0038] Adverse reactions were reported following exposure to the combination extended-release injectable suspension (median exposure time: 54 weeks) and data from cabotegravir and rilpivirine tablets administered concomitantly as oral induction therapy (median exposure time: 5.3 weeks). Adverse reactions included those attributable to both the oral and injectable formulations of cabotegravir and rilpivirine administered as a combination regimen.

[0039] The most common adverse reactions of any severity reported in ≥2% of adult subjects in the pooled analysis from FLAIR and ATLAS are shown in Table 3. No grade 5 adverse reactions occurred in subjects treated with cabotegravir and rilpivirine. Selected laboratory abnormalities are included in Table 4.

[0040] Adverse events not related to the injection site that led to discontinuation and occurred in more than one subject were hepatitis A, acute hepatitis B, headache, and diarrhea, which occurred at an incidence of 1% or less.

[0041] [Table 3]

[0042] The following adverse reactions (grade 2-4) occurred in 1% or less of subjects receiving cabotegravir and rilpivirine: Gastrointestinal disorders: abdominal pain (including upper abdominal pain), diarrhea, flatulence, nausea, vomiting; General disorders and administration site conditions: asthenia, fatigue, discomfort; Hepatobiliary disorders: hepatotoxicity. In the pivotal Phase 3 trial, no cases of hepatotoxicity were observed. Phase 1 and Phase 2 Study: Weight Gain Confirmed with Cabotegravir. At week 48, the median weight gain for FLAIR and ATLAS participants receiving cabotegravir and rilpivirine was 1.5 kg, compared with 1.0 kg for participants on their current antiretroviral regimen (pooled analysis). In the individual FLAIR and ATLAS trials, median weight gains in subjects receiving cabotegravir and rilpivirine were 1.3 kg and 1.8 kg, respectively, compared with 1.5 kg and 0.3 kg in subjects receiving current antiretroviral therapy. Musculoskeletal and connective tissue disorders: myalgia; nervous system disorders: dizziness, headache; psychiatric disorders: anxiety, depression, insomnia; skin and subcutaneous tissue disorders: rash (including erythematous rash, generalized rash, macular rash, maculopapular rash, morbilliform rash, papular rash, and pruritic rash). The following grade 1 adverse reactions occurred in subjects receiving cabotegravir and rilpivirine: nervous system disorders: somnolence (<1%); psychiatric disorders: abnormal dreams (1%).

[0043] Local injection site reactions (ISRs) were the most common adverse event associated with intramuscular administration of the combination. After 14,682 injections, 3,663 ISRs were reported. The proportion of subjects reporting ISRs decreased over time (70% at Week 4 and 16% at Week 48). A combined 1% of subjects in the FLAIR and ATLAS groups discontinued treatment with the combination due to an ISR. In the FLAIR and ATLAS groups at Week 48 analysis, 84% of subjects experienced at least one local ISR at some time during the analysis period, primarily consisting of local pain / discomfort (79%), based on all grades, regardless of association. Other symptoms of ISR reported in >1% of subjects during the analysis period included nodules (14%), induration (12%), swelling (8%), erythema (4%), pruritus (4%), bruising (3%), flushing (2%), and hematoma (2%). Injection site abscesses and cellulitis were reported in less than 1% of subjects each. ISR severity was generally mild (grade 1, 75%) or moderate (grade 2, 36%). Four percent of subjects experienced severe (grade 3) ISR, and no subjects experienced grade 4 ISR. The median duration of ISR events was 3 days. The proportion of subjects reporting ISR decreased over time (70% at week 4 and 16% at week 48).

[0044] Selected laboratory abnormalities that worsened in grade from baseline and represented the worst-grade toxicity are shown in Table 4.

[0045] [Table 4]

[0046] Transaminase Changes: Several patients demonstrated transaminase elevations in the Phase 1 and 2 studies, likely due to hepatotoxicity associated with oral cabotegravir exposure. Elevations in hepatic transaminases (AST / ALT) were seen in subjects receiving cabotegravir and rilpivirine during the pivotal phase 3 trial, but the primary reason for these elevations was the occurrence of acute viral hepatitis (hepatitis A, B, or C).

[0047] Total bilirubin changes: Small, non-progressive increases in total bilirubin (without clinical jaundice) were seen with cabotegravir and rilpivirine. These changes are not considered clinically relevant as they may reflect competition between cabotegravir and unconjugated bilirubin for a common clearance pathway (UGT1A1).

[0048] Creatine phosphokinase (CPK) changes: Asymptomatic elevations of CPK, primarily associated with exercise, have also been reported with cabotegravir and rilpivirine.

[0049] The following adverse reactions have been identified during postmarketing experience in patients receiving oral rilpivirine-containing regimens. Because these reactions are spontaneously reported from a population of indeterminate size, it is not always possible to reliably estimate their frequency or to establish a causal relationship to drug exposure: Severe skin and hypersensitivity reactions, including DRESS.

[0050] In accordance with another aspect of the main embodiment, concomitant use with other medications should be monitored or avoided.

[0051] Because this combination is a complete regimen, its concomitant administration with other antiretroviral drugs for the treatment of HIV-1 infection is not recommended. There are no restrictions on the use of other antiretroviral drugs after discontinuing this combination.

[0052] Cabotegravir is metabolized primarily by UGT1A1, with some contribution from UGT1A9. Drugs that are strong inducers of UGT1A1 or 1A9 are expected to decrease cabotegravir plasma concentrations, potentially resulting in loss of virologic response; therefore, coadministration with these drugs is contraindicated. Simulations using physiologically based pharmacokinetic (PBPK) modeling indicate that no clinically significant interactions are expected during coadministration of cabotegravir with drugs that inhibit these enzymes.

[0053] Cabotegravir is a substrate of breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp) in vitro, but due to its high permeability, cabotegravir absorption is unlikely to be altered when coadministered with BCRP or P-gp inhibitors.

[0054] Rilpivirine is primarily metabolized by CYP3A, and drugs that induce or inhibit CYP3A can affect rilpivirine clearance. Coadministration of this combination with drugs that induce CYP3A may result in decreased rilpivirine plasma concentrations, loss of virologic response, and potential resistance to rilpivirine or non-nucleoside reverse transcriptase inhibitors (NNRTIs). Coadministration of this combination with drugs that inhibit CYP3A may result in increased rilpivirine plasma concentrations.

[0055] QT Prolonging Drugs: Oral rilpivirine at the recommended dose of 25 mg once daily is not associated with clinically relevant effects on QTc. Plasma rilpivirine concentrations after rilpivirine injection are comparable to concentrations during rilpivirine therapy. In healthy subjects, oral rilpivirine at doses of 75 mg and 300 mg once daily has been shown to prolong the QTc interval on the electrocardiogram. This combination should be used with caution in combination with drugs known to have a risk of torsades de pointes.

[0056] Information about potential drug interactions with cabotegravir and rilpivirine is provided in Table 5. These recommendations are based either on drug interaction studies after oral administration of the individual components or on predicted interactions due to the expected magnitude of the interaction and the potential for loss of efficacy.

[0057] [Table 5]

[0058] Based on drug interaction study results, the following medications may be co-administered with cabotegravir without dose adjustment: etravirine, midazolam, oral contraceptives containing levonorgestrel and ethinyl estradiol, and rilpivirine.

[0059] Based on drug interaction study results, the following medications may be co-administered with rilpivirine: acetaminophen, atorvastatin, cabotegravir, chlorzoxazone, dolutegravir, ethinyl estradiol, norethindrone, raltegravir, ritonavir-boosted atazanavir, ritonavir-boosted darunavir, sildenafil, tenofovir anafenamide, and tenofovir disoproxil fumarate. Rilpivirine had no clinically significant effect on the pharmacokinetics of digoxin or metformin. Clinically relevant drug-drug interactions are expected when rilpivirine is co-administered with maraviroc, ribavirin, or nucleoside reverse transcriptase inhibitors (NRTIs), such as abacavir, emtricitabine, lamivudine, stavudine, and zidovudine.

[0060] In accordance with another aspect of the main embodiment, caution should be exercised in administering the combination to certain patient populations.

[0061] There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to the combination during pregnancy. There are insufficient human data regarding the use of the combination during pregnancy to adequately assess the drug-associated risk of birth defects or miscarriage. While the use of cabotegravir has not been evaluated in pregnant women, the use of rilpivirine during pregnancy has been evaluated with over 200 first-trimester exposures reported to the Antiretroviral Pregnancy Register (APR). Available data from the APR indicate that the risk of all major birth defects with exposure to rilpivirine during first trimester is not increased compared to the background rate of major birth defects of 2.7% in the Metropolitan Atlanta Congenital Defects Program (MACDP) U.S. reference population.

