1. Investigational Approaches to Antiretroviral Therapy: New Strategies and Novel Agents
Joseph J. Eron MD
Professor of Medicine
University of North Carolina
Chapel Hill, North Carolina

2. Financial Relationships With Commercial Entities
Dr Eron has served as an ad hoc consultant to Janssen, ViiV Healthcare, Merck, and Gilead Sciences, Inc. His institution receives contracts for clinical research on which Dr Eron is the local principal investigator from Janssen Therapeutics, ViiV Healthcare, and Gilead Sciences, Inc.

3. Learning Objectives
After attending this presentation, learners will be able to:
List several two-drug combinations that are being evaluated for initial or maintenance therapy
Describe characteristics of the long acting injectable antiretroviral therapy in late-stage development
Describe the mechanisms of action and potential uses of 2 entry inhibitors in development for patients with resistant virus

4. Outline of the Talk
New Two-drug Strategies for Initial ART and treatment switch (long-acting therapy)
Novel Agents for Resistant Virus
New Agents in Early Development

5. ARS Question 1 Your ”go to” initial ART is Bictegravir/FTC/TAF
Dolutegravir/abacavir/lamivudine
Dolutegravir plus TAF (or TDF)/FTC
Elvitegravir/cobi/TAF (or TDF)/FTC
Darunavir/r (or cobi) plus TAF(or TDF)/FTC
Rilpivirine/TAF (or TDF)/FTC
Something else

6. What is needed for initial therapy?
We have convenient, safe, effective unboosted integrase inhibitor therapy – do we need something else?
Alternatives to INSTI – based therapy?
NNRTI – based therapy
with better tolerability,
less resistance and fewer dosing restrictions?
PI - based therapy
more convenient
Fewer drug-drug interactions
Exposure to fewer agents?
Two drug combinations
Alternative dosing strategies

7. Two Drug Regimens for Initial Therapy
Rationale
”nuc-sparing” – a need that seems less critical now
advanced renal disease or TFV or ABC intolerance
Minimize ARV exposure for therapy that will last for decades
Cost
Strategies
Boosted PI plus INSTI (NEAT 001)
Boosted PI plus 3TC (GARDEL and ANDES studies)
Dolutegravir plus 3TC (PADDLE, A5353, GEMINI)

8. Snapshot Analysis by Visit: Pooled ITT-E Population
Virologic outcome
Adjusted treatment difference (95% CI) at Week 48a
DTG + TDF/FTC
DTG + 3TC
Intention-to- treat–exposed
-1.7
-4.4
1.1
DTG + 3TC (N=716)
DTG + TDF/FTC (N=717)
Per protocol
-1.3
-3.9
1.2
DTG + 3TC is non-inferior to DTG + TDF/FTC with respect to proportion achieving HIV-1 RNA <50 c/mL at Week 48 (snapshot, ITT-E population) in both studies
aBased on Cochran-Mantel-Haenszel stratified analysis adjusting for the following baseline stratification factors: plasma HIV-1 RNA (≤100,000 vs >100,000 c/mL) and CD4+ cell count (≤200 vs >200 cells/mm3). bCalculated from a repeated measures model adjusting for study, treatment, visit (repeated factor), baseline plasma HIV-1 RNA, baseline CD4+ cell count, treatment and visit interaction, and baseline CD4+ cell count and visit interaction.
Cahn et al. Lancet [Epub ahead of print].
Slide 11 of 37
Eron et al. HIV DART and Emerging Viruses 2018; Miami, FL. Slides 7.

9. Difference in proportion, % (95% CI)
Proportion of Participants With Plasma HIV-1 RNA <50 c/mL at Week 48 (Snapshot Analysis) by Baseline Plasma HIV-1 RNA
Difference in proportion, % (95% CI)
DTG + TDF/FTC
DTG + 3TC
DTG + 3TC (N=716)
DTG + TDF/FTC (N=717)
138/153
129/140
41/46
45/51
20/24
16/18
12/15
11/13
531/564
526/576
Slide 12 of 37
Eron et al. HIV DART and Emerging Viruses 2018; Miami, FL. Slides 7.
Cahn et al. Lancet [Epub ahead of print].

