Presented at the 10th Eu Meeting on HIV & Hepatitis, 28-30 March 2012, Barcelona

CCR5 Antagonists:

Where to now?

Richard Harrigan BC Centre for Excellence in HIV/AIDS

Vancouver Canada

Presented at the 10th Eu Meeting on HIV & Hepatitis, 28-30 March 2012, Barcelona

Outline

♦Diagnostics for R5 antagonists

♦New Therapies and Approaches ♦Maraviroc ♦Other Small Molecules ♦Other Approaches

Presented at the 10th Eu Meeting on HIV & Hepatitis, 28-30 March 2012, Barcelona

Base Calling Mixtures Need for Standardization

Presented at the 10th Eu Meeting on HIV & Hepatitis, 28-30 March 2012, Barcelona Woods et al. J Clin Micro, Mar 2012 http://pssm.cfenet.ubc.ca

• 1,000,000 bases of protease/RT reanalysed in one second of “hands on time” with 99.6% agreement

• Validated for tropism in MOTIVATE/1029/MERIT

Free Software for Data Processing

Presented at the 10th Eu Meeting on HIV & Hepatitis, 28-30 March 2012, Barcelona

Effect of different g2P Cut-offs for HIV DNA

HIV DNA sequences determined in triplicate from 181 samples from MOTIVATE/1029, ~ half R5 and half non-R5. Data from Swenson et al CROI_2011.

-3

-2

-1

00 20 40 60

Mea

n pV

L ch

ange

week

wOBTss<1 - FPR 3

R5 <1 (N=31)

non-R5 <1(N=15)

-3

-2

-1

00 20 40 60

Astit

el

Astitel

wOBTss <1 - FPR 5.75

R5 <1 (N=27)

non-R5 <1(N=19)

-3

-2

-1

00 20 40 60

Mea

n pV

L ch

ange

week

wOBTss<1 - FPR 10

R5 <1 (N=25)

non-R5 <1(N=21)

-3

-2

-1

00 20 40 60

Astit

el

Astitel

wOBTss <1 - FPR 20

R5 <1 (N=18)

non-R5 <1(N=28)

<1 other active drug

Mea

n ch

ange

in p

VL

(log)

Presented at the 10th Eu Meeting on HIV & Hepatitis, 28-30 March 2012, Barcelona

Presented at the 10th Eu Meeting on HIV & Hepatitis, 28-30 March 2012, Barcelona

Presented at the 10th Eu Meeting on HIV & Hepatitis, 28-30 March 2012, Barcelona

Rarely, samples may be misaligned

CTRPYSNTRKSINMGPGXYRXPGRAFFTTTITGXIXQAYC

Presented at the 10th Eu Meeting on HIV & Hepatitis, 28-30 March 2012, Barcelona

CCR5 Antagonist Trials in Progress

Presented at the 10th Eu Meeting on HIV & Hepatitis, 28-30 March 2012, Barcelona

Maraviroc ♦ MARCH study (and others) look to validate

the approach of using HIV DNA tropism to switch to MVC-containing regimens Current therapy vs MVC BID* (1:2:2)

♦ MODERN study (and others) examine special aspects of MVC therapy (eg Nuc sparing)

MVC vs TDF/FTC (in combination with boosted DRV)

Presented at the 10th Eu Meeting on HIV & Hepatitis, 28-30 March 2012, Barcelona

Other small molecule CCR5 antagonists

Presented at the 10th Eu Meeting on HIV & Hepatitis, 28-30 March 2012, Barcelona

Other Small Molecule Drugs

♦Vicriviroc (halted)

♦Cenicriviroc (Tobira) ♦A CCR5 and CCR2 antagonist

♦Phase 2b studies ongoing

One of two doses CNV vs EFV in combination with Truvada

Presented at the 10th Eu Meeting on HIV & Hepatitis, 28-30 March 2012, Barcelona

Society has enough co-receptor antagonists

Presented at the 10th Eu Meeting on HIV & Hepatitis, 28-30 March 2012, Barcelona

Individuals do not have enough co-receptor

antagonists

Presented at the 10th Eu Meeting on HIV & Hepatitis, 28-30 March 2012, Barcelona

Orphan Drugs in the US & Europe

The Orphan Drug Act (1983): “drugs, biologics, medical devices, and medical foods that are indicated for …. fewer than 200,000 people in the United States.

European definition: “. . . a rare disease is a disease affecting less than 5

per 10,000 inhabitants, is fatal, or severely debilitating.”

To apply for orphan designation of the same medicinal

product for the same use in both the US and Europe a common application can be submitted.

Presented at the 10th Eu Meeting on HIV & Hepatitis, 28-30 March 2012, Barcelona

PRO-140 (Progenics)

♦ A humanized anti-CCR5 monoclonal antibody for SC injection

♦ Phase 2 study in comparison to placebo with dosing every two weeks (?)

- in previously non-adherent IDUs

Presented at the 10th Eu Meeting on HIV & Hepatitis, 28-30 March 2012, Barcelona

Berlin Patient

Presented at the 10th Eu Meeting on HIV & Hepatitis, 28-30 March 2012, Barcelona

Berlin Patient

“ultradeep sequencing analysis… revealed a small proportion of X4 variants before the allogeneic stemcell transplantation”

Presented at the 10th Eu Meeting on HIV & Hepatitis, 28-30 March 2012, Barcelona

Zinc Finger Antagonist (SB-728-T Sangamo)

♦ Removes CD4 cells from patients and genetically modifies with adenovirus/plasmid ZFN to specifically “edit” out CCR5 gene

♦ ~30 percent efficient; cells are expanded and re-infused 5-30 billion cells back into same patient

♦ Modified cells remain for at least a year

Presented at the 10th Eu Meeting on HIV & Hepatitis, 28-30 March 2012, Barcelona

Results in 6 patients with CD4 >450 after HAART interuption

Adapted from Tebas et al; CROI 2012

CCR5 ∆32

Most folks

Presented at the 10th Eu Meeting on HIV & Hepatitis, 28-30 March 2012, Barcelona

Diagnostics Summary

♦ Free software for genotype analysis available (tropism and other genes)

♦ You should check your final g2P results make sense

♦ A g2P cut-off in range of 5.75 to 10 distinguishes responders from non-responders for HIV DNA as well as RNA

♦ Tropism inferred from HIV DNA is much more variable than from HIV RNA

Presented at the 10th Eu Meeting on HIV & Hepatitis, 28-30 March 2012, Barcelona

Drugs Summary

♦ Various approaches for the use of MVC under study

♦ Few other small molecules are in development – role for orphan drug status?

♦ Interesting approaches continue to be developed based on CCR5 use