Sina Bavari, Ph.D. US Army Medical Research Institute of Infectious Diseases (USAMRIID) Frederick, MD

Transcription

1 Lassa Virus Therapeutics and Target Product Profile Sina Bavari, Ph.D. US Army Medical Research Institute of Infectious Diseases (USAMRIID) Frederick, MD

2 Objectives: 1) How to identify and evaluate potential therapeutics 2) Current bench research and clinical grade therapeutics" 4) Ideal therapeutics for emerging pathogens under difficult situation 4) Target Product Profile for therapeutic use of drugs agisnt Lassa Fever Virus

3 Lassa Fever Virus Target Product Profile This presentation will not cover IPEP, PEP, or other prophylaxis types of use.

4 Therapeutic Targets for high consequence Viruses Fusion/ entry inhibitors Kinase inhibitors Proteasome inhibitors Nucleoside analogs Bunyaviruses (RVFV) Arenaviruses (GP2) Paramyxoviruses (F protein) Coronaviruses (S protein) Bunyaviruses (RVFV) Arenaviruses (LASV) Bunyaviruses (RVFV) RNA polymerase (Bunya, Arena, Paramyxo) Viral proteins: Coronaviruses (S protein) Arenaviruses (GP1, GP2) Paramyxoviruses (G, F proteins) Bunyaviruses (Gn, Gc proteins) Cellular receptors: Coronaviruses (DPP4) Paramyxoviruses (ephrin-b2/-b3) Arenaviruses (multiple) Viral proteases: Coronaviruses (3CLpro, PLpro) Cellular proteases: Coronaviruses (cathepsins B, L, TMPRSS2) Arenaviruses (SKI-1) Abs Protease inhibitors Host modulators/ immunomodulators Bunyaviruses Coronaviruses Paramyxoviruses (M protein) Bunyaviruses (SKI-1) Arenaviruses (Z protein) Paramyxoviruses (M protein) Bunyaviruses (RVFV) Assembly inhibitors Egress inhibitors From Campbell Biology: Concepts & Connections (5 th ed)

5 High Content Imaging Assay for Viral Infection PE Janus MDT 1. Cell Plating 20 hrs 2. Compound Treatment 2 hrs 3. Virus Dispensing 48 hrs +24hrs BSL2,3,4 DRAQ5 anti-virus IgG-Alexa Immuno-fluorescence Staining PE Opera 5. Confocal High Throughput Imaging 6. Image Analysis Nuclei Cytoplasm Pathogen Pos. Cells 7. Multi-parametric Data Analysis GeneData Screener and PE SpotFire Veronica Soloveva,, 8 April

6 % Inhibition h itio n Therapeutic evaluation of compounds against viral infection Viral infection of HeLa Cells DMSO (+ control) [Inhibitor ] No infection (- control) HCI P laque RT-PCR EC50, um HCI Plaque assay RT-PCR lo g M Log Concentration [M] N=2 Veronica Soloveva,, 8 April 2018

7 Potential Lassa Virus Therapeutics Antivirals Host-response modifiers

8 Potential Lassa Virus Therapeutics Antivirals Synthetic Small Molecule Nucs NA-based (T-705) Small Molecule non-nucs (LHF-535) SiRNA PMO Biologics mabs Blood product IFNab

9 Ideal therapeutics for emerging infections 1) Easy to access, easy to store, and widely available 2) Inexpensive 3) Safety/safety/safety 4) Easy to administer 5) Long-shelf life 6) Clear uncomplicated regulatory path for approval 7) Broad activity against multiple families of viruses 8) Treat/intervene at any stages of infection 9) Can be added to other treatment options 10)Well distributed to multiple tissues based on the infection pattern

