Best in Class Agents for Global HCV Eradication
Raymond F. Schinazi, PhD, DSc Frances Winship Walters Professor
Director, Scientific Working Group on Viral Eradication, Emory University CFAR/VAMC
University of Miami Emory Institute for Drug Discovery
Boston June 27, 2013 [email protected]
Introduc)on: Hepa))s C Virus and Treatment
• ~170 million infected with HCV worldwide (USA: 2.7-‐3.9 million) • Six different genotypes worldwide • Chronic disease leads to liver cirrhosis and cancer • No latency – hence curable • Virus dynamic
• Standard of care: Ribavirin + peg-‐INF-‐α + Protease Inhibitors – Treatment complicated – coinfecUon even more complicated – Side effects, subopUmal efficacy, genotype-‐dependent, injectable
• Oral, direct acUng anUvirals (DAA): – NS5B, Entry, Protease, NS5A, Cyclophilins, microRNA, etc.
• Nucleoside Analog Inhibitors (NAI) are Best in Class: – High potency – Pan-‐genotypic – High barrier to resistance – Low pill burden and orally bioavailable
• 2
Ultimate Goal For HCV Therapy One size fits all
♦ Once a day oral Rx - Easier for doctors & patients
♦ Pan-genotypic ♦ No clinical resistance ♦ No response guided therapy ♦ Short duration – 12 weeks or less ♦ Safe with no or manageable side effects ♦ High cure rates - Lowers cost to healthcare ♦ Suitable for all populations at low cost
4
Analysis of Treatment Costs of HCV Infections
-
10,000
20,000
30,000
40,000
50,000
60,000
2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021
Cumu
lative
Cos
t of N
on-T
rmt ($
Ms)
-
5.0
10.0
15.0
20.0
25.0
30.0
35.0
40.0
Avera
ge Pe
r Pati
ent C
ost ($
000s
)
Cost of Non-TreatmentAverage Per Patient Cost
Source: UBS research, Milliman 2009 report
“The times, they are a-changin’”
Bob Dylan “The times, they have changed’”
HCV Therapies: Changing Landscape Advances for Unmet Medical Needs
6
Market Will See An Influx of New Drugs Over the Next Few Years
QD BID TID
ABT-‐450 Asunaprevir Telaprevir = Nucleos(t)ide Polymerase Inhibitor
ACH-‐1625 Danoprevir Boceprevir = NS5a Inhibitor
BI 201335 GS-‐9256 = Protease Inhibitor
TMC435 Vaniprevir = Non-‐nucleos(t)ide Polymerase Inhibitor
MK-‐5172 ABT-‐333
Narlaprevir Filibuvir
GS-‐7977 BI 207127
VX-‐135 BMS 791325
IDX184 Setrobuvir
Daclatasvir Tegobuvir
GS-‐5885 VX-‐222
ABT-‐267 ABT-‐072
ACH-‐3102 Mericitabine
2011 2012 2013 2014 2015 2016 2017 2018 20192011 2012 2013 2014 2015 2016 2017 2018 2019
VRTX ’s Incivek & MRK’s Victrelis approved
GILD’s sofosbuvir (GS-‐7977) likely approved for all genotypes
Following GS-‐7977 data, “Patients warehousing themselves”
ABT’s all-‐oral DAA combination likely approved
Bristol’s all-‐oral DAA triple combination likely approved
Other all-‐oral possible approvals:ACHN (PI/NS5a)VRTX (VX-‐135)IDIX (nuc/NS5a)
GILD’s single-‐pill combo (GS-‐7977+5885) likely approved
BMY ’s daclatasvir, JNJ’s TMC -‐435 likely approved
Source: UBS research
Market Time Lines: Shaping the Future
2011 2012 2013 2014 2015 2016 2017 2018 20192011 2012 2013 2014 2015 2016 2017 2018 2019
VRTX ’s Incivek & MRK’s Victrelis approved
GILD’s sofosbuvir (GS-‐7977) likely approved for all genotypes
Following GS-‐7977 data, “Patients warehousing themselves”
ABT’s all-‐oral DAA combination likely approved
Bristol’s all-‐oral DAA triple combination likely approved
Other all-‐oral possible approvals:ACHN (PI/NS5a)VRTX (VX-‐135)IDIX (nuc/NS5a)
GILD’s single-‐pill combo (GS-‐7977+5885) likely approved
BMY ’s daclatasvir, JNJ’s TMC -‐435 likely approved
Source: UBS research
IDX184 (G) & IDX-19368 (G) (Idenix)
Phase 2b Clinical hold/abandoned
INX-189 (G) (BMS/Inhibitex)
Phase 2a Cardiotoxicity
PSI-938 (G) (Gilead/PSI)
Phase 1 Liver toxicity
Changing Nucleoside Landscape for HCV
IDX20963 (U) (Idenix)
Preclinical hold
In development
On hold with FDA
Development discontinued
R1626 (C) (Roche)
Safety issues
NM-283 (C) (Idenix)
GI toxicity
RG7348 (Roche-Ligand) Phase I stopped
RG7432 (Roche)
Phase I stopped
TMC649128 (Medivir)
Insufficient activity
GS-7977 (U-like) (Gilead/PSI)
Phase 3
RG7128 (C & U) (Roche/PSI)
Phase 2b
ALS-2200 (U) (Vertex/Alios)
Phase 2a
RS-27 (U/C-like) RS-28 (U/C-like)
(RFSP) Preclinical
MK-0608 (A) (Merck)
Preclinical
PSI-661 (G) (Gilead/PSI) Preclinical
GS-6620 (Gilead) Phase 1
Suboptimal PK/activity
ALS-2158 (Vertex/Alios)
Phase 1
BCX-5191 (Biocryst) Preclnical
Development status unknown
DAPD-PD1 (A/G-like) DAPN-PD2 (A/G-like)
(RFSP) Preclinical
8
Drug Discovery Algorithm for Nucs For HIV, HBV and HCV: Fail fast - Fail cheap
Efficacy in small animal model (Combo)
Pharmacokinetics in rats/monkeys/dogs
Toxicology & Stability Intracellular Pharmacology
Antiviral Spectrum NIH Test (confirm)
HITS (Activity/Toxicity)
Design & Synthesis
Kin & pol Enzyme (Mechanism)
Cell-based Testing
Cytotoxicity Spectrum
Different Cell Lines Mitochondria Bone Marrow
Compound Scale-up
Clinical Candidate
Reducing the risk - the path of least resistance
PSI-6130 is metabolized to two active NTP of HCV Polymerase
Murakami, Schinazi et al, AAC: 51, 503-9, 2007
PSI-‐7977 (Sofosbuvir)
HCV 1b replicon: EC90 = 0.42 µM (WT);
7.8 µM (S282T); 0.11 µM (S96T)
Activity of Diastereomericaly Pure Nucleotide Phosphoramidates
OPO
NH
CH3O
O CH3FHO
NNH
OOH3C
CH3O
O
Sp
OPO
NH
CH3O
O CH3FHO
NNH
OOH3C
CH3O
O
Rp
PSI-‐7976
HCV 1b replicon: EC90 = 7.5 µM (WT);
> 100 µM (S282T); 1.3 µM (S96T) 11
PSI-7977
Sp isomer
HCV 1b replicon: EC90 = 0.42 µM (WT), 7.8 µM (S282T mutant), 0.11 µM (S96T mutant).
In a 28 day Phase IIa clinical study of genotype 1 treatment-naïve HCV patients dosed in combination with peg IFN/RBV at 100 mg, 200 mg, and 400 mg: RVR rates of 88%, 94%, and 93% respectively. 14 day monotherapy of genotype 1 treatment-naïve HCV patients showed an average of -5.0 log10 decline in viral load with 88% of patients reaching undetectability (<15 IU/mL) after 14 days.
OPO
NH
CH3O
O CH3FHO
NNH
OOH3C
CH3O
O
Diastereomericaly Pure Nucleotide Phosphoramidates for HCV*
• *Summarized in part from: 1) J Org Chem. 2011 Sep 14. [Epub ahead of print], Synthesis of Diastereomerically Pure Nucleotide Phosphoramidates. Ross BS, Reddy PG, Zhang HR, Rachakonda S, Sofia MJ.; 2) J. Med. Chem. 2010, 53, 7202-7218, Discovery of a β-D-2-Deoxy-2-α-fluoro-2-β-C-methyluridine Nucleotide Prodrug (PSI-7977) for the Treatment of Hepatitis C Virus. Sofia MJ, Bao D., Chang W, et al. and Antivir. Chem. Chemoth. 2011, 22, 23-49, Nucleotide prodrugs for HCV therapy. Sofia MJ.
Sofosbuvir (NS5B) + GS 5885 (NS5A) + RBV
HCV RNA < 15 UI/mL
SOF + RBV SOF + GS-5885 + RBV
Treatment-naïve (n = 25)
Null responder (n = 10)
Treatment-naïve (n = 25)
Null responder (n = 9)
Week 1 8/25 (32) 1/10 (10) 11/25 (44) 0/9 (0)
Week 2 17/25 (68) 7/10 (70) 22/25 (88) 4/9 (44)
Week 4 25/25 (100) 10/10 (100) 25/25 (100) 8/9 (89)
EOT 25/25 (100) 10/10 (100) 25/25 (100) 9/9 (100)
SVR4 22/25 (88) 1/10 (10) 25/25 (100) 9/9 (100)
SVR12 21/25 (84) 1/10 (10)
25/25 (100)
9/9 (100)
Gane et al. AASLD 2012 Press Release, 7 January 2013, gilead.com,
Ongoing IFN-free trials
§ Faldaprevir + BI-‐207127 (Deleobuvir -‐ Boehringer-‐Ingelheim)
§ ABT-‐450/r + ABT-‐333 ± ABT-‐267 ± RBV (AbbVie) – 5D
§ Sofosbuvir + GS-‐5885 ± RBV (Gilead)
§ Sofosbuvir + GS-‐5885 + RBV (Gilead) (G2 and G3)
§ Asunaprevir + daclastavir + BMS-‐791325 (BMS)
Inter/Intra-Company Combinations Good Example: Two Molecules QD
(Truvada-like for HCV)
GILD/PSI Sofosbuvir nuc
(GS-7977; 400 mg QD)
BI-201335 PI or TMC-435 PI
(120 mg or 75 mg QD)
Bristol Myers Squibb NS5A inhibitor
(BMS-790052; Daclatasvir 20 mg QD)
Gilead NS5A inhibitors
(GILD-5885 or 5816; 25-100 mg QD)
AASLD 2012: 7977+5885+ Riba = 100% SVR4
v Assuming Sofosbuvir (PSI/GS-7977) is approved by Q4 2013; new IND are behind by < 3 years.
v Gilead may be able to treat at most half a million people per year. With only 1.5 – 2 MM people treated over 3 yrs, there is still majority of the world and US market available.
v > 60 MM people who can pay will be available for treatment
v No pan-genotypic regimen has advanced to Phase 3. No effective combo for cirrhotic yet
The Game is not over
• 16
Several unmet needs remain: • DAA/PR failures – DONE • Null-responders – DONE • Co-infected with HIV or HBV – ALMOST DONE • non-GT1, especially GT3 – DONE • IFN intolerant or contraindicated - DONE • Cirrhosis • Bleeding disorders (hemolysis) • Pediatrics & transplant subjects • Opiate substitution therapy Too few Tx persons to come to any definitive conclusion – Real World
There are still other opportunity: Shift in focus to difficult to treat persons
Adapted from A. Kwang
Three Waves of DAA Treatments with Sofosbuvir Leading to Cure Tsunamis
• Sofosbuvir as a single DAA plus Riba • Sofosbuvir/NS5a or PI for genotype 1
• Final regimen, short in duration, one size fits all that is pangenotypic and SVR rates > 90% in the real world (nuc as backbone + PI/NS5a or two nucs or perhaps one v potent nuc).
19
One prodrug provides two active metabolites that are incorporated by HCV polymerase as G- and A-like NTP analogs.
Inhibition of NS5B and
Chain Termination!
TP 2’-C-Me-G
DAPN-PD1
TP DAPN
Novel Multi-metabolite Prodrug Approach for HCV Inhibition
DAPN-PD2
• Increased potency • Reduced resistance • Pan-genotypic activity • Prodrug metabolite not toxic (food additive & coloring agent)
or
Schinazi et al., Patent WO 2012/158811
0 0.05 0.1 0.15 0.2 0.25 0.3 0.35 0.4
gt1a
gt1a NS5a Y93H
gt1b
gt1b NS3 R155K
gt1b S282T
gt1b C316Y
gt1b C316Y:C445F
gt1b M414I
gt1b P495A
gt2a
gt2b (chimera)
gt3a (chimera)
gt4a (chimera)
gt5a (chimera)
Pan-Genotypic Activity (EC50, µM) of DAPN-PD1 Versus Wild-Type/Mutant HCV Strains
Excellent activity across 14 strains with EC50 ranging from 0.08-0.39 µM. 20
O
OHHO
N
NN
N
O NH2PO
OHN
CH3
O
O
Me
OMe
Addressing Toxicity
BMS acquired Inhibitex in 2012
INX-‐189 (BMS-‐986094) 2’-‐C-‐methyl-‐GTP
Phase II clinical: • 9 paUents suffered heart and kidney toxicity • Trial halted aoer paUent death
Potential sources of toxicity: • Prodrug group, byproducts, metabolites or drug as a
whole (too much NTP formed in wrong compartment)
21
Compound Base EC50, µM
Huh-7 CC50, µM
DAPN Prodrug 1 G/A-like 0.26 > 10
DAPN Prodrug 2 G/A-like 0.9 > 10
INX-189 G-like 0.006 0.8
Cytotoxicity, CC50 (µM)
MTS, Huh-‐7 > 100
1° human lymphocytes
> 100
CEM > 100
Vero > 100
PC3 (human prostate cancer cell line)
> 100
GADPH > 100
Thymidine uptake > 100
Cytotoxicity with various cell types and assays
The effect of prodrug group choice on potency and toxicity
Assessment of DAPN Prodrug Cytotoxicity
22
Mitochondrial Toxicity with DAPN Prodrugs
No mitochondrial toxicity was observed for DAPN prodrugs
Although both compounds share the same active metabolite, the choice of prodrug can impact both potency and cytotoxicity
CC50 (µM) in HepG2 cells LacUc acid levels (% of ß-‐acUn-‐control) + SD
mtDNA ß-‐acUn DNA 1 µM 10 µM 50 µM
DAPN Prodrug 1 > 50 > 50 43 + 3.2 56 + 6.5 90 + 14
DAPN Prodrug 2 > 100 > 100 90 + 5.1 81 + 0.1 80 + 3.0
Parent > 50 > 50 100 + 13 140 + 2.0 90 + 4.5
INX-‐189 3.4 < 1 190 + 20 ND ND
3TC > 10 > 10 ND 91 + 2.5 ND
ddC < 10 < 10 ND 220 + 11 ND
23
Conclusions • DAPN prodrugs represent new investigational compounds against HCV • Potent and non-toxic in several cell culture systems
§ Novel prodrug produced non-toxic metabolite (food additive) § No mitochondrial toxicity or lactic acid increase (below 100) § Choice of prodrug reduces cytotoxicity when compared to INX-189
• Two active metabolites were observed intracellularly:
§ Prodrug group may modulate ratio of active metabolites § 2’-C-methyl-GTP metabolite acts as a G analog § DAPN-TP metabolite acts as an A analog § Combined delivery of nucleotide analogs with different viral RNA
incorporation profiles – may be synergistic and prevent selection of mutant viruses
§ Advanced toxicological studies with a DAPN prodrug is proceeding towards an IND in 1Q2014
• 24
DAPN-PD Additional Highlights
v DAPN-PDs exhibit prolonged stability in gut (SGF) and intestine (SIF) similar to GS-7977.
v In human microsomes, DAPN-PD rapidly metabolized suggesting high liver exposure.
v DAPN-PD2 is a more lipophilic and more metabolically stable follow-up prodrug of DAPN-PD1. It has similar potency to DAPN-PD1 in the HCV 1b replicon assay with no toxicity in Huh-7, CEM, human PBM, or Vero cells.
v The phosphorous diastereomers of DAPN-PD2 are equipotent in vitro; thus, no need to separate diastereomers resulting in >significant cost savings in manufacturing.
v 1 kg of non-GMP DAPN-PD1 and DAPN-PD2 parent nucleoside prepared (97.4% pure).
v Extensive exploration of nucleoside prodrugs and unique IP portfolio.
….The US and EU are Only ~15% (11 MM) of the Total Worldwide HCV Population (170 MM)
Source: Pharmasset/Idenix Investor Relations Slide Deck.
170MM People HCV Infected Worldwide
26
Egypt’s Burden: HCV prevalence is nearly 5x greater in Egypt than many other countries
• Source: Yahia M. A uniquely EgypUan epidemic. Nature 2011; 474: S12-‐S13. 27
• 28
Before … After …
HCV shows no visible scars like HIV that inspire the public to advocate solutions
Never forget the need for assistance to the Developing World
Near future with effective oral agents Who to screen? Who to treat first?
Modifird: piceh.org
What is a life worth: Sticker shock New drugs for cancer and rare diseases come with big price tags
HCV causes cancer! DRUG COST
Gattexa $295,000/year
Kalydecoa $294,000/year
Juxtapida $200,000-$300,000/year
Elelysoa $150,000/year
Iclusiga,b $115,000/year
Zaltrapb $11,000/month
Cometriqa,b $9,900/month
Kyprolisb $9,550/month
Stivargaa,b $9,350/month
Inlytab ~$8,900/month
Bosulifa,b $8,200/month
Erivedgeb $7,500/month
Xtandib $7,450/month a Drug for orphan disease b Cancer treatment
SOURCE: Chemical & Engineering News, February 4, 2013
Supported by NIH, CFAR, and the Department of Veterans Affairs COI: I am a founder & shareholder of Idenix & RFS Pharma LLC
“The ultimate benefit of cures for HCV will not be measured by the costs they avoid, but by the lives they save”
