Clinical implications of Long Acting Antivirals - Virology ...

Clinical implications of Long Acting Antivirals

Andrea Calcagno

University of Torino

I have read and understood ICMJE policy on declaration of interest and I declare that I have no conflicting interest

In the past five years I received:

• research grants from Gilead, Viiv and BMS;

• speaker’s honoraria from Abbvie, BMS, Gilead, Janssen-Cilag, MSD, Viiv.

Disclosures

What happens with other Long-Acting drugs?

A. LA-antipsychotics: improve patients’ adherence (usually poor with rates of discontinuation as high as 44%) → HOSPITALIZATION

B. LA-bisphosphonates: improve patients’ adherence (usually incomplete, decreasing over time, low in subjects with cognitive deficits) →FRACTURES

C. LA-contraceptives: discontinuation rates (implants!)

D. LA-antimigraine agents: migraine frequency, the effects of migraines on daily activities, and the use of acute migraine-specific medication

Kaplan G, et al. Pat Pref Adher 2013; Lorentzon M, J Int Med 2019; Goadsby PJ, et al. NEJM 2017.

What else other Long-Acting drugs share?

Lozano MJF, Sanchez-Fidalgo S. Eur J Hosp Pharmacy 2019

Patient’s Preference

• Approved• Ibalizumab• Albuvirtide (in China)

• Phase 3+• Cabotegravir-LA• Rilpivirine-LA

LA ARVs – available and future drugs

• Phase 3• PRO-140 (Leronlimab)

• Phase 2+• Broadly-neutralizing

monoclonal antibodies• MK8591 (EfDA)

• Phase 2• GS-6207 (Capsid Inhibitor)

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-140 CCR5 binding 3 daysi.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.?

LA ARVs – available and future drugs (2)

What will not change?

The Italian Republic has had 65 governments in 73 years — one every 13 months.


EFFICACY

Efficacy of LA CAB-RPV

Margolis DA, et al. Lancet 2017; Swindells S, et al. CROI 2019; Orkin C, et al. CROI 2019; Viiv Press Release 2019

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

LATTE-2 LATTE-2* ATLAS FLAIR ATLAS-2

4 WEEKS 8 WEEKS ORAL

160 weeksNaïve, vs. Oral

48 weeksSwitch, vs. SOC

48 weeksNaïve, vs. DTG/ABC/3TC

48 weeksContin, 4 vs. 8

?Non inferiority

64 weeksContin, 4 vs. 8

How many patients discontinued LA CAB-RPV for virological failure?

Margolis DA, et al. Lancet 2017; Swindells S, et al. CROI 2019; Orkin C, et al. CROI 2019

• 2/309 in the LATTE-2

• 4/308 in the ATLAS

• 6/283 in the FLAIR

12/900 = 1.3%

Why patients stop LA-CAB RPV (ATLAS)?

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

LA CAB + RPVN=308

CARN=308

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)

Hepatitis A (2)Acute Hepatitis B (1)Acute Hepatitis C (1)Headache (1)Depression suicidal (1)Memory impairment (1)Diarrhea/nausea/headache (1)

Colitis (1)Blood creatinine increased (1)Methamphetamine overdose (1)Renal impairment (1)Anxiety disorder/depression/suicidal ideation (1)


EFFICACY

Selection of RAMs

Resistance in pts failing on LA-CAB RPV

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

• 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

A. One additional PDVF without treatment-emergent resistance occurred during the oral induction period due to oral medication non-adherence.

B. One PDVF at W4: no detectable RPV at W4 and W8, suggesting maladministration.

C. One PDVF at W48 at HIV-1 RNA 463 c/mL (confirmed at 205 c/mL).

Maintenance period

Q8W IM (n=115)

Q4W IM(n=115)

Oral CAB(n=56)

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

INI-r mutations 1c 0 0

NRTI-r mutations 0 0 0

NNRTI-r mutations 1c 0 0

Resistance in pts failing on LA-CAB RPV

Overton et al. IAS 2019; Mexico City, Mexico. Poster MOPEB257.

