PRIORITY ANTIRETROVIRALS FOR THE MEDICINES PATENT POOL Third Edition | December 2013 Advancing innovation, access, and public health 1 CONTENTS 3 Introduction 4 Section 1: ARV Prioritisation in Light of New WHO Treatment Guidelines 5 Priority Regimens for Adults 9 Priority Regimens for Children and Adolescents 13 Section 2: Prioritisation of New ARVs and ARVs in the Pipeline 16 Conclusions 18 Annex I - Methodology 22 Annex II - Product Cards 23 Annex IIa: Product Cards for ARVs Prioritised in Light of New WHO Treatment Guidelines 36 Annex IIb: Product Cards for New ARVs and ARVs in the Pipeline 45 Annex IIc: Products in Early Stages of Development* 48 Annex III - Acronyms and Definitions 51 References ACKNOWLEDGMENTS The lead authors of this Working Paper were Esteban Burrone, Head of Policy, and Fernando Pascual, Medical/Pharmaceutical Consultant, of the Medicines Patent Pool. The paper also benefitted from extensive inputs from Robyn Harshaw, Sandeep Juneja, Kaitlin Mara, Chan Park, and Greg Perry. The Medicines Patent Pool (MPP) wants to thank the following external peer reviewers for their comments on an earlier draft: Jintanat Ananworanich, Pascale Boulet, Pedro Cahn, Polly Clayden, Jennifer Cohn, Meg Doherty, Diane Gibb, Raul Gonzalez, Andy Gray, Andrew Hill, Janice Lee, Rohit Malpani, Carmen Pérez-Casas, David Ripin, Marco Vitoria, and the MPP Expert Advisory Group composed of: Labeeb Abboud, Jonathan Berger, Alexandra Calmy, Shing Chang, Carlos Correa, Nelson Juma Otwoma, Eun-Joo Min, Lita Nelsen, Achal Prabhala, Gracia Violeta Ross, Maximiliano Santa Cruz, and Wim Vandevelde. 2 INTRODUCTION TO THE THIRD EDITION OF THE WORKING PAPER Since the first antiretroviral (ARV) information on the patent status, regulatory status received regulatory approval by the US and market trends for different ARVs. Since the previous edition of this working paper in November Food and Drug Administration in 1987, 2012, the World Health Organization (WHO) issued 27 single compounds have been approved for the new consolidated treatment guidelines (in July 2013), treatment of HIV in various dosage forms, as well as including a number of changes in the recommended several fixed-dose combinations (FDCs) that combine ARV treatments for adults, adolescents and children. more than one ARV in a single pill. The constant flow The patent status and regulatory status of various of innovation in the field of HIV has led to treatment ARVs have also changed. This paper takes into recommendations that evolve over time, and are consideration these changes and recommendations likely to continue evolving as new drugs are approved and considers whether new formulations of a and new formulations considered better suited to the given ARV are needed that have currently not been needs of certain patients are developed. Prioritising developed, and for which the MPP could potentially ARVs is therefore a dynamic process: Treatment play a role. This may be the case, for example, for recommendations and needs change, market FDCs needed to treat children. Based on these conditions shift, our understanding of HIV and of analyses, a new list of priority ARVs for the MPP is different ARVs evolves, and the regulatory and patent presented in the conclusions of this document. status of ARVs also changes. For the third edition of this working paper, the The purpose of this working paper, now in its third document structure has been revised in order annual edition, is to review the ARVs available today, to make it simpler and easier to read. Section 1 as well as those in late stage clinical development, to focuses on the treatment regimens recommended prioritise among them and understand which of them by the new WHO treatment guidelines, with sub- should be the focus of the work of the Medicines sections devoted to adults on the one hand and Patent Pool (MPP). The central mandate of the MPP children and adolescents on the other. Section is to negotiate open, transparent and public health- 2 includes an assessment of new ARVs that have oriented licences on patented HIV medicines in order recently obtained regulatory approval and ARVs that to enhance access to more affordable and better- are in Phase III clinical trials. Detailed descriptions adapted formulations to treat HIV in developing of the working paper’s methodology, as well as countries. It is therefore important that it focuses on product cards with an analysis of each ARV, are those medicines for which licences are likely to yield included in the annexes. The annexes also include the greatest public health impact. preliminary information on products in early stages In order to develop a list of priority ARVs for the of development (clinical trial Phases I and II). MPP, this paper analyses the current treatment guidelines, the latest data from clinical trials, and 3 SECTION 1 ARV PRIORITISATION IN LIGHT OF NEW WHO TREATMENT GUIDELINES In July 2013, the WHO published a new