HIV Drug Update with LATTE Study - Albany Medical … · 4/3/2015 1 HIV Drug Update with LATTE...

4/3/2015

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HIV Drug Update with LATTE Study

Long‐Acting Antiretroviral Treatment Enabling Study

Alyssa Shon, MDAssistant Professor

Infectious Disease, University at BuffaloErie County Medical Center Immunodeficiency Services

April 3, 2015

Disclosure

• Synaxis, GSK/ViiV, Pfizer, Merck, EMD Serono, Cubist, Actelion (Clinical trials)

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Pre‐Test

• Which of the following is NOT true about cabotegravir?1. Cabotegravir is an investigational integrase DNA

strand transfer inhibitor2. It can be used for intramuscular injection as a long‐

acting formulation.3. It is an analogue of dolutegravir.4. It is a novel nucleoside reverse transcriptase

inhibitor that can be used with rilpivirine.5. Its long‐acting intramuscular formulation may be a

possible PrEP therapy as quarterly injections in high risk patients.

Objectives

• Discuss key components of the LATTE study including safety and efficacy considerations

• Describe novel injectable therapy options in the role of maintenance therapy in HIV treatment

• Review the role of injectable therapy options in pre‐exposure prophylaxis (PrEP)

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CabotegravirGSK1265744 (744)

• Next generation integrase strand transfer inhibitors (INI) – Once daily dosing without PK

booster– Improved in vitro resistance

profile with potential to treat first generation INI resistance

– Analogue of dolutegravir– Oral administration with T1/2 =

40 hours– Good virologic response at 5

and 30mg/day as oral 10 –day monotherapy

– No significant CYP induction

Margolis et al. CROI 2014; Boston, MA. Abstract 91LB.

Spreen et al. HIV Clin Trials. 2013;14:192‐203.

Cabotegravir Fold Change Against RAL/EVG Resistant Signature Mutation Site‐Directed Molecular Clones (SDMs)

Fold Chan

ge

Cabotegravir retains substantial activity against RAL/EVG resistant signature mutation SDMs

T66A

T66I

T66K

E92Q

E92V

N155H

Q148H

Q148K

Q148R

Y143C

Y143H

Y143R

0

20

40

60

80

100 S/GSK1265744

Dolutegravir

Raltegravir

Elvitegravir

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LATTE Objectives

• Investigate the safety, tolerability and efficacy of cabotegravir across 3 doses for HIV treatment

• Select an oral dose of cabotegravir for further evaluation

• Demonstrate safety and efficacy with a novel 2‐drug regimen for maintenance therapy, cabotegravir + rilpivirine

• Facilitate the conduct of a second phase IIb study, evaluating the long‐acting injectable regimen, cabotegravir LA and rilpivirine LA


• Phase IIb, randomized, multicenter, partially blind, dose‐ranging study• 744 + NRTI subjects with a W20 HIV‐1 RNA <50 c/mL simplified to 744 + RPV at W24

• Primary endpoint: % HIV‐1 RNA <50 c/mL at 48 weeks (FDA “Snapshot”) – Intent‐to‐treat exposed (ITT‐E) – received at least one dose of Investigational Product (IP)– Intent‐to‐treat maintenance exposed (ITT‐ME) – received at least one maintenance dose

LATTE Study Design

*ABC/3TC or TDF/FTC

2416 20 48 9672

HIV ART‐naive

HIV‐1 RNA ≥1000 c/mL

CD4 ≥200 cells/mm3

1:1:1:1 Randomization

Stratified by VL

and NRTI

744 30 mg + 2 NRTIs

744 10 mg + 2 NRTIs*

Oral Induction Phase

744 60 mg + 2 NRTIs

EFV 600 mg + 2 NRTIs

Oral Maintenance Phase

744 10 mg + RPV 25 mg

744 30 mg + RPV 25 mg

744 60 mg + RPV 25 mg

WeekD1

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744 10 mg n=60

744 30 mgn=60

744 60 mgn=61

EFV 600 mgn=62

Age Median (y) 32.0 32.5 36.0 32.5

Gender Male 95% 97% 93% 98%

Race White 62% 65% 59% 63%

African American/African 35% 28% 30% 32%

Ethnicity Hispanic/Latino 15% 27% 23% 19%

Baseline HIV‐1 RNA Median (log10 c/mL) 4.281 4.178 4.349 4.343

Median (c/mL) 19,099 15,066 22,336 22,029

≥100,000 c/mL 13% 12% 20% 13%

Baseline CD4+ Median (cells/mm3) 415.0 404.0 420.0 416.5

<200 cells/mm3 3% 7% 3% 2%

Hepatitis coinfection HCV Ab + 0% 8% 7% 2%

Investigator‐selected dual NRTIs at Day 1

TDF/FTC 62% 62% 61% 61%

ABC/3TC 38% 38% 39% 39%

Baseline Characteristics – ITT‐E


Subjects withdrawnW24‐W48

744 10 mgn=60

744 30 mgn=60

744 60 mgn=61

744 totaln=181

EFV600 mgn=62

Subtotal 2 (3%) 3 (5%) 1 (2%) 5 (3%) 3 (5%)

