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Switch to CAB LA + RPV LA IM
LATTE-2 Study

2. LATTE-2 Study: switch to cabotegravir LA + rilpivirine LA IM
Design
Randomisation
2 : 2 : 1
Induction (oral)
Maintenance
(if HIV RNA < 50 c/mL at W-4 and Day 1)
ARV naive
> 18 years
HIV RNA > c/mL
CD4 > 200/mm3
HBs Ag negative
ALT < 5 UNL
Creatinine clearance
> 50 mL/min
CAB 30 mg QD + ABC/3TC
(N = 309)
CAB 600 mg IM + RPV 900 mg IM Q8W * (N = 115)
CAB 400 mg IM + RPV 600 mg IM Q4W ** (N = 115)
CAB 30 mg QD + ABC/3TC QD (oral) (N = 56)
W-20
W-4 D1
W32
W48
W96
addition of RPV 25 mg QD oral
* CAB IM, loading dose 800 mg at D1 and 600 mg at W4
** CAB IM, loading dose 800 mg at D1
Q8W: injection every 8 weeks ; Q4W: injection every 4 weeks
Induction phase: HIV RNA < 50 c/mL (ITT-E) after 20 weeks = 91.3 % ; discontinuation in 18/309 patients, including 6 for adverse event and 2 for lack of efficacy
Objective
Primary: % HIV RNA < 50 c/mL at W32 of maintenance phase: selection of dosing schedule for phase III studies (confirmation of dose on W48 analysis) ; safety
Margolis DA. Lancet Sep 23;390(10101):
LATTE-2
Margolis DA. Lancet Sep 23;390(10101):

3. LATTE-2 Study: switch to cabotegravir LA + rilpivirine LA IM
ARV-trial.com
LATTE-2 Study: switch to cabotegravir LA + rilpivirine LA IM
Baseline characteristics (ITT-maintenance exposed)
and patient disposition
Q8W IM
N = 115
Q4W IM
Oral CAB
N = 56
Median age, years 35 36
Female, % 7 5 18
White / African American, %
81 / 15
82 / 10
70 / 27
CDC Class C, %
< 1 2
HIV RNA, log10 c/mL, median
4.42
4.46
4.29
CD4 cell count (/mm3), median
449
499
518
Discontinuation by W48, N (%)
For lack of efficacy, N
For adverse event, N
Withdrew consent / other
4 (3.5%) 1
1 / 1
11 (9.6%)
1 / 3
6 (10.7%)
2 / 2
Discontinuation between W48 and W96, N
Withdrew consent, N 3
LATTE-2
Margolis DA. Lancet Sep 23;390(10101): 3

4. LATTE-2 Study: switch to cabotegravir LA + rilpivirine LA IM
Primary endpoint: HIV RNA < 50 c/mL at W32
(snapshot analysis, ITT-ME) 95 4
< 1 94 5 20 40 60 80
100
Virologic success
Virologic
Non response
No virologic data % 91
Q8W IM (N = 115)
Q4W IM (N = 115)
CAB oral (N = 56)
Difference (95% CI)
Oral
Intramuscular
Q8W
3.7
- 4.8
12.2
‒ 10%
+ 10%
Q4W
2.8
- 5.8
11.5
‒ 10%
+ 10%
Non inferiority of the 2 IM regimens vs oral CAB
LATTE-2
Margolis DA. Lancet Sep 23;390(10101):

5. LATTE-2 Study: switch to cabotegravir LA + rilpivirine LA IM
HIV RNA < 50 c/mL at W48 and W96 (snapshot analysis, ITT-ME) 92 7
< 1 91 8 20 40 60 80
100
Virologic success
Virologic non response
No virologic data % 89 2 9
Q8W IM (N = 115)
Q4W IM
(N = 115)
Oral
(N = 56)
W48
W96 94 87 84 4 13 14
Difference, % (95% CI)
Oral
Intramuscular
Q8W
2.9
W48
12.6
- 6.6 10
W96
- 0.6
20.5
‒ 10 %
+ 10 %
Q4W
2.0
W48
11.6
- 7.6
3.0
W96
14.4
- 8.4
‒ 10 %
+ 10 %
Non inferiority of the 2 IM regimens vs oral CAB, at W48 and W96
Lower performance of Q4W (vs Q8W) at W96 due to more discontinuations for AE (9 vs 1)
Protocol-defined virologic failure: 1 in oral arm (no resistance), 2 in Q8W arm (emergence of resistance at failure: K103N, E138G, K238T (NNRTI) and Q148R (INSTI) in 1, R269R/G in 1
LATTE-2
Margolis DA. Lancet Sep 23;390(10101):

6. LATTE-2 Study: switch to cabotegravir LA + rilpivirine LA IM
Virologic non response and no data in window (snapshot analysis at W96)
Q8W IM, N = 115
Q4W IM, N = 115
Oral, N = 56
HIV RNA in window not < 50 c/mL 2
1 patient with HIV RNA 87 c/mL at W96; 1 patient with repeated blips then failure (HIV RNA: c/mL between W72-W96)
Discontinuation for lack of efficacy
1 (rebound > 400 c/mL at W4) 1
Discontinuation for other reason, while HIV RNA not < 50 c/ml
56 c/mL at W4 with injection intolerance ; HIV RNA > 400 c/mL at W48, physician decision
Discontinuation for AE
9 *, (7/9 before W48)
2 ** (at W36)
Discontinuation for other reason
5 ***
6 ****
Missing data during window but on study
1 (HIV RNA < 40 c/mL at all visits)
* Rash, N = 1, liver stopping criteria, N = 1, QT prolongation, N = 1, mesenteric vein thrombosis, N = 1, Churg-Strauss vasculitis, N = 1, epilepsy leading to death, N = 1, psychosis, N = 1, depression, N = 1, hepatitis C, N = 1
** Acute hepatitis C, N = 1, liver stopping criteria, N = 1
*** Withdrawal by subject, N = 3 ; protocol deviation, N = 2
**** Withdrawal by subject, N = 5 ; lost to follow-up, N = 1
LATTE-2
Margolis DA. Lancet Sep 23;390(10101):

