1.2 million Americans are living with HIV, 50,000 are newly diagnosed each year

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1 Medicines in Development HIV/AIDS PRESENTED BY AMERICA S BIOPHARMACEUTICAL RESEARCH COMPANIES 2012 REPORT Biopharmaceutical Researchers Are Testing More Than 70 Medicines and Vaccines For HIV Infection Medicines in Development for HIV/AIDS million Americans are living with HIV, 50,000 are newly diagnosed each year Antivirals Cell/Gene Therapy Immunomodulators Vaccines Medicines in Development for HIV/AIDS by Phase of Development I 5 Unspecified 4 Application Submitted * Some medicines are listed in more than one phase of development. Biopharmaceutical research companies are developing 73 medicines and vaccines, focusing on improved treatment regimens, more effective therapies and promising new preventative vaccines. Although HIV/AIDS is one of the most devastating diseases affecting people around the world, the number of new infections has been steadily declining. In the United States, the AIDS-related death rate has fallen by 79 percent due to antiretroviral therapy. Over the past 30 years, nearly 40 medicines have been approved to treat HIV/AIDS. Testing for the disease also has advanced dramatically, enabling earlier treatment. While these medicines have helped to prolong the lives of HIV-infected patients, making HIV a manageable chronic disease, opportunities for even greater progress remain. For example, biopharmaceutical companies are intensifying their efforts to develop vaccines that would help prevent HIV. Current estimates show that a 50 percent effective vaccine given to only a third of the population could reduce new HIV infections by 24 percent over 15 years. The medicines in the development pipeline include: A gene therapy that uses genetic material to remove disease-causing aspects of the virus. A transdermal vaccine that helps suppress virus replication and destroys HIV-infected cells. HIV virus from breaking through the cell membrane. Despite the incredible progress to date, the HIV/AIDS epidemic remains a complex problem. America s biopharmaceutical research companies are continuing their efforts to develop novel and more effective therapies, vaccines to prevent the disease, and potentially a cure, so the millions of patients suffering today have hope for a better tomorrow.

2 Medicines in Development for HIV/AIDS ANTIVIRALS * abacavir/dolutegravir/lamivudine (integrase inhibitor/reverse transcriptase inhibitor) ViiV Healthcare HIV infection therapy in treatment-naive patients I (877) amdoxovir (DAPD) RFS Pharma Tucker, GA (404) BI (integrase inhibitor) Gilead Sciences Foster City, CA completed (800) CB1922 (synthetic steroidal lactone) Canopus BioPharma Studio City, CA cenicriviroc (CCR5 receptor antagonist) Tobira Therapeutics South San Francisco, CA (650) CMX157 (tenofovir PIM conjugate) Merck Whitehouse Station, NJ completed (800) cobicistat (PK enhancer) Gilead Sciences Foster City, CA application submitted (800) cobicistat/darunavir (PK enhancer/protease inhibitor) Gilead Sciences Foster City, CA Janssen Therapeutics Titusville, NJ HIV infection (800) (800) cobicistat/darunavir/ emtricitabine/gs-7340 Gilead Sciences Foster City, CA Janssen Therapeutics Titusville, NJ HIV-1 infection (800) (800) cobicistat/elvitegravir/ emtricitabine/gs-7340 Gilead Sciences Foster City, CA HIV-1 infection (800) dapivirine (NNRTI) International Partnership for Microbicides Silver Spring, MD (vaginal ring) (vaginal gel) /II completed (301) /II completed (301) dolutegravir (S/GSK ) (integrase inhibitor) Shionogi Florham Park, NJ ViiV Healthcare I (973) (877)

