HIV Pipeline P P P P Phase I Phase II Phase III TMB-60711

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HIV Pipeline P P P P Phase I Phase II Phase III TMB-60711 (MK-8122, PPL-100) Protease inhibitor Ambrilia TaiMed GSK3640254 Maturation Inhibitor GSK ABX464 Rev inhibitor5 Abivax Dapivirine (TMC120; DPV) IVR for PrEP NNRTI Janssen  IPM Filed with EMA Fostemsavir (BMS-663068) Prodrug of BMS-626529 Attachment inhibitor BMS  ViiV MK-4250 MOA unknown Merck GSK2838232 Requires a booster Maturation Inhibitor GSK VRC family8 (VRC01LS, VRC07, VRC07-523LS, 10E8VLS, N6LS …) bNAbs against gp120 For prevention or treatment NIH Cabotegravir-LA (GSK-744; CAB) For PrEP INI ViiV MK-8504 NRTI (TFV prodrug) Merck PRO-140 (PA14)3 Not for X4-tropic HIV Entry inhibitor; mAb (not an ARV) CytoDyn MK-8591 (EFdA) NRTTI6 Merck MK-8527 MOA unknown Merck P Cabotegravir-LA + Rilpivirine-LA Maintenance strategy ViiV + Janssen GS-9131 NRTI Gilead UB-4214 (TMB-355) mAb against CD4 (not an ARV) United Biopharma 10-1074(LS) + 3BNC117(LS)14 bNAbs against gp120 For prevention or treatment Rockefeller; NIH MK-8583 NRTI Merck Cenicriviroc7 (TBR-652; CVC) Not for X4-tropic HIV Entry inhibitor Takeda  Tobira Vesatolimod (GS-9620)9 TLR7 agonist / Immunomodulator (not an ARV) Gilead PGDM1400 + PGT121 bNAbs against gp120 For prevention or treatment IAVI Sources: ClinicalTrials.gov; WHO ICTRP (international clinical trials registry platform); aidsinfo.nih.gov Recent approvals: - NNRTI named Elsulfavirine (VM1500), brandname Elpida® received approval in Russia on June 30, 2017. This product is not approved in the US or EU. Entry inhibitor named Albuvirtide (FB006M), brandname Aikening® received approval in China on June 5, 2018. Albuvirtide consists of large synthetic peptides given by IV. Note this is a different molecule from T-20 (enfuvirtide), it is not simply a long-acting version of T-20. This product is not approved in the US or EU. NNRTI doravirine (both standalone and doravirine/TDF/3TC) received approval by the USFDA on Aug 30, 2018. Footnotes: “Long-acting” defined as once monthly or less frequent. Owen A and Rannard S (2016) Advanced Drug Delivery Reviews 103, p144–156 Doravirine nanoformulations were also explored in a PK/bioavailability study. DOR and DOR/TDF/3TC were filed with USFDA in Jan 2018, action date expected in Oct 2018 PRO-140: Q1W SC injection, “self injectable”, humanized mAb against CCR5. In Ph2b/3, including as single agent maintenance strategy UB-421 is a mAb against/targeting CD4 given as (likely biweekly) IV infusion. It is being investigated in Ph3 as a monotherapy in suppressing viral rebound in place of ART, and separately in Ph2 in combination with OBR for MDR-HIV ABX464: potentially first-in-class, this oral candidate that targets the HIV Rev protein and prevents unspliced HIV RNA from being exported out of the nucleus, thereby blocking HIV replication NRTTI stands for nucleoside reverse transcriptase translocation inhibitor. Ph2 on EfdA+DOR+3TC is scheduled to start in Nov 2017 Cenicriviroc: oral dual inhibitor of CCR2 and CCR5, does not work for X4-tropic virus. Development focus appears to have shifted from HIV treatment to non-alcoholic steatohepatitis (NASH). There is a Ph2 investigator-led trial on CVC for neuroAIDS VRC01, a broadly neutralizing mAb