1 surveyor-i: 98% – 100% svr4 in hcv genotype 1 non-cirrhotic treatment-naïve or pegylated...

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SURVEYOR-I: 98% – 100% SVR4 in HCV Genotype 1 Non-Cirrhotic Treatment-Naïve or Pegylated Interferon/Ribavirin Null-Responders with the Combination of the Next Generation NS3/4A Protease Inhibitor ABT-493 and NS5A Inhibitor ABT-530

Fred Poordad,1 Franco Felizarta,2 Armen Asatryan,3 Tarek Hassanein,4 Humberto Aguilar,5 Jacob Lalezari,6 J. Scott Overcash,7 Teresa I. Ng,3 Ran Liu,3 Chih-Wei Lin,3 Federico J. Mensa,3 Jens Kort3

66th Annual Meeting of the American Association for the Study of Liver Diseases• San Francisco, CA •

15 November 2015

1Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, USA; 2Private practice, Bakersfield, CA, USA; 3AbbVie Inc., North Chicago, IL, USA; 4Southern California GI and Liver Centers and Southern California Research Center, Coronado, CA, USA; 5Louisiana Research Center, Shreveport, LA, USA; 6Quest Clinical Research, San Francisco, CA, USA; 7eStudySite, San Diego, CA, USA

SURVEYOR-I: ABT-493 and ABT-530 for HCV Genotype 1 Infection | AASLD | 15 November 2015

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DisclosuresF Poordad: Grant/Research support: Abbvie, Achillion Pharmaceuticals, Anadys Pharmaceuticals, Biolex Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Gilead Sciences, GlaxoSmithKline, GlobeImmune, Idenix Pharmaceuticals, Idera Pharmaceuticals, Intercept Pharmaceuticals, Janssen, Medarex, Medtronic, Merck, Novartis, Santaris Pharmaceuticals, Scynexis Pharmaceuticals, Vertex Pharmaceuticals, ZymoGenetics. Speaker: Gilead, Kadmon, Merck, Onyx/Bayer, Genentech, GlaxoSmithKline, Salix, Vertex. Consultant/Advisor: AbbVie, Achillion Pharmaceuticals, Anadys Pharmaceuticals, Biolex Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, GlobeImmune, Idenix, Merck, Novartis, Tibotec/Janssen, Theravance, VertexF Felizarta: Research support (principal investigator): AbbVie, Achillion, BMS, Gilead, Janssen, Merck, and Novartis. Speaker: AbbVie, Gilead, Janssen, MerckT Hassanein: Grants/Research support: AbbVie (Advisory Board), Boehringer-Ingelheim, Bristol-Myers Squibb (Advisory Board), Eisai, Gilead Sciences, Janssen, Idenix, Ikaria, Mochida, Roche, Ocera, Taigen, Takeda, Salix, Sundise, Vertex. Speaker: Baxter, Bristol-Myers Squibb, Gilead, SalixH Aguilar: Grants: AbbVie. Speaker: Santarus, Ironwood, AbbVieJ Lalezari: Research support (principal investigator): AbbVieJS Overcash: No relevant conflicts to discloseA Asatryan, TI Ng, R Liu, CW Lin, F Mensa, and J Kort: AbbVie employees and may hold AbbVie stock or stock options.The design, study conduct, analysis, and financial support of the SURVEYOR-I (NCT02243280) study were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the content. All authors had access to all relevant data and participated in writing, review, and approval of this presentation. Medical writing support was provided by Sharanya Ford, PhD, of AbbVie. This presentation contains information on the investigational products ABT-493 and ABT-530.


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Next Generation Direct-Acting Antivirals

ABT-493: pangenotypic HCV NS3/4A protease inhibitor* (EC50 0.9 – 2.8 nM)

ABT-530: pangenotypic HCV NS5A inhibitor (EC50 1 – 4 pM)

In vitro characteristics:1,2

• Higher barrier to resistance

• Additive/synergistic antiviral activity

• Active against common variants • eg, GT1 NS3: R155K, D168A/E/V• eg, GT1 NS5A: M28T/V, Q30E/H/R, L31M/V, P32L, Y93C/H/N

*ABT-493 identified by AbbVie and Enanta.1. Ng TI, et al. Abstract 636. 21st Conference on Retroviruses and Opportunistic Infections., Boston, 2014.2. Ng TI, et al. Abstract 639. 21st Conference on Retroviruses and Opportunistic Infections., Boston, 2014.


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Protease Inhibitor Stable HCV Replicon EC50 (nM)

GT1a GT1b GT2a GT3a GT4a GT6aABT-493 0.85 0.94 2.7a 1.6 2.8 0.86

Paritaprevir 1.0 0.21 5.3a 19 0.09 0.68Simeprevir1,2 13 9.4 15 472 NA NAAsunaprevir3 4.0 1.2 230 1162 NA NAGrazoprevir 0.38 0.87 1.3 36 1.2 0.89

GS-94514 13 5.4 316 NA NA NAGS-98575 3.9 3.3 3.7 6.1 2.9 1.5

aStudy conducted at Southern Research Institute.NA, not available.