Subject Disposition ‐ ITT‐E

Subjects withdrawnthrough W48

744 10 mg n=60

744 30 mgn=60

744 60 mgn=61

744 totaln=181

EFV 600 mgn=62

Total 10 (17%) 10 (17%) 7 (11%) 27 (15%) 18 (29%)

Adverse event 1 (2%) 1 (2%) 4 (7%) 6 (3%) 8 (13%)

Lack of efficacy 5 (8%) 2 (3%) 2 (3%) 9 (5%) 5 (8%)

Insufficient viral load 3 (5%)* 0 1 (2%)† 4 (2%) 1 (2%)‡

PDVF 2 (3%) 2 (3%) 1(2%) 5 (3%) 4 (6%)

Protocol deviation 1 (2%) 1 (2%) 1 (2%) 3 (2%) 0

Lost to follow‐up 1 (2%) 2 (3%) 0 3 (2%) 3 (5%)

Withdrew consent 2 (3%) 3 (5%) 0 5 (3%) 1 (2%)

Week 20 HIV‐1 RNA = *744 10 mg ‐ 51; 107; 189 c/mL; †744 60 mg ‐ 108 c/mL; ‡EFV 600 mg ‐ 146 c/mL


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Primary Endpoint Virologic Success: HIV‐1 RNA <50 c/mL by FDA Snapshot (ITT‐E)

Week

744 overall response W4882%

EFV response W4871%

744 overall response W2487%

EFV response W2474%

Median (IQR) change from baselineCD4+ cell count (cells/mm3)

Week 48744 overall +219 (141,343)

EFV +227 (134,369)

Proportion, %

242 4 8 12 16 4032 48362628BL0

20

40

60

80

100

744 10 mg (N=60) 744 30 mg (N=60) 744 60 mg (N=61) EFV 600 mg (N=62)

Induction Phase Maintenance Phase


Secondary Endpoint – Maintenance Population Virologic Success: HIV‐1 RNA <50 c/mL by Snapshot (ITT‐ME)

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Week

Proportion, %

2 4 8 12 16 4032 48362628BL

*EFV patients with a week 24 visit

0

20

40

60

80

100

744 10 mg (N=52) 744 30 mg (N=53) 744 60 mg (N=55) EFV 600 mg (N=47)

Induction Phase Maintenance Phase

Percent <50 c/mL ‐ Snapshot (ITT‐ME)

Week 24 Week 48

744 10 mg (n=52) 50 (96%) 48 (92%)

744 30 mg (n=53) 50 (94%) 48 (91%)

744 60 mg (n=55) 53 (96%) 53 (96%)

EFV (n=47)* 45 (96%) 44 (94%)


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• Similar response rate for CAB + RPV, relative to continuing EFV + NRTIs

• Similar response across CAB doses

Treatment Outcomes ‐Maintenance Population HIV‐1 RNA <50 c/mL by Snapshot (ITT‐ME)

Outcome at Week 48

74410 mg n=52

74430 mgn=53

74460 mgn=55

744totaln=160

EFV 600 mgn=47*

Virologic success 48 (92%) 48 (91%) 53 (96%) 149 (93%) 44 (94%)

Virologic failure 3 (6%) 5 (9%) 1 (2%) 9 (6%) 2 (4%)

Data in window not <50 c/mL 3 (6%) 3 (6%) 1 (2%) 7 (4%) 1 (2%)

Discontinued for lack of efficacy 0 0 0 0 1 (2%)

Change in ART 0 2 (4%)† 0 2 (1%) 0

No virologic data at Week 48 1 (2%) 0 1 (2%) 2 (1%) 1 (2%)

Discontinued due to AE‡ 1 (2%) 0 1 (2%) 2 (1%) 1 (2%)

*EFV patients with a W24 visit†Carried forward from Induction Phase‡Abnormal ECG (10 mg); anxiety (60 mg); colitis (EFV)


Protocol‐Defined Virologic Failure

744 totaln=181

EFVn=62

Subjects with PDVF during Induction 3* (2%) 3 (5%)*1 subject per 744 doseNo NRTI, NNRTI or INI treatment‐emergent mutations

