Investigational Antiretroviral Drugs in Development

1
Investigational Antiretroviral Drugs in
Development
Jeffrey L. Lennox, MD Professor of MedicineEmory
University School of Medicine
The International AIDS SocietyUSA
2
Dad always thought laughter was the best
medicine, which I guess is why several of us died
of tuberculosis." -   --  Jack Handey
3
Investigational ARVs 2008
Yellow data presented at IAC
4
Inhibitors of Binding or Entry
5
Improved and New Boosters

• Tablet Ritonavir1
• New RTV formulations have been plagued by
  moisture absorption and stability.
• At IAS Abbott presented PK data on new 100mg
  tablet vs existing SGC.
• Compared to SGC, RTVtab produces Cmax 1.264,
  AUC12 1.103.
• GS 93502
• Gilead has developed a new compound to boost
  elvitegravir.
• A Phase I study in healthy volunteers is
  nearing completion, and initial data show that GS
  9350 does increase the blood levels of midazolam
  (as hoped).
• The company is examining stability of a pill
  that contains TDF/FTC/ELV/GS 9350

1 IAS 2008, TUPE0076 2 http//seekingalpha.com/
article/88407-gilead-sciences-inc-q2-2008-earnings
-call-transcript?page2
6
Vicriviroc 48w results of VICTOR E1 study

• Triple-class experienced, gt1 RTI and gt1 PI
  resistance mutation, R5 tropic at screening,
  HIV-RNA gt1000 copies/mL on stable regimen gt6
  weeks
• OBT plus VCV 20mg or 30mg daily vs placebo daily

Baseline Characteristics
Zingman B,15th CROI 2008, 39LB
7
VICTOR E1-Patient Disposition Through Week 48
8
Vicriviroc Victor E1 Study with HIV-1 RNA lt50
copies/mL at Week 48
By No. Active Drugs in OBT
Overall
3
2
1
0
100
90
83
p0.0002 30 mg
77
80
71
67
70
62
60
56
53
VCV 30 mg OBT
of Subjects
50
VCV 20 mg OBT
38
40
Placebo OBT
29
27
30
18
20
14
12
10
0
0
0
24
9
7
6
6
6
13
11
16
13
11
N 26
7
8
7
Grade 3 or 4 AE 21_at_ 30mg, 20_at_ 20mg, 20_at_ PLA
Zingman B,15th CROI 2008, 39LB
9
Vicriviroc Victor E1 StudyDetection of
Dual/Mixed or X4 Tropic Variants
45

• Occurrence by 8 weeks
• 30 mg
• 10/12 (83)
• 20 mg
• 4/8 (50)
• Placebo
• 3/5 (60)

40
35
30
25
20
15
10
5
0
30 mg
20 mg
PBO
Total Subjects
Number with DM/X4
10
Novel CCR5 Inhibitors

• PF-232,798- Retains some activity against
  maraviroc resistant isolates. Well tolerated in
  humans following single daily doses. Pfizer
• ESN-196 Binds to CCR5 and causes the receptor
  to be internalized into the cell. Theoretically
  a new method to reduce R5 HIV binding to the
  cell. Two Belgian companies

Dorr P, 15th CROI 2008, 737 and Ferian T 738
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PRO 140 monoclonal antibodyCCR5 antagonist
Virologic response to PRO 140

• Randomized, double-blind, placebo-controlled
  trial
• N39 CD4 gt250 cells/mm3, HIV RNA gt5,000 c/mL,
  R5 only, no prior ARV x 3 months
• 1111 randomization for single IV dose of 0.5,
  2 or 5 mg/kg (or placebo) 59-day F/U
• Results
• Anti-viral effect correlated with PK and R5
  occupancy
• Well tolerated, no serious drug-related AEs

5 mg/kg
p
lt
0.01


p
lt
0.001



p
lt
0.0001




Olson WC, et al. 4th IAS, Sydney 2007, WESS201
12
PRO 140 possible activity against MVC-resistant
virus

• HIV passed repeatedly in CD8-depleted, stimulated
  PBMC MVC
• MVC-resistant virus appeared at Week 31. It was
  still R5-tropic
• Selected virus susceptible to PRO 140 with a
  maximal inhibition 1.1-FC similar to original
  isolate prior to passage
• However, since gt60 of MVC failures are via
  emergence of D/M virus, which would not be
  inhibited by PRO 140, the clinical relevance of
  this finding is limited.