edition of its treatment guidelines that combines in one document all the recommendations for the diagnosis, treatment, and care of people living with HIV, as well as the prevention of HIV infection (1). The 2013 guidelines include important changes in recommendations for treatment regimens. The guidelines increased the numbers of people needing treatment significantly by recommending antiretroviral therapy begin earlier in disease progression, moving from a CD4 count of 350 to a CD4 count of 500. The WHO has recommended all children under five years of age be given treatment regardless of CD4 count (previous recommendations stated that children under three should be given treatment regardless of CD4). The WHO also streamlines its recommendations on particular treatment regimens. This section provides an overview of the key treatment recommendations of the latest WHO guidelines and a brief analysis of the current market trends and patent status for the recommended regimens. Where possible, the focus is on treatment regimens rather than on individual ARVs, in order to be aligned with WHO recommendations. A detailed analysis of each individual ARV is included in the product cards in the annexes. 4 PRIORITY REGIMENS1 FOR ADULTS Preferred First-Line Regimens for this triple combination are still somewhat limited, the number of quality-assured suppliers The once-daily FDC TDF/3TC (or FTC)/EFV, previously has increased over the past year and more recommended as one of two preferred options for manufacturers are undergoing regulatory approval adults initiating ARV therapy, is now recommended or are under assessment by WHO PQ. Patents on as the preferred option for first-line treatment. This EFV, 3TC and FTC have generally expired and the recommendation extends to adolescents, pregnant voluntary licences on TDF negotiated by the MPP and breast-feeding women, women of childbearing have helped to open the market for TDF-based age, and people co-infected with tuberculosis. combinations in most low and middle-income countries. However, there are patents pending or TDF/3TC (or FTC)/EFV2: As the first-line treatment of granted on the FTC-containing option, which will choice, the market for this regimen will likely be likely affect procurement choices for TDF/FTC/EFV significant and growing as treatment is initiated (but may not apply to the regimen containing 3TC) in earlier3 and countries phase out the use of d4T countries for which licences are not available. and gradually shift from other regimens. While manufacturing capacity and procurement options In light of new evidence, regimens based on NVP are now considered by the WHO to be alternative regimens in first-line,4 which should lead Other important to a decrease in demand for these regimens over time. Nevertheless, in the short term, certain NVP-containing regimens, such as AZT/3TC/ regimens in NVP and TDF/3TC+NVP (currently under development as an FDC) are likely to continue to be widely used, especially in patients already on first-line these regimens. Patents on these compounds have generally expired5 and should therefore not impact on the competitive procurement of this combination.6 1 Some combinations may be difficult to co-formulate due 4 This is the result of new evidence showing higher rate of to, for example, the pill size or different dosing schedules. treatment discontinuations due to adverse events for NVP, as In these situations a co-blister pack would be desirable. compared to EFV (2). In addition, new data show use of EFV is Therefore, the sign “/” has been used only when co- safe during pregnancy(1). formulation exists or is known to be possible. Otherwise, the 5 Note, however, that patents on once-daily NVP or on the sign “+” has been used. paediatric formulation may be pending or granted in some 2 The WHO guidelines confirm that 3TC and FTC are countries. pharmacologically comparable and interchangeable. 5 Other regimens using ABC and/or ddI as backbones 3 WHO expanded ART eligibility by changing CD4 threshold with SQV/r, or triple NRTIs may be needed in special for treatment initiation from 350 to 500 cells/mm3 in adults, circumstances, like alternative for TB co-infected patients adolescents and older children. and in HIV-2. 5 Preferred Second-Line Regimens more complex. Patents on LPV or on the heat-stable tablet formulation of LPV/r are pending or have been The new treatment guidelines recommend AZT/3TC granted in many developing countries, thus limiting as the preferred NRTI backbone for second-line the countries that generic ARV manufacturers can adult treatment, combined with one of two boosted supply. While there are no voluntary licences on protease inhibitors: LPV/r or ATV/r. In cases in which LPV/r today7, public health-oriented licensing could AZT or d4T was used in first-line, the guidelines enable competitive procurement of LPV/r in many recommend using TDF instead of AZT. LIC/MICs and help reduce costs.