bristol-myers squibb hcv full development portfolio...

Bristol-Myers Squibb HCV Full Development Portfolio

Overview

1

Richard Bertz Int Workshop CP HIV Meeting

Amsterdam, Netherlands 24 April 2013

BMS Agents in Clinical Development: DAAs and INF Lambda

NS3 Inhibitor • Inhibits activity of NS3 protease • Prevents processing of HCV

proteins required for replication • BMS: Asunaprevir (ASV) NS5A Inhibitor

• Inhibits activity of NS5A, a multifunction protein essential for viral replication

• Prevents viral replication • BMS: Daclatasvir (DCV)

NS5B Inhibitor • Inhibits NS5B RNA replicase • Prevents replication of viral genome • BMS-791325 (-325)

Shaw-Stiffel T. Reference to Hepatitis C Infection. 2004; Tibotec. HCV Discovery. 2009. Available at: http://www.tibotec.com. Accessed December 1, 2009.

Lambda IFN • Type III pegylated interferon • Expression of receptor is more

limited than Alfa, should lead to improved tolerability and safety

Daclatasvir: Clinical Pharmacology Summary • NS5A inhibitor with picomolar potency and pan-genotypic HCV antiviral in vitro • T-half 12-15 hours supports QD dosing;~ 99% protein bound • Dose proportional PK in range of 1 to 100 mg • No effect on cardiac conduction at supratherapeutic dose (3x 60mg)

Intrinsic Factors: • No effect of hepatic impairment on unbound concentrations • Plasma PK similar by gender, race or ethnicity , minimal effect of BW

DDI : • Substrate for CYP3A4 and P-gp; manageable DDI with HIV co-meds

• ATV/RTV : decrease dose by half & EFV: increase dose by 50% • No clinically relevant effect of gastric acid modifiers • No clinically relevant effect of DCV on CYP3A4 probe midazolam • No effect on oral contraceptives • Moderate inhibitor of OATP1B and P-gp

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• Based on the integrated exposure-response, safety and efficacy data from Phase 2 (3 to 60 mg QD dose) the 60 mg daily dose was selected for Phase 3 studies

• Comparable Safety and Efficacy at 20 and 60 mg QD DCV doses tested in Phase 2B

• A 60 mg dose may provide additional benefit in difficult-to-treat patients, while compensating for reduced exposures due to food, pH modifiers and CYP3A4 inducers

• A single 60 mg tablet QD used in Phase 3 without regard to meals

Daclatasvir Phase 3 Dose Selection

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Asunaprevir: Clinical Pharmacology Summary • Potent NS3 protease inhibitor with in vitro activity against HCV GT 1, 4, 5 and 6 • High CL/F despite terminal T-HALF ~20 h ; > 99% protein bound • Time dependent PK (autoinduction) • Low plasma concentrations/high liver concentrations (>20 fold in animals) • TQT study ongoing; no conduction effects noted in animal studies

Intrinsic Factors: • Moderate and severe liver impairment increase plasma exposures by 10 & 32 fold • Difference in Asian plasma AUC (1.5-2 x increase) ; no diff based on gender or BW • Older subjects (> 60) appear to have higher (~30%) exposure

DDI data: • Sensitive OATP1B1/2B1 substrate; single dose rifampin increased AUC ~15 fold • Moderate CYP2D6 inhibitor; weak CYP3A4 inducer; weak OATB1B1 inhibitor • No meaningful effect on CYP1A2, 2C9 or 2C19 in vivo • Clinically significant effect of potent CYP3A4 inhibitors (>5 x increase plasma AUC) • No clinically significant PK interaction when ASV and DCV co-administered

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Asunaprevir: Phase 3 Dose Selection • Study AI447016 (200 mg BID, 600 mg QD and 600 mg BID ASV tablet),

served as the Phase 2a/b dose ranging study • Exposure-response (anti-viral response) and exposure-safety

(probability of ALT elevation) assessment conducted prior to transition from the 2a to 2b portion of AI447016

• Improved safety profile at 200 mg BID tablet with similar anti-viral response relative to higher doses

• 200 mg BID dose was selected for the Phase 2b portion and all other ongoing studies

• 100 mg BID of a lipid-based soft gel capsule was selected as the Phase 3 dose for ASV based on the results of a relative BA study (AI447024)

• 100 mg BID softgel capsule (given with or without meals) produces similar AUC to 200 mg BID Phase 2 tablet formulation that has been demonstrated to be safe and efficacious

Phase 3 Dose Softgel capsule at 100 mg BID without regard to food in Phase 3

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AI447011: Daclatasvir + Asunaprevir (Dual/Quad) Sentinel Cohort Study Design: PR Null Responders

24 weeks

Follow-up (up to 48 weeks post-treatment) DCV 60 mg QD + ASV 600 mg BID

Group A (n = 11)

Follow-up (up to 48 weeks post-treatment)

DCV 60 mg QD + ASV 600 mg BID + alfa/RBV

Group B (n = 10)

alfa/RBV: peginterferon alfa-2a 180 µg SC once weekly; RBV 1000-1200 mg daily according to body weight

• Lok A, et al. Preliminary Study of Two Antiviral Agents for Hepatitis C Genotype 1. N Engl J Med 2012 2012; 366;3: 216-224.