7. LATTE-2 Study: switch to cabotegravir LA + rilpivirine LA IM
Adverse events and laboratory abnormalities (ITT, maintenance period D0-W96), %
Q8W IM
(N = 115)
Q4W IM
Oral
(N = 56)
Drug-related adverse events, excluding ISRs
Pyrexia
Headache
Influenza-like illness
Fatigue 3
3 3 2 4
Grade 3-4 adverse event, excluding ISRs
Drug-related
11 2 * 16
4 **
7 2
Serious adverse event (none drug-related) 10 13
Adverse event leading to withdrawal 7
Grade 3 and 4 laboratory abnormalities 19 29 21
Injection site reactions (ISR) *** D1 W8
W48
W96 85 48 37 31 88 40 30 28 -
* Influenza-like illness, N = 1, chills and pain, N = 1
** Influenza-like illness, N = 1, rash, N = 1, depression, N = 1, QT prolongation, N = 1
*** ISR = pain (66%), nodules (8%), swelling( 6%), pruritus (6%), resolved < 7 days: 89%
LATTE-2
Margolis DA. Lancet Sep 23;390(10101):

8. LATTE-2 Study: switch to cabotegravir LA + rilpivirine LA IM
Draft version 1-5
LATTE-2 Study: switch to cabotegravir LA + rilpivirine LA IM
Overall injection site reaction incidence, by visit Day 1-Day 96 (% patients with ISR)
Day 1 W4 W8
W12
W16
W20
W24
W28
W32
W36
W40
W44
W48
W64
W72
W96 84 88 38 42 46 40 35 31 28 57 29 50 32 30 37 45 33 20 60 80
100
Q8W IM
Q4W IM
Subjects at visit
114
113
112
111
112
109
109
112
107
107
111
105
105
111
104
110
102
109
103
109
101
Q8W IM
Q4W IM
99% of ISRs were mild (84%) or moderate (15%)
Median duration was 3.0 days in both groups, and 89% resolved within 7 days
Most common ISR events : pain (66%), nodules (8%), swelling (6%) and pruritus (6%)
The number of subjects reporting ISRs decreased over time, from 86% (D1) to 35% (W48) and 30% (W96)
2/230 subjects (< 1%) withdrew as a result of injection reactions (both in Q8W group)
LATTE-2
Margolis DA. Lancet Sep 23;390(10101):

9. LATTE-2 Study: switch to cabotegravir LA + rilpivirine LA IM
Pharmacokinetics (mean + SD plasma concentration (mg/mL)
100
1 000
CAB
RPV
PA-IC90
Q4W
Q4W
25 mg PO Cτ
Q8W
Q8W 10
100 1
PA-IC90
10 mg PO Cτ
30 mg PO Cτ
Q8W: 7/9 patients with
virological non-response at W48 had
RPV Cτ in the lowest 25th quartile
0,1 10 1 4 8 12 16 20 24 28 32 36 40 44 48 1 4 8 12 16 20 24 28 32 36 40 44 48
Week
Week
Mean (95% CI) Cτ at W48
Q8W
Q4W
Oral
2.58
( )
1.46
( )
4.47 ( )
x times PA-IC90 16 19 27
Mean (95% CI) Cτ at W48
Q8W
Q4W
94.64
( )
64.48
( )
x times PA-IC90 8 5
Cτ, trough concentration ; PA-IC90, protein binding-adjusted 90% inhibitory concentration
LATTE-2
Margolis DA. Lancet Sep 23;390(10101):

10. LATTE-2 Study: switch to cabotegravir LA + rilpivirine LA IM
Patient reported-outcomes
(HIV Treatment satisfaction questionnaire, status version) 20 40 60 80
100
Q4W (N = 100)
Q8W (N = 108)
Oral CAB + ABC/3TC
(N = 46) 76 85 21 14 15 4 2
< 1 3
IM CAB LA + RPV LA %
Q4W (N = 100)
Q8W (N = 108)
Oral CAB + ABC/3TC
(N = 46) 20 40 60 80
100 88 89 43 11 10 35 9 7 4 2
< 1 1
IM CAB LA + RPV LA % 6 5 4 3 2 1
Very satisfied
Very dissatisfied
LATTE-2
Margolis DA. Lancet Sep 23;390(10101):

11. LATTE-2 Study: switch to cabotegravir LA + rilpivirine LA IM
ARV-trial.com
LATTE-2 Study: switch to cabotegravir LA + rilpivirine LA IM
Conclusion
LATTE-2 results successfully demonstrate ability to maintain HIV-1 RNA < 50 c/mL with IM CAB + RPV LA, dosed every 4 or 8 weeks
Three subjects met PDVF criteria during maintenance
Q8W (N = 2), oral CAB (N = 1) ; one Q8W subject with emergent RPV and CAB resistance, and one Q8W subject with minor INSTI mutation emergence
Injection tolerability
Majority of ISRs were grade 1 to 2 pain, with a median duration of 3 days
Few subjects had an ISR that led to discontinuation, with higher rate in Q4W group
High overall reported satisfaction
Dose selection
Q4W dosing resulted in lower rates of virologic non-response with similar safety to Q8W
Q4W dosing was selected for pivotal phase III studies
LATTE-2
Margolis DA. Lancet Sep 23;390(10101): 11