10 Therapeutics: Lassa Virus Compound Mechanism Stage Notes Ribavirin Nucleoside analog Approved in humans Favipiravir Nucleobase In vivo efficacy small animals Some effect if administered early; Tx efficacy needs to be formally investigated. Synergistic effect in combination with Ribavirin? ST-193 Entry inhibitor In vivo efficacy guinea pigs Inhibits ph-induced membrane fusion Genistein, many others Entry inhibitor/host modulator/replication In vitro data EC50 nm-um LHF-535 Entry inhibitor Finishing Pre-clinical humabs Clinical disease: Ranges from mild flu-like illness to severe hemorrhagic fever Deafness is a sequelae in some survivors Therapeutic strategies: Difficult to target entry different arenaviruses use different cellular receptors; Target cell processes critical for entry and replication (e.g. kinase inhibitors) Antiviral In vivo efficacy guinea pigs/nhps IFN-alfacon-1 Immune modulator Approved in humans Isoflavone; kinase inhibitor/nuc Kineta/Wellcome Trust Finishing pre-ind studies May not be consistent with TPP (cost, manufacturing, etc) IFN consensus; combination with

11 LASV Therapeutic (Reactive/Emergency Use) TPP (Preliminary Draft Apr 2018) Category Threshold Optimal Patient Population Safety Tolerability Efficacy Adults (18-62 years), excluding pregnant & lactating women 42d - 3mo: Regulated NHP safety or other appropriate models No critical or severe adverse events; tolerable AEs acceptable (eg: rash, GI) Effective vs various LASV (Broad Spectrum/outbreak strain), 2-log reduction viremia in serum, Decrease clinical signs by 50%, Survival benefit >50% Children, Adults, Geriatrics (2-62+ years), suitable for pregnant & lactating women Human safety evaluated: NHV/patients (<50 subjects) Well tolerated, transient, manageable AEs - No drug-drug interactions - Acceptable for use in pregnant women Effective vs 2 arenaviruses (current outbreak strain and or other AVs), 3-log reduction viremia in serum, Decrease clinical signs by 80%, Survival benefit >80% Route of Administration Parenteral (IV/IM/subcutaneous) Oral and parenteral Frequency of Dosing Continuous infusion or TID QD or BID Duration of Treatment 21 days days Onset of Action Efficacy <24hr after confirmed infection Efficacy >24hr after confirmed infection Storage Condition 2-8 o C 20 o C 35 o C Shelf Life 2 years (cold chain acceptable) 5 years (room temperature) Manufacturing/Stockpilling Cost of Goods Synthesis (100-1,000) treatments) Affordable in limited healthcare areas Efficient, high yield synthesis (1,000-Ms treatments) Global deployment opportunity $1-5

12 Patient Population Safety Tolerability Efficacy Route of Administration Frequency of Dosing Duration of Treatment Onset of Action Storage Condition Shelf Life Manufacturing/Stock-pilling Cost of Goods

13 Lassa Virus Therapeutics: Target Product Profile Category Threshold Optimal Patient Population Safety Tolerability Adults (18-62 years), excluding pregnant & lactating women 42d - 3mo: Regulated NHP safety or other appropriate models No critical or severe adverse events; tolerable AEs acceptable (eg: rash, GI) Children, Adults, Geriatrics (2-62+ years), suitable for pregnant & lactating women Human safety evaluated: NHV/patients (<50 subjects) Well tolerated, transient, manageable AEs - No drug-drug interactions - Acceptable for use in pregnant women

14 Lassa Virus Therapeutics: Target Product Profile Category Threshold Optimal Efficacy Route of Administration Frequency of Dosing Duration of Treatment Effective vs various LASV Broad Spectrum/outbreak strain), 2-log reduction viremia in serum, Decrease clinical signs by 50%, Survival benefit >50% Parenteral (IV/IM/subcutaneous) Continuous infusion or TID Effective vs 2 arenaviruses (current outbreak strain and or other AVs), 3-log reduction viremia in serum, Decrease clinical signs by 80%, Survival benefit >80% Oral and parenteral QD or BID 21 days days

15 Lassa Virus Therapeutics: Target Product Profile Category Threshold Optimal Onset of Action Storage Condition Shelf Life Manufacturing/ Stock-pilling Cost of Goods Efficacy <24hr after confirmed infection Efficacy >24hr after confirmed infection 2-8 o C 20 o C 35 o C 2 years (cold chain 2-8 o C acceptable) Synthesis (100s-1,000) treatments) Affordable in limited healthcare areas $ years (room temperature) Efficient, high yield synthesis (more than 1,000-treatments) Global deployment opportunity $1-5