10. ARS Question 2
Based on the GEMINI 48 week data, in what setting will you use dolutegravir/3TC?
As initial therapy with any baseline viral load
As initial therapy in specific patients with lower viral loads
As maintenance therapy in patients who are suppressed on 3-drug treatment
I will wait until we have longer term (96 week data) with DTG/3TC to decide
Only when insurance companies tell me to use it
Something else

11. Draft version 1-5
LATTE-2: Study of Long Acting Cabotegravir and Rilpivirine – 96 week data
Induction period
Maintenance perioda
CAB 400 mg IM + RPV 600 mg IM
Q4W (n=115)
Inclusion criteria
≥18 years old
Naive to antiretroviral therapy
CD4+ ≥200 cells/mm3
Exclusion criteria
Positive for hepatitis B
ALT ≥5 × ULN
Creatinine clearance <50 mL/min
Qualification for maintenance
HIV-1 RNA <50 c/mL between Week -4 and Day 1
CAB 30 mg + ABC/3TC PO QD for 20 weeks
(N=309)
CAB 30 mg + ABC/3TC for 20 weeks
CAB loading dose at Day 1 (800 mg)
CAB 600 mg IM + RPV 900 mg IM
Q8W (n=115)
CAB loading doses at Day 1 (800 mg) and Week 4 (600 mg)
CAB 30 mg + ABC/3TC PO QD (n=56)
Add RPV PO QD
4 weeks
Day 1 Randomization
2:2:1
Week 32 Primary analysis Dosing regimen selection
Week 48 Analysis Dosing regimen confirmation
Week 96b
ABC/3TC, abacavir/lamivudine; ALT, alanine aminotransferase; IM, intramuscular; PO, orally; QD, once daily; Q4W, every 4 weeks; Q8W, every 8 weeks; ULN, upper limit of normal. aSubjects who withdrew after at least 1 IM dose entered the long-term follow-up period. bSubjects can elect to enter Q4W and Q8W LA extension phase beyond Week 96.
Talk through mg and volume of injection
Eron et al. IAS 2017; Paris, France. Slides MOAX0205LB.

12. Treatment differences (95% CI)
Comparable Response Across Arms Week 96 HIV-1 RNA <50 c/mL by Snapshot (ITT-ME)
Virologic outcomes
Treatment differences (95% CI)
Oral IM
Q8W IM
− 0.6%
20.5%
−8.4%
14.4%
Q4W IM
CAB, cabotegravir; CI, confidence interval; IM, intramuscular; ITT-ME, intent-to-treat maintenance exposed; LA, long acting; NRTI, nucleoside reverse transcriptase inhibitor; PO, orally; Q4W, every 4 weeks; Q8W, every 8 weeks; RPV, rilpivirine.
Eron et al. IAS 2017; Paris, France. Slides MOAX0205LB.

13. Latte 2 Outcomes at 160 Weeks

14. Letendre Glasgow 2018

15. LA CAB and LA RPV Phase III studies
ATLAS – randomized, open label, non-inferiority study in participants stably suppressed on 3-drug ART comparing CAB LA 400 mg + RPV LA 600 mg q 4 weeks with maintenance of current ARV regimen (2 NRTIs plus an INI, NNRTI, or a PI) participants were randomized (1:1) to continue current ART or switch to oral therapy with CAB 30 mg + RPV 25 mg daily for 4 Weeks followed by Q4 weekly CAB LA + RPV LA injections.
FLAIR - randomized, open label, non-inferiority study in ART-naïve adult participants comparing CAB LA 400 mg + RPV LA 600 mg q 4 weeks to remaining on ABC/DTG/3TC over 48 weeks. 631 participants started ABC/DTG/3TC for 20 weeks and those with HIV RNA <50 c/mL after 16 weeks were randomized at 20 weeks to continue ABC/DTG/3TC or switch to oral therapy with CAB 30 mg + RPV 25 mg daily for 4 week, followed by monthly CAB LA + RPV LA injections
Both studies met their primary endpoints at 48 week (ViiV Press Releases)
ATLAS-2M study compares q 8 wk CAB LA + RPV LA to q 4 wk CAB LA + RPV LA over a 48-week treatment period in approximately 1020 adult HIV-1 infected subjects.
600 and 900 for the first injection
Documented evidence of at least two plasma HIV-1 RNA measurements <50 c/mL in the 12 months prior to Screening: one within the 6 to 12 month window, and one within 6 months prior to Screening;
Any switch to a second line regimen, defined as change of a single drug or multiple drugs simultaneously, due to virologic failure to therapy (defined as a confirmed plasma HIV-1 RNA measurement ≥400 c/mL after initial suppression to <50 c/mL while on first line HIV therapy regimen)