[0062] Rates of miscarriage are underreported in the APR. The background risk of major birth defects and miscarriage for the populations represented is unknown. The estimated background rate of miscarriage in clinically recognized pregnancies in the general U.S. population is 15% to 20%. The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP assesses women and infants from a limited geographic area and does not include birth outcomes occurring before 20 weeks of gestation.

[0063] Cabotegravir and rilpivirine have been detected in the systemic circulation for up to 12 months or more after discontinuing injections of this combination; therefore, potential fetal exposure during pregnancy should be considered.

[0064] Animal reproductive studies have not seen evidence of adverse developmental outcomes with oral cabotegravir in rats (exposures greater than 30 times the maximum recommended human dose [MRHD] of oral cabotegravir 30 mg / day or 400 mg intramuscular dose) or rabbits (exposures 0.66 times the MRHD of oral cabotegravir 30 mg / day or approximately 1 times the MRHD of 400 mg intramuscular dose). Similarly, there were no adverse outcomes with oral rilpivirine at exposures greater than 12 times (rats) and 57 times (rabbits) the MRHD of oral rilpivirine 25 mg once daily and 600 mg intramuscular dose.

[0065] Decreased exposure was observed with oral rilpivirine during pregnancy. Patients should be closely monitored for viral load if they continue this combination during pregnancy.

[0066] Human Data: Rilpivirine: Based on prospective reporting to the APR of 524 exposures to oral rilpivirine during pregnancy that resulted in live birth, there was no difference in the overall risk of birth defects with rilpivirine compared to the background birth defect rate of 2.7% in the U.S. MACDP reference population. The prevalence of birth defects was 0.9% (95% Cl: 0.2%-2.5%) and 1.24% (95% Cl: 0.1%-4.1%) after early and mid / late exposure to rilpivirine-containing regimens, respectively. In clinical trials, total oral rilpivirine exposure was generally lower during pregnancy compared with the postpartum period.

[0067] Animal Data: Cabotegravir: In prenatal and postnatal development studies in rats, cabotegravir was administered orally at 0.5, 5, or 1,000 mg / kg / day during organogenesis and during parturition and lactation. At 1,000 mg / kg / day (more than 30 times the systemic exposure of the MRHD oral dose of 30 mg / day or an intramuscular dose of 400 mg), cabotegravir delayed the onset of labor, and in some rats, this delay was associated with an increase in stillbirths and neonatal deaths shortly after birth. Growth and development of surviving offspring were unchanged at doses up to 1,000 mg / kg / day. Similar neonatal mortality rates were observed when rat pups born to cabotegravir-treated mothers were fostered at birth and then reared by control mothers, and neonatal survival of control pups reared from birth by cabotegravir-treated mothers was unaffected. Cabotegravir at doses as low as 5 mg / kg / day (exposure [AUC] >10-fold the MRHD of the 30 mg / day oral or 400 mg intramuscular dose) was not associated with delayed parturition or neonatal mortality in rats. When cabotegravir was administered orally to pregnant rats and rabbits during organogenesis (1,000 or 2,000 mg / kg / day, respectively), there was no effect on fetal survival when delivered by cesarean section. In fetal rabbits, no adverse effects on embryo-fetal development were observed up to 2,000 mg / kg / day (0.66 times the MRHD for a 30 mg / day oral dose or approximately 1 times the 400 mg intramuscular dose), and in rats, altered fetal growth (reduced body weight) in the presence of maternal toxicity (reduced weight gain, transient reduction in food consumption) was seen at 1,000 mg / kg / day (more than 30 times the systemic exposure at the MRHD for a 30 mg / day oral dose or a 400 mg intramuscular dose), but there were no test article-related fetal malformations or variations at any dose. Studies in pregnant rats have shown that cabotegravir crosses the placenta and can be detected in fetal tissues.

[0068] Rilpivirine: Rilpivirine was administered orally to pregnant rats (40, 120, or 400 mg / kg / day) and rabbits (5, 10, or 20 mg / kg / day) throughout organogenesis (gestational days 6-17 and 6-196, respectively). Embryo-fetal toxicity studies conducted with rilpivirine in rats and rabbits showed no significant toxicological effects at exposures greater than 12 times (rats) and 57 times (rabbits) the human exposure to rilpivirine at MRHD 25 mg once daily or 600 mg intramuscular doses in HIV-1-infected patients. Prenatal and postnatal development studies with rilpivirine did not show any significant adverse effects directly related to the drug in the offspring when rats were dosed up to 400 mg / kg / day throughout lactation.

[0069] The U.S. Centers for Disease Control and Prevention recommends that HIV-1-infected mothers in the United States not breast-feed their infants to avoid the risk of postnatal transmission of HIV-1 infection. It is unknown whether the components of this combination are present in human breast milk, affect human breast milk production, or have an effect on breast-fed infants. When administered to lactating rats, cabotegravir and rilpivirine were present in the milk. Cabotegravir and rilpivirine may be present in human breast milk for more than 12 months after the last injection was administered.

[0070] Instruct mothers not to breastfeed if receiving this combination because of the potential for (1) HIV-1 infection (in HIV-negative infants), (2) development of viral resistance (in HIV-positive infants), and (3) adverse reactions in breastfed infants similar to those in adults.

[0071] Animal Data: Cabotegravir: In animals, no studies have been conducted to directly assess the excretion of cabotegravir in milk; however, cabotegravir is present in the plasma of rat pups exposed via the milk of lactating rats (dosed up to 1,000 mg / kg / day), with mean plasma concentrations in the pups being approximately 70% of those occurring on day 20 of gestation in pregnant female rats.

[0072] Rilpivirine: In animals, no studies have been conducted to directly assess the secretion of rilpivirine into milk, but rilpivirine has been present in the plasma of rat pups exposed via the milk of lactating rats (doses up to 400 mg / kg / day).

[0073] The safety and effectiveness of the components of this combination have not been established in pediatric patients.

[0074] Clinical trials of this combination did not include sufficient numbers of subjects aged 65 years or older to determine whether they responded differently from younger subjects. In general, caution is advised when administering this combination to elderly patients, reflecting a higher frequency of decreased hepatic, renal, or cardiac function, and concomitant illness or other medications.

[0075] This combination has not been studied in patients with renal impairment. Based on population pharmacokinetic studies of oral cabotegravir and oral rilpivirine, no dose adjustment of this combination is necessary in patients with mild or moderate renal impairment (creatinine clearance ≥ 30 mL / min) who are not undergoing dialysis. However, in patients with severe renal impairment (creatinine clearance < 30 mL / min) or end-stage renal disease, this combination should be used with caution, and increased monitoring for adverse effects is recommended.

[0076] This combination has not been studied in patients with hepatic impairment. Based on independent studies of oral cabotegravir and oral rilpivirine, no dose adjustment of this combination is necessary in patients with mild or moderate hepatic impairment (Child-Pugh score A or B). The effect of severe hepatic impairment (Child-Pugh score C) on the pharmacokinetics of cabotegravir or rilpivirine is unknown.

[0077] According to another aspect of the main embodiment, a treatment for overdose of one or both components of the combination is provided. There is no known specific treatment for overdose of cabotegravir or rilpivirine. In the event of an overdose, the patient should be monitored and, if necessary, standard supportive care should be applied, including monitoring vital signs and ECG (QT interval), as well as observing the patient's clinical condition. Because both cabotegravir and rilpivirine are highly bound to plasma proteins, neither is likely to be significantly removed by dialysis. When assessing the need for treatment and recovery, long-term exposure to cabotegravir and rilpivirine (components of the combination) after injection should be taken into consideration.

[0078] According to another aspect of the main embodiment, the combination contains an HIV INSTI, cabotegravir extended-release injectable suspension, and an HIV NNRTI, rilpivirine extended-release injectable suspension; in particular, the combination contains an HIV INSTI, cabotegravir extended-release injectable suspension, co-packaged with an HIV NNRTI, rilpivirine extended-release injectable suspension. In one embodiment, the combination contains an HIV INSTI, cabotegravir extended-release injectable suspension, packaged separately from the HIV NNRTI, rilpivirine extended-release injectable suspension.

[0079] Cabotegravir: The chemical name of cabotegravir is (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide, and the empirical formula is C 19 H 17 It is F2N3O5 and has a molecular weight of 405.35 g / mol. Cabotegravir has the following structural formula: [ka]

[0080] Cabotegravir extended-release injectable suspension is a white to pale pink, free-flowing suspension for intramuscular injection. Each sterile, single-dose vial contains: 2mL vial Cabotegravir 400 mg and the following inactive ingredients: mannitol (70 mg), polysorbate 20 (40 mg), polyethylene glycol (PEG) 3350 (40 mg), and water for injection. 3mL vial Cabotegravir 600 mg and the following inactive ingredients: mannitol (105 mg), polysorbate 20 (60 mg), polyethylene glycol (PEG) 3350 (60 mg), and water for injection.

