Bristol-Myers Squibb: Pipeline Asset Update for Daclatasvir (DCV; BMS-790052)
 
Pipeline Asset Update for Daclatasvir (DCV; BMS-790052)
Pipeline Asset: Discovered by Bristol-Myers Squibb through a genomics approach, daclatasvir, also known as BMS-790052 or DCV, is the first NS5A replication complex inhibitor to be investigated in hepatitis C clinical trials.
Current Phase of Development: Phase III
Meeting or Publication: Conference on Retroviruses and Opportunistic Infections (CROI)
Study Title: Assessment Of HIV Antiretroviral Drug Interactions with the HCV NS5A Replication Complex Inhibitor BMS-790052 Demonstrates a Pharmacokinetic Profile Which Supports Coadministration with Tenofovir, Efavirenz and Atazanavir/Ritonavir
Presentation Number: Poster Number 618
Date/Time of Presentation: Thursday, March 8, 2012 from 2:00 – 4:00 PST
Study Objective: To evaluate the potential for drug-drug interactions (DDI) between daclatasvir (DCV) and HIV antiretrovirals (ARVs) in healthy subjects prior to beginning clinical trials in HIV-HCV co-infected patients, establishing dosing modifications, if needed.
Study Conclusion:

Daclatasvir (DCV) plus tenofovir (TDF) had no clinically relevant drug-drug interactions.

A dose adjustment for daclatasvir is necessary when administered with atazanavir boosted with ritonavir (ATV/r) and when administered with efavirenz (EFV). A daclatasvir dose adjustment of 30 mg QD with atazanavir plus ritonavir (300/100 mg QD) and 90 mg QD with efavirenz (600 mg QD) is expected to generate daclatasvir exposure similar to that for 60 mg of daclatasvir administered alone.

Safety profiles were unremarkable in all three ARVs. No unexpected safety signals were observed. See full safety analysis in adverse events section below.

Study Results:

The PK results for all three studies are as follows:

Table 1: Daclatasvir and tenofovir gave similar Cmax and AUCtau for each drug relative to administration alone (See Table 1)

TABLE1: GMR (90% CI) for DCV or TDF alone vs coadministered

DCV

TDF

Cmax (ng/mL)

1.06 (0.98, 1.15)

0.95 (0.89, 1.02)

AUCtau (ng.h/mL)

1.10 (1.01, 1.21)

1.10 (1.05, 1.15)

C24 (ng/mL)

1.15 (1.02, 1.30)

1.17 (1.10, 1.24)

Table 2: Daclatasvir and atazanavir/ritonavir

  • Dose-normalized increases in daclatasvir maximum plasma concentrations (Cmax) and area under the concentration-time curve in one dosing interval (AUCtau) were observed when dosed with ATV/r (See Table 2):
    • Geometric mean ratios (GMR) for Cmax and AUCtau of daclatasavir 20 mg when coadministered with atazanavir/ritonavir vs. daclatasvir 60 mg alone were below the predicted estimations. Non-normalized GMR for Cmax and AUCtau for the adjusted doses were less than 1.0 with atazanavir/ritonavir
    • Dose normalized (60 mg DCV) Cmax and AUCtau were 35% and 110% higher, respectively, when daclatasvir was co-administered with atazanavir/ritonavir
    • Based on linear pharmacokinetics, extrapolated doses of daclatasvir 30 mg once daily with atazanavir/ritonavir are estimated to give AUCtau similar to the daclastasvir 60 mg dose administered alone
    • Exposure of atazanavir was similar to historical data

TABLE 2: DCV PK with (test) vs without (ref) ATV/r

GMR (90% CI)

test:ref

20 mg DCV +ATV/R 300/100 mg

Dose-Normalized

(60 mg DCV ATV/R 300/100 mg)

30 mg DCV + ATV/R 300/100 mg

(Projected)

Cmax

(ng/mL)

0.45

(0.41, 0.49)

1.35

(1.24, 1.47)

0.68

(0.62, 0.74)

AUCtau

(h×ng/mL)

0.70

(0.65, 0.75)

2.10

(1.95, 2.26)

1.05

(0.98, 1.13)

C24

(ng/mL)

1.22

(1.08, 1.37)

3.65

(3.25, 4.11)

1.83

(1.62, 2.05)

Table 3: Daclatasvir and efavirenz

  • Dose-normalized decreases in daclatasvir maximum plasma concentrations (Cmax) and area under the concentration-time curve in one dosing interval (AUCtau) were observed when dosed with efavirenz (See Table 3):
    • Geometric mean ratios (GMR) for Cmax and AUCtau of daclatasavir 120 mg when coadministered with efavirenz vs. daclatasvir 60 mg alone were above the predicted estimations. Non-normalized GMR for Cmax and AUCtau for the adjusted doses were significantly greater than 1.0 with efavirenz
    • Dose normalized (60 mg DCV) Cmax and AUCtau were 17% and 32%, lower, respectively, when daclatasavir was co-administered with efavirenz.
    • Based on linear pharmacokinetics extrapolated doses of daclatasvir 90 mg once daily with efavirenz are estimated to give AUCtau similar to the daclastasvir 60 mg dose administered alone
    • Exposure of efavirenz was similar to historical data

TABLE 3: DCV PK with (test) vs without (ref) EFV

GMR (90% CI)

test:ref

120 mg DCV + EFV 600 mg

Dose-Normalized

(60 mg DCV + EFV 600 mg)

90 mg DCV + EFV 600 mg

(Projected)

Cmax

(ng/mL)

1.67

(1.51, 1.84)