targeting the CD4 binding site on gp120 (note not “targeting CD4”), is being studied in two large Ph2 studies (HPTN081 & 085) for the prevention of HIV infections. VRC01LS utilizes the Xtend antibody half-life extension technology from Xencor. The NIAID has progressed additional mAbs from the VRC family (VRC07, VRC07-523LS, 10E8VLS, N6LS) into Phase 1 studies, which are being studied separately or as 2 bNAbs combination GS-9620: TLR activation has been linked with the stimulation of antiviral immunity. GS-9620 is a TLR7 agonist that could activate HIV production in late cells and may be potentially coupled with immunotherapy (therapeutic vaccine or bNAbs). GS-9620 development for hepatitis B has been discontinued. Development of vicriviroc for HIV treatment was discontinued in 2010. Intravaginal rings containing vicriviroc are now being studied in Phase 1, with or without MK-2048 (combination IVR=MK-2048A) TMB-607 (formerly known as PPL-100 from Ambrilia, and MK-8122 under Merck partnership that was terminated) is a PI discovered over a decade ago. It is now being investigated in Ph1 as nanoformulated IM or SC injection (likely monthly) GS-6207 is a potential first-in-class capsid inhibitor and an analogue of GS-CA1, and is being formulated as LAIs potentially given monthly (Formulation A) or quarterly. (Formulation B) Ph1 study announced but not yet found in trial registries. GS-9722 is a bNAb and a derivative of PGT121. Not yet found in clinical trial registries. PGT121 family of antibodies that target gp120 and have also been shown to interfere with gp120’s binding to CD4 (allosterically) PGT121 was licensed from Theraclone, which has proprietary I-STAR technology for antibody discovery and collaborates with IAVI (IAVI retains vaccine rights, Theraclone retinas therapeutic rights) 14. Monoclonal antibodies 10-1074 and 3BNC117 are being studied in combination, including the combination of their long-acting versions (LS). 10-1074 resistant escape variants have been shown to have cross resistance with PGT121 but remain sensitive to 3BNC117 and VRC01 VRC018 bNAb against gp120 For prevention NIH P Vicriviroc (MK-4176) ± MK-2048 IVR for PrEP10 Entry Inhibitor ± INI NIH; Merck Oral Topical microbicide GS-972213 bNAb against gp120 Gilead PC-1005 (MIV-150+zinc acetate) Multipurpose gel including for PrEP NNRTI Population Council; NIH Other parenteral Potential first-in-class to reach market Long-acting (LA) parenteral1 GS-620712 (GS-CA2) Capsid inhibitor Gilead P Being studied in adolescents and/or children Medicines Patent Pool List not exhaustive. Last updated on: 10/2018

Child & Adolescent HIV Pipeline Preclinical, PIP Phase I Phase II Phase III Also Ph1/2 Also Ph2/3 Ibalizumab (Trogarzo®, TMB355) mAb against CD4 TaiMed Biologics; Theratechnologies VRC01, VRC01-LS bNAb against gp120 As prophylaxis NIH [Neonates] VRC01, VRC01-LS bNAb against gp120 As maintenance NIH [up to 5y] Dolutegravir Integrase inhibitor ViiV [down to 4w] PIP Confirmed Preclinical or Formulation Development Bictegravir Integrase inhibitor Gilead [2-17y, VS] Cabotegravir-LAI + Rilpivirine-LAI Maintenance strategy ViiV + Janssen [12-17y] TAF§ NRTI Gilead [1m-17y, VS] Microneedle Patch (of RAL, or EfdA?) Queens’ Univ. of Belfast; PATH Doravirine NNRTI MSD [12-17y] Dapivirine IVR for PrEP NNRTI Janssen  IPM Filed with EMA [15-17y] Solid Drug Nanoparticles (SDN of DRV/r, LPV/r…) Univ. Liverpool Sources: ClinicalTrials.gov; WHO ICTRP (international clinical trials registry platform); aidsinfo.nih.gov Licensed to MPP VS Virologically suppressed Topical microbicide Other parenteral Medicines Patent Pool List not exhaustive. Last updated on: 11/19/2018 §TAF is also being studied in children with chronic hepatitis B in Ph2/3 study Oral Long-acting (LA) parenteral1

