Verso terapie long- acting: cosa cambia nella gestione ... · Verso terapie long-acting: cosa...

103
Verso terapie long- acting: cosa cambia nella gestione clinica del paziente Andrea Calcagno Università di Torino

Transcript of Verso terapie long- acting: cosa cambia nella gestione ... · Verso terapie long-acting: cosa...

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Verso terapie long-

acting: cosa cambia

nella gestione

clinica del paziente Andrea Calcagno

Università di Torino

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Nano-formulations?

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Solid lipid nanoparticles Liposomes

Dendrimers

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TARGETING

PASSIVE ACTIVE

NANOEMULSIONNANOSUSPENSION

TISSUE

PENETRATION

BIOAVAILABILITY

SOLUBILITY

BIO-POLYMERS

TOPICAL

ADMINISTRATION

LIPOSOME

NANO

MATERIA

L

BIOAVAILABILITY

PATHOGEN

TARGETINGTISSUE

TARGETING

SMALL LIGANDS

ANTIBODIES NUCLEIC ACIDS

PEPTIDES

PROTEINS

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LA-Cabotegravir (GSK-744)

Trezza C, et al. Current Opinion HIV AIDS 2015

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Spreen W, et al. JAIDS 2014

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Time (Weeks)

0 2 4 6 8 10 12 14 16

Me

an (

SD

) R

PV

(ng/m

L)

0

20

40

60

80

100

120

140

160

RPV 1200mg IM/900mg IM (+GSK1265744 200mg IM )

RPV 1200mg IM/600mg IM (+GSK1265744 400mg IM )

RPV Mean C0 observed in Phase III Studies of 25mg QD (80ng/mL )

Mean RPV plasma concentration-time profilesM

= q 28 day injection

Rilpivirine Plasma Concentrations Following TMC278 LA Injections are Comparable to Oral 25mg/day in HIV-infected Subjects

7

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I Long-acting in

altri ambiti di

terapia

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• Schizophrenia -- adherence

• Osteoporosis -- convenience

• Contraception -- choice

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• The majority of patients with schizophrenia relapse after 5 years and poor adherence is the most common cause.

• The discontinuation rate for oral antipsychotics is 26%-44%.

• Up to a third of patients are at least partially non-adherent.

• Non-adherence is associated with increased relapse, hospitalization and suicide.

• Long-acting injectable treatment is associated with lower rates of relapse, discontinuation and hospitalization versus oral anti-psychotics, and increased cost-effectiveness, functionality, quality of life and patient satisfaction.

• Improved quality of life reported with less frequent injections.

Use of LA in Chronic

Schizophrenia

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• Adherence to oral bisphosphonates for the treatment of osteoporosis is low.

• At least one-third of patients do not consistently take oral bisphosphonates as

prescribed.

• Rates of adherence to oral tablets decrease over time.

• Patients overwhelmingly prefer a once-yearly injectable product (IV zoledronic

acid).

• Once-yearly injectable treatment improves adherence and drug persistence and may be

especially suitable for people who do not

tolerate or adhere to oral drugs (e.g.,

people with cognitive dysfunction,

polypharmacy, physical limitations).

Use of LA in Osteoporosis

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Uptake of contraceptive implants

in SSA

- Rattan J et al., Global Health: Sci Prac 2016; 4: Suppl 2

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Uptake of contraceptive implants in

SSA

- Rattan J et al., Global Health: Sci Prac 2016; 4: Suppl 2

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• Over 40 million women worldwide use injectable contraception, and nearly half (47%) of modern

contraception users in sub-Saharan Africa rely on

injectable or implantable contraceptives to

prevent pregnancy.

• Returning to a health care provider for an injection every 2-3 months is considered a

disadvantage of DMPA. Discontinuation rates of

injectable contraceptives in sub-Saharan Africa

are high, contributing to the growing popularity

of longer-acting implants.

• Norplant-2 (levonorgestrel; JadelleTM, Levoplant, Sinoplant – 2 rods, 5-year duration) is now used

by millions of women in SSA. Cost per generic

implant is less than $15 USD (~$3 pppy for

effective hormonal contraception).

Use of LA in Hormonal Contraception

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LA Antiretrovirals

ApprovedIbalizumab (in U.S.)

Albuvirtide (in China)

Phase 3Cabotegravir-LA

Rilpivirine-LA

Phase 2+PRO-140 (Leronlimab)

Broadly-neutralizing monoclonal

antibodies

VRC01 and -LS; 3BNC117 and -LS;

10-1074 and -LS, etc.

EFdA; MK8591

Phase 1+GS-6207

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LA-CAB future companion drugs?

Mechanism Half-lifeRoute of

administration

Ibalizumab CD4 binding 3-4 days i.v. every 2 weeks

Albuvirtide Entry inhibition 10-13 days i.v. weekly

PRO-140CCR5 binding 3 days

i.v. or s.c. every

week*

BnMAb Gp120/gp41 binding Variable, days i.v.

MK8591 NRT translocation Months? implant

GS-6207 Capsid 40 days s.c.

LA-TAF NtRTI Months? implant

LA-FTC NRTI 10 days? i.m., s.c.?

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Caskey et al., New Engl J Med 2016; 375: 2019

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PK profile of

VRC01-LS

Gaudinski MR et al., PLoS Med 2018; January 24

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PK profile of PGT 121Anti V3 Env broad (60-70%)

-1.7 Log in HIV RNA at 10 days (rebound at

28)

Half-life 13-19 days in PLWH

Stephenson KE, et al. CROI 2019 #145

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Efficacy profile of PGT 1215/9 participants responded

2 had a sustained viral suppression (after

one single infusion) for more than 6 months

Stephenson KE, et al. CROI 2019 #145

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Albuvirtide + LPV/r

20 naïve patients randomized to ABT by intravenous infusion at dose

levels of 160 or 320 mg on Day 5–7 daily and then weekly plus LPV/r

(400/100 mg) twice daily

Zhang H, et al AIDS Res and Ther 2016

+52

CD4

-5

CD4

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MK-8591(4’-Ethynyl-2-Fluoro-2’-Deoxyadenosine, EFdA)

• Potent and long acting nucleoside reverse transcriptase translocationinhibitor (NRTTI)

• Multiple mechanisms of action• Immediate chain termination by inhibition of primer translocation

• Delayed chain termination which prevents nucleotide excision (a significant mechanism of NRTI drug resistance) from occurring

• MK-8591-TP concentrates in both rectal and cervical tissue

Michailidis et al 2009, 2014 J Biol Chem; Grobler et al 2017 CROI, Seattle, WA

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Ruane PJ, et al. JAIDS 2013; Friedman CROI 2016

EFdA PK and Antiviral

Effect

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Cosa non cambia?

1. Efficacia

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Phase IIb, multicenter, parallel-

group, open-label study in

ART-naive HIV-infected adults

LATTE-2 – 160

weeks

Margolis et al. HIV Glasgow; Glasgow, UK. Poster P118.

ART, antiretroviral therapy; CAB, cabotegravir; EP, extension period; IM,

intramuscular; LA, long acting; MP, maintenance period; PO, oral; QD, once daily;

Q4W, every 4 wk; Q8W, every 8 wk; RPV, rilpivirine.

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309 patients were enrolled (ITT-exposed): 91% male,

20% non-white, and 19% >100,000 c/mL HIV-1 RNA. 286

patients were randomized into the MP; 258 completed

MP with 252 entering EP

Snapshot Outcomes at Week

160

Margolis et al. HIV Glasgow; Glasgow, UK. Poster P118.

aData presented for the randomized Q8W/Q4W IM arms are inclusive of MP and EP. Data

presented for the optimized Q8W/Q4W IM arms are inclusive of on-treatment events

occurring from the first date of first injection in the EP, W100. b77 c/mL. c>50 c/mL at W96 and did not qualify for EP. dAdded in EP: CAD; MI (death);

motor neuron disease. eRelocation; entered LTFU; burden of travel; lost to FU. fAdded

in EP: PD; lost to FU; WD by patient.

Outcome at W160a

Q8W IMn (%)

Q4W IMn (%)

OptimizedQ8W IM

n (%)

OptimizedQ4W IM

n (%)

Snapshot (ITT-ME) N=115 N=115 N=34 N=10

HIV-1 RNA <50 c/mL 104 (90) 95 (83) 33 (97) 10 (100)

HIV-1 RNA ≥50 c/mL 5 (4) 0 1 (3) 0

Data in window not <50 c/mL 1 (<1)b 0 0 0

DC for lack of efficacy 1 (<1) 0 1 (3) 0

DC for other reason while not<50 c/mL

3 (3)c 0 0 0

No virologic data in window 6 (5) 20 (17) 0 0

W/D due to AE or death 1 (<1) 12 (10)d 0 0

W/D due to other reasons 5 (4)e 8 (7)f 0 0

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• Through 160 weeks, there were 2 PDVFs,

both Q8W

• No additional PDVFs occurred after Week 48 in any arm

• Resistance data were previously reported1

Protocol-Defined Virologic

Failure

Margolis et al. HIV Glasgow; Glasgow, UK. Poster P118.

PDVF, protocol-defined virologic failure; Q8W, every 8 wk.

1. Margolis et al. Lancet. 2017;390:1499-1510.

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1University of Nebraska Medical Center, Omaha, NE, United States; 2University of Guadalajara, Guadalajara, Mexico; 3Broward Health Medical Center, Fort Lauderdale, FL, United States; 4Fatebenefratelli Sacco Hospital, Milan, Italy; 5Center for Infectious Diseases, ZIBP, Berlin, Germany; 6Hospital General Universitario de Elche, Alicante, Spain; 7Maxwell Centre, Durban, South Africa; 8Central Research Institute of Epidemiology, Moscow, Russian Federation; 9ViiV Healthcare, Research Triangle Park, NC, United States; 10GlaxoSmithKline, Mississauga, ON, Canada; 11Janssen Research and Development, Beerse, Belgium

LONG-ACTING CABOTEGRAVIR + RILPIVIRINE FOR MAINTENANCE THERAPY: ATLAS WEEK 48 RESULTS

S Swindells,1 JF Andrade-Villanueva,2 GJ Richmond,3 G Rizzardini,4 A Baumgarten,5

M Masiá,6 G Latiff,7 V Pokrovsky,8 JM Mrus,9 J Huang,10 KJ Hudson,9

DA Margolis,9 KY Smith,9 P Williams,11 WR Spreen9

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ATLAS Study Design: Randomized, Multicenter, International, Open-Label, Noninferiority Study in Adults with Virologic Suppression (Ongoing)

Swindells S, et al. CROI 2019; Seattle, WA. Abstract 1475.

ART, antiretroviral therapy; CAB, cabotegravir; CAR, current ART; IM, intramuscular; INSTI, integrase strand transfer inhibitor;LA, long-acting; NNRTI, non-nucleoside RTI; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; RPV, rilpivirine; VL, viral load.

*Uninterrupted ART 6 months and VL <50 c/mL at Screening, 2× VL <50 c/mL ≤12 months; †INSTI-based regimen capped at 40% of enrolment; Triumeq excluded from study; ‡Optional switch to CAB LA + RPV LA at Week 52 for those on CAR; §Participants who withdraw/complete IM CAB LA + RPV LA must complete 52 weeks of follow-up;

‖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.

CAB LA (400 mg) + RPV LA (600 mg)§

IM monthly n=303

Screening Phase Maintenance Phase Extension Phase‡

PI, NNRTI or INSTI†

Current daily oral ART n=308N=705

PI-, NNRTI-, or

INSTI-based

regimen with

2 NRTI

backbone* Ra

nd

om

iza

tio

n

1:1

Extension Phase or

transition to the

ATLAS-2M studyOral CAB +

RPV n=308

Primary endpoint

Day 1

Baseline

Week

96

Week

48Week 4‖ Week

52

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ATLAS – Baseline Characteristics: ITT-E Population

Swindells S, et al. CROI 2019; Seattle, WA. Abstract 1475.

3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; CAB, cabotegravir; CAR, current ART; FTC, emtricitabine; INSTI, integrase strand transfer inhibitor; ITT-E, intention-to-treat exposed; LA, long-acting; NNRTI, non-nucleoside RTI; PI, protease inhibitor; RPV, rilpivirine; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate.

*Common backbone regimens included: FTC/TDF (LA 60% vs CAR 56%), FTC/TAF (LA 16% vs CAR 17%), ABC/3TC (LA 13% vs CAR 13%).

Parameter

CAB LA + RPV LA

N=308

CAR

N=308

Total

N=616

Median age (range) – year 40.0 (21–74) 43 (18–82) 42 (18–82)

Age ≥50 years – n (%) 66 (21) 96 (31) 162 (26)

Female gender – n (%) 99 (32) 104 (34) 203 (33)

Race – n (%)

White 214 (70) 207 (67) 421 (68)

Black or African American 62 (20) 77 (25) 139 (23)

Other 32 (10) 24 (8) 56 (9)

Median body mass index (range) – kg/m2 26 (15–51) 26 (18–58) 26 (15–58)

Median CD4+ cell count (range) – cells/mm3 654 (185–1903) 653 (150–2543) 653 (150–2543)

Median duration of prior ART (range) – year 4 (1–19) 4 (1–21) 4 (1–21)

Baseline third ART agent class – n (%)*

NNRTI 155 (50) 155 (50) 310 (50)

INSTI 102 (33) 99 (32) 201 (33)

PI 51 (17) 54 (18) 105 (17)

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

Swindells S, et al. CROI 2019; Seattle, WA. Abstract 1475.

