Regimens for treating HIV infections and AIDS

Abstract

A method of treating HIV comprising intramuscular administration once every 4 weeks or less frequently of a combination of cabotegravir or a pharmaceutically acceptable salt thereof and rilpivirine or a pharmaceutically acceptable salt thereof, including the option of discontinuing administration of a first oral anti-retroviral regimen and intramuscularly administering, once four weeks or less often said combination of cabotegravir and rilpivirine.

Claims

1. A method of treating HIV comprising intramuscularly administering to a subject in need thereof a dosage regimen consisting of either (a) 400 mg of cabotegravir or a pharmaceutically acceptable salt thereof and 600 mg of rilpivirine or a pharmaceutically acceptable salt thereof administered every four weeks or once a month in two separate 2-mL injections, or (b) 600 mg of cabotegravir or a pharmaceutically acceptable salt thereof and 900 mg of rilpivirine or a pharmaceutically acceptable salt thereof administered every 8 weeks or once every two months in two separate 3-mL injections.

2. The method according to claim 1, wherein the dosage regimen for administration is every month or 4 weeks.

3. The method according to claim 2, wherein the dosage regimen for administration is every 4 weeks.

4. A method of modifying an anti-HIV dosage regimen for a subject in need thereof comprising discontinuing administration of a first oral anti-HIV regimen to the subject; and intramuscularly administering to the subject, once every month or four weeks a dosage regimen consisting of 600 mg rilpivirine, or a pharmaceutically acceptable salt thereof in a 2-mL injection; and 400 mg cabotegravir, or a pharmaceutically acceptable salt thereof in a 2-mL injection.

5. The method of claim 4, wherein the dosage regimen is two separate 2-mL injections administered every four weeks.

6. The method according to claim 1, wherein the dosage regimen for administration is every 8 weeks or 2 months.

7. The method according to claim 6, wherein the dosage regimen for administration is every 8 weeks.

8. A method of modifying an anti-HIV dosage regimen for a subject in need thereof comprising discontinuing administration of a first oral anti-HIV regimen to the subject; and intramuscularly administering to the subject, once every two months or eight weeks a dosage regimen consisting of 900 mg rilpivirine, or a pharmaceutically acceptable salt thereof in a 3-mL injection; and 600 mg cabotegravir, or a pharmaceutically acceptable salt thereof in a 3-mL injection.

9. The method according to claim 1, wherein the subject exhibits a viral load of less than or equal to 50 copies of HIV-1 virus particles per mL of blood plasma (≤50 c/mL) after at least 96 weeks of administration of the dosage regimen.

10. The method of claim 4, wherein the first oral anti-HIV regimen comprises cabotegravir; and two nucleoside reverse transcriptase inhibitors.

11. The method of claim 10, wherein the first oral anti-HIV regimen comprises cabotegravir; and abacavir and lamivudine.

12. The method of claim 1, wherein the subject is infected with HIV-1.

13. The method of claim 1, wherein the subject exhibits a viral load of less than or equal to 50 copies of HIV-1 virus particles per mL of blood plasma (≤50 c/mL) prior to the administration of the dosage regimen.

14. The method of claim 1, wherein the subject exhibits the same or an improved cluster of differentiation (CD) 4+cell count after at least 96 weeks, of once every month or 4 weeks, or once every two months or eight weeks, administration of the dosage regimen, as compared to the subject's CD4+count prior to the administration.

15. The method of claim 1, wherein the subject does not exhibit an emergent resistance-associated mutation in an HIV virus after at least 96 weeks, of once every month or four weeks, or once every two months or eight weeks administration of the dosage regimen.

16. The method of claim 1, wherein the method comprises intramuscularly administering to the subject in need thereof a dosage regimen consisting of either (a) 400mg of cabotegravir and 600mg of rilpivirine or a pharmaceutically acceptable salt thereof administered every four weeks or once a month in two separate 2-mL injections, or (b) 600mg of cabotegravir and 900mg of rilpivirine or a pharmaceutically acceptable salt thereof administered every 8 weeks or once every two months in two separate 3-mL injections.

17. The method of claim 1, wherein the method comprises intramuscularly administering to the subject in need thereof a dosage regimen consisting of either (a) 400mg of cabotegravir or a pharmaceutically acceptable salt thereof and 600mg of rilpivirine administered every four weeks or once a month in two separate 2-mL injections, or (b) 600mg of cabotegravir or a pharmaceutically acceptable salt thereof and 900mg of rilpivirine administered every 8 weeks or once every two months in two separate 3-mL injections.

18. The method according to claim 2, wherein the dosage regimen for administration is once every month.

19. The method according to claim 4, wherein the dosage regimen is two separate 2-mL injections, administered once every month.

20. The method according to claim 6, wherein the dosage regimen for administration is once every two months.

21. The method according to claim 8, wherein the dosage regimen for administration is once every two months.

22. The method according to claim 8, wherein the dosage regimen for administration is once every eight weeks.

23. The method of claim 1, wherein the method comprises intramuscularly administering to the subject in need thereof a dosage regimen consisting of either (a) 400mg of cabotegravir and 600mg of rilpivirine administered every four weeks or once a month in two separate 2-mL injections, or (b) 600mg of cabotegravir and 900mg of rilpivirine administered every 8 weeks or once every two months in two separate 3-mL injections.

Description

DESCRIPTION OF THE FIGURES

(1) FIG. 1. LATTE-2 trial profile. IM, intramuscular; LA, long acting; PDVF, protocol-defined virologic failure; Q4W, every four weeks; Q8W, every eight weeks. *Multiple reasons for screening failure were reported for two subjects. .sup.†A total of 310 subjects were enrolled, but one subject withdrew consent after baseline visit procedures were performed and before study treatment was initiated. .sup.‡Two subjects completed the induction period (and had Day 1 assessments) but did not enter the maintenance period and were not randomized (because of investigator discretion and lack of efficacy). .sup.§Subject experienced suspected PDVF at the time of withdrawal, which was subsequently confirmed.

(2) FIG. 2. Proportion of subjects with HIV-1 RNA concentration <50 copies per mL (FDA snapshot algorithm) by visit in the maintenance-exposed population and snapshot outcomes at Week 48. AE, adverse event; BL, baseline; D, day; FDA, US Food and Drug Administration; IM, intramuscular; ME, maintenance-exposed; LA, long acting; PDVF, protocol-defined virologic failure; Q4W, every four weeks; Q8W, every eight weeks; W, week.

(3) FIG. 3. Mean concentration-time profiles following Q4W and Q8W administration of (A) cabotegravir LA and (B) rilpivirine LA through Week 48. C.sub.τ, concentration at the end of dosing interval; IM, intramuscular; LA, long acting; PA-IC.sub.90, protein-adjusted 90% inhibitory concentration; PO, orally; Q4W, every four weeks; Q8W, every eight weeks; SD, standard deviation.