Week

LLOQ LLOD

PT, post-treatment.

HC

V R

NA

(log 1

0 IU

/mL)

0 1 2 3 4 6 8 10 12 16 20

1

2

3

4

5

6

7

24 PT4 PT12 PT24

DCV + ASV + alfa/RBV Follow-up

• 10/10 patients undetectable by week 6 of therapy with no viral breakthrough • 10/10 patients achieved SVR12 and 9/10 achieved SVR24

- 1 patient <LLOQ at week 24 post-treatment undetectable on retesting 1 and 3 months later

AI447011: DCV + ASV + Alfa/RBV (DCV/ASV Quad) HCV RNA by Patient: Group B Sentinel

alfa/RBV: pegIFNα-2a / Ribavirin

• Six patients (all GT 1a) experienced viral breakthrough on therapy • One patient with EOTR experienced viral relapse at 4 weeks post-treatment • 2/2 GT 1b patients and 2/9 GT1a patients achieved SVR24

Week

LLOQ LLOD

PT, post-treatment.

0 1 2 3 4 6 8 10 12 16 20

1

2

3

4

5

6

7

24 PT4 PT12 PT24

Follow-up DCV + ASV

HC

V R

NA

(log 1

0 IU

/mL)

AI447011: DCV+ ASV (DCV/ASV Dual) HCV RNA by Patient: Group A

AI447017: BMKK Study in Japanese Subjects Phase 2a Sentinel Cohort (DCV/ASV Dual): PR Null-Responders & Ineligible/Intolerants

Non-cirrhotic Japanese adults with HCV genotype 1 infection, HCV RNA ≥ 105 IU/mL Null responders: < 2 log10 HCV RNA decline after ≥ 12 weeks of peg-alfa/RBV

Ineligible/intolerant: previously intolerant to peg-alfa/RBV OR peg-alfa/RBV medically unsuitable

Sentinel cohort of 10 null responders reported previously (SVR24 90%);1 results combined here with data for additional null responders Primary efficacy endpoint: SVR12

cEVR, complete early virologic response; EOTR, end of treatment response; eRVR, extended rapid virologic response; RVR, rapid virologic response; SVR sustained virologic response 1Chayama K, et al. Hepatology 2012; 55:742-748.

Suzuki F, et al. EASL 2012. Oral 2344.

DCV 60 mg QD + ASV 200 mg BID Follow-up x 24 weeks

Week 4 (RVR)

Week 12 (cEVR)

Week 24 (EOTR)

Post-treatment Week 12 (SVR12)

Post-treatment Week 24 (SVR24)

DCV 60 mg QD + ASV 200 mg BID* Follow-up x 24 weeks Null responders (N = 21)

Ineligible/intolerant (N = 22)

*ASV initially 600 mg BID in sentinel cohort of 10 null responders, reduced to 200 mg BID during treatment

AI447017 (DCV/ASV Dual): Virologic Endpoints - All Patients

a End of treatment = Week 24 or last on-treatment visit for patients who discontinued early

Intention to treat (missing = failure) analysis RVR, rapid virologic response; cEVR, complete early virologic response; SVR, sustained virologic response Lower limit of quantitation for HCV RNA determinations = 15 IU/mL

70

91 88 81

77 77

0102030405060708090

100

Week 4 RVR

Week 12 cEVR

End of treatmenta

SVR12 SVR24

HC

V R

NA

unde

tect

able

(%

of p

atie

nts)

30/43 39/43 38/43 33/43 33/43 35/43

SVR4


AI447017: On-Treatment AEs (Any Grade) and Grade 3 or 4 Laboratory Abnormalities


Event, n (%) Null Responders

(N = 21) Ineligible/Intolerant

(N = 22) Ad

vers

e Ev

ents

Occ

urrin

g in

≥

3 Pa

tient

s in

Eith

er G

roup

Headache 8 (38) 6 (27) Nasopharyngitis 6 (29) 8 (36) ALT increase 6 (29) 6 (27) Diarrheaa 9 (43) 2 (9) AST increase 6 (29) 4 (18) Pyrexia 3 (14) 5 (23) Eosinophilia 1 (5) 4 (18) Abdominal discomfort 3 (14) 2 (9) Malaise 2 (10) 3 (14) Constipation 2 (10) 3 (14) Back pain 3 (14) 1 (5) Decreased appetite 0 3 (14)