PDVF: <1.0 log10 c/mL decrease in plasma HIV‐1 RNA by Week 4 OR confirmed HIV‐1 RNA ≥200 c/mL at or after Week 16 or after prior suppression to <200 c/mL

744 totaln=160

EFVn=47

Subjects with PDVF during Maintenance 2** (1%) 1 (2%)IN genotypic results at BL and time of PDVF 1 1INI‐r mutations 1 0

PR/RT genotypic results at BL and time of PDVF 2 1NRTI‐r mutationsNNRTI‐r mutations

01

00

**744 10 mg – treatment emergent INI (Q148R) and NNRTI (E138Q) at W48; 744 FC = 3; RPV FC = 2744 and RPV concentrations <50% of expected; extreme calorie restricted diet W40‐W48

**744 30 mg – PDVF at W36; no treatment‐emergent mutations


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744 10 mg n=60

744 30 mgn=60

744 60 mgn=61

EFV 600 mgn=62

Grade 2‐4 drug‐related events (total) 5 (8) 8 (13) 13 (21) 12 (19)(>3% any arm)Insomnia 1 (2) 2 (3) 0 4 (6)Nausea 0 2 (3) 3 (5) 1 (2)Fatigue 0 2 (3) 1 (2) 1 (2)Headache 1 (2) 1 (2) 3 (5) 0Rash 0 0 1 (2)* 5 (8)

Grade 2‐4 drug‐related events (W24+)† 1 (2) 2 (4) 3 (5) 2 (4)

Serious adverse events (all) 6 (10) 2 (3) 3 (5) 3 (5)‡

AEs leading to withdrawal 1(2) 1 (2) 4 (7) 8 (13)Events with >1 subjectDizziness 0 0 0 2 (3)ALT increased 0 0 2 (3)** 0

*Grade 2; concomitant acute syphilis†All Grade 2‡One drug‐related SAE: suicide attempt (EFV)**Two subjects with steatohepatitis developed asymptomatic Grade 4 ALT elevations, with normal bilirubin levels, at Week 4 and Week 8, which resolved off IP.

• Neuropsychiatric AEs more commonly seen with EFV

• Headache was more commonly seen with 744 (22%) than EFV (11%)

– Predominantly Grade 1 and 2; no withdrawals due to headache

Adverse Events


LATTE Study – Week 48 Analysis Conclusions


• Following induction therapy, oral CAB+RPV maintained virologic suppression at a rate similar to EFV+NRTIs

• Primary Endpoint: 82% of 744+RPV and 71% of EFV+NRTIs subjects had HIV‐1 RNA <50 copies/mL

• Secondary Endpoint (ITT‐ME): 93% of 744+RPV and 94% of EFV+NRTIs subjects had HIV‐1 RNA <50 copies/mL

• Similar response rate across 744 10mg, 30mg, and 60mg arms

• One subject, with persistently low 744 and RPV drug concentrations, developed treatment emergent INI and NNRTI mutations

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LATTE Study Week 96 Analysis Conclusions

1. Following induction therapy, oral CAB + RPV maintained virologic suppression at a rate similar to EFV + NRTIs through 96 weeks.

2. Primary endpoint: 76% of CAB + RPV and 63% of EFV + NRTIs subjects had HIV‐1 RNA <50 c/mL.

3. Secondary endpoint (ITT‐ME): 86% of CAB + RPV and 83% of EFV + NRTIs subjects had HIV‐1 RNA <50 c/mL.

4. Numerically lower response rate of CAB 10 mg and 30 mg, relative to 60‐mg arm is largely due to non‐virologic discontinuations, with a low PDVF rate across all arms.

5. CAB + RPV was well tolerated, with few drug‐related AEs leading to withdrawal.

6. CAB 30‐mg once‐daily dose was selected for further oral development.

7. These regimen POC results support evaluation of long‐acting injectable regimens of CAB LA + RPV LA as maintenance therapy.