(4) FIG. 4. Summary of subject-reported outcomes at (A) Week 48 (maintenance treatment) and (B) Week 96. The data are based on the observed case data set of subjects who completed questionnaires at Week 48 and Week 96 (HIV Treatment Satisfaction Questionnaire status version). IM, intramuscular; LA, long acting; Q4W, every four weeks; Q8W, every eight weeks.

DETAILED DESCRIPTION OF THE INVENTION

(5) Definitions

(6) HIV” or “human immunodeficiency virus” each means HIV-1 or HIV-2, or any mutant, group, clinical isolate, subtype, or clade thereof.

(7) “Adult” as used herein means at least eighteen (18) years of age. The term “adult” may therefore be used to a reference a subject who is at least 18 years of age.

(8) “Subject(s)” or “Human” or “Human subject(s)” or “Person(s)” herein are used to refer to a Homo sapiens.

(9) Antiretroviral drug” or “ARV drug” as used herein means a molecule or compound classified as being a reverse transcriptase, protease, and/or integrase inhibitor

(10) “Pharmaceutically acceptable” as used herein means capable of administration to a subject without undesirable physiological effects. For example, “pharmaceutically acceptable salt thereof” encompasses solvates, polymorphs, and/or salts of the referenced compound.

(11) “Sequential administration” or “adjacent administration” as used herein mean that at least two of the two or more referenced molecules, compounds, drugs, agents, etc., are not co-administered and are administered in succession (one after the other). In a particular embodiment of the invention, the two ARV drugs are sequentially administered within 1 hour. In a particular embodiment of the invention, the two ARV drugs are sequentially administered within 0.5 hour (i.e., 30 minutes). As used herein “within” is inclusive such that “within 1 hour,” for example, includes 1 hour and times less than 1 hour.

(12) “Simultaneous administration” as used herein means the two or more referenced molecules, compounds, drugs, agents, etc., are administered at the same time but not necessarily together in one composition. For example, in an embodiment of the invention two ARV drugs are administered at the same time but each is within a distinct (separate) pharmaceutical composition (i.e., not together). In an embodiment of the invention, “simultaneous” is defined as a time interval of 0 minutes.

(13) The present invention demonstrates that subjects who were virologically suppressed on an oral cabotegravir-based therapy, switching to a long-acting combination of cabotegravir and rilpivirine maintained virologic suppression in 90% of patients overall through week 96 following four- or eight-week injectable administration at rates comparable to remaining on daily oral cabotegravir-based therapy thus representing a paradigm shift in the HIV treatment landscape by circumventing the burden of chronic daily dosing.

(14) In one aspect of the present invention there is provided a method of treating HIV comprising intramuscular administration once every 4 weeks or longer of a combination of cabotegravir or a pharmaceutically acceptable salt thereof and rilpivirine or a pharmaceutically acceptable salt thereof.

(15) In one embodiment, the treatment is every month or 4 weeks.

(16) In one embodiment, the treatment is every 2 months or 8 weeks.

(17) In a further aspect if the invention the subject is treatment naïve.

(18) In a further aspect of the invention the subject is already receiving oral antiviral therapy.

(19) In a further aspect of the invention, there is provided a method of modifying an anti-retroviral dosage regimen for a subject comprising discontinuing administration of a first oral anti-retroviral regimen to the subject; and intramuscularly administering to the subject, once every four weeks or longer a combination comprising rilpivirine, or a pharmaceutically acceptable salt thereof; and cabotegravir, or a pharmaceutically acceptable salt thereof;

(20) The subject being switched from an oral antiviral regimen may particularly be on a three-drug regimen. In one embodiment, the first anti-retroviral regimen comprises cabotegravir; and two nucleoside reverse transcriptase inhibitors particularly abacavir and lamivudine

(21) In a further aspect of the invention, at the time of commencing treatment with the regimen of the present invention, as either a treatment-naïve subject or a subject being switched from an oral drug regimen, the subject exhibits a viral load of less than or equal to 50 copies of HIV-1 virus particles per mL of blood plasma (≤50 c/mL).

(22) In a further aspect of the invention, after administration, the subject is virologically suppressed. In one embodiment, virologically suppressed consists of a viral load no more than 50 copies of HIV RNA per milliliter (<50 c/mL) of the subject's plasma.

(23) In a further embodiment, the subject preferably exhibits a viral load of less than or equal to 50 copies of HIV-1 virus particles per mL of blood plasma (≤50 c/mL) after at least 96 weeks of the once every month or four weeks or longer administration of the dosage form.

(24) In one embodiment, the treatment is every 4 weeks or one month, more particularly the treatment is every 4 weeks. In this embodiment, the dose is 400 mg cabotegravir and 600 mg rilpivirine, administered every four weeks. In a further embodiment the 400 mg cabotegravir and 600 mg rilpivirine, are administered separately in two 2-mL injections, every four weeks.

(25) In one embodiment, the treatment is every 8 weeks or 2 months, more particularly the treatment is every 8 weeks. In this embodiment, the dose is 600 mg cabotegravir and 900 mg rilpivirine, administered every eight weeks. In a further embodiment, the 600 mg cabotegravir and 900 mg rilpivirine, are administered separately in two 3-mL injections, every 8 weeks.

(26) Particular methods of treatment according to the present invention include

(27) A method of modifying an anti-retroviral dosage regimen for a subject comprising discontinuing administration of a first oral anti-retroviral regimen to the subject; and intramuscularly administering to the subject, once every month or four weeks a combination comprising rilpivirine, or a pharmaceutically acceptable salt thereof; and cabotegravir, or a pharmaceutically acceptable salt thereof
wherein the subject exhibits a viral load of less than or equal to 50 copies of HIV-1 virus particles per mL of blood plasma (≤50 c/mL) after at least 96 weeks of the once every month or four weeks administration of the dosage form.

(28) A method of modifying an anti-retroviral dosage regimen for a subject comprising discontinuing administration of an first oral anti-retroviral regimen to the subject; and intramuscularly administering to the subject, once every 2 months or eight weeks a combination comprising rilpivirine, or a pharmaceutically acceptable salt thereof; and cabotegravir, or a pharmaceutically acceptable salt thereof
wherein the subject exhibits a viral load of less than or equal to 50 copies of HIV-1 virus particles per mL of blood plasma (≤50 c/mL) after at least 96 weeks of the once every month or four weeks administration of the dosage form.

(29) In a further aspect, the present invention provides a combination of cabotegravir or a pharmaceutically acceptable salt thereof and rilpivirine or a pharmaceutically acceptable salt thereof for use in the treatment of HIV by the above methods.

(30) In a further aspect of the invention there is provided a pharmaceutical composition comprising a combination of cabotegravir or a pharmaceutically acceptable salt thereof and rilpivirine or a pharmaceutically acceptable salt thereof for use in the treatment of HIV by the above methods.