[0081] Cabotegravir tablets contain cabotegravir as cabotegravir sodium, which is a white to almost white solid that is slightly soluble in water. Each cabotegravir immediate-release film-coated tablet for oral administration contains 30 mg of cabotegravir (equivalent to 31.62 mg of cabotegravir sodium) and the inactive ingredients: hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The tablet film coating contains hypromellose, polyethylene glycol, and titanium dioxide.

[0082] Rilpivirine: The chemical name of rilpivirine is 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile. Its molecular formula is C 22 H 18 N6 and its molecular weight is 366.42. Rilpivirine has the following structural formula: [ka]

[0083] Rilpivirine sustained-release injectable suspension is a white to off-white suspension for intramuscular injection. Each sterile, single-dose vial contains: 2mL vial Rilpivirine 600 mg and the following inactive ingredients: poloxamer 338 (100 mg), citric acid monohydrate (2 mg); glucose monohydrate, sodium dihydrogen phosphate monohydrate, sodium hydroxide for pH adjustment and tonicity, and water for injection. 3mL vial Rilpivirine 900 mg and the following inactive ingredients: poloxamer 338 (150 mg), citric acid monohydrate (3 mg); glucose monohydrate, sodium dihydrogen phosphate monohydrate, sodium hydroxide for pH adjustment and tonicity, and water for injection. Vial stoppers are not made from natural rubber latex.

[0084] According to another aspect of the main embodiment, the combination exhibits particular clinical pharmacology.

[0085] The effect of this combination on the QT interval has not been studied. Cabotegravir: In a randomized, placebo-controlled, three-period crossover study, 42 healthy subjects were randomized into six random sequences to receive placebo, cabotegravir 150 mg (C) every 12 hours, or max Patients received three oral doses of moxifloxacin 400 mg (approximately three times the dose of 30 mg once daily) and three single doses of moxifloxacin 400 mg (active control). After baseline and placebo adjustment, the maximum time-matched mean QTc change for cabotegravir based on Fridericia's correction method (QTcF) was 2.62 msec (one-sided 95% upper limit of Cl: 5.26 msec). Cabotegravir did not prolong the QTc interval over 24 hours after administration.

[0086] Rilpivirine: The effect of rilpivirine at the recommended oral dose of 25 mg once daily on the QTcF interval was evaluated in a randomized, placebo- and active-agent (moxifloxacin 400 mg once daily)-controlled crossover study in 60 healthy adults, with 13 measurements taken over 24 hours at steady state. The baseline-corrected difference in maximum mean time agreement (95% upper confidence interval) from placebo was 2.0 (5.0) milliseconds (i.e., below the threshold for clinical concern). When once-daily oral doses of 75 mg and 300 mg of rilpivirine (three and 12 times the recommended oral dose, respectively) were tested in healthy adults, the baseline-corrected difference in maximum mean time agreement (95% upper confidence interval) from placebo was 10.7 (15.3) and 23.3 (28.4) milliseconds, respectively. At steady state, rilpivirine 75 mg once daily and 300 mg once daily resulted in a mean steady-state C max were approximately 4.4-fold and 11.6-fold, respectively, exceeding the mean steady-state C observed with the recommended monthly 600 mg dose of rilpivirine sustained-release injectable suspension. max It became higher than.

[0087] The pharmacokinetic properties of the components of this combination are shown in Table 6. Multiple dose pharmacokinetic parameters are shown in Table 7.

[0088] [Table 6]

[0089] [Table 7]

[0090] Cerebrospinal fluid (CSF): Cabotegravir is present in the CSF. In HIV-1-infected subjects receiving both cabotegravir extended-release injectable suspension and rilpivirine extended-release injectable suspension, the median cabotegravir CSF / plasma concentration ratio (n=16) was 0.304-0.344 (range: 0.218-0.449), higher than the corresponding median unbound cabotegravir concentration after 1 week of steady-state cabotegravir and rilpivirine extended-release injectable suspension administered monthly or every two months. Rilpivirine is present in the CSF. In the same 16 subjects, the median rilpivirine CSF / plasma ratio was 1.07-1.32% (range: unquantifiable-1.69%). Consistent with therapeutic cabotegravir and rilpivirine concentrations in CSF, CSF HIV-1 RNA concentrations (n=16) were <50 copies / mL in 100% of subjects and <2 copies / mL in 15 / 16 (94%). At the same time points, plasma HIV-1 RNA concentrations (n=18) were <50 copies / mL in 100% of subjects and <2 copies / mL in 12 / 18 (66.7%).

[0091] According to another aspect of the main embodiment, the pharmacokinetics vary depending on the particular patient population.

[0092] Pediatric Patients: The pharmacokinetics of the components of this combination have not been studied in pediatric patients.

[0093] Geriatric patients: Population pharmacokinetic analyses showed that age had no clinically relevant effect on the pharmacokinetics of cabotegravir or rilpivirine. Pharmacokinetic data in subjects aged 65 years and older are limited.

[0094] Patients with Renal Impairment: No clinically important pharmacokinetic differences were observed with oral cabotegravir between subjects with severe renal impairment (CrCl <30 mL / min, not undergoing dialysis) and matched healthy subjects. No dose adjustment is necessary for patients with mild to severe renal impairment (not undergoing dialysis). Cabotegravir has not been studied in patients requiring dialysis.

[0095] Population pharmacokinetic analyses showed that mild renal impairment did not have a clinically relevant effect on oral rilpivirine exposure.There is limited or no information regarding the pharmacokinetics of rilpivirine in patients with moderate or severe renal impairment, end-stage renal disease, or those requiring dialysis.

[0096] Patients with Hepatic Impairment: No clinically important pharmacokinetic differences were observed for oral cabotegravir between subjects with moderate hepatic impairment and matched healthy subjects. No dose adjustment is necessary in patients with mild to moderate hepatic impairment (Child-Pugh score A or B). The effect of severe hepatic impairment (Child-Pugh score C) on the pharmacokinetics of cabotegravir has not been studied.

[0097] Rilpivirine exposure was 47% higher in subjects (n=8) with mild hepatic impairment (Child-Pugh score A) and 5% higher in subjects (n=8) with moderate hepatic impairment (Child-Pugh score B) compared with matched controls. The effect of severe hepatic impairment (Child-Pugh score C) on rilpivirine pharmacokinetics has not been studied.

[0098] Patients with HBV / HCV Coinfection: Cabotegravir and rilpivirine have not been studied in patients with hepatitis B coinfection. There is limited experience in patients with hepatitis C coinfection who have received cabotegravir and rilpivirine.

[0099] Gender and Race: Population pharmacokinetic analysis revealed that gender and race had no clinically relevant effects on the pharmacokinetics of cabotegravir or rilpivirine.

[0100] Polymorphisms in drug-metabolizing enzymes: A meta-analysis of studies in healthy and HIV-1-infected subjects showed that HIV-infected subjects with UGT1A1 genotypes that confer poor cabotegravir metabolism had significantly lower mean steady-state cabotegravir AUC and C after long-acting cabotegravir injection compared with subjects with genotypes associated with normal metabolism via UGT1A1.max , and C tau showed a 12-fold increase. No dose adjustment is necessary in subjects with UGT1A1 polymorphisms.

[0101] Body Mass Index (BMI): Population pharmacokinetic analyses did not reveal a clinically relevant effect of BMI on cabotegravir and rilpivirine exposure, so dose adjustment based on BMI is not necessary. Consider the patient's BMI to ensure the needle length is sufficient to reach the gluteal muscle.

[0102] According to another aspect of the main embodiment, drug interaction studies were conducted with oral cabotegravir or oral rilpivirine as individual components and other drugs that may be co-administered or commonly used as probes for pharmacokinetic interactions.

[0103] Cabotegravir is not a clinically relevant inhibitor of the following enzymes and transporters: CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4; UGT1A1, 1A3, 1A4, 1A6, 1A9, 2B4, 2B7, 2B15, and 2B17; P-gp; BCRP; bile salt export pump (BSEP); organic cation transporter (OCT)1, OCT2; organic anion transporter polypeptide (OATP)1B1, OATP1B3; multidrug and toxin extrusion transporter (MATE)1, MATE2-K; multidrug resistance protein (MRP)2, or MRP4.

[0104] In vitro, cabotegravir inhibits renal organic anion transporter (OAT) 1 (IC 50 = 0.81 μM) and OAT3 (IC 50 = 0.41 μM). However, based on PBPK modeling, no interaction with OAT substrates is predicted at clinically relevant concentrations.

[0105] In vitro, cabotegravir did not induce CYP1A2, CYP2B6, or CYP3A4. Based on these data and the results of drug interaction studies, cabotegravir is not expected to affect the pharmacokinetics of drugs that are substrates of these enzymes.

[0106] Rilpivirine is primarily metabolized by CYP3A. Rilpivirine injection is unlikely to have a clinically relevant effect on the exposure of drugs metabolized by CYP enzymes.

