For virologically suppressed adults with HIV-1. See Full Indication.

Clinical Trials for CABENUVA

Two Phase 3 clinical trials—ATLAS and FLAIR—evaluated once-monthly long-acting CABENUVA versus continuing daily oral antiretroviral (ARV) therapy* for the treatment of HIV-1 infection in adult patients who were virologically suppressed.1,2 The objective of the two studies was to establish non-inferiority of monthly CABENUVA to continuing daily oral maintenance therapy.2 Week 48 efficacy data for both trials are presented below, as well as additional Week 96 results from FLAIR.

*In ATLAS, daily oral ARV therapy consisted of 2 NRTIs + a third agent (INSTI, NNRTI, or PI).3 In FLAIR, daily oral ARV therapy included ABC/DTG/3TC (or DTG + 2 NRTIs if HLA-B*5701 positive).4

3TC=lamivudine; ABC=abacavir; DTG=dolutegravir; HLA-B=human leukocyte antigen complex B; INSTI=integrase strand transfer inhibitor; NNRTI=non-nucleoside reverse transcriptase inhibitor; NRTI=nucleoside reverse transcriptase inhibitor; PI=protease inhibitor.

ATLAS & FLAIR Trial Designs for CABENUVA

CABENUVA was studied in two robust, Phase 3, non-inferiority trials

ATLAS and FLAIR were clinical trials designed to evaluate the efficacy and safety of long-acting CABENUVA in adult (≥18 years) patients with HIV-1 who were virologically suppressed at time of randomization.1,2

The primary endpoint for both studies was the proportion of patients with HIV-1 RNA ≥50 copies/mL at Week 48.3,4 CABENUVA was shown to be non-inferior to continuing daily oral regimen in both trials.2

Selected Exclusion Criteria:

  • Patients with hepatitis B virus infection at screening
  • Patients with moderate to severe hepatic impairment
  • Women who are pregnant, breastfeeding, or plan to become pregnant or breastfeed during the study

CI=confidence interval.

ATLAS & FLAIR: Phase 3, International, open-label, randomized trials

ATLAS TRIAL DESIGN1,3

FLAIR TRIAL DESIGN1-3

FLAIR TRIAL DESIGN1,4

ATLAS trial design

*≥18 years of age.3,4 HIV-1 RNA <50 copies/mL.1 Third agent included INSTI, NNRTI, or Pl.3 §Oral lead-in regimen consisted of 30-mg cabotegravir and 25-mg rilpivirine once daily for at least 1 month.1 ||On the last day of the oral lead-in, patients received initation injections of cabotegravir and rilpivirine followed by continuation injections 1 month later and then monthly thereafter.1 Defined as ≤10 days of prior therapy with any ARV following a diagnosis of HIV-1 infection. Screening HIV-1 RNA ≥1000 copies/mL.4 #Or DTG + 2 NRTIs if HLA-B*5701-positive.1 **Patients required to have HIV-1 RNA <50 copies/mL by 4 weeks prior to randomization.4

LA=long-acting; W=week.

*≥18 years of age.3,4 HIV-1 RNA <50 copies/mL.1 Third agent included INSTI, NNRTI, or Pl.3 §Oral lead-in regimen consisted of 30-mg cabotegravir and 25-mg rilpivirine once daily for at least 1 month.1 ||On the last day of the oral lead-in, patients received initation injections of cabotegravir and rilpivirine followed by continuation injections 1 month later and then monthly thereafter.1 Defined as ≤10 days of prior therapy with any ARV following a diagnosis of HIV-1 infection. Screening HIV-1 RNA ≥1000 copies/mL.4 #Or DTG + 2 NRTIs if HLA-B*5701-positive.4 **Patients required to have HIV-1 RNA <50 copies/mL by 4 weeks prior to randomization.4

LA=long-acting; W=week.