(31) In one embodiment, the pharmaceutical composition comprises separate compositions of rilpivirine or a pharmaceutically acceptable salt thereof and cabotegravir or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition of rilpivirine or a pharmaceutically acceptable salt thereof contains 300 mg (of rilpivirine as free compound) per mL. In one embodiment, the pharmaceutical composition of cabotegravir or a pharmaceutically acceptable salt thereof contains 200 mg (of cabotegravir as free compound) per mL. In one embodiment, both formulations are for intra-muscular administration.

(32) In an embodiment of the invention, the subject is infected with Human Immunodeficiency Virus Type 1 (HIV-1).

(33) The compounds of Formula (I) may be in the form of a salt.

(34) Typically, the salts of the present invention are pharmaceutically acceptable salts. Salts encompassed within the term “pharmaceutically acceptable salts” refer to non-toxic salts of the compounds of this invention. For a review on suitable salts see Berge et al, J. Pharm. Sci. 1977, 66, 1-19.

(35) While it is possible that, for use in therapy, the compound of the invention may be administered as the raw chemical, it is possible to present the compound of the invention as the active ingredient as a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. Accordingly, the invention further provides pharmaceutical compositions comprising a combination of cabotegravir or a pharmaceutically acceptable salt thereof and rilpivirine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. The excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof. In accordance with another aspect of the invention there is also provided a process for the preparation of a pharmaceutical composition including the agent, or pharmaceutically acceptable salts thereof, with one or more pharmaceutically acceptable excipients. The pharmaceutical composition can be for use in the treatment and/or prophylaxis of any of the conditions described herein. The combination of cabotegravir or a pharmaceutically acceptable salt thereof and rilpivirine or a pharmaceutically acceptable salt thereof may be formulated together in one composition, or each of the active ingredients may be present in its own pharmaceutical composition.

(36) Generally, the combination is administered in a pharmaceutically effective amount. The amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound—administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like. Amounts suitable for the treatment of the present invention are detailed above.

(37) The pharmaceutical composition is preferably suitable for parenteral, particularly intramuscular administration.

(38) Pharmaceutical compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

(39) The active ingredients for use in the methods of the invention) may be employed in combination by administration simultaneously in a unitary pharmaceutical composition including both compounds. Alternatively, the combination may be simultaneously administered separately in separate pharmaceutical compositions, each including one of the compounds in a sequential manner wherein, for example, cabotegravir or a pharmaceutically acceptable salt thereof is administered first and rilpivirine or a pharmaceutically acceptable salt thereof second and vice versa. Suitably, both compounds are administered intramuscularly.

(40) The combinations may be presented as a combination kit. By the term “combination kit” “or kit of parts” as used herein is meant the pharmaceutical composition or compositions that are used to administer the combination according to the invention. The combination kit can contain both compounds in a single pharmaceutical composition, or in separate pharmaceutical compositions either in a single package or in separate pharmaceutical compositions in separate packages.

(41) The combination kit can also be provided by instruction, such as dosage and administration instructions. Such dosage and administration instructions can be of the kind that are provided to a doctor, for example by a drug product label, or they can be of the kind that are provided by a doctor, such as instructions to a patient.

(42) When the combination is administered separately in a sequential manner wherein one is administered first and the other second or vice versa, such sequential administration may be close in time or remote in time. For example, administration of the other agent several minutes to several dozen minutes after the administration of the first agent. Conveniently they are administered simultaneously.

(43) METHODS

(44) Cabotegravir and rilpivirine are antiretroviral drugs in development as long-acting injectable formulations. The LATTE-2 study evaluated long-acting cabotegravir+rilpivirine for maintenance of HIV-1 viral suppression through 96 weeks.

(45) Methods

(46) In this randomized, phase IIb, open-label study (Clinicaltrials.gov identifier, NCT02120352), HIV-1-infected, treatment-naive adults initially received oral cabotegravir 30 mg+abacavir/lamivudine 600/300 mg once daily. After 20 weeks, subjects with plasma HIV-1 RNA <50 copies per mL were randomized 2:2:1 to intramuscular long-acting cabotegravir+rilpivirine at four- or eight-week intervals or continued oral cabotegravir+abacavir/lamivudine. Endpoints included proportion of subjects with plasma HIV-1 RNA <50 copies per mL, protocol-defined virologic failures and safety events through 96 weeks for the maintenance-exposed population.

(47) Results

(48) Among 309 enrolled subjects, 286 were randomized into the maintenance period. Thirty-two weeks after randomization, viral suppression (HIV-1 RNA <50 copies per mL) was maintained in 91% (n=51) of subjects receiving oral cabotegravir+abacavir/lamivudine, 94% (n=108) in the four-week intramuscular group (+2.8% vs cabotegravir+abacavir/lamivudine, 95% CI, −5.8 to 11.5), and 95% (n=109) in the eight-week intramuscular group (+3.7% vs cabotegravir+abacavir/lamivudine; 95% CI, −4.8 to 12.2). Through Week 96, viral suppression was maintained in 84%, 87%, and 94% of subjects, respectively. Three subjects (1%) experienced protocol-defined virologic failure (eight-week intramuscular, n=2; oral, n=1). Injection-site reactions were mild (84%) or moderate (15%) in intensity and rarely resulted in discontinuation (<1%); injection-site pain was reported most frequently (96%). Serious adverse events were reported in 11% and 16% of subjects in the intramuscular and oral cabotegravir+abacavir/lamivudine groups, respectively; none were drug related.

(49) Study Design

(50) LATTE-2 is an ongoing phase IIb, randomized, multicenter, open-label, parallel-group study, consisting of a 20-week induction period, 96-week maintenance period, extension period, and long-term follow-up period. The study was conducted at 50 sites in the United States, Canada, Spain, France, and Germany. The first subject was screened in April 2014, and the last subject's Week 96 visit occurred in November 2016.

(51) The study was performed in accordance with the principles of the Declaration of Helsinki. Written informed consent was obtained from all participants, and the protocol was approved by the institutional review board of each study site (ClinicalTrials.gov identifier, NCT02120352).

(52) Study Participants

(53) Subjects who were HIV-1 positive, were ≥18 years old, and had no more than ten days of previous ART treatment, with screening HIV-1 RNA ≥1000 copies per mL and CD4+T-cell counts ≥200 cells/mm.sup.3, were eligible for inclusion. Key exclusion criteria included the presence of any major antiretroviral resistance—associated mutation, pregnancy, moderate or severe hepatic impairment, clinically relevant hepatitis, hepatitis B infection, laboratory values of clinical concern, creatinine clearance <50 mL/min, and a need for chronic anticoagulants.

