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•HCV•TB ABOUT HIV I-BASE HIV•HCV•TB ABOUT HIV i-BASE HIV i-Base is a London-based HIV treatment activist organization. HIV i-Base works in the United Kingdom and internationally to ensure that people living with HIV are actively engaged in their own treatment and medical care and are included in policy discussions about HIV treatment recommendations and access. www.i-base.info ABOUT TAG Treatment Action Group (TAG) is an independent AIDS research and policy think tank fighting for better treatment, a vaccine, and a cure for AIDS. TAG works to ensure that all people with HIV receive lifesaving treatment, care, and information. www.treatmentactiongroup.org 2014 PIPELINE REPORT HIV, HEPATITIS C VIRUS (HCV), AND TUBERCULOSIS (TB) DRUGS, DIAGNOSTICS, VACCINES, PREVENTIVE TECHNOLOGIES, RESEARCH TOWARD A CURE, AND IMMUNE-BASED AND GENE THERAPIES IN DEVELOPMENT By Polly Clayden, Simon Collins, Colleen Daniels, Mike Frick, Mark Harrington, Tim Horn, Richard Jefferys, Karyn Kaplan, Erica Lessem, Lindsay McKenna, and Tracy Swan Edited by Andrea Benzacar JULY 2014 HIV i-BASE/TREATMENT AcTION GROUP AUTHORS Polly Clayden, Simon Collins, Colleen Daniels, Mike Frick, Mark Harrington, Tim Horn, Richard Jefferys, Karyn Kaplan, Erica Lessem, Lindsay McKenna, and Tracy Swan EXECUTIVE EDITOR Andrea Benzacar DESIGNER Lei Chou ACKNOWLEDGMENTS i-Base thanks the Monument Trust and UNITAID for support for this work. Thanks to the TAG staff, board, and donors for supporting the production of the 2014 Pipeline Report. HIV i-Base Treatment Action Group 4th Floor, 57 Great Suffolk Street 261 Fifth Avenue, Suite 2110 London SE1 0BB. New York, NY 10016 Tel + 44 (0) 20 7407 8488 Tel +1 212 253 7922 Fax +1 212 253 7923 http://i-base.info [email protected] www.treatmentactiongroup.org [email protected] ISBN 978-0-9895740-7-5 This report is dedicated to Marvin Oscar Shulman May 17, 1932–January 15, 2014 Photo: Thomas M. Keane Marvin pictured, seated, second from left. A fierce AIDS warrior, principled leader, and beloved friend, Marvin Shulman was an activist’s activist. He dedicated himself completely to the fight against AIDS, first as a member of ACT UP/NY, where he served as treasurer and as a member of the coordinating committee, and later as the first treasurer of TAG. His years of work for both organizations, without ego or fanfare, made possible historic actions leading to changes that continue to save lives today. Without Marvin, there would have been no “Storm the NIH,” no “Seize Control of the FDA,” no giant condom on Jesse Helm’s house…and none of the lifesaving drugs that have changed the landscape of the epidemic in the ensuing years. Marvin was fiercely loyal to his friends and a man of legendary generosity in his personal life as well as in his activism. He was loving, blunt, savagely funny, and deeply courageous. He saved many situations with his ability to call bulls**t for the greater good. He was the best kind of activist because he cared—first, last, and always—about the work. Marvin wanted the AIDS crisis to end. He wanted the ignorance and injustice underlying the crisis to end. He didn’t care who took the credit. And so he just did great things. And so can we all. And so must we all. Marvin’s life and his approach to work were and are a model for other activists, including his colleagues at TAG. Marvin leaves a tremendous legacy. We thank him, and we miss him greatly. TABLE OF CONTENTS Introduction and Executive Summary 1 The Antiretroviral Pipeline 19 Preventive Technologies: Antiretroviral and Vaccine Development 55 Research Toward a Cure and Immune-Based and Gene Therapies 83 Fit for Purpose: Treatment Optimization 103 The Pediatric Antiretroviral Pipeline 131 Hepatitis C Pipeline: BONANZA! The Gold Rush Is Under Way 153 Global Update: Hepatitis C Treatment Activism 179 The Tuberculosis Diagnostics Pipeline 183 Tuberculosis Drug Development Hobbles Forward 197 Playing Catch-Up: Pediatric Tuberculosis Treatment Pipeline 217 The Tuberculosis Vaccines Pipeline 233 Introduction and Executive Summary Introduction and Executive Summary By Polly Clayden and Mark Harrington INTRODUCTION Last year we wrote: [Getting] the best drugs to the most people as quickly as possible… requires that the compounds and combination products be: • Discovered and developed in a high-quality research program; • Approved by a national or multinational regulatory authority; • Recommended by national or multinational guidelines groups; • Available in formulations suitable for use in the proposed population; • Affordable to public-sector programs and through private insurance; and • Accessible to patients through local health systems.1 One year later, the research, regulatory, and access landscape for people with HIV, hepatitis C virus (HCV), or tuberculosis (TB) remains one of stark contrasts among the three diseases, and between people with access to affordable health care—whether they live in rich or developing countries—and those without. The research pipelines described in this year’s report show substantial progress in