Cabenuva: Package Insert and Label Information (Page 6 of 7)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Two-year carcinogenicity studies in mice and rats were conducted with cabotegravir. In mice, no drug-related increases in tumor incidence were observed at cabotegravir exposures (AUC) up to approximately 8 times (males) and 7 times (females) higher than those in humans at the RHD. In rats, no drug-related increases in tumor incidence were observed at cabotegravir exposures up to approximately 26 times higher than those in humans at the RHD.

Two-year carcinogenicity studies in mice and rats were conducted with rilpivirine. In mice, rilpivirine was positive for hepatocellular neoplasms in both males and females. The observed hepatocellular findings in mice may be rodent-specific. At the lowest tested dose in the mouse carcinogenicity study, the systemic exposure to rilpivirine was 21 times that observed in humans at the RHD. In rats, no drug-related neoplasms were observed at exposures 3 times those observed in humans at the RHD.

Mutagenesis

Cabotegravir and rilpivirine were not genotoxic in the bacterial reverse mutation assay, mouse lymphoma assay, or in the in vivo rodent micronucleus assay.

Impairment of Fertility

In rats, no effects on fertility were observed at cabotegravir exposures (AUC) >20 times (male) and 28 times (female) the exposure in humans at the RHD. Similarly, no effects on fertility were observed in rats at rilpivirine exposures (AUC) >36 times (male) and 40 times (female) the exposure in humans at the RHD.

14 CLINICAL STUDIES

14.1 Clinical Trials in Adults

Monthly Dosing Trials

The efficacy of CABENUVA has been evaluated in 2 Phase 3 randomized, multicenter, active-controlled, parallel-arm, open-label, non-inferiority trials:

•

Trial 201584 (FLAIR [NCT02938520]), (n = 629): HIV-1–infected, antiretroviral treatment (ART)-naive subjects received a dolutegravir INSTI-containing regimen for 20 weeks (either dolutegravir/abacavir/lamivudine or dolutegravir plus 2 other NRTIs if subjects were HLA-B*5701 positive). Subjects who were virologically suppressed (HIV-1 RNA <50 copies/mL, n = 566) were then randomized (1:1) to receive either a cabotegravir plus rilpivirine regimen or remain on the current antiretroviral regimen. Subjects randomized to receive cabotegravir plus rilpivirine initiated treatment with daily oral lead-in dosing with one 30-mg VOCABRIA (cabotegravir) tablet plus one 25-mg EDURANT (rilpivirine) tablet for at least 4 weeks followed by monthly injections with CABENUVA for an additional 44 weeks [see Dosage and Administration (2.2, 2.3)].

•

Trial 201585 (ATLAS [NCT02951052]), (n = 616): HIV-1–infected, ART-experienced, virologically-suppressed (for at least 6 months; median prior treatment duration was 4.3 years) subjects (HIV-1 RNA <50 copies/mL) were randomized and received either a cabotegravir plus rilpivirine regimen or remained on their current antiretroviral regimen. Subjects randomized to receive cabotegravir plus rilpivirine initiated treatment with daily oral lead-in dosing with one 30-mg VOCABRIA (cabotegravir) tablet plus one 25-mg EDURANT (rilpivirine) tablet for at least 4 weeks followed by monthly injections with CABENUVA for an additional 44 weeks [see Dosage and Administration (2.2, 2.3)].

The primary analysis was conducted after all subjects completed their Week 48 visit or discontinued the trial prematurely.

At baseline, in FLAIR and ATLAS the median age was 34 years and 40 years, 22% and 32% were female, and 24% and 31% were non-White, respectively. In both studies, 7% had CD4+ cell count <350 cells/mm³ ; these characteristics were similar between treatment arms. In ATLAS, subjects received an NNRTI (50%), integrase inhibitor (33%), or protease inhibitor (17%) as their baseline third-agent class prior to randomization; this was similar between treatment arms. Subjects with hepatitis B co-infection were excluded from the trial.

The primary endpoint of FLAIR and ATLAS was the proportion of subjects with plasma HIV-1 RNA ≥50 copies/mL at Week 48.

The primary endpoint and other Week 48 outcomes, including outcomes by key baseline factors, for FLAIR and ATLAS are shown in Tables 17 and 18.