[0107] Based on their in vitro and clinical drug interaction profiles, cabotegravir and rilpivirine are not expected to alter concentrations of other antiretrovirals, including protease inhibitors, NRTIs, NNRTIs, integrase inhibitors, entry inhibitors, and ibalizumab.

[0108] Cabotegravir is metabolized primarily by UGT1A1, with some contribution from UGT1A9. Drugs that are strong inducers of UGT1A1 or 1A9 are expected to decrease cabotegravir plasma concentrations, leading to a lack of efficacy, and therefore coadministration with these drugs is contraindicated.

[0109] In vitro, cabotegravir was not a substrate of OATP1B1, OATP1B3, or OCT1. Cabotegravir is a substrate of P-gp and BCRP in vitro, but due to its high permeability, no changes in cabotegravir absorption are expected when coadministered with P-gp or BCRP inhibitors.

[0110] The effects of cabotegravir or rilpivirine on the exposure of coadministered drugs are summarized in Tables 8 and 10, and the effects of coadministered drugs on cabotegravir or rilpivirine exposure are summarized in Tables 9 and 11, respectively. No drug interaction studies have been conducted with injectable cabotegravir or rilpivirine extended-release suspension. The drug interaction data provided are from studies with oral cabotegravir or oral rilpivirine. Recommended doses as a result of established and other potentially important drug-drug interactions with cabotegravir and rilpivirine are listed in Table 5.

[0111] [Table 8]

[0112] [Table 9]

[0113] [Table 10] TIFF0007791083000013.tif94166

[0114] [Table 11]

[0115] Cabotegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral deoxyribonucleic acid (DNA) integration, which is essential for the HIV replication cycle. The mean median inhibitory concentration (IC) of cabotegravir in a strand transfer assay using purified recombinant HIV-1 integrase was 50 ) value was 3.0 nM.

[0116] Rilpivirine is a diarylpyrimidine NNRTI for HIV-1 that inhibits HIV-1 replication through noncompetitive inhibition of HIV-1 reverse transcriptase (RT). Rilpivirine does not inhibit human cellular DNA polymerases α, β, and γ.

[0117] Cabotegravir demonstrated antiviral activity against laboratory strains of HIV-1 (subtype B, n=4) with mean 50% effective concentrations (EC 50 Cabotegravir demonstrated antiviral activity in PBMCs against a panel of 24 HIV-1 clinical isolates (three each of group M subtypes A, B, C, D, E, F, and G, and three of group O), and EC 50 The median EC value was 0.19 nM (range: 0.02 nM to 1.06 nM). 50 The median value was 0.05 nM (range: 0.02–0.50 nM, n = 3). 50 The median value was 0.12 nM (range: 0.10 nM to 0.14 nM, n = 4).

[0118] Rilpivirine is active against laboratory strains of wild-type HIV-1 in acutely infected T-cell lines and inhibits HIV-1 IIIB EC 50 The median EC value was 0.73 nM (0.27 ng / mL). Rilpivirine exhibited antiviral activity against a broad panel of primary isolates of HIV-1 group M (subtypes A, B, C, D, F, G, and H), with an EC 50 The EC values ​​ranged from 0.07 nM to 1.01 nM (0.03 to 0.37 ng / mL), indicating low activity against group O primary isolates. 50 The values ​​ranged from 2.88 to 8.45 nM (1.06 to 3.10 ng / mL).

[0119] In cell culture, cabotegravir was not antagonistic when combined with the NNRTI rilpivirine, or the NRTIs emtricitabine (FTC), lamivudine (3TC), or tenofovir disoproxil fumarate (TDF).

[0120] The antiviral activity of rilpivirine was not antagonistic when combined with the NNRTIs efavirenz, etravirine, or nevirapine; the NRTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, or zidovudine; the protease inhibitors amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, or tipranavir; the fusion inhibitor enfuvirtide; the CCR5 coreceptor antagonist maraviroc; or the INSTI raltegravir.

[0121] Cell culture: Cabotegravir-resistant viruses were selected during subculture of HIV-1 strain IIIB in MT-2 cells in the presence of cabotegravir. Amino acid substitutions in integrase that emerged and conferred reduced susceptibility to cabotegravir included Q146L (fold change: 1.3-4.6), S153Y (fold change: 2.8-8.4), S153Y (fold change: 6.3-6.4), and I162M (fold change: 2.8). The integrase (IN) substitution T124A also emerged alone (fold change in cabotegravir susceptibility: 1.1-7.4) and in combination with S153Y (fold change in cabotegravir susceptibility: 3.6-6.6) or I162M (fold change in cabotegravir susceptibility: 2.8). Cell culture passages of viruses containing the integrase substitutions Q148H, Q148K, or Q148R were selected for additional substitutions (C56S, V72I, L74M, V75A, T122N, E138K, G140S, G149A, and M154I), and the substituted viruses had reduced cabotegravir susceptibility, ranging from 2.0 to 410-fold. The combinations E138K+Q148K and V72I+E138K+Q148K conferred the greatest reductions, ranging from 53-fold to 260-fold and 410-fold, respectively.

[0122] Rilpivirine-resistant strains were selected in cell culture starting from wild-type HIV-1 of different origins and subtypes, as well as from NNRTI-resistant HIV-1. Frequent amino acid substitutions that emerged and conferred reduced phenotypic susceptibility to rilpivirine included L100I; K101E; V106I and A; V108I; E138K and G, Q, and R; V179F and I; Y181C and I; V189I; G190E; H221Y; F227C; and M230I and L.

[0123] Clinical Trials: In the pooled phase 3 FLAIR and ATLAS trials, there were seven confirmed virologic failures (HIV-1 RNA >200 copies / mL on two consecutive doses) with cabotegravir and rilpivirine (7 / 591, 1.2%) and seven confirmed virologic failures with current antiviral regimens (CARs) (7 / 591, 1.2%). Of the seven virologic failures in the cabotegravir and rilpivirine group, six had post-baseline resistance data: all six had treatment-associated rilpivirine resistance substitutions K101E, E138A, or E138K in reverse transcriptase, and five of them showed reduced phenotypic susceptibility to rilpivirine (range: 2.4-7.1-fold).

[0124] Furthermore, four of six (67%) cabotegravir and rilpivirine virologic failures with post-baseline resistance data had treatment-emergent INSTI resistance-associated substitutions resulting in reduced phenotypic susceptibility to cabotegravir (Q148R [n=2; 5-fold and 9-fold reduced susceptibility to cabotegravir], G140R [n=1; 7-fold reduced susceptibility to cabotegravir], or N155H [n=1; 3-fold reduced susceptibility to cabotegravir]).

[0125] In comparison, two of the seven virologic failures in the CAR group (29%) that had post-baseline resistance data had on-treatment resistance substitutions and phenotypic resistance to antiretrovirals; both had on-treatment NRTI substitutions, M184V or I, conferring resistance to emtricitabine or lamivudine in the regimen, and one also had on-treatment NNRTI resistance substitution G190S, conferring resistance to efavirenz in the regimen.

[0126] In the phase 2 clinical trial LATTE-2, virologic failure to cabotegravir and rilpivirine was associated with the emergence of genotypic and phenotypic cabotegravir and rilpivirine resistance (accompanied by the emergence of the INSTI resistance-associated substitution Q148R and the NNRTI resistance-associated substitutions K103N, E138G, and K238T).

[0127] In the phase 2 clinical trial LATTE, virologic failure to oral cabotegravir and rilpivirine was accompanied by the emergence of genotypic and phenotypic cabotegravir and NNRTI resistance (INSTI resistance-associated substitutions Q148R, E138K+Q148R, E138K+G140A+Q148R, and G140S+Q148R, and rilpivirine resistance-associated substitutions E138Q, K101K / E+E138E / A, K101K / E+E138E / K, ​​K101E+M230L, and K101E).

[0128] Five of the seven cabotegravir and rilpivirine virologic failures in FLAIR and ATLAS had HIV-1 subtype A1 and had a detectable integrase L74I substitution (IN L74I) at baseline and at the time of failure. Subtype A1-infected subjects whose viruses lacked INL74I at baseline did not experience virologic failure (FLAIR results are shown in Table 12). Furthermore, there was no detectable phenotypic resistance to cabotegravir conferred by the presence of IN L74I at baseline.

[0129] The other two virologic failures involved subtype AG and were associated with the INL74I substitution. Six of the virologic failures involving subtypes A1 and AG were from Russia, where the prevalence of subtypes A, A1, and AG is high. Subtypes A, A1, and AG are uncommon in the United States.

[0130] The presence of the INL74I substitution in other subtypes, such as subtype B commonly found in the United States, was not associated with virologic failure (Table 12). In contrast to the phase 3 trials, in which all virologic failures were subtypes A1 or AG, in the phase 2 clinical trials, the subtypes of virologic failure for cabotegravir and rilpivirine included A1, A, B, and C.