new treatments and preventive interventions against HIV. Revolutionary changes are afoot in the treatment of HCV, which allow—for the first time—the prospect of universal cure and disease eradication—if only cost and access barriers can be overcome. But, in the case of TB, few new diagnostics, even fewer new drugs, poor access, and declining political will create a pipeline woefully underpopulated, slow-moving, and resource-deprived. Here we highlight the first of the essential requirements outlined above, the requirement that new interventions be “discovered and developed in a high- quality research program.” A quick scan of worldwide trials data maintained by the U.S. National Institutes of Health (NIH) at clinicaltrials.gov reveals many disparities between research 1 2014 PIPELINE REPORT and development programs for treatments of HIV, HCV, and TB. Newly approved drugs for the three diseases—dolutegravir (for HIV), sofosbuvir (for HCV), and delamanid (for TB)—have respectively 61, 67, and 6 clinical trials registered to investigate their use. The 61 studies of dolutegravir cover: treatment-naive and -experienced patients (including those with resistance to other integrase inhibitors); comparisons, use, and interactions with the most commonly used antiretrovirals (and a couple of investigative ones); interactions with potential concomitant medicines that include studies with methadone, rifampin, and oral contraceptives; an investigation into how the drug performs in women; use in people with hepatic and renal impairment; pregnancy pharmacokinetics; a pediatric investigation program down to four weeks of age conducted by the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) network; and pharmacokinetics of the pediatric granule formulation. This list is not exhaustive. Despite the limitations of the registrational studies, with the usual underrepresentation of women, people with coinfections, etc., by the time all the studies are completed as well as several in the planning stage that are not yet registered, we will have a pretty good idea how the drug will perform across a diverse population (Polly Clayden looks at some of these that will help with our understanding of how the drug will perform in low- and middle-income settings in her chapter on antiretroviral dose optimization). Registered sofosbuvir trials are also abundant and include patients with varying treatment experience, liver disease stage, and genotypes. But a closer look reveals limited investigations into regimens with other sponsors’ drugs, nothing in pregnant women or children, few in HIV coinfection (and nothing in other comorbidities), and just one (not yet recruiting) in people who inject drugs. As yet there are very few trials registered by independent investigators (and notably these are usually HIV networks or centers). Tracy Swan details the shortcomings of HCV trial enrollment in her chapter. The tally for delamanid trials is a paltry 10 percent of those for the other two recently approved agents. It is at least encouraging that two of these trials will provide information for use in children with multidrug-resistant TB (MDR-TB). However, approval of delamanid by the European Medicines Agency (EMA) was delayed due to confusingly presented results from the phase II program, which included a two-month study, a six-month study, and an open-label study. The sponsor claimed a mortality benefit for those treated for six rather than two 2 Introduction and Executive Summary months, but neglected to mention that those not surviving or lost to follow-up between the two- and six-month endpoints were excluded from this survival analysis—producing a biased readout.2 The sponsor’s inexperience and the lack of validated treatment options in multidrug-resistant (MDR) TB cannot excuse the poor design and presentation of this phase II program. A phase III study, now fully enrolled, may shed more light on delamanid’s use. The other recently approved drug to treat MDR-TB, Janssen’s bedaquiline, had stronger evidence of efficacy at two and six months, but in the “placebo- controlled C208 trial, however, an imbalance of all-cause mortality has been observed with more deaths reported in the bedaquiline group (10/79 versus 2/81 in the placebo group in C208 Stage 2). Causes of death were varied and all but one occurred after the treatment period with bedaquiline.”3 The U.S. Food and Drug Administration (FDA) carried out a thorough review of each death in the phase II program and could not rule out an association with bedaquiline,4 resulting in a black box warning on the label and a requirement that Janssen open a U.S. patient registry to monitor safety post-marketing.5 The excess mortality seen in phase II should have induced Janssen to accelerate its confirmatory phase III study, which has not yet even begun. Rather than mounting its own phase III study, Janssen is trying to piggyback onto an ongoing USAID/British Medical Research Council (BMRC) study of a modified so-called Bangladesh regimen compared with standard of care (SOC).
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