Marozson AJ, et al. XVII IAC2008, TUAA0305
13
Inhibitors of Reverse Transcriptase
14
Novel NRTI Apricitabine (ATC)

• Cytidine analogue
• 50 patients failing therapy, all with 184V 52
  with 3 or more TAMs and 76 NNRTIR.
• Randomized to receive ATC 600 mg BID, ATC 800 mg
  BID or 3TC 150 mg BID
• Monotherapy for 21 days, then background ART
  modified.

At week 24, 71-73 in the two ATC arms had HIV
RNAlt50, vs 58 in the control.
Cahn P, 15th CROI 2008, 793
15
Novel NRTI Amdoxivir (DAPD)

• Synergistic in vitro with ZDV
• 10 day, double-blind, placebo-controlled trial in
  24 patients off Rx, HIV RNA gt 5000 cop/mL
• -DAPD 500mg BID
• -DAPD 500mg BID ZDV 200/300mg BID
• -ZDV 200/300mg BID
• Co-formulated DAPD/ZDV planned

Murphy R, 15th CROI 2008, 794
16
Novel NRTI Racivir

• 5050 Mixture FTC
• Has shown potent 14 day ARV activity in naïve
  subjects
• Protocol double blind study to replace (26) or
  continue (16) 3TC in patients with M184V
• At week 2 produced 0.7 log decrease HIV RNA

Cahn CROI 2007, 488
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Elvucitabine 24-week study in ART-naïve
patients

• L-cytosine NRTI half-life 80100 h
• In-vitro activity vs M184V
• Phase II study patients randomized to
• 10 mg elvucitabine QD TDF EFV vs
• 300 mg 3TC QD TDF EFV
• Results
• 7 SAEs in 6 patients, all on elvucitabine none
  judged drug related
• Longer-term follow-up underway

Week 24 HIV RNA lt50 c/mL ITT and AT
Worsening bipolar disorder, Castlemans disease,
pyelonephritis, suicide, recurrent tonsillitis,
appendicitis/ enterocutaneous fistula)
DeJesus E, et al. XVII IAC, Mexico City 2008,
TUPE0010
18
Rilpivirine (TMC278) vs EFV- A Phase II Study C204
HIV RNA lt50c/mL (ITT-TLOVR algorithm)

• Next generation NNRTI, initial data indicated
  less rash and CNS side effects
• Phase II/III trial, 96-week data n368 ARV naïve
  patients
• HIV RNA gt5000 c/mL
• Randomized to
• EFV 600 mg OD or
• TMC 278 at dose of 25, 75 or 150 mg QD
• 2 NRTIs (ZDV/3TC or FTC/TDF)

Santoscoy M, et al. XVII IAC, Mexico City 2008,
TUAB0103
19
Rilpivirine (TMC278) vs EFV Adverse Events
All rashes were Grade 1 or 2, except for one
patient with Grade 3 rash in the TMC278 75 mg
group (associated with fever) probably related to
dapsone plt0.01 vs EFV plt0.05 vs EFV
plt0.01 plt0.19 for EFV vs TMC278 (nonparametric
Wilcoxon rank sum test, post-hoc analysis)
20
Rilpivirine (TMC278) vs EFV-Cardiac Effects?
25 mg dose to be used in future studies
21
Novel NNRTI UK-453,061

• Tested against 62 HIV isolates from patients with
  transmitted NNRTI resistance
• K103N 48, Y181 11, K101 11, Y188 11
• 61/62 viruses were inhibited, but not the triple
  mutant K101EV106I/MY188F/L
• In healthy volunteers, lopinavir/ritonavir
  reduced UK-453,061 exposure by 50
• Manufactured by Pfizer

Mori J, 15th CROI 2008, 728 and Langdon G 763
22
Novel NNRTI IDX 899

• Active against K103N and G190A, but not Y181C if
  in the presence of 2 other NNRTI mutations
• In healthy subjects 800mg QD and 400mg BID were
  tested.
• Bioavailability 61. Absorption increased 2x
  with food. T ½ 10 hours.
• Levels of IDX 899 boosted 2x by ATV 3
• No obvious adverse events in this small study
• Manufactured by Idenex Pharma