(54) Study Treatments

(55) Eligible subjects received the induction period regimen of oral cabotegravir 30 mg+abacavir/lamivudine 600 mg/300 mg once daily for 20 weeks. Rilpivirine 25 mg once daily was added four weeks before randomization (Week—4 [Week 16 of the induction period]) and continued until the first injection visit (Day 1). Subjects who tolerated the induction period regimen and achieved plasma HIV-1 RNA <50 copies per mL at Week—4 were eligible to enter the maintenance period at Day 1. Eligible subjects were randomized 2:2:1 to receive intramuscular injections every four weeks (long-acting cabotegravir 400 mg+rilpivirine 600 mg; two 2-mL injections) or every eight weeks (long-acting cabotegravir 600 mg+rilpivirine 900 mg; two 3-mL injections), with a provision for a 14-day dosing window, or to continue receiving oral cabotegravir 30 mg+abacavir/lamivudine once daily for 96 weeks. Long-acting injectable formulations contained 200 mg per mL of cabotegravir and 300 mg per mL of rilpivirine for administration as two separate IM injections into the gluteus medius muscle at each dosing visit. Both four-week and eight-week dosing regimens had an initial loading dose of cabotegravir 800 mg (two 2-mL injections). Subject randomization, including stratification by HIV-1 RNA (≥or <50 copies per mL) before Week—8 (ie, 12 weeks of induction treatment), utilized the validated randomization software, RandALL (Version 2.10; GlaxoSmithKline, Research Triangle Park, N.C., USA).

(56) Study Assessments

(57) Planned analyses were conducted after all subjects had completed Weeks 32, 48, and 96 of the maintenance period (or discontinued earlier).

(58) Primary endpoints included the proportion of subjects in the maintenance-exposed population (which consisted of randomized subjects who received at least one dose of study drug during the maintenance period) with HIV-1 RNA <50 copies per mL at maintenance Week 32 (using the US Food and Drug Administration [FDA] snapshot algorithm), proportion of subjects with protocol-defined virologic failures, and incidence and severity of adverse events and laboratory abnormalities.

(59) Key secondary endpoints included the proportion of subjects with HIV-1 RNA <50 copies per mL at maintenance Week 48 and Week 96 (FDA snapshot algorithm), cabotegravir and rilpivirine plasma PK parameters during the maintenance period, and an assessment of regimen acceptability through subject-reported outcomes. Protocol-defined virologic failure following randomization was defined as having two consecutive plasma HIV-1 RNA measurements ≥200 copies per mL. Subjects who met the definition of protocol-defined virologic failure prior to receiving any cabotegravir+rilpivirine injections were discontinued from the study; those who had received one or more injections entered a 52-week long-term follow-up period.

(60) Adverse events were graded according to the Division of AIDS Table for Grading the Severity of Adverse and Pediatric Events (2009)..sup.17 Liver stopping criteria was met when alanine aminotransferase values met or exceeded the upper limit of normal by 8-fold, 5-fold for 14 days, or 3-fold with bilirubin ≥2x (>35% direct). Pharmacokinetic samples for cabotegravir and rilpivirine were collected at Day 1 and at Weeks 1, 4, 8, 12, 16, 20, 24, 25, 28, 32, 36, 40, 41, 44, and 48.

(61) Treatment satisfaction was measured using the HIV Treatment Satisfaction Questionnaire (HIVTSQ). The HIVTSQ status version (HIVTSQ[s]) was completed by subjects at Weeks—16 and —4 of the induction period and at Day 1 (long-acting predose) and Weeks 8, 32, 48, and 96 of the maintenance period or at withdrawal.

(62) Statistical Analyses

(63) For the primary analysis, comparability in antiviral response (HIV-1 RNA <50 copies per mL) was assessed at Week 32 (and repeated at Week 48) using a Bayesian probability model. The primary decision criterion for efficacy was a posterior probability >90% that the intramuscular response rate was inferior to the oral response rate by no more than 10%. To incorporate prior beliefs, a beta (23, 2) distribution was assumed for the oral group response rate (mean, 92%; 2.5th/97.5th percentile, 78%/99%) and a noninformative prior distribution was assumed for the intramuscular response rate. Sample sizes of 45 subjects in the oral cabotegravir+abacavir/lamivudine group and 90 subjects each in the intramuscular groups were chosen to ensure a high probability that a two-drug long-acting regimen with poor response relative to oral cabotegravir+abacavir/lamivudine once daily would be identified. With the chosen number of subjects per treatment group, and assuming true response rates of 82% for long-acting cabotegravir+rilpivirine versus 92% for oral cabotegravir+abacavir/lamivudine, there was a low probability of falsely concluding that long-acting cabotegravir+rilpivirine was comparable with oral cabotegravir+abacavir/lamivudine (simulated probability=0.064). Each long-acting regimen was evaluated against the oral cabotegravir+abacavir/lamivudine group in the primary analysis; comparability in antiviral response rates between the two intramuscular regimens was assessed as a prespecified key secondary comparison. Data for the maintenance and induction plus maintenance periods combined, respectively, are summarized by randomized arm using the maintenance-exposed population, while data for the induction period and study population characteristics are summarized using the intent-to-treat exposed population (subjects who received at least one study dose during the induction period [Week—20 to Day 1]).

(64) Change from baseline in CD4+ cell counts and subject-reported outcomes endpoints are summarized using observed data with no imputation for missing data. Laboratory abnormalities are presented as maintenance period treatment emergent, which refers to graded toxicities that developed or increased in intensity while on treatment in the maintenance period relative to the last recorded toxicity up to and including the date of the first dose of the maintenance period treatment.

(65) Pharmacokinetic plasma concentrations following long-acting cabotegravir+rilpivirine administration are summarized using evaluable data that met sample collection window criteria, excluding samples affected by dosing errors (wrong dose) or oral bridging. Sampling windows for intramuscular dosing were set relative to the previous injection as follows: ±0.5 hours for two-hour postdose samples; ±one day for one-week postinjection visits; ±two days for predose samples in the four-week group, Weeks 4 and 8 cabotegravir samples in the eight-week group, and midcycle concentrations four weeks postinjection in the eight-week group; and ±four days for predose samples in the eight-week group (except for Weeks 4 and 8 cabotegravir samples, as described earlier).

(66) RESULTS

(67) Study Subjects

(68) Of 386 subjects screened, 309 were enrolled in the study (FIG. 1). A majority of subjects (91%) were male; the average age of subjects was 36.6 years. Nearly one-quarter of subjects (23%) had a CD4+ cell count ≤350 cells/mm.sup.3, and 19% of subjects had baseline HIV-1 RNA ≥100,000 copies per mL. There were 288 subjects (93%) who completed the 20-week induction period (intent-to-treat exposed). A total of 21 subjects (7%) discontinued treatment during the induction period (withdrew consent, n=5; lack of efficacy, n=5; adverse event, n=3; met predefined liver chemistry stopping criteria, n=3; protocol deviation, n=2; lost to follow-up, n=2; investigator discretion, n=1). A total of 286 subjects qualified for and entered the maintenance period. Subjects were randomized (2:2:1) to receive intramuscular injections of long-acting cabotegravir+rilpivirine every four weeks (n=115) or every eight weeks (n=115) or continue the oral cabotegravir+abacavir/lamivudine regimen (n=56; Table 1).

