The following slides and audio are taken from a public HIV health and treatments update forum held in Sydney,

Australia on 25 November 2008. The slides and audio have been edited for presentation on the web.

The speaker is Bill Whittaker, NAPWA Health, Treatments and Research portfolio co-convenor.

For more presentations from this event, visit the sponsor organisations’ websites:

HIV Treatment and Health UpdateHIV Treatment and Health Update25 November 2008

Part 4

New HIV treatment pipeline

HIV Antivirals in Use - 1994

Nucleoside RTI’s Non-Nucleoside RTI’s Protease Inhibitors

- AZT

- ddI

- d4T

- ddC

Nucleotide RTIs Other

- Hydroxyurea

4 HIV antiviral drugs in use in 1994……………

HIV Antivirals in Use - 1998

Nucleoside RTI’s Non-Nucleoside RTI’s Protease Inhibitors

- AZT - Nevirapine - Indinavir

- 3TC - Delavirdine - Nelfinavir

- ddI - Efavirenz - Saquinavir &

- ddCFortovase

- d4T - Ritonavir

- Abacavir - Amprenavir

Nucleotide RTIs Other

- Adefovir - Hydroxyurea

16 HIV antiviral drugs in use in 1998……………

Most 1998 HIV Antivirals – By 2008Withdrawn, Reformulated, Redesigned

Nucleoside RTI’s Non-Nucleoside RTI’s Protease Inhibitors

- AZT - Nevirapine - Indinavir

- 3TC - Delavirdine - Nelfinavir

- ddI - Efavirenz - Saquinavir #

- ddC Fortovase #

- d4T - Ritonavir *

- Abacavir - Amprenavir #

Nucleotide RTIs Other

- Adefovir - Hydroxyurea

* Only for boosting other PIs# Reformulated/redesigned

10/16 antiviral drugs from 1998 either withdrawn, reformulated, redesigned, no longer commonly used in HIV………..

“The white ones help my immune system but raise my blood pressure. The red ones lower my blood

pressure but screw up my stomach. The green ones help my stomach but fuck with my immune system. Then these yellow ones simply ensure an attractive

colour combination.”

22 Antiviral Drugs available Nov 2008

Nucleoside RTIs Abacavir (Ziagen) Didanosine ddi (Videx-EC) Emtricitabine FTC (Emtriva) Lamivudine 3TC (Epivir) Stavudine d4T (Zerit) Zidovudine AZT (Retrovir)

Non Nucleoside RTIs

Efavirenz (Sustiva) Nevirapine (Viramune) Etravirine (Compassionate Access)

Nucleotide RTIs Tenofovir (Viread)

Combination Pills Trizivir (AZT + 3TC + Abacavir) Kivexa (3TC + Abacavir) Combivir (AZT + 3TC) Truvada (FTC + TNF) Atripla (FTC + TNF + Efavirenz)

Protease Inhibitors Atazanavir (Reyataz) Fosamprenavir (Lexiva) Indinavir (Crixivan) Lopinavir (Kaletra) Nelfinavir (Viracept) Ritonavir (Norvir) Saquinavir ( Invirase) Tipranavir (Aptivus) Duranavir

Fusion Inhibitor Fuzeon (T-20)

Integrase Inhibitor Raltegravir

CCR5 Inhibitor Maraviroc (Compassionate Access)

HIV drug resistance – treatment failure.

Toxicities and side effects have greatly improved – but they are still a problem for some.

More potent, longer acting drugs - more forgiving of missed doses.

We shouldn’t settle for lifelong daily treatment – not desirable and ? feasible. Good for pharma.

New HIV Treatment Pipeline

Why do we need more HIV treatments?

HIV drug resistance – treatment failure.

Toxicities and side effects have greatly improved – but they are still a problem for some.

More potent, longer acting drugs - more forgiving of missed doses.

We shouldn’t settle for lifelong daily treatment – not desirable and ? feasible. Good for pharma.

New HIV Treatment Pipeline

Why do we need more HIV treatments?

Treatment needs to be more than HIV antivirals – immune boosters and restorers.

The Cure

Gold Standard for New HIV Treatments

Potent Potent and and durabledurable – work with other HIV drugs to drive the virus – work with other HIV drugs to drive the virus to undetectable and keep it there.to undetectable and keep it there.

Low side effectsLow side effects & & Convenient Convenient - once or twice daily.- once or twice daily.

Minimise toxicitiesMinimise toxicities - less potential for diabetes, cardiovascular - less potential for diabetes, cardiovascular problems, bone density, body fat changes, etc.problems, bone density, body fat changes, etc.

Must offer an advantage….Must offer an advantage….not just “copy cat”not just “copy cat” drugs. drugs.

Attack a Attack a variety ofvariety of targetstargets in the life cycle of HIV. in the life cycle of HIV.

What doctors and community activists expect drug companies to deliver in their new drugs –

Nucleosides

eg. 3TC

Non-Nucleosides

eg. Efavirenz

Fusion eg. T20

Proteaseseg. Kaletra

CD4 T-CellCD4 T-Cell

HIV antiviral drugs interrupt the making of new HIV virus

MaturationMaturation

Integraseeg.

Raltegravir

HIV attaching & taking over CD4 T-cell

Newly made HIV going off to work

CD4

CCR5

HIV

CD4 T cell surface

CCR5 blocker

CD4 T cell surface

CCR5

CCR5 blocker

CCR5

CD4 T cell surface

This HIV virus particle…….gives up and goes away…..

ARV Drugs in Early Research (pre-people)

In 2007 there are 86 that we know of, but no doubt more……..