Richman D, 15th CROI 2008, 729 and Mayers D
764, 3. Zhou XJ, IAS 2008, TUPE0089
23
IDX899 in ART-naïve subjects

• Phase Ib/IIa, placebo-controlled, single-center
  study in ARV-naïve Argentinean patients
• 82 randomization to 1 week PBO vs daily IDX899
  800, 400, 200 mg
• On day 8 LPV/r or HAART started
• Patients with CAH excluded
• 8 patients/arm. Median CD4 over 400.
• All doses exceeded the trough needed for 90
  inhibition
• A 100mg/day study has started

Change in HIV RNA
Zala C, et al. XVII IAC 2008, THAB0402
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Novel NNRTI RDEA 806

• A developmental NNRTI with activity against
  K103N, L100I, G190S
• In vitro selection of K104E, E138K, T240I
• Metabolism- multiple CYP enzymes, but not 3A4 or
  2B6, so interactions are expected to be few.
• 99.5 protein bound
• T1/2 12hrs, so should be able to be given once a
  day
• Developed as an enteric coated capsule.
• Manufactured by Ardea Pharmaceuticals

25
RDEA 806 7 day dosing study

• Phase Ia/IIb, placebo-controlled study
• 7 day monotherapy in patients randomized 31 to
  RDEA 806 vs PBO, and to capsules or to tablets
• 4 doses
• Capsules 400 mg BID fasted
• Capsules 600 mg QD fasted
• Tablets 800 mg QD fed
• Tablets 1000 mg QD fasted
• Safety
• Uric acid decreased

Moyle G, et al. XVII IAC 2008, THAB0403
26
Inhibitors of Integrase
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Elvitegravir- Gilead 9137

• Randomized, controlled trial, blinded to dose.
• Designed as a non-inferiority comparison to
  boosted PI.
• In the elvitegravir arm bPI not allowed, but T20
  was.
• Midway through the study the lowest dose arm was
  stopped due to failures, and TPV and DRV allowed.

28
Study Outcomes
DAVG Time-weighted average change from baseline
in HIV RNA
Zolopa A, et al. 14th CROI, Los Angeles, CA,
February 25-28, 2007. Abst. 143LB.
29
Change in HIV RNA With EVG (125 mg) Influence
of Activity of OBT
CCO Elion
EVG (125 mg)
EVG (125 mg)
With No Active
With 1 Active
Drugs in OBT
NRTI or First Use
(n26)
of T-20 (n47)
Mean Change From Baseline in HIV RNAlog10
Copies/mL

Week
Data from EVG (125 mg) patients after addition
of a PI were excluded
Zolopa A, et al. 14th CROI, Los Angeles, CA,
February 25-28, 2007. Abst. 143LB.
30
Integrase Novel compounds

• INH-1001 Inhibits both the 3' processing and
  the strand transfer steps of integration. In
  rats has a gt80 bioavailability and a T1/2 of 4.4
  hours. Not metabolized by CYP450. Inhibitex
  INC
• PEA-64 A peptide that interferes with binding
  of integrase to essential cellular cofactors.
  Now trying to develop a drug that mimics the
  peptide. Katholieke Univ.
• S/GSK 364735 Resistance profile similar to
  raltegravir. Shionagi GSK

Nair V, 15th CROI 2008, 234 and Christ F 735
Yoshinaga T 860
31
Other Inhibitors
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Bevirimat (PA-457) Maturation Inhibitor

• Inhibits Gag processing at the CA-Sp1 cleavage
  site.
• In vitro study of the development of resistance
  to bevirimat in the setting of wild type or
  protease inhibitor resistant virus.
• Implies that PR-resistant virus will be slow to
  develop bevirimat resistance.
• A phenotype assay to detect resistance has been
  developed.

Adamson C, 15th CROI 2008, 859 Choe S 880
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Other Developmental Compounds
34
Prediction

• By 2011 we may have 5 triple-drug regimens with
  non-overlapping resistance patterns (not taking
  into account convenience and toxicity)

Caution

• Every gain made is almost instantly taken for
  granted. Aldous Huxley