(69) TABLE-US-00001 TABLE 1 Baseline Demographics and Disease Characteristics (Maintenance-Exposed Population) Subjects* Oral Cabotegravir Cabotegravir cabotegravir + LA + LA + abacavir/ rilpivirine LA rilpivirine LA lamivudine Q4W IM Q8W IM 30 mg Total (n = 115) (n = 115) (n = 56) (n = 286) Age, median (range) 36 (19-62) 35 (20-64) 35 (19-57) 35 (19-64) Sex, male, n (%) 109 (95) 107 (93) 46 (82) 262 (92) Ethnic origin, n (%) White 94 (82) 93 (81) 39 (70) 226 (79) African 12 (10) 17 (15) 15 (27) 44 (15) American/African heritage Other 9 (8) 5 (4) 2 (4) 16 (6) Baseline HIV-1 RNA Median (IQR) log.sub.10 4.46 (4.00-4.97) 4.42 (4.05-4.80) 4.29 (4.01-4.74) 4.39 (4.03-4.83) copies per mL ≥100,000 copies 28 (24) 16 (14) 7 (12) 51 (18) per mL, n (%) Baseline CD4+ cell count, 499 (359-624) 449 (343-618) 518 (417-630) 489 (359-624) median (IQR), cells/mm.sup.3 Hepatitis C coinfection, 5 (4) 3 (3) 2 (4) 10 (3) n (%) NRTI during induction, n (%) Abacavir/lamivudine 107 (93) 107 (93) 53 (95) 267 (93) Tenofovir/emtricitabine 8 (7) 8 (7) 3 (5) 19 (7) IM, intramuscular; IQR, interquartile range; LA, long acting; NRTI, nucleoside reverse transcriptase inhibitor; Q4W, every four weeks; Q8W, every eight weeks. *Data are number of subjects (%) unless otherwise indicated.

(70) In the maintenance period, 14 (12%), 5 (4%), and 9 (16%) subjects in the four-week, eight-week, and oral cabotegravir+abacavir/lamivudine groups, respectively, withdrew from the study (FIG. 1). The most common reasons for withdrawal during the maintenance period were adverse events (n=10 [3%]) and withdrawn consent (n=10 [3%]). Eight of the ten subjects who withdrew during the maintenance period because of adverse events were in the four-week group.

(71) Efficacy

(72) During the 20-week induction period, oral cabotegravir 30 mg+abacavir/lamivudine induced viral suppression (HIV-1 RNA <50 copies per mL) in 91% of subjects at Day 1 (Week 20 of induction period), with 90% of subjects achieving <50 copies per mL of HIV-1 RNA within the first eight weeks of treatment. One subject met the criteria for protocol-defined virologic failure (two consecutive plasma HIV-1 RNA measurements ≥200 copies per mL), as a result of poor medication compliance, without experiencing treatment-emergent resistance.

(73) Following randomization, the proportion of subjects who achieved the primary efficacy endpoint (plasma HIV-1 RNA <50 copies per mL; FDA snapshot algorithm) at Week 32 was 94% for the four-week group, 95% for the eight-week group, and 91% for the oral cabotegravir+abacavir/lamivudine group (FIG. 2; Table S1), meeting prespecified criteria for claiming comparability (posterior probability of noninferiority >90%, Table S2).

(74) TABLE-US-00002 TABLE S1 Snapshot Outcomes (HIV-1 RNA <50 copies per mL) in the Maintenance-Exposed Population Subjects, n (%) Cabotegravir Cabotegravir Oral cabotegravir + LA + LA + abacavir/ rilpivirine LA rilpivirine LA lamivudine Q4W IM Q8W IM 30 mg (n = 115) (n = 115) (n = 56) Week 32 Virologic response 108 (94) 109 (95) 51 (91) Difference vs oral 2.8 (−5.8, 11.5) 3.7 (−4.8, 12.2) cabotegravir, % (95% CI) Virologic nonresponse 1 (<1) 5 (4) 2 (4) Data in window not <50 1 (<1) 3 (3) 1 (2) copies per mL* Discontinued for lack of 0 1 (<1) 1 (2) efficacy Discontinued for other reason 0 1 (<1) 0 while not <50 copies per mL No virologic data in window 6 (5) 1 (<1) 3 (5) Discontinued due to adverse 4 (3) 0 1 (2) event or death Discontinued for other 2 (2) 1 (<1) 2 (4) reasons Week 48 Virologic response 105 (91) 106 (92) 50 (89) Difference vs oral 2.0 (−7.6, 11.6) 2.9 (−6.6, 12.4) cabotegravir, % (95% CI) Virologic nonresponse 1 (<1) 8 (7) 1 (2) Data in window not <50 1 (<1) 6 (5) 0 copies per ml.sup.† Discontinued for lack of 0 1 (<1) 1 (2) efficacy Discontinued for other reason 0 1 (<1) 0 while not <50 copies per mL No virologic data in window 9 (8) 1 (<1) 5 (9) Discontinued due to adverse 6 (5) 0 2 (4) event or death Discontinued for other 3 (3) 1 (<1) 3 (5) reasons Week 96 Virologic response 100 (87) 108 (94) 47 (84) Difference vs oral 3.0 (−8.4, 14.4) 10.0 (−0.6, 20.5) cabotegravir, % (95% CI) Virologic nonresponse 0 5 (4) 1 (2) Data in window not <50 0 2 (2) 0 copies per mL.sup.‡ Discontinued for lack of 0 1 (<1) 1 (2) efficacy Discontinued for other reason 0 2 (2).sup.II 0 while not <50 copies per mL No virologic data in window 15 (13) 2 (2) 8 (14) Discontinued due to adverse 9 (8) 1 (<1) 2 (4) event or death.sup.§ Discontinued for other 5 (4) 1 (<1) 0 reasons Missing data during window 1 (<1) 0 0 but on study DILI, drug-induced liver injury; HCV, hepatitis C; IM, intramuscular; ISR, injection-site reaction; LA, long acting; Q4W, every four weeks; Q8W, every eight weeks. *Week 32 HIV-1 RNA, Q4W: 70 copies per mL; oral cabotegravir: 243 copies per mL; Q8W: 53 copies per mL, 70 copies per mL, 91 copies per mL. .sup.†Week 48 HIV-1 RNA, Q4W: 59 copies per mL; Q8W: 50 copies per mL, 57 copies per mL, 97 copies per mL, 110 copies per mL, 135 copies per mL, 463/205 copies per mL. .sup.‡Week 96 HIV-1 RNA, 87 copies per mL, 118 copies per mL. .sup.§Q8W: ISR/chills/body pain (n = 1); Q4W: HCV (n = 1), rash (n = 1), depressive reaction (n = 1), psychotic state (n = 1), Churg-Strauss vasculitis (n = 1), epilepsy (death; n = 1), mesenteric vein thrombosis (n = 1), QT prolongation/sinus tachycardia (n = 1), met liver stopping criteria (n = 1); Oral: acute HCV (n = 1), DILI (n = 1). .sup.IIIncludes one subject who withdrew consent due to intolerance of injections.

