ACH-3102, A Second Generation NS5A Inhibitor, Demonstrates Potent Antiviral Activity in Patients

with Genotype-1 HCV Infection

A. Muir1, J. Hill2, E. Lawitz3, T. Marbury4, L. Robarge5, H. Robison5, J. Hui5, M. Huang5, A. Agarwal5, A. Perelson6, M. Deshpande5, H. Kocinsky5

1Duke Clinical Research Institute, Durham, NC; 2Avail Clinical Research, LLC, DeLand, FL; 3Alamo Medical Research, San Antonio, TX; 4Orlando, FL; 5Achillion Pharmaceuticals, Inc., New Haven, CT, 6Los Alamos National Laboratory, Los Alamos, NM

1

10

100

1000

10000

100000

Pare

nt

L28M L31F

L31V

P32L

P58S

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Y93N

P58S

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L31F

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L31M

-Y93

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Pare

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M28

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ACH-3102Daclatasvir

GT-1b GT-1a

BACKGROUND • ACH-3102 is a second-generation NS5A inhibitor with picomolar potency.

— ACH-3102 shows improved potency against the majority of GT-1 replicon variants carrying NS5A mutations resistant to first-generation NS5A inhibitors.

— ACH-3102 retains potent activity against GT-2 replicons carrying L31M polymorphism.

• ACH-3102 is a second-generation NS5A inhibitor with picomolar potency.

• ACH-3102 has been studied in healthy volunteers in single doses up to 1000 mg, and in multiple doses up to 300 mg (loading dose) followed by 100 mg (maintenance dose) for 14 days. – An acceptable safety profile has been demonstrated at all tested

doses.

• Presented here are results from a Phase I proof-of-concept study in subjects with chronic GT-1 HCV infection.

BACKGROUND

OBJECTIVES

• Primary objectives:

– To demonstrate the safety and tolerability of ACH-3102 in hepatitis C patients following single oral doses.

– To evaluate the PK profile of ACH-3102 in hepatitis C patients following single oral doses.

– To evaluate initial HCV kinetics in subjects who have received a single oral dose of ACH-3102.

• Secondary objective:

– To monitor amino acid changes in NS5A following a single oral dose of ACH-3102.

STUDY DESIGN AND METHODS

• Resistance-associated mutations were evaluated – by clonal sequencing for baseline GT-1a samples. – by population sequencing for baseline GT-1b samples and samples post

dosing. o by clonal sequencing if a complicated pattern was found.

Demographic

MaleFemale

WhiteBlack/African AmericanNative Hawaiian

Hispanic/LatinoNot Hispanic/Latino

Mean (SD)

Mean (SD)

Placebo

N = 5

05 (100)

4 (80)0

1 (20)

2 (40)3 (60)

42.4 (8.4)

83.9 (17.2)

27.8 (6.4)

25 mg

N = 6

2 (33)4 (67)

4 (67)2 (33)

0

2 (33)4 (67)

45.2 (6.5)

77.4 (9.5)

27.1 (3.7)

50 mg

N = 4

1 (25)3 (75)

3 (75)1 (25)

0

2 (50)2 (50)

52.0 (7.5)

85.1 (17.7)

29.5 (3.5)

150 mg

N = 4

1 (25)3 (75)

3 (75)1 (25)

0

1 (25)3 (75)

49.0 (11.2)

86.5 (23.5)

28.5 (3.9)

300 mg

N = 4

1 (25)3 (75)

4 (100)00

1 (25)3 (75)

39.8 (10.2)

91.5 (19.1)

30.5 (2.7)

N = 18

5 (28)13 (72)

14 (78)4 (22)

0

6 (33)12 (67)

46.3 (9.1)

84.3 (16.5)

28.7 (3.5)

ACH-3102 �Subjects

1a1b

Mean (SD)MedianRange

5 (100) 3 (50) 4 (100) 4 (100) 4 (100) 15 (83)3 (50)0 0 0 0 3 (17)

6.60 (0.5) 6.94 (0.3) 6.48 (0.2) 6.77(0.3) 6.76 (0.3) 6.76 (0.3)6.49 7.06 6.48 6.74 6.78 6.77

5.87, 7.26 6.29, 7.24 6.26, 6.69 6.38, 7.20 6.37, 7.09 6.26, 7.24

Mean (SD)

Sex, n (%)

Race, n (%)

Ethnicity, n (%)

Age (yrs)

Weight (kg)

BMI (kg/m2)

Genotype

RNA (log10 IU/mL)

BASELINE DEMOGRAPHICS AND CHARACTERISTICS

, n (%)

SAFETY

• No TEAEs were reported by subjects dosed with ACH-3102.

• There were no SAEs or discontinuations due to safety in subjects dosed with ACH-3102.

• One placebo subject died by suicide (23 days post-placebo dose).

• There were no treatment-related or dose-related trends in 12-lead ECG parameters, vital sign measurements or laboratory abnormalities.

PHARMACOKINETICS

• AUC(0-24), AUC(0-168) and Cmax increased dose-proportionally from 25 to 300 mg.

• Mean AUC(0-168) values were 4.4, 7.0, 20 and 52 µg•hr/mL for the 25, 50, 150 and 300 mg dose groups, respectively.

