adherence to long-acting injectable cabotegravir ... · atlas and flair: injection tolerability...

IDWeek; October 2–6, 2019; Washington, DC, USA

1ViiV Healthcare, Research Triangle Park, NC, 2GSK, Upper Providence, PA, 3GSK, Mississauga, Canada, 4Janssen R&D, Beerse, Belgium.

Adherence to Long-Acting Injectable Cabotegravir +

Rilpivirine through 48 Weeks of Maintenance Therapy in

the Phase 3 ATLAS and FLAIR Studies

Paula Teichner, PharmD1, Amy Cutrell, MS1, Ronald D’Amico, DO, MSc1, David Dorey2,

Sandy Griffith, PharmD1, Conn Harrington, BA1, Jenny Huang, MSc3, Krischan Hudson, PhD, MPH1,

David Margolis, MD, MPH1, Joseph Mrus, MD, MSc1, Joseph W. Polli, PhD1, William Spreen, PharmD1,

Peter Williams, PhD4, Rodica Van Solingen-Ristea, MD4, Mark Shaefer, PharmD1


• The ATLAS and FLAIR studies were funded by ViiV Healthcare and Janssen Pharmaceuticals

• Paula Teichner:

– North America Medical Lead, Cabotegravir, ViiV Healthcare

– Employed by ViiV Healthcare and owns company stocks in GlaxoSmithKline

Financial Disclosures


• Cabotegravir (CAB) and rilpivirine (RPV) injectable formulations are under development as a

novel long-acting (LA) therapeutic regimen for the maintenance of HIV virologic suppression

• ATLAS (NCT02951052) and FLAIR (NCT02938520) are two randomized, open-label,

international Phase 3 studies that demonstrated non-inferiority of switching to monthly

intramuscular (IM) injections of CAB + RPV LA vs. current antiretroviral regimen (CAR)

• CAB + RPV LA formulations require monthly injection visits within a pre-specified dosing

window, representing a paradigm-shift for patients from daily oral dosing

• The present analysis describes:

1. Adherence to injection visits within the dosing window, timeliness of injections relative to projected dosing date,

and injection tolerability

2. Use of oral therapy (oral bridging) for participants who planned to miss injection visit(s)

ATLAS and FLAIR: Background and Objectives


ATLAS and FLAIR Study Designs Randomized, Multicenter, International, Open-Label, Noninferiority Studies

1. Swindells S, et al. Abstract 139. Presented at: Conference on Retroviruses and Opportunistic Infections; March 4-7, 2019; Seattle, WA;

2. Orkin C, et al. Abstract 140. Presented at: Conference on Retroviruses and Opportunistic Infections; March 4-7, 2019; Seattle, WA.

3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; CAB, cabotegravir; CAR, current antiretroviral; DTG, dolutegravir; IM, intramuscular; INSTI, integrase strand transfer inhibitor; HBsAg, hepatitis B surface

antigen; HLA, human leukocyte antigen; LA, long-acting; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; RAM, resistance-associated

mutation; RPV, rilpivirine; VL, viral load. *Uninterrupted ART 6 months and VL <50 c/mL at Screening, 2× VL <50 c/mL ≤12 months; Triumeq excluded from study; ‡Optional switch to CAB LA + RPV LA at Week 52 for

those on CAR; ‖Participants received an initial loading dose of CAB LA (600 mg) and RPV LA (900 mg) at Week 4b. From Week 8 onwards, participants received CAB LA (400 mg) + RPV LA (600 mg) injections every 4

weeks; ¶NNRTI RAMs but not K103N were exclusionary; ††Participants who withdraw/complete CAB LA + RPV LA enter 52-week long-term follow-up. **DTG plus 2 alternative non-ABC NRTIs was permitted if participant

was intolerant or HLA-B*5701-positive (n=30 as last regimen during induction: n=2 discontinued during induction, n=14 randomized to CAB LA + RPV LA, n=14 randomized to DTG/ABC/3TC arm and continued on DTG

plus 2 alternative non-ABC NRTIs in Maintenance Phase).

PI, NNRTI, or INSTI†

Current daily oral ART n=308

100484‖ 96 −4−20 52Day 1

Induction Phase

Maintenance Phase Extension Phase‡

Extension

N=629

DTG/ABC/3TC

single-tablet

regimen for 20

weeks**

Screening Phase

ART-naïveN=809HIV-1 RNA ≥1000Any CD4 countHBsAg-negativeNNRTI RAMs excluded¶

Confirm HIV-1 RNA <50 c/mL

Study Week

ART-experiencedN=705PI-, NNRTI-, or INSTI-based regimen with 2 NRTI backbone*

Extension Phase or

transition to the

ATLAS-2M studyAT

LA

S1

FL

AIR

2

Day 1

N=618

Randomization

Primary Endpoint

100484‖ 96 52

Oral CAB +

RPV n=308

CAB LA (400 mg) + RPV LA (600 mg)§

IM monthly n=303

Oral CAB +

RPV n=283

DTG/ABC/3TC

Oral daily n=283

CAB LA (400 mg) + RPV LA (600 mg)††

IM monthly n=278


ATLAS and FLAIR: Virologic Snapshot Outcomes at Week 48 for ITT-E Noninferiority Achieved for Primary and Secondary Endpoints

CAB, cabotegravir; CAR, current antiretroviral; CI, confidence interval; ITT-E, intention-to-treat exposed; LA, long-acting; NI, noninferiority; RPV, rilpivirine.