(75) TABLE-US-00003 TABLE S2 Probabilities of Noninferiority From Primary Bayesian Analysis* Comparison of Estimated posterior Estimated posterior treatment probability given Week 32 probability given Week 48 groups.sup.† response rates, %.sup.† response rates, %.sup.† Q4W vs oral 99.9 99.4 Q8W vs oral 100 99.7 Q8W vs Q4W 99.9 99.8 IM, intramuscular; P, probability; Q4W, every four weeks; Q8W, every eight weeks. *Posterior probability >90% was the prespecified margin to conclude comparability in response rates (HIV-1 RNA concentration <50 copies per mL by FDA snapshot algorithm). For comparisons between IM and oral treatment groups, comparability criterion was P.sub.IM > P.sub.oral − 10%; for comparison between the Q8W and Q4W treatment groups, comparability criterion was |P.sub.Q8W − P.sub.Q4W| < 10%. .sup.†Rates assumed to follow noninformative beta (1, 1) prior distributions for P.sub.Q8W and P.sub.Q8W and informative beta (23, 2) prior distribution for P.sub.oral.

(76) Treatment differences at Week 32 for each group receiving long-acting injections compared with daily oral cabotegravir+abacavir/lamivudine were 3.7% (95% CI, −4.8 to 12.2) for the four-week group and 2.8% (95% CI, −5.8 to 11.5) for the eight-week group. At Week 48, comparability between regimens was confirmed (Table S2), with virologic suppression achieved in 91%, 92%, and 89% of subjects in the four-week, eight-week, and oral cabotegravir+abacavir/lamivudine groups, respectively, (FIG. 2; Table S1). Through 96 weeks of maintenance treatment, 87%, 94% and 84% of subjects in the four-week, eight-week and oral cabotegravir+abacavir/lamivudine groups maintained virologic suppression, respectively (FIG. 2; Table S1). Virologic nonresponse, as defined by the FDA snapshot algorithm, occurred in six subjects (eight-week group, n=5; oral cabotegravir+abacavir/lamivudine group, n=1; FIG. 2). Through 96 weeks, no subjects in the four-week group failed for virologic reasons. In comparison, at Week 48, ten subjects met virologic nonresponse criteria (four-week group, n=1; eight-week group, n=8; oral cabotegravir+abacavir/lamivudine group, n=1). For the eight-week group, four subjects with virologic nonresponse at Week 48 (HIV-1 RNA >50 copies per mL) were resuppressed with HIV-1 RNA <50 copies per mL at Week 96 without a change in therapy. Of the five eight-week subjects with virologic nonresponse at Week 96, two had HIV-1 RNA ≥50 copies per mL at Week 96 (one of which had HIV-1 ≥50 copies per mL at Week 48), one discontinued due to protocol-defined virologic failure at Week 4, one withdrew consent due to intolerability of injections at Week 8, and one withdrew due to investigator discretion at Week 48 while not suppressed (and subsequently confirmed as a protocol-defined virologic failure). One of the two subjects with HIV-1 RNA >50 copies per mL at Week 96 remained on the study and had HIV-1 levels <50 copies per mL at the next scheduled visit. The four-week group subject with virologic nonresponse at Week 48 (HIV-1 RNA, 59 copies per mL) remained on the study beyond Week 48 and had subsequent viral resuppression with HIV-1 <50 copies per mL at Week 96. The virologic nonresponder in the oral cabotegravir+abacavir/lamivudine group discontinued as a result of protocol-defined virologic failure at Week 8.

(77) Three randomized subjects (eight-week group, n=2 (Week 4 and Week 48); oral cabotegravir+abacavir/lamivudine group, n=1 (Week 8) met the criteria for protocol-defined virologic failure through Week 96. Viral genotyping analysis for the subject in the oral cabotegravir+abacavir/lamivudine group demonstrated no treatment-emergent resistance mutations in the genes encoding viral reverse transcriptase, protease, or integrase. Of the two subjects in the eight-week group, a mixture emerged for one at integrase codon 269 (R269R/G), which did not decrease cabotegravir susceptibility. The second subject harbored virus with treatment-emergent reverse transcriptase mutations K103N, E138G, and K238T, with phenotypic resistance to efavirenz, rilpivirine, and nevirapine, and an integrase mutation Q148R, with phenotypic resistance to raltegravir, elvitegravir, and cabotegravir, while remaining sensitive to dolutegravir.

(78) CD4+ cell counts increased from the beginning of the induction period by median (interquartile range) of 226 (145-393) cells/mm.sup.3, 239 (111-359) cells/mm.sup.3, and 317 (214-505) cells/mm.sup.3 in subjects in the four-week (n=100), eight-week (n=109), and oral cabotegravir+abacavir/lamivudine (n=47) groups, respectively, at Week 96 of the maintenance period.

(79) Safety

(80) Adverse Events

(81) During the induction and maintenance period, in the maintenance-exposed population, total adverse events of any grade and attribution occurred in 100%, 100%, and 96% of subjects in the four-week, eight-week, and oral cabotegravir+abacavir/lamivudine groups, respectively (Table 2).