[0131] [Table 12]

[0132] Cabotegravir: Cross-resistance has been observed among INSTIs. Cabotegravir is less susceptible to viruses of the recombinant HIV-1 NL432 strain harboring the following integrase amino acid substitutions (fold change >5): G118R, Q148K, Q148R, T66K+L74M, E92Q+N155H, E138A+Q148R, E138K+Q148K / R, G140C+Q148R, G140S+Q148H / K / R, and Q148R+N155H (range: 5.1-81-fold). The substitutions E138K+Q148K and Q148R+N155H conferred the greatest reductions in susceptibility, 81-fold and 61-fold, respectively.

[0133] Cabotegravir is active against viruses with the NNRTI substitutions K103N or Y188L, or the NRTI substitutions M184V, D67N / K70R / T215Y, or V75I / F77L / F116Y / Q151M.

[0134] Cross-resistance has been observed between rilpivirine and NNRTIs. Single NNRTI substitutions K101P, Y181I, and Y181V resulted in 52-fold, 15-fold, and 12-fold changes in susceptibility to rilpivirine, respectively. The K103N substitution by itself did not reduce susceptibility to rilpivirine. Combinations of two or three NNRTI resistance-associated substitutions resulted in 3.7- to 554-fold changes in susceptibility to rilpivirine in 38% and 66% of substitutions, respectively. Considering all available cell culture and clinical data, any of the following amino acid substitutions, if present at baseline, may reduce the antiviral activity of rilpivirine: K101E and P; E138A, G, K, R, and Q; V179L; Y181C, I, and V; Y188L; H221Y; F227C; M230I and L, and the L100I / K103N combination.

[0135] According to another aspect of the main embodiment, carcinogenesis, mutagenesis, and reproductive impairment are addressed.

[0136] Cabotegravir was not efficacious in long-term studies in mice and rats. Rilpivirine was not carcinogenic in rats. In mice, rilpivirine was positive for hepatocellular tumors in both males and females. The hepatocellular findings observed in mice may be rodent-specific. At the lowest dose tested in mice, systemic exposure to rilpivirine (based on AUC) was more than 17-fold higher than the MRHD of 25 mg once daily in HIV-1-infected patients or the exposure in humans at a 600 mg IM injection dose of rilpivirine sustained-release injectable suspension.

[0137] Cabotegravir was not genotoxic in bacterial reverse mutation assays, mouse lymphoma assays, or in vivo rodent micronucleus assays.

[0138] Rilpivirine was not genotoxic in bacterial reverse mutation assays, mouse lymphoma assays, or in vivo rodent micronucleus assays.

[0139] No human data are available regarding the effects of cabotegravir on fertility. Oral administration of cabotegravir to male and female rats at 1,000 mg / kg / day (exposure [AUC] >30 times the MRHD of a 30 mg / day oral dose or a 400 mg intramuscular dose) for up to 26 weeks did not produce adverse effects on male or female reproductive organs or spermatogenesis. No functional effects on mating or fertility were seen in male or female rats when cabotegravir was administered at doses up to 1,000 mg / kg / day.

[0140] There are no human data regarding the effects of rilpivirine on fertility. Studies conducted in rats have shown no effect on mating or fertility with rilpivirine at doses up to 400 mg / kg / day, a dose that demonstrated maternal toxicity. This dose is associated with exposures greater than 28 times the human exposure at the MRHD of 25 mg once daily or a 600 mg intramuscular dose of rilpivirine sustained-release injectable suspension.

[0141] The efficacy of this combination is being evaluated in two phase 3, randomized, multicenter, active-controlled, parallel-arm, open-label, non-inferiority trials. Study 201584 (FLAIR, [NCT02938520]), (n=629): HIV-1-infected, antiretroviral therapy (ART)-naive subjects received a 20-week regimen containing dolutegravir INSTI (dolutegravir / abacavir / lamivudine or dolutegravir plus HLA-B * Virologically suppressed subjects (HIV-1 RNA <50 copies / mL, n=566) were randomized (1:1) to receive cabotegravir and rilpivirine or to continue their current antiretroviral regimen. Subjects randomized to receive cabotegravir and rilpivirine began treatment with a daily oral induction dose of one 30 mg cabotegravir tablet and one 25 mg rilpivirine tablet for at least 4 weeks, followed by an additional 44 weeks of treatment with cabotegravir extended-release injection suspension and rilpivirine extended-release injection suspension.

[0142] Study 201585 (ATLAS, [NCT02951052]), (n=616): HIV-1 infected, ART-experienced, virologically suppressed (at least 6 months, median prior treatment duration 4.3 years) subjects (HIV-1 RNA <50 copies / mL) were randomized to receive either a cabotegravir and rilpivirine regimen or continued their current antiretroviral regimen. Subjects randomized to receive cabotegravir and rilpivirine began treatment with a daily oral induction dose of one 30 mg cabotegravir tablet and one 25 mg rilpivirine tablet for at least 4 weeks, followed by an additional 44 weeks of treatment with cabotegravir extended-release injectable suspension and rilpivirine extended-release injectable suspension.

[0143] The primary analysis was performed after all subjects had completed the 48-week visit or prematurely discontinued the study.

[0144] At baseline in the pooled analysis, subjects randomized to receive this combination had a median age of 38 years, 27% were female, 27% were non-white, and 7% had a CD4+ cell count <350 cells / mm 3 These characteristics were similar across treatment groups. In ATLAS, subjects received an NNRTI (50%), integrase inhibitor (33%), or protease inhibitor (17%) as a baseline third medication before randomization, which was similar across treatment groups.

[0145] The primary endpoint for FLAIR and ATLAS was the proportion of subjects with plasma HIV-1 RNA ≥ 50 copies / mL at week 48 (snapshot algorithm for the Intent-to-Treat-Efficacy [ITT-E] population).

[0146] In the pooled analyses of FLAIR and ATLAS, the combination was noninferior to current antiretroviral regimens with respect to the proportion of subjects with plasma HIV-1 RNA ≥ 50 copies / mL at week 48 (1.9% and 1.7%, respectively). The adjusted treatment difference between the combination and current antiretroviral regimens for the pooled analysis (0.2; 95% CI: -1.4, 1.7) met the noninferiority criterion (upper limit of 95% CI: < 4%). Furthermore, in the pooled analysis, the combination was noninferior to current antiretroviral regimens with respect to the proportion of subjects with plasma HIV-1 RNA < 50 copies / mL at week 48 (93.1% and 94.4%, respectively). The adjusted treatment difference between cabotegravir and rilpivirine and current antiretroviral regimens for the pooled analysis (-1.4; 95% CI: -4.1, 1.4) met the noninferiority criterion (lower limit of 95% CI: > -10%).

[0147] The non-inferiority results established in FLAIR and ATLAS showed that the length of HIV-1 RNA virologic suppression before initiation of the combination (i.e., less than 6 months or more than 6 months) did not affect the overall response rate.

[0148] The primary endpoints for FLAIR and ATLAS and other 48-week outcomes, including outcomes by key baseline factors, are shown in Tables 13 and 14.

[0149] [Table 13]

[0150] [Table 14]

[0151] Treatment differences by baseline characteristics (CD4+ count, sex, age, race, BMI, and baseline third drug class) were comparable in both the FLAIR and ATLAS trials. Subjects in both the FLAIR and ATLAS trials were virologically suppressed before day 1 or at study entry, respectively, and had no clinically relevant changes from baseline in CD4+ cell counts.

[0152] According to another aspect of the main embodiment, the combination is supplied in a two-dosage kit containing cabotegravir extended-release injectable suspension 200 mg / mL and rilpivirine extended-release injectable suspension 300 mg / mL, co-packaged as follows: 2mL (NDC 49702-253-15) contains: One 2 mL single-dose vial of cabotegravir extended-release injectable suspension containing 400 mg of cabotegravir One 2 mL single-dose vial of rilpivirine extended-release injectable suspension containing 600 mg of rilpivirine 3mL (NDC 49702-240-15) contains: One 3 mL single-dose vial of cabotegravir extended-release injectable suspension containing 600 mg of cabotegravir One 3 mL single-dose vial of rilpivirine extended-release injectable suspension containing 900 mg of rilpivirine

[0153] Each 2 mL and 3 mL administration kit also contains two syringes, two vial adapters, and two intramuscular needles (23 gauge, 1 1 / 2 inches). Vial stoppers are not made from natural rubber latex.

[0154] In one embodiment, a 2 mL single-dose vial of cabotegravir sustained-release injectable suspension containing 400 mg of cabotegravir, a 2 mL single-dose vial of rilpivirine sustained-release injectable suspension containing 600 mg of rilpivirine, a 3 mL single-dose vial of cabotegravir sustained-release injectable suspension containing 600 mg of cabotegravir, and a 3 mL single-dose vial of rilpivirine sustained-release injectable suspension containing 900 mg of rilpivirine are packaged separately. In one embodiment, each of the 2 mL and 3 mL packages also includes a syringe, a vial adapter, and an intramuscular needle (23 gauge, 1 1 / 2 inches). The vial stoppers are not made of natural rubber latex.