3 Medicines in Development for HIV/AIDS ANTIVIRALS efavirenz/lamivudine/ tenofovir fumarate Mylan Laboratories Canonsburg, PA application submitted (724) elvitegravir (integrase inhibitor) Gilead Sciences Foster City, CA application submitted (800) elvucitabine (NRTI) Achillion Pharmaceuticals New Haven, CT (203) GS-7340 (NtRTI) Gilead Sciences Foster City, CA (800) HIV attachment inhibitor Bristol-Myers Squibb Princeton, NJ (800) HIV maturation inhibitor Bristol-Myers Squibb Princeton, NJ in clinical trials (800) ibalizumab (TMB-355) (fusion inhibitor) TaiMed Biologics USA Irvine, CA (intravenous) (Fast Track) (subcutaneous) (949) (949) Intelence etravirine (NNRTI) Janssen Therapeutics Titusville, NJ HIV infection combination therapy in treatment-naive patients (Fast Track) (800) KD-247 (monoclonal antibody) Kaketsuken Kumamoto, Japan KP-1461 (replication inhibitor) Koronis Pharmaceuticals Redmond, WA (425) lamivudine (3TC)/lopinavir/ combination Abbott Laboratories Abbott Park, IL in clinical trials (847) lamivudine (3TC)/maraviroc/ combination GlaxoSmithKline HIV infection completed (888) lersivirine (UK ) (NNRTI) ViiV Healthcare (877) Lexiva fosamprenavir (PI) Vertex Pharmaceuticals Cambridge, MA ViiV Healthcare in adolescents, children and infants (617) (877)

4 Medicines in Development for HIV/AIDS ANTIVIRALS MK-1439 (NNRTI) Merck Whitehouse Station, NJ (800) Norvir ritonavir powdered formulation (PI) Abbott Laboratories Abbott Park, IL in clinical trials (847) NRT inhibitor Bristol-Myers Squibb Princeton, NJ (800) Prezista darunavir (once-daily 800 mg) Janssen Therapeutics Titusville, NJ HIV infection application submitted (800) PRO 140 (CCR5 receptor antagonist) CytoDyn Lake Oswego, OR HIV-1 infection prevention and treatment completed (971) RAP101 (CCR5 receptor antagonist) RAPID Pharmaceuticals Huenenberg, Switzerland RPI-MN ReceptoPharm Plantation, FL (954) S/GSK (integrase inhibitor) Shionogi Florham Park, NJ ViiV Healthcare (973) (877) SPL-7013 (vaginal gel) Starpharma Melbourne, Australia (Fast Track) completed TBR-220 (CCR5 receptor antagonist) Tobira Therapeutics South San Francisco, CA (650) tenofovir vaginal gel (NtRTI) CONRAD Arlington, VA International Partnership for Microbicides Silver Spring, MD (703) TMC (PI) Janssen Therapeutics Titusville, NJ completed (800)

5 Medicines in Development for HIV/AIDS ANTIVIRALS UB-421 (FI) United Biomedical Hauppauge, NY (631) VRX806 (NNRTI) Valeant Pharmaceuticals Mississauga, Canada (905) CELL THERAPY/GENE THERAPY HIV gene therapy Adaptimmune Philadelphia, PA Cardiff University Cardiff, Wales University of Pennsylvania Philadelphia, PA HIV infection (267) lexgenleucel-t (replication inhibitor) VIRxSYS Gaithersburg, MD HIV infection therapy in treatment-experienced patients (301) SB-728-T Sangamo BioSciences Richmond, CA (510) Stealth Vector HGTV-43 antisense gene medicine Enzo Therapeutics New York, NY /II (212) IMMUNOMODULATORS AMZ0026 Amazon Biotech New York, NY /II (212) CYT107 (recombinant human interleukin-7) Cytheris Rockville, MD (301) Cytolin anti-cd8 mab CytoDyn Lake Oswego, OR (971) IRT-103 (low-dose naltrexone) TNI BioTech New York, NY 5

6 Medicines in Development for HIV/AIDS VACCINES ADVAX (DNA vaccine) Aaron Diamond AIDS Research Center New York, NY International AIDS Vaccine Initiative New York, NY Ichor Medical Systems San Diego, CA (new delivery system) completed (212) (212) completed (212) (212) AGS-004 (autologous dendritic cell vaccine-intradermal injection) Argos Therapeutics Durham, NC (919) AVX101 (single gene ) AlphaVax HIV-1 infection prevention (919) DCVax-001 (recombinant protein vaccine) Celldex Therapeutics Needham, MA Rockefeller University New York, NY and treatment (781) DermaVir Patch DNA topical patch vaccine Genetic Immunity McLean, VA (703) HIV gp41 vaccine Mymetics Epalinges, Switzerland HIV recombinant vaccine GlaxoSmithKline HIV-1 infection prevention (888) Crucell Leiden, The Netherlands Beth Israel Deaconess Medical Center Boston, MA International AIDS Vaccine Initiative New York, NY (212) GeoVax Labs Smyrna, GA (678) GeoVax Labs Smyrna, GA /II (678)