Study

Sex, Country, HIV-1

SubtypePrevious

CAR

Baseline RAMs†

Viral Load atSVF /

CVF (c/mL)

SVF Timepoint RAMs

Drug Sensitivity

at SVF(Fold

Change)§RT INSTI RT INSTI‡

ATLAS

F, Russia,A/A1

3TC, AZT, LPV/rE138E/

ANone 79,166 / 25,745 E138A None

RPV (2.4)CAB (0.8)DTG (0.9)

F, France,AG

3TC, AZT, NVP to 3TC, ABC, NVP

V108V/IE138K

None695 /258

V108I E138K

NoneRPV (3.7)CAB (1.2)DTG (1.0)

M, Russia,A/A1

FTC, RAL, TDF to ABC, EFV, 3TC

None None 544 / 1841 E138E/K N155HRPV (6.5)CAB (2.7)DTG (1.2)

FLAIR

F, Russia,A1

– None None373 / 456

E138E/A/K/T Q148RRPV (7.1)CAB (5.2)DTG (1.0)

M, Russia,A1


K101E G140RRPV (2.6)CAB (6.7)DTG (2.2)

F, Russia,A1


E138K Q148RRPV (1.0)CAB (9.4)DTG (1.1)


EFFICACY

Selection of RAMs

Tolerability

Tolerability

• 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)

• 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 (none after week 48)

Margolis DA, et al. Lancet 2017

Tolerability (ATLAS + FLAIR)

Overton ET, et al. IAS 2019

CAB+RPV LAN=591

CARN=591

Any drug-related AE 165 (28%) 35 (6%)

Any AEs leading to withdrawal 17 (3%) 9 (2%)

Any serious AE 24 (4%) 25 (4%)

Serious AEs related to study treatment† 1 (<1%) 1 (<1%)

Common AEs (≥5%)

Nasopharyngitis 108 (18%) 90 (15%)

Headache 73 (12%) 38 (6%)

Upper respiratory tract infection 70 (12%) 53 (9%)

Diarrhea 54 (9%) 40 (7%)

Back pain 43 (7%) 23 (4%)

Influenza 42 (7%) 34 (6%)

Pyrexia 43 (7%) 13 (2%)

AEs of special interest

Anxiety 27 (5%) 20 (3%)

Depression 16 (3%) 14 (2%)

Suicidal ideation/behavior 4 (<1%) 5 (<1%)

Injection-site reaction incidence by week1% discontinuation due to ISRs

No weight gain with LA-CAB (HPTN 077)

Lanodvitz RJ, et al. CID 2019


EFFICACY

Selection of RAMs

Tolerability

Tissue exposure

Genital exposure - LA RPV

Jackson A, et al. CPT 2014

Genital exposure - LA CAB

Spreen W, et al. JAIDS 2014

Cerebrospinal fluid concentrations and HIV RNA

Letendre S, et al. Glasgow 2018 O346

PharmacokineticsCAB (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)

Antiviral activity

Abbott real-time assay

HIV-1 RNA <50 c/mL

n/N (%)

SuperLow assay

HIV-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)

9/15*

(60)

3/3

(100)

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

(100)

3/3

(100)

12/13§

(92)

3/3

(100)

*3, 5, 5, 10, 15, and 42 c/mL

§CSF HIV-1 RNA of 2 c/mL and plasma HIV-1 RNA of <2 c/mL.

What WILL change?

What WILL change?

Treatment satisfaction

Treatment satisfaction - LA CAB RPV

Margolis DA, et al. Lancet 2017 and Kerrigan D, et al. PlosOne 2018 ; Overton ET, et al. IAS 2019.

How satisfied would you be to continue with your

present form of treatment?

Very satisfied Very dissatisfied

6 5 4 3 2 1 0

Treatment satisfaction - LA CAB RPV (2)

Murray M, et al. IAS 2019; Mexico City, Mexico. Oral MOAB0103.

Your willingness to continue with your present form of treatment?

The flexibility of your treatment recently?

The convenience of your treatment?

How easy or difficult your treatment has been recently?†

The extent to which the treatment fits in with your lifestyle?

Your current treatment?

Your willingness to recommend the treatment to someone else for HIV treatment?

The demands made by your current treatment?

Any side effects of your present treatment?

Your understanding of your HIV?

Your control of your HIV?

The amount of discomfort or pain involved with your treatment?*†

ImprovementDeterioration

How satisfied are you with:Mean HIVTSQs Change From Baseline Item Scores at Week 44

1.1

0.9

0.8

0.6

0.6

0.5

0.5

0.4

0.3

0.2

0.1

0

0.2

0.2

0

0.1

0

-0.1

0

-0.1

0

0.2

-0.1

0.2

-0.5 0 0.5 1 1.5

CAB + RPV LA CAR

What WILL change?