Gra

de 3

or 4

Lab

Ab

norm

aliti

es ALT 2 (10) 2 (9)

AST 1 (5) 2 (9) Lymphocytes 2 (10) 1 (5) Phosphorus 1 (5) 1 (5) Bilirubin, total 1 (5) 0 Leukocytes 1 (5) 0

a All reports of diarrhea were grade 1 and did not result in discontinuation ALT, alanine aminotransferase; AST, aspartate aminotransferase

BMS-791325: Clinical Pharmacology

• Potent NS5B non-nucleoside polymerase inhibitor with In vitro activity against HCV GT 1, 3, 4, 5 and 6

• T-HALF 7-9 h, BID dosing • HCV-infected have ~2x plasma AUC vs healthy subjects • Active metabolite approximately 25% of parent in plasma • Auto induction of metabolism (CYP3A4) • No cardiac conduction defects noted preclinically

•No clinically relevant effect on PK of ASV/DCV/-325 in combination

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Phase 2a Open-Label Study (AI443-014)

■ Patients: treatment-naïve, non-cirrhotic, HCV GT 1 stratified by subtype 1a/1b ■ Treatment: DCV 60 mg QD + ASV 200 mg BID + BMS-791325 either 75 mg BID (Part 1) or 150 mg BID (Part 2) ■ HCV RNA endpoints: per FDA guidance, HCV RNA < LLOQTD = target detected but below the assay lower

limit of quantitation (LLOQ; 25 IU/mL); LLOQTND = below LLOQ and target not detected (previously referenced as HCV RNA undetectable or < LOD; ≈ 10 IU/mL for this study)

■ Primary endpoint: HCV RNA < LLOQ 12 weeks posttreatment (SVR12) – Modified intent-to-treat analysis: missing, breakthrough, or relapse = failure

■ Interim analysis: Part 1 results reported through posttreatment week 4 (Group 1; SVR4) or posttreatment week 12 (Group 2; SVR12); Part 2 enrolled and ongoing, results not yet available

Study Week

Part 1

Part 2

Group 1

Group 3

Group 2

Group 4

Primary endpoint: SVR12

Additional follow-up to

SVR48

12-week follow-up

12-week follow-up

24 0 12 36

DCV + ASV + BMS-791325 75 mg

DCV + ASV + BMS-791325 150 mg

12-week follow-up

12-week follow-up DCV + ASV + BMS-791325 150 mg

DCV + ASV + BMS-791325 75 mg

Everson GT, et al. AASLD 2012. Oral LB-3

HCV RNA Outcomes by HCV Genotype 1 Subtype Modified Intention-to-Treat Analysis


0102030405060708090

100

N = 12 12 12 12 4 4 4 4

EOT b EOT b PT4 (SVR4)

PT4 (SVR4)

GT 1a GT 1b 92a 100 92 100 100 100 100 75 % < LLOQTD or TND

Missing data HCV RNA < LLOQTD or TND

24-week (Group 1)

Missing data HCV RNA < LLOQTD or TND

12-week (Group 2)

Patie

nts a

chie

ving

end

poin

t (%

)

a Includes 1 patient with HCV RNA 118 IU/mL at last on-treatment visit but < LLOQTND 2 and 4 weeks posttreatment (SVR4). b EOT, end of treatment; includes patients who discontinued prior to the protocol-defined last treatment visit. < LLOQTD or TND, HCV RNA below assay lower limit of quantitation (25 IU/mL) and target detected (LLOQTD) or target not detected (LLOQTND; HCV RNA < LOD ≈ 10 IU/mL, previously reported as HCV RNA undetectable); PT, posttreatment.

Safety, Adverse Events, and Laboratory Abnormalities On Treatment

Number of Patients (%)

24-Wk Treatment

Group 1, N = 16

12-Wk Treatment

Group 2, N = 16

Total N = 32

Serious AEs a 0 1 (6) 1 (3)

AEs leading to discontinuation 0 0 0

Grade 3–4 AE b 0 1 (6) 1 (3)

Grade 3–4 laboratory abnormalities c 0 1 (6) 1 (3)

AE in > 10% of patients in combined treatment groups

Headache 4 (25) 6 (38) 10 (31)

Diarrhea 2 (13) 6 (38) 8 (25)

Asthenia 2 (13) 3 (19) 5 (16) a Renal calculus, considered by the investigator to be unrelated to study therapy. b Grade 3 headache, resolved after 7 days with continued study treatment. c Lymphopenia at a single study visit concomitant with influenza; there were no grade 3-4 bilirubin or transaminase elevations.