Margolis et al. CROI 2015; Seattle, WA. Abstract 554LB

Long‐Acting Parenteral Therapy

• Cabotegravir physicochemical attributes

– Low solubility and correct particle size to control release kinetics

– Low metabolic clearance

– Appropriate formulation factors

– Limited cross‐resistance to both raltegravir and elvitegravir

– A high barrier to resistance in vitro

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GSK744 and TMC278 Nanosuspensions

• Drug nanocrystal suspended in liquid = nanosuspension

• Nanomilled to increase surface area and drug dissolution rate

• Allows ~100% drug loading vs. matrix approaches for lower inj. volumes

R H. Müller, et al. European Journal of Pharmaceutics and Biopharmaceutics 78 (2011) 1‐9

Component Function

GSK1265744A (d50 ~200 nm) Active

Mannitol Tonicity agent

Surfactant System Wetting/Stabilizer

Water for Injection Solvent

GSK744 200mg/mL

TMC278 300mg/mL

Component Function

TMC278 (d50 ~200 nm) Active

Glucose Tonicity agent

Surfactant System Wetting/Stabilizer

Water for Injection Solvent

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Parameter Names Units

NONMEM Estimates

Point Estimate %RSE

Inter‐individualVariability (CV%)

Central Clearance (CL) (L/h) 0.144 3.63 30.9Central Volume (V2) (L) 5.78 4.15 31.4Intercompartment Clearance (Q) (L/h) 0.288 11.6Peripheral Volume (V3) (L) 1.65 12.5 202

Oral Lag‐time (LAG) (h) 0.381 8.11Oral Relative bioavailability (F) 0.644 3.93Oral Absorption rate constant (KA) (h‐1) 2.16 14.2 106

LA Absorption rate constant (KA LA) (h‐1) 0.000454 9.34 63.6

Parameter Estimates: Population PK Model

Ford et al. ICAAC 2014; Washington, DC. Abstract H‐645.

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BMI and SEX: Clinically Relevant Covariates Retained in Final Model

Ford et al. ICAAC 2014; Washington, DC. Abstract H‐645.

SEXBMI 50th Percentile

(10th, 90th)(kg/m2)

Mean Estimate of KA LA (h‐1) by BMI Quantile(Relative Difference from TV KA LA)

10% 50% 90%

Males26.8

(22.8, 30.3)

0.00114(1.35)↑35%

0.000845(1.00)

0.000675(0.799)↓20%

Females26.3

(21.7, 30.4)

0.000407(1.43)↑43%

0.000285(1.00)

0.000217(0.762)↓24%

•KA LA Males > Females•KA LA decreases with increasing BMI

Cabotegravir Nanosuspension for Injection

1 Spreen et al. 19th IAC Jul 2012. Abstract TUPE040

• GSK744 LAP 200mg/mL formulation for IM or SC use– Phase 1 single dose study of 100‐800mg IM/SC reported at IAC 20121

– Single dose GSK744 LAP injections in healthy subjects (n= 42) were generally well tolerated and produced apparent plasma half‐life range of 21‐50 days

– Data support once‐monthly to once‐quarterly dosing

PA‐IC90

4xPA‐IC90

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T im e (w e e k s )0 4 8 1 2 1 6 2 0 2 4 2 8

Pla

sma

GS

K12

657

44 ( g

/mL

)

0

1

2

3

4

58 0 0 m g IM L D , 2 0 0 m g S C q 4 w x 3

8 0 0 m g IM L D , 2 0 0 m g IM q 4 w x 3

8 0 0 m g IM L D , 4 0 0 m g IM q 4 w x 3

8 0 0 m g IM q u a rte r ly x 2

4 * P A -IC 9 0 (0 .6 6 4g /m L )

GSK744 LAP q 4 Week or q 12 Week Regimens Achieve Plasma Concentrations >4 x PA‐IC90 in

Healthy Adults Mean GSK744 plasma concentration‐time profiles

= q 28 day injection


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GSK744 5mg/day po Ctau = 0.6 ug/mL

Spreen et al. 19th IAC Jul 2012. Abstract TUPE040

Time (Weeks)

0 2 4 6 8 10 12 14 16

Mea

n (S

D)

RP

V (

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 profiles


Rilpivirine Plasma Concentrations Following TMC278 LA Injections are Comparable to Oral

25mg/day in HIV‐infected Subjects

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GSK744 LA (IM) GSK744 LA (SC) TMC278 LA (IM)

No. subjects w/ injections N=40 N=10 N=19Max no. inj. per subject/actual total per group 5 / 156 3 / 30 3 / 57No. subjects reporting any ISR on study 32 (80%) 10 (100%) 18 (95%)

ISR: n (%) or mean (range)

ISR Events, n(% of total events) mild mod

Duration(days) mild mod

Duration(days) mild mod

Duration(days)

Any116(81)

28(19)

‐‐ 130(98)

2(2)

‐‐ 39(87)

6(13)

‐‐

Pain76(53)

28(19)

5 (1‐32)

25(19)

1(1)

7(3‐14)

31(69)

6(13)

5 (1‐10)

Erythema11(8) 0

9 (1‐31)

28(21) 0

11(1‐33)

