ISSN 1472-4863 HIV pipeline2020-lite New drugs in development htb supplement: 2020 Vol 21:(1) C O N T E N T S Targets in the HIV lifecycle HIV pipeline 2020: targets in the HIV lifecycle 1 HIV attaches to a CD4 cell. 2 HIV enters a CD4 cell and HIV proteins and enzymes Entry inhibitors 1 HIV Monoclonal antibodies (mAb) are released into the cell. gp120 3 combinectin capsid Reverse transcriptase (RT) (GSK3732394) gp41 UB-421 (CD4 receptor) makes double strand HIV. 4 VRC01/LS and VRC07/LS Integrase enables HIV to CD4 receptor 3BNC117/LS and10-1074/LS join the cell DNA. CCR5 coreceptor 5 PGDM1400, 10E8.4/iMab Protease cuts and 6 reassembles new HIV. NRTIs/NRTTIs 2 PGT121 and elipovimab (GS-9722) (nukes) Final stages include N6LS (gp120) maturation and budding islatravir (EFdA) leronlimab PRO-140 (CCR5) as each cell produces MK-8504, MK-8583 hundreds of new virions. HIV RNA CD4 cell NNRTIs Rev inhibitor (non-nukes) 3 Cell nucleus elsulfavirine ABX-464 HIV DNA Protease cuts new viral material Capsid inhibitors 4 5 GS-6207 Integration GSK (pre-clinical) INIs (INSTIs) Maturation cabotegravir LA inhibitors 6 Maturation GSK’254 (oral) and budding GSK ’937 (LA) i-base.info (2020) HIV i-Base. March 2020 (www.i-Base.info) New HIV HIV pipeline 2020 update: new drugs in development 2 Maturation inhibitors 9 Introduction: eight months since IAS 2019 2 • GSK3640254 Regulatory approvals and submissions 2 Other compounds 9 Compounds in development by class 3 • elsulfavirine/VM-1500A Integrase inhibitors 3 • combinectin (GSK3732394) - adnectin/fusion inhibitor • cabotegravir LA • ABX464 NRTIs 3 • BIT225 • islatravir (EFdA) Development stopped or on hold 10 • MK-8504 and MK-8583 • GS-9131 - NRTI • GSK NRTTI • GS-PI1 - protease inhibitor bNAbs 5 Conclusion 10 • leronlimab (PRO140) References 11 • UB-421 i-Base publications 1 2 • VRC01 and VRC01LS ................................................................... • VRC07 and VR07-523LS • PGT-121 and GS-9722 (elipovimab) Figures and tables • 3BNC117, 10-1074 and LS formulations Figure 1: HIV pipeline 2020: targets in the HIV lifecycle 3 • N6 and N6-LS Table 1: Recent regulatory approvals and submissions 4 • Other mAbs: 10E8, trispecific bNAbs, PGDM1400 Table 2: HIV pipeline compounds by development phase 4 Capsid inhibitors 8 Table 3: bNAbs for HIV prevention, treatment or cure research 6 • GS-6207 Table 4: Compounds with long-acting formulations 10 Table 5: Likely positioning for new drugs 10 Published by HIV i-Base HIV PIPELINE HIV pipeline 2020 update: new drugs Introduction: eight months since IAS in development 2019 Simon Collins, HIV i-Base This report is based on new developments over the last eight months since the pipeline report This is the fourth year that i-Base has produced the HIV pipeline review as part of our Fit for Purpose report on produced for the IAS conference in July 2019. [1] antiretroviral treatment optimisation. This includes the move towards simplified ART and Two versions are available: long-acting compounds in several drug classes that allows less frequent dosing than daily oral ARVs. 1. The full version includes more information for each drug, with full references. It also includes using bNAbs as a rescue treatment 2. This “Pipeline-lite” version has a summary for each drug and is for people with multiclass HIV resistance. So while included in the i-Base Fit For Purpose report. ibalizumab has already been approved with an orphan- Both electronic versions (web and PDF) include hyperlinks to all drug designation for multidrug resistance, this potential research sources and references. is shared with dozens of other bNAbs and other new classes including long-acting capsid inhibitors. This review is based on HTB reports over the last eight months and coverage from CROI, IAS, EACS and other conferences. It is notable that the companies developing new drugs http://www.i-Base.info/hiv-pipeline-report-2020 for treatment and prevention are also investing in HIV cure. The report also includes references to 30 studies at CROI 2020 that cover a wide range of pipeline compounds. They include islatravir, MK-8504 and 8583, bNAbs (including VRC01, PGT-121, GS- h-tb 9722, 3BNC117, 10-1074, N6-LS), GS-6207 (capsid inhibitor), GSK3640254 (maturation inhibitor), HIV TREATMENT BULLETIN elsulfavirine, combinectin, ABX464, BIT255 and GS- Editor: Simon Collins 9131. Contributing Editor: Polly Clayden Regulatory approvals and Medical consultants: submissions (Table 1) Dr Tristan Barber, Royal Free Hospital, London. Dr Karen Beckerman, Albert Einstein College of Medicine, NYC. Dr Sanjay Bhagani, Royal Free Hospital, London. Recent approvals include the HIV monoclonal antibody Prof. Diana Gibb, Medical Research Council, London. ibalizumab (Trogarzo) in the EU (18 months after approval Dr Gareth Hardy, PhD. in the US). [2, 3] See Table 1. Prof. Saye Khoo, University of Liverpool Hospital. The gp-120 attachment inhibitor fostemsavir was submitted to Prof. Clive Loveday, International Laboratory