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

*Adjusted for sex and baseline third agent class.

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

-6.7 0.7

-3.0

CAR LA

−10% NImargin

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

-1.2 2.5

0.6

CARLA

6% NImargin

Virologic outcomes Adjusted treatment difference (95% CI)*

1,6

92,5

5,81,0

95,5

3,6

0

20

40

60

80

100

Pro

po

rtio

n o

f P

art

icip

an

ts % CAB LA + RPV LA

(n=308)

CAR (n=308)

Virologic

nonresponse

(≥50 c/mL)

Virologic

success

(<50 c/mL)

No virologic

data

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ATLAS Snapshot Outcomes at Week 48 for ITT-E

Swindells S, et al. CROI 2019; Seattle, WA. Abstract 1475.

AE, adverse event; CAB, cabotegravir; CAR, current ART; ITT-E, intention-to-treat exposed; LA, long-acting; RPV, rilpivirine.

*Discontinued due to AEs: LA arm (n) – ISR (3); Hepatitis A (2); acute Hepatitis B (1); acute Hepatitis C (1); headache (1); depression suicidal (1); memory impairment (1); diarrhea/nausea/headache (1); CAR arm (n) – colitis (1); blood creatinine increased (1); methamphetamine overdose (1); renal impairment (1); Anxiety disorder/depression/suicidal ideation (1);

†Other reasons for discontinuation included: LA arm (n): pregnancy (4), lost to follow up (1), non-compliance with treatment (1) and relocation (1); CAR arm: pregnancy (1), lost to follow up (1), and withdrawal by participant due to frequency of visits (4).

n (%)

CAB LA + RPV LA

N=308

CAR

N=308

HIV-1 RNA <50 copies/mL 285 (92.5) 294 (95.5)

HIV-1 RNA ≥50 copies/mL 5 (1.6) 3 (1.0)

Data in window not below threshold 1 (0.3) 1 (0.3)

Discontinued for lack of efficacy 3 (1.0) 2 (0.6)

Discontinued for other reason while not

below threshold1 (0.3) 0

No virologic data 18 (5.8) 11 (3.6)

Discontinued due to AE or death* 11 (3.6) 5 (1.6)

Discontinued for other reasons† 7 (2.3) 6 (1.9)

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FLAIR Study Design: Randomized, Multicenter, International, Open-label, Noninferiority Study in ART-Naïve Adults (Ongoing)

Orkin C, et al. CROI 2019; Seattle, WA. Abstract 3947.

3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; CAB, cabotegravir; DTG, dolutegravir; IM, intramuscular; HBsAg, hepatitis B surface antigen; LA, long-acting; NNRTI, non-nucleoside reverse transcriptase inhibitor; RPV, rilpivirine.

*NNRTI RAMS but not K103N were exclusionary. †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). ‡Participants who withdraw/complete CAB LA + RPV LA enter 52-week long-term follow-up. §Participants received initial loading doses of CAB LA 600 mg and RPV LA 900 mg at Week 4. Beginning Week 8, participants received CAB LA 400 mg + RPV LA 600 mg injections every 4 wks.

Day 1 100484§ 96

Induction Phase Maintenance Phase Extension Phase

Extension

DTG/ABC/3TC Oral daily n=283

N=629

DTG/ABC/3TC

single-tablet

regimen for

20 weeks†

Randomization (1:1)

Oral CAB+ RPV n=283

Primary endpoint

Screening Phase

N=809ART-naïveHIV-1 RNA ≥1000Any CD4 countHBsAg negativeNNRTI RAMs excluded*

−4

Confirm HIV-1 RNA<50 copies/mL

−20

CAB LA (400 mg) + RPV LA (600 mg)‡

IM monthly n=278

Study Week

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FLAIR Baseline* Characteristics: ITT-E Population

Orkin C, et al. CROI 2019; Seattle, WA. Abstract 3947.

3TC, lamivudine; ABC, abacavir; CAB, cabotegravir; DTG, dolutegravir; HCV, hepatitis C virus; ITT-E, intention-to-treat exposed; LA, long-acting; RPV, rilpivirine.

*Baseline was Week −20 .

Parameter

CAB LA + RPV LA

N=283

DTG/ABC/3TC

N=283

Total

N=566

Median age (range) – year 34 (19–68) 34 (18–68) 34 (18–68)

Age ≥50 years – n (%) 33 (12) 29 (10) 62 (11)

Female gender – n (%) 63 (22) 64 (23) 127 (22)

Race – n (%)

White 216 (76) 201 (71) 417 (74)

Black or African American 47 (17) 56 (20) 103 (18)

Other or missing 20 (7) 26 (9) 46 (8)

Median body mass index (range) – kg/m2 24 (17–45) 24 (13–47) 24 (13–47)

HIV-1 RNA, copies/mL – n (%)

<100,000 227 (80) 227 (80) 454 (80)

≥100,000 56 (20) 56 (20) 112 (20)

Median Baseline CD4+ cell count (IQR) – cells/mm3 437 (314, 609) 452 (321, 604) 444 (320, 604)

<200 cells/mm3 – n (%) 16 (6) 23 (8) 39 (7)

Median Day 1 CD4+ cell count (IQR) – cells/mm3 624 (473, 839) 625 (472, 799) 625 (473, 818)

HIV-1 – HCV co-infection – n (%) 19 (7) 9 (3) 28 (5)

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FLAIR Virologic Snapshot Outcomes at Week 48 for ITT-E:

Noninferiority Achieved for Primary and Secondary Endpoints

Orkin C, et al. CROI 2019; Seattle, WA. Abstract 3947.

3TC, lamivudine; ABC, abacavir; CAB, cabotegravir; CI, confidence interval; DTG, dolutegravir; ITT-E, intention-to-treat exposed; LA, long-acting; NI, noninferiority; RPV, rilpivirine.

*Adjusted for sex and baseline HIV-1 RNA (< vs ≥100,000 c/mL).

Virologic outcomes

2,1

93,6

4,22,5

93,3

4,2

0

20

40

60

80

100

Pro

po

rtio

n o

f P

art

icip

an

ts (

%)

CAB LA + RPV LA

(n=283)

ABC/DTG/3TC

(n=283)

Primary endpoint:

LA noninferior to DTG/ABC/3TC (≥50 c/mL) at Week 48

Difference (%)

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

−2.8 2.1

−0.4

DTG/ABC/3TCCAB LA + RPV LA

Adjusted treatment difference (95% CI)*

6% NImargin

Key secondary endpoint:

LA noninferior to DTG/ABC/3TC (<50 c/mL) at Week 48

Difference (%)

CAB LA + RPV LA

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

−3.7 4.5

0.4

DTG/ABC/3TC

−10% NImargin

Virologic nonresponse

(≥50 c/mL)

Virologic success

(<50 c/mL)

No virologic data

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FLAIR Snapshot Outcomes at Week 48 for ITT-E

Orkin C, et al. CROI 2019; Seattle, WA. Abstract 3947.

3TC, lamivudine; ABC, abacavir; AE, adverse event; CAB, cabotegravir; DTG, dolutegravir; ITT-E, intention-to-treat exposed; LA, long-acting; RPV, rilpivirine.

*Relocation (1), lost to follow-up (1); †LA arm: Hepatitis A (1); acute hepatitis B (1); acute hepatitis C (1); transaminases increase (1) hepatitis A/secondary syphilis (1), injection site pain (1); injection site pain/discomfort/diarrhoea/vomiting (1); adenocarcinoma of colon (1). ** DTG/ABC/3TC arm: Renal failure (1); suicide attempt (1); ‡Tolerability of injections (1), incarceration (1), lost to follow-up (2); §Frequency of visits (participant decision [4]), noncompliance with study treatment and protocol procedures (2), relocation (1), participant decision to stop treatment (1), late to attend visits (1), lost to follow-up (1).

n (%)

CAB LA + RPV LA

N=283

DTG/ABC/3TC

N=283

HIV-1 RNA <50 copies/mL 265 (93.6) 264 (93.3)

HIV-1 RNA ≥50 copies/mL 6 (2.1) 7 (2.5)

Data in window not below threshold 2 (0.7) 2 (0.7)

Discontinued for lack of efficacy 4 (1.4) 3 (1.1)

Discontinued for other reason while

not below threshold0 2 (0.7)*

No virologic data 12 (4.2) 12 (4.2)

Discontinued due to AE† 8 (2.8) † 2 (0.7) **

Discontinued for other reasons 4 (1.4)‡ 10 (3.5)§

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Cosa non cambia?

1. Efficacia

2. Selezione di

Resistenze

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• NNRTI—K103N, E138G, and K238T (FC RPV=3.3; etravirine=1.9); INI—Q148R (FC CAB=5.1; dolutegravir=1.38)c

• No additional PDVFs beyond W48 on any arm (all subjects through W160)d

LATTE-2 - RAMs

Margolis D, et al. AIDS 2016; Abstract THAB0206LB.

PDVF: <1.0 log10 c/mL decrease in plasma HIV-1 RNA by W4, OR confirmed HIV-1 RNA ≥200 c/mL after prior suppression to <200 c/mL, OR >0.5 log10 c/mL increase from nadir HIV-1 RNA value ≥200 c/mL. aOne additional PDVF without treatment-emergent resistance occurred during the oral induction period due to oral medication non-adherence. bOnePDVF at W4: no detectable RPV at W4 and W8, suggesting maladministration. cOne PDVF at W48 at HIV-1 RNA 463 c/mL (confirmed at 205 c/mL). dContains data beyond W48.

Maintenance perioda

Q8W IM

(n=115)

Q4W IM

(n=115)

Oral CAB

(n=56)

Subjects with PDVF, n (%) 2 (1)b 0 1 (2)

INI-r mutations 1c 0 0

NRTI-r mutations 0 0 0

NNRTI-r mutations 1c 0 0

Only two subjects met PDVF criteria across the CAB IM arms through W48

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ATLAS Confirmed Virologic Failure: CAB LA + RPV LA Arm

Swindells S, et al. CROI 2019; Seattle, WA. Abstract 1475.

3TC, lamivudine; ABC, abacavir; AZT, azidothymidine; CAB, cabotegravir; CAR, current ART; CVF, confirmed virologic failure; DTG, dolutegravir; EFV, efavirenz;

FTC, emtricitabine; INSTI, integrase strand transfer inhibitor; LA, long-acting; LPV, lopinavir; NVP, nevirapine; PBMC, peripheral blood mononuclear cell; r, ritonavir; RAL, raltegravir; RAM, resistance-associated mutation; RPV, rilpivirine; RT, reverse transcriptase; SVF, suspected virologic failure; TDF, tenofovir disoproxil fumarate.

*L74I is not considered an INSTI RAM by IAS-US guidelines and has no impact on CAB activity.

Gender,

Country,

HIV-1

Subtype

Previous CAR

Baseline RAMs

(PBMC/HIV-1 DNA;

Day 1)SVF

Timepoint

Viral Load at

SVF/CVF

(c/mL)

SVF Timepoint RAMs

(HIV-1 RNA)Drug Sensitivity at

SVF

(Fold Change) RT INSTI* RT INSTI

F, Russia

A3TC, AZT, LPV/r E138E/A L74I Week 8 79,166 / 25,745 E138A L74I

RPV (2.4)

CAB (0.8)

DTG (0.9)

F, France

AG

3TC, AZT, NVP

to 3TC, ABC,

NVP

V108V/I

E138KNone Week 12 695 / 258

V108I

E138KNone

RPV (3.7)

CAB (1.2)

DTG (1.0)

M, Russia

A1

FTC, RAL, TDF

to ABC, EFV,

3TC

None L74I Week 24 544 / 1841 E138E/KN155H

L74I

RPV (6.5)

CAB (2.7)

DTG (1.2)

• Plasma CAB and RPV concentrations at the time of failure were below the population means but within the range for the large majority of individuals who maintained virologic suppression

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ATLAS Confirmed Virologic Failure: CAR Arm

Swindells S, et al. CROI 2019; Seattle, WA. Abstract 1475.

3TC, lamivudine; AZT, azidothymidine; c, cobicistat; CAR, current ART; CVF, confirmed virologic failure; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; INSTI, integrase strand transfer inhibitor; PBMC, peripheral blood mononuclear cell; RAM, resistance-associated mutation; RT, reverse transcriptase; SVF, suspected virologic failure; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate.

Gender,

Country,

HIV-1

Subtype

Study CAR

Baseline RAMs

(PBMC/HIV-1 DNA; Day 1) SVF

Timepoint

Viral Load at

SVF/CVF

(c/mL)

SVF timepoint RAMs

(HIV-1 RNA)

RT INSTI RT INSTI

M, Russia

A1 EFV, 3TC, AZT M184M/I L74I Week 20 1295 / 9727

M184V

G190SL74I

M, USA

BEVG/c, FTC, TAF None None Week 20 339 / 264 None None

F, USA

BEVG/c, FTC, TDF None None Week 32 524 / 815 M184I None

M, USA

BEVG/c, FTC, TDF None None Week 40 392 / 512 M230M/I None

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RPV resistance under LA-RPV

Penrose KJ, et al. JID 2016

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Cosa non cambia?