7 Medicines in Development for HIV/AIDS VACCINES Massachusetts General Hospital Boston, MA Opal Therapeutics Parkville, Australia HIV infection (617) Novartis Vaccines & Diagnostics Cambridge, MA National Institutes of Health Bethesda, MD HIV infection (617) PaxVax San Diego, CA in clinical trials (858) (MAG pdna) Profectus Biosciences Baltimore, MD HIV-2 infection prevention (866) (rvsv) Profectus Biosciences Baltimore, MD (866) (SAV001) Sumagen Seoul, South Korea HIV-1 infection HIVAX replication-defective HIV-1 vaccine GeneCure Biotechnologies Norcross, GA HIV-1 infection (770) ITV-1 immune therapeutic vaccine Immunotech Laboratories Pasadena, CA in clinical trials (818) Pennvax -B DNA vaccine (clade B) Inovio Pharmaceuticals Blue Bell, PA and treatment (267) Pennvax -G DNA vaccine (clades A, C, D) Inovio Pharmaceuticals Blue Bell, PA (267) TUTI-16 (lipoprotein vaccine) Thymon Short Hills, NJ /II (973) vacc-4x (intradermal vaccine) Bionor Pharma Oslo, Norway 7

8 Medicines in Development for HIV/AIDS VACCINES VRC-HIVADV VP (HIV-1 recombinant adenovirus vaccine) GenVec Gaithersburg, MD Vaccine Research Center (NIAID) Bethesda, MD completed VRC-HIVADV VP (HIV adenovector Ad35 vaccine) GenVec Gaithersburg, MD Vaccine Research Center (NIAID) Bethesda, MD VRC-HIVDNA VP Vaccine Research Center (NIAID) Bethesda, MD The content of this report has been obtained through public, government and industry sources, and the Adis R&D Insight database based on the latest information. Report current as of November 16, tion about a particular product, contact the individual company directly or go to The entire series of Medicines in Development is available on PhRMA s web site. A publication of PhRMA s Communications & Public Affairs Department. (202) Provided as a Public Service by PhRMA. Founded in 1958 as the Pharmaceutical Manufacturers Association. Copyright 2012 by the Pharmaceutical Research and Manufacturers of America. Permission to reprint is awarded if proper credit is given. Pharmaceutical Research and Manufacturers of America 950 F Street, NW, Washington, DC

9 Approved Medicines for HIV Infection/AIDS Entry Inhibitors Selzentry (maraviroc) ViiV Healthcare Fuzeon (enfuvirtide) Genentech, Trimeris Integrase Inhibitor Isentress (raltegravir) Merck Nucleoside Reverse Transcriptase Inhibitors (NRTI) Combivir (lamivudine/zidovudine) ViiV Healthcare Emtriva (emtricitabine) Gilead Sciences Epivir (lamivudine) ViiV Healthcare Epzicom (abacavir/lamivudine) ViiV Healthcare Hivid (zalcitabine) Roche, marketing discontinued Retrovir (zidovudine) ViiV Healthcare Trizivir (abacavir/lamivudine/zidovudine) ViiV Healthcare Videx (didanosine) Bristol-Myers Squibb Videx EC (didanosine delayed release) Bristol-Myers Squibb Zerit (stavudine) Bristol-Myers Squibb Zerit XR (stavudine extended-release) Bristol-Myers Squibb, marketing discontinued Ziagen (abacavir) ViiV Healthcare Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI) Edurant (rilpivirine) Janssen Therapeutics Intelence (etravirine) Janssen Therapeutics Rescriptor (delvaridine) ViiV Healthcare Sustiva (efavirenz) Bristol-Myers Squibb Viramune (nevirapine) Boehringer Ingelheim Pharmaceuticals Viramune XR (nevirapine extended-release) Boehringer Ingelheim Pharmaceuticals 9