2(4) 0

5(5‐5)

Nodule6(4) 0

31(5‐71)

23(17) 0

59(5‐140)

3(7) 0

48(24‐65)

Injection Site Safety Results: Local Injection Site Reactions (ISRs) Are Common but Generally Well‐tolerated and Self‐limited

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LATTE‐2

265 subjects enrolled

HIV RNA ≥ 1000CD4 ≥ 200ART naïve

Week ‐ 8

Week ‐ 4

Day 1

Induction PeriodIM Q4WRegimen

GSK744 30 mg + ABC/3TCOrally Once Daily

Add RPV 25 mg

once daily

2

2

1

Week ‐4

Qualification Visit for Maintenance Addition of RPV 25 mg for All Subjects

Day 1

Start of Maintenance and Randomization Visit Randomization 2:2:1 Stratified by HIV-1 RNA prior to Week (-8)

(<50 c/mL, yes or no)

Week ‐ 20

Week ‐ 16

Week‐ 12

IM Q8WRegimen

Cont OralRegimen

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• After single dose of 800mg CAB LAP injection, concentrations may be measurable for up to 52 weeks.

• For 600mg RPV LAP injection x 1, concentrations may be measurable for up to 24 weeks.

• If subject stops CAB LAP and RPV LAP for any reason, he/she should remain on suppressive HAART for at least 52 weeks after the last LAP dose.

• “lost to follow‐up” possible selection of resistant mutants

Potential Issues

Pre‐exposure Prophylaxis

• TDF/FTC once daily approved by FDA for HIV PrEP in adults who are at high risk for becoming HIV‐infected in July 2012

• 4 trials showing efficacy when taken as prescribed leading to FDA approval (iPREX trial 92% efficacy by detection of drug)

• FEM‐PrEP trial in women did not show a benefit secondary to poor adherence

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Cabotegravir LA

• A study on female rhesus macaques showed that 30 and 50mg/kg of CAB LA were equally potent at preventing SIV infection from multiple intravaginal challenge.1

– Targeting >4x PA‐IC90 in plasma may be sufficient to protect against vaginal SIV transmission in macaques

• In Male macaques, cabotegravir plasma concentration >3x PA‐IC90 resulted in 100% protection while the efficacy was 97% at plasma levels ≥ 1x PA‐IC90.

2

1. Andrews et al. CROI 2015; Seattle, WA. Abstract 941LB2. Andrews et al. CROI 2014; Boston, MA Abstract 39

Cabotegravir Nanosuspension for Injection

1 Spreen et al. 19th IAC Jul 2012. Abstract TUPE040

• GSK744 LAP 200mg/mL formulation for IM or SC use– Phase 1 single dose study of 100‐800mg IM/SC reported at IAC 20121

– Single dose GSK744 LAP injections in healthy subjects (n= 42) were generally well tolerated and produced apparent plasma half‐life range of 21‐50 days

– Data support once‐monthly to once‐quarterly dosing

PA‐IC90

4xPA‐IC90

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ECLAIRStudy to Evaluate the Safety Tolerability and Acceptability of Long Acting Injections of the HIV Integrase Inhibitor, GSK1265744, in

HIV Uninfected Men

• PrEP trial using cabotegravir 800mg IM once every 12 weeks after oral 30mg po daily lead‐in for 4 weeks and 1 week washout period

• Male population at risk – defined as having at least one casual sex partner in the past 24 months

Summary

• Cabotegravir is a well‐tolerated integrase inhibitor with potential to treat first generation INI resistance.

• Following induction therapy, oral CAB + RPV maintained virologic suppression at a rate similar to EFV + NRTIs through 96 weeks.

• Long‐acting parenteral therapy is possible through nanoparticle suspension.

• Potential once a month injectable therapy CAB + RPV IM

• Possible PrEP using CAB 800mg IM every 12weeks which is important as Adherence is the key in successful PrEP outcome.

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Post‐Test

• Which of the following is NOT true about cabotegravir?1. Cabotegravir is an investigational integrase DNA

strand transfer inhibitor2. It can be used for intramuscular injection as a long‐

acting formulation.3. It is an analogue of dolutegravir.4. It is a novel nucleoside reverse transcriptase

inhibitor that can be used with rilpivirine.5. Its long‐acting intramuscular formulation may be a

possible PrEP therapy as quarterly injections in high risk patients.

Questions?

HIV Drug Update with LATTE Study - Albany Medical … · 4/3/2015 1 HIV Drug Update with LATTE...

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Transcript of HIV Drug Update with LATTE Study - Albany Medical … · 4/3/2015 1 HIV Drug Update with LATTE...