(82) TABLE-US-00004 TABLE 2 Summary of Total Adverse Events and Treatment-Related Adverse Events Through Week 96 in the Safety Maintenance Population* Subjects, n (%) Oral cabotegravir + Cabotegravir LA + Cabotegravir LA + abacavir/ rilpivirine LA Q4W rilpivirine LA Q8W lamivudine IM IM 30 mg (n = 115) (n = 115) (n = 56) Total adverse events Grade Grade Grade Grade Grade Grade 1-4.sup.† 3-4.sup.§ 1-4.sup.† 3-4.sup.§ 1-4.sup.† 3-4.sup.§ Any event 115 (100) 21 (18) 115 (100) 24 (21) 54 (96) 7 (13) Injection-site pain 112 (97)  6 (5) 110 (96)  8 (7)  0 0 Nasopharyngitis  39 (34)  0  35 (30)  0 22 (39) 0 Injection-site nodule  36 (31)  1 (<1)  29 (25)  1 (<1)  0 0 Injection-site swelling  34 (30)  0  29 (25)  1 (<1)  0 0 Diarrhoea  32 (28)  0  27 (23)  0 11(20) 0 Injection-site pruritus  33 (29)  0  25 (22)  0  0 0 Headache  27 (23)  0  29 (25)  1 (<1) 14 (25) 1 (2) Injection-site induration  25 (22)  0  29 (25)  1 (<1)  0 0 Injection-site warmth  21 (18)  0  23 (20)  1 (<1)  0 0 Upper respiratory tract  13 (11)  0  23 (20)  0  7 (13) 0 infection Injection-site bruising  14 (12)  0  20 (17)  0  0 0 Nausea  18 (16)  0  16 (14)  0  9 (16) 0 Injection-site erythema  19 (17)  0  13 (11)  1 (<1)  0 0 Pyrexia  16 (14)  0  16 (14)  0  3 (5) 0 Gastroenteritis  15 (13)  0  14 (12)  0  6 (11) 1 (2) Fatigue  14 (12)  0  14 (12)  0  4 (7) 0 Syphilis  11(10)  0  17 (15)  0  6 (11) 0 Back pain  13 (11)  0  15 (13)  0 10 (18) 0 Insomnia  13 (11)  0  12 (10)  0  4 (7) 0 Bronchitis  12 (10)  1 (<1)  12 (10)  0  6 (11) 0 Cough  13 (11)  0  11(10)  0  7 (13) 0 Influenza  16 (14)  0  6 (5)  0  2 (4) 0 Arthralgia  10 (9)  0  12 (10)  0  4 (7) 0 Anogenital warts  11 (10)  0  9 (8)  0  2 (4) 0 Pharyngitis  8 (7)  0  12 (10)  0  5 (9) 0 Respiratory tract infection  11 (10)  0  6 (5)  0  6 (11) 0 Asthenia  10 (9)  0  7 (6)  0  9 (16) 0 Treatment-related adverse events Grade Grade Grade Grade Grade Grade 1-4.sup.‡ 3-4.sup.§ 1-4.sup.‡ 3-4.sup.§ 1-4.sup.‡ 3-4.sup.§ Any event 113 (98) 10 (9) 110 (96) 10 (9) 21 (38) 1 (2) Injection-site pain 112 (97)  6 (5) 109 (95)  8 (7)  0 0 Injection-site nodule  35 (30)  1 (<1)  29 (25)  1 (<1)  0 0 Injection-site swelling  34 (30)  0  29 (25)  1 (<1)  0 0 Injection-site pruritus  33 (29)  0  24 (21)  0  0 0 Injection site induration  25 (22)  0  28 (24)  1 (<1)  0 0 Injection-site warmth  21 (18)  0  22 (19)  1 (<1)  0 0 Injection-site bruising  14 (12)  0  19 (17)  0  0 0 Injection-site erythema  19 (17)  0  12 (10)  1 (<1)  0 0 Nausea  12 (10)  0  8 (7)  0  5 (9) 0 Headache  7 (6)  0  6 (5)  0  4 (7) 0 Pyrexia  7 (6)  0  5 (4)  0  0 0 Injection site discolouration  6 (5)  0  3 (3)  0  0 0 Dyspepsia  6 (5)  0  1 (<1)  0  1 (2) 0 Asthenia  3 (3)  0  2 (2)  0  3 (5) 0 IM, intramuscular; LA, long acting; Q4W, every four weeks; Q8W, every eight weeks. *Includes all post-baseline induction period and maintenance period adverse events, as well as long-term follow-up period adverse events for subjects withdrawing from intramuscular dosing that occurred within 35/63 days (Q4W/Q8W) of the last maintenance period IM injection until up to and including the start date of the long-term follow-up period oral highly active antiretroviral treatment. .sup.†≥10%in any treatment group. .sup.‡5% in any treatment group. .sup.§Includes only events listed in the grade 1-4 column; other grade 3-4 events that did not meet the 5% or 10% cut-off for the grade 1-4 column are not shown.

(83) Injection-site pain, the most common injection-site reaction (ISR), was the most frequently reported adverse event in the intramuscular groups (four-week group, 97%; eight-week group, 96%). Most ISRs were mild (84%) or moderate (15%) in intensity, with median symptom duration of three days (Table S3).

(84) TABLE-US-00005 TABLE S3 Summary of Injection-Site Reactions in Q4W and Q8W Cabotegravir Plus Rilpivirine IM Treatment Groups Subjects, n (%) Cabotegravir Cabotegravir Cabotegravir LA + LA + LA + rilpivirine LA rilpivirine LA rilpivirine LA Q4W IM Q8W IM IM subtotal (n = 115) (n = 115) (n = 230) Number of injections 5419 3160 8579 Number of ISR events 2435 1925 4360 Grades, n (%) Grade 1 2105 (86) 1543 (80) 3648 (84) Grade 2 314 (13) 359 (19) 673 (15) Grade 3 14 (<1) 16 (<1) 30 (<1) Grade 4   0   0   0 Duration, days  ≤7 2172 (89) 1718 (89) 3890 (89) 8-14 162 (7) 133 (7) 295 (7) >14 78 (3) 51 (3) 129 (3) Median (range) 3.0 (1-138) 3.0 (1-176) 3.0 (1-176) IM, intramuscular; ISR, injection-site reaction; LA, long acting; Q4W, every four weeks; Q8W, every eight weeks.

(85) The most commonly reported non-ISR adverse events were nasopharyngitis (four-week group, 34%; eight-week group, 30%; oral cabotegravir+abacavir/lamivudine groups, 39%), diarrhea (four-week group, 28%; eight-week group, 23%; oral cabotegravir+abacavir/lamivudine group, 20%), and headache (four-week group, 23%; eight-week group, 25%; oral cabotegravir+abacavir/lamivudine group, 25%). Serious adverse events occurred in 11% of subjects in each of the intramuscular treatment groups and 16% of subjects in the oral cabotegravir+abacavir/lamivudine group, only one of which was drug related (migraine, which occurred in the initial oral induction period of the study). During the maintenance period, serious adverse events occurred in 10% of subjects in each intramuscular group compared with 13% in the oral cabotegravir+abacavir/lamivudine group. However, none was considered to be related to study treatment. Eleven subjects (4%) developed an adverse event during the maintenance period, which led to withdrawal: eight subjects (7%) in the four-week group, two subjects in the eight-week group (2%), and one subject in the oral cabotegravir+abacavir/lamivudine group (2%). Two subjects (both in the eight-week group) had ISRs leading to withdrawal within eight weeks of initiating dosing. Two deaths occurred during the study: one resulted from a motor vehicle accident that occurred in the initial oral induction period of the study, and the second occurred after an epileptic seizure in a subject in the four-week intramuscular treatment group who had received 48 weeks of cabotegravir and 32 weeks of rilpivirine treatment. Neither death was considered to be related to study treatment.

(86) Laboratory Abnormalities

(87) Grade≥3 maintenance period treatment-emergent laboratory abnormalities occurred in 29% of subjects in the four-week group, 19% of subjects in the eight-week group, and 21% of subjects in the oral cabotegravir+abacavir/lamivudine group. Grade ≥3 maintenance period treatment-emergent ALT elevations occurred in 3% of subjects in both four-week and eight-week intramuscular dosing, and in 5% of subjects receiving oral cabotegravir+abacavir/lamivudine. Among subjects meeting pre-defined liver stopping criteria, possible drug-induced liver injury occurred in two subjects (both treated with oral cabotegravir+abacavir/lamivudine; one during the induction period [before randomization] and one during the maintenance period). In both cases, liver chemistry abnormalities resolved following treatment discontinuation, and the subjects remained clinically asymptomatic.