• Mean Cmax values were 178, 265, 801 and 1,547 ng/mL for the 25, 50, 150 and 300 mg dose groups, respectively.

• Mean terminal T1/2: approximately 250 hr.

Cmax

0

10,000

20,000

30,000

40,000

50,000

60,000

70,000

80,000

0 50 100 150 200 250 300 350

AU

C(n

ghr

/mL)

Single Dose (mg)

AUC(0-24)AUC(0-168)

0

200

400

600

800

1,000

1,200

1,400

1,600

1,800

2,000

2,200

0 50 100 150 200 250 300 350

Cm

ax(n

g/m

L)

Single Dose (mg)

Mea

n

Mea

n

Maximum HCV RNA Change From Baseline

ANTIVIRAL ACTIVITY

NMean (SD)MedianRange

5-0.68 (0.5)

-0.60-1.39, -0.09

6-4.04 (0.6)

-4.16-4.62, -3.32

4-3.78 (0.3)

-3.80-4.16, -3.35

4-3.52 (0.5)

-3.59-3.98, -2.91

4-3.93 (0.5)

-3.87-4.60,-3.40

300 mgPlacebo 25 mg 50 mg 150 mg

• ACH-3102 demonstrated potent antiviral activity:

– Mean maximum reductions in HCV RNA were comparable across all four active dose groups.

-5.00

-4.50

-4.00

-3.50

-3.00

-2.50

-2.00

-1.50

-1.00

GT1b(n=3)

Chan

gein

HCV

RNA

(log 1

0 IU

/mL)

from

Bas

elin

e

25 mg GT-1a/1b (n=6) 50 mg GT-1a (n=4)150 mg GT-1a (n=4) 300 mg GT-1a (n=4)

Max

imum

Log

10 H

CV R

NA

Chan

ge IU

/mL)

-4.50

-4.00

-3.50

-3.00

-2.50

-2.00

-1.50

-1.00

-0.50

0.00

0.500 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

HC

VR

NA

Cha

nge

(log 1

0IU

/mL)

Days Post Single Dose

Placebo GT-1a (n=5)

25 mg GT-1a (n=3)

25 mg GT-1b (n=3)

50 mg GT-1a (n=4)

150 mg GT-1a (n=4)

300 mg GT-1a (n=4)

Mea

n Lo

g 10 H

CV R

NA

Chan

ge IU

/mL)

ANTIVIRAL ACTIVITY

• Rapid and sharp decline in viral load occurred across all four active dose groups. • Mean plasma HCV RNA levels returned to baseline no earlier than 14 days post-

dose. – HCV RNA levels returned to baseline more slowly for patients in the 300 mg

group and GT-1b patients in the 25 mg group.

GENOTYPIC AND PHENOTYPIC ANALYSES

• Variants carrying mutations at loci associated with viral resistance to NS5A inhibitors were detected in all baseline GT-1a samples. – In all cases but one, the frequency was <10%. – Y93 variants were found in four GT-1a subjects.

• The presence of these variants appeared not to affect HCV RNA reduction upon dosing ACH-3102. – One GT-1a subject with 36% of HCV carrying L31M

mutation at baseline also achieved 3.2 log10 IU/mL HCV RNA reduction.

• Amino acid changes in NS5A following a single dose of ACH-3102 in one patient is shown in next slide.

Cloned Chimeric Replicons with Substitution(s) ACH-3102 EC50 (nM)

H58Q 0.0091 Y93C 1.5 Y93H 38

M28T-Q30H-Y93C >100

GENOTYPIC AND PHENOTYPIC ANALYSES – Y93C and Y93H were minor

species at early time points, yet rapid and profound HCV RNA reduction was observed following a single dose of ACH-3102.

– Y93C re-emerged later in combination with M28T-Q30H as the major species.

– The phenomenon suggests that ACH-3102 concentration was sufficient to inhibit the single Y93 mutants or that the single Y93 mutants were not fit.

– Clonal sequencing and long-term follow up of the patient are ongoing.

CONCLUSIONS

• All tested doses of ACH-3102 were safe and well-tolerated in subjects with chronic GT-1 HCV infection.

• Variants carrying mutations at loci associated with viral resistance to NS5A inhibitors were detected in all baseline GT-1a samples.

• Robust, rapid and sustained suppression of plasma HCV RNA levels was observed across all doses tested.

• These data provide evidence that ACH-3102 is a promising direct-acting anti-viral agent.

• Clinical investigation of ACH-3102 in combination with other direct-acting antiviral agents is warranted.

ACKNOWLEDGEMENTS • Organizers of the 8th International Workshop on Hepatitis C

• Participating Study Sites and Personnel

• Participating Subjects

• Achillion Team

−Clinical Development o Mary Donohue o Bart Bradbury o Kathy Decker

−Virology Group o Joanne Fabrycki o Yongsen Zhao o Dharaben Patel o Guangwei Yang o Steve Podos o Wengang Yang

−Preclinical Group o Kathe Stauber o Christopher Marlor o Jose Rivera

−Medicinal Chemistry o Avinash Phadke o Jason Wiles o Qiuping Wang o Venkat Gadhachanda o Akihiro Hashimoto o Dawei Chen o Godwin Pais o Xiangzhu Wang