16. New Therapy for resistant virus
Recently approved or in Phase III
New Therapy for resistant virus

17. HIV Entry Inhibitors CD4 Coreceptor Virus-Cell Binding Binding Fusion
CCR5 Inhibitors
maraviroc*
fostemsavir
ibalizumab
enfuvirtide*
gp41
gp120
V3 loop
CD4
HIV Entry can be divided into 3 discrete steps: attachment of the viral glycoprotein 120 to the CD4 receptor, followed by subtle conformational changes in gp 120 which expose structural elements on the V3 loop that bind to co- receptor, either CCR5 or CXCR4. This induces a structural rearrangement in gp41 which inserts a hydrophobic fusion peptide region into the target cell membrane which brings the virus and cell membrane in close apposition to initiate fusion and ultimately entry of the virus into the target cell.
HIV Entry Inhibitors can be thought of as 3 distict subclasses, each tageting one of the 3 previous steps. I wanted to highlight those small molecules that are furthest along in development. BMS has a series of attachment inhibitors which prevents gp120 from binding to CD was presented last year but the follow-on 043 has improved in vitro activity and a longer half-life. Monotherapy data were presented at CROI mg and 1800 mg twice daily gave a mean VL reduction of 0.7 and 1 log at Day 8, respectively. The 3 CCR5 antagonists that are furthest along include UK-427, SCH-D and the GW SCH-C had been in Phase 2 but was shelved due to QTc issues. SCH-D is now in Phase 2. Monotherapy data were presented at retrovirus as well, demonstrating a log reduction at 14 days from doses which ranged from mg twice daily and a Phase 2b study in TE patients is being conducted by ACTG. The GSK compound licensed from ONO is reportedly also in Phase 2 of development.
GSK - compound was also presented at CROI. SD and MD data were presented and the drug was given BID. Food increased absorption. Dose limiting toxicity was GI intolerance and there was no QTc prolongation.
Finally, enfuvirtide which is a twice daily injectable fusion inhibitor from Roche was approved last year. Its follow-on, T-1249 was discontinued due to issues of production and cost.
Cell
Membrane
CCR5/CXCR4
(R5/X4)
* = FDA approved
Slide courtesy of Trip Gulick, MD; Adapted from Moore JP, PNAS 2003;100:

18. Ibalizumab
Humanized monoclonal Ab: binds CD4 on host cells; blocks HIV entry (post attachment inhibitor)1
Active against CCR5 and CXCR4 tropic HIV
No cross resistance with other ARVs2
IV infusion: 2,000 mg loading dose then 800 mg every 2 wks
Duration of infusion: min
1Emu B et al, Abstract 1686, IDWeek 2017;
2Weinheimer S et al, CROI 2018
Slide courtesy of Raj Gandhi

19. Ibalizumab in Persons with Multi-Drug Resistant HIV
Phase 3 trial: 40 heavily treatment experienced pts with 3-class ARV resistance, ≥1 active drug
Primary endpt: VL drop >0.5 log10 c/mL:
3% during control period
83% after loading dose
Regimen optimized at day 14
Wk 24: VL <200 in 50%
Expanded access: viral suppression to wk 48 A
Approved March 6, 2018
Emu B et al, Abstract 1686, IDWeek 2017; Weinheimer S et al, CROI 2018, #561

20. Fostemsavir (FTR): Oral HIV Attachment Inhibitor
Prodrug of temsavir: binds to gp120, inhibits HIV attachment to CD4
Phase 3 trial in heavily treatment experienced patients with VF (BRIGHTE)
Kozal M et al, 16th EACS, 2017
Slide courtesy of
Raj Gandhi