Virology Centre. the FDA in December 2019 and to the EMA in January 2020 Prof. James McIntyre, Chris Hani Baragwanath Hosp. South Africa based on 96-week results from the BRIGHTE study. [4, 5, 6] Dr Graeme Moyle, Chelsea & Westminster Hosp, London. However, the regulatory application for the long-acting injections Dr Stefan Mauss, Düsseldorf. of cabotegravir LA and rilpivirine LA (Cabenuva) was not Prof. Caroline Sabin, UCL Medical School, London. approved by the FDA within the fast-track timeline. [7] This was Dr Graham P Taylor, Imperial College, London. unexpected given good results from the phase 3 FLAIR and Dr Stephen Taylor, Birmingham Heartlands Hospital. ATLAS studies. [8] The was due to manufacturing problems Dr Gareth Tudor-Williams, Imperial College, London. from scaling up to industrial production and there are no safety and efficacy concerns. Ongoing studies are already looking at Dr Edmund Wilkins, Manchester General Hospital, Manchester. practical issues of using these injectable drugs. [9, 10, 11] HTB is a not-for-profit community publication that aims to provide a review ViiV has also submitted a new application to the FDA for a switch of the most important medical advances related to clinical management of indication for the dual combination of dolutegravir/lamivudine HIV and its related conditions as well as access to treatments. Comments to (Dovato), based on 48-week results from the phase 3 TANGO articles are compiled from consultant, author and editorial responses. study, presented at IAS 2019. [12, 13] HIV i-Base is a registered charity no 1081905 and company reg no 3962064. HTB was formerly known as DrFax. 2 March 2020 www.i-Base.info HIV PIPELINE Figure 1: HIV pipeline 2020: targets in the HIV lifecycle Targets in the HIV lifecycle HIV pipeline 2020: targets in the HIV lifecycle 1 HIV attaches to a CD4 cell. 2 HIV enters a CD4 cell and HIV proteins and enzymes Entry inhibitors 1 HIV Monoclonal antibodies (mAb) are released into the cell. gp120 3 combinectin capsid Reverse transcriptase (RT) (GSK3732394) gp41 UB-421 (CD4 receptor) makes double strand HIV. 4 VRC01/LS and VRC07/LS Integrase enables HIV to CD4 receptor 3BNC117/LS and10-1074/LS join the cell DNA. CCR5 coreceptor 5 PGDM1400, 10E8.4/iMab Protease cuts and 6 reassembles new HIV. NRTIs/NRTTIs 2 PGT121 and elipovimab (GS-9722) (nukes) Final stages include N6LS (gp120) maturation and budding islatravir (EFdA) leronlimab PRO-140 (CCR5) as each cell produces MK-8504, MK-8583 hundreds of new virions. HIV RNA CD4 cell NNRTIs Rev inhibitor (non-nukes) 3 Cell nucleus elsulfavirine ABX-464 HIV DNA Protease cuts new viral material Capsid inhibitors 4 5 GS-6207 Integration GSK (pre-clinical) INIs (INSTIs) Maturation cabotegravir LA inhibitors 6 Maturation GSK’254 (oral) and budding GSK ’937 (LA) i-base.info (2020) HIV i-Base. March 2020 (www.i-Base.info) New HIV Key: INSTI: integrase strand transfer inhibitor; LA: long-acting; mAb: monoclonal antibody; NRTI: nucleoside/tide reverse transcriptase inhibitor; NNRTI: non-nucleoside reverse transcriptase inhibitor. Dolutegravir/lamivudine was approved in the EU as first-line ART However, the US National Institute for Allergy and Infectious in July 2019 [14] and extended follow-up to 96-weeks for the Diseases (NIAID) recently announced a new study using GEMINI 1 and 2 studies in treatment naive participants were cabotegravir LA (without rilpivirine) in a dual combination with presented at IAS 2019. [15] VRC07-523LS - a long-acting bNAb. [16, 17] Updates from CROI 2020 include looking at the importance of ViiV also recently announced an agreement to develop another other background drugs with ibalizubmab. [82] It also includes bNAb developed by NIAID called N6LS (see later below). [18] results from the ATLAS-2M study reporting that cabotegravir/ Cabotegravir is also being developed as a 6-monthly PrEP rilpivirine LA injections can be used every two months. [83] implant. About a dozen posters look at dual ART, largely dolutegravir/ lamivudine, including updates from the phase 3 GEMINI and TANGO studies. [84, 85, 86] NRTIs Compounds in development by class islatravir (EFdA) Islatravir is an NRTI in development by Merck that is notable for very high potency, a long plasma half-life (~120 Integrase inhibitors hours) that allows weekly and perhaps monthly oral dosing and a slow-release removable implant that might only require annual dosing. cabotegravir LA Ongoing studies are for use as both treatment and PrEP. It is The 2019 pipeline report summarised the clinical efficacy classified as a nucleoside reverse transcriptase translocation and safety of long-acting cabotegravir and rilpivirine inhibitor (NRTTI) and has multiple mechanisms of action. [19] injections and the regulatory complications are discussed above. [1] www.i-Base.info March 2020 3 HIV PIPELINE Table 1: Recent regulatory approvals and submissions Compound/formulation Class Approved / submitted Company ibalizumab bNAb. Approved US: April 2018.