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Health & Research A to Z ottiei jafax'Daml drug* (iVKb'c) tudcccne v uurlel, Snrt the pill* wpi tally de lived aesi tom AIM fcr aly a iem >". H." Hraan vy* Belle felly ef tree MkL ftrowi loot i m lulyand upon uk abv Ibe gym agiii.'1 e* djing ( HIV/AIDS 9 £J E3 Hu a Research Basic Research Epidemiology Treatment Prevention Vaccines Cure Grants Awarded Finding a Cure Research to find a cure for HIV/AIDS is among NIAID top priorities- NIAID supports a large portfolio of investigator-initiated grants in HIV cure research to identify where HIV hides, known as the HIV reservoir, and to determine how these hideouts are established and maintained. In addition, high on oxycodone NIAID also funds research to control and eliminate the viral reservoir. Vi v-y .-.I Goals of NIAID HIV Cure Research iii LUnat'i: levelond National Institute of Allergy and Infectious Diseases Labs & Scientific Resources Vacc-4x Vaccine Candidate Vacc-4x - Advanced HIV Therapeutic Vaccine Therapeutic Vaccine Based on Conserved Domains of HIV-1 Core Protein p24CA Vacc-4x consists of four modified peptides and educates the cellular immune system to kill virus producing cells Dahirel V et al.

PNAS 2011 108:11530-11535 Vacc-4x targeted regions in p24 (yellow spheres) >Vacc-4x targets conserved regions of p24 located at intra/inter hexamer interfaces (red/green) of the core subunits - overlap with peptides targeted by HIV controllers >Vacc-4x has been studied in five previous clinical studies >Vacc-4x is found to be safe online canadian pharmacy tramadol and reduces viral load over placebo >Vacc-4x has the potential to become the 9 backbone in a future Functional Cure for HIV # 'AT .

i "i ' (tm) £5Lra ill Vacc-4x Large Phase II Study Study Design >Phase II randomized, placebo- controlled, double-blind, multinational (Germany, UK, Italy, Spain, USA) clinical study >18 study sites; 135 subjects patients were enrolled >2:1 buy domain hydrocodone pisem net ratio of Vacc-4x to placebo >Subjects given Vacc-4x or placebo while on cART, followed by an cART-free period of up to 6 months - The ability to control viral load during the cART free period was determined Data From Randomized, Double Blinded and Placebo Controlled Phase II Study with 135 Patients Statistically Significant Reduction in Viral Load by log online canadian pharmacy tramadol 0.44 in The Treated Group Compared to Placebo - Follow up with Reboost Study Weeks Week 28 32 36 40 44 48 52 Placebo: n = 38 38 34 32 27 25 24 Vacc-4x: n = 86 88 79 71 63 59 56 Median ± upper and lower quartile Mann-Whitney U-test Week 48: *p = 0.025 Week 52: * p = 0.041 11 Viral Load Kinetics after Stopping ART Kick, Kill & Boost Strategy The Latent HIV Reservoir Unaffected by cART Medication and Invisible to The Immune System Apoptosis/ Immune clearance Virion production Reverse transcription Integration m & Entry (a) 5£* Quiescence^ Direct infection Reactivated HIV-1 expression •V & (b) A Winckelmann, unpublished Activated CD4+ T cell Reactivation - ' Latently infected memory CD4+ T cell Resting CD4+ T cell >HIV patients have variable degrees of reservoir size >Re-activation ("Kick") of the latent virus reservoir likely prerequisite for immune eradication of infected cells > Therapeutic vaccination ("Kill") and potentially other forms of immune priming ("Boost") prior to 13 virus reactivation ("Kick") may provide for virus eradication and a Functional Cure for HIV r IMiD 1 i "F 11VI1 ^ nnc- L ooosi J r 1 L KICK A Clinical Development Strategy & Pipeline Bionor Pharma Positioning for The Functional Cure First Mover in Therapeutic Vaccines for HIV >Bionor has the largest pipeline in the industry and the furthest advanced therapeutic vaccine within the HIV space >Bionor has the potential to spearhead the development of a Functional Cure for HIV >Development strategy centered around the exploration of vaccine monotherapy as well as combinations of vaccine(s) with other treatment modalities for -The Functional Cure in all patients or in subsets of online canadian pharmacy tramadol patients -Add-on to cART in specific patient populations The Largest Therapeutic Vaccine Pipeline in the HIV Space Current R&D Pipeline - HIV Products Being Developed for the Functional Cure Drug discovery Pre-clinical development Phase I Phase II Phase III Registration A A ▲ Candidate Drug Selection IND = online canadian pharmacy tramadol Investigational New Drug CTA = Clinical Trial Application BLA = Biologics License Application MAA = Marketing Authorization Approval Clinical Development Program Vacc-4x Reboost Mono Therapy Study Revaccination of Patient Population from the Previous Phase II Study >Revaccination with Vacc-4x in patients from the previous Phase II Vacc-4x study to explore a further reduction in viral load >The Vacc-4x Reboost study explores the monotherapy option for the Functional Cure Vacc-4x-VIRAL LOAD REDUCTION >The primary endpoints: changes in viral load compared to the previous study, and immune responses to the vaccine >Data expected in late Q1 2014 Vacc-4x- REBOOSTHYPOTHISIS Time Time Off cART On cART Off cART Off cART On cART Off cART The aim of reboost with Vacc-4x is a online canadian pharmacy tramadol stepwise viral load reduction as a result of vaccination while on ART, following periods without ART.

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