• IFNα receptors widely distributed throughout body

Potential for more IFN-associated abnormalities:

Neutropenia Thrombocyopenia Flu-Like Symptoms Musculoskeletal Symptoms

• Lambda receptors not widely distributed throughout body Potential for less IFN-associated

abnormalities: Neutropenia Thrombocyopenia Flu-Like Symptoms Musculoskeletal Symptoms

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Potential Impact of Lambda Receptor Distribution

EMERGE GT1,4: AEs (Any Grade) Occurring in ≥ 20% of Patients in Any Treatment Group

Lambda Alfa

Preferred term 120 µg

(N = 98) 180 µg

(N = 102) 240 µg

(N = 104) 180 µg

(N = 103)

AE (any grade), % 87.8 88.2 91.3 97.1 Fatigue 37.8 46.1 37.5 42.7 Headache 26.5 27.5 27.9 41.7 Myalgia 10.2 5.9 12.5 33.0 Pyrexia 12.2 7.8 4.8 33.0 Nausea 25.5 21.6 31.7 30.1 Pruritus 19.4 17.6 27.9 29.1 Insomnia 31.6 17.6 22.1 25.2 Rash 13.3 14.7 11.5 24.3 Chills 4.1 3.9 1.9 21.4 Arthralgia 14.3 5.9 9.6 20.4

Muir AJ, et al. AASLD 2012. Oral 214. > 2-fold difference in frequency, Lambda 180 µg vs alfa 180 µg.

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EMERGE: Changes in Hematologic Parameters Over Time and Hematology-Associated PegIFN and RBV Dose Reductions

%

Lambda 180 µg

(N = 102)

Alfa 180 µg

(N = 103)

Hgb low < 9 g/dL OR ∆ ≥ 4.5 g/dL 5.9 31.1

RBV reduction (Hgb-associated) 0 23.3

Neutrophils low < 750/mm3

1.0 20.4

Platelets low < 50,000/mm3 0 1.9

PegIFN reduction (hematologic abnormality) 0 20.4

Lambda 240 µg Alfa 180 µg Lambda 120 µg Lambda 180 µg

Muir AJ, et al. AASLD 2012. Oral 214.

110

130

150

1

3

5

100

200

300

0 8 12 20 28 44 72 weeks 4 36 52

EOT

Hgb

(g/L

) (m

ean)

N

eutr

ophi

ls (G

I/L)

(m

ean)

Pl

atel

ets (

GI/

L)

(mea

n)

LLN

LLN

LLN

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EMERGE GT1,4: Treatment-Emergent Liver-Related Laboratory Abnormalities

Lambda Alfa

Lab toxicity Severity

120 µg (N = 98)

180 µg (N = 102)

240 µg (N = 104)

180 µg (N = 103)

High ALT and/or AST levels, %

> 5.0–10 × ULN 2.0 2.9 18.3 4.9 > 10 × ULN 0 0 2.9 1.0

Total bilirubin high, %

2.6–5.0 × ULN 2.0 5.0 7.8 3.9 > 5.0 × ULN 0 2.0 2.0 1.0

PegIFN dose reductions due to liver-related lab abnormality, % 1.0 1.0 11.5 1.0

PegIFN discontinuations due to liver-related lab abnormality, %a 0 2.9 3.8 1.9

Muir AJ, et al. AASLD 2012. Oral 214.

a All cases of hyperbilirubinemia resolved following discontinuation of study drug without sequelae.

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BMS HCV Full Development Program Summary

Comprehensive development program with lead NS5A inhibitor daclatasvir being extensively studied as a key component of DAA-based treatment regimens: First all-DAA, Dual oral combination of DCV +ASV in GT1b patients with

both a global and Japan-specific development program [in Phase 3] First highly-effective Quad regimen of DCV + ASV + alfa/RBV in GT1 Null

Responders [in Phase 3] Triple DAA alfa-interferon-, ribavirin- and ritonavir-sparing regimen

combining DCV + ASV + NS5B non-nucleoside BMS-791325 [in Phase 2B]

Interferon Lambda being studied as a differentiated alternative to Interferon Alfa [in Phase 3]

bristol-myers squibb hcv full development portfolio...

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