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Switch to INSTI + NNRTI - PowerPoint Presentation

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Switch to INSTI + NNRTI - PPT Presentation

Switch to DTG RPV SWORD Study Switch to CAB LA RPV LA IM LATTE2 Study LATTE2 Study switch to cabotegravir LA rilpivirine LA IM Objective Primary HIV RNA lt 50 cmL at W32 of maintenance phase selection of dosing schedule for phase III studies confirmation of dose on ID: 615856

q8w latte q4w cab latte q8w cab q4w w48 rna w96 oral 2017 115 switch study hiv rpv cabotegravir

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Slide1

Switch to INSTI + NNRTI

Switch to DTG + RPV

SWORD

Study

Switch to CAB LA + RPV LA IM

LATTE-2 Study

Slide2

LATTE-2 Study: switch to cabotegravir LA + rilpivirine LA IM

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

Randomisation

2 : 2

: 1

Q8W: injection every 8 weeks ; Q4W: injection every 4 weeks

CAB 30 mg QD + ABC/3TC(N = 309)

Induction (oral)

Maintenance(if HIV RNA < 50 c/mL at W-4 and Day 1)

CAB 600 mg IM + RPV 900 mg IM Q8W *(N = 115)

CAB 30 mg QD + ABC/3TC QD (oral) (N = 56)

CAB 400 mg IM + RPV 600 mg IM Q4W **(N = 115)

* CAB IM, loading dose 800 mg at D1 and 600 mg at W4 ** CAB IM, loading dose 800 mg at D1

ARV naive> 18 yearsHIV RNA > 1 000 c/mLCD4 > 200/mm3HBs Ag negativeALT < 5 UNLCreatinine clearance> 50 mL/min

addition of

RPV 25 mg QD oral

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

Design

LATTE-2

W48

W96

W32

W-20

D1

W-4

Margolis DA. Lancet. 2017 Sep 23;390(10101):1499-1510.

Margolis

DA. Lancet. 2017 Sep 23;390(10101):1499-1510.Slide3

LATTE-2 Study: switch to cabotegravir LA +

rilpivirine

LA IM

Q8W IM

N = 115

Q4W IM

N = 115

Oral CAB

N = 56

Median age, years

35

36

35

Female, %

7

5

18

White / African American, %

81 / 15

82 / 10

70 / 27

CDC Class C, %

< 1

2

0

HIV RNA, log

10

c/mL, median

4.42

4.46

4.29

CD4 cell count (/mm

3

), median

449

499

518

Discontinuation by W48, N (%)For lack of efficacy, NFor adverse event, NWithdrew consent / other4 (3.5%)111 / 111 (9.6%)071 / 36 (10.7%)112 / 2Discontinuation between W48 and W96, NFor adverse event, NWithdrew consent, N101312303

LATTE-2

Baseline characteristics (ITT-maintenance exposed) and patient disposition

Margolis DA. Lancet. 2017 Sep 23;390(10101):1499-1510.Slide4

LATTE-2 Study: switch to cabotegravir LA +

rilpivirine

LA IM

Oral

Intramuscular

Q4W

‒ 10%

+ 10%

12.2

- 4.8

3.7

Difference (95% CI)

0

‒ 10%

+ 10%

11.5

- 5.8

2.8

Q8W

95

4

< 1

94

< 1

5

0

20

40

60

80

100

Virologic success

Virologic

Non response

No virologic data

%

91

45Q8W IM (N = 115)Q4W IM (N = 115)CAB oral (N = 56)LATTE-2Non inferiority of the 2 IM regimens vs oral CABPrimary endpoint: HIV RNA < 50 c/mL at W32 (snapshot analysis, ITT-ME)Margolis DA. Lancet. 2017 Sep 23;390(10101):1499-1510.Slide5

Oral

Intramuscular

Q4W

‒ 10 %

+ 10 %

20.5

- 0.6

10

Difference, % (95% CI)

0

‒ 10 %

+ 10 %

14.4

- 8.4

3.0

Q8W

92

7

< 1

91

< 1

8

0

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

0

2

2

13

14

Margolis

DA. Lancet. 2017 Sep 23;390(10101):1499-1510.