[0155] According to another aspect of the main embodiment, the combination is stored in the original carton in a refrigerator at 2-8°C (36-46°F) until ready for use. Preferably, neither the combination nor any of the components of the combination is frozen. Preferably, neither the combination nor any of the components of the combination is mixed with other products or diluents.

[0156] Before administration, the vial must be brought to room temperature (not to exceed 25°C [77°F]). The vial may remain in the carton at room temperature for up to 6 hours. If not used after 6 hours, it must be discarded.

[0157] Once the suspension is drawn into each syringe, the injection should be given as soon as possible, but it can be left in the syringe for up to 2 hours. If it is left for more than 2 hours, the medication, syringe, and needle must be discarded.

[0158] As used throughout, those skilled in the art will recognize that "monthly" or similar terms are interchangeable with "every 4 weeks" or "Q4W." Similarly, terms referring to every two months are equivalent for administration purposes to every 8 weeks or "Q8W." For purposes of this specification, any monthly to four-week period (or multiples thereof) shall be considered as alternative embodiments.

[0159] Second Main Embodiment According to a second main embodiment, there is provided a method of treating HIV-1, comprising: administering regularly scheduled intramuscular injections of cabotegravir or a salt thereof and rilpivirine or a salt thereof; discontinuing one or both of the regularly administered intramuscular injections after at least one intramuscular injection of each of the cabotegravir or a salt thereof and rilpivirine or a salt thereof; and replacing the discontinued intramuscular injection(s) with regularly administered oral therapy.

[0160] The method for treating HIV comprises the use of oral cabotegravir and / or rilpivirine therapy administered after at least one injection of cabotegravir and / or rilpivirine. According to one embodiment, oral cabotegravir therapy is administered after at least one injection of cabotegravir. Alternatively, oral rilpivirine therapy is administered after at least one injection of rilpivirine.

[0161] According to this embodiment, if a patient is scheduled to miss a scheduled injection visit, oral therapy is used in place of one or more injections after the start of the injection schedule. Injection administration can be resumed as scheduled after oral administration, in which case oral administration serves as a bridging administration between injections. In one embodiment, if a period of more than two months needs to be covered, i.e., if more than two months of injections are missed, the alternative oral regimen should be initiated one or two months (±7 days) after the last intramuscular injection. In one embodiment, if a period of more than two months needs to be covered, i.e., if more than one month of injections is missed for every two months of injections, the alternative oral regimen should be initiated two months (±7 days) after the last intramuscular injection.

[0162] For example, if a patient is scheduled to miss a scheduled injection visit by more than seven days, oral therapy (e.g., one 30 mg tablet of cabotegravir and one 25 mg tablet of rilpivirine once daily) can be used to replace the injection. Preferably, oral therapy replaces no more than two injections. The first dose of oral therapy should be taken approximately when the missed injection would have been administered, e.g., one month after the last injection in the case of a monthly dosing schedule. Injection administration should resume on the day oral administration is completed (see Table 2 above). The first dose of oral therapy should be taken approximately when the missed injection would have been administered, e.g., two months (±7 days) after the last injection in the case of a two-month dosing schedule. Injection administration should resume on the day oral administration is completed.

[0163] As an example, if a patient receiving monthly injections of long-acting rilpivirine misses an injection or oral therapy or is on oral bridge therapy for up to two months, the patient should continue on the monthly 600 mg (2 mL) injection schedule as soon as possible. As an example, if a patient receiving monthly injections of long-acting rilpivirine misses an injection or oral therapy or is on oral bridge therapy for more than two months, the patient should resume on the 900 mg (3 mL) dose and continue on the monthly 600 mg (2 mL) injection schedule thereafter. (Table 15)

[0164] For example, if a patient receiving two months of long-acting rilpivirine injections misses a scheduled injection visit or oral therapy, or if they are receiving oral bridging therapy within two months, they should resume treatment with a 3 mL (900 mg) injection of the rilpivirine long-acting formulation as soon as possible and continue the bimonthly injection schedule. In one embodiment, the patient missed injection 2 (month 3). For example, if a patient receiving two months of long-acting rilpivirine injections misses a scheduled injection visit or oral therapy, or if they are receiving oral bridging therapy for more than two months, they should resume treatment with a 3 mL (900 mg) injection of the rilpivirine long-acting formulation, followed one month later by a second 3 mL (900 mg) starting injection of the rilpivirine long-acting formulation. Thereafter, they should follow the bimonthly injection schedule. In one embodiment, the patient missed injection 2 (month 3). (Table 16)

[0165] For example, if a patient receiving a two-month injectable regimen of long-acting rilpivirine misses a scheduled injection visit or oral therapy, or if the patient is receiving oral bridging therapy within the past three months, the patient should resume treatment with a 3 mL (900 mg) injection of the rilpivirine long-acting formulation as soon as possible and continue the bimonthly injection schedule. In one embodiment, the patient missed an injection after the third day (after the fifth month). For example, if a patient receiving a two-month injectable regimen of long-acting rilpivirine misses a scheduled injection visit or oral therapy, or if the patient is receiving oral bridging therapy for more than three months, the patient should resume treatment with a 3 mL (900 mg) injection of the rilpivirine long-acting formulation, and then begin a second 3 mL (900 mg) injection of the rilpivirine long-acting formulation one month later. The bimonthly injection schedule should then be followed. In one embodiment, the patient missed injection three or more days (after the fifth month). (Table 16)

[0166] [Table 15]

[0167] [Table 16]

[0168] Third Main Embodiment According to a third main embodiment, there is provided a method of treating HIV, comprising: administering regularly scheduled intramuscular injections of cabotegravir or a salt thereof and rilpivirine or a salt thereof; discontinuing one or both of the regularly administered intramuscular injections after at least one intramuscular injection of each of said cabotegravir or a salt thereof and rilpivirine or a salt thereof; and re-establishing intramuscular administration of one or both of cabotegravir or a salt thereof and rilpivirine or a salt thereof by first administering a loading dose of the discontinued cabotegravir or a salt thereof and / or rilpivirine or a salt thereof, and then continuing the regularly administered intramuscular injections.

[0169] According to this embodiment, a restart injection of the combination is given after at least one prior injection and after a delay in a subsequent scheduled injection outside the acceptable therapeutic window, wherein the restart injection is at a higher dose than the scheduled injection.

[0170] According to one embodiment, resumption uses a 3 mL dose of cabotegravir, followed by continuing to follow a monthly 2 mL injection administration schedule for cabotegravir. According to one embodiment, resumption uses a 3 mL dose of rilpivirine, followed by continuing to follow a monthly 2 mL injection administration schedule for rilpivirine. According to one embodiment, resumption uses a 3 mL dose of the combination, followed by continuing to follow a monthly 2 mL injection administration schedule for the combination.

[0171] Fifth Main Embodiment According to a fifth main embodiment, there is provided a method of treating HIV comprising administering periodically intramuscular injections of cabotegravir or a salt thereof and rilpivirine or a salt thereof after viral suppression with a bictegravir-containing regimen. Alternatively, according to one aspect of this embodiment, there is provided cabotegravir or a salt thereof and rilpivirine or a salt thereof for use in therapy comprising administering periodically intramuscular injections of cabotegravir or a salt thereof and rilpivirine or a salt thereof after viral suppression with a bictegravir-containing regimen, particularly in the treatment of HIV infection.

[0172] According to this embodiment, the bictegravir-containing regimen is a bictegravir / emtricitabine / tenofovir anafenamide single tablet regimen. Further, according to this embodiment, bictegravir is administered at 50 mg / day.

[0173] According to this embodiment, the periodically administered intramuscular injections are administered approximately every four weeks, or alternatively, monthly. According to another embodiment, the periodically administered intramuscular injections are administered approximately every eight weeks, or alternatively, every two months.

[0174] According to this embodiment, the method of periodically administering intramuscular injections of cabotegravir or a salt thereof and rilpivirine or a salt thereof is clinically non-inferior to treatment with a bictegravir-containing regimen. According to a further embodiment, the method of periodically administering intramuscular injections of cabotegravir or a salt thereof and rilpivirine or a salt thereof is clinically non-inferior over a period of at least 12 months. [Example]

[0175] Example 1 ATLAS (NCT02951052) and FLAIR (NCT02938520) are two randomized, open-label, international phase 3 trials that demonstrated noninferiority of monthly intramuscular (IM) injections of CAB LA+RPV LA to switching current antiretroviral therapy (CAR). The injectable CAB+RPV LA regimen requires monthly injection visits within a pre-specified time window and represents a paradigm shift for patients from daily oral administration.

