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HIV Pipeline 2017: Targets in the HIV Lifecycle Targets in the HIV Lifecycle 1 HIV Attaches to a CD4 Cell

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ISSN 1472-4863 HIV pipeline2017 New drugs in development htb supplement: 2017 Vol 18:(1) HIV pipeline 2017: targets in the HIV lifecycle Targets in the HIV lifecycle 1 HIV attaches to a CD4 cell. 1 HIV Monoclonal Entry inhibitors 2 HIV enters a CD4 cell and gp120 antibodies (mAb) fostemsavir capsid HIV proteins and enzymes combinectin gp41 UB-421 (CD4 receptor) are released into the cell. ibalizumab (CD4 receptor) 3 Reverse transcriptase (RT) CD4 receptor (CCR5 recept.) makes double strand HIV. CCR5 coreceptor PRO-140 4 Integrase enables HIV to join the cell DNA. NRTIs/NtRTIs 2 5 Protease cuts and (nukes) reassembles new HIV. EFdA (MK-8591) 6 Each cell produces GS-9131 CD4 hundreds of new virions. HIV RNA cell NNRTIs (non-nukes) 3 Cell doravirine nucleus Protease inhibitor elsufavirine HIV DNA New viral GS-PS1 rilpivirine LA material 4 5 Capsid inhibitor Integration GS-CA1 INIs (or INSTIs) Maturation Maturation bictegravir and budding inhibitor cabotegravir 6 cabotegravir LA GSK3640254 C O N T E N T S HIVi-base.info i-Base (2017)(www.i-Base.info) New HIV HIV pipeline 2017 2 Introduction to HIV pipeline in 2017 2 Figure 1: HIV pipeline 2017: targets in the HIV lifecycle 3 Recently approved new HIV drugs 3 • Raltegravir HD • Generic dolutegravir • Generic TDF/FTC Submitted applications: completed phase 3 results 4 • Darunavir/cobicistat/FTC/TAF - FDC • Bictegravir/FTC/TAF - FDC • Dolutegravir/rilpivirine - two-drug FDC Table 1: HIV pipeline compounds by development phase 5 Compounds in phase 3 development 6 • Doravirine - NNRTI • Cabotegravir and cabotegravir/rilpivirine long-acting (LA) FDC • Dolutegravir/lamivudine - two drug FDC • Ibalizumab - mAb • PRO 140 - mAb • Fostemsavir (GSK3684934) attachment inhibitor Compounds in phase 2 studies 10 • UB-421 - mAb • VRC01 - mAb • ABX464 - Rev inhibitor Phase 1 and preclinical compounds 10 • MK-8591 (EFdA) - NRTI • GS-9131 - NRTI • GSK3640254 - maturation inhibitor • Combinectin (GSK3732394) - adnectin/fusion inhibitor • GS-PI1 - protease inhibitor • GS-CA1 - capsid inhibitor Compounds developed for low and middle-income markets 11 • Albuvirtide - fusion inhibitor • Elsulfavirine - NNRTI Other compounds: trailing or lost 12 • GS-9695 and GS-9822 - integrase inhibitors • BMS-955176 - maturation inhibitor Conclusion 12 References 13 i-Base publications 16 Published by HIV i-Base HIV PIPELINE HIV pipeline 2017 Introduction This has been a lively year for HIV research. This year i-Base has produced the HIV pipeline review as part of our Fit for Purpose report on HIV Even though only one new drug was approved (a once- treatment optimisation. daily version of raltegravir) several key generic approvals (dolutegravir and TDF/FTC) are perhaps just as important. Two main versions are available: Three new fixed-dose combinations (FDCs) have been 1. The full version reports key research in detail for each submitted to the US Food and Drug Administration drug. (This version) (FDA)/European Medicines Agency (EMA) with expected 2. The new “Pipeline-lite” version has a summary for each decisions soon, including one with a new integrase inhibitor drug with less data. (bictegravir). Both electronic versions (web and PDF) include hyperlinks Early data presented for several new compounds, including to all research sources and references. from new drug classes that are in early stages of research, are an optimistic sign that HIV is still a potential market 3. We will also publish an early update from the IAS for new drugs. conference being held in Paris from 23–26 July. While current ART is safe and effective there are ways it All three reports are available online: could become better still: formulations with smaller pills, http://i-base.info/pipeline-2017 less frequent dosing, long-acting compounds (weekly, monthly, yearly), with lower doses, fewer side effects and drug interactions, stronger resistance profiles – and it could be cheaper and more accessible. Some of these factors feature in compounds already filed for regulatory approval. h-tb This year the pipeline includes compounds in current classes (NRTIs, NNRTIs, PIs and integrase inhibitors) HIV TREATMENT BULLETIN and compounds with new targets and mechanisms of Editor: Simon Collins action (including a capsid inhibitor and several monoclonal Contributing Editor: Polly Clayden antibodies), see Figure 1. It also includes a two-drug combination submitted with an indication as maintenance Medical consultants: therapy (dolutegravir/rilpivirine). Dr Tristan Barber, Chelsea & Westminster Hosp, London. Importantly, compounds from new classes – monoclonal Dr Karen Beckerman, Albert Einstein College of Medicine, NYC. antibodies (mAbs), entry inhibitors, maturation inhibitors Dr Sanjay Bhagani, Royal Free Hospital, London. and capsid inhibitors – are all expected to work for people Prof. Diana Gibb, Medical Research Council, London. with multiple drug resistant (MDR) HIV who are dependent Dr Gareth Hardy, PhD. on new drugs. Prof. Saye Khoo, University of Liverpool Hospital. Prof. Clive Loveday, International Laboratory Virology Centre. Some of these drugs have potential to be used in very Prof. James McIntyre, Chris Hani Baragwanath Hosp. South Africa different ways – as treatment, as part of a cure strategy Dr Graeme Moyle, Chelsea & Westminster Hosp, London. and for prevention as PrEP. Dr Stefan Mauss, Düsseldorf. Prof. Caroline Sabin, UCL Medical School, London. Dr Graham P Taylor, Imperial College, London. Dr Stephen Taylor, Birmingham Heartlands Hospital. Dr Gareth Tudor-Williams, Imperial College, London. Dr Edmund Wilkins, Manchester General Hospital, Manchester. HTB is a not-for-profit community publication that aims to provide a review of the most important medical advances related to clinical management of HIV and its related conditions as well as access to treatments. Comments to articles are compiled from consultant, author and editorial responses. HIV i-Base is a registered charity no 1081905 and company reg no 3962064. HTB was formerly known as DrFax. 2 July 2017 www.i-Base.info PROOF FOR COMMENT ONLY PROOF FOR COMMENT ONLY HIV PIPELINE Figure 1: HIV pipeline 2017: targets in the HIV lifecycle HIV pipeline 2017: targets in the HIV lifecycle Targets in the HIV lifecycle 1 HIV attaches to a CD4 cell. 1 HIV Monoclonal Entry inhibitors 2 HIV enters a CD4 cell and gp120 antibodies (mAb) fostemsavir capsid HIV proteins and enzymes combinectin gp41 UB-421 (CD4 receptor) are released into the cell. ibalizumab (CD4 receptor) 3 Reverse transcriptase (RT) CD4 receptor (CCR5 recept.) makes double strand HIV. CCR5 coreceptor PRO-140 4 Integrase enables HIV to join the cell DNA. NRTIs/NtRTIs 2 5 Protease cuts and (nukes) reassembles new HIV. EFdA (MK-8591) 6 Each cell produces GS-9131 CD4 hundreds of new virions. HIV RNA cell NNRTIs (non-nukes) 3 Cell doravirine nucleus Protease inhibitor elsufavirine HIV DNA New viral GS-PS1 rilpivirine LA material 4 5 Capsid inhibitor Integration GS-CA1 INIs (or INSTIs) Maturation Maturation bictegravir and budding inhibitor cabotegravir 6 cabotegravir LA GSK3640254 HIVi-base.info i-Base (2017)(www.i-Base.info) New HIV Key: INSTI: Integrase strand transfer inhibitors; NRTI: Nucleoside/tide reverse transcriptase inhibitors; NNRTI Non-nucleoside reverse transcriptase inhibitors. Recently approved new HIV drugs Generic dolutegravir • In September 2016, tentative approval by the FDA of a generic formulation of dolutegravir has the potential to improve treatment options in countries who have access to in-patent generics, Raltegravir once-daily especially once the fixed dose combination (with TAF/FTC) also becomes available. [3] The only new HIV drug approval since the pipeline report in July 2016 was for a once-daily formulation of raltegravir. [1] Coming