LATTE-2 Study: switch to

cabotegravir

LA +

rilpivirine

LA IM

HIV RNA < 50 c/mL at W48 and W96 (snapshot analysis, ITT-ME)

11.6

- 7.6

2.0

12.6

- 6.6

2.9

W48

W96

W48

W96

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-2Slide6

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: 90-151 c/mL between W72-W96)

0

0

Discontinuation for lack

of efficacy

1 (rebound > 400 c/mL at W4)

0

1

Discontinuation for other reason, while HIV RNA

not < 50 c/ml

2

56 c/mL at W4 with injection intolerance ; HIV RNA > 400 c/mL at W48,

physician decision

0

0

Discontinuation for AE

1

9 *, (7/9 before W48)

2 ** (at W36)

Discontinuation for other reason

1

5 ***

6 ****

Missing data during window but on study

0

1

(HIV

RNA

< 40 c/mL at all visits)0Virologic non response and no data in window (snapshot analysis at W96)* 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 = 1Margolis DA. Lancet. 2017 Sep 23;390(10101):1499-1510.LATTE-2 Study: switch to cabotegravir LA + rilpivirine LA IMLATTE-2Slide7

Q8W IM

(N = 115)

Q4W IM

(N = 115)

Oral

(N = 56)

Drug-related adverse events, excluding ISRs

Pyrexia

Headache

Influenza-like illness

Fatigue

3

3

3

2

6

3

3

3

0

4

0

2

Grade 3-4 adverse

event

,

excluding ISRs

Drug-related

11

2 *

16

4 **

72

Serious adverse event (none drug-related)10

10

13

Adverse event leading to withdrawal

272Grade 3 and 4 laboratory abnormalities192921Injection site reactions (ISR) ***D1W8W48W968548373188403028-Adverse events and laboratory abnormalities (ITT, maintenance period D0-W96), %* 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%Margolis DA. Lancet. 2017 Sep 23;390(10101):1499-1510.LATTE-2 Study: switch to cabotegravir LA + rilpivirine LA IMLATTE-2Slide8

LATTE-2

LATTE-2 Study: switch to

cabotegravir

LA +

rilpivirine LA IM

Overall injection site reaction incidence,by visit Day 1-Day 96 (% patients with ISR)

Q8W IM

Q4W IM

Q8W IM

Q4W IM

115

115

115115114115

114

113112111112109109112107107

111

105105111

104

Subjects at visit

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)

Margolis

DA. Lancet. 2017 Sep 23;390(10101):1499-1510.

Day 1

W4

W8

W12

W16

W20

W24

W28

W32

W36

W40

W44W48

W64

W72

W96

84

88

38

42

46

40

35

46

31

28

57

35

31

38

29

29

50

32

30

37

30

45

31

29

33

31

28

0

20

40

60

80

100

109

103

109

101

110

102Slide9

LATTE-2 Study: switch to cabotegravir LA +

rilpivirine

LA IM

LATTE-2

Pharmacokinetics (mean

+ SD plasma concentration (mg/mL)

Margolis

DA. Lancet. 2017 Sep 23;390(10101):1499-1510.Q4W

Q8W

Cτ, trough concentration ; PA-IC90, protein binding-adjusted 90% inhibitory concentrationQ8W: 7/9 patients with virological

non-response at W48 had RPV Cτ in the lowest 25th quartile

Mean (95% CI)

C

τ at W48

Q8WQ4W

Oral

2.58

(2.4 - 2.8)

1.46

(1.3 - 1.6)

4.47

(3.9 - 5.2)

x times PA-IC

90

16

19

27

Mean (95% CI)

C

τ

at W48

Q8W

Q4W

94.64

(86.6 - 103.4)

64.48

(

60.0 - 69.3)x times PA-IC9085

0

1

4

8

12

16

20

24

28

32

36

40

44

48

Week

0,1

1

10

100

10

100

1 000

0

1

4

8

12

16

20

24

28

32

36

40

44

48

Week

CAB

RPV

PA-IC

90

10 mg PO C

τ

30 mg PO C

τ

PA-IC

90

25 mg PO C

τ

Q4W

Q8WSlide10

LATTE-2 Study: switch to cabotegravir LA +

rilpivirine

LA IM

Patient reported-outcomes

(HIV Treatment satisfaction questionnaire, status version)

Margolis DA. Lancet. 2017 Sep 23;390(10101):1499-1510.

6

5

4

3

2

1

0

Very satisfied

Very dissatisfied

LATTE-2

0

20

40

60

80

100

Q4W

(N = 100)

Q8W

(N = 108)

Oral CAB + ABC/3TC

(N = 46)

76

85

76

21

14

15

4

2

2

< 13IM CAB LA + RPV LA%

Q4W

(N = 100)

Q8W

(N = 108)

Oral CAB + ABC/3TC

(N = 46)

0

20

40

60

80

100

88

89

43

11

10

35

9

7

4

2

< 1

1

IM CAB LA + RPV LA

%Slide11

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 weeksThree 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 emergenceInjection tolerabilityMajority of ISRs were grade 1 to 2 pain, with a median duration

of 3 daysFew subjects had an ISR that led to discontinuation, with higher rate in Q4W group

High overall reported satisfactionDose selectionQ4W dosing resulted in lower rates of virologic non-response with similar safety to Q8WQ4W dosing was selected for pivotal phase III studies

LATTE-2Margolis

DA. Lancet. 2017 Sep 23;390(10101):1499-1510.