ATLAS and FLAIR were designed to evaluate the efficacy and safety of long-acting CABENUVA in a range of virologically suppressed adult patients with HIV-1

BASELINE PATIENT CHARACTERISTICS BY TRIAL1,3,4

FLAIR TRIAL DESIGN1-3
FLAIR TRIAL DESIGN1-3

INSTI, NNRTI, or PI.3 #Or DTG + 2 NRTIs if HLA-B*5701-positive.4 ††Two patients in FLAIR who were male at birth identified as transgender at enrollment.5 ‡‡Baseline race information was missing for 2 patients in the oral comparator arm in FLAIR.4 §§Baseline HIV-1 RNA measured prior to induction with abacavir/dolutegravir/lamivudine.5  ‖‖For FLAIR, baseline was considered as Day 1.4 ¶¶Patients in FLAIR had no previous ARV exposure prior to induction with abacavir/dolutegravir/lamivudine.4 ##Patients with hepatitis B co-infection were excluded from the trials.3,4

IQR=interquartile range.

INSTI, NNRTI, or PI.3 #Or DTG + 2 NRTIs if HLA-B*5701-positive.4 ††Patients with hepatitis B co-infection were excluded from the trials.3,4 ‡‡Two patients in FLAIR who were male at birth identified as transgender at enrollment.5 §§Baseline race information was missing for 2 patients in the oral comparator arm in FLAIR.4 ‖‖Baseline HIV-1 RNA measured prior to induction with abacavir/dolutegravir/lamivudine.5 ¶¶For FLAIR, baseline was considered as Day 1.4 ##Patients in FLAIR had no previous ARV exposure prior to induction with abacavir/dolutegravir/lamivudine.4

IQR=interquartile range.

Efficacy of CABENUVA

CABENUVA was proven as effective as continuing a daily oral regimen*

The efficacy and safety of CABENUVA were evaluated in 2, Phase 3 clinical trials (ATLAS and FLAIR). CABENUVA was found to be non-inferior to daily oral comparator (upper bound of 95% CI for the treatment difference was <4%) at Week 48 for the primary endpoint (HIV-1 RNA ≥50 copies/mL).2

POOLED ANALYSIS: ITT-E FDA SNAPSHOT VIROLOGIC OUTCOMES AT WEEK 482

CABENUVA efficacy data

*In ATLAS, the oral comparator consisted of 2 NRTIs + a third agent (INSTI, NNRTI, or PI). In FLAIR, the oral comparator consisted of ABC/DTG/3TC (or DTG + 2 NRTIs if HLA-B*5701-positive).3,4

FDA=Food and Drug Administration; ITT-E=intent-to-treat efficacy.

  • No virologic data at Week 48: 5% (30/591) CABENUVA; 4% (23/591) oral comparator2

FLAIR 96 Weeks: Efficacy data

Proven as effective as continuing ABC/DTG/3TC through Week 96

FLAIR: ITT-E FDA SNAPSHOT VIROLOGIC OUTCOMES AT WEEK 966

CABENUVA found to be non-inferior to ABC/DTG/3TC (upper bound of the 95% CI for the treatment difference was <6%)6

Pooled analysis of incidence of injection site reactions from  Week 4 to Week 48
flair mobile
  • No virologic data at Week 96: 10% (29/283) CABENUVA; 7% (21/283) ABC/DTG/3TC6†

Or DTG plus 2 NRTIs if HLA-B*5701-positive.1

Confirmed Virologic Failure

Similar incidence of confirmed virologic failure across both arms

POOLED ANALYSIS: CONFIRMED VIROLOGIC FAILURE THROUGH WEEK 481,2,5

confirmed virologic
confirmed virologic
  • Confirmed virologic failure is defined as 2 consecutive plasma HIV-1 RNA ≥200 copies/mL3,4

*A 7th confirmed virologic failure (CVF) was a patient in FLAIR who did not receive an injection dose of CABENUVA.4 In ATLAS, the oral comparator consisted of 2 NRTIs + a third agent (INSTI, NNRTI, or PI). In FLAIR, the oral comparator consisted of ABC/DTG/3TC (or DTG + 2 NRTIs if HLA-B*5701-positive).3,4

FLAIR 96 Weeks: CVF data

FLAIR: CONFIRMED VIROLOGIC FAILURE BETWEEN WEEK 48 AND WEEK 966

Pooled analysis of incidence of injection site reactions from  Week 4 to Week 48
flair
  • A total of 3 CVFs|| were reported through Week 96 in the CABENUVA arm vs 4 CVFs in the ABC/DTG/3TC arm6
  • Three patients in the CABENUVA arm and 0 patients in the ABC/DTG/3TC arm developed treatment-emergent genotypic resistance through Week 966