10 Approved Medicines for HIV Infection/AIDS Nucleotide Reverse Transcriptase Inhibitor (NtRTI) Viread (tenofovir disoproxil fumarate) Gilead Sciences Protease Inhibitors Agenerase (amprenavir) GlaxoSmithKline, Vertex Pharmaceuticals Aptivus (tipranavir) Boehringer Ingelheim Pharmaceuticals Crixivan (indinavir) Merck Fortovase (saquinavir soft-gel) Roche, marketing discontinued Invirase (saquinavir) Genentech Kaletra (lopinavir/ritonavir) Abbott Laboratories Lexiva (fosamprenavir) ViiV Healthcare, Vertex Pharmaceuticals Norvir (ritonavir) Abbott Laboratories Prezista (darunavir) Janssen Therapeutics Reyataz (atazanavir) Bristol-Myers Squibb Viracept Combination Medicines NNRTI/NRTI/NtRTI Atripla (efavirenz/emtricitabine/tenofovir disoproxil fumarate) Bristol-Myers Squibb, Gilead Sciences NRTI/NNRTI/NtRTI Complera (emtricitabine/rilpivirine/tenofovir, disoproxil fumarate) Gilead Sciences Integrase Inhibitor/PK Enhancer/NRTI/NtRTI Stribild (elvitegravor/cobicistat/emtricitabine/tenofvoir disoproxil fumarate) Gilead Sciences NRTI/NtRTI Truvada (emtricitabine/tenofovir disoproxil fumarate) Gilead Sciences 10

11 Glossary application submitted An application for marketing has been submitted by the company to the Food and Drug Administration (FDA). entry inhibitor Unlike other HIV drugs that work after HIV has entered the human immune cell, entry inhibitors work outside the CD4 cell, blocking the virus from entering the cell. The process of HIV entry into a cell requires a series of steps in sequence involving several key proteins. Different entry inhibitors target separate proteins in the process. One type of entry inhibitor blocks the attachment of the HIV protein gp120 to CD4 cell receptors on the cell surface. Another inhibitor targets the binding of the virus to CCR5 or CXCR4 co-receptors involved in the virus entering the cell. And a third entry inhibitor interferes with the fusion of the HIV virus with T-cells at the cell membrane. HIV infection The presence of antibodies in (the virus that causes AIDS). HIV-1 refers to the most common strain of the virus found in U.S. AIDS patients. integrase inhibitor A class of antiretroviral drugs designed to block the action of integrase, an enzyme that inserts the virus into the DNA of human cells. Since integration is a vital step in the virus replication, blocking it can halt further spread of the virus. PK enhancer Pharmacokinetic (PK) enhancer increases the effectiveness of pharmaceutical treatment. reverse transcriptase inhibitor (RTI) When HIV infects a cell, reverse transcriptase changes the single-stranded RNA into a double-stranded viral DNA. The new viral DNA is then integrated into the human DNA cells, allowing reproduction of the virus. RTIs block this action and prevent completion of synthesis of the double-stranded viral DNA, preventing HIV from multiplying. RTIs are a class of antiretroviral drugs. NRTI Nucleoside reverse transcriptase inhibitor. NNRTI Non-nucleoside reverse transcriptase inhibitor. NtRTI Nucleotide reverse transcriptase inhibitor. Phase 0 First-in-human trials conducted in accordance with FDA s 2006 guidance on exploratory Investigational New Drug (IND) studies designed to speed up development of promising drugs by establishing very early on whether the agent behaves in human subjects as was anticipated from preclinical studies. Researchers test the drug in a small group of people, usually between 20 and 80 healthy adult volunteers, to evaluate its initial safe dosage range, and identify potential side effects. The drug is given to volunteer patients, usually between 100 and 300, to see if it is effective, identify an optimal dose, and to further evaluate its short-term safety. I The drug is given to a larger, more diverse patient population, often involving between 1,000 and 3,000 patients (but sometime many more thousands), to generate statistically effectiveness. They are the longest studies, and usually take place in multiple sites around the world. PI Protease inhibitors are a class of antiretroviral drugs used to treat HIV infection. They prevent the HIV virus from replicating by inhibiting the activity of proteases, such as HIV-1. 11