Table 17. Virologic Outcomes of Randomized Treatment in FLAIR and ATLAS Trials at Week 48

CAB = Cabotegravir, RPV = Rilpivirine, CAR = Current Antiretroviral Regimen, n = Number of subjects in each treatment group, CI = Confidence interval.a Includes subjects who discontinued for lack of efficacy and discontinued while not suppressed.
Virologic Outcomes	FLAIR Monthly Dosing		ATLAS Monthly Dosing
	CAB plus RPV (n = 283)	CAR (n = 283)	CAB plus RPV (n = 308)	CAR (n = 308)
HIV-1 RNA ≥50 copies/mLa	2%	2%	2%	1%
Treatment difference	-0.4%		0.7%
	(95% CI: -2.8%, 2.1%)		(95% CI: -1.2%, 2.5%)
HIV-1 RNA <50 copies/mL	94%	93%	93%	95%
No virologic data at Week 48 window	4%	4%	6%	4%
Discontinued due to adverse event or death	3%	<1%	4%	2%
Discontinued for other reasons	1%	4%	2%	2%
Missing data during window but on study	0	0	0	0

Adjusted for study and randomization stratification factors, treatment difference of HIV-1 RNA ≥50 copies/mL for the pooled data was 0.2% with 95% CI (-1.4%, 1.7%).

Table 18. Proportion of Subjects in FLAIR and ATLAS Trials with Plasma HIV-1 RNA ≥50 copies/mL at Week 48 for Key Baseline Factors

CAB = Cabotegravir, RPV = Rilpivirine, CAR = Current Antiretroviral Regimen.
Baseline Factors	FLAIR Monthly Dosing		ATLAS Monthly Dosing
	CAB plus RPV (N = 283) n/N (%)	CAR (N = 283) n/N (%)	CAB plus RPV (N = 308) n/N (%)	CAR (N = 308) n/N (%)
Baseline CD4+ (cells/mm3)
<350	0/19	1/27 (4%)	0/23	1/27 (4%)
≥350 to <500	3/64 (5%)	0/60	2/56 (4%)	0/60
≥500	3/200 (2%)	6/196 (3%)	3/299 (1%)	2/224 (<1%)
Gender
Male	3/220 (1%)	6/219 (3%)	3/209 (1%)	3/204 (1%)
Female	3/63 (5%)	1/64 (2%)	2/99 (2%)	0/104
Race
White	6/216 (3%)	5/201 (2%)	3/214 (1%)	2/207 (<1%)
African American/African Heritage	0/47	2/56 (4%)	2/62 (3%)	1/77 (1%)
Asian/Other	0/20	0/24	0/32	0/24
Body mass index
<30 kg/m2	3/243 (1%)	7/246 (3%)	3/248 (1%)	1/242 (<1%)
≥30 kg/m2	3/40 (8%)	0/37	2/60 (3%)	2/66 (3%)
Age (years)
<50	5/250 (2%)	6/254 (2%)	4/242 (2%)	2/212 (<1%)
≥50	1/33 (3%)	1/29 (3%)	1/66 (2%)	1/96 (1%)
Baseline antiviral therapy at randomization
Protease inhibitor-containing regimen	0	0	1/51 (2%)	0/54
Integrase inhibitor-containing regimen	6/283 (2%)	7/283 (2%)	0/102	2/99 (2%)
Non-nucleoside reverse transcriptase inhibitor-containing regimen	0	0	4/155 (3%)	1/155 (<1%)

Subjects in both the FLAIR and ATLAS trials were virologically suppressed prior to Day 1 or at study entry, respectively, and no clinically relevant change from baseline in CD4+ cell counts was observed.

In FLAIR at Week 96, the proportion of subjects with HIV-1 RNA ≥50 copies/mL was 3.2 % for both the cabotegravir plus rilpivirine (n = 283) and current antiretroviral regimen (n = 283) treatment arms; adjusted treatment difference was 0.0% with 95% CI (-2.9%, 2.9%). The proportion of subjects with HIV-1 RNA <50 copies/mL was 87% and 89% for the cabotegravir plus rilpivirine and the current antiretroviral regimen arms, respectively; adjusted treatment difference was -2.8% with 95% CI (-8.2%, 2.5%).

Optional Oral Lead-in: FLAIR Extension Phase

In the FLAIR study during the Extension Phase (Week 100 to Week 124), the efficacy of CABENUVA was evaluated in patients who switched (at Week 100) from their current antiretroviral regimen to CABENUVA, with and without an oral lead-in phase. A total of 121 subjects chose to start the treatment with oral lead-in and 111 subjects chose direct to injection. Subjects were not randomized during the Extension Phase. At Week 124, the proportion of subjects with HIV-1 RNA ≥50 copies/mL was 0.8% and 0.9% for the oral lead-in and direct to injection groups, respectively. The rates of virologic suppression (HIV-1 RNA <50 copies/mL) were similar in both the oral lead-in (93%) and direct to injection (99%) groups.