HCV Direct-Acting Antivirals (DAAs) Marketed or under active clinical development Phase I Phase II Phase III Marketed AT-527 NS5B inhibitor - nuc Atea Pharmaceuticals Furaprevir (TG-2349) NS3/4A inhibitor TaiGen Ravidasvir 9 (PPI-668; ASC16; RDV) NS5A inhibitor Presidio  Pharco; Ascletis Filed with CFDA Ledipasvir (GS-5885; LDV) NS5A inhibitor Gilead Sofosbuvir (GS-7977/PSI-7977; SOF) NS5B inhibitor – nuc 2 Gilead TD-6450 NS5A inhibitor Theravance  TREKtx Dasabuvir (ABT-333) NS5B inhibitor – non-nuc AbbVie Daclatasvir (BMS-790052; DCV) NS5A inhibitor BMS CC-31244 NS5B inhibitor – non-nuc Cocrystal Pharma Faldaprevir 7 (BI 201335) NS3/4A inhibitor BI  TREKtx Paritaprevir/r (ABT-450/r) NS3/4A inhibitor Enanta + AbbVie GSK2878175 8 Oral & LAP NS5B inhibitor – non-nuc GSK Ombitasvir (ABT-267; OBV) NS5A inhibitor AbbVie Grazoprevir (MK-5172; GZR) NS3/4A inhibitor Merck Elbasvir (MK-8742; EBR) NS5A inhibitor Merck MB-110 NS5A inhibitor Microbio Co. AL-335 NS5B inhibitor – nuc Alios (now Janssen) Asunaprevir 3 (BMS-650032) NS3/4A inhibitor BMS SH229 NS5B inhibitor Nanjing Sanhome Pharmaceuticals Odalasvir (ACH-3102) NS5A inhibitor Achillion  Janssen Velpatasvir (GS-5816; VEL) NS5A inhibitor Gilead Vaniprevir 4 (MK-7009) NS3/4A inhibitor Merck Uprifosbuvir (MK-3682; UPR) NS5B inhibitor – nuc Merck Voxilaprevir (GS-9857; VOX) NS3/4A inhibitor Gilead Sources: ClinicalTrials.gov; WHO ICTRP (international clinical trials registry platform) Footnotes: Based on in vitro anti-HCV activity as published. “Pangenotypic” as in effectiveness demonstrated for genotypes 1 – 6. Certain DAAs are referred to as “pangenotypic” by its originator but in vitro evidence for all six genotypes has not been publicly available. Occasionally multi-genotypic DAA (covering most but not all genotypes) may also be referred to misleadingly as “pangenotypic”, hence being differentiated here according to published in vitro evidence. “Nuc” is short for NS5B nucleoside/nucleotide inhibitors, which are believed to have higher inherent barrier to resistance than non-nuc NS5B inhibitors Asunaprevir was approved in Japan but US NDA has been withdrawn 4. MK-7009 was approved in Japan, but not by USFDA ABT-493: its in vitro activity against GT5 has been “N/A” or not mentioned in publications so far. In ILC 2016, AbbVie preferred to it as pangenotypic DAA just like ABT-530. The combination is being studied across GT1-6 Danoprevir: requires ritonavir boosting. Early in vitro results published by InterMune suggested pangenotypic activity. Following a Phase 3 in China, Ascletis has filed danoprevir/r + PegIFN+RBV with the CFDA in Jan 2017 and received approval in June 2018 in China. Faldaprevir had once reached Phase 3 in combination with PegIFN and RBV by BI for GT1, followed by BI withdrawing NDA. Now TREK Therapeutics has in-licensed worldwide