*ATLAS adjusted for sex and baseline third-agent class, FLAIR adjusted for sex and induction baseline HIV-1 RNA (<100,000 vs. ≥100,000 copies/mL).

Virologic Outcomes Adjusted Treatment Difference (95% CI)*

1.9

93.1

5.11.7

94.4

3.9

0

20

40

60

80

100

Pro

po

rtio

n o

f P

art

icip

an

ts (

%)

CAB + RPV LA(n=591)

CAR (n=591)

Virologic

Nonresponse

(≥50 c/mL)

Virologic

Success

(<50 c/mL)

No Virologic

Data

Primary Endpoint:

LA noninferior to CAR

(HIV-1 RNA ≥50 c/mL)

at Week 48

Difference (%)

-10 -8 -6 -4 -2 0 2 4 6 8 10

-1.4 1.7

0.2

CARCAB + RPV LA

4% NI

margin

Key Secondary

Endpoint:

LA noninferior to CAR

(HIV-1 RNA <50 c/mL)

at Week 48

Difference (%)

-10 -8 -6 -4 -2 0 2 4 6 8 10

-4.1 1.4

-1.4

CAR CAB + RPV LA

−10% NI

margin


• Injections were scheduled every 4 weeks with a ± 7-day dosing window* around the projected

(target) dosing date**

• Adherence was calculated as the number of injection visits occurring within the dosing window,

divided by the number of expected dosing visits through Week 48†

• Oral bridging (the use of oral dosing to cover planned missed injections) was permitted to enable

dosing flexibility for planned absences from a clinical site (e.g., vacation or travel)

• Injection visits outside the ± 7-day dosing window and missed injection visits with/without use

of oral bridging were quantified

• Injection tolerability and acceptability were assessed via adverse event reporting (injection site

reactions [ISRs]) and Perception of Injection (PIN) patient questionnaire

ATLAS and FLAIR Methods

ISR, injection site reaction; PIN, perception of injection. *Dosing window: -7 days for the second and third injections, and ±7 days thereafter. **Projected dosing date is relative to date of first injection at Week 4b. †Includes FLAIR data for subjects beyond Week 48, i.e., as collected by the Week 48 primary analysis data cutoff.


• 14,682 injections of CAB and RPV LA were administered to 581 participants during 6920 injection visits*,**

• 46% (3194/6920) of injection visits occurred on the projected visit date

• 2% (152/6920) of injection visits occurred early or late (outside of the injection window)

High Adherence to Injection Visits in ATLAS and FLAIR

98% (6759/6920)

of injection visits

occurred within the

± 7-day window

46%<1% 2%

98%

Nu

mb

er

of in

jectio

n v

isits

Days from projected visit date

3500

3000

2500

2000

1000

1500

500

0< -14 -14 to -8 -7 to -4 -3 to -2 -1 0 1 2 to 3 4 to 7 8 to 14 >14

CAB, cabotegravir; RPV, rilpivirine. *The number of expected injection visits was 3343 for the ATLAS study and 3577 for the FLAIR study.

**Note that the 6920 expected injection visits does not include injections received at Week 4b or at unscheduled visits, although these are reflected in the total number of injections (14,682).


• For late injections (after the +7 days dosing window, n=106):

– The mean number of days after the projected visit date was 11 (range 8–28 days), with the

majority (96/106=91%) administered within one week after the dosing window

Late Injections Outside of the + 7 Day Dosing Window

CVF, confirmed virologic failure; VL, viral load. *Defined as rebound as indicated by two consecutive plasma HIV-1 RNA levels ≥200 copies/mL after prior suppression to <200 copies/mL. **Using FDA snapshot algorithm.

Number of days relative to projected visit date Late injection visits

8–14 days 96/6920

(1%)

>14–28 days10/6920

(0.1%)

No participant with injections outside of the +7 days

dosing window met CVF criteria* or had VL ≥50 c/mL at Week 48**


Example of participant #7 timeline with injections and oral bridging:

Example of Oral Bridging

Study

Week:

Viral

load:

Oral

bridging

for 29 days

<50 copies/mL <50 copies/mL

0 481284 16 20 24 28 32 36 40 44

<50 copies/mL


• 7 participants received oral bridging* to cover planned missed visits (CAB 30 mg + RPV 25 mg)

– 1 additional participant missed an injection visit at Week 32 without oral bridging (dosing interrupted due to acute hepatitis A);

however, LA therapy was continued at Week 36 and viral suppression was maintained

Oral Bridging for Planned Missed Injections Maintained Viral Suppression

*8 additional participants received oral dosing: 6 participants used oral bridging but did not miss an injection visit, 2 participants received oral bridging but were unable to continue on LA

therapy (1 participant was lost to follow-up due to visa issues, 1 participant required chronic anticoagulation). Viral suppression was maintained in all 8 participants. CAB, cabotegravir; LA, long-acting; RPV, rilpivirine.