1. Efficacia

2. Selezione di

Resistenze

3. Tollerabilità

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• Through Week 160, the most commonly reported

non-ISR AEs for the randomized Q8W/Q4W IM arms

included nasopharyngitis (38%; 87/230), diarrhea

(22%; 50/230), and headache (22%; 50/230)

• The most commonly reported non-ISR, drug-related (per investigator) AEs for the

randomized Q8W/Q4W IM arms included pyrexia

(5%; 12/230), headache (3%; 7/230), and

fatigue (3%; 6/230)

• The most commonly reported non-ISR AEs for the

optimized Q8W/Q4W IM arms included

nasopharyngitis (14%; 6/44), back pain (11%;

5/44), and influenza (11%; 5/44)

• The most commonly reported non-ISR, drug-

related (per investigator) AEs for the

optimized Q8W/Q4W IM arms were asthenia,

fatigue and palpitations, each at 2% (1/44)

LATTE-2 Adverse Events

Margolis et al. HIV Glasgow; Glasgow, UK. Poster P118.

AE, adverse event; IM, intramuscular; ISR, injection-site reaction; Q4W, every 4 wk; Q8W, every 8 wk; RPV, rilpivirine.

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LATTE-2 Adverse Events

Margolis et al. HIV Glasgow; Glasgow, UK. Poster P118.

aData presented for the randomized Q8W/Q4W IM arms are inclusive of MP and EP. Data presented for the

optimized Q8W/Q4W IM arms are inclusive of on-treatment events occurring from the first date of first

injection in the EP, W100. bMI (possibly drug-related, fatal), epilepsy (fatal). cAdded in EP: Q8W: Hep

C; Q4W: CAD, MI, motor neuron disease, hypoesthesia/muscular weakness/fatigue; Optimized Q4W: injection

site pain.

Week 160 Safetya

Q8W IM

N=115

n (%)

Q4W IM

N=115

n (%)

Optimized

Q8W IM

N=34

n (%)

Optimized

Q4W IM

N=10

n (%)

Grade 3/4 AEs, excluding ISRs 24 (21) 29 (25) 0 1 (10)

Drug-related grade 3/4 AEs,

excluding ISRs

2 (2) 6 (5) 0 0

Serious AEs 17 (15) 21 (18) 2 (6) 0

Drug-related SAEs 0 1 (<1)b 0 0

Fatal SAEs 0 2 (2)b 0 0

AEs leading to withdrawalc 3 (3) 12 (10) 0 1 (10)

Grade 3/4 hematology labs 4 (3) 2 (2) 0 0

Grade 3/4 chemistry labs 28 (24) 38 (33) 3 (9) 1 (10)

Select grade 3-4 laboratory abnormalities

Creatine kinase (CK) 11 (10) 13 (11) 1 (3) 0

Alanine aminotransferase (ALT) 6 (5) 5 (4) 0 0

Lipase 8 (7) 7 (6) 1 (3) 1 (10)

Total neutrophils 3 (3) 2 (2) 0 0

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• In the randomized Q8W/Q4W IM arms, 99% of ISR

events were mild (85%) or moderate (14%), and 87%

resolved within 7 days

• 2/230 (<1%) had an ISR that led to discontinuation (both Q8W subjects) through

Week 160

• No randomized IM patient had an ISR that led to discontinuation after Week 48

• In the optimized Q8W/Q4W IM arms, 98% of ISR

events were mild (81%) or moderate (17%), and 91%

resolved within 7 days

• 1/44 (2%) had an ISR that led to discontinuation (Q4W)

LATTE-2 Adverse Events

Margolis et al. HIV Glasgow; Glasgow, UK. Poster P118.

IM, intramuscular; ISR, injection-site reaction; LA, long acting; Q4W, every 4 wk; Q8W, every 8 wk; RPV, rilpivirine.

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• 83/88 (94%) of CAB + RPV subjects with drug related AEs had max Grade 1 or 2*

• No cases of drug related SAEs, drug hypersensitivity (HSR) or drug induced liver injury observed on CAB + RPV arm

• AE’s leading to withdrawal: 10 (3%) on CAB + RPV vs. 5 (1%) on CAR1

ATLAS Adverse Events (excluding ISRs)

Orkin C, et al. CROI 2019; Seattle, WA. Abstract 3947.

*Grade 3 DR-AE LA arm(n): pyrexia (1), nausea (1), diarrhea (1), and headache (2), and grade 4 lipase increased (1); 1AEs leading to withdrawal: LA arm (n) – Hepatitis A (2); acute Hepatitis B (1); acute Hepatitis C (1); headache (1); depression suicidal (1); memory impairment (1); diarrhea/nausea/headache (1); asthenia & myalgia (1); anxiety (1); CAR arm (n) – colitis (1); blood creatinine increased (1); fatal methamphetamine overdose (1); renal impairment (1); anxiety disorder/depression/suicidal ideation (1);, lamivudine; ABC, abacavir; AE, adverse event; CAB, cabotegravir; DTG, dolutegravir; ISR, injection site reaction; RPV, rilpivirine.

Drug Related AEs (≥3%), n (%)Any event (per subject) 88 (29) 8 (3)

Fatigue 11 (4) 0

Pyrexia 11 (4) 0

Headache 11 (4) 0

Any AE (≥10%), n (%)

CAB + RPV

(N=308)

CAR

(N=308)

Any event (per subject) 264 (86) 220 (71)

Nasopharyngitis 52 (17) 42 (14)

Upper respiratory tract infection 32 (10) 25 (8)

Headache 34 (11) 17 (6)

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• The majority (99% [1439/1460]) of ISRs were grade 1–2 and most (88%) resolved within ≤7 days

ATLAS Injection Site Reactions (ISRs)

Swindells S, et al. CROI 2019; Seattle, WA. Abstract 1475.

CAB, cabotegravir; ISR, injection site reaction; LA, long-acting; RPV, rilpivirine.

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

Event

CAB LA + RPV LA

N=308

Participants receiving injections 303

Injections given, n 6978

ISR events, n (%) 1460 (20.9)

Pain 1208 (82.7)

Nodule 54 (3.7)

Induration 54 (3.7)

Swelling 48 (3.3)

Grade 3 ISR pain, no. of events (%) 20 (1.7)

Median duration of ISRs, days 3

Participants with ISR leading to

withdrawal, n (%)4 (1.3)

0

20

40

60

80

100

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

Pa

rtic

ipa

nts

wit

h I

SR

s (%

)

Study Week

ISR Incidence by Week

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• 75/79 (95%) of CAB + RPV subjects with drug related AEs had max Grade 1 or 2

• 1 drug-related SAE on CAB + RPV – Right knee monoarthritis (0 - DTG/ABC/3TC)

• No cases of drug hypersensitivity (HSR) or drug induced liver injury observed

• AE’s leading to withdrawal: 9 (3%) on CAB + RPV vs. 4 (1%) on DTG/ABC/3TC1

FLAIR Adverse Events (excluding ISRs)

Orkin C, et al. CROI 2019; Seattle, WA. Abstract 3947.

1Events leading to withdrawal included: CAB LA + RPV LA arm: Acute hepatitis A (n=1), B (n=2), C (n=1), Acute hepatitis A/secondary syphilis (n=1), injection site pain (n=1), injection site pain/general discomfort/diarrhea/vomiting (n=1), increased transaminases (n=1), and adenocarcinoma of colon (n=1); DTG/ABC/3TC arm: fatigue/nausea/dizziness (n=1), amnesia/disturbance in attention/dysarthria(n=1), suicide attempt (n=1) and renal failure (n=1)

3TC, lamivudine; ABC, abacavir; AE, adverse event; CAB, cabotegravir; DTG, dolutegravir; ISR, injection site reaction; RPV, rilpivirine.

Any AE (≥10%), n (%)

CAB + RPV

(N=283)

DTG/ABC/3TC

(N=283)Any event (per subject) 246 (87) 225 (80)

Nasopharyngitis 56 (20) 48 (17)

Headache 39 (14) 21 (7)

Upper respiratory tract infection 38 (13) 28 (10)

Diarrhea 32 (11) 25 (9)

Drug Related AEs (≥3%), n (%)Any event (per subject) 79 (28) 28 (10)

Headache 14 (5) 1 (4)

Pyrexia 13 (5) 0Body Temperature Increase 8 (3) 0

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• The majority (99% [2189/2203]) of ISRs were grade 1–2 and most (88%) resolved within ≤7 days

FLAIR Injection Site Reactions

Orkin C, et al. CROI 2019; Seattle, WA. Abstract 3947.

CAB, cabotegravir; ISR, injection site reaction; LA, long-acting; RPV, rilpivirine.

Bars represent incidence of onset ISRs relative to the most recent IM injection visit.*No events worse than grade 3 were reported; †ISR leading to withdrawal: 2 due to ISR pain. Two additional participants withdrew due to injection intolerability.

Event

CAB LA + RPV LA

N=283

Participants receiving injections, n 278

Injections given, n 7704

ISR events, n (%) 2203 (28.6)

Pain 1879 (85.3)

Nodule 86 (3.9)

Induration 82 (3.7)

Swelling 38 (1.7)

Warmth 38 (1.7)

Grade 3 ISR pain events, n (%) 12 (<1)*

Median duration of ISRs, days 3

Participants with ISR leading to

withdrawal, n (%)2 (<1)†

0

20

40

60

80

100

4B 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72

Pa

rtic

ipa

nts

wit

h I

SR

s (%

)

Study Week

ISR Incidence by Week

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HPTN 077

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Cosa non cambia?

1. Efficacia

2. Selezione di

Resistenze

3. Tollerabilità

4. Penetrazione nei

santuari

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1UCSD Antiviral Research Center, San Diego, CA, USA; 2Mills Clinical Research, Los Angeles, CA, USA; 3Chatham County Health Department,

Savannah, GA, USA; 4University of Nebraska Medical Center, Omaha, NE, USA; 5Office of Franco Felizarta, MD, Bakersfield, CA, USA; 6Long

Beach Education and Research Consultants, Long Beach, CA, USA; 7North Texas Infectious Diseases Consultants, P.A., Dallas, TX, USA; 8PAREXEL International, Durham, NC, USA; 9GlaxoSmithKline, Research Triangle Park, NC, USA; 10ViiV Healthcare, Research Triangle Park, NC,

USA; 11GlaxoSmithKline, Collegeville, PA, USA; 12Janssen Research and Development, Beerse, Belgium

Distribution in Cerebrospinal Fluid (CSF) of Cabotegravir (CAB) and Rilpivirine (RPV) After Intramuscular Administration of Long-Acting (LA) Injectable Suspensions in HIV-1-Infected Patients

Scott Letendre,1 Anthony Mills,2 Debbie Hagins,3 Susan Swindells,4

Franco Felizarta,5 Jerome DeVente,6 Christopher Bettacchi,7 Yu Lou,8

Susan Ford,9 Annie Cameron,9 Kenneth Sutton,10 Jafar Sadik Shaik,11

Herta Crauwels,12 Ronald D’Amico,10 Parul Patel10

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• CAB and RPV are LA injectables in phase III development for the maintenance of HIV virologic suppression

• CAB LA + RPV LA administered IM Q4W or Q8W may offer a better tolerability profile, improved adherence, and greater treatment satisfaction relative to daily oral ART

• The CNS typically has lower concentrations of ARV agents compared with blood

• This study assessed CAB and RPV distribution into the CSF and HIV-1 RNA levels within this “sanctuary” site

Background

Letendre et al. HIV Glasgow; Glasgow, UK. Oral O346.

ART, antiretroviral therapy; ARV, antiretroviral; CAB, cabotegravir; CNS, central nervous system; CSF, cerebrospinal fluid; IM, intramuscularly; LA, long-acting; Q4W, every 4 wk; Q8W, every 8 wk; RPV, rilpivirine.

CAB RPV

RPV CAB

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• To determine plasma and CSF CAB and RPV concentrations and to determine the CSF-to-plasma concentration ratio of CAB and RPV following LA administration

• To assess HIV-1 RNA suppression in plasma and CSF and the relationship between CAB and RPV concentrations in the CSF and CSF HIV-1 RNA levels

• To assess the safety and related AEs reported during the sub-study

Objectives

Letendre et al. HIV Glasgow; Glasgow, UK. Oral O346.

AE, adverse event; CAB, cabotegravir; CSF, cerebrospinal fluid; LA, long-acting; RPV, rilpivirine.

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• LATTE-2 parent studya

• HIV-1 infected adults receiving monthly (Q4W) or bimonthly (Q8W) injections during the LATTE-2 Extension period were eligible for the CNS sub-study following Week 152

Study Design

Letendre et al. HIV Glasgow; Glasgow, UK. Oral O346.

ABC, abacavir; CAB, cabotegravir; CNS, central nervous system; IM, intramuscularly; LA, long-acting; PO, oral; QD, once a day; Q4W, every 4 wk; Q8W, every 8 wk; RPV, rilpivirine; 3TC, lamivudine. aLATTE-2 Week 160 data are being presented as a poster (P118) and a thistle presentation (Wednesday, 31 October at 12:15–13:05). bParticipants who withdrew after ≥1 IM dose in the Maintenance or Extension periods entered the long-term follow-up period. cParticipants who successfully completed 96 weeks of oral CAB in the maintenance period had the option of continuing study participation in the extension period by switching to an optimized IM regimen of their choice (either Q4W and Q8W LA dosing).