21. Fostemsavir (FTR): Phase 3 Trial (BRIGHTE)
Mean VL Change at day 8
Virologic response through wk 24 (observed analysis)
Difference† (95% CI) =
(-0.810, ) P<0.0001‡
Adjusted Mean† (95% CI)
N=69
N=201§
Kozal M et al, 16th EACS, 2017
“Regulatory submissions are currently anticipated to take place in the 2019/2020 timeframe”
At wk 24, 54% of randomized and 36% of non-randomized ppts who received FTR + OBR achieved VL <40
Slide courtesy of Raj Gandhi

22. BRIGHTE: Efficacy at Wk 48 (FDA Snapshot)
Outcome at Wk 48, n (%)
Randomized Cohort
(n = 272)
Nonrandomized Cohort
(n = 99)
HIV-1 RNA < 40 c/mL (virologic success)
146 (54)
38 (38)
HIV-1 RNA < 200 c/mL/< 400 c/mL
187 (69)/191 (70)
43 (43)/44 (44)
HIV-1 RNA ≥ 40 c/mL (virologic failure)
104 (38)
52 (53)
Data in window not below threshold
72 (26)
33 (33)
D/c for lack of efficacy
6 (2)
2 (2)
D/c for other reason while not below threshold
9 (3)
3 (3)
Change in OBT
17 (6)
14 (14)
No virologic data
22 (8)
9 (9)
D/c due to AE or death
15 (6)
8 (8)
D/c due to other reasons
5 (2)
1 (1)
Missing data during window but on study
2 (< 1)
Median CD4+ cell count change vs BL, cells/mm3 (IQR)
127 (54 to 204)
35 (-1 to 121)
AE, adverse event; BL, baseline; d/c, discontinuation; OBT, optimized background regimen.
Aberg. Glasgow Abstr O344A. Reproduced with permission.

23. Novel agents in Early development

25. Long-acting NRTTI: MK-8591 (EFdA)
Phase 1b, single-dose, monotherapy study
Study population: ART naïve (N=30)
MK mg MK mg
MK mg MK mg
MK mg
Nucleoside RT translocation inhibitor (NRTTI)
Half life of active anabolite: ≈ hr
Humans: single oral dose as low as 0.5 mg suppressed HIV RNA for >7 days
Grobler et al CROI 2017 #435
Matthews et al IAS 2017 #TUPDB0202LB

26. Long-acting NRTTI: MK-8591 (EFdA)
Study in healthy volunteers: daily doses as low as 0.25 mg expected to lead to HIV suppression
Phase 2b trial in people with HIV, in combination with doravirine (NNRTI) and 3TC, has started (DRIVE2Simplify)
Daily dosing
Potential for once weekly or even once monthly dosing
“Partners wanted”
MK-8591 achieve target levels with only 0.25 mg dose
Matthews RP et al CROI 2018 #26

27. Grobler et al CROI 2016

28. HIV Capsid Acts at Multiple Stages in the Viral Life Cycle
GS-6207
HIV Capsid Acts at Multiple Stages in the Viral Life Cycle
Nucleus
Reverse Transcription
Nuclear Translocation
Capsid Core Disassembly
Target Cell
Integration
Pre-integration complex
Capsid Core
Producer Cell X
Capsid Core
Assembly
Gag
Gag-Pol
Maturation
Nucleus
Capsid Core
Gilead’s capsid inhibitors inhibit HIV capsid function, resulting in aberrant core assembly/disassembly via multiple steps in HIV replication cycle
Transition:
Gilead HIV antiretroviral pipeline is robust and includes a capsid inhibitor which is a novel mechanism of action.
Main Messages:
During maturation into an infectious virion the capsid core is assembled. When a new target cell is infected the capsid core is inserted and the capsid core is disassembled and nuclear translocation occurs prior to integration of HIV genetic material into the DNA.
Inhibitors of HIV capsid function results in aberrant core assembly and disassembly
As well, the nuclear translocation step is impacted since the capsid inhibitor binding site is shared by host nuclear translocation factors (CPSF6 and NUP153)
Background:
GS-CA1 was used in these experiments to determine EC50 values which are not shown
Tse W, et al. CROI Seattle, WA. Oral #38