1. Simeprevir prescribing information2. Chase R, et al. IAPAC, 20133. McPhee F, et al. AAC, 20124. Yang H, et al. AAC, 20145. Taylor J, et al. EASL, 2015

Next Generation Direct-Acting Antivirals: ABT-493

ABT-493 demonstrates potent activity against major HCV genotypes in vitro


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NS5A Inhibitor Stable HCV Replicon EC50 (pM)

GT1a GT1b GT2a GT2b GT3a GT4a GT5a GT6aABT-530 2 4 2a 2 2 2 1 3

Ombitasvir 14 5 12 4 19 2 3 366Daclatasvir1 22 3 13,000 NA 530 13 5 74Ledipasvir2 31 4 21,000 16,000 168,000 390 150 1100Velpatasvir3 12 15 9 8 12 9 75 6

Elbasvir4 4 3 3 3000 20 3 1 3MK-84085 1 2 1 4 2 2 1 4ACH-31026 26 5 21 ~150 NA NA NA NA

IDX7197 8 3 24 NA 17 2 37 NAaStudy conducted at Southern Research Institute.NA, not available.

Next Generation Direct-Acting Antivirals: ABT-530

1. Wang C, et al. AAC, 20142. Cheng G, et al. EASL, 2012; Harvoni prescribing information.3. Cheng G, et al. EASL, 20134. Liu R, et al. EASL, 2012

5. Asante-Appiah E, AASLD, 20146. Zhao Y, et al. EASL, 20127. Dousson C, et al. EASL, 2011

ABT-530 demonstrates potent pangenotypic activity against HCV in vitro


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Key Pharmacokinetics:

• Once-daily oral dosing

• Minimal metabolism and primary biliary excretion

• No renal excretion (<1%)

SURVEYOR-I Part 1: Study Design

Day 1 Week 12 PT Week 24Post-treatment (PT) periodTreatment period

n=40 ABT-493 200 mg + ABT-530 120 mg

n=39 ABT-493 200 mg + ABT-530 40 mg

ClinicalTrials.gov: NCT02243280.


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SURVEYOR-I Part 1: Key Eligibility Criteria and Endpoints

Key inclusion criteria• 18 to 70 years of age, inclusive• HCV GT1 infection, HCV RNA >10,000 IU/mL• HCV treatment-naïve or PegIFN/RBV null-responders • Absence of cirrhosis

Key exclusion criteria• Previous use of any HCV DAAs• ALT or AST >5x ULN, CrCl <50 ml/min, platelet count <120 109/L• Herbal supplements and potent P-gp inducers were prohibited

*Commonly prescribed concomitant medications (e.g., PPIs) were allowed

Endpoints• Efficacy: SVR12 (primary) and virologic failure• Safety: adverse events (AEs) and laboratory abnormalities


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SURVEYOR-I Part 1: Demographics and Patient Characteristics

ABT-493 200 mg + ABT-530 40 mg

(n = 39)

ABT-493 200 mg + ABT-530 120 mg

(n = 40)Male, n (%) 18 (46) 23 (58)White race, n (%) 35 (90) 34 (85)Hispanic or Latino ethnicity, n (%) 9 (23) 7 (18)Age, mean (range), years 53 (30 – 70) 52 (26 – 68)BMI, mean ± SD, kg/m2 28 ± 4.3 28 ± 5IL28B non-CC genotype, n (%) 32 (82) 31 (78)HCV RNA, mean ± SD, log10 IU/mL 6.6 ± 0.6 6.7 ± 0.6HCV GT1a, n (%) 30 (77) 34 (85)Prior PegIFN/RBV experience, n (%)

Naïve 25 (64) 25 (63) Null-responder 14 (36) 15 (37)

Baseline fibrosis stage, n (%)F0 – F1 27 (69) 22 (55)F2 5 (13) 5 (13)F3 7 (18)a 13 (32)

aIncludes one patient with baseline F4 fibrosis stage.


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SURVEYOR-I Part 1: ITT SVR12 Rates

SVR1

2, %

Pati

ents

0

20

40

60

80

10097 100

40 40

38a

39

ABT-493 200 mg+

ABT-530 120 mg aOne treatment-naïve patient with GT1a infection experienced virologic failure.

200 mg+

120 mg

200 mg+

40 mg

ABT-493+

ABT-530


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SVR1

2, %

Pati

ents

0

20

40

60

80

10097 100

40 40

38a

39

aOne treatment-naïve patient with GT1a infection experienced relapse.