CAB loading doses at Day 1 (800 mg) and Week 4 (600 mg)

Induction

Week 32

Primary analysis Dosing regimen

selection

Day 1

Randomization2:2:1

Week 48

Analysis Dosing regimen

confirmation

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

Week 96b

CAB loading dose at Day 1 (800 mg) CAB 30 mg + ABC/3TC for

20 wk

CAB 30 mg + ABC/3TC PO QD (n=56)

Maintenance periodb

Add RPV

4 wk

Extension periodc

CAB 400 mg IM + RPV 600 mg IM Q4W (n=101)

CAB 600 mg IM + RPV 900 mg IM Q8W (n=107)

Week 160

CAB 400 mg IM + RPV 600 mg IM Q4W (n=10)

CAB 600 mg IM + RPV 900 mg IM Q8W (n=34)

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• Paired plasma and CSF samples were collected 7 days (±3) after an injection visit

• CAB concentrations: total and unbound in plasma; total in CSF

• RPV concentrations: total in plasma and CSF

• Paired plasma and CSF samples for HIV-1 RNA were assessed using Abbott (<50 c/mL; plasma) and SuperLow (<2 c/mL; plasma and CSF) assays

Methods

Letendre et al. HIV Glasgow; Glasgow, UK. Oral O346.

CAB, cabotegravir; CSF, cerebrospinal fluid; LP, lumbar puncture; PK, pharmacokinetics; RPV, rilpivirine.

• A follow-up visit by phone occurred 2 weeks following LP for safety assessment

• 6 US sites participated in the CSF PK sub-study

• A sample size of 10 participants with evaluable PK per dosing arm was targeted for this sampling of CAB and RPV PK concentrations

Screening LP visit

1 wk post (±3 d)

Day 1 injection

Follow-up

2 wk

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Baseline Characteristics of CSF Sub-Study Population

Letendre et al. HIV Glasgow; Glasgow, UK. Oral O346.

BMI, body mass index; IM, intramuscularly; Q4W, every 4 wk; Q8W, every 8 wk; SD, standard deviation.

Demographics

Q8W IM

(N=15)

Q4W IM

(N=3)

Total

(N=18)

Age, mean (SD), y 37.2 (11.12) 44.0 (13.08) 38.3 (11.35)

Male gender, n (%) 12 (80) 3 (100) 15 (83)

BMI, mean (SD), kg/m2 26.7 (5.28) 26.0 (1.51) 26.5 (4.83)

Weight, mean (SD), kg 82.2 (15.27) 87.0 (18.81) 83.0 (15.40)

Race/Ethnicity, n (%)

Not Hispanic/Latino 11 (73) 3 (100) 14 (78)

White 9 (60) 2 (67) 11 (61)

Black/African American 5 (33) 0 5 (28)

Asian 1 (7) 1 (33) 2 (11)

Plasma HIV-1 RNA <50 c/mL, n (%) 15 (100) 3 (100) 18 (100)

CD4 cell count, mean (SD), cells/mm3 827 (280) 685 (164) 803 (266)

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• CSF concentrations exceeded the upper limit of the in vitro IC50 for wild-type HIV (CAB, 0.0003 µg/mL; RPV, 0.081 ng/mL), except for 1 patient with CSF RPV concentration <1 ng/mL (NQ)

• CAB CSF concentrations were significantly positively correlated with total plasma CAB concentrations (r=0.899; P<0.001)

Plasma and CSF CAB and RPV Pharmacokinetics

Letendre et al. HIV Glasgow; Glasgow, UK. Oral O346.

CAB, cabotegravir; CSF, cerebrospinal fluid; IC50, half maximal inhibitory concentration; Q4W, every 4 wk; Q8W, every 8 wk; NP, not performed; NQ, not quantifiable; RPV, rilpivirine. aCSF collection was successful in 13/15 Q8W participants.b1 participant had NQ RPV CSF concentrations (HIV-1 RNA <2 c/mL in CSF and 5 c/mL in plasma).

Pharmacokinetics

CAB (µg/mL) median (min, max) RPV (ng/mL) median (min, max)

Q8W (N=15) Q4W (N=3) Q8W (N=15) Q4W (N=3)

Total plasma 3.92(1.30, 6.41)

3.02 (2.37, 5.10)

192 (91.7, 378)

134 (83.0, 187)

Plasma unbound 0.0047 (0.0007, 0.0220)

0.0019 (0.0014, 0.0698)

NP NP

Unbound fraction in plasma, %

0.103 (0.056, 0.912)

0.075 (0.062, 1.45)

NP NP

Total CSF 0.0106 (0.0053, 0.0245)a

0.0127 (0.0082, 0.0159)

1.84 (NQ, 2.90)a,b

1.67 (1.40, 2.47)

CSF/Total plasma, %

0.304 (0.218, 0.449)a

0.344 (0.312, 0.421)

1.07 (NQ, 1.52)a,b

1.32 (1.25, 1.69)

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Plasma and CSF HIV-1 RNA

Letendre et al. HIV Glasgow; Glasgow, UK. Oral O346.

CSF, cerebrospinal fluid; Q4W, every 4 wk; Q8W, every 8 wk.

aActual HIV-1 RNA levels in plasma on Day 8 for the 6 participants who were not <2 c/mL: 3, 5, 5, 10, 15, and 42 c/mL. bN=13, failed to collect CSF for 2 participants. cAll except 1 participant in the Q8W arm had CSF viral load <2 c/mL. This participant had CSF HIV-1 RNA of 2 c/mL and plasma HIV-1 RNA of <2 c/mL.

All patients maintained high rates of virologic suppression in plasma and CSF

Antiviral activity

Abbott real-time assayHIV-1 RNA <50 c/mL

n/N (%)

SuperLow assayHIV-1 RNA <2 c/mL

n/N (%)

Q8W(N=15)

Q4W(N=3)

Q8W(N=15)

Q4W(N=3)

Plasma HIV-1 RNA on Day 8 15/15(100)

3/3(100)

9/15a

(60)3/3

(100)

CSF HIV-1 RNA on Day 8 13/13b

(100)3/3

(100)12/13b,c

(92)3/3

(100)

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Relationship Between CAB and RPV Concentration in Plasma and CSF

Letendre et al. HIV Glasgow; Glasgow, UK. Oral O346.

Individual unbound plasma cabotegravir concentrations are represented as mean of the 4 replicates.CSF, cerebrospinal fluid; IM, intramuscularly; LLQ, lower limit of quantification; Q4W, every 4 wk; Q8W, every 8 wk.

LLQ of total plasma and CSF

LLQ of total plasma

LLQ of free plasma and CSF

Q4W IM Q8W IM Q4W IM Q8W IMQ4W IM Q8W IM

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• CAB median CSF/total plasma ratios of 0.30% to 0.34% were similar for Q4W and Q8W

• CAB total concentrations in CSF exceeded unbound CAB concentrations in plasma

• RPV median CSF-to-plasma ratios of 1.07% to 1.32% were consistent with observations following oral RPV 25 mg once daily

• CAB and RPV concentrations exceeded their respective in vitro IC50 values for wild-type HIV-1, suggesting CAB and RPV achieve therapeutic concentrations in the CSF at steady-state following LA administration

• High rates of virologic suppression in plasma and CSF were observed in this sub-study with 92% to 100% of participants achieving CSF HIV-1 RNA levels <2 c/mL following CAB LA + RPV LA IM administration either Q4W or Q8W

Conclusions

Letendre et al. HIV Glasgow; Glasgow, UK. Oral O346.

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Cosa cambia?

1. Comodità dei

pazienti

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LATTE-2 Patient-Reported Outcomes at Week 96 Maintenance Treatment

Eron et al. IAS 2017; Paris, France. Slides MOAX0205LB.

CAB, cabotegravir; IM, intramuscular; LA, long acting; Q4W, every 4 weeks; Q8W, every 8 weeks; RPV, rilpivirine. aBased on observed case data set of subjects who completed HIV Treatment Satisfaction Questionnaire status version at Week 96.

How satisfied are you with your current treatment?

How satisfied would you be to continue with your present form of treatment?

Very satisfied Very dissatisfied

6 5 4 3 2 1 0

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0,44

6,12

1,05

6,43CAB LA + RPV LA (Wk

24, n=300; Wk 44,

n=300)

CAR (Wk

24, n=288; Wk 44,

n=294)

Week 24*

Week 44*

Single-item question on participants’ preference at Week 48

• ITT-E population: 86% (266/308) preferred LA; 2% (7/308) preferred daily oral therapy

• Responding participants: 97% (266/273) preferred the LA regimen over previous oral therapy

ATLAS: High Participant Satisfaction (HIVTSQs) and Preference For Injectable Therapy

Swindells S, et al. CROI 2019; Seattle, WA. Abstract 1475.

CAB, cabotegravir; CAR, current ART; HIVTSQs, HIV Treatment Satisfaction Questionnaire Status; ITT-E, intention-to-treat exposed; LA, long-acting; RPV, rilpivirine.

*Adjusted mean change from baseline; adjusted for baseline score, sex, age, race, and baseline third agent class. Error bars show 95% confidence interval.

55 66ImprovementHIVTSQs total score 50

***p<0.001

***p<0.001

Patient Preference Survey (LA arm)

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• Change in satisfaction with current treatment vs induction phase treatment was significantly higher for LA vs DTG/ABC/3TC

FLAIR: High Participant Satisfaction (HIVTSQc) and Preference For Injectable Therapy

Orkin C, et al. CROI 2019; Seattle, WA. Abstract 3947.

3TC, lamivudine; ABC, abacavir; CAB, cabotegravir; CI, confidence interval; DTG, dolutegravir; HIVTSQc, HIV Treatment Satisfaction Questionnaire (change version); ITT-E, intention-to-treat exposed; LA, long-acting; RPV, rilpivirine; SE, standard error.

*Adjusted for baseline HIV-1 RNA (< vs ≥100,000 c/mL), sex, age, and race, ± SE. Based on observed dataset of participants who completed the questionnaire at Week 48 or early withdrawal. Maintenance (Day 1) HIVTSQs baseline mean score comparable between both arms with the same mean value of 59 out of 66 points.

Patient Preference Survey

0 ImprovementHIVTSQc total score*

25,5

29,6

0 10 20 30

Week 48CAB LA + RPV LA (n=263)

ABC/DTG/3TC (n=266)

Single-item question on participants’ preference at Week 48:

• ITT-E population: 91% (257/283) preferred LA; 1% (2/283) preferred daily oral therapy

– Responding participants: 99% (257/259) preferred the LA regimen over previous oral therapy

33-33

95% CI for difference: 2.8, 5.5p<0.001

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Cosa cambia?

1. Comodità dei

pazienti

2. Aderenza

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100%

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CAB PK profile tail

Trezza C Curr Opin HIV AIDS. 2015 Jul; 10(4):

239 245

Spreen et al. JAIDS 2014;

After last dose CAB oral monotherapy

still> PA-IC90 over 14-15 days.

By Day 3, all regimens achieved mean plasma concentrations in excess of 0.67 μg/ml

(4X the PA – IC 90%). Cabotegravir concentrations remained above this threshold

throughout the monthly or quarterly dosing interval for each of the tested regimens

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HPTN 077 – LA CAB PK

tail

• 135/177 participants (33 placebo) who had follow up 76-weeks after

the final injection13%

31%

11%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

(n=40) (n=82) (n=30) (n=64)

Men Women Men Women

Week 60 Week 76

<LLOQ LLOQ to <1xPA-IC90 1x to 4 x PA-IC90

In multivariate

analysis, factors

associated with

longer PK tail

were female sex

at birth [1.45

(95%CI: 1.17 to

1.81) p=0.001]

and higher BMI

per unit increase

[1.02 (95%CI 1.01

to 1.04)

p<0.003].

Landovitz R, et al. HIVR4P 2018 OA15.06LB.

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Cosa cambia?

1. Comodità dei

pazienti

2. Aderenza

3. Organizzazione

ambulatoriale

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Cosa cambia?

1. Comodità dei

pazienti

2. Aderenza

3. Organizzazione

ambulatoriale

4. Farmacocinetica e

interazioni

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Cabotegravir Clinical Pharmacology Attributes

AttributeCabotegravir

Oral IM

Dose (Phase 3) 30mg600mg loading dose (3 ml)

400mg maintenance dose (2 ml)

Dosing frequency (Phase 3) Once daily Once monthly or Q2 months

Absorption Rapidly absorbed; Tmax 1-3 hrs Slowly absorbed, Tmax 1 week

Impact of Food None Not Applicable

Inter-subject PK variability Low (%) Moderate to High (%) consistent with IM dosing

Impact of covariates on PK No age, race, or gender impactSlower absorption rate in females and subjects with

high BMI; not clinically significant

Elimination half-life ~40 hours ~40 days (18-50 days) (absorption-limited t1/2)

Metabolism/protein bindingPrimarily metabolized by UGT1A1, with minor UGT1A9 component

Protein binding 99% protein bound

Drug Interaction Liability Low potential to cause or be a victim of drug-drug interactions

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• Plasma concentrations of IM CAB and RPV were comparable with those using oral dosing

ATLAS Plasma CAB and RPV Trough Concentrations

Swindells S, et al. CROI 2019; Seattle, WA. Abstract 1475.

CAB, cabotegravir; IM, intramuscular; LA, long-acting; RPV, rilpivirine.

Median (5th, 95th percentile) concentration–time data for CAB (left) and RPV (right) following monthly LA administration.