Adherence

LA CAB Pharmacokinetic “tail”

Trezza C Curr Opin HIV AIDS. 2015 Jul; 10(4): 239–245

Very long PK “tail” may favour RAMs selection?

Landovitz R, et al. HIVR4P 2018 OA15.06LB; Penrose KJ, et al. JID 2016.

13%

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

LA CABFemale and high BMI

LA RPV (300 mg)

What WILL change?


Adherence

Services Organization

What WILL change?


Adherence


PK and DDIs

PK (brief, I know it’s usually boring!)

AttributeCabotegravir

Oral IM

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

400mg maintenance dose (2 ml)

Dosing frequency (Phase 3)

Once daily Once monthly (Q2 months)

AbsorptionRapidly absorbed; Tmax 1-

3 hrsSlowly 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 impact

Slower 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 binding

Primarily 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

AttributeRilpivirine

Oral IM

Dose (Phase 3) 25mg900 mg loading dose

600 mg maintenance dose

Dosing frequency (Phase 3)

Once daily Once monthly (Q2 months)

Absorption Tmax 3-4 hrs Slowly absorbed, Tmax 5-8 days

Impact of Food High Not Applicable

Inter-subject PK variability

Moderate (%)Moderate to High (%) consistent

with IM dosing

Impact of covariates on PK

No age, race, or gender impact

Slower absorption rate in females

Elimination half-life 45-50 hours ~40 days (26-43 days)

Metabolism/protein binding

Primarily metabolized by CYP 3A. Potential contribution from CYP2C19.

Protein binding 99.7% protein bound

Drug Interaction Liability

Low potential to cause drug-drug interactions, potentially being a victim of CYP3A4 inducers

Low CAB PK (injection 1, male and low BMI)

Landovitz R, et al. PlosOne 2018

Drug-to-drug Interactions

FIRST PASS METABOLISM

SYSTEMIC CLEARANCE

ORAL IM

Drug-to-drug Interactions (victim)

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 cabotegravirOral cabotegravir

Rajoli RKR, et al. Clin Pharmacok 2018

Drug-to-drug Interactions (victim) (2)

Cherie BS, et al. CROI 2019

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)


(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)


(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

Drug-to-drug Interactions (perpetrator)

Taskar Ks, et al. CROI 2019. #470

• 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) was modified <25%

What WILL change?


Adherence


PK and DDIs

New technologies

Implants

Flexner C, Residential Course on HIV Pharmacology, Torino, January 2019

✓ Removable

✓ More consistent and predictable drug release

✓ PK not dependent on injection site

✓ May remain in place for years (inert, non-degradable subcutaneous versions)

o Specialized device required for insertion

o Minor surgical procedure to remove

o Regulated as both a drug and a device

o Difficulty moving to a generic marketplace

Implants and ARVs

Gunawardana M, et al. AAC 2015; Matthews R, et al. IAS 2019

Micropatches

Vora LK et al. J Contr Release 2017 and courtesy of Charles Flexner

What WILL change?


Adherence


PK and DDIs

New technologies

New drugs

New (companion?) drugs

Groble JA, et al. CROI 2019; Stephenson KE, et al. CROI 2019 #145

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 (WT) 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 WT 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 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

• 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

% In

hib

itio

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

84I

K70

E +

M1

84

I/V

WT

M1

84I

M18

4V

L7

4V

L7

4V

+ M

18

4V

Q15

1M

Q1

51

M +

M1

84

I/V

69

ins

69in

s +

M1

84

I/V

K6

5R

K65

R +

M1

84

I/V

K65

R +

L7

4I

+ M

18

4V

K6

5R

+ L

74

V +

Y1

15

F +

M18

4V

K65

R +

T6

9I

+ Q

151

MK

65

R +

T6

9I

+ Q

151

M +

M1

84

V

2 T

AM

s +

L7

4I

2 T

AM

s +

M1

84I

2 T

AM

s +

L7

4I

+ M

184

V3

TA

Ms

3 T

AM

s +

L74

V3

TA

Ms +

M1

84I/

V4

TA

Ms

4 T

AM

s +

M1

84

V5 T

AM

s +

L74

V6

TA

Ms

6 T

AM

s +

M1

84I/

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

-859

1-T

P] P

BM

C

(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

IC5

0

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 GJ, 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-8