nearly ten years after the initial approval of raltegravir, the new Generic TDF/FTC version still requires a two-pill dose (2 x 600 mg) but has improved • Also in September 2016, in Europe the EMA approved three pharmacokinetic (PK) properties that allow once-daily dosing without generic formulations of TDF/FTC [4] that use a different base salt regard to food, with lower peak drug concentrations and higher for tenofovir, challenging Gilead’s patent for Truvada. Currently, trough levels, and less interpatient variability. the UK court has deferred the patent decision to the European Approval was based on 48-week results from the phase 3 Court, making the timeline for access to more affordable versions treatment-naive ONCEMRK study that similar efficacy and safety uncertain as this report went to press. [5] to the original formulation: 89% of participants is each arm had • The FDA also approved a generic version of TDF/FTC. [6] The undetectable viral load and similar CD4 responses. An updated patent implications and timeline for US generic access and pricing analysis presented at Glasgow 2016 also showed similar responses is unclear and might take years: generic drugs are sometimes with both formulations. [2] priced very highly in the US. [7] The regulatory approval of several generic formulations over the last Access to use lower-priced options is essential if PrEP is to have year is also important. the maximum impact on reducing HIV incidence. www.i-Base.info July 2017 3 HIV PIPELINE Submitted applications: completed the bictegravir vs dolutegravir arms, median viral load was 4.41 vs 4.48 log, with 15 vs 21 people >100,000 copies/mL and median phase 3 results CD4 count was 441 vs 455 cells/mm3, with 5 vs 9 participants with CD4 <200 cells/mm3. Several compounds have already been submitted for regulatory At week 24, viral suppression to <50 copies/mL (snapshot analysis) evaluation based on primary endpoint results from phase 3 studies. was achieved by 97% vs 94% in the bictegravir vs dolutegravir groups respectively (difference +2.9; 95%CI: –8.5% to +14.2%, p=0.50 NS). For the secondary endpoint at week 48, these rates were 97% vs Darunavir/cobicistat/FTC/TAF - FDC 91% (difference: +6.4; 95%CI: –6.0% to 18.8%, p=0.17 NS), with no statistical difference between groups.
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  • BIKTARVY (Bictegravir, Emtricitabine, and Tenofovir

    BIKTARVY (Bictegravir, Emtricitabine, and Tenofovir

    HIGHLIGHTS OF PRESCRIBING INFORMATION or below 15 mL per minute who have no antiretroviral treatment These highlights do not include all the information needed to use history. (2.3) BIKTARVY safely and effectively. See full prescribing information • Hepatic impairment: BIKTARVY is not recommended in patients for BIKTARVY. with severe hepatic impairment. (2.4) BIKTARVY® (bictegravir, emtricitabine, and tenofovir alafenamide) ----------------------DOSAGE FORMS AND STRENGTHS--------------------- tablets, for oral use Tablets: 50 mg of bictegravir (equivalent to 52.5 mg of bictegravir Initial U.S. Approval: 2018 sodium), 200 mg of emtricitabine, and 25 mg of tenofovir alafenamide (equivalent to 28 mg of tenofovir alafenamide fumarate). (3) WARNING: POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B -------------------------------CONTRAINDICATIONS------------------------------- See full prescribing information for complete boxed warning. BIKTARVY is contraindicated to be co-administered with: • dofetilide. (4) Severe acute exacerbations of hepatitis B have been • rifampin. (4) reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing -----------------------WARNINGS AND PRECAUTIONS------------------------ emtricitabine (FTC) and/or tenofovir disoproxil fumarate • Immune reconstitution syndrome: May necessitate further evaluation (TDF), and may occur with discontinuation of BIKTARVY. and treatment. (5.3) Closely monitor hepatic function in these patients. If • New onset or worsening renal impairment: