Achillion Pharmaceuticals

Achillion Pharmaceuticals
David Apelian MD, PhD, MBA
Senior VP and Chief Medical Officer
HepDart 2013
1
Forward-Looking Statements
This presentation includes forward-looking statements about Achillion Pharmaceuticals, Inc.
and its business, including, without limitation, statements regarding drug discovery, clinical
development, regulatory approval processes, market opportunities, intellectual property,
competition, and financial results. All statements other than statements relating to historical
matters (including statements to the effect that we “believe,” “expect,” “anticipate,” “plan,”
“target,” “intend” and similar expressions) should be considered forward-looking statements.
These forward looking statements are subject to risks and uncertainties that may cause
actual events or results to differ materially from our current expectations. These risks and
uncertainties are detailed in the "Risk Factors" section of our annual report on Form 10-K for
the year ended December 31, 2012, which was filed with the SEC on February 20, 2013, and
updated quarterly in our Forms 10-Q.
All forward-looking statements contained in this presentation speak only as of the date
hereof, and we undertake no obligation to update any of these statements, except as
required by law.
2
Advancement Toward a Simple Cure for HCV
3
HCV Portfolio Strategy
• Achillion is focused on developing and participating in the
commercialization of once-daily, all-oral treatments for HCV
• These regimens must have competitive:
— SVR rates (~ 90%)
— Safety and tolerability
— 6 – 12 week treatment duration
— Potential to standardize treatment across patient populations
• Breadth of our HCV portfolio offers Achillion the ability to
deliver a simple regimen that addresses the broad HCV market
4
HCV Portfolio: Once Daily Oral Regimens
Breadth of the HCV portfolio provides ability to systematically address
all HCV patient segments
Preclinical
Phase 1
Phase 2
Phase 3
Asset and Mechanism of Action:
ACH-3102
(NS5A inhibitor)
ACH-2684
(NS3 protease inhibitor)
Sovaprevir
ACH-3422
(NS3 protease inhibitor)
(NS5B nuc inhibitor)
5
Clinical Development Plan
Timeline for Portfolio Advancement
ACH-PI: Denotes use of either ACH-2684 or sovaprevir
Graphical representation.
Does not indicate specific dates within each quarter
6
ACH-3422
NS5B Polymerase Inhibitor
7
ACH-3422 – NS5B Polymerase Inhibitor
A Novel Nucleotide Prodrug of a Uridine Analog
• Virology
— Specific for HCV polymerase
— Highly potent and specific for HCV
— Pan-genotypic activity with a high barrier to resistance
• PK and Metabolism
— Rapid conversion of prodrug to monophosphate in microsomes and
in hepatocytes
— PK profiles suggests once-daily (QD) dosing
• Safety
— 14-day animal toxicity completed
— High exposure of triphosphate in liver
— Low risk for mitochondrial toxicity based on in vitro studies
— Non-clinical safety supports further development
Sources: Achillion Pharmaceuticals, Inc. (2013). Achillion Nominates ACH-3422 as Nucleotide for the Treatment of Chronic HCV [Press release]. Retrieved
from http://ir.achillion.com/releasedetail.cfm?ReleaseID=768019; Data on File. Achillion Pharmaceuticals, Inc. 2013.
8
ACH-3422 Preclinical
Demonstrated Potent Pan-genotypic Activity Against HCV
Genotypes
ACH-3422 displays anti-HCV potency similar to slightly better than
sofosbuvir against multiple HCV replicons
EC50 in Cell Lines Harboring HCV Replicons
EC50 in nM
Inhibitor
GT-1b
GT-1a
GT-2a
GT-3a
GT-4a
ACH-3422
51
74
107
10.0
26
Sofosbuvir
80
223
106
72
77
Sources: Achillion Pharmaceuticals, Inc. (2013). Achillion Nominates ACH-3422 as Nucleotide for the Treatment of Chronic HCV [Press release]. Retrieved
from http://ir.achillion.com/releasedetail.cfm?ReleaseID=768019; Data on File. Achillion Pharmaceuticals, Inc. 2013.
9
ACH-3422 Preclinical
High Conversion rate to Triphosphate with Potential
Once-Daily Dosing
• Prodrug was rapidly converted to triphosphate in all cell types
examined
— Human hepatocytes consistently produced the highest ACH-3422
triphosphate concentrations
— Conversion of ACH-3422 to triphosphate is comparable to that seen with
sofosbuvir to triphosphate
• High hepatic triphosphate concentrations observed in rats at 24 hours
post dosing
Sources: Achillion Pharmaceuticals, Inc. (2013). Achillion Nominates ACH-3422 as Nucleotide for the Treatment of Chronic HCV [Press release]. Retrieved
from http://ir.achillion.com/releasedetail.cfm?ReleaseID=768019; Data on File. Achillion Pharmaceuticals, Inc. 2013.
10
ACH-3422 Preclinical
In vitro studies demonstrate low risk for mitochondrial toxicity
• ACH-3422 IC50 values greater than 100 µM against DNA polymerases α
and β (nuclear) and Ƴ (mitochondrial)
• ACH-3422 has demonstrated high selectivity against human
mitochondrial RNA polymerase (IC50 > 1 mM)
Activity against Human DNA
Polymerases and RNA Polymerase II
Competition between UTP and ACH-3422-TP in
Human Mitochondrial RNA Polymerase
IC50 of ACH-3422-TP (µM)a
DNA pol α DNA pol β DNA pol γ RNA pol II
> 100
> 100
> 100
> 100
a. Aphidicolin, oleanic acid, ddTTP, and α-amanitin used
as positive control inhibitors for DNA pol α, DNA pol
β , and DNA pol γ , and RNA pol II, respectively.
Sources: Achillion Pharmaceuticals, Inc. (2013). Achillion Nominates ACH-3422 as Nucleotide for the Treatment of Chronic HCV [Press release]. Retrieved
from http://ir.achillion.com/releasedetail.cfm?ReleaseID=768019; Data on File. Achillion Pharmaceuticals, Inc. 2013.
11
ACH-3422 Preclinical
In vitro studies demonstrate low risk for mitochondrial toxicity
• Similar cell viability was seen under ACH-3422 treatment in glucose- or
galactose-containing media (1.5-fold shift in CC50 values)
• Results are similar to the non-mitochondrial toxicant tamoxifen (2.7-fold
shift) and significantly different from the mitochondrial toxicant oligomycin
(>1,000-fold shift).
CC50 Shift in Glucose- vs. Galactose-Containing Media
Sources: Achillion Pharmaceuticals, Inc. (2013). Achillion Nominates ACH-3422 as Nucleotide for the Treatment of Chronic HCV [Press release]. Retrieved
from http://ir.achillion.com/releasedetail.cfm?ReleaseID=768019; Data on File. Achillion Pharmaceuticals, Inc. 2013.
12
ACH-3422
Summary
Pan-genotypic activity in vitro
Generation of high triphosphate levels
Once daily dosing
Low potential for mitochondrial toxicity
Negative AMES tests
14-day animal tox studies
28-day animal tox studies
Ongoing
Phase 1 healthy subject study
1H2014
Phase 1 HCV proof-of-concept trial
1H2014
Phase 2 HCV all-oral combination trial
2H2014
ACH-3422 complements Achillion’s portfolio of PI and NS5A inhibitors
providing the ability to optimize HCV treatment duration and outcomes
13
ACH-3102
NS5A Inhibitor
14
ACH-3102: 2nd Generation NS5A Inhibitor
Potential Best-in-Class NS5A Inhibitor
• Virology
— Pico-molar potency
— Highly specific for HCV
— High barrier to resistance
— Pan-genotypic activity against all
subtypes in vitro
1st Generation
NS5A Inhibitor
Structurally distinct
design to optimize
against resistance
• Pharmacokinetics and
metabolism
— Once-daily (QD) dosing
• Safety
2nd
ACH-3102
Generation
NS5A Inhibitor
— Safe and well tolerated to date
(Phase 2)
1. Zhao et al. “Preclinical Characteristics of ACH3102: A Novel HCV NS5A Inhibitor with Improved Potency Against Genotype-1a Virus and Variants Resistant to 1st
Generation NS5A Inhibitors”. Presented At 47th Annual Meeting of the European Association for the Study of the Liver, Barcelona, Spain, April 18-22, 2012; Data
on File. Achillion Pharmaceuticals, Inc. 2013; 3. Achillion Pharmaceuticals, Inc. (2013). Achillion Announces Updated Phase 2 Results Including Early Sustained
Virologic Response on ACH-3102 Plus Ribavirin in Genotype 1b Treatment-Naive Hepatitis C Patients [Press release]. Retrieved from
http://ir.achillion.com/releasedetail.cfm?ReleaseID=758318.
15
ACH-3102 Phase 1
Summary of Results
• Healthy volunteers
– Single and multiple doses evaluated up to 14 days
– Well tolerated up to 1000mg with linear pharmacokinetics observed
• HCV-infected Patients
– Activity and safety of a single dose of ACH-3102 in treatment-naïve, GT1 patients
– Single dose was well tolerated and demonstrated robust and prolonged antiviral activity
16
ACH-3102 + RBV Phase 2a -005 Pilot Study
Interim Results
• Efficacy
— Treatment with ACH-3102 resulted in very rapid reduction in HCV RNA
— High barrier to resistance with no viral breakthrough on-treatment
— Viral suppression of HCV RNA continued in the presence of multiple
NS5A-resistant mutations
• Including patients with up to 6 baseline mutations
• Safety
Change in HCV RNA
Log10 (IU/mL)
— Well tolerated through 12 weeks of dosing
Data on File. Achillion Pharmaceuticals, Inc. 2012.
Achillion Pharmaceuticals, Inc. (2013). Achillion Announces Updated Phase 2 Results Including Early Sustained Virologic Response on ACH-3102 Plus
Ribavirin in Genotype 1b Treatment-Naive Hepatitis C Patients [Press release]. Retrieved from
http://ir.achillion.com/releasedetail.cfm?ReleaseID=758318.
(4 baseline mutations)
(6+ baseline mutations)
17
ACH-2684
Macrocyclic Protease Inhibitor
18
ACH-2684: Macrocylic Protease Inhibitor
Activity Against Resistant Mutations
• Potent inhibitor of NS3 protease in vitro
across HCV genotypes
• Improved potency against common NS3
protease mutations at 155, 156, and 168
Potency Against Resistant Mutations
IC50 (nM)
R155Q
R155K
A156S
A156T
D168A
D168V
simeprevir
17
40
0.21
4.5
6.2
34
ACH-2684
1.4
2.1
0.24
1.6
2.4
7.5
19
ACH-2684 Proof of Concept Study
Significant Antiviral Activity Demonstrated in GT1 Patients
• 3 day proof of concept study evaluated treatment-naïve HCV GT1
patients, either with and without cirrhosis
— Significant antiviral activity demonstrated in HCV GT1 patients
• Equivalent activity despite presence of cirrhosis
— ACH-2684 was well tolerated in the study with no SAEs or patient
discontinuations reported during treatment
Mean Change in HCV RNA
Log10 (IU/mL)
0
-1
Mean Maximum Change in HCV RNA from Baseline by Dose
-0.68
Placebo
-2
100mg QD
400mg QD non-cirrhotic
-3
-4
400mg QD cirrhotic
-3.36
-3.73
-3.67
-5
Source: Achillion Pharmaceuticals, Inc. (2012). Achillion Announces Additional Proof-of-Concept Data With ACH-2684 for the Treatment of Hepatitis C [Press
release]. Retrieved from http://ir.achillion.com/releasedetail.cfm?ReleaseID=675154.
20
ACH-2684
Summary and Next Steps
• Overview
— Potent activity demonstrated against multiple genotypes and common
NS3 protease mutations at 155, 156, and 168, in vitro
— Once-daily dosing without boosting demonstrated 3.73 log10 mean
maximal reduction in HCV RNA (400 mg)
•
Comparable activity demonstrated in cirrhotic versus non-cirrhotic patients
— Well tolerated by healthy subjects through 14 days of dosing and by HCV
patients during Phase 1 studies
•
Maximum daily doses of up to 1400mg evaluated
• Next steps
— Initiate all-oral, combination studies with ACH-3102 ±rbv
•
Drug-drug interaction study to begin 1Q14
•
Combo trial expected to begin during 1H2014
Sources: Achillion Pharmaceuticals, Inc. (2012). Achillion Announces Additional Proof-of-Concept Data With ACH-2684 for the Treatment of Hepatitis C [Press
release]. Retrieved from http://ir.achillion.com/releasedetail.cfm?ReleaseID=675154; Achillion Pharmaceuticals, Inc. (2012). Achillion Provides Updates on Clinical
HCV Development Programs [Press release]. Retrieved from http://ir.achillion.com/releasedetail.cfm?ReleaseID=720415; Data on File, Achillion Pharmaceuticals,
Inc. 2013.