rights and is studying this compound in combination with TD-6450 in Phase 2 GSK2878175: Regulus and GKS had previously announced plans to combine long-acting parenteral (LAP) formulation of GSK2878175 with miRNA therapy RG-101 in Ph2 study, which however did not happen following RG-101’s discontinuation due to safety issues in June 2017. No new clinical study on GSK2878175 since 2015. Ravidasvir is being studied by DNDi in combination with SOF, and separately by Ascletis in combination with danoprevir (+RBV). Ascletis has filed the ravidasvir with the CFDA in Aug 2018 Discontinued products: In Aug 2014, Vertex announced its discontinuation of telaprevir production In Jan 2015, Merck announced its withdrawal of boceprevir from market On Sept 211, 017, Janssen announced that the development of triple regimen SIM+AL-335+odalasvir was discontinued. Further, Janssen has discontinued Phase 1 candidate AL611 after terminating the study On Sept 29, 2017, Merck announced that the development of uprifosbuvir+ruzasvir+/-grazoprevir was also discontinued On Dec 10, 2017, Medivir announced Jassen’s decision to terminate its simeprevir licence effective June 2018. This may signal discontinuation / withdrawal of SIM starting 2018. Preclinical but may enter Ph1 soon (not yet found on clinical trials registry) MK-8831: Described to be pangenotypic NS3/4A inhibitor but only published activity on GT1-3. Described as entering Ph1 in publication, but none found in clinical trial registry yet MIV-802: NS5B nuc that Trek therapeutics acquired from Medivir Discontinued9 Boceprevir (SCH-503034) NS3/4A inhibitor Merck Ruzasvir (MK-8408; RZR) NS5A inhibitor Merck Pibrentasvir (ABT-530; PIB) NS5A inhibitor AbbVie Telaprevir (VX-950) NS3/4A inhibitor Vertex  Janssen NUC Glecaprevir (ABT-493; GLE) 5 NS3/4A inhibitor Enanta + AbbVie Individual pangenotypic potential per published in vitro data:1 Simeprevir (TMC435; SIM; SMV) NS3/4A inhibitor Janssen Pangenotypic coverage not verifiable Pangenotypic Not pangenotypic Danoprevir/ritonavir 6 (ITMN-191, ASC08) NS3/4A inhibitor Roche; Ascletis List not exhaustive. Host-targeting agents are not included Medicines Patent Pool. Last updated on: 8/2018

HCV DAA Combination Regimens Marketed HCV DAA Combination Regimens Sofosbuvir (GS-7977) NS5B – nuc Gilead Daclatasvir (BMS-790052) NS5A BMS Ombitasvir (ABT-267) NS5A AbbVie Paritaprevir/r (ABT-450/r) NS3/4A AbbVie Dasabuvir (ABT-333) NS5B – non-nuc AbbVie P P GT1~4b GT1 P Sofosbuvir (GS-7977) NS5B – nuc Gilead Ledipasvir (GS-5885) NS5A Gilead GT1, 4, 5, 6; + RBV for GT3a Ombitasvir (ABT-267) NS5A Paritaprevir/r (ABT-450/r) NS3/4A P ± RBV for GT4 Sofosbuvir (GS-7977) NS5B – nuc Gilead Velpatasvir (GS-5816) NS5A Gilead Pibrentasvir (ABT-530) NS5A AbbVie Glecaprevir (ABT-493) NS3/4A AbbVie P P GT1~6f GT1~6 Sofosbuvir (GS-7977) NS5B – nuc Gilead Velpatasvir (GS-5816) NS5A Gilead Voxilaprevir (GS-9857) NS3/4A Gilead GT1~6e Elbasvir (MK-8742) NS5A Merck Grazoprevir (MK-5172) NS3/4A Merck P Sofosbuvir (GS-7977) NS5B – nuc Gilead Simeprevir (TMC435) NS3/4A Janssen ± RBV GT1, 4; + SOF for GT3c + GT1, ± RBV for GT1, 4d Sources: ClinicalTrials.gov; WHO ICTRP (international clinical trials registry platform) Footnotes: a. SOF/LDV: EMA approved GT1, 3, 4 (GT3 only for cirrhotics as combination with RBV, 24w. But note 