[0176] Injections were scheduled for week Q4, with a dosing window of ±7 days from the scheduled dosing date. Adherence to LA therapy was calculated as the number of on-time injection visits observed within the dosing window divided by the number of expected dosing visits through week 48. Oral bridging (the use of oral dosing to cover missed scheduled injections) was allowed in both study protocols, allowing dosing flexibility for planned absences from clinical sites (e.g., for vacation or travel) while allowing subjects to continue LA administration for an extended period. Injection visits outside the prespecified window and missed injection visits with and without oral dosing were quantified.

[0177] From the ATLAS and FLAIR clinical trials, oral administration between injections (CAB 30 mg + RPV 25 mg) was used in 15 subjects over the 48-week study period.

[0178] Six subjects used oral bridging but did not miss a scheduled injection visit.

[0179] Two subjects were unable to continue LA therapy.

[0180] There were nine missed injections in both studies, eight of which were covered by oral bridging (seven subjects). One subject missed the planned infusion visit without oral bridging coverage at week 32 (met criteria for discontinuation due to acute hepatitis A), but LA therapy was continued at week 36 and viral suppression was maintained.

[0181] [Table 17]

[0182] For subjects scheduled to miss an injection visit, oral bridging proved to be an effective strategy for maintaining virologic suppression, with no confirmed cases of virologic failure during the oral bridging period or after resumption of IM dosing.

[0183] Example 2 A two-compartment model with first-order oral and intramuscular (IM) absorption and first-order elimination adequately describes data from 23,926 concentration recordings in 1647 subjects after oral and LA administration (Han K, Patel P, Baker M, et al. Population pharmacokinetics of cabotegravir in adult healthy subjects and HIV-1 infected patients following administration of oral tablet and long-acting intramuscular injection. Abstract WEPDB0205. 22nd International AIDS Conference 23-27 July 2018, Amsterdam, the Netherlands).

[0184] Covariates retained in the model included sex, BMI, needle length, and fractional injection of the absorption rate constant after LA administration (KA LA), as well as smoking status and weight at the time point relative to CL and volume. None of the covariates evaluated required dose adjustment for CAB.

[0185] The 5th percentile of the individual predicted trough concentration (IPRED) after the loading dose in a phase 3 trial from the final model output (0.65 μg / mL) was used as a benchmark to assess the impact of dosing anomalies on the standard regimen (Orkin C, Arasteh K, Hernandez-Mora MG, et al. Long-acting cabotegravir + rilpivirine for HIV maintenance: FLAIR week 48 results. Conference on Retroviruses and Opportunistic Infections (CROI). Abstract Number: 140. March 4-7, 2019, Seattle, WA.; Swindells S, Andrade-Villanueva JF, Richmond GJ, et al. Long-acting cabotegravir + rilpivirine as maintenance therapy: ATLAS week 48 results. Conference on Retroviruses and Opportunistic Infections (CROI). Abstract Number: 139. March 4-7, 2019, Seattle, WA. WA.) Protein-corrected IC90 (PA-IC90, 0.166 μg / mL) was also considered when assessing the tolerability of dose delays.

[0186] The long-term safety threshold was assigned to 13.1 μg / mL, which is the steady-state C value after the highest oral dose of CAB 60 mg QD administered for 96 weeks in Study LAI116482 (LATTE). max(Margolis DA, Brinson CC, Smith GHR, et al. LAI116482 Study Team. Cabotegravir plus rilpivirine, once a day, after induction with cabotegravir plus nucleoside reverse transcriptase inhibitors in antiretroviral-naive adults with HIV-1 infection (LATTE): a randomized, phase 2b, dose-ranging trial. Lancet Infect Dis. 2015 Oct;15(10):1145-1155).

[0187] Delays of 1 to 12 weeks in the administration of the second, third, and fourth injections were simulated (Table 1). Q4W administration was resumed after each delay.

[0188] A mixed population of men (80%) and women (20%) was estimated to represent the expected population. Each scenario included 5,000 virtual subjects to ensure 1,000 female virtual subjects. Individual PK parameters were calculated using subject-specific NONMEM intersubject error (ETA) samples from a distribution determined by population parameter estimates, an estimated variance-covariate matrix of intersubject variability, and subject-specific covariates.

[0189] Scenario for delayed administration of CAB monthly treatment regimen (CAB LA 600 mg (3 mL) initial injection followed by RPV LA 400 mg (2 mL) Q4W) (Table 18).

[0190] [Table 18]

[0191] When CABLA administration was resumed, oral bridging was resumed for missed injections for 1–2 months (Table 18). The fourth IM dose was assumed to be missed. Administration resumed on a Q4W pattern.

[0192] [Table 19]

[0193] The results of simulations performed as described above are shown in Figure 1. Simulated concentration versus time profiles for a) no delay (Sim#1), b) 1-week delay for injection 2 (Sim#2), c) 4-week delay for injection 3 restarted at 2 mL or 3 mL (Sim#15, Sim#16), d) 4-week delay for injection 4 restarted at 2 mL or 3 mL (Sim#25, Sim#26), e) 4-week delay for injection 4 with and without oral bridge (Sim#25, Sim#32), and f) 8-week delay for injection 4 with and without oral bridge (Sim#29, Sim#35).

Claims

1. 1. A pharmaceutical composition comprising cabotegravir or a salt thereof for use in combination with rilpivirine or a salt thereof for use in the treatment of HIV infection in a subject, said treatment comprising periodically administering intramuscular injections of each of cabotegravir or a salt thereof and rilpivirine or a salt thereof, wherein said periodically administering intramuscular injections (a) cabotegravir or a salt thereof is administered as an intramuscular injection of 400 mg once every month + / - 7 days, and rilpivirine or a salt thereof is administered as an intramuscular injection of 600 mg once every month + / - 7 days, or (b) cabotegravir or a salt thereof is administered as an intramuscular injection of 600 mg once every 2 months + / - 7 days, and rilpivirine or a salt thereof is administered as an intramuscular injection of 900 mg once every 2 months + / - 7 days; Including, discontinuing one or both of the regularly administered intramuscular injections after at least one intramuscular injection of each of cabotegravir or a salt thereof and rilpivirine or a salt thereof; and first administering a loading dose of discontinued cabotegravir or a salt thereof and / or rilpivirine or a salt thereof; wherein the loading dose comprises cabotegravir or a salt thereof administered as a single intramuscular injection of 600 mg, and rilpivirine or a salt thereof administered as a single intramuscular injection of 900 mg; Thereafter, by continuing regular intramuscular injections, and re-establishing intramuscular administration of one or both of cabotegravir or a salt thereof and / or rilpivirine or a salt thereof more than two months after discontinuing one or both of said regularly administered intramuscular injections.

2. 1. A pharmaceutical composition comprising rilpivirine or a salt thereof for use in combination with cabotegravir or a salt thereof for use in the treatment of HIV infection in a subject, said treatment comprising periodically administering intramuscular injections of each of cabotegravir or a salt thereof and rilpivirine or a salt thereof, wherein said periodically administering intramuscular injections (a) cabotegravir or a salt thereof is administered as an intramuscular injection of 400 mg once every month + / - 7 days, and rilpivirine or a salt thereof is administered as an intramuscular injection of 600 mg once every month + / - 7 days, or (b) cabotegravir or a salt thereof is administered as an intramuscular injection of 600 mg once every 2 months + / - 7 days, and rilpivirine or a salt thereof is administered as an intramuscular injection of 900 mg once every 2 months + / - 7 days; Including, discontinuing one or both of the regularly administered intramuscular injections after at least one intramuscular injection of each of rilpivirine or a salt thereof and cabotegravir or a salt thereof; and first administering a loading dose of discontinued cabotegravir or a salt thereof and / or rilpivirine or a salt thereof; wherein the loading dose comprises rilpivirine or a salt thereof administered as a single intramuscular injection of 900 mg, and cabotegravir or a salt thereof administered as a single intramuscular injection of 600 mg; Thereafter, by continuing regular intramuscular injections, and re-establishing intramuscular administration of one or both of cabotegravir or a salt thereof and / or rilpivirine or a salt thereof more than two months after discontinuing one or both of said regularly administered intramuscular injections.

3. 3. The pharmaceutical composition of claim 1 or 2, wherein the intramuscular injections of cabotegravir or its salt and rilpivirine or its salt are administered separately.

4. 4. The pharmaceutical composition of any one of claims 1 to 3, wherein the regularly administered injections comprise cabotegravir or a salt thereof administered as an intramuscular injection of 400 mg once every month + / - 7 days, and rilpivirine or a salt thereof administered as an intramuscular injection of 600 mg once every month + / - 7 days.

5. 5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the loading dose comprises cabotegravir or a salt thereof administered as a single intramuscular injection of 600 mg, followed by 400 mg intramuscular injections once every month + / - 7 days, and / or rilpivirine or a salt thereof administered as a single intramuscular injection of 900 mg, followed by 600 mg intramuscular injections once every month + / - 7 days.