12 Selected Facts about HIV/AIDS Overview U.S. AIDS Diagnoses through U.S. AIDS Deaths through Adults/Adolescents 1,119, ,394 Pediatric (under age 13) 9,475 4,986 TOTAL 1,163,575* 641,976* * Because totals for the estimated numbers were calculated independently of the values for the subpopulations, the subpopulation values may not equal these totals. HIV/AIDS Worldwide 2 In 2010, 2.7 million people became newly infected with HIV infection (including 390,000 children younger than age 15), down from 3.1 million in Although the annual number of people newly infected with HIV has dropped since its peak in the late 1990s, it is still occur- living with HIV that reached 34 million (including 3.4 million children younger than age 15) by the end of Globally, the annual number of people newly infected with HIV continues to decline, although there is stark regional variation. In sub-saharan Africa, where most of the people newly infected with HIV live, an estimated 1.9 million people became infected in That was 16 percent fewer than the estimated 2.2 million people newly infected with HIV in 2001, and 27 percent fewer than the annual number of people newly infected between 1996 and 1998, when the incidence of HIV in sub-saharan Africa peaked overall. Reductions in the number of people acquiring HIV infection, especially people ages in the countries in sub-saharan Africa that have a high burden of HIV, have been offset by increases in new infections in Eastern Europe and Central Asia. In those areas, where the primary mode of transmission of HIV is among people who inject drugs and their sexual networks, the number of people dying from AIDS-related causes increased 1,100 percent during the past decade: from an estimated 7,800 in 2001 to 89,500 in The annual number of people dying from AIDS-related causes worldwide is steadily decreasing from a peak of 2.2 million in 2005 to an estimated 1.8 million in That year, an estimated 250,000 children younger than age 15 died from AIDS-related causes, 20 percent fewer than in The number of people dying from AIDS-related causes began to decline in in sub-saharan Africa, South and Southeast Asia and the Caribbean and has continued subsequently. Introducing antiretroviral therapy has averted 2.5 million AIDS deaths in low- and middle-income countries globally since Sub- Saharan Africa accounts for the vast majority of the averted deaths: about 1.8 million. Providing antiretroviral prophylaxis to pregnant women living with HIV has prevented more than 350,000 children from acquiring HIV infection since Eighty-six percent of the children who avoided infection live in sub-saharan Africa, the region with the highest prevalence of HIV infection among women of reproductive age. 12