24w of SOF+RBV without LDV is an FDA-approved indication for GT3 already). FDA approved SOF+LDV for GT1, 4-6 and the addition of RBV is required in some cases of cirrhosis or liver transplant; also approved in children aged 12 & above weighing at least 35kg. b. SOF+DCV: FDA approved GT1, 3. EMA approved DCV for GT1, 2, 3, 4, but recommending DCV+SOF specifically for GT1, 3, 4 (data on DCV+SOF for GT2 are considered limited). EASL had recommend SOF+DCV across GT1-6 c. GZR/EBR: GT1a testing for baseline NS5A RAVs required; GT3 approved in Canada only for EBV+GZR+SOF d. SIM+SOF: FDA approved SIM+SOF only for GT1 (GT4 was for SIM+PEG+RBV). EMA approved SIM+SOF with or without RBV for GT1, 4. On Dec 10, 2017, Medivir announced Jassen’s decision to terminate its simeprevir licence effective June 2018. This may signal discontinuation / withdrawal of SIM starting 2018. e. SOF/VEL/VOX: FDA approved for GT1-6 PLHCVs previously treated with any NS5A inhibitor, but only for GT1a and GT3 if previously treated with SOF without an NS5A inhibitor. GLE/PIB: FDA approved for GT1-6 if treatment-naïve, or if previously treated with IFN, PegIFN, RBV and/or SOF; GT1 only, if previously treated with an NS5A inhibitor or NS3/4A inhibitor but not both Ravidasvir + danoprevir/r + RBV was only studied in GT1 non-cirrhotic patients in Greater China About Janssen DAA combinations: AL-335+ODV (without SIM): during ILC2017, company announced “no plans for further evaluation” of this 2DAA combination for GT1 due to “inadequate efficacy” per Study AL-335-604. There is a long-term follow-up study of patients who completed the study. AL-335+ODV+SIM: company announced on Sept 11, 2017 the discontinuation of its further development On Sept 29, 2017, Merck announced that the development of uprifosbuvir+ruzasvir+/-grazoprevir was also discontinued. Sofosbuvir (GS-7977) NS5B – nuc Gilead Ravidasvir (PPI-668; RDV) NS5A Presidio  Pharco, Ascletis + Fixed-dose combination Phase III P FDA-approved for age 12+ P Ravidasvir (PPI-668; RDV) NS5A Presidio  Pharco, Ascletis Danoprevir/ritonavir (ITMN-191, ASC08) NS3/4A inhibitor Roche; Ascletis Paediatric investigation underway + +RBVg Medicines Patent Pool List not exhaustive. Last updated on: 8/2018

Development Progress of Paediatric HCV Regimens Age 12+ Age 6 to <12 yrs Age 3 to < 6 yrs SOF + RBV Approved (GT2, 3; ≥35kg) Phase 2 (GT2, 3)1 (small tablet or granules for young children) SOF/LDV (GT1, 4-6; ≥35kg) Two Phase 2 studies (1/2-dose tablet) OBV/PTV/r ± DSV ± RBV Phase 3 SOF/LDV + RBV Phase 2 (GT3 only) (Tablet or “age-appropriate dose or formulation”) GRZ/EBR Phase 2 (GT1, 4 only) (Tablet or granules for young children) SOF/VEL Phase 2 (Tablet of “age-appropriate dose”) SOF/VEL/VOX May be covered in Registry for paediatric & adolescent patients SOF + DCV (Age 8-18, GT4 only, Egypt; 1 or ½ tablet)2 -- GLE/PIB Phase 3, with Expanded Access Program (“Paediatric formulation” for 3 to <12 yrs) A separate Phase 2/3 study is ongoing at the National Liver Institute, Egypt, on SOF+RBV in children aged 10-18, n=41 only Several Phase 3-4 studies on SOF+DCV by the Tehran University of Medical Sciences also enroll adolescents Pangenotypic Not pangenotypic List not exhaustive. Some studies are investigator-initiated. Medicines Patent Pool. Last updated 11/2018