Or DTG plus 2 NRTIs if HLA-B*5701-positive.4 §CVF occurred at Week 64 with no resistance mutations.6   ||One additional CVF was a patient who did not receive an injection dose of CABENUVA.6

Adverse Reactions

Majority of adverse reactions were Grades 1-2

Injection site reactions (ISRs) were the most common side effect associated with CABENUVA, the majority of which were mild to moderate.1

POOLED ANALYSIS: ADVERSE REACTIONS* (ALL GRADES) REPORTED IN ≥2% OF PATIENTS THROUGH WEEK 481,5

Pooled analysis of incidence of injection site reactions from  Week 4 to Week 48

*Adverse reactions defined as “treatment-related” as assessed by the investigator.1 Grade 1=mild; Grade 2=moderate; Grade 3=severe; Grade 4=potentially life-threatening; Grade 5=death.7 Pyrexia: includes pyrexia, feeling hot, chills, influenza-like illness, body temperature increased.1 §Fatigue: includes fatigue, malaise, asthenia.1 Musculoskeletal pain: includes musculoskeletal pain, musculoskeletal discomfort, back pain, myalgia, pain in extremity.1 Sleep disorders: includes insomnia, poor quality sleep, somnolence.1 #Rash: includes erythema, pruritis, pruritis generalized, purpura, rash-erythematous, generalized, macular.1

AE=adverse event.

  • 4% of patients experienced Grade 3 ISRs, and no patients experienced Grades 4-5 ISRs1
  • Non-injection site-related AEs leading to discontinuation and occurring in >1 patient were headache, diarrhea, hepatitis A, and acute hepatitis B (all with an incidence ≤1%)1
Risks and Side Effects

FLAIR 96 Weeks: Safety data

Adverse reactions were similar at Week 48 and Week 966

SAFETY OVERVIEW 6

Pooled analysis of incidence of injection site reactions from  Week 4 to Week 48

**Or DTG plus 2 NRTIs if HLA-B*5701-positive.1††Includes 1 subject at Week-48 data analysis who is not present at Week-96 data analysis.1 ‡‡2 pyrexia, 2 fatigue, 2 dizziness, 1 headache/nausea, 1 presyncope, 1 depressed mood, 1 pyrexia/chills, 1 chronic sinusitis/chronic tonsillitis, 1 back pain nasopharyngitis, 1 musculoskeletal pain, 1 anxiety, 1 influenza-like illness, 1 asthenia/depressed mood.1 §§1 diarrhea/abdominal pain/nasopharyngitis/eye pain, 1 insomnia, 1 abnormal dreams, 1 poor quality sleep, 1 nausea, 1 hypercholesterolemia/vitamin D decreased.4  ‖‖Grade 3=severe; Grade 4=potentially life-threatening.7

AE=adverse event; ISR=injection site reaction; SAE=serious adverse event.

Safety Overview

**Or DTG plus 2 NRTIs if HLA-B*5701-positive.1 ††Includes 1 subject at Week-48 data analysis who is not present at Week 96 data analysis.1 ‡‡Grade 3=severe; Grade 4=potentially life-threatening.7 §§2 pyrexia, 2 fatigue, 2 dizziness, 1 headache/nausea, 1 presyncope, 1 depressed mood, 1 pyrexia/chills, 1 chronic sinusitis/chronic tonsillitis, 1 back pain nasopharyngitis, 1 musculoskeletal pain, 1 anxiety, 1 influenza-like illness, 1 asthenia/depressed mood.1 ‖‖1 diarrhea/abdominal pain/nasopharyngitis/eye pain, 1 insomnia, 1 abnormal dreams, 1 poor quality sleep, 1 nausea, 1 hypercholesterolemia/vitamin D decreased.4

AE=adverse event; ISR=injection site reaction; SAE=serious adverse event.