13 Selected Facts about HIV/AIDS HIV/AIDS in the United States 1 In 2010, an estimated 48,298 people were newly diagnosed with HIV infection name-based HIV infection reporting. In the 46 states, 46,912 adults and adolescents were newly diagnosed with HIV infection, with 37,045 diagnoses in males and 9,868 diagnoses in females. Among children younger than age 13, there were an estimated 217 diagnoses of HIV infection. At the end of 2009, an estimated 1,148,200 people age 13 and older were living with HIV infection in the United States, including 207,600 people whose infections had not been diagnosed. In 2009, the estimated number of deaths of people with a diagnosis of HIV infection in the 46 states and 5 U.S. dependent areas with 21,601. In the 46 states only, that included 21,007 adults and adolescents and 8 children younger than age 13. In 2010, the estimated number of people diagnosed with AIDS in the United States and 6 U.S. dependent areas was 33,630. In the 50 states and the District of Columbia, 24,749 AIDS diagnoses were among adult and adolescent males, 8,242 were among adult and adolescent females, and 23 diagnoses were among children younger than age 13. In 2009, the estimated number of deaths of people with an AIDS diagnosis in the United States and 6 U.S. dependent areas was 18,234. In the 50 states and the District of Columbia, that included 17,770 adults and adolescents and 4 children younger than age 13. HIV/AIDS Economic Impact The lifetime treatment cost of an HIV infection can be used as a conservative threshold value for the cost of averting one infection. Currently, the lifetime treatment cost of an HIV infection is estimated at $379,668 (in 2010 dollars);; therefore, a prevention intervention is deemed cost-saving if its cost-effectiveness (CE) ratio is less than $379,668 per infection averted. The average annual cost of HIV care in the antiretroviral (ART) era is estimated to be $19,912 (in 2006 dollars;; $23,000 in 2010 dollars). One study has estimated the medical savings from infections averted by United States prevention programs from to be $129.9 billion with 361,878 HIV infections averted. 1 Nearly 30 years into the HIV epidemic, HIV continues to take a heavy toll in the United States. More than 1.1 million people are currently living with HIV, nearly 18,000 people with AIDS still die each year, and lifetime medical care for those who become infected with HIV each year is estimated to cost $20 billion. 1 Without intervention, a perinatal HIV transmission rate of 25 percent would result in 1,750 HIV-infected infants born annually in the United States with lifetime medical costs estimated to be $282 million. The cost of intervention (HIV counseling, testing, and zidovudine treatment) was estimated to be $67.6 million. That intervention would prevent 656 pediatric HIV infections, saving $105.6 million in medical care costs a net cost-savings of $38.1 million annually. 3 Sources: 1. U.S. Centers for Disease Control and Prevention, HIV Surveillance Report: Diagnoses of HIV Infection and AIDS in the United States and Dependent Areas, 2010;; Vol. 22., 2. World Health Organization (WHO), 3. KidSource OnLine, Inc., 13

14 The Drug Discovery, Development and Approval Process Developing a new medicine takes an average of years; For every 5,000-10,000 compounds in the pipeline, only 1 is approved. The Drug Development and Approval Process The U.S. system of new drug approvals is perhaps the most rigorous in the world. It takes years, on average, for an experimental drug to travel from lab to U.S. patients, according to the Tufts Center for the compounds that enter preclinical testing make is approved for sale. On average, it costs a company $1.2 billion, including the cost of failures, to get one new medicine from the laboratory to U.S. patients, according to a 2007 study by the Tufts Center for the Study of Drug Development. the laboratory, medicines are usually developed as follows: Preclinical Testing. A pharmaceutical company conducts laboratory and animal studies to show biological activity of the compound against the targeted disease, and the compound is evaluated for safety. Investigational New Drug Application (IND). After completing preclinical testing, a company Administration (FDA) to begin to test the drug in people. The IND shows results of previous experiments;; how, where and by whom the new studies will be conducted;; the chemical structure of the compound;; how it is thought to work in the body;; any toxic effects found in the animal studies;; and how the compound is manufactured. All clinical trials must be reviewed and approved by the Institutional Review Board (IRB) where the trials will be conducted. Progress reports on clinical trials must be submitted at least annually to FDA and the IRB. Clinical Trials, Researchers test the drug in a small group of people, usually between 20 and 80 healthy adult volunteers, to determine a safe dosage range, and identify potential side effects. Clinical Trials, The drug is given to volunteer patients, usually between 100 and 300, to see if it iseffective, identify an optimal dose, and to further evaluate its short-term safety. Clinical Trials, I The drug is given to a larger, more diverse patient population, often involving between 1,000 and 3,000 patients (but sometime many more thousands), to generate safety and effectiveness. They are the longest studies, and usually take place in multiple sites around the world. New Drug Application (NDA)/Biologic License Application (BLA). Following the completion of all three phases of clinical trials, NDA or BLA with FDA if the data successfully demonstrate both safety and effectiveness. information that the company has gathered. Applications typically run 100,000 pages or more. Approval. Once FDA approves an NDA or BLA, the new medicine becomes available for physicians to prescribe. A company must continue to submit periodic reports to FDA, including any cases of adverse reactions and appropriate quality-control records. For some medicines, FDA requires additional trials (V) to evaluate long-term effects. Discovering and developing safe and effective process. PhRMA member companies invested an estimated $49.5 billion in research and development in 2011.