21
Sovaprevir
NS3 Protease Inhibitor
22
Sovaprevir
Program summary
• Clinical
–
–
–
–
–
12-week Phase 2a trials completed
ACH-3102 DDI study completed
Multiple supporting DDIs completed
FDA cleared combination study with ACH-3102 for GT 1 HCV
Total of more than 560 subjects exposed to sovaprevir to date
• CMC
– Tablet formulation completed
• Preclinical
– 3-, 6-, and 9-month toxicology completed
– ADME profile supported combination development
23
Sovaprevir FDA Clinical Hold
Summary
• Clinical hold after elevated liver enzymes observed in drug-drug interaction
with ritonavir boosted atazanavir
— Sovaprevir concentrations observed 50-fold to 300-fold higher than 400mg and
200mg therapeutic doses
• FDA allowed continuation of Phase 2 -007 clinical trial evaluating
sovaprevir + ACH-3102 + RBV for 12 weeks
• Achillion provided integrated safety and PK data to FDA August 2013
• FDA requested supplemental information to assess additional intrinsic and
extrinsic factors that may lead to elevated exposures to sovaprevir
• Achillion will work diligently with the FDA to address their concerns
Source: Achillion press release, July 1, 2013; 2. Sovaprevir – 007 Update. http://ir.achillion.com/eventdetail.cfm?eventid=135206. Accessed on
September 30, 2013.
24
Sovaprevir + ACH-3102 Combination
Phase 2: -007 Study Overview
RVR
Segment 1
Week 0
EOT
SVR4
Treatment naive, GT1
N = 15 (10 active/5 placebo)
Sovaprevir (200) + 3102 (150/50) + RBV
Follow-up
Follow-up
Treatment naive, GT1
N = 15 (10 active/5 placebo)
Sovaprevir (400) + 3102 (150/50) + RBV
Follow-up
Follow-up
Week 4
Week 12
SVR12
Week 24
• Randomized, double-blind, placebo-controlled study enrolling treatmentnaïve GT1a/1b patients
• Primary endpoints consist of safety and efficacy including RVR, ETR and SVR
• WW study being conducted in the US, Canada, Australia, and NZ
• Enrollment completed with SVR4 anticipated for all patients in 4Q13
25
Sovaprevir + ACH-3102 + RBV
007 Study Interim Virology Results (Segment 1)
• Very rapid reduction in HCV RNA demonstrated with
sovaprevir + ACH-3102 + RBV in GT1
— All GT1 subjects achieved vRVR, defined as an HCV RNA <25 IU/mL
by week 2
• Potent anti-viral activity demonstrated against GT1b
— 100 % RVR in the 200mg and 400mg dose groups
— All subjects achieved HCV RNA <10 IU/ml at week 4
— Subject with the Y93H mutation at baseline, which is highly
resistant to first-generation NS5A inhibitors, achieved RVR
• RVR was achieved in 79% of GT1 subjects overall
• Activity supportive of continued development pending
regulatory discussions
Source: Achillion press release, September 27, 2013; 2. Data on File. Achillion Pharmaceuticals, Inc. 2013.
26
HCV Portfolio: Once Daily Oral Regimens
Breadth of the HCV portfolio provides ability to systematically address
all HCV patient segments
Preclinical
Phase 1
Phase 2
Phase 3
Asset and Mechanism of Action:
ACH-3102
(NS5A inhibitor)
ACH-2684
(NS3 protease inhibitor)
Sovaprevir
ACH-3422
(NS3 protease inhibitor)
(NS5B nuc inhibitor)
27
Achillion Pharmaceuticals, Inc.
NASDAQ: ACHN
28