(88) Pharmacokinetics

(89) At Week 48, cabotegravir geometric mean trough concentrations (C.sub.0; 95% confidence interval [CI]) were 2.58 μg/mL (2.4 to 2.8 μg/mL), 1.46 μg/mL (1.3 to 1.6 μg/mL), and 4.47 μg/mL (3.9 to 5.2 μg/mL) for the four-week, eight-week, and oral cabotegravir+abacavir/lamivudine groups, respectively, which were 16-fold, 9-fold, and 27-fold greater than the in vitro protein-adjusted 90% inhibitory concentration (PA-IC.sub.90) of 0.166 μg/mL against wild-type HIV-1. For rilpivirine, Week 48 geometric mean C.sub.0 (95% CI) values were 94.64 ng/mL (86.6 to 103.4 ng/mL) and 64.48 ng/mL (60.0 to 69.3 ng/mL) for the four-week and eight-week regimens, respectively (FIG. 3), which were 8-fold and 5-fold greater than in vitro PA-IC.sub.90 of 12 ng/mL against wild-type HIV-1. Accumulation of rilpivirine was observed through 48 weeks of dosing, with the lowest rilpivirine trough concentrations observed after initial intramuscular injections in both arms (FIG. 3). No relationship was observed between cabotegravir concentrations and virologic nonresponse at Week 48. In seven of the nine subjects in the eight-week regimen with virologic nonresponse at Week 48 (FDA snapshot algorithm), rilpivirine trough concentrations at Week 48 (or last available trough concentration before Week 48) were in the lowest 25th quartile among all rilpivirine samples, whereas cabotegravir trough concentrations were distributed throughout the quartile ranges. Of the two subjects in the eight-week regimen with protocol-defined virologic failure during the maintenance period through Week 48, one subject had nonquantifiable rilpivirine concentration four weeks post injection (indicative of accidental partial intravenous administration) without treatment-emergent resistance, and there was no clear correlation between cabotegravir or rilpivirine concentrations at the time of viral rebound with the other subject. Sparse PK sampling obtained after Week 48 and through Week 96 was not assayed as a matter of routine and therefore is not reported.

(90) Subject-Reported Health Outcomes

(91) High levels of treatment satisfaction were observed across all treatment groups (FIG. 4). At Week 96, subjects reported very high levels of satisfaction with all three arms, four-week, eight-week, and oral cabotegravir+abacavir/lamivudine, via the HIVTSQ(s), with 95% of these subjects selecting a score of 5 or 6 on a 6-point satisfaction scale. A similar percentage of subjects in each of the intramuscular groups (≥99%) reported they would be highly satisfied to continue their current long-acting regimen, while a lower percentage, 78%, would elect to continue on oral dosing. Subjects who discontinued for any reason before Week 96 did not complete the questionnaire at this time point, introducing a small degree of selection bias in these results.

(92) Discussion

(93) LATTE-2 was the first study to analyze the efficacy and safety of a fully injectable two-drug long-acting ART regimen in subjects with HIV-1 infection. Both the long-acting injectable four-week and eight-week regimens maintained virologic suppression at rates comparable to oral daily three-drug ART, with two protocol-defined virologic failures occurring among the 230 subjects who received long-acting therapy during the 96-week maintenance period. The long-acting cabotegravir+rilpivirine regimens were generally well tolerated, with no drug-related serious adverse events and few adverse event-related withdrawals. While injection-site reactions were common, they were transient in nature, mild or moderate in severity, and did not appear to compromise high levels of subject-reported satisfaction. The long-term acceptability of administering chronic IM injections to patients was also demonstrated in LATTE-2, with very few withdrawals resulting from injection-site reactions, two subjects (<1%) through 96 weeks.

(94) Treatment with the four-week and eight-week regimens maintained virologic suppression in 87% and 94% of subjects, respectively, compared with 84% of subjects treated with oral cabotegravir+abacavir/lamivudine. These proportions are consistent with multiple other studies examining efficacy of oral switch regimens in subjects with viral suppression on an initial regimen..sup.18-20 Few virologic nonresponders, as determined by the rigorous FDA snapshot algorithm, were observed with either long-acting regimen in the LATTE-2 study, with a higher rate of nonresponse observed in the eight-week group (n=5 [4%]) than in the four-week group (n=0). Only two subjects in the eight-week group, and none in the four-week group, met the criteria for protocol-defined virologic failure. One participant had emergence of well-described NNRTI and INSTI mutations that conferred reduced susceptibility. No NNRTI mutations were observed in the second participant, who had undetectable rilpivirine concentrations, and a mixture emerged at an integrase codon not associated with INSTI resistance.sup.21 with no change in cabotegravir susceptibility. The efficacy profile and lack of virologic failures in the four-week regimen has led to the selection of an optimized four-week dosing regimen in the ongoing phase III clinical program, while the eight-week regimen remains under longer-term evaluation within the LATTE-2 study.

(95) One of the potential challenges of injectable long-acting agents is the potential for serious systemic adverse events without the possibility to curtail exposure to the agent. The LATTE-2 study implemented a period of cabotegravir and rilpivirine oral dosing, prior to long-acting cabotegravir or rilpivirine dosing, as a strategy to identify any early-onset acute safety issues before administering the long-acting injectable formulations. No drug hypersensitivity reactions were observed in the LATTE-2 study. An oral lead-in strategy has been implemented in phase III HIV treatment studies, to determine if there is a need for continued use of the oral lead-in. Injection-site reactions were common with intramuscular treatment, but most were short in duration and mild in severity, and rarely led to treatment discontinuation, consistent with previously reported studies with healthy adults. (Spreen W, Williams P, Margolis D, et al. Pharmacokinetics, safety, and tolerability with repeat doses of GSK1265744 and rilpivirine (TMC278) long-acting nanosuspensions in healthy adults. J Acquir Immune Defic Syndr2014; 67(5): 487-92).

(96) The high satisfaction reported by subjects in the LATTE-2 study suggests that long-acting regimens may provide a preferential alternative to oral daily therapy for HIV-infected patients..sup.23 The acceptability and tolerability of injectable dosing options will be an important component of long-term treatment success, and a high degree of treatment satisfaction will avail this option for patients burdened by life-long daily oral medication compliance.

(97) Results from the LATTE-2 study demonstrate high rates of efficacy and an acceptable safety profile for long-acting cabotegravir+rilpivirine as injectable two-drug maintenance therapy in virologically suppressed subjects with HIV. These results support the further evaluation of monthly long-acting cabotegravir+rilpivirine as the first ever injectable ART regimen.