NAPWA’s Treatment Horizons: Pathways to a Functional CureIAS 2011, Rome, Italy19th July 2011

Vacc4x: A Therapeutic HIV-1 Vaccine

Based on Modified Peptides

Maja A. Sommerfelt Ph.D.CSO

Therapeutic vaccination Antiviral responses

T-cell approaches:Kill infected cellsAntibody approaches: Block/inactivate the virus

Generalised immune activation induced by HIV

Immune responses induced by therapeutic vaccination can reach regions of the body not accessed by ART

An effective therapeutic vaccine will provide valuable information that can help towards a successful preventative vaccine

Therapeutic Vaccination and Functional Cure for HIV-1 Infection

Vacc-4x

Vacc-C5

Vacc-4x: Based on conserved domains of HIV-1 p24CA

*Weber et al. 1987 Lancet 1:119-22 ; Cheingsov-Popov et al. 1991 BMJ 302 :23-6 ;¤ Kiepiela et al. 2007 Nature Med. 13:46-53; Zuniga et al. 2006 J. Virol. 80:3122-5.§Dahirel et al. 2011 www.pnas.org/cgi/doi/10.1073/pnas.1105315108; # Schoofs 2011 Wall Street Journal (WSJ) 21st June

• 4 modified peptides to p24CA

• Sustained immune responses to p24CA are associated with delayed disease progression*

• Strong responses to Gag are associated with virus control (LTNP) in the absence of ART¤

• Conserved ‘Sectors’ within p24CA particularly immunologically vulnerable and important for virus control§

• Vacc-4x largely corresponds to ‘Sector 3’

p24CA

Image WSJ

Images Dahirel et al. 2011

Bionor Immuno Peptide Design Considers

Human Diversity Virus Diversity

Peptides are modified using a proprietary design technology to improve• Uptake

• Antigen processing & presentation• Simple & cost-effective manufacture

• Conserved Domains• Cross Clade

• Most prevalent HLA in diverse human populations• Human-like sequences excluded

Vacc-4x: Phase IIB Study

Inclusion criteria

Endpoints

Study design

• 18-55 y of age• Chronic HIV infection (>1 y)• Stable on ART >6 months (VL < 50 copies/mL)• Pre-study CD4 cell count > 400 x 106 / L• Nadir CD4 cell count > 200 x 106 / L

• Primary: Resumption of ART CD4 < 350 x106 / L or 50% decrease VL >300.000 copies/mL

• Co-primary: Change of CD4 • Secondary: Viral Load / ELISPOT / Proliferation / ICS

• 135 patients (US+EU); 2/3 active and 1/3 placebo• 6 immunizations (1,2 mg Vacc-4x + GMCSF over 18wks)• Off ART wk 28-52 (LTFU during year 2)

IIB Study Schedule

Vacc-4x IIB study: 18 sites

Last Patient Completed wk52: June 2010Last Patient Completed wk104: June 2011

No Vacc-4x -related SAE reported

UK Germany Italy Spain USAPeters Van Lunzen Lazzarin Clotet FischlFisher Rockstroh Gatell Hardy

Moyle Schürmann Podzamczer Mitsuyasu

Plettenberg Taiwo

Fätkenheuer Asmuth

Arasteh

Central Labs (Immunology)

USA UC Davis Pollard

EU Univ Lausanne Pantaleo

Bionor Labs Jelmert

Phase IIB Baseline Characteristics

Parameters Vacc-4x (n=92) Placebo (n=43)

Male 78 (85%) 38 (88%)Female 14 (15%) 5 (12%)

Age Median years 44 (40-48) 45 (40-50)Time of HIV infection, years 10.7 (5.7-14.3) 12.4 (10.0-17.1)

Time on ART, years 8.0 (3.3-11.7) 9.3 (3.4-12.3)

Nadir CD4 cells/µl 300 (240-374) 285 (241-363)

Pre ART CD4 339 (272-454) 370 (293-450)

Pre ART Viral Load 94 810 (35 722-184 476) 25 630 (9 644-85 000)

Pre Study CD4 712 (562-928) 619 (518-761)

Primary End Points

There was no difference in the time to return to ART (p=0.89)

There was no difference in mean change in CD4 counts over time (p=0.12)

Treatment difference week 52 (Subjects who remained OFF ART until week 52)

Vacc-4x

VL/mL

Placebo

VL/mLMedian week 28 0 (n=55) 0 (n=25)Median week 52 19,550 (n=56) 40,300 (n=25)Mean week 28 1,351 (n=55) 1,629 (n=25)Mean week 52 35,220 (n=56) 65,070 (n=25)P-value 0.0022

Secondary End Points: Viral Load

Treatment difference week 52 (Subjects who remained OFF ART until week 52)

Vacc-4x

VL/mL

Placebo

VL/mLMedian week 28 0 (n=55) 0 (n=25)Median week 52 19,550 (n=56) 40,300 (n=25)Mean week 28 1,351 (n=55) 1,629 (n=25)Mean week 52 35,220 (n=56) 65,070 (n=25)P-value 0.0022

Secondary End Points: Viral Load Change from PreARTSubjects who remained off ART until week 52. Vacc-4x group change from preART 0.55 log, p=0.0003, n=44.Placebo group change from preART 0.08 log, p=0.89, n=18

Secondary End Points: ELISPOT Responses

This indicates a potential  qualitative rather than a quantitative difference in immunological responses to p24 between Vacc-4x and placebo groups. Further immunological analyses are ongoing.

Acknowledgments

All Participating Study Volunteers

Phase I & IIA Phase IIBHaukeland Hospital Participating Clinical Trial Sites

Ullevål University Hospital University of Lausanne & UC Davis

Mericon AS SRA Global Clinical Development Ltd.

Bionor Laboratories ASCovanceMericon AS

The phase IIB study is supported in part by a grant from the Research Council of Norway GLOBVAC program