Every-2-Month Dosing Trial

The efficacy of CABENUVA dosed every 2 months has been evaluated in 1 Phase 3b randomized, multicenter, parallel-arm, open-label, non-inferiority trial:

•

Trial 207966 (ATLAS-2M [NCT03299049]), (n = 1,045): HIV-1–infected, ART‑experienced, virologically suppressed subjects, including 504 subjects from the ATLAS trial (randomized to CAB plus RPV [n = 253] or CAR [n = 251]; prior exposure to cabotegravir plus rilpivirine [n = 391]), were randomized and received a cabotegravir plus rilpivirine regimen administered as injection doses of cabotegravir 400 mg plus rilpivirine 600 mg either monthly or cabotegravir 600 mg plus rilpivirine 900 mg every 2 months. Subjects without prior exposure to cabotegravir plus rilpivirine initiated treatment with daily oral lead-in dosing with one 30-mg VOCABRIA (cabotegravir) tablet plus one 25-mg EDURANT (rilpivirine) tablet for at least 4 weeks followed by monthly or every-2-month injections with CABENUVA for an additional 44 weeks.

The primary analysis was conducted after all subjects completed their Week 48 visit or discontinued the study prematurely.

At baseline, the median age was 42 years, 27% were female, 27% were non-White, and 6% had a CD4+ cell count <350 cells per mm³ ; these characteristics were similar between the treatment arms. Subjects received either an NNRTI (29%), an integrase inhibitor besides cabotegravir plus rilpivirine (26%), a protease inhibitor (7%), or cabotegravir plus rilpivirine (37%) as their baseline third-agent class prior to randomization.

The primary endpoint of ATLAS-2M was the proportion of subjects with a plasma HIV-1 RNA ≥50 copies/mL at Week 48.

The primary endpoint and other Week 48 outcomes, including outcomes by key baseline factors, for ATLAS-2M are shown in Tables 19 and 20.

Table 19. Virologic Outcomes of Randomized Treatment in ATLAS 2-M Trial at Week 48

a Includes subjects who discontinued for lack of efficacy, discontinued while not suppressed.n = Number of subjects in each treatment group, CI = Confidence interval.
Virologic Outcomes	Cabotegravir plus Rilpivirine
	Every-2-Month Dosing n = 522	Monthly Dosing n = 523
HIV-1 RNA ≥50 copies/mLa	2%	1%
Treatment difference	0.8
	(95% CI: -0.6%, 2.2%)
HIV-1 RNA <50 copies/mL	94%	94%
No virologic data at Week 48 window	4%	6%
Discontinued study due to adverse event or death	2%	3%
Discontinued for other reasons	2%	3%
Missing data during window but on study	0	0

Table 20. Proportion of Subjects in ATLAS 2-M Trial with Plasma HIV-1 RNA ≥50 copies/mL at Week 48 for Key Baseline Factors

Baseline Factors	Cabotegravir plus Rilpivirine
	Every-2-Month Dosing (N = 522) n/N (%)	Monthly Dosing (N = 523) n/N (%)
Baseline CD4+ (cells/mm3)
<350	1/35 (3%)	1/27 (4%)
≥350 to <500	1/96 (1%)	0/89
≥500	7/391 (2%)	4/407 (1%)
Gender
Male	4/385 (1%)	5/380 (1%)
Female	5/137 (4%)	0/143
Race
White	5/370 (1%)	5/393 (1%)
Black/African American Asian/Other	4/101 (4%) 0/51	0/90 0/40
Body mass index
<30 kg/m2	3/409 (1%)	3/425 (1%)
≥30 kg/m2	6/113 (5%)	2/98 (2%)
Age (years)
<35	4/137 (3%)	1/145 (1%)
35 to <50	3/242 (1%)	2/239 (1%)
≥50	2/143 (1%)	2/139 (1%)
Prior exposure to cabotegravir plus rilpivirine
None	5/327 (2%)	5/327 (2%)
1 to 24 Weeks	3/69 (4%)	0/68
>24 Weeks	1/126 (1%)	0/128
Baseline third-agent class
Protease inhibitor-containing regimen	1/40 (3%)	1/30 (3%)
Integrase inhibitor-containing regimen	3/136 (2%)	2/141 (1%)
NNRTI-containing regimen	1/151 (1%)	2/156 (1%)
Cabotegravir plus rilpivirine	4/195 (2%)	0/196