4 488 12 16 20 24 28 32 36 40 44

Visit (week)

0.1

1

10

Pla

sm

a C

AB

g/m

L)

ATLAS (n=308)

PA-IC90 (0.166 µg/mL)

4 488 12 16 20 24 28 32 36 40 44

Visit (week)

10

100

Pla

sm

a R

PV

(n

g/m

L)

ATLAS (n=308)

PA-IC90 (12 ng/mL)

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FIRST PASS METABOLISM

SYSTEMIC CLEARANCE

ORAL

IM

Pharmacokinetic IM cabotegravir (800 mg IM) with and without rifampicin (600 mg OD oral)

AUC = -25%

Rifampin decreased the cabotegravir area under the concentration-time curve from 0 h to infinity and the half-life by 59% and 57%

Long-acting cabotegravir

Oral cabotegravir

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DDIs and transporters

Trezza C, et al. Current Opinion HIV AIDS 2015

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OAT1 and OAT3

• In vitro studies indicated that CAB inhibits renal transporters OAT1 and OAT3 with half maximal inhibitory concentrations of 0.81 and 0.41 µM

• A mechanistic PBPK model of CAB in the adult population was built using the Simcyp® v17.1 simulator

• the exposure of OAT1/OAT3 substrates(methotrexate, tenofovir, ciprofloxacin, cidofovir, cefuroxime, oseltamivir carboxylate, baricitinib, and S44121).

• <25%Taskar Ks, et al. CROI 2019. #470

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Exp(β)

Any Contraceptive Use

Not of Reproductive Potential

Oral Contraceptive

Injectable Contraceptive

Vaginal Ring

Contraceptive

Implantable

Contraceptive

Other Contraceptive

0.97; 0.80-1.17; p=0.74

1.02; 0.88-1.18; p=0.80

1.01; 0.83-1.23; p=0.91

0.72; 0.42-1.26; p=0.26

0.92; 0.81-1.05; p=0.22

0.94; 0.84-1.04; p=0.20

0.91; 0.80-1.04; p=0.16

1.13; 0.77-1.67; p=0.54

0.94; 0.84-1.05; p=0.28

1.01; 0.93-1.10; p=0.82

0.97; 0.87-1.08; p=0.58

1.05; 0.76-1.45; p=0.75

1.04; 0.94-1.15; p=0.45

1.01; 0.93-1.09; p=0.89

1.05; 0.95-1.16; p=0.34

0.89; 0.66-1.20; p=0.44

0.79; 0.57-1.09; p=0.16

0.83; 0.64-1.07; p=0.15

0.83; 0.62-1.11; p=0.22

1.27; 0.53-3.03; p=0.59

1.07; 0.93-1.24; p=0.33

1.06; 0.94-1.18; p=0.35

1.08; 0.94-1.25; p=0.27

0.81; 0.53-1.24; p=0.34

1.08; 0.94-1.25; p=0.26

1.04; 0.94-1.16; p=0.45

1.03; 0.90-1.19; p=0.63

0.97; 0.65-1.45; p=0.87

Log (Cmax)

Log (Cτ)

Log (T1/2)

Log (AUC)

Log (Cmax)

Log (Cτ)

Log (T1/2)

Log (AUC)

Log (Cmax)

Log (Cτ)

Log (T1/2)

Log (AUC)

Log (Cmax)

Log (Cτ)

Log (T1/2)

Log (AUC)

Log (Cmax)

Log (Cτ)

Log (T1/2)

Log (AUC)

Log (Cmax)

Log (Cτ)

Log (T1/2)

Log (AUC)

Log (Cmax)

Log (Cτ)

Log (T1/2)

Log (AUC)

Hormonal Contraceptives Do Not Alter Cabotegravir PK in HIV Uninfected Women: HPTN 077 Cheríe S Blair1, Sue Li2, Gordon Chau2, Leslie Cottle2, Paul Richardson3, Mark A Marzinke3, Susan H Eshleman3, Adeola Adeyeye4, David Burns4, Alex R Rinehart5, David Margolis5, Marybeth McCauley6, Craig W Hendrix3, and Raphael J Landovitz1 on behalf of the HPTN 077 Study Team

1UCLA Center for Clinical AIDS Research & Education, 2Statistical Center for HIV/AIDS Research and Prevention, 3Johns Hopkins University School of Medicine, 4NIH/DAIDS, 5ViiV Healthcare, 6FHI360

Presented at the 2019 CROI Conference

Seattle, WA, USA, March 6, 2019

The HIV Prevention Trials Network is funded by the National Institute of Allergy and Infectious Diseases (UM1AI068619, UM1AI068613, UM1AI1068617), with co-funding from the National Institute of Mental Health, and the National Institute on Drug Abuse, all components of the U.S. National Institutes of Health. The work presented here was funded by NIH grants

UM1AI068619 (and UM1AI068613 or UM1AI1068617), and study products were provided by ViiV Healthcare. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

For more information, visit hptn.org and follow us:

Facebook: HIVptn | Twitter: @HIVptn | Youtube: HIVptn

Univariate Regression Analysis of Contraceptive Use, Contraceptive Type and Select PK Parameters [log (Cτ) and log (T1/2)]

• Long-acting injectable cabotegravir (CAB LA) is a strand-transfer integrase inhibitor, currently in development for HIV prevention and treatment

• Hormonal contraception is crucial for women of reproductive potential who are at-risk or infected with HIV to prevent the vertical transmission of HIV1

• Unexpected drug-drug interactions between ARVs and hormones for contraception or cross-sex therapy have been noted in several previous studies:

– Oral contraceptives containing ethinyl estradiol/desogestrel reduced efavirenz serum concentrations by 18% (p=0.03)2

– Ethinyl estradiol/norelgestromin transdermal patch with lopinavir/ritonavir resulted in lower ritonavir maximum concentration and AUC (8% and 24%, respectively, p=0.03)3

– Medroxyprogesterone acetate has been noted to decrease intracellular levels of tenofovir-diphosphate concentrations in blood CD4+ T cells, resulting in reduced anti-HIV activity of tenofovir4

– Estrogen with or without anti-androgen use has been noted to result in 13-38% reduction in tenofovir exposure (AUC)5-6

– In a fixed sequence crossover study, oral CAB was shown to have no impact on oral ethinyl estradiol or levonorgestrel7

• Given the widespread use of hormones for both contraception and cross-sex hormone therapy, understanding potential DDIs between sex hormones and ART is critical to the complete understanding of safety, efficacy, and acceptability of novel treatment and prevention paradigms

N PK Parameter Exp(β) 95% CI p Value

Contraceptive Use 79 log (Cτ) 0.99 0.84-1.17 0.94

log (T1/2) 0.83 0.50-1.38 0.47

Not of Reproductive Potential

12 log (Cτ) 0.95 0.84-1.06 0.33

log (T1/2) 1.15 0.78-1.70 0.48

Oral Contraceptive 18 log (Cτ) 1.00 0.90-1.10 0.92

log (T1/2) 1.08 0.78-1.49 0.64

Injectable Contraceptive

26 log (Cτ) 1.00 0.92-1.09 0.98

log (T1/2) 0.95 0.71-1.27 0.74

Vaginal Ring Contraceptive

2 log (Cτ) 0.81 0.62-1.05 0.12

log (T1/2) 1.19 0.50-2.83 0.69

Implantable Contraceptive

10 log (Cτ) 1.07 0.94-1.21 0.30

log (T1/2) 0.79 0.52-1.21 0.28

Other Contraceptive 11 log (Cτ) 1.04 0.93-1.17 0.46

log (T1/2) 0.89 0.60-1.32 0.57

BACKGROUND

CONTACT: Cherίe Blair 10833 Le Conte Ave (Room 37-121 CHS) Los Angeles, CA 90095 [email protected]

METHODS

STUDY POPULATION AND DESIGN

• We performed a secondary analysis of 85 cisgender women who were enrolled and randomized to CAB in HPTN 077, a Phase 2a multicenter study that enrolled HIV-uninfected, low-risk individuals in Malawi, Brazil, South Africa, and the United States from February 2015 – May 20168

• Participants received CAB 30mg orally daily x 4 weeks, followed by

– CAB LA 800mg IM every 12 weeks for 3 injections (Cohort 1), or

– CAB LA 600mg for 5 injections (Cohort 2)

• First two injections separated by 4 weeks, the remainder by 8 weeks

– Primary endpoint was at week 41 for both cohorts

• CAB plasma concentration measurements were obtained at weeks:

– 6, 9, 13, 18, 23, 30, 35, and 41 (Cohort 1)

– 6, 10, 13, 18, 21, 26, 29, 34, 37, 41 (Cohort 2)

• Participants were followed 52-76 weeks subsequent to their final injection

STATISTICAL ANALYSIS

• Linear regression was used to evaluate pharmacokinetic (PK) parameters between hormonal contraception (use vs not based on self-report) and contraception type (oral, injectable, vaginal ring, implants, other)

• As all women not of reproductive potential were on a hormonal contraceptive, they were included as a separate group in the analysis

• Peak concentration [Cmax], trough [Cτ], exposure after the last injection [AUC0-τ] were

estimated for each injection, and apparent terminal half-life after the last injection [T1/2app] was included in the analysis.

• A linear mixed model was used to assess associations of hormonal contraception between Cmax, Cτ, and AUC0-τ in order to account for correlations of these PK parameters across injections

• Linear regression analysis was utilized for T1/2app

• Cohorts 1 and 2 were combined in univariate and multivariate analysis

• Multivariate analysis assessed baseline covariates associated with PK parameters, adjusting for BMI and CAB dose cohort

• P-values ≤ 0.05 were considered statistically significant

Multivariate Regression Analysis of Contraceptive Use (yes vs no), Contraceptive Type and PK Parameters [log(Cmax), log(Cτ), log(AUC), and log(T1/2)], Controlling for BMI and Cohort

• Among HIV-uninfected females in HPTN 077, use of hormonal contraception (regardless of type used) did not alter the CAB LA concentration profile during injections or during the pharmacokinetic tail in either univariate or multivariate analysis

• In the multivariate analysis, the sample size of this study can rule out an effect size of a 2-fold change for log(Cmax), 2-fold change for log(Cτ), 1.8-fold change for log(AUC), and 2.1-fold change for log(T1/2) with 80% power using a 5% type 1 error rate for any hormonal contraceptive use vs not.

• No significant associations were found between hormonal contraception use and PK parameters among the women who received CAB injections in HPTN 077

• The findings in this study are consistent with the expectation that there would not be an interaction of hormonal contraception on CAB PK, since CAB is metabolized by UGT1A1 and A99.

• While we did not measure the effect of CAB on hormone concentration profiles in this study, it is expected that there would be no interaction, as oral CAB had no significant effect on PK profiles of levonorgestrel/ethinyl estradiol oral contraceptives in a prior fixed-sequence crossover study 7

• Future research regarding the effect of CAB on sex hormone levels gender-affirming therapy is warranted

CONCLUSIONS

1. Robinson et al, “Contraception for the HIV-positive woman: a review of interactions between hormonal contraception and antiretroviral therapy” J InfectiDis Obgyn 2012

2. Landolt et al, “Efavirenz, in contrast to nevirapine, is associated with unfavorable progesterone and antiretroviral levels when co-administered with combined oral contraceptives” JAIDS 2013

3. Vogler et al, “Contraceptive efficacy of oral and transdermal hormones when co-administered with protease inhibitors in HIV-1–infected women: pharmacokinetic results of ACTG trial A5188” JAIDS 2010

4. Shen et al, “Hormonal contraceptives differentially suppress TFV and TAF inhibition of HIV infection and TFV-DP in blood and genital tract CD4+ t-cells” Scientific Reports 2017

5. Hendrix et al, “Transgender women on estrogen have significantly lower tenofovir/emtricitabine concentrations during directly observed dosing when compared to cis men” HIV R4P 2018

6. Hiransuthikul et al, “Drug-drug interactions between the use of feminizing hormone therapy and pre-exposure prophylaxis among transgender women: the iFACT study” 22nd International AIDS Conference 2018

7. Trezza et al. “Lack of effect of oral cabotegravir on the pharmacokinetics of a levonorgestrel/ethinyl oestradiol-containing oral contraceptive in

8. healthy adult women” Br J Clin Pharmacol 2017

9. Landovitz et al, “Safety, tolerability, and pharmacokinetics of long-acting injectable cabotegravir in low-risk HIV-uninfected individuals: HPTN 077, a phase 2a randomized controlled trial” PLOS Medicine

2018

10. Bowers et al, “Disposition and metabolism of cabotegravir: a comparison of biotransformation and excretion between different species and routes of administration in humans” Xenobiotica 2016

REFERENCES

Women Enrolled in Study (n=132)

Cohort 1

(n=72)

Randomized to CAB (n=54)

Received at least 1 injection (n=49)

Included in Analysis (n=46)

Not of Reproductive

Potential (n=5)

Oral Contraceptive (n=11)

Injectable Contraceptive

(n=12)

Vaginal Ring Contraceptive

(n=2)

Implantable Contraceptive

(n=6)

Other Contraceptive

(n=8)

No Contraceptive (n=2)

Transgender Men Excluded from Analysis (n=3)

Randomized to Placebo (n=18)

Cohort 2

(n=60)

Randomized to CAB (n=46)

Received at least 1 injection (n=39)

Included in Analysis (n=39)

Not of Reproductive

Potential (n=7)

Oral Contraceptive (n=7)

Injectable Contraceptive

(n=14)

Vaginal Ring Contraceptive

(n=0)

Implantable Contraceptive

(n=4)

Other Contraceptive

(n=3)