591

0.75 mg Q

DMK-8

591

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

oug

h I

nh

ibito

ry Q

uo

tien

t

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

uotie

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 +

M1

84I/

VK

65

RK

65

R +

M1

84I/

VK

65

R +

L7

4I

+ M

18

4V

K6

5R

+ L

74

V +

Y1

15

F +

M1

84V

K65

R +

T6

9I

+ Q

15

1M

K6

5R

+ T

69

I +

Q1

51M

+ M

18

4V

K7

0E

+ M

18

4I/

V

2T

AM

s +

L74

I2

TA

Ms +

M1

84

I2T

AM

s +

L7

4I

+ M

18

4V

3 T

AM

s3

TA

Ms +

L7

4V

3 T

AM

s +

M1

84

I/V

4 T

AM

s4

TA

Ms +

M1

84

I4

TA

Ms +

M1

84

V5

TA

Ms +

L7

4V

6 T

AM

s6

TA

Ms +

M1

84

I/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, WA, USA; March 4-7, 2019.

3530

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 (WT) 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 WT virus.

Conclusion: The IQs of MK-8591 for both WT 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 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

• 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

% In

hib

itio

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

84I

K70

E +

M1

84

I/V

WT

M1

84I

M18

4V

L7

4V

L7

4V

+ M

18

4V

Q15

1M

Q1

51

M +

M1

84

I/V

69

ins

69in

s +

M1

84

I/V

K6

5R

K65

R +

M1

84

I/V

K65

R +

L7

4I

+ M

18

4V

K6

5R

+ L

74

V +

Y1

15

F +

M18

4V

K65

R +

T6

9I

+ Q

151

MK

65

R +

T6

9I

+ Q

151

M +

M1

84

V

2 T

AM

s +

L7

4I

2 T

AM

s +

M1

84I

2 T

AM

s +

L7

4I

+ M

184

V3

TA

Ms

3 T

AM

s +

L74

V3

TA

Ms +

M1

84I/

V4

TA

Ms

4 T

AM

s +

M1

84

V5 T

AM

s +

L74

V6

TA

Ms

6 T

AM

s +

M1

84I/

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

-859

1-T

P] P

BM

C

(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

IC5

0

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 GJ, 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-8

591

0.75 mg Q

DMK-8

591

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

oug

h I

nh

ibito

ry Q

uo

tien

t

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

uotie

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 +

M1

84I/

VK

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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, WA, USA; March 4-7, 2019.

3530

PGT 121 (b-MoAb)5/9 participants responded

2 had a sustained viral suppression (after one single infusion) for more than 6 months

MK-8591 (Islatravir)Nucleoside Reverse Trasncriptase Translocation inhibitor

A5357 a study of long-acting cabotegravir plus VRC01LS to maintain virologic suppression in adults living with HIV

New (companion?) drugs

Dhody K, et al. CROI 2019; Sager JE, et al. CROI 2019;

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

High genetic barrier to virus resistance

PRO 140 (leronlimab) broadly inhibits genotypically diverse viruses in vitro

Wild-type and multidrug-resistant HIV-1

Viruses resistant to maraviroc (SELZENTRY®)

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

Age 18 years

Receiving combination antiretroviral therapy for last 24 weeks

Exclusive R5-tropic virus (Trofile™ DNA Assay)

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

Nadir CD4 count >200 cells/mm3

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

Key Exclusion Criteria

Hepatitis B

A history of an AIDS-defining illness

≥ 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%)



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).


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



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.

PRO140 (leronlimab) binds to CCR5Subcutaneously, weekly

Maintenance therapy in pts with HIV RNA <50 and R5-tropic viruses

GS6207 (Capsid Inhibitor)Subcutaneous, every ? weeks

-1.8-2.2 Log10 HIV RNA in 10 day monotherapy

• Adherence

• PLWH usually come to the clinic 2-3 times/year

• What to do in case patients missing their shots? (LA-RPV much shorter half-life!) → oral drugs “reserve”?

• 6 virological failures in the ATLAS and FLAIR studies: Genotype A, 5/6 from Russia…

• “Extreme” phenotypes (very low and very high BMI)?

• Drug to drug interactions: switch to oral drugs?

Open issues?

Conclusions

Conclusions

▪ Long acting antiretrovirals will be a game-changing introduction to the anti-HIV armamentarium and will probably increase patients’ preference and quality of life;

▪ A few issues still need to be assessed in the clinical practice (BMI, adherence, certain DDIs, NNRTI resistance, etc.) as well as outpatient services organization (fridges, appointments, etc);

▪ Patients’ selection vs. patients exclusion

▪ New drugs and technologies will probably improve the efficacy and tolerability of LA-based treatments

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