Participant

#

Study Injection visit(s)

covered by oral

bridging

(Study Week)

Duration of

oral bridging

(days)

Viral load at restart of

LA (c/mL)

Viral load at 48 Weeks

(c/mL)

1 FLAIR 16 and 20 55 <50 <50

2 FLAIR 48 29 <50 <50

3 FLAIR 48 20 <50 <50

4 ATLAS 36 28 <50 <50

5 ATLAS 36 28 <50 <50

6 ATLAS 24 21 <50 <50

7 ATLAS 16 29 <50 <50


• Most ISRs were grade 1–2 (99%), of short duration (median 3 days), with few associated discontinuations (<1%)

• 85% of CAB + RPV LA participants rated pain as ‘totally/very acceptable’ at Week 48,* as assessed by PIN

ATLAS and FLAIR: Injection Tolerability

Event

CAB + RPV LA

N=591

Participants receiving injections, n 581

Injections given, n (%) 14,682

ISR events 3663 (24.9)

Pain 3087 (21.0)

Nodule 140 (1.0)

Induration 136 (0.9)

Swelling 86 (0.6)

Grade 3 ISR pain 32 (0.2)

Median duration of ISRs, days 3

Participants with ISR leading to withdrawal, n (%) 6 (1)

0

20

40

60

80

100

4 8 12 16 20 24 28 32 36 40 44 48

Pa

rtic

ipa

nts

wit

h IS

Rs

(%

)

Study Week

ISR Incidence by Week

Over the 48 week treatment period,

the majority of participants (55%)

reported ≤3 injection pain events.

CAB, cabotegravir; ISR, injection site reaction; LA, long-acting; RPV, rilpivirine. *Based on a last observation carried forward (LOCF) dataset. Overton ET, et al. IAS 2019; Mexico City, Mexico. Poster MOPEB257.

Bars represent incidence of onset ISRs relative to the most recent LA injection visit


Breakdown of ISRs by age, gender, and race showed:

• Overall, minimal differences in cumulative ISR reports by subgroup over the 48-week time period

• Slightly lower reporting of pain in female and African American/African heritage participants

• Slightly higher reporting of induration in female and white participants

ATLAS and FLAIR: Injection Tolerability by Subgroup

ISR*

Subgroup Pain Nodule Induration Swelling

Age (years)<50 (n=492) 386 (78%) 67 (14%) 56 (11%) 38 (8%)

≥50 (n=99) 72 (73%) 14 (14%) 12 (12%) 9 (9%)

GenderMale (n=429) 351 (82%) 56 (13%) 36 (8%) 31 (7%)

Female (n=162) 107 (66%) 25 (15%) 32 (20%) 15 (9%)

Race

African

American/African

Heritage (n=109)

66 (61%) 17 (16%) 5 (5%) 6 (6%)

White (n=430) 351 (82%) 57 (13%) 60 (14%) 37 (9%)

Asian/Other (n=52) 41 (79%) 7 (13%) 3 (6%) 3 (6%)

Patient cumulative data on ISRs over the 48-week time period

AE, adverse event; ISR, injection site reaction. *Data are number and percentages of participants with at least 1 of the respective AEs through Week 48.


• Participants receiving CAB LA + RPV LA in the ATLAS and FLAIR studies demonstrated high

rates of adherence to injection visits through Week 48, with 98% of injections occurring within

the ± 7-day dosing window

– 2% (152/6920) of injection visits occurred outside of the +7 day injection window;

no participant with late injections met CVF criteria or had VL ≥50 c/mL at Week 48

• Injections were well tolerated

– Overall, 21% of the injections were associated with pain; 85% of CAB + RPV LA participants rated pain as ‘totally/very acceptable’ at Week 48

– The majority of participants (55%) reported ≤3 injection pain events

– Most ISRs were grade 1–2, with few associated discontinuations (<1%) of CAB + RPV LA

• For participants with planned missed injection visits, short-term oral bridging was found

to be an effective strategy for maintaining virologic suppression

ATLAS and FLAIR: Conclusions

CAB, cabotegravir; CVF, confirmed virologic failure; ISR, injection site reaction; LA, long-acting; RPV, rilpivirine; VL, viral load.


• The authors thank all study participants and their families, the ATLAS and FLAIR clinical investigators

and their staff, and study team members at ViiV Healthcare, GlaxoSmithKline, and Janssen. Professional

medical writing and editorial assistance was provided by Anna Woroniuk of SciMentum, with funding

provided by ViiV Healthcare.

Acknowledgments

adherence to long-acting injectable cabotegravir ... · atlas and flair: injection tolerability...

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