No Contraceptive (n=4)

Randomized to Placebo (n=14)

Study Consort Diagram of Women Included in Analysis and Contraceptive Use

Exp β-estimate; 95% CI; p-value

0 0.5 1 1.5 2 2.5 3 3.5

Poster Number: 1791

RESULTS

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Exp(β)

Any Contraceptive Use

Not of Reproductive Potential

Oral Contraceptive

Injectable Contraceptive

Vaginal Ring Contraceptive

Implantable Contraceptive

Other Contraceptive

0.97; 0.80-1.17; p=0.74

1.02; 0.88-1.18; p=0.80

1.01; 0.83-1.23; p=0.91

0.72; 0.42-1.26; p=0.26

0.92; 0.81-1.05; p=0.22

0.94; 0.84-1.04; p=0.20

0.91; 0.80-1.04; p=0.16

1.13; 0.77-1.67; p=0.54

0.94; 0.84-1.05; p=0.28

1.01; 0.93-1.10; p=0.82

0.97; 0.87-1.08; p=0.58

1.05; 0.76-1.45; p=0.75

1.04; 0.94-1.15; p=0.45

1.01; 0.93-1.09; p=0.89

1.05; 0.95-1.16; p=0.34

0.89; 0.66-1.20; p=0.44

0.79; 0.57-1.09; p=0.16

0.83; 0.64-1.07; p=0.15

0.83; 0.62-1.11; p=0.22

1.27; 0.53-3.03; p=0.59

1.07; 0.93-1.24; p=0.33

1.06; 0.94-1.18; p=0.35

1.08; 0.94-1.25; p=0.27

0.81; 0.53-1.24; p=0.34

1.08; 0.94-1.25; p=0.26

1.04; 0.94-1.16; p=0.45

1.03; 0.90-1.19; p=0.63

0.97; 0.65-1.45; p=0.87

Log (Cmax)

Log (Cτ)

Log (T1/2)

Log (AUC)

Log (Cmax)

Log (Cτ)

Log (T1/2)

Log (AUC)

Log (Cmax)

Log (Cτ)

Log (T1/2)

Log (AUC)

Log (Cmax)

Log (Cτ)

Log (T1/2)

Log (AUC)

Log (Cmax)

Log (Cτ)

Log (T1/2)

Log (AUC)

Log (Cmax)

Log (Cτ)

Log (T1/2)

Log (AUC)

Log (Cmax)

Log (Cτ)

Log (T1/2)

Log (AUC)

Multivariate Regression Analysis of Contraceptive Use (yes vs no), Contraceptive Type and PK Parameters [log(Cmax), log(Cτ), log(AUC), and log(T1/2)], Controlling for BMI and Cohort

Exp β-estimate; 95% CI; p-value

0 0.5 1 1.5 2 2.5 3 3.5

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Nuove tecnologie per

LA ARVs?

Page 86: Verso terapie long- acting: cosa cambia nella gestione ... · Verso terapie long-acting: cosa cambia nella gestione clinica del paziente Andrea Calcagno Università di Torino. Nano-formulations?

• Potential advantages over injectables• Removable• More consistent and predictable drug release• PK not dependent on injection site• May remain in place for years (inert, non-

degradable subcutaneous versions)

• Potential disadvantages over injectables• Specialized device required for insertion• Minor surgical procedure to remove• Regulated as both a drug and a device• Difficulty moving to a generic marketplace

Long Acting ARV Implants

- Flexner C. Current Opin HIV/AIDS 2018; 13: 289

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LA ARV Implants – Tenofovir Alafenamide

M Gunawardana et al., Antimicrob Agents Chemother 2015; 59: 3913

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LA ARV Implants – Tenofovir Alafenamide

M Gunawardana et al., Antimicrob Agents Chemother 2015; 59: 3913

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MK-8591 (EFdA) Implant Formulations Release Effective Drug Levels for >180 days

- Barrett SE et al. Antimicrob Agents Chemother 2018; DOI: 10.1128/AAC.01058-18

>180-day extended release from solid state formulations after a single injection in rats.

Data suggest the potential to provide coverage for durations up to 1 year.

Page 90: Verso terapie long- acting: cosa cambia nella gestione ... · Verso terapie long-acting: cosa cambia nella gestione clinica del paziente Andrea Calcagno Università di Torino. Nano-formulations?

- Vora et al. J Contr Release 2017

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- Vora LK et al. J Contr Release 2017

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- Vora et al. J Contr Release 2017

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What is it like to wear a microneedle patch?

Page 94: Verso terapie long- acting: cosa cambia nella gestione ... · Verso terapie long-acting: cosa cambia nella gestione clinica del paziente Andrea Calcagno Università di Torino. Nano-formulations?

Estimated

cabotegravir

concentrations after

applying a 30-60 cm2

microneedle patch

(adults)

- Rajoli et al. CROI 2018

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LA @ CROI 2019

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MK-8591 Potency and PK Provide High Inhibitory Quotients at Low Doses QD and QW

AbstractBackground: MK-8591, a nucleoside reverse transcriptase translocation inhibitor (NRTTI), has demonstrated HIV-1 suppression for ≥7 days with single doses as low as 0.5 mg. It is currently in a Phase 2 clinical trial (NCT03272347) for the treatment of HIV-1 infection with once-daily (QD) administration of 0.25 mg, 0.75 mg, or 2.25 mg in combination with doravirine. Inhibitory quotients (IQ) for nucleoside inhibitors, based on the ratio of intracellular phosphorylated drug concentrations at trough (Ctrough,IC) and the intracellular concentrations required for efficacy (IC50,IC), predict virologic response. We evaluated the IQ of MK-8591-triphosphate (MK-8591-TP) in relation to other NRTIs for W T and NRTI-resistant HIV-1 to assess the likelihood of virologic response and barrier to resistance at clinically relevant doses.

Methods: MK-8591-TP, TFV-DP, 3TC-TP, and FTC-TP IC50,IC levels were determined in activated, uninfected human peripheral blood mononuclear cells (hPBMC) after 24 hr incubation with varying concentrations of MK-8591, TDF, 3TC, or FTC, followed by lysis and analysis by LC-MS/MS. MK-8591 IQs for wild-type (W T) HIV-1 were calculated as the ratio of steady-state Ctrough,IC, as observed with QD or weekly (QW) dosing in Phase 1 clinical studies, to the IC50,IC in hPBMCs. TDF, TAF, 3TC, and FTC IQs were calculated using their corresponding Ctrough,ICs, as determined after dosing in humans at clinical dose levels, and hPBMC IC50,ICs. IQs for NRTI-resistant HIV-1 were calculated using fold-shifts for NRTI-resistant clinical isolates.

Results: The MK-8591-TP IC50,IC for W T HIV-1 is >4-fold lower than any marketed NRTI. MK-8591 IQs at steady state with 0.25 mg QD and 10 mg QW dosing are 85.3 and 101, respectively, and proportionately greater for higher dose levels. Common NRTI mutations, including M184I/V, thymidine analog mutations, K65R, and K70E, confer low fold-shifts in antiviral potency, and MK-8591 retains greater IQs against these NRTI-resistant viruses than those of TDF, TAF, and 3TC with W T virus.

Conclusion: The IQs of MK-8591 for both W T and NRTI-resistant HIV-1 at low QD and QW doses are substantially higher than those of any NRTIs approved for HIV treatment. Coupled with the long intracellular half-life of MK-8591-TP, these IQs suggest the opportunity for multiple low dosing options with the potential for a high barrier to the development of resistance.

BACKGROUND

MK-8591: A Novel Nucleoside With a Unique Mechanism of Action

• MK-8591 (4’-ethynyl-2-fluoro-2’-deoxyadenosine; EFdA), licensed from Yamasa

• First-in-class nucleoside reverse transcriptase translocation inhibitor (NRTTI)

– Inhibits HIV replication through multiple mechanisms

• Potency, pharmacokinetics, and physical properties amenable to once-daily, once-weekly, and long-acting parenteral administration

• Currently being investigated in a Phase 2 clinical trial (NCT03272347) for the treatment of HIV-1 infection with once-daily (QD) administration of 0.25 mg, 0.75 mg, or 2.25 mg in combination with doravirine

N N

N

N

F

NH2

O

OH

OH

EFdA

Jay A. Grobler1; Kerry L. Fillgrove2; Daria J. Hazuda1; Qian Huang1; Ming-Tain Lai1; Randolph P. Matthews3; Deanne J. Rudd2; Ryan C. Vargo2

Departments of 1Infectious Disease and Vaccines; 2PPDM; 3Translational Pharmacology;

Merck & Co., Inc., Kenilworth, NJ, USA

SUMMARY AND CONCLUSIONS

• The MK-8591-TP IC50,IC for WT HIV-1 is >4-fold lower than any marketed NRTI

• MK-8591 IQs at steady state with 0.25 mg QD and 10 mg QW dosing are 85.3 and 101, respectively, and proportionately greater for higher dose levels

• Common NRTI mutations, including M184I/V, thymidine analog mutations, K65R, and K70E, confer low fold-shifts in antiviral potency, and MK-8591 retains greater IQs against these NRTI-

resistant viruses than those of TDF, TAF, and 3TC with WT virus

• Coupled with the long intracellular half-life of MK-8591-TP, these IQs suggest the opportunity for multiple low dosing options with the potential for a high barrier to the development of resistance

MK-8591 Exhibits Potent Antiviral Activity Against Wild-Type and NRTI-Resistant HIV-1

150

Log [Compound] (M)

MK-8591 (WT virus)

MK-8591 (M184I virus)

MK-8591 (M184V virus)

TAF (WT virus)

AZT (WT virus)

3TC (WT virus)

100

% I

nh

ibitio

n

50

0

-50

Compound Virus

IC50 (nM)

HIVNL4-3-GFPa HIVIIIB

b

MK-8591

WT 0.2 ± 0.1 (n=68) 0.2 ± 0.1 (n=6)

M184I 1.0 ± 0.4 (n=9) ND

M184V 1.6 ± 0.3 (n=10) ND

TAF WT 2.8 ± 0.8 (n=22) ND

AZT WT 2.6 ± 0.3 (n=5) 10.1 ± 3.9 (n=4)

TDF WT 73.3 ± 37.1 (n=20) 48.0 ± 29.5 (n=4)

3TC WT 112.3 ± 19.9 (n=10) 144 ± 68 (n=4)

Results are geometric means ± standard deviations, with number of replicates displayed in parentheses.aIC50s were determined by quantification of GFP-positive PBMCs infected with an HIV reporter virus in the presence of increasing compound concentrations and 10% normal human serum.bIC50s were determined by monitoring p24 production from infected PBMCs in the presence of increasing compound concentration and 10% fetal bovine serum.

MK-8591 Is More Potent Against Most Resistant Mutants Than Approved NRTIs

4 T

AM

s +

M1

84

I

K7

0E

+ M

184

I/V

WT

M1

84

IM

18

4V

L7

4V

L7

4V

+ M

18

4V

Q15

1M

Q1

51

M +

M1

84

I/V

69in

s6

9in

s +

M1

84

I/V

K65

RK

65

R +

M1

84

I/V

K65

R +

L74

I +

M18

4V

K6

5R

+ L

74

V +

Y1

15

F +

M18

4V

K65

R +

T6

9I

+ Q

15

1M

K6

5R

+ T

69I

+ Q

15

1M

+ M

18

4V

2 T

AM

s +

L74

I2

TA

Ms

+ M

184

I2 T

AM

s +

L74

I +

M18

4V

3 T

AM

s3

TA

Ms

+ L

74V

3 T

AM

s +

M1

84

I/V

4 T

AM

s

4 T

AM

s +

M18

4V

5 T

AM

s +

L7

4V

6 T

AM

s6

TA

Ms

+ M

184

I/V

0.01

0.1

1

10

100

1000

Ca

lcu

late

d h

PB

MC

IC

50 (

nM

)

MK-8591 3TC TAF AZT

Antiviral Activity of MK-8591 and NRTIs Requires Intracellular Phosphorylation to Their Active Anabolites

MK-8591-TP Accumulates to High Levels at Low Doses in Humans and Exhibits a Long Intracellular t1/2

Time (days) Time (days)

Week 1

0 1 2 3 4 5 6 7

[MK

-85

91

-TP

] PB

MC

(pm

ol/1

06 c

ells

)

[MK

-85

91

-TP

] PB

MC

(pm

ol/1

06 c

ells

)

0.1

1

10

100

0 10 20

Time (days)

30 40

0.1

1

10

0

0.1

1

10

100

Week 3

1 2 3 4 5 6 7 8 9 10 11 12 13 14

MK-8591-TP Concentration-Time Profile with QW Dosing

MK-8591-TP Concentration-Time Profile with QD Dosing

10 mg QW 30 mg QW 100 mg QW

0.25 mg MK-8591

0.75 mg MK-8591

5 mg MK-8591

Matthews, CROI 2018

Grobler et al., CROI 2016

RESULTS

Intracellular MK-8591-TP and NRTI-TP Concentrations at IC50

0.002

0.02

0.2

2

MK-8591 3TC FTC TDF

pm

ol/m

illio

n c

ells

at

IC50

MP

DP

TP

Drug Dose Levels Active Form

IC50

(fmol/106

hPBMCs)Mean ± SD

Steady-State

Ctrough

(fmol/106

hPBMCs)Mean (CV%) N IQ (90% CI)

MK-8591

0.25 mg QD

MK-8591-TP 9.74 ± 4.063

831 (28.5) 9 85.3 (44.8-126)

0.75 mg QD 3320 (23.6) 9 341 (221-460)

10 mg QW 983 (26) 6 101 (53.1-149)

3TC150 mg BID/

300 mg QD3TC-TP 635 ± 3312 2620 (112)4,5,6 68 4.13 (1.47-6.79)

FTC 200 mg QD FTC-TP 1131 4160 (63.7)7,8,9 64 36.9 (32.1-41.7)

TAF 25 mg QD TFV-DP 41.5 ± 19.72 311 (19.8)11,12 160 7.48 (3.37-11.6)

TDF 300 mg QD TFV-DP 41.5 ± 19.72 95.0 (59.7)7,8,10 63 2.29 (1.00-3.58)

1N=1, 2N=2, 3N=44Moore KH, et al. AIDS. 1999;13(16):2239-2250.5Rodriguez JF, et al. Antimicrob Agents Chemother. 2000;44(11):3097-3100.6Yuen G J, et al. Antimicrob Agents Chemother. 2004;48(1):176-182.7Jackson A, et al. J Acquir Immune Defic Syndr. 2013;62(3):275-281.8Seifert SM, et al. AIDS Res Hum Retroviruses. 2016;32(10-11):981-991.9Wang LH, et al. AIDS Res Hum Retroviruses. 2004;20(11):1173-1182.10Pruvost A, et al. Antimicrob Agents Chemother. 2009;53(5):1937-1943.11Clinical Pharmacology Review. NDA208215 FTC/TAF.12Ruane PJ, et al. J Acquir Immune Defic Syndr. 2013;63(4):449-455.