Nucleoside RTI’s Non-Nucleoside RTI’s Protease Inhibitors

Integrase Inhibitors Maturation Inhibitors Entry Inhibitors Others

1113 7

13 5 20 17

Drug Target Clinical Trial progress

Pharma Comment

Apricitabine NRTI Phase III Avexa Australian

Amdoxovir NRTI Phase II RFS

Elvucitabine NRTI Phase II Achillion

IDX899 Non-NRTI Phase I/II Idenix

UK-453,061 Non-NRTI Phase I/II Pfizer

Rilpivirine (TMC-278) Non-NRTI Phase III Tibotec/JJ

RDEA806 Non-NRTI Phase I/II Ardea

SPI-256 Protease I Phase I/II Sequoia

Beviramat (PA-457) Maturation Phase I/II Panacos

Elvitegravir Integrase Phase II Gilead

TBR-652 CCR5 Phase I Tobira

Vicriviroc CCR5 Phase III Schering

SCH532706 CCR5 Phase I Schering Phase I Aust.

PRO 140 CCR5 Phase II Progenics

TNX-355 CD4 Phase II Genentech

SPI-452 Enhancer Phase I Sequoia RTV like booster

GS 93502 Enhancer Phase II Gilead RTV like booster

2008 Experimental HIV Antiviral DrugsClinical Trials in People

Protease Inhibitors

NNRTIs (Non Nukes)

NRTIs (Nukes)

Maturation inhibitor

Integrase inhibitors

Entry inhibitors

HIV TREATMENT PIPELINE - 2007

2008 2009 2010 2011 2012

BevirimatPanacos

AmdoxovirRFS Pharma

GW 385 GSK

TNX 355Genentech

GS1937Gilead

AVX754Apricitabine

Avexa

ReversetPharmasset

RacivirPharmasset

TMC-278Rilpivirine

Tibotec BILR-355BMS

INCB9471 Incyte Corp

? Timelines for First Access

KP-1461Koronis

Protease Inhibitors

NNRTIs (Non Nukes)

NRTIs (Nukes)

Maturation inhibitor

Integrase inhibitors

Entry inhibitors

HIV TREATMENT PIPELINE - 2007

2008 2009 2010 2011 2012

BevirimatPanacos

AmdoxovirRFS Pharma

TNX 355Genentech

AVX754Apricitabine

Avexa

TMC-278Rilpivirine

Tibotec

? Timelines for First Access5/12 remain

today

Protease Inhibitors

NNRTIs (Non Nukes)

NRTIs (Nukes)

Maturation inhibitor

Integrase inhibitors

Entry inhibitors

2008 2009 2010 2011 2012

BeviramatPanacos

TNX 355Genentech

AVX754Apricitabine

Avexa

TMC-278Rilpivirine

Tibotec

HIV TREATMENT PIPELINE - Now

? Timelines for First Access

SPI-256Sequoia

VicrivirocSchering

AmdoxovirRFS Pharma

ACH-126Elvucitabine

Achillion

IDX899Idenix

UK 453,061Pfizer

RDEA806 Ardea

SCH 532706Schering

PRO 140Progenics

Failure of the most promising preventive vaccine (Merck).

Actually increased the risk of infection.

Prominent scientists says vaccine may never happen.

Major rethink – back to basics (March US meeting).

But knowing what doesn’t work can be helpful.

10 years ago “vaccine 10 years away” – same message today?

Vaccines - Pipeline

Two kinds – prevent infection and help those already infected:

Immune based Treatments

Immune based treatments use the human immune system to provide a different way of treating HIV (defensive rather than offensive):

Three approaches –

therapies to boost the immune response to HIV itself (e.g., therapeutic vaccines).

therapies to improve immune function and/or overall health (e.g. cytokines and anti-inflammatory approaches).

gene therapies to alter the makeup of parts of the immune system to reduce or eliminate the harmful effects of HIV.

Immune based Treatments

Poor cousin of HIV research.

No immune based treatments for HIV approved in Australia, or elsewhere.

But research ongoing – information limited - few products close to advanced clinical trials.

1 Source: Treatment Action Group NYC 08.08

A great variety of experimental and innovative approaches.1

18 HIV therapeutic vaccines.1

13 Gene Therapy, Cytokine, and Immunomodulator agents in early human trials.1

Interleukin 2 (IL2) results soon.

The Pipeline - summing it up:

HIV antiviral treatment pipeline slower over next few years.

Unprecedented recent rush of new drugs – ebbs and flows.

Most antiviral drugs in the pipeline look like offering small, but important, improvements over existing approved drugs.

Immune-based therapy pipeline isn’t as advanced - but a lot going on - may lead to new directions for treatment and better understanding of HIV and the immune system.

Scientists and activists are thinking about how to make a quantum leap to the next level – curing HIV or disabling it.

Overall, HIV treatment pipeline suggests progress and hope.

The Pipeline – Summing it Up

Now lots of experimental drugs and new pharmas – very strategic about lobbying for which new drugs.

Clinical Trials & Compassionate Access Schemes – equity.

Local and overseas negotiation – drug companies, researchers.

Pharmaceutical Advisory Boards = local & international.

Forging contact = clinicians, scientists, pharmas, O/S activists.

Tracking the drug regulatory and approval systems.

Many of our doctors are activists too!

Very time and resource demanding.

Getting New Treatments to You

New HIV treatments don’t just miraculously arrive on the pharmacy shelf………..

Getting New Treatments to You

Activism is still necessary!!Activism is still necessary!!

Many of the topics in tonight’s update are covered in this Guide…..

Pick up a copy at Positive Life, ACON or download from http://treataware.info/

For more presentations from this event, visit

www.napwa.org.au

or

www.acon.org.au