0.83

(0.76, 0.92)

1.25

(1.13, 1.38)

AUCtau

(h×ng/mL)

1.37

(1.21, 1.55)

0.68

(0.60, 0.78)

1.03

(0.90, 1.16)

C24

(ng/mL)

0.83

(0.69, 1.00)

0.41

(0.34, 0.50)

0.62

(0.52, 0.75)


Adverse Events:

Most Common Adverse Events (>25% in Any Study) by System Organ Class and Treatment:

Number of subjects (%)

DCV 60 mg

N = 49

(pooled)a

TDF 300 mg

N = 20

DCV 20 mg + ATV/r

N = 14

DCV + EFV

N = 15b

DCV 60 mg + TDF

N = 20

60 mg DCV

120 mg DCV

Eye disorders

2 (4)

0

10 (71)

3 (20)

0

0

Gastrointestinal disorders

19 (39)c

7 (35)

9 (64)

4 (27)

4 (27)

6 (30)

General/administration site disorders

4 (8)

3 (15)

6 (43)

7 (47)

1 (7)

2 (10)

Nervous system disorders

15 (31)d

6 (30)

9 (64)

14 (93)

7 (47)

10 (50)

Psychiatric disorders

2 (4)

0

1 (7)

12 (80)

1 (7)

0

Vascular disorders

1 (2)

0

0

4 (27)

0

0

aCombined data from studies AI444032, AI444033 and AI444034 (exposure 4–7 days); bAll subjects initially received EFV with DCV 60 mg (9 days) then 120 mg (5 days); cInter-study incidence range 33% to 45%; dInter-study incidence range 25% to 40%

Overall:

  • No serious adverse events occurred in any study
  • 2/17 subjects enrolled to AI444034 discontinued for adverse events (treatment-unrelated myalgia, day 15; treatment-related dizziness, nausea and panic attack, day 7) and were not included in the evaluable population for DDI assessment
  • 1/21 subjects enrolled to AI444033 discontinued for adverse events (vomiting and syncope on daclatasvir alone considered treatment related) and was not included in the evaluable population for DDI assessment
  • Events in the most common classes on daclatasvir alone (GI and nervous system) occurred at similar rates in subjects receiving tenofovir alone

Daclatasvir (DCV) Background:

Daclatasvir (DCV) or BMS-790052 is an investigational, potentially first-in-class, highly selective hepatitis C virus replication complex inhibitor with broad genotypic coverage and picomolar potency in vitro.

Daclatasvir is one of several molecules Bristol-Myers Squibb is studying for the potential treatment of hepatitis C. The portfolio of investigational compounds, which also includes an NS3 inhibitor, an NS5B nucleotide polymerase inhibitor, and PEGInterferon Lambda, fits into the company’s overall R&D focus on diseases where there is unmet medical need.

Future studies are warranted to evaluate daclatasvir in HCV/HIV coinfected patients. Further DDI studies for daclatasvir plus boosted darunavir and daclatasvir plus lopinavir are planned.

Study Background:

These three open-label studies in healthy subjects evaluated steady-state pharmacokinetic interactions between daclatasvir and representative antiretroviral agents: nucleoside/tide reverse transcriptase inhibitors (or NRTI; tenofovir disoproxil fumarate), non-nucleoside reverse transcriptase inhibitors (or NNRTIs; efavirenz), and boosted protease inhibitors (or boosted PIs; atazanavir/ritonavir).

Three open-label studies in healthy subjects were evaluated for this assessment:

  • DCV + ATV/r: 14 healthy subjects received daclatasvir 60 mg, once daily on days 1 – 4; and then received daclatasvir 20 mg, once daily plus atazanavir/ritonavir 300 mg/100 mg, once daily, on days 5 – 14
  • DCV + EFV: 15 healthy subjects received daclatasvir 60 mg, once daily on days 1 – 4; then received daclatasvir 60 mg, once daily plus efavirenz 600 mg once daily on days 5 – 13; then received daclatasvir 120 mg plus efavirenz 600 mg once daily on days 14 - 18
  • DCF + TDF: 20 healthy subjects received daclatasvir 60 mg, once daily, or tenofovir 300 mg once daily or both for seven (7) days in a 3x3 crossover design

Key Inclusion Criteria:

  • Men and women, 18 to 49 years of age, inclusive
  • Healthy subjects as determined by no clinically significant deviation from normal in medical history, physical examination, vital signs, ECGs, and clinical laboratory determinations
  • Body Mass Index (BMI) of 18.0 to 32.0 kg/m2, inclusive

Key Exclusion Criteria:
  • Any significant acute or chronic medical illness
  • Current or recent (within 3 months of study drug administration) gastrointestinal disease indicated as clinically relevant by the Medical Investigator
  • Smoking more than 5 cigarettes per day
  • Recent (within 6 months of study drug administration) drug or alcohol abuse as defined in DSM IV, Diagnostic Criteria for Drug and Alcohol Abuse
  • History of cardiac conduction abnormalities
  • Evidence of organ dysfunction or any clinically significant deviation from normal in physical examination, vital signs, ECG or clinical laboratory determinations beyond what is consistent with the target population
  • Positive blood screen for hepatitis C antibody, hepatitis B surface antigen, HIV viral load, or HIV-1, -2 antibody
  • Pregnancy or lactation

Request for More Information and Media Interviews: Investors: John Elicker, 609-252-4611, john.elicker@bms.com
Media: Carrie Fernandez,
609-252-4831, carrie.fernandez@bms.com
Supporting information: The abstract and the presentation can be viewed on the CROI website.
 
 
 
 


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