No new safety signals identified through Week 96

INJECTION SITE REACTIONS

88% of patients experienced at least one ISR through Week 966

  • The majority (3082/3100, 99%) of ISRs were Grades 1-2 and most (89%) resolved within ≤7 days (median duration of 3 days [interquartile range, 2 to 4])6
  • Between Week 48 and Week 96, 1 patient withdrew due to an ISR6
  • An additional 3 patients receiving CABENUVA withdrew from the study through Week 96; the primary reason for discontinuation given was "withdrew consent due to intolerability of injections"6

ADVERSE REACTIONS* (ALL GRADES, EXCLUDING LOCAL ISRs) REPORTED IN ≥3% OF PATIENTS IN EITHER ARM THROUGH WEEK 966

Adverse reactions chart
Adverse Reactions

*Adverse reactions defined as “treatment-related” as assessed by the investigator.1 **Or DTG plus 2 NRTIs if HLA-B*5701-positive.1 ¶¶Between Weeks 48 and 96, discontinuations occurred due to: hepatitis A (3); acute hepatitis B (2); depression (2); and 1 each acute hepatitis C, hepatitis C, secondary syphilis, discomfort, diarrhea, vomiting, aminotransferase increased, and adenocarcinoma of colon; a participant could have more than one reason for withdrawal.

Patient-Reported Outcomes for CABENUVA

Because CABENUVA is the first long-acting, complete therapy for HIV-1, it was important to incorporate patient-reported outcome data collection into the ATLAS and FLAIR trials.1,8 

These data, collected directly from patients, should not be used to infer clinical significance and should not be interpreted as a reflection of the safety or efficacy of a regimen.

Prespecified exploratory endpoint

At Week 48, a single dichotomous preference question was posed to patients in the CABENUVA arm to assess patient preference between CABENUVA injections and their previous daily oral ARV therapy.4,5

Composite Question4,5

For the past 44 weeks, you have received long-acting injectable HIV medication every month. Today, we would like you to compare your experience on the long-acting injections with the oral medications you received previously. Which therapy do you prefer? 

Preferred by 9 out of 10 patients in clinical trials2-4

As an exploratory endpoint in ATLAS and FLAIR Phase 3 clinical trials, patients completed a single-item question assessing preference for CABENUVA compared to their previous daily oral ARV regimen.* In the ITT-E population, 532/591 patients responded to the preference question at Week 48.2

EXPLORATORY ANALYSIS OF PATIENT-REPORTED PREFERENCE2-4

  • In a post-hoc analysis that included only patients who responded to the preference question at Week 48 (n=532), 98% (n=523/532) of patients preferred CABENUVA vs 2% (9/532) who preferred their previous daily oral ARV therapy2*

*In ATLAS, the oral comparator consisted of 2 NRTIs + a third agent (INSTI, NNRTI, or PI). In FLAIR, the oral comparator consisted of ABC/DTG/3TC (or DTG + 2 NRTIs if HLA-B*5701-positive).3,4

References:

  1. CABENUVA [packaged insert]. Research Triangle Park, NC: ViiV Healthcare; 2021.
  2. Rizzardini G, Overton ET, Orkin C, et al. Long-acting injectable cabotegravir + rilpivirine for HIV maintenance therapy: week 48 pooled analysis of phase 3 ATLAS and FLAIR trials. J Acquir Immune Defic Syndr. 2020;85(4):498-506.
  3. Swindells S, Andrade-Villanueva JF, Richmond GJ, et al. Long-acting cabotegravir and rilpivirine for maintenance of HIV-suppression. N Engl J Med. 2020; 382(12):1112-1123.
  4. Orkin C, Arasteh K, Górgolas Hernández-Mora M, et al. Long-acting cabotegravir and rilpivirine after oral induction for HIV‑1 injection. N Engl J Med. 2020;382(12):1124-1135.
  5. Data on file, ViiV Healthcare.
  6. Orkin C, Oka S, Philibert P, et al. Long-acting cabotegravir plus rilpivirine for treatment in adults with HIV-1 infection: 96-week results of the randomised, open-label, phase 3 FLAIR study. Lancet HIV. 2021;8:e185–96.
  7. National Institute of Allergy and Infectious Diseases. DAIDS RSC Regulatory Support Center. DAIDS Adverse Event Grading Tables. Corrected version 1.2, July 2017. https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-tables.
  8. Mercieca-Bebber R, King MT, Calvert MJ, Stockier MR, Friedlander M. The importance of patient-reported outcomes in clinical trials and strategies for future optimization. Patient Relat Outcome Meas. 2018;9:353-367.

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