29. Potency GS-6207 is a potent inhibitor of all major HIV-1 subtypes
GS-6207: Novel HIV Capsid Inhibitor with Long-Acting Potential
Potency
EC50
(nM)a
paEC95 (nM)b
GS-6207
0.10 ± 0.01
4.0 ± 0.4
EFV
0.79 ± 0.06
44 ± 3
RPV
0.57 ± 0.03
45 ± 2
DTG
1.34 ± 0.14
156 ± 16
ATV
7.23 ± 0.50
150 ± 11
GS-6207 is a potent inhibitor of
all major HIV-1 subtypes
HIV-1 Subtype
Antiviral EC50, pM A B C D F G
CRFs E
Human
PBMCs
MT-4
cells
CAB
HIV-1 IIIb
Mean: 50 pM
Range: 20–160 pM
GS-6207 is more potent
than currently marketed ARVs
ATV, atazanavir. DTG, dolutegravir. EFV, efavirenz. paEC, protein-adjusted effective concentration. RPV, rilpivirine
a EC50, CC50 and Hill slope values (mean ± SD) obtained from at least 3 independent experiments performed in quadruplicate
b EC95 = EC50 x (95/5)1/hillslope; paEC95 = human serum shift X EC95
Zheng J, et al. IDWeek San Francisco, CA. Poster #539

30. Plasma PK in Rats and Dogs Following a Single SC Dose*
GS-6207: Novel HIV Capsid Inhibitor with Long-Acting Potential
Plasma PK in Rats and Dogs Following a Single SC Dose*
paEC95
24 wks 4
Single subcutaneous injection maintains plasma concentrations well above paEC95 for >24 weeks in dogs
PK supports long acting administration, potentially Q3M or longer, in humans
Transition:
The PK of GS-CA2 extended release formulation was evaluated in rats.
Main Messages:
As stated
Background:
paEC95, plasma-binding-adjusted effective concentration required to inhibit replication by 95%
* 400 mg/mL dose concentration
Zheng J, et al. IDWeek San Francisco, CA. Poster #539

31. Broadly Neutralizing Antibodies against HIV
Phase 2 studies in HIV infected patients
Clear antiretroviral activity
Combinations likely necessary
Can be modified for longer half-life
Every 3 to 6 month infusions possible

32. September 27, 2018
Combination bNAb, long-acting bNAb being studied for treatment, prevention
For the 11 individuals who had complete viral suppression (HIV-1 RNA <20 copies per ml) during the screening period and at day 0, combination antibody therapy was associated with maintenance of viral suppression for between 5 and more than 30 weeks (Fig. 1b, c and Supplementary Table 2). The median time to rebound was 21 weeks compared to 2.3 weeks for historical controls who participated in previous non-interventional ATI studies10 and 6–10 weeks for monotherapy with 3BNC1179 (Fig. 1c). Together, 9 of the 11 participants maintained viral suppression for at least 15 weeks, although two rebounded at weeks 5 and 7 (Fig. 1b, c).

33. Antiretroviral Therapy: The Future
Implantable ART
bNAbs for therapy
Long Acting Injectable?
2-drug regimens
The Integrase Era
Single Tablet Regimens
Triple Drug Therapy
ZDV/3TC
ZDV monotherapy
HIV-1 discovered
So what can we expect in the future? If we look back we can see that we have had substantial shifts in therapy in each decade since the virus was discovered. ZDV monotherapy in the late 80’s, triple therapy that changed everything in the late 90’s, fewer pills and STR in the mid-2000’s and now maybe a shift to integrase-inhibitor based therapy. I think it is likely that simple oral tablets will remain a major component of our treatment for years but innovation and technology may well broaden our treatment options to reach more and more people – which is, of course, the ultimate goal.
1983
1987
1995
1996
2006
2019
2025

34. Acknowledgements Judy Currier Dan Kuritzkes Raphael Landovitz
Carey Hwang
Michael Aboud
Chloe Orkin
Kathleen Squires
Trip Gulick
Raj Gandhi
Jay Glober

35. Question-and-Answer