MK-8591 Administered at Low Doses Exhibits Substantially Higher Inhibitory Quotients Than Marketed NRTIs

MK-8591

0.25 mg Q

DMK-8591

0.75 mg Q

DMK-8591

10 mg Q

W FTC

200 mg Q

D

3TC 150 mg B

ID/

300 mg Q

D

TAF 25 mg Q

D

TDF 300 mg Q

D

100

Ctr

ough I

nh

ibito

ry Q

uo

tie

nt

10

1

Inhibitory Quotients of MK-8591 and NRTIs Against Wild-Type and NRTI-Resistant HIV-1

0.01

0.1

1.0

10

100

1000

10000

MK-8591 0.25 mg QD 3TC TAF TDFMK-8591 0.75 mg QD

Inh

ibito

ry Q

uo

tie

nt

(Ctr

ou

gh/I

C5

0)

WT

M1

84

IM

18

4V

L7

4V

L7

4V

+ M

18

4V

Q1

51M

Q1

51

M +

M1

84

I/V

69

ins

69

ins

+ M

18

4I/

VK

65

RK

65

R +

M1

84

I/V

K6

5R

+ L

74

I +

M1

84

VK

65

R +

L7

4V

+ Y

11

5F

+ M

18

4V

K6

5R

+ T

69

I +

Q1

51

MK

65

R +

T6

9I

+ Q

15

1M

+ M

18

4V

K7

0E

+ M

18

4I/

V

2T

AM

s +

L74

I2

TA

Ms

+ M

184

I2T

AM

s +

L7

4I

+ M

18

4V

3 T

AM

s3

TA

Ms

+ L

74

V3

TA

Ms

+ M

18

4I/

V4

TA

Ms

4 T

AM

s +

M1

84

I4

TA

Ms

+ M

18

4V

5 T

AM

s +

L7

4V

6 T

AM

s6

TA

Ms

+ M

18

4I/

V

Copyright © 2019 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved.Presented at CROI: Conference on Retroviruses and Opportunistic Infections; Seattle, W A, USA; March 4-7, 2019.

3530

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GS-6207 (Capsid Inhibitor) –

Sager JE

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PRO 140 (leronlimab) SC: Long-Acting Single-Agent Maintenance Therapy (SAMT) for HIV-1 Infection

Kush Dhody1, Kazem Kazempour1, Nader Pourhassan2 and Paul J. Maddon3

1Amarex Clinical Research, LLC, Germantown, MD 2CytoDyn Inc., Vancouver, WA, 3Maddon Advisors LLC, Scarsdale, NY

PRO 140 (leronlimab) is a humanized IgG4 monoclonal

antibody that blocks HIV-1 from entering and infecting

immune cells by binding to CCR5 with high affinity

Potently inhibits CCR5-mediated HIV-1 entry without

blocking the natural activity of CCR5 in vitro

q High genetic barrier to virus resistance

PRO 140 (leronlimab) broadly inhibits genotypically

diverse viruses in vitro

q Wild-type and multidrug-resistant HIV-1

q Viruses resistant to maraviroc (SELZENTRY®)

q Both laboratory and low-passage clinical strains

PRO 140 has been administered intravenously or

subcutaneously to more than 650 healthy and HIV-1

infected individuals in Phase I/II/III studies showing

potent, long-term antiviral activity in clinical studies.

No dose-limiting toxicity in animals and generally well

tolerated following intravenous administration of single

doses of 0.5 to 10 mg/kg or up to 700 mg weekly doses

as subcutaneous (SC) injection in clinical studies. The

longest duration of exposure lasting more than 4 years at

350 mg SC weekly dose.

Designated FDA Fast Track drug candidate

Contact: Nader Pourhassan, President & CEO, CytoDyn Inc. Email: [email protected], Phone: 503-348-4173 Kush Dhody, Vice President, Clinical Operations, Amarex Clinical Research, LLC, Email: [email protected], Phone:301-956-2536

Introduction

Conclusions and Path Forward

Results Safety Summary

Figure 1. PRO 140 (leronlimab) IC50

Fold Changes For HIV Subtypes

Figure 2. PRO 140 (leronlimab)

Concentration - Viral Inhibition Curve

Figure 3. Antiviral Activity of Short-Term Monotherapy with PRO 140

The CD03 study was designed to assess the clinical safety

and treatment strategy of PRO 140 (leronlimab) SC as a

long-acting, single-agent, maintenance therapy in virally

suppressed HIV-1 patients with CCR5-tropic HIV-1

receiving combination antiretroviral therapy.

Objectives

Key Inclusion Criteria

q Age 18 years

q Receiving combination antiretroviral therapy for last 24

weeks

q Exclusive R5-tropic virus (Trofile™ DNA Assay)

q Plasma HIV-1 RNA <50 c/mL at Screening and no

documented detectable viral loads (>50 c/mL) within the

last 24 weeks prior to Screening

q Nadir CD4 count >200 cells/mm3

q CD4 count >350 cells/mm3 at in preceding 24 weeks and

at Screening

Key Exclusion Criteria

q Hepatitis B

q A history of an AIDS-defining illness

q ≥ Grade 4 DAIDS lab abnormality

Patients were shifted from combination antiretroviral

regimen to weekly PRO 140 (leronlimab) monotherapy

for 48 weeks during the Treatment Phase with the one

week overlap of existing retroviral regimen and PRO 140

(leronlimab) at the beginning of the study treatment.

Patients who experienced virologic failure were given the

option of receiving a higher dose of PRO 140 under

rescue arm or returning to their prior ART regimen .

The first ~150 eligible subjects were enrolled to receive

PRO 140 (leronlimab) 350mg SC weekly injection in a

single-arm study. Subsequently, next ~150 subjects were

randomized 1:1 to PRO 140 (leronlimab) 350mg (Group

A) or PRO 140 (leronlimab) 525mg (Group B). An

additional ~200 subjects will be randomized 1:1 to PRO

140 (leronlimab) 525mg (Group B) or PRO 140

(leronlimab) 700mg (Group C).

Methods and Materials

Baseline Characteristics

Group A (350 mg)

Efficacy

Note: 20 subjects were early terminated from the study.

3 subjects were randomized, not treated

Note: 7 subjects were early terminated from the study.

Note: 1 subject was early terminated from the study.

Based on preliminary results, the majority of patients receiving higher doses of PRO 140 (leronlimab) (525 or 700 mg) as single-

agent maintenance therapy (SAMT) were able to maintain virologic suppression.

Pharmacokinetic parameters demonstrated dose-proportionality over the range of three doses tested in this study.

Additionally, there were no significant anti-drug antibodies to PRO 140 (leronlimab) detected in subjects.

Now that response rates for higher doses are more aligned with standard of care and the drug has been generally well-tolerated,

PRO 140 (leronlimab) could be a paradigm shift in the treatment of HIV as a single-agent maintenance therapy.

In 2019, CytoDyn is targeting a BLA submission for PRO 140 (leronlimab) in treatment of HIV-1 in treatment-experienced patients

with CCR5-tropic virus and demonstrated evidence of HIV-1 replication despite ongoing antiretroviral therapy with documented

genotypic or phenotypic multi-drug resistance. As the results from the recently completed CD02 study demonstrated that the

proportion of subjects in the PRO 140 (leronlimab) group with reductions ≥ 0.5 log10 copies/mL was significantly higher than

subjects in the placebo group (p=0.0032).

Prior clinical experience of PRO 140 (leronlimab) in over 650 subjects has provided a strong foundation for upcoming clinical trials

for cancer and graft vs. host disease (GvHD) indications.

Group B (525 mg)

Group C (700 mg)

Note: No enrolled subjects at 700mg dose have reached the 24 week time point as of 1 Jan 2019.

Parameter Statistic

PRO 140 (leronlimab)

350 mg 525 mg 700 mg

N=227 N=115 N=43

Age Mean (SD) 49.9 ( 12.5) 49.3 ( 12.0) 49.4 ( 11.7)

Gender Male, n(%) 183 ( 81.0%) 87 ( 75.7%) 34 ( 79.1%)

Race Caucasian, n(%) 149 ( 65.9%) 59 ( 51.3%) 31 ( 72.1%)

Time since HIV

Diagnosis (yrs) Mean (SD) 17.1 (9.57) 15.1 (10.3) 14.6 (10.0)

Years of HAART Mean (SD) 15.1 (8.93) 12.7 (8.26) 12.3 (9.10)

PRO 140 (leronlimab)

350 mg 525 mg 700 mg

Parameter N=226 N=115 N=43 Total # of subjects with ≥1 AE 170 (75.2%) 65 (56.5%) 21 (48.8%)

Total Number of AEs 983 314 69

Mild 62 (27.4%) 33 (28.7%) 16 (37.2%)

Moderate 90 (39.8%) 28 (24.3%) 4 (9.3%)

Severe 18 (8.0%) 3 (2.6%) 1 (2.3%)

Missing 0 (0.0%) 1 ( 0.9%) 0 (0.0%) All percentages are based on the number of subjects in the treatment group (N).

A subject is counted only once within each category.

PRO 140 (leronlimab)

350 mg 525 mg 700 mg

Parameter N=226 N=115 N=43 Total Number of Subjects with ≥1 AE 170 (75.2%) 65 (56.5%) 21 (48.8%)

Total Number of AEs 983 314 69

Definitely Related 42 ( 18.6%) 21 ( 18.3%) 5 ( 11.6%)

Probably Related 14 ( 6.2%) 0 ( 0.0%) 1 ( 2.3%)

Possibly Related 35 ( 15.5%) 2 ( 1.7%) 1 ( 2.3%)

Unlikely 22 ( 9.7%) 12 ( 10.4%) 7 ( 16.3%)

Unrelated 57 ( 25.2%) 30 ( 26.1%) 7 ( 16.3%) All percentages are based on the number of subjects in the treatment group (N).

A subject is counted only once within each category.

PRO 140 (leronlimab)

350 mg 525 mg 700 mg

Parameter N=226 N=115 N=43

Number of subjects with any reported SAE, n(%) 19 (8.4%) 4(3.5%) 2 (4.7%)

Incidence of all SAEs 23 5 2

All percentages are based on the number of subjects in the treatment group (N).

A subject is counted only once within each category.

PRO 140 (leronlimab)

350 mg 525 mg 700 mg

Parameter N=226 N=115 N=43 Total Number of Subjects with ≥ Injection Site Reaction

59 ( 26.1%) 19 ( 16.5%) 1 ( 2.3%)

Total Number of Injection Site

Reactions 164 78 1

All percentages are based on the number of subjects in the treatment group (N).

A subject is counted only once within each category.

Summary of AEs by Relationship Summary of Adverse Events (AEs) by Severity

Summary of Serious Adverse Events (SAEs) Injection Site Reactions (ISR)

Virologic failure is defined as two consecutive plasma HIV-1 RNA levels of ≥200 c/mL.

None of the reported SAEs were definitely or probably related to PRO 140 (leronlimab).

Overall, the majority of AEs were considered mild in nature and there were no patterns of drug-related toxicities observed.

Approximately 95% of injection site reactions were mild in intensity and considered to be self-resolving.

No dose-proportional increase in incidence and severity of AEs were reported with higher doses of PRO 140 (leronlimab).

Subjects who experienced virologic failure were able to achieve viral suppression upon re-initiation of baseline HAART regimens

without the loss of any treatment options.

No evidence of emergence of viral isolates with reduced susceptibility to PRO 140 (leronlimab) or altered viral tropism in subjects

experiencing virologic failure.