200 mg+

120 mg

200 mg+

40 mg

ABT-493+

ABT-530


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SVR1

2, %

Pati

ents

0

20

40

60

80

10097 100

40 40

38a

39

aOne treatment-naïve patient with GT1a infection experienced relapse.

200 mg+

120 mg

200 mg+

40 mg

ABT-493+

ABT-530

• 100% (29/29) treatment-experienced patients achieved SVR12

• 98% (49/50) treatment-naïve patients achieved SVR12


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One patient in the low dose arm relapsed at post-treatment week 4

SURVEYOR-I Part 1: Treatment Failure

Patient CharacteristicsTreatment arm ABT-493 200 mg + ABT-530 40 mgAge, years 55Gender MaleRace WhiteBaseline fibrosis stage F0 – F1HCV subgenotype 1aIL28B genotype C/CTreatment experience Naïve Resistant variants at baseline NoneResistant variants at relapse NS5A: Q30K + H58D


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46 (58%) patients had baseline variants in NS3 and/or NS5A

Amino Acid Variant Analysis by Population Sequencing

aBased on HCV Drug Resistance Working Group review of clinically relevant variants: Lontok E, et al. Hepatology. 2015; 62(3):715.• NS3: 36, 43, 54, 55, 56, 80, 122, 155, 156, 168, and 170 • NS5A: 28, 29, 30, 31, 32, 58, 92, and 93

NS3 onlyNS5A only

NS3 and NS5A

0

20

40

60

80

100

Pat

ien

ts (

%)

8%

47%

4%

All patients with baseline NS3 and/or NS5A variantsa achieved SVR12


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100% SVR12 in Patients with Baseline Variants

Viral Target Genotype Baseline Variant Number of Patients (N=79)

NS3

1a

T54S 1T54S, R155K, I170V 1

V55A 2V55A, Q80K 1

V55A, Q80K, S122G 1Q80K 21

Q80K, I170V 3S122G 1R155K 1I170V 3

1b

V36I, S122N 1S122G 1S122N 2S122T 1

NS5A 1a

M28V 2M28V, Q30H 1

Q30H 1L31M 3

Q30H, Y93H 11b Y93H 1

Amino Acid Variant Analysis by Population Sequencing


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SURVEYOR-I Part 1: Summary of Adverse Events

Event, n (%)

ABT-493 200 mg + ABT-530 40 mg

(n = 39)

ABT-493 200 mg + ABT-530 120 mg

(n = 40)Any AE 30 (77) 26 (65)AEs leading to study discontinuation 0 0Any Grade 3 (severe) AE 1 (3)a 2 (5)b,c

Any serious AE 0 1 (3)c

Deaths 0 0AEs in >10% of patients

Fatigue 5 (13) 9 (23)Headache 8 (21) 5 (13)Nausea 8 (21) 5 (13)

AEs were graded per National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE).aOne patient experienced a decrease in blood phosphorus deemed related to study drugs. bOne patient experienced elevated blood glucose levels deemed not related to study drugs. cA serious Grade 3 AE of metastatic prostate cancer was deemed not related to study drugs and had onset after completion of study treatment.


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SURVEYOR-I Part 1: Laboratory Abnormalities

Event, n (%)

ABT-493 200 mg + ABT-530 40 mg

(n = 39)

ABT-493 200 mg + ABT-530 120 mg

(n = 40)ALT

Grade 2+ (>3 x ULN) 0 0AST

Grade 2+ (>3 x ULN) 0 0

Alkaline phosphataseGrade 2+ (>2.5 x ULN) 0 0

Total bilirubin Grade 2+(>1.5 x ULN) 0 0

HemoglobinGrade 2 (<10 – 8 g/dL) 0 1 (3)Grade 3 (<8 g/dL) 0 0

Presented are laboratory elevations that were increased levels from baseline.


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SURVEYOR-I Part 1: Summary

12-week dose-ranging study in non-cirrhotic patients with GT1 showed high SVR12 rates with once-daily ABT-493 + ABT-530

• All but one patient achieved SVR12– This patient was treated with the lower ABT-530 40 mg dose and

experienced relapse • All patients with baseline NS3 and/or NS5A variants achieved SVR12• AEs were mostly mild in severity


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• Up to 100% SVR12 achieved with ABT-493 + ABT-530

• The combination was well tolerated

• Based on these results and data in other genotypes, the selected doses moving forward are:

• ABT-493: 300 mg QD

• ABT-530: 120 mg QD

• The SURVEYOR-I study has been expanded to assess:• Patients without cirrhosis (8-week treatment)• Patients with compensated cirrhosis (12-week treatment)

SURVEYOR-I Part 1: Conclusions


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Acknowledgments

The authors would like to express their gratitude to the patients and their families, investigators, study coordinators, and AbbVie/CRO study staff who made this study possible.

1 surveyor-i: 98% – 100% svr4 in hcv genotype 1 non-cirrhotic treatment-naïve or pegylated...

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