6. 4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the cabotegravir or its salt is administered as an intramuscular injection of 600 mg once every 2 months + / - 7 days, and the rilpivirine or its salt is administered as an intramuscular injection of 900 mg once every 2 months + / - 7 days.

7. 7. The pharmaceutical composition of claim 6, wherein administration of cabotegravir or a salt thereof and / or rilpivirine or a salt thereof administered as a single 600 mg intramuscular injection, followed by one 600 mg intramuscular injection every two months + / - seven days, and / or rilpivirine or a salt thereof administered as a single 900 mg intramuscular injection, followed by one 900 mg intramuscular injection every two months + / - seven days, re-establishes administration of one or both of cabotegravir or a salt thereof and / or rilpivirine or a salt thereof more than two months but not more than three months after discontinuing one or both of the regularly administered intramuscular injections.

8. 3. The pharmaceutical composition according to claim 1 or 2, wherein the regular administration is once every month + / - 7 days.

9. 3. The pharmaceutical composition of claim 1 or 2, wherein the regular administration is once every 2 months + / - 7 days.

10. 10. The pharmaceutical composition of any one of claims 1 to 9, wherein the oral loading doses of both cabotegravir or a salt thereof and rilpivirine or a salt thereof are provided before starting intramuscular injection.

11. 1. A pharmaceutical composition comprising cabotegravir or a salt thereof for use in combination with rilpivirine or a salt thereof for use in the treatment of HIV infection in a subject, said treatment comprising administering periodic intramuscular injections of cabotegravir or a salt thereof and rilpivirine or a salt thereof, wherein said periodic intramuscular injections Cabotegravir or a salt thereof is administered as an intramuscular injection of 600 mg once every 2 months + / - 7 days, and rilpivirine or a salt thereof is administered as an intramuscular injection of 900 mg once every 2 months + / - 7 days. Including, 1. A pharmaceutical composition comprising: after at least one intramuscular injection of each of cabotegravir or a salt thereof and rilpivirine or a salt thereof, discontinuing one or both of the regularly administered intramuscular injections two months (+ / - 7 days) later; and replacing the discontinued intramuscular injection(s) with a regularly administered oral therapy comprising one 30 mg tablet of cabotegravir or a salt thereof once daily and / or one 25 mg tablet of rilpivirine or a salt thereof once daily.

12. 1. A pharmaceutical composition comprising rilpivirine or a salt thereof for use in combination with cabotegravir or a salt thereof for use in the treatment of HIV infection in a subject, said treatment comprising administering periodic intramuscular injections of cabotegravir or a salt thereof and rilpivirine or a salt thereof, wherein said periodic intramuscular injections Cabotegravir or a salt thereof is administered as an intramuscular injection of 600 mg once every 2 months + / - 7 days, and rilpivirine or a salt thereof is administered as an intramuscular injection of 900 mg once every 2 months + / - 7 days. Including, 1. A pharmaceutical composition comprising: after at least one intramuscular injection of each of cabotegravir or a salt thereof and rilpivirine or a salt thereof, discontinuing one or both of the regularly administered intramuscular injections two months (+ / - 7 days) later; and replacing the discontinued intramuscular injection(s) with a regularly administered oral therapy comprising one 30 mg tablet of cabotegravir or a salt thereof once daily and / or one 25 mg tablet of rilpivirine or a salt thereof once daily.

13. 13. The pharmaceutical composition of claim 11 or 12, wherein the intramuscular injections of cabotegravir or its salt and rilpivirine or its salt are administered separately.

14. 14. The pharmaceutical composition according to any one of claims 11 to 13, wherein the cabotegravir or its salt is administered as a single 600 mg intramuscular injection, followed by 600 mg once every 2 months + / - 7 days, and the rilpivirine or its salt is administered as a single 900 mg intramuscular injection, followed by 900 mg once every 2 months + / - 7 days.

15. 15. The pharmaceutical composition of any one of claims 11 to 14, wherein an oral loading dose of both cabotegravir or a salt thereof and rilpivirine or a salt thereof is provided prior to intramuscular injection.

16. The pharmaceutical composition of any one of claims 11 to 15, wherein intramuscular administration of cabotegravir or its salt is discontinued and replaced with one 30 mg tablet of cabotegravir or its salt once daily.

17. The pharmaceutical composition according to any one of claims 11 to 16, wherein intramuscular administration of rilpivirine or a salt thereof is discontinued and replaced with one 25 mg tablet of rilpivirine or a salt thereof once daily.

18. The pharmaceutical composition according to any one of claims 11 to 17, wherein regular intramuscular administration of cabotegravir or a salt thereof and / or rilpivirine or a salt thereof is resumed after oral therapy with cabotegravir or a salt thereof and / or rilpivirine or a salt thereof.

19. 19. The pharmaceutical composition of any one of claims 11 to 18, wherein regularly administered oral therapy is discontinued after two months or less and intramuscular administration is resumed with cabotegravir or a salt thereof as a 600 mg intramuscular injection once every two months + / - 7 days and rilpivirine or a salt thereof as a 900 mg intramuscular injection once every two months + / - 7 days.

20. 19. The pharmaceutical composition of any one of claims 11 to 18, wherein regularly administered oral therapy is discontinued after more than two months and intramuscular administration is resumed as cabotegravir or a salt thereof as a single 600 mg intramuscular injection, followed by one 600 mg injection every two months + / - 7 days thereafter, and rilpivirine or a salt thereof as a single 900 mg intramuscular injection, followed by one 900 mg injection every two months + / - 7 days thereafter.

21. 1. A pharmaceutical composition comprising cabotegravir or a salt thereof for use in combination with rilpivirine or a salt thereof for use in the treatment of HIV infection in a subject, said treatment comprising periodically administering intramuscular injections of each of cabotegravir or a salt thereof and rilpivirine or a salt thereof, wherein said periodically administering intramuscular injections (a) cabotegravir or a salt thereof is administered as an intramuscular injection of 400 mg once every month + / - 7 days, and rilpivirine or a salt thereof is administered as an intramuscular injection of 600 mg once every month + / - 7 days, or (b) cabotegravir or a salt thereof is administered as an intramuscular injection of 600 mg once every 2 months + / - 7 days, and rilpivirine or a salt thereof is administered as an intramuscular injection of 900 mg once every 2 months + / - 7 days; Including, discontinuing one or both of the regularly administered intramuscular injections after at least one intramuscular injection of each of cabotegravir or a salt thereof and rilpivirine or a salt thereof; and resuming said one or both of said regularly administered intramuscular injections no more than two months after discontinuing said one or both of said regularly administered intramuscular injections. Pharmaceutical compositions.

22. 1. A pharmaceutical composition comprising rilpivirine or a salt thereof for use in combination with cabotegravir or a salt thereof for use in the treatment of HIV infection in a subject, said treatment comprising periodically administering intramuscular injections of each of cabotegravir or a salt thereof and rilpivirine or a salt thereof, wherein said periodically administering intramuscular injections (a) cabotegravir or a salt thereof is administered as an intramuscular injection of 400 mg once every month + / - 7 days, and rilpivirine or a salt thereof is administered as an intramuscular injection of 600 mg once every month + / - 7 days, or (b) cabotegravir or a salt thereof is administered as an intramuscular injection of 600 mg once every 2 months + / - 7 days, and rilpivirine or a salt thereof is administered as an intramuscular injection of 900 mg once every 2 months + / - 7 days; Including, discontinuing one or both of the regularly administered intramuscular injections after at least one intramuscular injection of each of rilpivirine or a salt thereof and cabotegravir or a salt thereof; and resuming said one or both of said regularly administered intramuscular injections no more than two months after discontinuing said one or both of said regularly administered intramuscular injections. Pharmaceutical compositions.

23. 23. The pharmaceutical composition of claim 21 or 22, wherein the intramuscular injections of cabotegravir or its salt and rilpivirine or its salt are administered separately.

24. 24. The pharmaceutical composition of any one of claims 21 to 23, wherein the regularly administered injections comprise cabotegravir or a salt thereof administered as an intramuscular injection of 400 mg once every month + / - 7 days, and rilpivirine or a salt thereof administered as an intramuscular injection of 600 mg once every month + / - 7 days.

25. 24. The pharmaceutical composition of any one of claims 21 to 23, wherein the cabotegravir or its salt is administered as an intramuscular injection of 600 mg once every 2 months + / - 7 days, and the rilpivirine or its salt is administered as an intramuscular injection of 900 mg once every 2 months + / - 7 days.

26. The pharmaceutical composition according to any one of claims 21 to 24, wherein the regular administration is once every month + / - 7 days.

27. 26. The pharmaceutical composition of any one of claims 21 to 23 and 25, wherein the regular administration is once every 2 months + / - 7 days.

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