47.3%

65.4%

81.4%

73.0%

86.8% 88.6% 83.7%

100.0%

0.0%

10.0%

20.0%

30.0%

40.0%

50.0%

60.0%

70.0%

80.0%

90.0%

100.0%

12 Weeks 24 Weeks 48 Weeks

% S

ub

ject

s

Timepoint

Summary of Virologic Suppression (VL <50 c/mL)

350 mg

525 mg

700 mg

47.3%

22.6%

14.0%

30.8%

13.2%

0.0%

12.9%

6.8%

0.0%

10.0%

20.0%

30.0%

40.0%

50.0%

60.0%

70.0%

80.0%

90.0%

100.0%

350 mg 525 mg 700 mg

% S

ub

ject

s

Dose Group

Summary of Virologic Failure (Two consecutive VL>200 c/mL)

0-12 Weeks

12-24 Weeks

24-48 Weeks

Note: The PRO 140_CD03 study is currently ongoing. The baseline characteristics and results presented in

this poster are based on interim data as of 01 Jan 2019.

Page 99: Verso terapie long- acting: cosa cambia nella gestione ... · Verso terapie long-acting: cosa cambia nella gestione clinica del paziente Andrea Calcagno Università di Torino. Nano-formulations?

Group A (350 mg)

Note: 20 subjects were early terminated from the study.

3 subjects were randomized, not treated

Note: 7 subjects were early terminated from the study.

Note: 1 subject was early terminated from the study.

Group B (525 mg)

Group C (700 mg)

Virologic failure is defined as two consecutive plasma HIV-1 RNA levels of ≥200 c/mL.

Efficacy

Note: No enrolled subjects at 700mg dose have reached the 24 week time point as of 1 Jan 2019

47.3%

65.4%

81.4%

73.0%

86.8% 88.6% 83.7%

100.0%

0.0%

10.0%

20.0%

30.0%

40.0%

50.0%

60.0%

70.0%

80.0%

90.0%

100.0%

12 Weeks 24 Weeks 48 Weeks

% S

ub

ject

s

Timepoint

Summary of Virologic Suppression (VL <50 c/mL)

350 mg

525 mg

700 mg

47.3%

22.6%

14.0%

30.8%

13.2%

0.0%

12.9%

6.8%

0.0%

10.0%

20.0%

30.0%

40.0%

50.0%

60.0%

70.0%

80.0%

90.0%

100.0%

350 mg 525 mg 700 mg %

Su

bje

cts

Dose Group

Summary of Virologic Failure (Two consecutive VL>200 c/mL)

0-12 Weeks

12-24 Weeks

24-48 Weeks

Page 100: Verso terapie long- acting: cosa cambia nella gestione ... · Verso terapie long-acting: cosa cambia nella gestione clinica del paziente Andrea Calcagno Università di Torino. Nano-formulations?

Long-Acting Emtricitabine Prodrugs Provide Protection From HIV Infection In VivoPaul Curley1, James J Hobson2, Neill J Liptrott1, Amer Al-khouja3, David Meyers3, Caren L. Freel Meyers3, Charles Flexner4, Marco Siccardi1, Steve Rannard2

Larisa Poluektova5 and Andrew Owen1

1 Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool,, UK, 2 Department of Chemistry, University of Liverpool, Crown Street,, UK , 3 Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine,

Baltimore, MD, USA , 4 Johns Hopkins University School of Medicine and Bloomberg School of Public Health, Baltimore, MD, USA , 5 Department of Pharmacology & Experimental Neuroscience, University of Nebraska Medical Centre, Omaha, NE, USA

Poster Number: 2262 Contact: [email protected]

Funded by National Institutes of Health - 1R01AI114405-01

• Antiretroviral drugs are predominantly administered orally for both

therapy and pre-exposure prophylaxis (PrEP).

• Despite ease of administration, oral delivery is prone to patient non-

adherence exacerbated for some drugs by pill fatigue and

gastrointestinal intolerance (1).• By decreasing frequency of administration, long-acting injectables

(LAIs) may offer an effective strategy to circumvent these issues (2).• We report here a preclinical assessment of LAI semi-solid prodrug

nanoparticle (SSPN) formulations of novel emtricitabine (FTC)

prodrugs to prevent HIV infection.

Background• SSPNs of FTC carbamate/carbonate prodrugs were generated using a proprietary

emulsion-templated freeze-drying technology.

• 2 lead formulations were tested for their ability to prevent HIV infection in NSG-

cmah-/- mice humanised by CD34+ cell transplantation.

• Animals received 140 mg/kg FTC equivalent (SSPN 9 or 10) via 2 intramuscular

injections vs an untreated control (n= 7-6 per group).

• At days 7 and 14 mice were challenged intraperitoneally with a 103 TCID50 dose of

HIVADA.

• Animals were sacrificed at 28 days post infection.

• Plasma samples were taken for determination of viral load (VL). Tissue samples were

collected for viral RNA and proteins detection via RT-PCR and immunohistology.

Methods

Conclusions

Results • Mice treated with SSPN 9 and 10 demonstrated undetectable VL

(700 copies/mL detection limit), and HIV RNA remained

undetectable 28 days post infection in plasma, spleen, lung and

liver in all animals for the 7 day challenge.

• Following 14-day challenge, mice treated with SSPN 9

demonstrated undetectable HIV in plasma and all tissues.

• Mice treated with SSPN 10 demonstrated 2 mice had detectable

plasma VL (4.77 x 103 copies/mL) and 3 mice showed presence

of HIV RNA in plasma and proteins in spleen, lung and liver in

day 28.

• HIV was detectable in all untreated animals.

• The data presented here demonstrate both

formulations were 100% effective at

preventing HIV infection 7 days post LAI

administration.

• Following 14 days, SSPN 9 prevented HIV

infection in 100% of mice while SSPN 10

prevented infection in 50% of mice.

• These data indicate great potential for

delivering FTC via LAI and the approach

may support LAI development for PrEP.

• Further studies will aim to optimise

formulations to produce exposure beyond 14

days and to assess applications in therapy as

part of a combination.

References(1) Curley et al, Advances in nanomedicine drug delivery applications for HIV therapy, Future Science OA, 2017(2) Owen A & Rannard S, Strengths, weaknesses, opportunitiesand challenges for long acting injectable therapies: Insights forapplications in HIV therapy, Advanced Drug Delivery Reviews,2016

Figure 1 shows the experimental design used to investigate the potential for LAI SSPN formulations to prevent HIV infection

Co

nt r

ol

SS

PN

9

SS

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10

0

1 0

2 0

3 0

4 0

S p l e e n

C o n d i t i o n

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14 Day Challenge

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7 Day Challenge

Control SSPN 9

Figure 3 plasma viral load at 7 and 14 days post IM injection.Plasma samples were taken 14 days and 28 days post HIVinfection.

Figure 4 Characterisation of human PBMCs by flow cytometry. Blood samples were collectedat point of termination and stained for expression of CD45 mononuclear cells and CD3 T Cells.T cells were also stained for CD4 and CD8 expression assessed.

Figure 5 shows detection of HIV-1 Gag-p24 rna via PCR in humanised mice following HIV infection 7 and 14days post IM injection. Tissue samples from spleen, lung and liver were taken 28 days post HIV infection.

Figure 6 Representativehistopathology samplestaken from spleen, liverand lung tissues 7 dayspost IM injection from theA) control group and B)SSPN 9 treated group.Tissue samples werecollected 28 days postHIV infection. Sampleswere stained for HLA- DRand Gag-p24 6A highlightGag-p24 positive stainingin the control group(brown). No Gag-p24 wasdetected in the SSPN 9treated group.

A B

0 2 0 0 4 0 0 6 0 0 8 0 0

1

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1 0 0 0

T i m e ( h o u r s )

FT

C P

las

ma

co

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en

tr

atio

n (

ng

/mL

)

Figure 2 PK profile of the SSPN 9 over 28 days following2 intra-muscular injections (1 injection in each leg, 70mg/kg mg/kg based on FTC content). PK was examinedin BALB/c mice in order to inform PD studies.

SSPN 9 Plasma Concentrations

HLA-DR HIV-1 p24 HLA-DR HIV-1 p24

U n t r e a t e d S D N 9 S D N 1 0

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14 days post infection 28 days post infection

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Page 102: Verso terapie long- acting: cosa cambia nella gestione ... · Verso terapie long-acting: cosa cambia nella gestione clinica del paziente Andrea Calcagno Università di Torino. Nano-formulations?

Cost-effectiveness of Long-Acting ART for Adolescents and Young Adults in Kenya

Jessica Culhane1, Monisha Sharma1, Kate Wilson1, D. Allen Roberts1, Cyrus Mugo2, Dalton Wamalwa2, Irene Inwani2, Ruanne Barnabas1, Pamela Kohler1 1University of Washington, 2University of Nairobi/Kenyatta National Hospital

RESULTS

• We project an LA-ART intervention for Kenyan AYA would prevent 9,800-40,500 new HIV infections in the overall population over ten years, along with 4,500-20,500 deaths averted

• The maximum incremental cost of LA-ART administration to remain cost-effective is between $18-$231 USD depending on uptake/adherence scenario and cost-effectiveness threshold ($500/DALY averted or Kenya’s GDP ($1,508) / DALY averted)

CONCLUSIONS

• Providing LA-ART to AYA in Kenya has the potential to avert thousands of HIV infections and save thousands of lives through increased treatment adherence.

• For LA-ART to be cost-effective in this population, it needs to be low-cost.

• Results were sensitive to the rate of viral suppression under LA-ART

#1076

Figure 1. Model transition diagram: Schematic of HIV natural history progression by CD4 count, viral load, and ART use.

Table 1: Modeled scenarios

2017 2029

Proportion of HIV-positive Kenyans on ART 75% 81%a

Adherence Scenario

Base High Medium Low Variable

Proportion of AYA on ART

who switch to LA-ARTb0% 85% 85% 85%

Varies by

agec

Viral suppression of AYA

on LA-ARTd n/a 94% 85% 75%e 94%

Overall (oral and long-

acting) viral suppression of

AYA ART users

75% 91% 83% 79% 90%

a Assumes UNAIDS target of 90% aware of status, 90% on ART is reached by 2029.

b 85% of AYA on ART switching to LA-ART based on LA-ART interest surveys in U.S.6,7

c 95% of AYA who are not virally suppressed under oral ART and 75% who are suppressed under oral ART

d 94% viral suppression based on LATTE-2 phase 2 trial3e Assumes non-adherent LA-ART users receive one injection per year

OBJECTIVES

BACKGROUND

• Adolescents and young adults (AYA) ages 10–24 years in sub-Saharan Africa (SSA) are disproportionately affected by HIV1

• Despite high efficacy of oral ART, viral suppression among AYA living with HIV in SSA remains low2

• Long-acting ART (LA-ART) may simplify adherence and consequently decrease transmission, morbidity, and mortality in this priority population

• In a phase II trial, injectable LA-ART with 8-week duration resulted in 94% viral suppression at 96 weeks; HIV patients have shown high interest in LA-ART3

• LA-ART will likely cost more to administer than oral ART ($147/person on ART in Kenya4,5), and the cost needs to be balanced with the health benefits

• Adapted a compartmental mathematical model from a previously published HIV model, with new AYA age-specific parameters

• Simulated HIV acquisition, transmission, natural history, and viral suppression, calibrated to HIV prevalence in Kenya

• Model stratified by age, sex, sexual activity (low, medium, high), circumcision status, and ART use

• Modeled four LA-ART adherence scenarios (Table 1).

• Assessed population-level effects of LA-ART over a 10-year time horizon and calculated the maximum incremental cost of LA-ART at which it would be considered cost-effective compared to oral ART

• Project health benefits of providing LA-ART to AYA currently on oral ART in Kenya

• Determine the maximum cost at which LA-ART will remain cost-effective in Kenya

METHODS

Figure 2. Model Calibration: Comparison of modeled age-specific HIV prevalence to the observed 2012 Kenya AIDS Indicator Survey prevalence

$82

$229

$42

$121

$18 $50

$83

$231

$500 ICER KENYA GDP ($1,508) ICER

High Medium Low Variable

40,540

20,480 17,804 11,061 9,836

4,488

38,251

19,504

HIV INFECTIONS AVERTED DEATHS AVERTED

High Medium Low Variable

Funding: National Institutes of Health R01HD08507 (PI: Kohler)

Figure 3. Proportion of HIV-positive AYA who are on ART and virally suppressed under each model scenario

Figure 4. Cumulative HIV infections and deaths averted over 10-year projection by model scenario

Figure 5. Maximum incremental cost of LA-ART in order to be cost-effective by model scenario and ICER threshold ($500 and 1,508/DALY averted)

References: 1 UNAIDS 2018, 2Adejumo 2015, 3Margolis 2017, 4Eaton 2014, 5CHAI 2018, 6Williams 2013, 7Weld 2018

LIMITATIONS

• Model results are specific to Kenya, but we expect our qualitative findings to apply to other settings in SSA with generalized HIV epidemics

• Increases in drug resistance due to non-adherence to LA-ART would decrease health benefits and should be evaluated in future analyses

Page 103: Verso terapie long- acting: cosa cambia nella gestione ... · Verso terapie long-acting: cosa cambia nella gestione clinica del paziente Andrea Calcagno Università di Torino. Nano-formulations?

CONCLUSIONI

• LA CABO + RPV associati a una

elevata efficacia (rarissima

selezione di RAMs), ottima

tollerabilità e una netta

preferenza da parte dei

pazienti arruolati

• Cambierà l’approccio alla

visita ambulatoriale

• Servizio dedicato?

• In caso di mancata visita?

• Dovremo generare dati negli

«stati estremi» (peso, età,

insufficienza d’organo) e con

co-trattamenti