sina bavari, ph.d. us army medical research institute of ... · ifn-alfacon-1 immune modulator...
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Lassa Virus Therapeutics and Target Product Profile
Sina Bavari, Ph.D. US Army Medical Research Institute of
Infectious Diseases (USAMRIID) Frederick, MD
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
Lassa Fever Virus Target Product Profile
This presentation will not cover IPEP, PEP, or other prophylaxis types of use.
Therapeutic Targets for high consequence Viruses
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)
RNA polymerase (Bunya, Arena, Paramyxo)
Abs
Fusion/ entry
inhibitors
Protease inhibitors
Nucleoside analogs
Assembly inhibitors Host modulators/ immunomodulators
Egress inhibitors
Arenaviruses (Z protein) Paramyxoviruses (M protein) Bunyaviruses (RVFV)
Paramyxoviruses (M protein) Bunyaviruses (SKI-1)
Viral proteases: Coronaviruses (3CLpro, PLpro) Cellular proteases: Coronaviruses (cathepsins B, L, TMPRSS2) Arenaviruses (SKI-1)
Bunyaviruses (RVFV) Arenaviruses (GP2) Paramyxoviruses (F protein) Coronaviruses (S protein)
Proteasome inhibitors
Bunyaviruses (RVFV)
Kinase inhibitors
Bunyaviruses (RVFV) Arenaviruses (LASV)
Bunyaviruses Coronaviruses
From Campbell Biology: Concepts & Connections (5th ed)
High Content Imaging Assay for Viral Infection
1. Cell Plating
2. Compound Treatment
3. Virus Dispensing
4. Immuno-fluorescence Staining
DRAQ5 anti-Virus IgG-Alexa488
5. Confocal High Throughput Imaging
6. Image Analysis Nuclei Cytoplasm Pathogen Pos. Cells
7. Multi-parametric Data Analysis
PE Janus MDT
PE Opera
BSL2,3,4
20 hrs
2 hrs
48 hrs
+24hrs
GeneData Screener and PE SpotFire
Veronica Soloveva, , 8 April 2018
5
Therapeutic evaluation of compounds against viral infection
EC50, uM
HCI 0.215
Plaque assay 0.145
RT-PCR 0.172
[Inhibitor ] DMSO (+ control)
No infection (- control)
Viral infection of HeLa Cells
-9 -8 -7 -6 -5
-2 5
0
2 5
5 0
7 5
1 0 0
lo g M
% I
nh
ibit
ion
HCI
P laque
RT-PCR
N=2
% In
hib
itio
n
Log Concentration [M]
Veronica Soloveva, , 8 April 2018
Potential Lassa Virus Therapeutics
Antivirals
Biologics
NA-based
Small Molecule non-Nucs (LHF-535)
Small Molecule Nucs (T-705) Blood product
mAbs
IFNab
SiRNA PMO
Synthetic
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
Therapeutics: Lassa Virus
Compound Mechanism Stage Notes
Ribavirin Nucleoside analog Approved in humans Some effect if administered early; Tx
efficacy needs to be formally investigated.
Favipiravir Nucleobase In vivo efficacy –small
animals 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 Isoflavone; kinase inhibitor/Nuc
LHF-535 Entry inhibitor Finishing Pre-clinical Kineta/Wellcome Trust
Finishing pre-IND studies
huMAbs Antiviral In vivo efficacy – guinea
pigs/NHPs May not be consistent with TPP (cost,
manufacturing, etc)
IFN-alfacon-1 Immune modulator Approved in humans IFN consensus; combination with
Ribavirin or other antivirals
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)
LASV Therapeutic (Reactive/Emergency Use) TPP (Preliminary Draft Apr 2018)
Category Threshold Optimal
Patient Population Adults (18-62 years), excluding pregnant
& lactating women
Children, Adults, Geriatrics (2-62+ years),
suitable for pregnant & lactating women
Safety 42d - 3mo: Regulated NHP safety or
other appropriate models
Human safety evaluated: NHV/patients
(<50 subjects)
Tolerability No critical or severe adverse events;
tolerable AEs acceptable (eg: rash, GI)
Well tolerated, transient, manageable
AEs
- No drug-drug interactions
- Acceptable for use in pregnant women
Efficacy
Effective vs various LASV (Broad Spectrum/outbreak strain), 2-log reduction viremia in serum , Decrease clinical signs by 50%, Survival benefit >50%
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 10-14 days
Onset of Action Efficacy <24hr after confirmed infection Efficacy >24hr after confirmed infection
Storage Condition 2-8oC 20oC – 35oC
Shelf Life 2 years (cold chain acceptable) 5 years (room temperature)
Manufacturing/Stock-
pilling Synthesis (100-1,000) treatments)
Efficient, high yield synthesis (1,000-Ms
treatments)
Cost of Goods Affordable in limited healthcare areas
$10-20 Global deployment opportunity $1-5
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
Patient
Population
Adults (18-62 years),
excluding pregnant &
lactating women
Children, Adults, Geriatrics
(2-62+ years), suitable for
pregnant & lactating
women
Safety
42d - 3mo: Regulated NHP
safety or other
appropriate models
Human safety evaluated:
NHV/patients (<50
subjects)
Tolerability
No critical or severe
adverse events; tolerable
AEs acceptable (eg: rash,
GI)
Well tolerated, transient,
manageable AEs
- No drug-drug interactions
- Acceptable for use in
pregnant women
Category Threshold Optimal
Lassa Virus Therapeutics: Target Product Profile
Efficacy
Effective vs various LASV Broad Spectrum/outbreak strain), 2-log reduction viremia in serum , Decrease clinical signs by 50%, Survival benefit >50%
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 10-14 days
Category Threshold Optimal
Lassa Virus Therapeutics: Target Product Profile
Onset of Action Efficacy <24hr after
confirmed infection
Efficacy >24hr after
confirmed infection
Storage
Condition 2-8oC 20oC – 35oC
Shelf Life 2 years (cold chain 2-8oC
acceptable)
5 years (room
temperature)
Manufacturing/
Stock-pilling
Synthesis (100s-1,000)
treatments)
Efficient, high yield
synthesis (more than
1,000-treatments)
Cost of Goods Affordable in limited
healthcare areas $10-20
Global deployment
opportunity $1-5
Category Threshold Optimal
Lassa Virus Therapeutics: Target Product Profile